NOVEL SYNTHESIS

Abstract: The present invention relates to a novel method for synthesizing imidazole derivatives having 4-aryl, 5-pyrimidine heterocyclic rings using a novel cycloaddition reaction.

Description: Novel Synthesis Field of the Invention: The present invention relates to a novel method for synthesizing imidazole derivatives having 4-aryl, 5-pyrimidine heterocyclic rings. Background of the Invention: The present invention describes a novel, and general method to prepare 5-pyrirnidinyl substituted imidazoles. Previous syntheses of this class of molecules utilized the van Leusen reaction (van Leusen, A.M., et. al. J. Org. Chem. 1977, 42, 1153), which involves the cycloaddition of an imine and a tosylisonitrile. Difficulties in preparing the aldehyde precursors to the desired imines limited the scope of this approach. In Adams et al., WO 95/02591 an improvement on the cycloaddition reaction is shown for similar compounds. However addition of a pyrimidine ring in an environmentally favourable and commercially feasible manner is still needed. The present invention employs a novel method of cycloaddition of a tosylisonitrile with an α-ketoaldimine to produce a 5-keto imidazole derivative. The 5-keto group serves as an excellent precursor for addition of the optionally substituted pyrimidine ring. Summary of the Invention: The present invention is to a process of making compounds of Formula (I), wherein Rl is an optionally substituted pyrimidin-4-yl ring; R4 is an optionally substituted phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl ring; m is 0, or the integer 1 or 2; m' is an integer having a value of 1 or 2, R2 is -(CRioR20)n* OR9, heterocyclyl, heterocyclylCi-io alkyl, Ci-ioalkyl, halo- substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-.7 cycloalkyl, C3-7cycloalkylCi-io alkyl, C5.7 cycloalkenyl, C5-7cycloalkenyl-Ci-l0-alkyl, aryl, arylCi-io alkyl, heteroaryl, heteroaryl-Ci-io-alkyl, (CRioR20)nORl l, (CRioR20)nS(O) m Ri8, (CRlθR2θ)nNHS(O)2Rl8, (CRioR20)nNRl3Rl4> (CRioR20)nNO2, (CRiθR20)nCN, (CRioR20)n'SO2Rl8, (CRi0R20)nS(O) m 'NRi3Rl4, (CRlθR20)nC(Z)Rπ, (CRioR20)nOC(Z)Rn, (CRioR20)nC(Z)ORi l, (CRioR20)nC(Z)NRi3Rl4, (CRioR20)nC(Z)NRi 1OR9, (CRioR2θ)nNRlθC(Z)Rι 1, (CRιoR2θ)nNRlθC(Z)NRi3Ri4, (CRl0R20)nN(OR6)C(Z)NRi3Rl4, (CRi0R20)nN(OR 6 )C(Z)Ri i, (CRioR20)nC(=NOR6)Rl 1, (CRiθR2θ)nNRlθC(=NRi9)NRi3Rl4, (CRlθR2θ)nOC(Z)NRi3Rl4, (CRlθR2θ)nNRK)C(Z)NRi3Rl4, (CRιoR2θ)nNRlθC(Z)ORιo, 5-(Ri8)-l,2,4-oxadizaol-3-yl or 4-(Ri2)-5-(Ri8Ri9)-4,5-dihydro-l,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted; n is an integer having a value of 1 to 10; n' is 0, or an integer having a value of 1 to 10; Z is oxygen or sulfur; R3 is heterocyclyl, heterocyclylCi-io alkyl or Rs; R6 is hydrogen, a pharmaceutically acceptable cation, Ci-io alkyl, C3.7 cycloalkyl, aryl, arylCi- 4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or Ci-io alkanoyl; R8 is Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylC 1.10 alkyl, heteroaryl, heteroarylC 1 - 10 alkyl, (CRioR20)nORl l, (CRlθR2θ)nS(O) m Ri8, (CRιoR2θ)nNHS(O)2Rl8, (CRioR20)nNRl3Rl4; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted; R9 is hydrogen, -C(Z)Ri 1 or optionally substituted Ci-io alkyl, S(O)2Rl8> optionally substituted aryl or optionally substituted aryl-C 1.4 alkyl; RlO and R20 is each independently selected from hydrogen or Ci-4 alkyl; Rl 1 is hydrogen, Ci-io alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl Ci-ioalkyl, aryl, arylCl-l0 alkyl, heteroaryl or heteroarylC i- 10 alkyl; Rl2 is hydrogen or Ri6; R13 and R14 is each mdependently selected from hydrogen or optionally substituted C 1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; Ri6 is Ci-4 alkyl, halo-substituted-Ci-4 alkyl, or C3-7 cycloalkyl; Rl8 is Ci-io alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Ci-ioalkyl, heteroaryl or heteroarylalkyl; and Rl9 is hydrogen, cyano, -4 alkyl, C3-7 cycloalkyl or aryl; which process comprises: a) reacting a compound of below wherein R is the optional substituent on the pyrimidinyl (Ri) moiety in Formula (I), or is hydrogen, an optionally substituted alkyl or an optionally substituted aryl, with a compound of the Formula R2NH2 (III), wherein R2 is as defined for Formula (I), to yield a compound of Formula (IV) wherein R and R2 are as defined above; and b) reacting a compound of Formula (IV) with a compound of Formula (V) and a suitable base, Ar 1 wherein Ar is an optionally substituted aryl; and R4 is as defined for Formula (I); to yield a compound of Formula (VI) wherein R, R2 and R4 are as defined above; and c) reacting a compound of Formula (VI) with a compound of Formula VII wherein R a is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocychcalkyl group all of which may be optionally substituted; and Rb is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocychcalkyl group all of which may be optionally substituted; to yield a compound of Formula (VIII) wherein Rb is as defined above for Formula (VII), R is as defined above, and R2 and R4 are defined as for Formula (I); d) reacting a compound of Formula (VLTI) with a compound of Formula (LX) wherein Z is N(R d )2 , SR e , OR e , or R d . R d is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocychcalkyl; R e is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocychcalkyl; and Y is O, S, or NH; to yield a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Another aspect of the present invention are the novel compounds of Formula (VI), and (VLTI) as defined herein. Detailed Description of the Invention: The present invention relates to a novel synthesis of a group of imidazole compounds, whose general structure is shown above in Formula (I) above, and further as described in Adams et al., WO 95/02591; Adams et al., WO 96/21452, published 18 July 1996; Adams et al., WO 96/21654, published 18 July 1996; and Adams et al., Attorney Docket No. P50347-2, USSN 08/659,102 filed 3 June 1996; whose disclosures are all incorporated herein by reference. Preferred compounds of Formula (I) have the structure: wherein Rl is pyrimidin-4-yl which ring is optionally substituted with one or two substituents each of which is independently selected from optionally substituted -10 alkyl, optionally substituted aryl, halogen, hydroxyl, thiol, Ci-io alkoxy, Ci-io alkylthio, Ci-io alkylsulfinyl, CH2OR12, amino, mono or di-Ci-iθ alkyl substituted amino, NHR21, N(Rιo)C(O)R a or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; R4 is an optionally substituted phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl ring; m is 0, or the integer 1 or 2; m' is an integer having a value of 1 or 2, m" is 0, or an integer having a value of 1 to 5; R2 is -(CRioR20)n' OR9, heterocyclyl, heterocyclylCi-io alkyl, Ci-ioalkyl, halo- substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-.7 cycloalkyl, C3-7cycloalkylCi-i0 alkyl, C5-.7 cycloalkenyl, C5-7cycloalkenyl-Ci-io-alkyl, aryl, arylCi-io alkyl, heteroaryl, heteroaryl-Ci-io-alkyl, (CRioR20)nORl l, (CRioR20)nS(O) m Ri8, (CRκ)R20)nNHS(O)2Rl8, (CRlθR2θ)nNRl3 l4, (CRioR20)nNO 2 , (CRioR20)nCN, (CRioR20)n'SO2Rl8, (CRioR20)nS(O)m'NRi3Ri4, (CRioR20)nC(Z)Rn, (CRioR20)nOC(Z)Rn, (CRι 0 R20)nC(Z)ORi 1, (CRioR20)nC(Z)NRi 3 Rl4, (CRι 0 R20)nC(Z)NRi 1OR9, (CRιoR2θ)nNRlθC(Z)Rι 1, (CRioR20)nNRioC(Z)NRi3Rl4, (CRioR20)nN(OR 6 )C(Z)NRi3Rl4, (CRioR20)nN(OR6)C(Z)Rι ι, (CRιoR20)nC(=NOR6)Rl 1, (CRlθR2θ)nNRlθC(=NRl9)NRi3Rl4, (CRιoR20)nOC(Z)NRi3Rl4, (CRioR20)nNRlθC(Z)NRι 3 Ri4, (CRiθR2θ)nNRlθC(Z)ORiθ, 5-(Rι 8 )- 1 ,2,4-oxadizaol-3-yl or 4-(Rl2)-5-(Ri8Rl9)-4,5-dihydro-l,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted; n is an integer having a value of 1 to 10; n' is 0, or an integer having a value of 1 to 10; Z is oxygen or sulfur; Ra is hydrogen, Ci-6 alkyl, C3 7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylC i^alkyl, heterocyclyl, or heterocyclylCi-4 alkyl; R3 is heterocyclyl, heterocyclylCi-io alkyl or Rs; R6 is hydrogen, a pharmaceutically acceptable cation, Ci-io alkyl, C3-7 cycloalkyl, aryl, arylCι.4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or Ci-io