US2010075967A1PendingUtilityA1
Pyrimidine derivatives for treatment of hyperproliferative disorders
Assignee: BAYER PHARMACEUTICALS CORPPriority: Oct 10, 2003Filed: Aug 28, 2009Published: Mar 25, 2010
Est. expiryOct 10, 2023(expired)· nominal 20-yr term from priority
Inventors:Julie A. DixonDhanapalan NagarathnamLei ZhangChunguang WangLin YiYuanwei ChenJianging ChenBrian BearMichael BrandsAlexander HillischDonald BiererMing WangWenlang FuMartin F. HentemannAnn-Marie BullionManoj Patel
C07D 401/14A61P 35/04C04B 35/632A61P 35/00C07D 413/14A61P 31/18A61P 43/00C07D 403/12C07D 401/12C07D 453/02C07D 239/47A61P 35/02C07D 417/14C07D 239/48C07D 409/14C07D 405/14
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 . 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 represents 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 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, 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;
G10)
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;
G19)
G20)
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;
G22)
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;
G24)
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;
G25)
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;
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 R 56 represents
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;
G35)
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, solvate, solvate of a salt, or stereoisomer thereof.
2 . 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, 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 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, 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;
G13) CN;
G22)
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 and 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 and R 54 independently represent H or (C 1 -C 3 )alkyl.
3 . The compound of claim 2 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 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
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;
G22)
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.
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 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;
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;
G25)
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 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 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;
G25)
wherein
Q iv is O or NR 34 ; and
R 34 is 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 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, 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;
G22)
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 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 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 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;
G22)
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 compound of selected from the group consisting of
(6-(2,6-dimethylphenyl)-N 4 -(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine)
(6-(6-aminopyridin-3-yl)-N 4 -{4-[(2-methylpyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine)
(N 6 -(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)-4,5′-bipyrimidine-2,6-diamine)
(6-phenyl-N 4 -(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine)
and
(6-(6-aminopyridin-3-yl)-N 4 -(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine)
10 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
11 . A method of treatment for a hyperproliferative disorder comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.
12 . The method of claim 10 wherein said hyperproliferative disorder is cancer.
13 . A packaged pharmaceutical composition comprising a container comprising the pharmaceutical composition of claim 10 and instructions for using the pharmaceutical composition to treat a disease or condition in a mammal.
14 . The packaged pharmaceutical composition of claim 13 , wherein the disease or condition is cancer.Cited by (0)
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