Claims for Patent: 7,538,108

Summary for Patent: 7,538,108

Title:	Prodrugs of 2,4-pyrimidinediamine compounds and their uses
Abstract:	The present disclosure provides prodrugs of biologically active 2,4-pyrimidinediamine compounds of structural formula shown below, compositions comprising these compounds, intermediates and methods for synthesizing these compounds, and methods of using these compounds in a variety of applications including treatment of autoimmune diseases.
Inventor(s):	Rajinder Singh, Esteban Masuda, Somasekhar Bhamidipati, Thomas Sun, Valentino J. Stella
Assignee:	Rigel Pharmaceuticals Inc
Application Number:	US11/453,731
Patent Claims:	1. A compound according to structural formula (I): or a salt and/or N-oxide thereof wherein: Y is O; Z1 is CH and Z2 is N; R2 is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R8 groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R8 groups, (C6-C14) aryl optionally substituted with one or more of the same or different R8 groups, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups; R5 is selected from the group consisting of halo, cyano, nitro, and trihalomethyl; each R8 is, independently of the others, selected from the group consisting of Ra, Rb, Ra substituted with one or more of the same or different Ra or Rb, —ORa substituted with one or more of the same or different Ra or Rb, —B(ORa)2, —B(NRcRc)2, —(CH2)m—Rb, —(CHRa)m—Rb, —O—(CH2)m—Rb, —S—(CH2)m—Rb, —O—CHRaRb, —O—CRa(Rb)2, —O—(CHRa)m—Rb, —O—(CH2)m—CH[(CH2)mRb]Rb, —S—(CHRa)m—Rb, —C(O)NH—(CH2)m—Rb, —C(O)NH—(CHRa)m—Rb, —O—(CH2)m—C(O)NH—(CH2)m—Rb, —S—(CH2)m—C(O)NH—(CH2)m—Rb, —O—(CHRa)m—C(O)NH—(CHRa)m—Rb, —S—(CHRa)m—C(O)NH—(CHRa)m—Rb, —NH—(CH2)m—Rb, —NH—(CHRa)m—Rb, —NH[(CH2)mRb], —N[(CH2)mRb]2, —NH—C(O)—NH—(CH2)m—Rb, —NH—C(O)—(CH2)m—CHRbRb and —NH—(CH2)m—C(O)—NH—(CH2)m—Rb; R17 is selected from the group consisting of hydrogen, halogen, and lower alkyl or, alternatively, R17 may be taken together with R18 to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; R18 is selected from the group consisting of hydrogen, halogen, and lower alkyl or, alternatively, R18 may be taken together with R17 to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; R19 is selected from the group consisting of hydrogen and lower alkyl or, alternatively, R19 may be taken together with R20 to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; R20 is selected from the group consisting of hydrogen and lower alkyl or, alternatively, R20 may be taken together with R19 to form an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms; each Ra is, independently of the others, selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, (C4-C11) cycloalkylalkyl, (C6-C10) aryl, (C7-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each Rb is independently selected from the group consisting of ═O, —ORa, (C1-C3) haloalkyloxy, ═S, —SRa, ═NRa, ═NORa, —NRcRc, halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Ra, —S(O)2Ra, —S(O)2ORa, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Ra, —OS(O)2Ra, —OS(O)2ORa, —OS(O)2NRcRc, —C(O)Ra, —C(O)ORa, —C(O)NRcRc, —C(NH)NRcRc, —C(NRa)NRcRc, —C(NOH)Ra, —C(NOH)NRcRc, —OC(O)Ra, —OC(O)ORa, —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)NRcRc, —[NHC(O)]nRa, —[NRaC(O)]nRa, —[NHC(O)]nORa, —[NRaC(O)]nORa, —[NHC(O)]nNRcRc, —[NRaC(O)]nNRcRc, —[NHC(NH)]nNRcRc and —[NRaC(NRa)]nNRcRc; each Rc is, independently of the others Ra, or, alternatively, the two Rc bonded to the same nitrogen atom are taken together with that nitrogen atom to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally comprise 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 Ra groups; R21, R22 and R23 are each, independently of one another, selected from the group consisting of hydrogen and Rp; RP has the formula —(CRdRd)-A-R3, where A is O or S; each Rd is, independently of the others, selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted (C6-C14) aryl and optionally substituted (C7-C20) arylalkyl; where the optional substituents are, independently of one another, selected from the group consisting of hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower alkoxyalkyl and halogen, or, alternatively, two Rd bonded to the same carbon atom, taken together with the carbon atom to which they are bonded, form a cycloalkyl group containing from 3 to 8 carbon atoms; R3 together with the heteroatom, A, to which it is bonded, is selected from the group consisting of an alcohol, an ether, a thioether, an ester, a thioester, an amide, a carbonate, a thiocarbonate, a carbamate, a thiocarbamate, a urea, a phosphate, a phosphate salt or a phosphate ester; each m is, independently of the others, an integer from 1 to 3; and each n is, independently of the others, an integer from 0 to 3, with the proviso that at least one of R21, R22, and R23 is Rp. 2. The compound of claim 1 in which R5 is fluoro. 