alkanoyl; R8 is Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylC 1.10 alkyl, heteroaryl, heteroarylC 1.10 alkyl, (CRioR20)nORl l, (CRlθR2θ)nS(O) m Ri8, (CRioR20)nNHS(O)2Rl8, (CRioR20)nNRl3Rl4; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted; R9 is hydrogen, -C(Z)Rι 1 or optionally substituted Ci-io alkyl, S(O)2Rl8 » optionally substituted aryl or optionally substituted aryl-C 1 -4 alkyl; RlO and R20 s each independently selected from hydrogen or Ci-4 alkyl; Rl 1 is hydrogen, Ci-io alkyl, C3.7 cycloalkyl, heterocyclyl, heterocyclyl Ci-ioalkyl, aryl, arylCi-iO alkyl, heteroaryl or heteroarylC I- 10 alkyl; Rl2 is hydrogen or Ri6; R 13 and R 14 is each independently selected from hydrogen or optionally substituted C 1 -4 alkyl, optionally substituted aryl or optionally substituted aryl-C 1 -4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; Ri5 is Rlθ or C(Z)-Ci-4 alkyl; Rl6 is Ci-4 alkyl, halo-substituted-Ci-4 alkyl, or C3-7 cycloalkyl; Rl8 is Ci-io alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Ci-ioalkyl, heteroaryl or heteroarylalkyl; Rl9 is hydrogen, cyano, C1-4 alkyl, C3_7 cycloalkyl or aryl; and R21 is alkyl, aryl, arylCi-6alkyl, heterocyclic, heterocyclylCi-6 alkyl, heteroaryl, heteroarylC i-6alkyl, wherein each of these moieties may be optionally substituted; or a pharmaceutically acceptable salt thereof. Preferably, for compounds wherein R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, the rings ares optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-l-yl, 5-naphth-2-yl or 6- naphth-2-yl substituent, is halogen, cyano, nitro, -C(Z)NR7Ri7, -C(Z)ORi6, -(CRιoR20)vCORi2, -SR5, -SOR5, -OR12, halo-substituted-Ci-4 alkyl, -4 alkyl, -ZC(Z)Ri2, -NRιoC(Z)Ri6, or -(CRioR2θ)vNRlθR20 and which, for other positions of substitution, is halogen, cyano, -C(Z)NRi3Ri4, -C(Z)OR3, -(CRiθR20)m"COR3, -S(O) m R3, -OR3, halo-substituted-Ci-4 alkyl, -Ci-4 alkyl, -(CRιoR20)m"NRlθC(Z)R3, -NRioS(O) m 'R8, -NRιoS(O) m 'NR7Rl7, -ZC(Z)R3 or -(CRlθR2θ)m"NRl3Rl4. Suitably, wherein R5 is hydrogen, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties -SR5 being -SNR7R17 and -SOR5 being -SOH.; v is 0, or an integer having a value of 1 or 2; and m" is 0, or an integer having a value of 1 to 5. Suitably, wherein R7 and Rn are each independently selected from hydrogen or Cl-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR15. Suitably, R15 is Rio or C(Z)-Ci-4 alkyl, and R Q and Z are as defined for Formula (I). The compounds of Formula (I) may be used in association with the treatment of cytokine mediated diseases in a mammal, or for the veterinary treatment of mammals who are in need of inhibition of cytokine production. Another embodiment of the present invention are the novel compounds of the Formula (VI) having the structure: wherein R is optionally substituted Ci-io alkyl, optionally substituted aryl, halogen, hydroxyl, thiol, Ci-io alkoxy, Ci-io alkylthio, Ci-io alkylsulfinyl, CH2OR12, amino, mono or di-C 1 -6 alkyl substituted amino, NHR21 , N(R 1 o)C(O)R a or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; R a is hydrogen, Ci-6 alkyl, C3-7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclyl, or heterocyclylCi-4 alkyl; R4 is an optionally substituted phenyl, naphth- 1 -yl or naphth-2-yl, or heteroaryl ring; R2 is -(CRioR20)n' OR9, heterocyclyl, heterocyclylCi-io alkyl, Ci-ioalkyl, halo- substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylCl-lθ alkyl, C5-7 cycloalkenyl, C5-7cycloalkenyl-Cl-io-alkyl, aryl, arylCi-10 alkyl, heteroaryl, heteroaryl-Ci-io-alkyl, (CRioR20)nORl 1, (CRioR20)nS(O) m Rl8, (CRioR20)nNHS(O)2Rl8, (CRlθR2θ)nNRl3Rl4, (CRioR20)nNO2, (CRioR20)nCN, (CRio 20)n'SO2Rl8, (CRi0R20)nS(O) m -NRi3Rl4. (CRioR20)nC(Z)Rn, (CRioR20)nOC(Z)Rn, (CRioR20)nC(Z)ORl l , (CRioR20)nC(Z)NRi3Rl4, (CRlθR2θ)nC(Z)NRι 1OR9, (CRιoR2θ)nNRlθC(Z)Ri 1, (CRιoR2θ)nNRlθC(Z)NRi3Rl4, (CRl0R20)nN(OR6)C(Z)NRi3Rl4, (CRl0R20)nN(OR6)C(Z)Rn, (CRioR20)nC(=NOR6)Rl 1, (CRιoR2θ)nNRlθC(=NRi9)NRl3 l4, (CRioR20)nOC(Z)NRi3Rl4, (CRioR2θ)nNRlθC(Z)NRi3Ri4, (CRiθR2θ)nNRlθC(Z)ORlθ, 5-(Ri8)-l,2,4-oxadizaol-3-yl or 4-(Ri2)-5-(Ri8Rl9)-4»5-dihydro-l,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted; n is an integer having a value of 1 to 10 n' is 0, or an integer having a value of 1 to 10; m' is an integer having a value of 1 or 2, Z is oxygen or sulfur; R9 is hydrogen, -C(Z)Ri 1 or optionally substituted Ci-io alkyl, S(O)2Rl8» optionally substituted aryl or optionally substituted aryl-C 1 -4 alkyl; Rio and R20 is each independently selected from hydrogen or C1-4 alkyl; Rl 1 is hydrogen, Ci-io alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl Ci-ioalkyl, aryl, arylQ-io alkyl, heteroaryl or heteroarylC i- 10 alkyl; Rl2 is hydrogen or Ri6; Rl3 and R14 is each independently selected from hydrogen or optionally substituted -4 alkyl, optionally substituted aryl or optionally substituted aryl-C 1 -4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; Rl5 s RlO or C(Z)-Q-4 alkyl; R 16 is C 1 -4 alkyl, halo-substituted-C 1 -4 alkyl, or C3-7 cycloalkyl; Rl8 is -io alkyl, C3-.7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Q-ioalkyl, heteroaryl or heteroarylalkyl; Rl9 is hydrogen, cyano, -4 alkyl, C3-7 cycloalkyl or aryl; and R21 is alkyl, aryl, arylQ-όalkyl, heterocyclic, heterocyclylQ-6 alkyl, heteroaryl, heteroarylC i-6alkyl, wherein each of these moieties may be optionally substituted. Yet another embodiment of the present invention are the novel compounds of Formula (VLTI) having the structure: wherein R is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocychcalkyl, all of which may be optionally substituted; R is optionally substituted alkyl, optionally substituted aryl, 1-4 alkyl, halogen, hydroxyl, thiol, Q-4 alkoxy, Q-4 alkylthio, Q-4 alkylsulfinyl, CH2OR12, amino, mono or di- C 1 -6 alkyl substituted amino, NHR21 , N(R 1 o)C(O)R a or an N-heterocycly 1 ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; Ra is hydrogen, Q-6 alkyl, C3-7 cycloalkyl, aryl, arylQ- 4 alkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclyl, or heterocyclylQ-4 alkyl; R4 is an optionally substituted phenyl, naphth- 1-yl or naphth-2-yl, or heteroaryl ring; R2 is -(CRioR20)n' OR9, heterocyclyl, heterocyclylQ-io alkyl, Q-ioalkyl, halo- substituted Q-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylQ-io alkyl, C5-7 cycloalkenyl, C5-7cycloalkenyl-Q-lθ-alkyl, aryl, arylQ-io alkyl, heteroaryl, heteroaryl-Q-io-alkyl, (CRlθR2θ)nORl 1, (CRioR20)nS(O)mRl8, (CRioR20)nNHS(O)2Rl8, (CRioR20)nNRl3 l4, (CRioR20)nNO2, (CRlθR2θ)nCN, (CRioR20)n'SO2Rl8, (CRioR20)nS(O)m'NRi3Rl4, (CRioR20)nC(Z)Rn, (CRlθR20)nOC(Z)Rπ, (CRioR20)nC(Z)ORi 1, (CRioR20)nC(Z)NRi3Rl4, (CRioR20)nC(Z)NRi 1OR9, (CRι 0 R20)nNRlθC(Z)Rι 1, (CRiθR20)nNRlθC(Z)NRi3Rl4, (CRιoR2θ)nN(OR6)C(Z)NRi 3 Rl4, (CRι 0 R20)nN(OR6)C(Z)Rι 1, (CRioR20)nC(=NOR6)Rl 1, (CRιθR2θ)nNRlθC(=NRi9)NRι 3 Ri4, (CRιoR 2 θ)nOC(Z)NRi3Rl4, (CRiθR2θ)nNRlθC(Z)NRl3Rl4, (CRιoR2θ)nNRlθC(Z)ORιo, 5-(Rιs)-l,2,4-oxadizaol-3-yl or 4-(Ri2)-5-(Ri8Rl9)-4,5-dihydro-l,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted; n is an integer having a value of 1 to 10 n' is 0, or an integer having a value of 1 to 10; m' is an integer having a value of 1 or 2, Z is oxygen or sulfur; R9 is hydrogen, -C(Z)Rι i or optionally substituted Q-io alkyl, S(O)2Rl8, optionally substituted aryl or optionally substituted aryl-C i -4 alkyl; R 10 and R20 s each independently selected from hydrogen or C 1.4 alkyl; Rl 1 is hydrogen, Q-io alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl Q-ioalkyl, aryl, arylQ-io alkyl, heteroaryl or heteroarylC l- 10 alkyl; Rl2 is hydrogen or Ri6; Rl3 and R14 is each independently selected from hydrogen or optionally substituted Q-4 alkyl, optionally substituted aryl or optionally substituted aryl-C 1 -4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; Rl5 is Rio or C(Z)-Q_4 alkyl; Ri6 is Q-4 alkyl, halo-substituted-Q-4 alkyl, or C3-7 cycloalkyl; Rl8 is Q-io alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Q-ioalkyl, heteroaryl or heteroarylalkyl; Rl9 is hydrogen, cyano, Q- 4 alkyl, C3- 7 cycloalkyl or aryl; R21 is C 1-6 alkyl, aryl, arylQ-6alkyl, heterocyclic, heterocyclylQ-6 alkyl, heteroaryl, heteroarylC 1 -6alkyl, wherein each of these moieties may be optionally. Unles otherwise defined in any of the references incorporated herein, the term "optionally substituted" as used herein shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted Q-ioalkyl; Q-io alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1 or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl; amino, mono & di-substituted amino, such as in the NR7R17 group; or where the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S; Q-io alkyl, cycloalkyl, or cycloalkyl alky] group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted Q-io alkyl, such CF2CF2H, or CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Q-io alkoxy; S(O) m alkyl; amino, mono & di-substituted amino, such as in the NR7R17 group; alkyl, or CF3. A general method of synthesis for compounds of Formula (I) is shown below Scheme 1. Scheme 1 The synthesis provided for in these Schemes is applicable for the producing compounds of Formula (I) having a variety of different Ri, R2, and R4 groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outhned herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the imidazole nucleus has been established, further compounds of Formula (I) may be prepared by applying standard techniques for functional group interconversion, well known in the art. For instance, on the pyrimidine ring, halogen from OH, by reacting with POX 3 or PX 3 , wherein X is halogen; Q-4 alkylsulfinyl from Q-4 alkylthio by oxidation of the sulfur with an appropriate oxidant; N(Rιo)C(O)R a from NH(Rιo) by acylation on nitrogen with an appropriate acylating agent; YC(O)R a where Y is any leaving group. For other alternative groups on the R2 or R4 moiety, such as -C(O)NRi3Ri4 from -CO2CH3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR13R14 in CH3OH; -OC(O)R3 from -OH with e.g., ClC(O)R3 in pyridine; -NRιo-C(S)NRi3Rl4 from -NHRio with an alkyUsothiocyante or thiocyanic acid; NR6C(O)OR6 from -NHR6 with the alkyl chloroformate; -NRioC(O)NRi3Ri4 from -NHR10 by treatment with an isocyanate, e.g. HN=C=O or RιoN=C=O; -NRιo-C(O)Rs from -NHRio by treatment with Cl-C(O)R3 in pyridine; -C(=NRιo)NRl3Rl4 from -C(NRi3Ri4)SR3 with H3NR3+OAC " by heating in alcohol; -C(NRl3Ri4)SR3 from -C(S)NRi3Ri4 with R6-I in an inert solvent, e.g. acetone; -C(S)NRi3Ri4 (where R13 or R14 is not hydrogen) from -C(S)NH2 with HNRl3Rl4-C(=NCN)-NRi3Ri4 from -C(=NRi3Rl4)-SR3 with NH2CN by heating in anhydrous alcohol, alternatively from -C(=NH)-NRi3Ri4 by treatment with BrCN and NaOEt in EtOH; -NRιo-C(=NCN)SRs from -NHRio by treatment with (RδS)2C=NCN; -NR10SO2R3 from -NHRio by treatment with CISO2R3 by heating in pyridine; -NRiθC(S)R3 from -NRιoC(O)R8 by treatment with Lawesson's reagent [2,4-f?«(4-methoxyphenyl)- 1 ,3,2,4-dithiadiphosphetane-2,4-disulfide] ; -NR10SO2CF3 from -NHR6 with triflic anhydride and base wherein R3, R6, RlO, Rl3 and R 14 are as defined in Formula (I) herein. Precursors of the groups Ri , R2 and R4 can be other Ri , R2 and R4 groups which can be interconverted by applying standard techniques for functional group interconversion. For example a compound of the formula (I) wherein R2 is halo - substituted C\. Q alkyl can be converted to the corresponding C\. \Q alkylN3 derivative by reacting with a suitable azide salt, and thereafter if desired can be reduced to the corresponding Cι.ιoalkylNH2 compound, which in turn can be reacted with Rι S(0)2X wherein X is halo (e.g., chloro) to yield the corresponding C . oalkylNHS(0)2R 18 compound. Alternatively a compound of the formula (I) wherein R2 is halo-substituted Cι_ιo-alkyl can be reacted with an amine R13R14NH to yield the corresponding Cι_ιo-alkylNRi3Ri4 compound, or can be reacted with an alkali metal salt of R sSH to yield the corresponding C .1 oalkylSR 1 s compound. In Scheme I the compounds of Formula (I) are suitably prepared by reacting a compound of the Formula (LI) with a compound of the Formula (HI) wherein R is any suitable group, such as H, alkyl, substituted alkyl, aryl, aryl alkyl, heterocyclic, heterocylic alkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or amino, and R2 is as defined herein, for Formula (I), or is a precursor of the group R2, and thereafter if necessary converting a precursor of R2 to the desired R2 group. Suitable precursor groups of R2 include various well known protecting groups, particularly when R2 is a nitrogen containing heterocyclic ring, such as piperidine. Suitable protecting groups are described in many references, for instance, Protecting Groups in Organic Synthesis, Greene T W, Wiley- Interscience, New York, 1981. When R2 is an optionally substituted cycloalkyl, such as a 4-hydroxy-cyclohexyl, the precursor cyclohexanone could be used, and then reduced to the alcohol. The compounds of Formula (TV) which are formed are either isolated, or more suitably reacted in situ with compounds of the Formula (V) and a suitable base, where Ar is an optionally substituted phenyl group and R4 is defined herein, for compounds of Formula (I), to produce compounds of the Formula (VI). Heating compounds of the Formula (VI) with an enaminating reagent such as a compound of Formula (VH), or derivatives thereof, such as reagents of similar structure and reactivity to DMFDMA which include tris(dimethylamino)methane or tert- butoxybis(dimethylamino)-methane, or any other reactive species known to behave as enaminating agents; which produces compounds of the Formula (VLTI), which can be isolated, or more preferably reacted in situ with reagents of Formula (LX), where Y and Z are defined for Formula (LX) above to produce the compounds of Formula (I). An alternative to using reagents of Formula (VLI) to produce an enamine of Formula (VLTI) is to react compounds of Formula (VI) with formylating agents, such as formate esters, or formamides, to produce 1 ,3-dicarbonyl compounds which, when in their tautomeric form, are similar to compounds of the Formula (VLII), where (R b ) 2 N = OR, wherein R is alkyl, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, heterocychcalkyl, or silyl. Compounds of the Formula (VLTI), where (R b ) 2 N = OR can be reacted directly with reagents of the Formula (LX) to produce compounds of the Formula (I). The process is exemplified, in Scheme I, by reaction of pyruvaldehyde (Formula LI, R = H), which is typically obtained as an aqueous solution, with a primary amine (Formula LTI) in a solvent to produce imines ofthe Formula (TV), employing a modification ofthe method of van Koten (see van der Poel and van Koten, Synth. Commun. 1978, 8, 305 whose disclosure is incorporated by reference herein in its entirety). Suitable solvents for this process include, but are not limited to, ethereal solvents, such as tetrahydrofuran (THF), t-butyl methyl ether (TBME), diethyl ether, acetonitrile (MeCN), ethyl acetate (EtOAc), N,N,-c methylformamide (DMF), and dimethylsulfoxide (DMSO). The reaction requires times of ~1 min to about 24 h, with the preferred times being from about 10-20 min. The reaction is suitably conducted at temperatures ranging from about 0 °C to room temperature, or may be performed at elevated temperatures, of at least 100 °C, if so desired. Imines of Formula (TV) can be dissolved in a solvent and reacted with compounds of Formula (V), with or without added base, to produce compounds of Formula (VI). A suitable base for this reaction is potassium carbonate, or those noted below and suitable solvents include DMF and DMSO as noted below. The reaction can be conducted at 0 °C, room temperature or as high as about 65 °C. A further embodiment of the present invention involves the preparation of the imines of the Formula (TV) in situ, followed by reaction with isonitriles of the Formula (V) to produce imidazoles of the Formula (VI). In this process, aldehydes of Formula (II) are combined with primary amines of Formula (HI) in a suitable solvent, and after the prescribed amount of time the imine formation is