Pyrimidine derivatives for treatment of hyperproliferative disorders
View Patent ↗Pyrimidine derivatives of formula (I) in which J and Y represent aromatic or heteroaromatic rings; R 2 , G, G′, and G″ represent substituent groups and R 2a represents H or halogen; L represents a linking group; and M represents CH or N. Pharmaceutical compositions containing these compounds, and methods of using these compounds in treatment of hyperproliferative diseases such as cancer are also disclosed and claimed.
1. A compound having the structure
wherein
R 1 represents H, (C 1 -C 3 )alkyl, or cyclopropyl;
R 2 represents (C 1 -C 3 )alkyl, cyclopropyl, O(C 1 -C 3 )alkyl, or NR 3 R 4 wherein R 3 and R 4 are H, (C 1 -C 3 )alkyl, or cyclopropyl;
R 2a represents H or halogen;
M represents CH or N;
L represents a carbonyl group, O, NR 5 , CR 6 R 7 , or (C 2 -C 3 )alkylenyl which is optionally substituted up to twice by groups independently selected from halogen and OH;
wherein
R 5 is H or (C 1 -C 3 )alkyl; and
R 6 and R 7 are independently H, CH 3 , 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 R 8 represents H or (C 1 -C 3 )alkyl;
G″ represents a substituent selected from the group consisting of (C 1 -C 3 )alkyl, cyclopropyl, O(C 1 -C 3 )alkyl, halogen, CF 3 , CN and CO 2 R 9 ;
wherein
R 9 H or (C 1 -C 3 )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 R 2 is NR 3 R 4 ;
G and G′ moieties are independently selected from the group consisting of:
G1) halogen;
G2) O(C 1 -C 4 alkyl which optionally is substituted up to two times by O(C 1 -C 2 )alkyl;
G3) OH;
G4) (C 1 -C 5 )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) OCF 3 ;
G6) NHC(O)(C 1 -C 3 )alkyl;
G7) NHSO 2 (C 1 -C 3 )alkyl;
G8) NR 10 R 11 , wherein
R 10 R 11 are independently selected from H, CH 3 , cyclopropyl, benzyl, NR 12 R 13 wherein
R 12 and R 13 are independently H or (C 1 -C 3 )alkyl, provided that both R 10 and R 11 are not NR 12 R 13 simultaneously, and
(C 2 -C 4 )alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C 1 -C 3 )alkyl, and NR 14 R 15 , wherein
R 14 and R 15 are independently H or (C 1 -C 3 )alkyl, or
R 14 and R 15 can join to form a heterocycle of formula
wherein
Q represents CH 2 , O, or NR 16 , and
R 16 H or (C 1 -C 3 )alkyl, or
R 10 and R 11 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by OH, NR 17 R 18 , wherein R 17 and R 18 are H or (C 1 -C 3 )alkyl, or by (C 1 -C 3 )alkyl which is optionally substituted up to two times by halogen, OH, or O(C 1 -C 3 )alkyl;
G9) (CH 2 ) a -NR 19 R 20 wherein
R 19 and R 20 are independently H, (C 1 -C 5 )alkyl, or (C 3 -C 6 )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 NR 21 ;
R 21 is H, (C 1 -C 3 )alkyl, or cyclopropyl; and
the subscript “b” is an integer of 1-3;
G11) CH 2 NR 22 (CH 2 ) c OCH 3 wherein
R 22 is H, (C 1 -C 3 )alkyl, or cyclopropyl; and
the subscript “c” is an integer of 2-4;
G12) OSO 2 NR 23 R 24 wherein
R 23 and R 24 independently represent H, CH 3 , or (C 2 -C 4 )alkyl which may optionally be substituted once by OH or NR 25 R 26 , wherein
R 25 and R 26 independently represent H or (C 1 -C 3 )alkyl;
G13) CN;
G14) NO 2 ;
G15) cyclopropyl;
G16) OR 27 , wherein
R 27 represents phenyl or benzyl;
G17) S(C 1 -C 3 )alkyl;
G18) CH═CH—(CH 2 ) 1-3 —OR 5 ; wherein
R 5 represents H or (C 1 -C 3 )alkyl;
G21) C(O)NR 28 R 29 , wherein R 28 and R 29 are independently selected from H, cyclopropyl, provided that both R 28 and R 29 are not simultaneously cyclopropyl,
provided that this group does not constitute both R 28 and R 29 simultaneously, and
(C 1 -C 3 )alkyl which is optionally substituted up to two times by OH; or
R 28 and R 29 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 (C 1 -C 3 )alkyl which in turn is optionally substituted up to two times by OH or O(C 1 -C 3 )alkyl;
wherein
Q″ is O or NR 30 , and
R 30 is H, cyclopropyl, or (C 1 -C 3 )alkyl which is optionally substituted once by halogen, OH, or O(C 1 -C 3 )alkyl;
G23) O—(CH 2 ) d -NR 31 R 32 wherein R 31 and R 32 are independently H, (C 1 -C 3 )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 NR 33 ; and
R 33 is H, (C 1 -C 3 )alkyl, or cyclopropyl;
wherein
Q iv is O or NR 34 ; and
R 34 H, (C 1 -C 3 )alkyl, or cyclopropyl;
G26) C(O)NR 35 (CH 2 ) f OR 36 wherein
R 35 is H, (C 1 -C 3 )alkyl, or cyclopropyl;
R 36 is (C 1 -C 6 )alkyl optionally substituted up to two times by halogen, OH, or O(C 1 -C 3 )alkyl, and the subscript “f” is an integer of 2-4;
G27) CO 2 R 37 wherein
R 37 is H or (C 1 -C 3 )alkyl;
G28) phenyl, which is optionally substituted by up to 2 groups selected from halogen, (C 1 -C 3 )alkyl, OR 38 , CN, CF 3 , and NR 39 R 40 wherein
R 38 represents H or (C 1 -C 3 )alkyl; and
R 39 and R 40 represent H or (C 1 -C 3 )alkyl;
G29) NR 41 SO 2 NR 42 R 43 wherein
R 41 represents H, or (C 1 -C 4 )alkyl, and
R 42 and R 43 independently represent H, CH 3 , or (C 2 -C 3 )alkyl which may optionally be substituted once by —OH or NR 44 R 45 , wherein
R 44 and R 45 independently represent H or (C 1 -C 3 )alkyl;
G30) OC(O)—CH 2 —NR 46 R 47 wherein
R 46 and R 47 independently represent H, (C 1 -C 3 )alkyl, or CO 2 (t-butyl), provided that R 46 and R 47 are not both simultaneously CO 2 (t-butyl);
G31) N(R 48 )C(O)R 49 wherein
R 48 represents H or (C 1 -C 3 )alkyl; and
R 49 represents (CH 2 ) 1-3 —CO 2 H, O(C 2 -C 4 alkyl, (CH 2 ) 1-4 —NR 50 R 51 wherein
R 50 and R 51 independently represent H or (C 1 -C 3 )alkyl, or CH(R 52 )—NR 53 R 54 wherein
R 52 represents (CH 2 ) 1-4 —NH 2 , CH 2 OH, CH(CH 3 )OH, or (C 1 -C 3 )alkyl; and
R 53 and R 54 independently represent H or (C 1 -C 3 )alkyl;
G32) C(O)—(C 1 -C 3 )alkyl;
G33) (CH 2 ) g -N(R 55 )—C(O)R 56 wherein
g represents 1, 2, or 3;
R 55 represents H or (C 1 -C 3 )alkyl;
R 56 represents
(C 1 -C 3 )alkyl optionally substituted up to two times by OR 57 or NR 58 R 59 , wherein
R 57 represents H or (C 1 -C 3 )alkyl, and
R 58 and R 59 each represents H or (C 1 -C 3 )alkyl, or represents wherein
wherein
R 60 represents halogen, (C 1 -C 3 )alkyl, O(C 1 -C 3 )alkyl, CN, OH, CF 3 , or NR 61 R 62 , wherein
R 61 and R 62 represent H or (C 1 -C 3 )alkyl; and
h represents 0, 1, or 2;
G34) (CH 2 ) i —N(R 63 )—C(O)—NR 64 R 65 wherein
i represents 1, 2, or 3;
R 63 represents H or (C 1 -C 3 )alkyl;
R 64 and R 65 each represents H or (C 1 -C 3 )alkyl; or
R 64 and R 65 may be joined to form
wherein Q V represents CH 2 , O or NR 66 wherein R 66 represents H or (C 1 -C 3 )alkyl;
wherein
j represents 1, 2, or 3;
R 67 represents H or (C 1 -C 3 )alkyl; and
R 68 represents H or (C 1 -C 3 )alkyl;
G36) (CH 2 ) k —N(R 69 )—SO 2 —R 70 wherein
k represents 1, 2, or 3;
R 69 represents H or (C 1 -C 3 )alkyl; and
R 70 represents (C 1 -C 4 alkyl, or phenyl which is optionally substituted up to perhalo by halogen or up to three times by OR 71 , CN, CF 3 , or NR 72 R 73 , wherein
R 71 represents H or (C 1 -C 3 )alkyl; and
R 72 and R 73 each represents H or (C 1 -C 3 )alkyl;
G37) CH═CH—(CH 2 ) 1-3 —NR 74 R 75 wherein R 74 and R 75 represent H or (C 1 -C 3 )alkyl;
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. The compound of claim 1 wherein R 1 H;
M represents CH;
J represents a heteroaromatic ring selected from the group consisting of
Y represents an aromatic or heteroaromatic ring selected from the group consisting of
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-G5 and G8, 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, G13, G22, G29, and G31;
and subject to the further proviso
4) when J is pyridyl, n is 1, 2, or 3;
and proviso 5 does not apply;
G and G′ moieties are independently selected from the group consisting of:
G1) halogen;
G2) O(C 1 -C 4 )alkyl which optionally is substituted up to two times by O(C 1 -C 2 )alkyl;
G3) OH;
G4) (C 1 -C 5 )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) OCF 3 ;
G8) NR 10 R 11 , wherein
R 10 R 11 are independently selected from H, CH 3 , cyclopropyl, benzyl, NR 12 R 13 wherein
R 12 and R 13 are independently H or (C 1 -C 3 )alkyl, provided that both R 10 and R 11 are not NR 12 R 13 simultaneously, and (C 2 -C 4 alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C 1 -C 3 )alkyl, and NR 14 R 15 , wherein
R 14 and R 15 are independently H or (C 1 -C 3 )alkyl, or
R 14 and R 15 can join to form a heterocycle of formula
wherein
Q represents CH 2 , O, or NR 16 , and
R 16 H or (C 1 -C 3 )alkyl, or
R 10 and R 11 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by OH, NR 17 R 18 , wherein R 17 and R 18 are H or (C 1 -C 3 )alkyl, or by (C 1 -C 3 )alkyl which is optionally substituted up to two times by halogen, OH, or O(C 1 -C 3 )alkyl;
G12) OSO 2 NR 23 R 24 wherein
R 23 and R 24 independently represent H, CH 3 , or (C 2 -C 4 alkyl which may optionally be substituted once by OH or NR 26 R 27 , wherein
R 25 and R 26 independently represent H or (C 1 -C 3 )alkyl;
G13) CN;
wherein
Q″ is O or NR 30 , and
R 30 is
H, cyclopropyl, or (C 1 -C 3 )alkyl which is optionally substituted once by halogen, OH, or O(C 1 -C 3 )alkyl;
G29) NR 41 SO 2 NR 42 R 43 wherein
R 41 represents H, or (C 1 -C 4 )alkyl, and
R 42 and R 43 independently represent H, CH 3 , or (C 2 -C 3 )alkyl which may optionally be substituted once by —OH or NR 44 R 45 , wherein
R 44 R 45 independently represent H or (C 1 -C 3 )alkyl; and
G31) N(R 48 )C(O)R 49 wherein
R 48 represents H or (C 1 -C 3 )alkyl; and
R 49 represents (CH 2 ) 1-3 —CO 2 H, O(C 2 -C 4 )alkyl, (CH 2 ) 1-4 —NR 50 R 51 wherein
R 50 and R 51 independently represent H or (C 1 -C 3 )alkyl, or
CH(R 52 )—NR 53 R 54 wherein
R 52 represents (CH 2 ) 1-4 —NH 2 , CH 2 OH, CH(CH 3 )OH, or (C 1 -C 3 )alkyl; and
R 53 R 54 independently represent H or (C 1 -C 3 )alkyl.