3. The compound of claim 1 in which R2 is a phenyl optionally substituted with one or more of the same or different R8 groups. 4. The compound of claim 3 in which R2 is 3,4,5 tri(lower alkoxy)phenyl. 5. The compound of claim 4 in which R2 is 3,4,5-(trimethoxy)phenyl. 6. The compound of claim 1 in which R17 and R18 are each methyl and R19 and R20 are taken together to form an oxo group. 7. The compound of claim 6 in which R2 is a phenyl optionally substituted with one or more of the same or different R8 groups. 8. The compound of claim 7 in which R2 is 3,4,5-tri(lower alkoxy)phenyl. 9. The compound of claim 8 in which R2 is 3,4,5-(trimethoxy)phenyl. 10. The compound of claim 9 in which only R21 is RP. 11. The compound of claim 10 in which RP is selected from the group consisting of an ester, a thioester, an ether, a thioether, a silyl ether, a thiosilyl ether, a carbonate, a thiourea, an amide, a thioamide, a carbamate and a urea linkage. 12. The compound of claim 10in which R3, together with the heteroatom, A, to which it is bonded, is a phosphate group. 13. The compound of claim 12 in which RP has the formula —(CRdRd)—O—P(O)(OH)2, or a salt thereof, where each Rd is, independently of the others, selected from the group consisting of optionally substituted lower alkyl, optionally substituted (C6-C14) aryl and optionally substituted (C7-C20) arylalkyl; where the optional substituents are, independently of one another, selected from hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower alkoxyalkyl, and halogen, or, alternatively, two Rd bonded to the same carbon atom are taken together with the carbon atom to which they are bonded to form a cycloalkyl group containing from 3 to 8 carbon atoms. 14. The compound of claim 10 in which RP comprises a phosphate ester group. 15. The compound of claim 14 in which RP is selected from the group consisting of —(CRdRd)—O—P(O)(ORe)(OH), —(CRdRd)—O—P(O)(ORe)(ORe), and salts thereof, wherein each Re is, independently of the others, selected from the group consisting of substituted or unsubstituted lower alkyl, substituted or unsubstituted (C6-C14) aryl, substituted or unsubstituted (C7-C20) arylalkyl, —(CRdRd)y—OR f, —(CRdRd)y—O—C(O)RdRd)y—O—C(O)ORf, —(CRdRd)y—S—C(O)Rf, —(CRdRd)y—S—C(O)ORf, —(CRdRd)y—NH—C(O)Rf, —(CRdRd)y—NH—C(O)ORf and —Si(Rd)3, wherein each Rf is, independently of the others, selected from the group consisting of unsubstituted or substituted lower alkyl, substituted or unsubstituted (C6-C14) aryl, and substituted or unsubstituted (C7-C20) arylalkyl; each Rg is, independently of the others, selected from the group consisting of hydrogen and lower alkyl; each Rh is, independently of the others, selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloheteroalkyl, substituted or unsubstituted (C6-C14) aryl, substituted or unsubstituted (C7-C20) arylalkyl and substituted or unsubstituted 5-14 membered heteroaryl; y is an integer ranging from 1 to 3; z is an integer ranging from 0 to 2; and each Rd is independently of the others, selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted (C6-C14) aryl and optionally substituted (C7-C20) arylalkyl; where the optional substituents are, independently of one another, selected from hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower alkoxyalkyl, and halogen, or, alternatively, two Rd bonded to the same carbon atom are taken together with the carbon atom to which they are bonded to form a cycloalkyl group containing from 3 to 8 carbon atoms. 16. A method of treating an autoimmune disease in a subject, and/or one or more symptoms associated therewith, comprising administering to the subject an amount of a compound according to claim 1 effective to treat the autoimmune disease, in which the autoimmune disease is selected from Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, membranous glomerulopathy, systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid. 17. A method of treating rheumatoid arthritis in a subject, comprising administering to a subject suffering from rheumatoid arthritis an amount of the compound according to claim 1 effective to provide therapeutic benefit. 18. The method of claim 17 in which the amount of the compound administered is effective to achieve a serum concentration of the corresponding drug that is at or above the IC50 of Syk inhibition of the drug, as measured in an in vitro assay. 19. The method of claim 17 in which the compound is according to structural formula (V), and/or a pharmaceutically-acceptable salt and/or N-oxide thereof: