Pyrimidine derivatives for treatment of hyperproliferative disorders

A compound having the structure

• wherein
• R1 represents H, (C1-C3)alkyl, or cyclopropyl;
• R2 represents (C1-C3)alkyl, cyclopropyl, O(C1-C3)alkyl, or NR3R4
• wherein R3 and R4 are H, (C1-C3)alkyl, or cyclopropyl;
• R2a represents H or halogen;
• M represents CH or N;
• L represents a carbonyl group, O, NR5, CR6R7, or (C2-C3)alkylenyl which is optionally substituted up to twice by groups independently selected from halogen and OH;
• wherein
• R5 is H or (C1-C3)alkyl;
• and
• R6 and R7 are independently H, CH3, halogen, or OH;
• J represents an aromatic or heteroaromatic ring selected from the group consisting of
• Y represents an aromatic or heteroaromatic ring selected from the group consisting of
• wherein R8 represents H or (C1-C3)alkyl;
• G″ represents a substituent selected from the group consisting of (C1-C3)alkyl, cyclopropyl, O(C1-C3)alkyl, halogen, CF3, CN and CO2R9;
• wherein
• R9 represents H or (C1-C3)alkyl;
• and
• m represents the number of substituents G″, and is 0, 1, or 2;
• G represents a substituent located on ring J;
• G′ represents a substituent located on ring Y;
• n represents the number of substituents G;
• and
• n′ represents the number of substituents G′;
• n and n′ are independently 0, 1, 2, or 3, subject to the provisos that
• 1) ring J and ring Y each may be substituted independently up to 3 times by substituents listed below as numbers G1-G2, to a maximum total of 4 substituents on rings J and Y,
• 2) ring J and ring Y each may be substituted independently up to 2 times by substituents listed below as numbers G3-G11, to a maximum total of 3 substituents on rings J and Y, and
• 3) ring J and ring Y each may be substituted independently once by a substituent selected from those listed below as numbers G12-G37;
• and subject to the further provisos
• 4) when J is phenyl, G is other than OH or alkylthio;
• and when J is phenyl or pyridyl, n is 1, 2, or 3;
• 5) when J is phenyl, and G is G4 shown below, then R2 is NR3R4;
• G and G′ moieties are independently selected from the group consisting of:
• G1) halogen;
• G2) O(C1-C4)alkyl which optionally is substituted up to two times by O(C1-C2)alkyl;
• G3) OH;
• G4) (C1-C5)alkyl, which is optionally substituted independently up to two times by groups selected from hydroxyl and cyano, or up to three times by halogen;
• G5) OCF3;
• G6) NHC(O)(C1-C3)alkyl;
• G7) NHSO2(C1-C3)alkyl;
• G8) NR10R11, wherein
• R10 and R11 are independently selected from
• H,
• CH3,
• cyclopropyl,
• benzyl,
• NR12R13 wherein
• R12 and R13 are independently H or (C1-C3)alkyl, provided that both R10 and R11 are not NR12R13 simultaneously,
• and
• (C2-C4)alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C1-C3)alkyl, and NR14R15, wherein
• R14 and R15 are independently H or (C1-C3)alkyl, or
• R14 and R15 can join to form a heterocycle of formula
• wherein
• Q represents CH2, O, or NR16, and
• R16 represents H or (C1-C3)alkyl,
• or
• R10 and R11 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times
• by
• OH,
• NR17R18, wherein
• R17 and R18 are H or (C1-C3)alkyl,
• or by
• (C1-C3)alkyl which is optionally substituted up to two times by halogen, OH, or O(C1-C3)alkyl;
• G9) (CH2)a—NR19R20 wherein
• R19 and R20 are independently H, (C1-C5)alkyl, or
• (C3-C6)cycloalkyl, or may be joined to form a saturated 5-6-membered N-containing ring;
• and
• the subscript “a” is an integer of 1-4;
• wherein
• Q′ is O or NR21;
• R21 is H, (C1-C3)alkyl, or cyclopropyl;
• and
• the subscript “b” is an integer of 1-3;
• G11) CH2NR22(CH2)cOCH3 wherein
• R22 is H, (C1-C3)alkyl, or cyclopropyl;
• and
• the subscript “c” is an integer of 2-4;
• G12) OSO2NR23R24 wherein
• R23 and R24 independently represent H, CH3, or (C2-C4)alkyl which may optionally be substituted once by OH or NR25R26, wherein
• R25 and R26 independently represent H or (C1-C3)alkyl;
• G13) CN;
