Claims for Patent: 8,153,632

Summary for Patent: 8,153,632

Title:	Oxygen linked pyrimidine derivatives
Abstract:	The present invention relates to pyrimidine compounds that are useful as anti-proliferative agents. More particularly, the present invention relates to oxygen linked and substituted pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumors and cancers as well as other disorders or conditions related to or associated with kinases.
Inventor(s):	Stephanie Blanchard, Cheng Hsia Angeline Lee, Harish Kumar Mysore Nagaraj, Anders Poulsen, Eric T. Sun, Yee Ling Evelyn Tan, Anthony Deodaunia William
Assignee:	Sobi Inc
Application Number:	US12/093,867
Patent Claims:	1. A compound of formula I: wherein: R1 and R2 are each independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR3, —COOR3, —CONHR3, —NHCOR3, —NHCOOR3, —NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR3, R4S(O)R6—, R4S(O)2R6—, R4C(O)N(R5)R6—, R4SO2N(R5)R6—, R4N(R5)C(O)R6—, R4N(R5)SO2R6—, R4N(R5)C(O)N(R5)R6— and acyl, each of which may be optionally substituted; each R3, R4, and R5 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; each R6 is independently selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; Z2 is —N(R7)—; each R7 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; Ar1 and Ar2 are both phenylene, each of which may be optionally substituted; L is a group of formula: —X1—Y—X2— wherein X1 is attached to Ar1 and X2 is attached to Ar2, and wherein X1, X2 and Y are selected such that the group L has between 5 and 15 atoms in the normal chain, X1 and X2 are each independently a heteroalkyl group containing at least one oxygen atom in the normal chain, Y is a group of formula —CRa═CRb—, wherein Ra and Rb are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted, or Ra and Rb may be joined such that when taken together with the carbon atoms to which they are attached they form a cycloalkenyl or cycloheteroalkenyl group; or a pharmaceutically acceptable salt or N-oxide thereof. 2. A compound according to claim 1 wherein Z2 is —N(H)—. 3. A compound according to claim 1 wherein Ar1 is selected from the group consisting of: wherein V1, V2, V3 and V4 are each independently C(R10); wherein each R10 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR3, —COOR3, —CONHR3, —NHCOR3, —NHCOOR3, —NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR3, R4S(O)R6—, R4S(O)2R6—, R4C(O)N(R5)R6—, R4SO2N(R5)R6—, R4N(R5)C(O)R6—, R4N(R5)SO2R6—, R4N(R5)C(O)N(R5)R6— and acyl, each of which may be optionally substituted. 4. A compound according to claim 1 wherein Ar1 is: wherein R10 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR3, —COOR3, —CONHR3, —NHCOR3, —NHCOOR3, —NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR3, R4S(O)R6—, R4S(O)2R6—, R4C(O)N(R5)R6—, R4SO2N(R5)R6—, R4N(R5)C(O)R6—, R4N(R5)SO2R6—, R4N(R5)C(O)N(R5)R6— and acyl, each of which may be optionally substituted; and k is an integer selected from the group consisting of 0, 1, 2, 3, and 4. 5. A compound according to claim 1 wherein Ar2 is a group selected from the group consisting of: wherein each R11 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR3, —COOR3, —CONHR3, —NHCOR3, —NHCOOR3, —NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR3, R4S(O)R6—, R4S(O)2R6—, R4C(O)N(R5)R6—, R4SO2N(R5)R6—, R4N(R5)C(O)R6—, R4N(R5)SO2R6—, R4N(R5)C(O)N(R5)R6— and acyl, each of which may be optionally substituted. 6. A compound according to claim 1 wherein the compound is: wherein R10 and R11 are independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR3, —COOR3, —CONHR3, —NHCOR3, —NHCOOR3, —NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR3, R4S(O)R6—, R4S(O)2R6—, R4C(O)N(R5)R6—, R4SO2N(R5)R6—, R4N(R5)C(O)R6—, R4N(R5)SO2R6—, R4N(R5)C(O)N(R5)R6— and acyl, each of which may be optionally substituted; k is an integer selected from the group consisting of 0, 1, 2, 3, and 4; and o is an integer selected from the group consisting of 0, 1, 2, 3 and 4; or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 1 wherein X1 and X2 are each independently selected from the group consisting of: (a) —OC1-5alkyl-, (b) —C1-5alkylO-, and (c) —C1-5alkylOC1-5alkyl. 8. A compound according to claim 1 wherein X1 is selected from the group consisting of: (a) —OCH2— (b) —CH2O—, (c) —OCH2CH2—, (d) —CH2CH2O—, (e) —CH2OCH2—, and (f) —CH2CH2OCH2—. 9. A compound according to claim 1 wherein X2 is selected from the group consisting of: (a) —OCH2— (b) —CH2O—, (c) —OCH2CH2—, (d) —CH2CH2O—, (e) —CH2OCH2—, and (f) —CH2CH2OCH2—. 