3. The compound of claim 2 wherein
R 1 H;
R 2 represents O(C 1 -C 3 )alkyl or NR 3 R 4 wherein R 3 and R 4 are H or (C 1 -C 3 )alkyl;
R 2a represents H;
L represents O or CR 6 R 7 wherein
R 6 R 7 independently H, CH 3 , or OH;
G″ represents a substituent selected from the group consisting of O(C 1 -C 3 )alkyl, halogen, and CF 3 ;
n and n′ are independently 0 or 1, and provisos 1-3 do not apply;
G and G′ moieties are independently selected from the group consisting of:
G1) Cl or F;
G2) O(C 1 -C 3 )alkyl;
G3) OH;
G4) (C 1 -C 3 )alkyl, which is optionally substituted up to three times by halogen;
G5) OCF 3 ;
G8) NR 10 R 11 , wherein
R 10 R 11 are independently selected from
H, CH 3 , cyclopropyl, benzyl,
NR 12 R 13 wherein
R 12 and R 13 are independently H or (C 1 -C 3 )alkyl, provided that both R 10 and R 11 are not NR 12 R 13 simultaneously, and
(C 2 -C 4 alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C 1 -C 3 )alkyl, and NR 14 R 15 , wherein
R 14 and R 15 are independently H or (C 1 -C 3 )alkyl, or
R 14 and R 15 can join to form a heterocycle of formula
wherein
Q represents CH 2 , O, or NR 16 , and
R 16 represents H or (C 1 -C 3 )alkyl,
G12) OSO 2 NR 23 R 24 wherein
R 23 and R 24 independently represent H, CH 3 , or (C 2 -C 4 )alkyl which may optionally be substituted once by OH or NR 25 R 26 , wherein
R 25 and R 26 independently represent H or (C 1 -C 3 )alkyl;
G13) CN;
wherein
Q″ is O or NR 30 , and
R 30 is H or (C 1 -C 3 )alkyl; and
G31) N(R 48 )C(O)R 49 wherein
R 48 represents H or (C 1 -C 3 )alkyl; and
R 9 represents (CH 2 ) 1-3 —CO 2 H, O(C 2 -C 4 alkyl,
(CH 2 ) 1-4 —NR 50 R 51 wherein
R 50 and R 51 independently represent H or (C 1 -C 3 )alkyl, or CH(R 52 )—NR 53 R 54 wherein
R 52 represents (CH 2 ) 1-4 —NH 2 , CH 2 OH, CH(CH 3 )OH, or (C 1 -C 3 )alkyl; and
R 53 and R 54 independently represent H or (C 1 -C 3 )alkyl.
4. The compound of claim 1 wherein
R 1 represents H;
M represents CH;
J represents a heteroaromatic ring selected from the group consisting of
Y represents an aromatic or heteroaromatic ring selected from the group consisting of
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-G5 and G8, 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, G21, G25, G26, and G31;
and subject to the further proviso
4) when J is pyridyl, n is 1, 2, or 3;
and proviso 5 does not apply;
G and G′ moieties are independently selected from the group consisting of:
G1) halogen;
G2) O(C 1 -C 4 alkyl which optionally is substituted up to two times by O(C 1 -C 2 )alkyl;
G3) OH;
G4) (C 1 -C 5 )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) OCF 3 ;
G8) NR 10 R 11 , wherein
R 10 and R 11 are independently selected from H, CH 3 , cyclopropyl, benzyl,
NR 12 R 13 wherein
R 12 and R 13 are independently H or (C 1 -C 3 )alkyl, provided that both R 10 and R 11 are not NR 12 R 13 simultaneously, and
(C 2 -C 4 alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C 1 -C 3 )alkyl, and NR 14 R 15 , wherein
R 14 and R 15 are independently H or (C 1 -C 3 )alkyl, or
R 14 and R 15 can join to form a heterocycle of formula
wherein
Q represents CH 2 , O, or NR 16 , and
R 16 H or (C 1 -C 3 )alkyl, or
R 10 and R 11 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by OH, NR 17 R 18 , wherein R 17 and R 18 are H or (C 1 -C 3 )alkyl, or by
(C 1 -C 3 )alkyl which is optionally substituted up to two times by halogen, OH, or O(C 1 -C 3 )alkyl;
G12) OSO 2 NR 23 R 24 wherein
R 23 and R 24 independently represent H, CH 3 , or (C 2 -C 4 )alkyl which may optionally be substituted once by OH or NR 25 R 26 , wherein
R 25 and R 26 independently represent H or (C 1 -C 3 )alkyl;
G21) C(O)NR 28 R 29 , wherein
R 28 and R 29 are independently selected from H, cyclopropyl, provided that both R 28 and R 29 are not simultaneously cyclopropyl,
provided that this group does not constitute both R 28 and R 29 simultaneously, and (C 1 -C 3 )alkyl which is optionally substituted up to two times by OH; or
R 28 and R 29 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 (C 1 -C 3 )alkyl which in turn is optionally substituted up to two times by OH or O(C 1 -C 3 )alkyl;
wherein
Q iv is O or NR 34 ; and
R 34 is H, (C 1 -C 3 )alkyl, or cyclopropyl;
G26) C(O)NR 35 (CH 2 ) f OR 36 wherein
R 35 is H, (C 1 -C 3 )alkyl, or cyclopropyl;
R 36 is (C 1 -C 6 )alkyl optionally substituted up to two times by halogen, OH, or O(C 1 -C 3 )alkyl, and the subscript “f” is an integer of 2-4; and
G31) N(R 48 )C(O)R 49 wherein
R 48 represents H or (C 1 -C 3 )alkyl; and
R 49 represents (CH 2 ) 1-3 —CO 2 H, O(C 2 -C 4 )alkyl,
(CH 2 ) 1-4 —NR 50 R 51 wherein
R 50 and R 51 independently represent H or (C 1 -C 3 )alkyl, or CH(R 52 )—NR 53 R 54 wherein
R 52 represents (CH 2 ) 1-4 —NH 2 , CH 2 OH, CH(CH 3 )OH, or (C 1 -C 3 )alkyl; and
R 53 and R 54 independently represent H or (C 1 -C 3 )alkyl.
5. The compound of claim 4 wherein
R 1 represents H;
R 2 represents O(C 1 -C 3 )alkyl or NR 3 R 4 wherein R 3 and R 4 are H or (C 1 -C 3 )alkyl;
R 2a represents H;
L represents O or CR 6 R 7 , wherein
R 6 R 7 are independently H, CH 3 , or OH;
G 41 represents a substituent selected from the group consisting of O(C 1 -C 3 )alkyl, halogen, and CF 3 ;
n and n′ are independently 0 or 1, and provisos 1-3 do not apply;
G and G′ moieties are independently selected from the group consisting of:
G1) Cl or F;
G2) O(C 1 -C 3 )alkyl;
G3) OH;
G4) (C 1 -C 3 )alkyl, which is optionally substituted up to three times by halogen;
G5) OCF 3 ;
G8) NR 10 R 11 , wherein
R 10 and R 11 are independently selected from H, CH 3 , cyclopropyl, benzyl, NR 12 R 13 wherein