• G14) NO2;
• G15) cyclopropyl;
• G16) OR27, wherein
• R27 represents phenyl or benzyl;
• G17) S(C1-C3)alkyl;
• G18) CH═CH—(CH2)1-3—OR5;
• wherein
• R5 represents H or (C1-C3)alkyl;
• G21) C(O)NR28R29, wherein
• R28 and R29 are independently selected from
• H,
• cyclopropyl, provided that both R28 and R29 are not simultaneously cyclopropyl,
• provided that this group does not constitute both R28 and R29 simultaneously,
• and
• (C1-C3)alkyl which is optionally substituted up to two times by OH;
• or
• R28 and R29 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by OH, or by (C1-C3)alkyl which in turn is optionally substituted up to two times by OH or O(C1-C3)alkyl;
• wherein
• Q″ is O or NR30, and
• R30 is
• H,
• cyclopropyl, or
• (C1-C3)alkyl which is optionally substituted once by halogen, OH, or O(C1-C3)alkyl;
• G23) O—(CH2)d—NR31R32 wherein
• R31 and R32 are independently H, (C1-C3)alkyl, or cyclopropyl, or may be joined to form a saturated 5-6-membered N-containing ring;
• and
• the subscript “d” is an integer of 2-4;
• wherein
• the subscript “e” is an integer of 2-3;
• and
• Q′″ is O or NR33;
• and
• R33 is H, (C1-C3)alkyl, or cyclopropyl;
• wherein
• Qiv is or NR34;
• and
• R34 is H, (C1-C3)alkyl, or cyclopropyl;
• G26) C(O)NR35(CH2)fOR36 wherein
• R35 is H, (C1-C3)alkyl, or cyclopropyl;
• R36 is (C1-C6)alkyl optionally substituted up to two times by halogen, OH, or O(C1-C3)alkyl, and
• the subscript “f” is an integer of 2-4;
• G27) CO2R37 wherein
• R37 is H or (C1-C3)alkyl;
• G28) phenyl, which is optionally substituted by up to 2 groups selected from halogen, (C1-C3)alkyl, OR38, CN, CF3, and NR39R40 wherein
• R38 represents H or (C1-C3)alkyl;
• and
• R39 and R40 represent H or (C1-C3)alkyl;
• G29) NR41SO2NR42R43 wherein
• R41 represents H, or (C1-C4)alkyl, and
• R42 and R43 independently represent H, CH3, or (C2-C3)alkyl which may optionally be substituted once by —OH or NR44R45, wherein
• R44 and R45 independently represent H or (C1-C3)alkyl;
• G30) OC(O)—CH2—NR46R47 wherein
• R46 and R47 independently represent H, (C1-C3)alkyl, or CO2(t-butyl), provided that R46 and R47 are not both simultaneously CO2(t-butyl);
• G31) N(R48)C(O)R49 wherein
• R48 represents H or (C1-C3)alkyl;
• and
• R49 represents
• (CH2)1-3—CO2H,
• O(C2-C4)alkyl,
• (CH2)1-4—NR50R51 wherein
• R50 and R independently represent H or (C1-C3)alkyl, or
• CH(R52)—NR53R54 wherein
• R52 represents (CH2)1-4—NH2, CH2OH, CH(CH3)OH, or (C1-C3)alkyl;
• and
• R53 and R54 independently represent H or (C1-C3)alkyl;
• G32) C(O)—(C1-C3)alkyl;
• G33) (CH2)g—N(R55)—C(O)—R56 wherein
• g represents 1, 2, or 3;
• R55 represents H or (C1-C3)alkyl;
• R56 represents
• (C1-C3)alkyl optionally substituted up to two times by OR57 or NR58R59, wherein
• R57 represents H or (C1-C3)alkyl, and
• R58 and R59 each represents H or (C1-C3)alkyl,
• or R56 represents
• wherein
• R60 represents halogen, (C1-C3)alkyl, O(C1-C3)alkyl, CN, OH, CF3, or NR61R62, wherein
• R61 and R62 represent H or (C1-C3)alkyl;
• and
• h represents 0, 1, or 2;
• G34) (CH2)i—N(R63)—C(O)—NR64R65 wherein
• i represents 1, 2, or 3;
• R63 represents H or (C1-C3)alkyl;
• R64 and R65 each represents H or (C1-C3)alkyl;
• or
• R64 and R65 may be joined to form
• wherein
• QV represents CH2, O or NR66 wherein
• R66 represents H or (C1-C3)alkyl;
• wherein
• j represents 1, 2, or 3;
• R67 represents H or (C1-C3)alkyl;
• and
• R68 represents H or (C1-C3)alkyl;
• G36) (CH2)k—N(R69)—SO2—R70 wherein
• k represents 1, 2, or 3;
• R69 represents H or (C1-C3)alkyl;
• and
• R70 represents (C1-C4)alkyl, or phenyl which is optionally substituted up to perhalo by halogen or up to three times by OR71, CN, CF3, or NR72R73, wherein
• R71 represents H or (C1-C3)alkyl;
• and
• R72 and R73 each represents H or (C1-C3)alkyl;
• G37) CH═CH—(CH2)1-3—NR74R75 wherein
• R74 and R75 represent H or (C1-C3)alkyl;
• or a pharmaceutically acceptable salt or stereoisomer thereof.