10. A compound according to claim 1 selected from the group consisting of: wherein R10 and R11 are independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR3, —COOR3, —CONHR3, —NHCOR3, —NHCOOR3, —NHCONHR3, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR3, R4S(O)R6—, R4S(O)2R6—, R4C(O)N(R5)R6—, R4SO2N(R5)R6—, R4N(R5)C(O)R6—, R4N(R5)SO2R6—, R4N(R5)C(O)N(R5)R6— and acyl, each of which may be optionally substituted; k is an integer selected from the group consisting of 0, 1, 2, 3, and 4; and o is an integer selected from the group consisting of 0, 1, 2, 3 and 4; or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 1 wherein R1 and R2 are independently selected from the group consisting of H and methyl. 12. A compound according to claim 4 wherein each R10 is independently selected from the group consisting of H, halogen, amino, alkyl, haloalkyl, haloalkenyl, heterocycloalkyl, aryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl, each of which may be optionally substituted. 13. A compound according to claim 4 wherein each R10 is independently selected from the group consisting of H, hydroxyl, methoxy, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, and 2-morpholino-ethoxy, each of which may be optionally substituted. 14. A compound according to claim 12 wherein each R11 is independently selected from the group consisting of H, alkoxy, heteroalkyl, heterocycloalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, and arylsulfonyloxy, each of which may be optionally substituted. 15. A compound according to claim 12 wherein each R11 is independently selected from the group consisting of: 16. A compound according to claim 1 wherein Y is selected from the group consisting of: 17. A compound according to claim 1 wherein the optional substituent is selected from the group consisting of: halogen, ═O, ═S, —CN, —NO2, —CF3, —OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, —COOH, —COR5, —C(O)OR5, —SH, —SR5, —OR6 and acyl. 18. A compound according to claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical composition including a compound according to claim 1 and a pharmaceutically acceptable diluent, excipient or carrier. 20. A method of inhibiting one or more protein kinase(s) including exposing the one or more protein kinase(s) and/or co-factor(s) thereof to an effective amount of a compound according to claim 1. 21. A method according to claim 20 wherein the one or more protein kinase(s) is a cyclin-dependent protein kinase or a protein tyrosine kinase. 22. A method according to claim 21 wherein the cyclin-dependent kinase is a Group I CMCG kinase selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRK1, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functional equivalent thereof. 23. A method according to claim 22 wherein the Group I CMCG kinase is CDK2 or a functional equivalent thereof. 24. A method according to claim 21 wherein the protein tyrosine kinase is a Group VII protein tyrosine kinase or a Group XIV protein tyrosine kinase. 25. A method according to claim 24 wherein the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. 26. A method according to claim 25 wherein the Group VII protein tyrosine kinase is JAK2 or a functional equivalent thereof. 27. A method according to claim 26 wherein the JAK2 includes a V to F mutation at position 617. 28. A method according to claim 24 wherein the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-β, PDGFR-α, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functional equivalent thereof. 29. A method according to claim 28 wherein the Group XIV protein tyrosine kinase is FLT3 or a functional equivalent thereof. 30. A method according to claim 29 wherein the FLT3 includes an internal tandem duplication of amino acids VDFREYEYDH at position 592-601. 31. A method of synthesis of a compound of formula I as defined in claim 1 the method including the steps of: (a) providing a compound of the formula (b) subjecting the compound to ring closing metathesis; (c) optionally reacting the double bond thus formed to form a cycloalkyl group. 32. A method according to claim 31 wherein step (b) involves treating the trifluoroacetic acid (TFA) or hydrochloric acid (HCl) salt of the compound with 5-10 mole % of Grubbs 2nd generation catalyst in dichloromethane at 40° C. 33. A method according to claim 31 wherein step (c) includes treating the metathesis product with a freshly prepared ethereal solution of diazomethane (CH2N2) in dichloromethane/dioxane at 0° C.