considered complete and isonitriles of the Formula (V) and a suitable base are added. Suitable solvents include, but are not limited to, acetonitrile, THF, MeCN, toluene, EtOAc, DMF, and DMSO and mixtures thereof. The imine formation requires times of ~5 min to about 6 hours, with the preferred times being about 10-20 min and can be conducted at temperatures ranging from about 0 °C to 60 °C. After addition ofthe isonitrile, the reaction typically requires an additional 2 to 24 hours at temperatures of 0 °C to 65 °C to go to completion. The reaction proceeds without bases or in the presence of suitable bases, including but not limited to including inorganic and organic amine bases, such as potassium carbonate, sodium carbonate, K3PO4, K2HPO4, Na2HPO4, including inorganic and organic amine bases, such as secondary amines, e.g. morpholine, pyrrolidine, piperidine, and tertiary amines, such as DBU or DBM, as well as tetramethyl guanidine. Imidazoles of the Formula (VI) can be converted to compounds of the Formula (VLTI) by the action of agents of the Formula (VLI), or agents of similar structure and reactivity. The process involves heating compounds of Formula (VI) with N,N-dimethylformamide dimethyl acetal (DMFDMA) with no solvent, or a suitable solvent, at temperatures higher than about 70 °C. Suitable solvents include, but are not limited to toluene, ethanol, 1 -propanol, 2-propanol, DMF, and DMSO. Reagents of similar structure and reactivity to DMFDMA include tris(dimethylamino)methane or tert-butoxybis(dimethylamino)methane, or other reactive species know to behave as enaminating agents. With some of the more reactive enaminating reagents, the temperature for this process can be lower than the 70 °C mentioned above. Compounds of the Formula (VLTI) can be isolated, or prepared in situ, and reacted further as shown in Scheme 1. In either case, the reaction involves reacting compounds of Formula (VLTI) with compounds of Formula (LX) in a suitable solvent, and a suitable base, if necessary. Suitable solvents include, but are not limited to, alcohols, such as methanol, ethanol, 1 -propanol and 2-propanol, toluene, alone or in combination with an alcohol, DMF, DMSO, or combinations of the above. Reagents of the Formula (LX), when Y is NH, are typically obtained as an acid salt, and as such, require the action of a base to react with compounds of the Formula (VLTI). When Y is O or S, the reaction may require either acid or base catalysis. Suitable bases include, but are not limited to, NaOMe, NaOEt, potassium carbonate, and KOH. Temperatures of about 25 to about 110 °C have been found to be useful for this conversion, with temperatures > 65 °C being preferred. A further embodiment of the present invention involves the preparation of imidazoles of the Formula (I) as shown in Scheme 1 in a single pot. The reaction conditions mentioned above are generally suitable for conducting the synthesis in one pot, with one modification. The conversion of compounds of the Formula (VI) to compounds of the Formula (VLTI) requires anhydrous conditions. Water is introduced into the reaction when using pyruvaldehyde (LI, R = H) as it is sold as a solution in water, which must be removed before proceeding. Following complete conversion of (TV) and (V) to form (VI), suitable methods of dehydration include, but are not limited to the following: using excess DMFDMA (- 10 equivalents) to both react with water and then with ketones (VI); azeotropically removing water with cosolvents such as toluene, or alcohols; adding other drying agents such as MgSO4; or triethyl orthoformate. SYNTHETIC EXAMPLES The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon atmosphere unless otherwise indicated. In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. 1 H-NMR (hereinafter "NMR") spectra were recorded at 300 MHz using a Bruker AM 300 spectrometer. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant. Flash chromatography is generally run over Merck Silica gel 60 (230 - 400 mesh). Example 1 Ethyl 4-(2-oxopropylidene)amino- 1 -piperidinecarboxylate To a solution of pyruvaldehyde (40% w/w solution in water, 2.67 mL, 3.15 g, 17.5 mmol) in 50 mL of Et 2 O at room temperature was added dropwise ethyl 4- amino-piperidinecarboxylate (3.0 mL, 3.01 g, 17.5 mmol). After 20 min, the solution was diluted with 50 mL of Et 2 O and washed with 3 X 30 mL of water. The solution was concentrated in vacuo to yield 2.3 g (58%) of the imine product which was used as such in the subsequent step: 1H NMR (CDC1 3 ) δ 7.58 (IH, s), 4.07 (2H, q, J = 7.1 Hz)), 4.04 (2H, m), 3.39 (IH, m), 3.02 (2H, m), 2.31 (3H, s), 1.65 (4H, m), 1.19 (3H, t, J = 7.1 Hz). Example (Ia): Alternative conditions utilized in above noted synthesis include MeCN as solvent and mixing the reagents at 0 °C. Example 2 1 -( 1 -Ethoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-acetylimidazole : Cθ 2 Et To a solution of the imine described in Example 1 above (1.12 g, 4.95 mmol) in 9 mL of DMF at room temperature was added α-(p-toluenesulfonyl)-4- fiuorobenzylisonitrile (1.30 g, 4.50 mmol) and K 2 CO 3 (0.68 g, 4.95 mmol). After 22 h, the solution was diluted with 75 mL of EtOAc and washed with 2 X 60 mL of 3 N HCl. The aqueous layers were combined and basified with excess solid K 2 CO 3 until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2 x 75 mL of EtOAc. The combined organics were washed with 3 X 50 mL of water and concentrated in vacuo. The residue was recrystallized from CHCl^exane to yield the imidazole product (1.05 g, 65%) which was used in subsequent steps: mp = 118-19 °C; IR (KBr) 1691, 1681, 1640 cm 1 ; Η NMR (CDC1 3 ) δ 7.74 (IH, s), 7.44 (2H, m), 7.14 (2H, t, J = 8.6 Hz), 5.00 (IH, tt, J = 3.7, 12.1 Hz), 4.35 (2H, m), 4.17 (2H, q, J = 7.1 Hz), 2.93 (2H, m), 2.18 (2H, br d, J = 12.9 Hz), 2.12 (3H, s), 1.80 (2H, dq, J = 4.2, 12.4 Hz), 1.28 (3H, t, J = 7.1 Hz); ,3 C NMR (CDCL 3 ) d 191.00, 164.74, 161.45, 155.31, 149.77, 137.39, 131.46, 131.35, 126.99, 115.63, 115.34, 61.59, 54.85, 43.29, 33.40, 30.45, 14.63; 13 C NMR (CDC1 3 ) δ 191.00, 164.75, 161.45, 155.31, 149.77, 137.39, 131.46, 131.35, 126.99, 115.63, 115.35, 61.59, 54.85, 43.29, 33.40, 30.45, 14.63; Anal. Calcd for C 19 H 22 N 3 O 3 F: C, 63.5; H, 6.2; N, 11.7. Found C, 63.1 ; H, 6.1 ; N, 11.5. In an alternative procedure to that listed above, the title compound was prepared in the following manner: To a solution of pyruvaldehyde (40% w/w solution in water, 3.97 mL, 4.68 g, 25.94 mmol) in 34 mL of DMSO at room temperature was added dropwise ethyl 4-amino-piperidinecarboxylate (4.45 mL, 4.47 g, 25.94 mmol). After 10 min α-(p-toluenesulfonyl)-4-fluoro-benzylisonitrile (5.0 g, 17.3 mmol) and K 2 CO 3 (2.39 g, 17.3 mmol) were added. After 15 h, the solution was diluted with 100 mL of EtOAc and washed with 2 X 100 mL of 3 N HCl. The aqueous layers were combined and basified with excess solid K 2 CO 3 until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2 x 150 mL of EtOAc. The combined organics were washed with 3 X 75 mL of water and concentrated in vacuo to yield the imidazole product (4.65 g, 75%) which was used as is in subsequent steps. Alternative conditions for this synthesis include the Examples shown below:: Solvent Base / eq Temp for imine Temp for Imine formation cycloaddition formation time DMF K 2 CO 3 /1.2 room temp. room temp. 15 min DMF K 2 CO 3 /l.l room temp. room temp. 15 min DMF K 2 CO 3 /1.2 room temp. room temp. 20 min DMF K 2 CO 3 /1.2 room temp. room temp. 17 min. DMF K 2 CO 3 /1.2 room temp. room temp. 80 min DMF K 2 CO 3 /1.2 room temp. room temp. 75 min DMF K 2 CO 3 /1.2 room temp. room temp. 6h DMF K 2 CO 3 /1.2 room temp. room temp. 2h DMF K 2 CO 3 /l.l room temp. room temp. 85 min DMF K 2 CO 3 /1.2 room temp. room temp. 12 min DMF K 2 CO 3 /1.2 45 °C 45 °C 12 min DMF K 2 CO 3 /1.2 60 °C 60 °C 14 min DMF/MgSO 4 K 2 CO 3 /1.2 room temp. room temp. 12min DMF K 2 CO 3 /1.2 rm temp, to 40 room temp. 12 min °C, distill DMF K 2 CO 3 /l.l 40 °C 40 °C 10 min. DMF K 2 CO 3 /1.25 0°C room temp. 4h DMF K 2 CO 3 /1.2 0°C 0°C 2.33 h DMF NaHCO 3 /1.3 room temp. room temp. 75 min. MeCN K 2 CO 3 /1.25 room temp. room temp. 25 min. MeCN K 2 CO 3 /1.2 room temp. room temp. 5 min. MeCN K 2 CO 3 /1.2 room temp. room temp. 10 min. MeCN K 2 CO 3 /1.25 0°C room temp. 15 min. MeCN K 2 CO 3 /1.2 0°C 0°C 145 min. DMSO K 2 CO 3 /1.25 room temp. room temp. 15 min. THF morpholine / 3 room temp. room temp. lh THF K 2 CO 3 /1.2 0°C 0°C 145 min. Toluene K 2 CO 3 /1.25 room temp. room temp. 15 min. EtOAc K 2 CO 3 /1.0 room temp. room temp. 11 min. Example 3 1 -( 1 -E oxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(3-N,N-d-jnethylarnino- trans- 1 -propenone)imidazole CQ 2 Et The ketoimidazole prepared in Example 2 above (0.4 g, 1.11 mmol) was dissolved in 4 mL of DMSO and N,N-dimethylformamide dimethyl acetal (0.18 mL, 0.16 g, 1.33 mmol) and was heated at 90 °C for 5.5 h. The solution was cooled to room temperature and the solvents were removed under vacuum by Kugel-Rohr distillation. The residue was purified by preparative TLC using hexanes/ethyl acetate (1:1) and eluting twice to give 0.3 g (65%) of the title compound as a brown solid: 1H NMR (CDC1 3 ) δ 7.65 (IH, s), 7.55 (2H, m), 7.48 (IH, m), 7.02 (2H, t, J = 8.7 Hz), 5.02 (IH, d, J = 12.6 Hz), 4.91 (IH, m), 4.30 (2H, m), 4.13 (2H, q, J = 7.1 Hz), 2.99 (3H, br s), 2.89 (2H, m), 2.51 (3H, br s), 2.18 (2H, d, J = 12.1 Hz), 1.78 (2H, dq, J = 4.3, 12.3 Hz), 1.26 (3H, t, J = 7.1 Hz). Example 4 1 -( 1 -Ethoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5- { 2-(methylamino)-4- pyrimidinyl)imidazole : C0 2 Et i ^ To a solution of the ketoimidazole prepared in Example 2 above (2.1 g,5.85 mmol) in 10.5 mL of 1 -propanol was added N,N-dimethylformamide dimethyl acetal (1.32 mL, 1.18 g, 9.94 mmol) and the solution was heated at 100 °C for 6 h. At this time, TLC indicated no starting material and N-methylguanidine » HCl (0.96 g, 8.77 mmol) and NaOEt (21% w/w solution, 3.50 mL, 3.05 g, 9.35 mmol) were added. After 18 hours, the solution was cooled to room temperature, diluted with 40 mL of water, 50 mL of 3N HCl and 50 mL of EtOAC. The layers were separated and the organic layer wash washed again with 20 mL of 3N HCl. The combined aqueous layers were basified with solid K j CO 3 until bubbling ceased. The aqueous layer was extracted with EtOAc (2 X 50 mL). The combined organics were washed with 3 X 100 mL of water, concentrated and the residue was recrystallized from EtOAc to give 1.24 g (50%) of the title compound: mp = 205-206 °C; LR (KBr) 3242, 3110, 1695, 1588, 1568, 1532, 1507 cm- '; 1H NMR (CDC1 3 ) δ 8.15 (IH, d, J = 5.0 Hz), 7.71 (IH, s), 7.44 (2H, m), 6.97 (2H, t, J = 8.7 Hz), 6.40 (IH, d, J = 5.0 Hz), 5.18 (IH, m), 4.83 (IH, m), 4.34 (2H, m),4.15 (2H, q, J = 7.1 Hz), 3.02 (3H, d, J = 5.0 Hz), 2.81 (2H, m), 2.19 (2H, m), 1.87 (2H, dq, J = 4.4, 12.5 Hz), 1.27 (3H, t, J = 7.1 Hz); ,3 C NMR (CDC1 3 ) δ 164.00, 163.03, 160.73, 158.51, 158.32, 155.31, 141.96, 135.57, 130.52, 130.07, 129.97, 125.01, 115.39, 115.11, 111.73, 61.61, 53.80, 43.42, 33.43, 28.43, 14.63; Anal. Cald for C.^N^F; C, 62.2; H, 5.9; N, 19.8; Found C, 61.9, H, 6.0; N, 19.4. Examples 4 (a) and (b) include the alternative conditions : Solvent DMFDMA temp Base Pyrimidine temp. EtOH 85 °C NaOMe 85 °C DMF 100 °C NaOMe 65 °C Example 5 1 -( 1 -Ethoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-(amino)-4- pyrimidinyl)imidazole : C0 2 Et To a solution of the ketoimidazole prepared in Example 2 above (2.6 g, 7.24 mmol) in 15 mL of DMF was added N,N-dimethylformamide dimethyl acetal (1.92 mL, 1.72 g, 14.5 mmol) and the solution was heated at 120 °C for 2 h. At this time, TLC and HPLC indicated no starting material and the solution was cooled to 95 °C and ethanol (30 mL), guanidine » HCl (2.77 g, 28.95 mmol) and K 2 CO 3 (4.0 g, 28.9 mmol) were added. After 16 hours, HPLC indicated that the reaction was complete and the solution was cooled to room temperature. The solution was diluted with 100 mL of EtOAc and washed with 2 X 150 mL of 3 N HCl. The aqueous layers were combined and basified with excess solid K 2 CO 3 until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2 x 150 mL of EtOAc. The combined organics were dried over Na 2 SO and activated charcoal, filtered through Celite, and concentrated in vacuo. The residue was recrystallized from EtOAc/MeOH/Hexanes to yield the imidazole product (0.9 g, 30%) as a beige solid: mp = 228-230 °C; LR (KBr) 3321, 3157, 1712, 1658, 1568, 1507, 1470, 1437 cm 1 ; 'H NMR (CDC1 3 ) δ 8.17 (IH, d, J = 5.3 Hz), 7.71 (IH, s), 7.43 (2H, m), 7.00 (2H, t, J = 8.7 Hz), 6.50 (IH, d, J = 5.3 Hz), 5.16 (2H, br s), 4.74 (IH, tt, J = 3.7, 12.0 Hz), 4.35 (2H, m), 4.15 (2H, q, J = 7.1 Hz), 2.82 (2H, t, J = 12.5 Hz), 2.15 (2H, d, J = 12.5 Hz), 1.85 (2H, m), 1.28 (3H, t, J = 7.1 Hz); 13 C NMR (DMSO-d 6 ) δ 163.61, 162.76, 159.54, 158.66, 158.01, 154.35, 138.88, 136.25, 131.00, 129.16, 129.05, 124.98, 115.08, 114.80, 110.84, 60.64, 53.06, 42.70, 32.48, 14.43; Anal. Calcd for C 21 H J3 N 6 O 2 F; C, 61.4; H, 5.7; N, 20.5; Found C, 61.0, H, 5.5; N, 20.3. Examples 5 (a) to (d) include the alternative conditions : Solvent DMFDMA temp Base Pyrimidine temp. EtOH 90 °C NaOMe 80 °C EtOH 90 °C NaOMe 85 °C DMF 120 °C K 2 CO 3 /EtOH 95 °C Toluene 115 °C K 2 CO 3 /EtOH/IPA 80-90 °C .ample 6 1 -(4-piperidinyl)-4-(4-fluorophenyl)-5- { 2-(amino)-4-pyrimidinyl)imidazole To a solution of the ketoimidazole prepared in Example 2 above (1.4 g, 3.89 mmol) in 5 mL of toluene was added N,N-dimethylformamide dimethyl acetal (1.04 mL, 0.93 g, 7.80 mmol) and the solution was heated at 115 °C for 4 h. At this time, TLC and HPLC indicated no starting material and the solution was cooled to 80 °C and 2-propanol (25 mL), guanidine»HCl ( 1.49 g, 15.6 mmol) and K 2 CO 3 (2.15 g, 15.6 mmol) were added. After 16.5 hours, HPLC indicated that the reaction was 60% complete. Ethanol (20 mL) was added and heating was continued at 90 °C for 24h, at which point HPLC showed none ofthe aminoenone remaining. AT this point, KOH (2.19 g, 38.9 mmol) and water (10 mL) were added and heating was continued at 95 °C for 8 h. An additional poriton of KOH (2.2 g, 38.9 mmol) was added. After 15 h of heating an additional 4.4 g of KOH was added and heated for 48 h. The solution was cooled to room temperature, diluted with 20 mL of water and the solid which formed was filtered, washed with water (50 mL) and Et 2 O (50 mL), and dried to yield 0.44 g (34%) of the tide compound as a beige solid: mp = 199-200 °C; LR (KBr) 3471, 3395, 3314, 3167, 1635, 1576, 1566, 1507, 1460 cm 1 ; Η NMR (DMSO-de) δ 8.20 (IH, d, J = 5.0 Hz), 7.98 (IH, s), 7.43 (2H, m), 7.12 (2H, t, J = 8.9 Hz), 6.81 (2H, br s), 6.41 (IH, d, J = 5.0 Hz), 4.31 (IH, m), 2.97 (2H, d, J = 12.4 Hz), 2.45 (2H, m), 1.86 (2H, m), 1.74 (2H, dq, J = 3.7, 11.8 Hz); 13 C NMR (DMSO-d 6 ) δ 163.67, 162.70, 159.47, 158.68, 158.33, 138.64, 135.79, 130.98, 128.98, 128.88, 125.05, 115.05, 114.77, 110.96, 53.84, 45.39, 34.08; Anal. Calcd for C 18 H 19 N 6 F » 0.5 FLO: C, 62.2; H, 5.8; N, 24.2. Found C, 61.9; H, 5.7; N, 23.9. In an alternative procedure, the substrate was dissolved in 1-PτOH and heated at about 95 °C with DMFDMA, then heated with guanidine » HCl and K 2 CO 3 at 95 °C and when the pyrimidine formation was completed, the reaction was heated with excess KOH until product formation was complete. Example 7 2,2,6,6-Tetramethyl-4-(2-oxopropylidene)aminopiperidine To a solution of pyruvaldehyde (40% w/w solution in water, 2.68 mL, 3.16 g, 17.5 mmol) in 30 mL of TBME at room temperature was added dropwise 2,2,6,6- tetramethyl-4-amino-piperidine (2.0 mL, 2.19 g, 14.0 mmol). After 30 min, the solution was diluted with 50 mL of TBME and washed with 3 X 25 mL of water and 25 mL of brine. The solution was concentrated in vacuo to yield 2.1 g (71%) of the imine product which was used as such in the subsequent step: Η NMR (CDC1 3 ) δ 7.64 (IH, s), 3.70 (IH, tt, J = 3.9, 11.6 Hz), 2.34 (3H, s), 1.61 (2H, dd, J = 3.9, 13.0 Hz), 1.32 (2H, t, J = 12.2 Hz), 1.21 (6H, s), 1.14 (6H, s). Example 8 l-(2,2,6,6-teframethyl-4-piperiά^yl)-4-(4-fluorophenyl)-5-acetylimidazole: :To a solution of pyruvaldehyde (40% w/w solution in water, 7.56 mL, 8.91 g, 49.5 mmol) in 90 mL of DMSO at room temperature was added dropwise 2,2,6,6- tetramethyl-4-amino-piperidine (9.24 mL, 8.43 g, 65.4 mmol). After 10 min α-(p- toluenesulfonyl)-4-fluorobenzylisonitrile (13.0 g, 44.95 mmol) and K 2 CO 3 (7.46 g, 53.95 mmol) were added. After 23 h, the solution was diluted with 250 mL of EtOAc and washed with 2 X 200 mL of 3 N HCl. The aqueous layers were combined and basified with excess solid K 2 CO 3 until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2 x 250 mL of EtOAc. The combined organics were washed with 3 X 100 mL of water and concentrated in vacuo to yield the title compound (11.6 g, 75%) as a brown oil, which could be recrystallized from CHCl 3 /hexanes: mp = 134-36 °C; LR (KBR) 3430, 3144, 1659, 1653, 1219 cm 1 ; 1H NMR (CDC1 3 ) δ 7.76 (IH, s), 7.43 (2H, m), 7.12 (2H, t, J = 8.7 Hz), 5.39 (IH, tt, J = 3.1, 12.5 Hz), 2.11 (3H, s), 2.10 (2H, m), 1.50 (2H, t, J = 12.2 Hz), 1.37 (6H, s), 1.22 (6H, s); ,3 C NMR (CDC1 3 ) δ 190.77, 164.69, 161.41, 149.79, 137.42, 131.47, 131.36, 127.03, 115.57, 115.29, 52.02, 50.57, 46.20, 34.61, 30.45, 28.06. Alternative reaction conditions for this synthesis included: Solvent Base / eq. Imine Cycloaddition Imine formation temp. formation time temp DMF K,CO, / 1.25 room temp. room temp. 15 min. DMF/toluene K,CO, / 1.15 room temp to room temp. 80 min. 65 °C (-LLO) DMF none room temp. room temp. 15 min. DMF/EtOAc K,CO 3 / 1.2 room temp. room temp. 15 min. DMSO K,CO, / 1.25 room temp. room temp. 20 min. DMSO/toluene K,CO, / 1.15 room temp to room temp. 35 min. 55 °C (-H,O) DMSO/ K,CO, / 1.2 room temp to room temp. 40 min. (MeO),CH 55 °C (-H,O) DMSO mo holine/1.3 room temp. room temp. 15 min. DMSO pyrrolidine/ 1.3 room temp. room temp. 15 min. DMSO K.PO/1.5 room temp. room temp. 15 min. DMSO K,HPO i.5 room temp. room temp. 15 min. DMSO DBU/1.1 room temp. room temp. 15 min. DMSO Na,CO, / 1.2 room temp room temp. 15 min. DMSO Na,HPO 4 /1.5 room temp. room temp. 15 min. DMSO K.HPO/3.0 room temp. room temp. 15 min. DMSO moφholine/1.05 room temp. room temp. 18 min. DMSO moφholine/1.0 room temp. room temp. 10 min. EtOAc moφholine/1.0 room temp. room temp. 10 min. EtOAc K,CO Λ / 1.0 room temp room temp. 12 min. EtOAc K,CO, / 1.0 room temp 50 °C 13 min. EtOAc K,CO, / 1.0 room temp 35 °C 15 min. EtOAc K,CO. / 1.0 room temp 40 °C 15 min. Example 9 l-(2,2,6,6-tetπιmetfryl-4-piperid nyl)-4~(4-fluorophenyl)-5-(3-N,N-ά me ylamino- trans- 1 -propenone)imidazole The ketoimidazole prepared in Example 8 above (0.75 g, 2.18 mmol) was dissolved in 10 mL of toluene and N,N-dimethylformamide dimethyl acetal (0.43 mL, 0.39 g, 3.28 mmol) and was heated at 115 °C for 20 h. The solution was cooled to room temperature and the solvents were removed under vacuum. The residue was passed through a short plug of silica gel and eluted with EtOAc/MeOH (1: 1), and concentrated to give the title compound (0.65 g 76%) of the title compound as a brown solid: 1H NMR (CDC1 3 ) δ 7.65 (IH, s), 7.56 (2H, m), 7.46 (IH, d, J = 12.2 Hz), 7.01 (2H, t, J = 8.8 Hz), 5.32 (IH, m), 5.01 (IH, d, J = 12.6 Hz), 2.96 (3H, br s), 2.48 (3H, br s), 2.09 (2H, dd, J = 3.1, 12.0 Hz), 1.44 (2H, t, J = 12.3 Hz), 1.31 (6H, s), 1.17 (6H, s). Example 10 1 -(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5- { 2-(methylamino)-4- pyrimidinyl)imidazole To a solution of the ketoimidazole prepared in Example 8 above (8.0 g,23.3 mmol) in 100 mL of DMSO was added N,N-dimethylformamide dimethyl acetal (6.19 mL, 5.55 g, 46.6 mmol) and the solution was heated at 100 °C for 16 h. At this time, HPLC indicated no starting material and guanidine » HCl (4.45 g, 46.6 mmol) and K 2 CO 3 (6.44 g, 46.6 mmol) were added and heating was continued at 100 °C. After 9 hours, the solution was cooled to room temperature, diluted with 100 mL of water, DMSO and MeOH, and filtered. The filtrate was diluted with 200 mL of EtOAc and 400 mL of water. The layers were separated and the aqueous layer was extracted 3 X 200 mL of EtOAc. The organic layers were combined and washed with 3 X 100 mL of water. The organics were washed with 50 mL of brine, dried over Na 2 SO and activated charcoal, concentrated and the residue was recrystallized from EtOAc /hexanes to give 3.3 g (36%) of the title compound: mp = 221-22 °C; LR (KBr) 3345, 3319, 3155,1645, 1562 cm 1 ; 1H NMR (CDC1 3 ) δ 8.17 (IH, d, J = 5.1 Hz), 7.72 (IH, s), 7.45 (2H, m), 7.00 (2H, t, J = 8.7 Hz), 6.49 (IH, d, J = 5.2 Hz), 5.30 (IH, tt, J = 3.2, 12.6 Hz), 5.12 (2H, br s), 2.04 (2H, dd, J = 3.2, 12.4 Hz), 1.48 (2H, t, J = 12.3 Hz), 1.24 (6H, s), 1.17 (6H, s); 13 C NMR (DMSO-d 6 ) δ 163.67, 162.72, 159.49, 158.77, 158.49, 138.68, 135.43, 130.92, 128.93, 128.82, 125.14, 115.09, 114.81, 111.00, 50.81, 48.67, 44.74, 34.06, 28.11. Anal. Calcd for C 22 H 27 N 6 F: C, 66.98; H, 6.90; N, 21.30. Found C, 67.37; H, 6.88; N, 21.39. Alternative conditions employed include: Solvent DMFDMA temp Base Pyrimidine temp. DMF 100 °C K 2 CO 3 120 °C DMSO 100 °C K 2 CO 3 100 °C DMSO 100 °C KOH 100 °C 1-PrOH 100 °C KOH/H 2 O 100 °C EtOH 85 °C NaOMe 85 °C 2-PrOH 85 °C NaOMe 85 °C In yet another alternative procedure to those listed above, the title compound was prepared in the following manner: To a solution of pyruvaldehyde (40% w/w solution in water, 5.82 mL, 6.85 g, 38.04 mmol) in 70 mL of DMSO at room temperature was added 2,2,6,6-tetramethyl-4-aminopiperidine (6.52 mL, 5.94 g, 38.04 mmol). After 15-20 min, α-(p-toluenesulfonyl)- -fluorobenzylisonitrile (10 g, 34.6 mmol) and K 2 CO 3 (5.02 g, 36.3 mmol) were added. After 19 h, an HPLC solution assay indicated that 6.79 g (57%) of the ketoimidazole (title compound of Example 8) had formed and that reaction was complete. To the solution was added 30 mL of toluene, and the solution was heated at 65 °C while the toluene was removed under vacuum. The toluene addition distillation was repeated two times more. N,N-dimethylformamide dimethyl acetal (DMFDMA) (9.2 mL, 8.24 g, 69.2 mmol) was added and the solution was heated at 100 °C. After 2 h, HPLC indicated no reaction, so an additional 9.2 mL of DMFDMA were added, and after 15 h an additional 5 mL of DMFDMA were added and heated for 1 h. Guanidine»HCl (6.61 g, 69.2 mmol) and K 2 CO 3 (9.56 g, 69.2 mmol) were added and heated at 100 °C for 6.75 h, at which point HPLC indicated that the reaction was complete. After cooling to room temperature, the solution was filtered through a pad of Celite, diluted with 250 mL of EtOAc and washed with 4 X 200 mL of 3 N HCl. The aqueous layers were combined and basified with solid KOH to pH = 14. The aqueous layer was transferred to a separatory funnel and extracted 3 x 200 mL of EtOAc. The combined organics were washed with 3 X 100 mL of 3N KOH solution and 50 mL of brine, dried over Na 2 SO and activated charcoal, filtered through Celite and concentrated in vacuo. The residue was dissolved in 50 mL of MeOH and the crystals which formed were filtered and washed with 100 mL of EtOAc to yield the title compound (4.89 g, 36%) as a tan solid. Example 11 1 -( 1 -t-Butoxycarbonyl-4-piperiώnyl)-4-(4-fluorophenyl)-5-acetylirnidazole To a solution of t-butyl 4-amino-piperidinecarboxylate (0.95 g, 4.75 mmol) in 40 mL of Et 2 O was added pyruvaldehyde (40% w/w solution in water, 0.94 mL, 1.11 g, 6.17 mmol) at room temperature. After 1.75 h, the solution was poured into a separatory funnel, diluted with 30 mL of Et 2 O and 10 mL of EtOAc, and washed with 2 X lO mL of water. The organics were concnetrated in vacuo and the residue was diluted in 10 mL of DMF and α-(p-toluenesulfonyl)-4-fluoro-benzylisonitrile (1.37 g, 4.75 mmol) and K 2 CO 3 (0.72 g, 5.23 mmol) were added. After 16 h, the solution was diluted with 100 mL of water and extracted with 2 X 40 mL of EtOAc. The combined organics were washed with 3 X 40 mL of 10% HCl. The aqueous layers were combined and neutralized with excess solid NaHCO 3 , then basified with 20 mL of 10% KOH. The aqueous layer was transferred to a separatory funnel and extracted 3 x 30 mL of EtOAc. The combined