R 12 and R 13 are independently H or (C 1 -C 3 )alkyl, provided that both R 10 and R 11 are not NR 12 R 13 simultaneously, and
(C 2 -C 4 alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C 1 -C 3 )alkyl, and NR 14 R 15 , wherein
R 14 and R 15 are independently H or (C 1 -C 3 )alkyl, or
R 14 and R 15 can join to form a heterocycle of formula
wherein
Q represents CH 2 , O, or NR 16 , and
R 16 represents H or (C 1 -C 3 )alkyl,
G12) OSO 2 NR 23 R 24 wherein
R 23 and R 24 independently represent H, CH 3 , or (C 2 -C 4 alkyl which may optionally be substituted once by OH or NR 25 R 26 , wherein
R 25 and R 26 independently represent H or (C 1 -C 3 )alkyl;
G21) C(O)NR 28 R 29 , wherein
R 28 and R 29 are independently selected from H and (C 1 -C 3 )alkyl which is optionally substituted up to two times by OH;
wherein
Q iv is O or NR 34 ; and
R 34 H or (C 1 -C 3 )alkyl;
G26) C(O)NR 35 (CH 2 ) f OR 36 wherein
R 35 is H or (C 1 -C 3 )alkyl;
R 36 is (C 1 -C 6 )alkyl optionally substituted up to two times by halogen, OH, or O(C 1 -C 3 )alkyl, and the subscript “f” is an integer of 2-4; and
G31) N(R 48 )C(O)R 49 wherein
R 48 represents H or (C 1 -C 3 )alkyl; and
R 49 represents (CH 2 ) 1-3 —CO 2 H, O(C 2 -C 4 alkyl,
(CH 2 ) 1-4 —NR 50 R 51 wherein
R 50 and R 51 independently represent H or (C 1 -C 3 )alkyl, or
CH(R 52 )—NR 53 R 54 wherein
R 52 represents (CH 2 ) 1-4 —NH 2 , CH 2 OH, CH(CH 3 )OH, or (C 1 -C 3 )alkyl; and
R 53 and R 54 independently represent H or (C 1 -C 3 )alkyl.
6. The compound of claim 1 wherein
R 1 represents H;
M represents CH;
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
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-G5 and G8, 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, G22, and G31;
and subject to the further proviso
4) when J is pyridyl, n is 1, 2, or 3;
and proviso 5 does not apply;
G and G′ moieties are independently selected from the group consisting of:
G1) halogen;
G2) O(C 1 -C 4 alkyl which optionally is substituted up to two times by O(C 1 -C 2 )alkyl;
G3) OH;
G4) (C 1 -C 5 )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) OCF 3 ;
G8) NR 10 R 11 , wherein
R 10 R 11 are independently selected from H, CH 3 , cyclopropyl, benzyl, NR 12 R 13 wherein
R 12 and R 13 are independently H or (C 1 -C 3 )alkyl, provided that both R 10 and R 11 are not NR 12 R 13 simultaneously, and
(C 2 -C 4 alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C 1 -C 3 )alkyl, and NR 14 R 15 , wherein
R 14 and R 15 are independently H or (C 1 -C 3 )alkyl, or
R 14 and R 15 can join to form a heterocycle of formula
wherein
Q represents CH 2 , O, or NR 16 , and
R 16 represents H or (C 1 -C 3 )alkyl, or
R 10 and R 11 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by OH, NR 17 R 18 , wherein
R 17 and R 18 are H or (C 1 -C 3 )alkyl, or by
(C 1 -C 3 )alkyl which is optionally substituted up to two times by halogen, OH, or O(C 1 -C 3 )alkyl;
G12) OSO 2 NR 23 R 24 wherein
R 23 and R 24 independently represent H, CH 3 , or (C 2 -C 4 alkyl which may optionally be substituted once by OH or NR 25 R 26 , wherein
R 25 and R 26 independently represent H or (C 1 -C 3 )alkyl;
wherein
Q″ is O or NR 30 , and
R 30 is H, cyclopropyl, or (C 1 -C 3 )alkyl which is optionally substituted once by halogen, OH, or O(C 1 -C 3 )alkyl; and
G31) N(R 48 )C(O)R 49 wherein
R 48 represents H or (C 1 -C 3 )alkyl; and
R 49 represents (CH 2 ) 1-3 —CO 2 H, O(C 2 -C 4 )alkyl,
(CH 2 ) 1-4 —NR 50 R 51 wherein
R 50 and R 51 independently represent H or (C 1 -C 3 )alkyl, or
CH(R 52 )—NR 53 R 54 wherein
R 52 represents (CH 2 ) 1-4 —NH 2 , CH 2 OH, CH(CH 3 )OH, or (C 1 -C 3 )alkyl; and
R 53 and R 54 independently represent H or (C 1 -C 3 )alkyl.
7. The compound of claim 6 wherein
R 1 represents H;
R 1 represents O(C 1 -C 3 )alkyl, or NR 3 R 4 wherein R 3 and R 4 are H or (C 1 -C 3 )alkyl;
R 2a represents H;
L represents O or CR 6 R 7 , wherein
R 6 and R 7 are independently H, CH 3 , or OH;
G″ represents a substituent selected from the group consisting of O(C 1 -C 3 )alkyl, halogen, and CF 3 ;
n and n′ are independently 0 or 1, and provisos 1-3 do not apply;
G and G′ moieties are independently selected from the group consisting of:
G1) Cl or F;
G2) O(C 1 -C 3 )alkyl;
G3) OH;
G4) (C 1 -C 3 )alkyl, which is optionally substituted up to three times by halogen;
G5) OCF 3 ;
G8) NR 10 R 11 , wherein
R 10 and R 11 are independently selected from H, CH 3 , cyclopropyl, benzyl, NR 12 R 13 wherein
R 12 and R 13 are independently H or (C 1 -C 3 )alkyl, provided that both R 10 and R 11 are not NR 12 R 13 simultaneously, and
(C 2 -C 4 )alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C 1 -C 3 )alkyl, and NR 14 R 15 , wherein
R 14 and R 15 are independently H or (C 1 -C 3 )alkyl, or
R 14 and R 15 can join to form a heterocycle of formula
wherein
Q represents CH 2 , O, or NR 16 , and
R 16 represents H or (C 1 -C 3 )alkyl;
G12) OSO 2 R 23 R 24 wherein
R 23 and R 24 independently represent H, CH 3 , or (C 2 -C 4 )alkyl which may optionally be substituted once by OH or NR 25 R 26 wherein
R 25 and R 26 independently represent H or (C 1 -C 3 )alkyl;
wherein
Q″ is O or NR 30 , and
R 30 is H or (C 1 -C 3 )alkyl; and
G31) N(R 48 )C(O)R 49 wherein
R 48 represents H or (C 1 -C 3 )alkyl; and
R 49 represents (CH 2 ) 1-3 —CO 2 H, O(C 2 -C 4 )alkyl,
(CH 2 ) 1-4 —NR 50 R 51 wherein
R 50 and R 51 independently represent H or (C 1 -C 3 )alkyl, or
(CH(R 52 )—NR 53 R 54 wherein
R 52 represents (CH 2 ) 1-4 —NH 2 , CH 2 OH, CH(CH 3 )OH, or (C 1 -C 3 )alkyl; and
R 53 and R 54 independently represent H or (C 1 -C 3 )alkyl.
8. A compound selected from the group consisting of
4-{3-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}-N-methylpyridine-2-carboxamide;
4-{3-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxamide;
4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile;
6-phenyl-N 4 -(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine;
N 4 -{4-[(2-chloropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine;
4-{2-amino-6-[(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenyl sulfamate;
N-(4-{2-amino-6-[(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenyl)glycinamide trifluoroacetate;
6-(4-aminophenyl)-N 4 -(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine;
6-(6-aminopyridin-3-yl)-N 4 -(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine;
6-pyridin-3-yl-N 4 -(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine;
N-[(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]-4-methoxybenzenesulfonamide trifluoroacetate;
N-[(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methyl]methanesulfonamide trifluoroacetate; and
(4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridin-2-yl)methanol trifluoroacetate (salt).
9. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
10. A method of treatment of breast cancer comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.