organics concentrated in vacuo to yield the imidazole product (0.5 g, 27%): Η NMR (CDC1 3 ) δ 7.74, 7.44 (2H, m), 7.13 (2H, t, J = 8.6 Hz), 4.97 (IH, tt, J = 3.7, 12.0 Hz), 4.29 (2H, m), 2.88 (2H, m), 2.15 (2H, m), 2.11 (3H, s), 1.78 (2H, dq, 4.2, 12.2 Hz), 1.48 (9H, s). Example 12 l-Ber-zyl-4-(2-oxopropylidene)aminopiperidine To a solution of pyruvaldehyde (40% w/w solution in water, 0.49 mL, 0.57 g, 3.19 mmol) in 10 mL of Et 2 O at room temperature was added dropwise 4-amino- 1-benzylpiperidine (0.5 mL, 0.46 g, 2.45 mmol). After 20 min, the solution was diluted with 40 mL of Et 2 O and washed with 2 X 5 mL of water. The solution was concentrated in vacuo to yield the imine product which was used as such in the subsequent step: 1H NMR (CDC1 3 ) δ 7.62 (IH, s), 7.29 (5H, m), 3.53 (2H, s), 3.28 (IH, m), 2.91 (2H, m), 2.38 (3H, s), 2.15 (2H, m), 1.84 (2H, m), 1.69 (2H, m). Example 13 1 -( 1 -Benzyl-4-piperidinyl)-4-(4-fluorophenyl)-5-acetyhmidazole Bn To a solution ofthe imine described in Example 12 above (assumed 100% yield for Example 12, 0.64 g, 2.44 mmol) in 5 mL of DMF at 0 °C was added α-(p- toluenesulfonylM-fluoroberizylisomtrile (0.85 g, 2.93 mmol) and K 2 CO 3 (0.40 g, 2.93 mmol). The solution was stirred at 0 °C for 2 h, then gradually warmed to room temperature over 15 h. The solution was diluted with 70 mL of EtOAc and washed with 100 and 50 mL of water. The organic layer was acidified with 2 X 55 mL of 3N HCl . The aqueous layers were combined and neutalized with solid NaHCO 3 then basified with 30 mL of 10% KOH. The aqueous layer was transferred to a separotary funnel, extracted with 2 x 50 mL of EtOAc and concentrated in vacuo to yield the title compound (0.38 g, 41%) which was used in subsequent steps: 1H NMR (CDC1 3 ) δ 7.78 (IH, s), 7.43 (2H, m), 7.27 (5H, m), 7.11 (2H, t, J = 8.6 Hz), 4.80 (IH, tt, J = 3.9, 11.8 Hz), 3.55 (2H, s), 3.02 (2H, d, J = 11.9 Hz), 2.16 (2H, m), 2.10 (3H, s), 1.94 (2H, m). Example 14 1 -( l-Benzyl-4-piperidinyl)-4-(4-fluorophenyl)-5- { 2-(amino)-4- pyrimidinyl)imidazole To a solution of the ketoimidazole prepared in Example 13 above (0.38 g, 1.01 mmol) in 5 mL of EtOH was added N,N-dimethylformamide dimethyl acetal (0.4 mL, 0.36 g, 3.02 mmol) and the solution was heated at 90 °C for 3 h. After 3 h, an additional 1 mL of DMFDMA was added and heated for 3 h. At this time, TLC indicated no starting material and the solution was cooled to 70 °C and guanidine » HCl (0.19 g, 2.02 mmol) and NaOMe (25% w/w solution, 0.46 mL, 0.44 g, 2.02 mmol) were added. After 15 hours, additional N-methylguanidine « HCl (0.19 g, 2.02 mmol) and NaOMe (25% w/w solution, 0.46 mL, 0.44 g, 2.02 mmol) were added and heated at 75 °C for 24 h. The solution was cooled to room temperature, diluted with 50 mL of water and extracted 2 X 50 mL of EtOAC. The combined organics were concentrated and the residue was recrystallized from EtOAc to give 0.2 g (47%) of the title compound: 1H NMR (CDC1 3 ) δ 8.19 (IH, d, J = 5.2 Hz), 7.76 (IH, s), 7.44 (2H, m), 7.33 (5H, m), 7.01 (2H, t, J = 8.6 Hz), 6.50 (IH, d, J = 5.2 Hz), 5.17 (2H, br s), 4.54 (IH, m), 3.53 (2H, s), 3.02 (2H, m), 2.09 (6H, m). Additional compounds produced using the analagous methods to those indicated above include: Example 15: 5-(2-Phenylam o-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(4- piperidinyl)imidazole Example 16: l-[l-Carboethoxy)piperidin-4-yl]-4-(4-fluorophenyl)-5-[[2-[3- benzyloxy)phenylamino]pyrimdin-4-yl]imidazole Example 17: l-[l-Carboethoxy)piperidin-4-yl]-4-(4-fluorophenyl)-5-[[2-[4- benzyloxy)phenylamino]pyrimdin-4-yl]imidazole Example 18: 1 -(T J iperdin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-trifluoromethylphenyl)- an mo]pyrimidin-4-yl)imidazole Example 19: l-(Piperdin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-4,difluorophenyl)- arn o]pyrirnidm-4-yl)imidazole The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the are can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embc>diments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims: What is Claimed Is: Claim 1. A process of making compounds of Formula wherein Rl is an optionally substituted pyrimidin-4-yl ring; R4 is an optionally substituted phenyl, naphth- 1-yl or naphth-2-yl, or heteroaryl ring; m is 0, or the integer 1 or 2; m' is an integer having a value of 1 or 2, R2 is -(CRioR20)n" OR9, heterocyclyl, heterocyclylQ-io alkyl, Q-ioalkyl, halo¬ substituted Q-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylCi-io alkyl, C5-7 cycloalkenyl, C5-7cycloalkenyl-Q-io-alkyl, aryl, arylCi-io alkyl, heteroaryl, heteroaryl-Q-io-alkyl, (CRioR20)nORl l, (CRioR20)nS(O) m Rl8, (CRlθR2θ)nNHS(O)2Rl8, (CRlθR2θ)nNRl3Rl4, (CRioR20)nNO2, (CRioR20)nCN, (CRioR20)n , SO2Rl8, (CRιoR2θ)nS(O)nϊNRi3Rl4, (CRlθR2θ)nC(Z)Rn, (CRioR20)nOC(Z)Rn, (CRlθR20)nC(Z)ORl 1, (CRioR2θ)nC(Z)NRι 3 Rι , (CRlθR2θ)nC(Z)NRnOR9, (CRi0R20)nNRl0C(Z)Rι 1, (CRιoR2θ)nNRlθC(Z)NRi3Rl4, (CRioR20)nN(OR6)C(Z)NRi3Rl4, (CRi(yR20)nN(OR6)C(Z)Rι 1, (CRioR20)nC(=NOR6)Rl l, (CRiθR2θ)nNRlθC(=NRi9)NRi3Rl4, (CRioR20)nOC(Z)NRi 3 Ri4, (CRioR2θ)nNRlθC(Z)NRi3Rl4, (CRioR2θ)nNRlθC(Z)ORιo, 5-(Rι 8 )-l,2,4-oxadizaol-3-yl or 4-(Ri2)-5-(Ri8Ri9)-4,5-dihydro-l,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted; n is an integer having a value of 1 to 10; n' is 0, or an integer having a value of 1 to 10; Z is oxygen or sulfur; R3 is heterocyclyl, heterocyclylQ-io alkyl or Rs; R6 is hydrogen, a pharmaceutically acceptable cation, Q-io alkyl, C3-7 cycloalkyl, aryl, arylQ-4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or Q-io alkanoyl; R8 is Q-10 alkyl, halo-substituted Q-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylQ-io alkyl, heteroaryl, heteroarylC i- 10 alkyl, (CRioR20)nORl l, (CRιoR2θ)nS(O) m Ri8, (CRioR20)nNHS(O)2Rl8, (CRioR20)nNRl3Rl4; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted; R9 is hydrogen, -C(Z)Rι 1 or optionally substituted Q-io alkyl, S(O)2Rl8. optionally substituted aryl or optionally substituted aryl-C 1 -4 alkyl; RlO and R20 is eacn independently selected from hydrogen or Q_4 alkyl; Rl 1 is hydrogen, Q-io alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl Q-ioalkyl, aryl, arylCi-io alkyl, heteroaryl or heteroarylQ-io alkyl; Rl2 is hydrogen or Ri6; R13 and R14 is each independently selected from hydrogen or optionally substituted Q-4 alkyl, optionally substituted aryl or optionally substituted aryl-C 1.4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; R 16 is C 1 -4 alkyl, halo-substituted-C 1 -4 alkyl, or C3-7 cycloalkyl; Rl8 is Q-io alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Q-ioalkyl, heteroaryl or heteroarylalkyl; and Rl9 is hydrogen, cyano, Q-4 alkyl, C3-7 cycloalkyl or aryl; which process comprises: a) reacting a compound of the formula wherein Rb is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocychcalkyl, all of which may be optionally substituted; R is a substituent group on the Rj moiety as defined for Formula (I), or is an optionally substituted alkyl or aryl group; and R2 and R4 are defined as for Formula (I); with a compound of the formula wherein Z is N(R α ) 2 , SR e , OR e , or R°, R d is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl, all of which may be optionally substituted; R e is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocychcalkyl, all of which may be optionally substituted; and Y is O, S, or NH; to yield a compound of Formula (I), or pharmaceutically acceptable salt thereof. 2. The process according to Claim 1 wherein the reaction is at a temperature of about 25°C to about 110°C. 3. The process according to Claim 1 wherein the reaction uses a solvent which is an alcohol, toluene, DMF, DMSO or mixtures thereof. 4. The process according to Claim 1 wherein the Y is Formula (LX) is NH. 5. The process according to Claim 1 wherein the reaction uses a bases which is NaOMe, NaOEt, potassium carbonate, or potassium hydroxide. 6. A compound of the formula: wherein R D is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl, all of which may be optionally substituted; R is optionally substituted alkyl, optionally substituted aryl, halogen, hydroxyl, thiol, Q . 104 alkoxy, Q-io alkylthio, Q-io alkylsulfinyl, CH2OR12, amino, mono or di- Q-io alkyl substituted amino, NHR21, N(Rιo)C(O)R a or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15; Ra is hydrogen, Q-6 alkyl, C3-7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclyl, or heterocyclylQ-4 alkyl; R4 is an optionally substituted phenyl, naphth- 1-yl or naphth-2-yl, or heteroaryl ring; R2 is -(CRioR20)n' OR9, heterocyclyl, heterocyclylCi-io alkyl, Q-lθalkyl, halo ¬ substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylQ-io alkyl, C5-7 cycloalkenyl, C5-7cycloalkenyl-Q-io-alkyI, aryl, arylCi-io alkyl, heteroaryl, heteroaryl-Q-io-alkyl, (CRioR20)nORl 1, (CRioR20)nS(O)mRl8, (CRioR20)nNHS(O)2 l8, (CRlθR2θ)nNRl3Rl4, (CRl0R20)nNO2, (CRioR20)nCN, (CRioR20)n'SO2Rl8, (CRioR20)nS(O) m -NRi3Rl4, (CRlθR2θ)nC(Z)Rπ, (CRioR20)nOC(Z)Rn, (CRl0R20)nC(Z)ORι 1, (CRioR20)nC(Z)NRi3Rl4, (CRioR20)nC(Z)NRι ιOR9, (CRιoR20)nNRlθC(Z)Ri 1, (CRiθR20)nNRlθC(Z)NRi3Rl4, (CRιoR2θ)nN(OR 6 )C(Z)NRi3Rl4, (CRi 0 R20)nN(OR6)C(Z)Ri 1, (CRl0R20)nC(=NOR6)Rl 1, (CRιoR2θ)nNRlθC(=NRi9)NRl3Rl4, (CRioR20)nOC(Z)NRi3Rl4, (CRιoR2θ)nNRlθC(Z)NRi3Rl4, (CRioR2θ)nNRlθC(Z)ORiθ, 5-(Rι 8 )-l,2,4-oxadizaol-3-yl or 4-(Ri2)-5-(Ri8Ri9)-4,5-dihydro-l,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted; n is an integer having a value of 1 to 10 n' is 0, or an integer having a value of 1 to 10; m' is an integer having a value of 1 or 2, Z is oxygen or sulfur; R9 is hydrogen, -C(Z)Rι 1 or optionally substituted Q-io alkyl, S(O)2Rl8. optionally . substituted aryl or optionally substituted aryl-C 1 -4 alkyl; RlO and R20 is each independently selected from hydrogen or Q-4 alkyl; Rl 1 is hydrogen, Q-io alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl Q-ioalkyl, aryl, arylQ-io alkyl, heteroaryl or heteroarylC i- 10 alkyl; Rl2 is hydrogen or Ri6; Rl3 and R14 is each independently selected from hydrogen or optionally substituted Q-4 alkyl, optionally substituted aryl or optionally substituted aryl-Q-4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; Rl5 is RlO or C(Z)-Q_4 alkyl; Rl6 is Q-4 alkyl, halo-substituted-Q-4 alkyl, or C3-7 cycloalkyl; Rl8 is Q-io alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Q-ioalkyl, heteroaryl or heteroarylalkyl; Rl9 is hydrogen, cyano, Q-4 alkyl, C3-7 cycloalkyl or aryl; R21 is alkyl, aryl, arylQ-6alkyl, heterocyclic, heterocyclylCi-6 alkyl, heteroaryl, heteroarylC i-6alkyl, wherein each of these moieties may be optionally substituted. 7. The compound according to Claim 6 wherein R4 is 4-fluorophenyl, and R2 is an optionally substituted heterocychc, C 1 _ 1 Q alkyl, 03.7 cycloalkyl, or C3.7 cycloalkyl Ci-10 alkyl. 8. The compound according to Claim 7 wherein R is C1.4 alkoxy, C1.4 alkyl thio, or amino. 9. The process according to Claim 1 wherein a compound of Formula (VLLT) is produced by reacting a compound of the formula wherein R, R2 and R4 are defined above; with a compound the formula .OR a (R b teN— ζ (VII) OR a wherein R a is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl, all of which may be optionally substituted; and R is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocychcalkyl, all of which maybe optionally substituted; to yield a compound of Formula (VIII). 10. The process according to Claim 9 wherein the compounds are heated with dimethylformamide dimethyl , tri(d-unethylamino)methane, tert-butoxybis- dimethylamino)methane, or any suitable enaminating agent, optionally in the presence of a solvent. 11. The process according to Claim 10 wherein the optional solvents are toluene ethanol, 1 -propanol, 2-propanol, DMF or DMSO, or mixtures thereof. 12. A compound of the formula wherein R is optionally substituted Q-io alkyl, optionally substituted aryl, halogen, hydroxyl, thiol, Q-io alkoxy, Q-io alkylthio, Q-io alkylsulfinyl, CH2OR12, amino, mono or di-Q-io alkyl substituted amino, NHR21, N(Rιo)C(O)R a or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; R a is hydrogen, Q-6 alkyl, C3.7 cycloalkyl, aryl, arylQ-4 alkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclyl, or heterocyclylCi-4 alkyl; R4 is an optionally substituted phenyl, naphth- 1-yl or naphth-2-yl, or heteroaryl ring; R2 is -(CRioR20)n" OR9, heterocyclyl, heterocyclylQ-io alkyl, Q-ioalkyl, halo¬ substituted Q-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylQ-io alkyl, C5-7 cycloalkenyl, C5-7cycloalkenyl-Q-io-alkyl, aryl, arylC 1.10 alkyl, heteroaryl, heteroaryl-C 1 - 10-alkyl, (CR 10R20)nOR 11 , (CRioR20)nS(O) m Ri8, (CRioR20)nNHS(O)2Rl8, (CRlθR2θ)nNRl3Rl4, (CRioR20)nNO2, (CRioR20)nCN, (CRioR20)n'SO2Rl8, (CRl0R20)nS(O) m -NRi3Rl4, (CRioR20)nC(Z)Rπ, (CRioR20)nOC(Z)Rn, (CRioR20)nC(Z)ORi 1, (CRiθR20)nC(Z)NRi3Rl4> (CRiθR2θ)nC(Z)NRi 1OR9, (CRioR2θ)nNRlθC(Z)Rn, (CRιoR2θ)nNRioC(Z)NRι 3 Rl4, (CRl0R20)nN(OR6)C(Z)NRl3Rl4, (CRiθR2θ)nN(OR6)C(Z)Ri 1, (CRioR20)nC(=NOR6)Rl 1, (CRιoR2θ)nNRlθC(=NRi9)NRι Rl4, (CRioR20)nOC(Z)NRi 3 Rl4, (CRι O R20)nNRlθC(Z)NRι 3 Rl4, (CRloR2θ)nNRlθC(Z)ORiθ, 5-(Rι 8 )-l,2,4-oxadizaol-3-yl or 4-(Ri2)-5-(RιgRi9)-4,5-dihydro-l,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocychc alkyl groups may be optionally substituted; n is an integer having a value of 1 to 10 n' is 0, or an integer having a value of 1 to 10; m' is an integer having a value of 1 or 2, Z is oxygen or sulfur; R9 is hydrogen, -C(Z)Rι 1 or optionally substituted Q-io alkyl, S(O)2Rl8 » optionally substituted aryl or optionally substituted aryl-C 1.4 alkyl; RlO and R20 s each independently selected from hydrogen or Q-4 alkyl; Rl 1 is hydrogen, Q-io alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl Q-ioalkyl, aryl, arylQ-io alkyl, heteroaryl or heteroarylC i- 10 alkyl; Rl2 is hydrogen or Ri6; R13 and R14 is each independently selected from hydrogen or optionally substituted Q..4 alkyl, optionally substituted aryl or optionally substituted aryl-C 1.4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; Ri5 is RlO or C(Z)-Q-4 alkyl; Rl6 is Q-4 alkyl, halo-substituted-Q-4 alkyl, or C3-7 cycloalkyl; Rl8 is Q-io alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Q-ioalkyl, heteroaryl or heteroarylalkyl; Rl9 is hydrogen, cyano, CM alkyl, C3.7 cycloalkyl or aryl; and R21 is alkyl, aryl, arylQ-6alkyl, heterocyclic, heterocyclylQ-6 alkyl, heteroaryl, heteroarylC i-6alkyl, wherein each of these moieties may be optionally substituted. 13. The compound according to Claim 12 wherein R4 is 4-fluorophenyl, and R2 is an optionally substituted heterocychc, _ιo alkyl, 03,7 cycloalkyl, or C3.7 cycloalkyl Ci-io alkyl. 14. The compound according to Claim 13 wherein R is C 1.4 alkoxy, C 1.4 alkyl thio, or amino. 15. A process according to Claim 9 wherein a compound of Formula VI is prepared by reacting a compound of the formula wherein R and R2 are as defined in Formula (I), with a compound of Formula (V) and a suitable base, Ar l SO 2 „ N = ≡ (V) wherein Ar is an optionally substituted aryl; and R4 is as defined for Formula (I); to yield a compound of Formula (VI). 16. The process according to Claim 15 wherein the imine of Formula (TV) is prepared in situ, followed by reaction with a compound of Formula (V). 17. The process according to Claim 16 wherein the imine is formed by reacting a compound of formula (LI), as defined below wherein R is as defined for according to Claim 1, with a compound of formula (LTI) R2NH2 (IH) wherein R2 is defined as for Formula (I). 18. The process according to Claim 16 wherein the imine formation uses a solvent of THF, MeCN, toluene, EtOAc, DMF, DMSO or mixtures thereof. 19. The process according to Claim 16 wherein the imine formation utilizes a temperature from about 0°C to about 65°C. 20. The process according to Claim 16 wherein the reaction may optionally include a base which is potassium carbonate, sodium carbonate, K3PO4, K2HPO4, Na2HPO4, secondary and tertiary amine bases, or tetramethyl guanidine.

Inventors: SISKO JOSEPH, SISKO, JOSEPH
Applicants: SISKO JOSEPH, SMITHKLINE BEECHAM CORP, SISKO, JOSEPH, SMITHKLINE BEECHAM CORPORATION
Application year: 1996
Main classification: C07D401
IPC codes: C07D401