	US 7,524,852 B2
	Bicyclic pyrimidine derivatives
Hitoshi Arai, Susono (Japan); Tsutomu Matsumura, Sakai (Japan); Hiroshi Ishida, Sunto-gun (Japan); Yosuke Yamaura, Ichikawa (Japan); Seiji Aratake, Sunto-gun (Japan); Etsuo Ohshima, Nagareyama (Japan); Koji Yanagawa, Sunto-gun (Japan); Motoki Miyama, Sunto-gun (Japan); Koji Suzuki, Mishima (Japan); Ari Kawabe, Sunto-gun (Japan); Satoshi Nakanishi, Yokohama (Japan); Katsuya Kobayashi, Sunto-gun (Japan); Takashi Sato, Sunto-gun (Japan); Ichiro Miki, Sunto-gun (Japan); Kimihisa Ueno, Mishima (Japan); Shinya Fujii, Sanuki (Japan); and Miho Iwase, Sunto-gun (Japan)
Assigned to Kyowa Hakko Kogyo Co., Ltd., Tokyo (Japan)
Appl. No. 10/516,750 PCT Filed Jun. 06, 2003, PCT No. PCT/JP03/07200 § 371(c)(1), (2), (4) Date Mar. 31, 2005, PCT Pub. No. WO03/104230, PCT Pub. Date Dec. 18, 2003.
Claims priority of application No. 2002-166504 (JP), filed on Jun. 07, 2002.
Prior Publication US 2007/0037834 A1, Feb. 15, 2007
Int. Cl. C07D 487/04 (2006.01); A61K 31/519 (2006.01); A61P 29/00 (2006.01)

U.S. Cl. 514—264.11 [544/279; 544/117; 544/61; 514/234.2; 514/228.5]

39 Claims

1. A bicyclic pyrimidine represented by following Formula (I):

{wherein

m represents 1,

n represents 2,

R¹represents

—NR⁴R⁵(wherein

R⁴and R⁵independently represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heteroalicyclic group, substituted or unsubstituted heteroaromatic-substituted alkyl or substituted or unsubstituted heteroalicyclic-substituted alkyl, or R⁴and R⁵are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heteroalicyclic group, provided that R⁴and R⁵are not simultaneously hydrogen atoms, and that when one of R⁴and R⁵is a hydrogen atom, the other of R⁴and R⁵is neither a substituted or unsubstituted pyrazol-3-yl nor a substituted or unsubstituted 1,2,4-triazol-3-yl);

R²represents Formula (II):

[wherein

r represents an integer of 0 to 4;

s represents a number ranging from 0 to a substitutable number;

G represents a nitrogen atom, CH, C(OH), C(CO₂H) or C(CN);

q represents an integer of 1 or 2 when G is a nitrogen atom, and q represents an integer of 0 to 2 when G is CH, C(OH), C(CO₂H) or C(CN);

E represents a single bond, —C(═O)—, —O—, —CH(OH)—, —CH₂CH(OH)—, —C(═O)O—, —C(═O)NR⁶— (wherein R⁶represents a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl) or

(wherein R^6Ahas the same meaning as R⁶defined above), and E is bonded to G at the left side in each group;

X^Arepresents substituted or unsubstituted lower alkyl or halogen, or two X^As on the same carbon atom are combined together to form oxo, wherein respective

X^As may be the same or different when s is 2 or more;

X^ahas the same meaning as X defined above, where respective X^as may be the same or different when r is 1 or more; and

R¹⁰represents

—NR^8AR^9A(wherein

R^8Aand R^9Aindependently represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heteroalicyclic group, substituted or unsubstituted heteroaromatic-substituted alkyl, substituted or unsubstituted heteroalicyclic-substituted alkyl, imino-(lower alkyl) or substituted or unsubstituted amidino),

a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heteroalicyclic group, substituted or unsubstituted heteroaromatic-substituted alkyl or substituted or unsubstituted heteroalicyclic-substituted alkyl];

A represents —C(═O)—, —SO₂—, —NR^6DC(═O)— (wherein R^6Drepresents a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl, or is combined together with R³and the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group), —NR^6DC(═S)—, —OC(═O)—, —OC(═S)—, —SC(═O)—, —SC(═S)—,

and A is bonded to R³at the left side in the each group; and with the provisio that

(a) when A is a single bond,

then R³represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heteroalicyclic group, substituted or unsubstituted heteroaromatic-substituted alkyl or substituted or unsubstituted heteroalicyclic-substituted alkyl, and

(b) when A is —C(═O)—, —SO₂—, —NR^6DC(═O)—, —NR^6DC(═S)—, —OC(═O)—, —OC(═S)—, —SC(═O)— or —SC(═S)—,

then R³represents substituted or unsubstituted lower alkyl substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted heteroalicyclic group, substituted or unsubstituted heteroaromatic-substituted alkyl, substituted or unsubstituted heteroalicyclic-substituted alkyl or —NR^8BR^9B(wherein R^8Band R^9Bhave the same meanings as R⁸and R⁹defined above, respectively)},

or a quaternary ammonium salt thereof, or a pharmaceutically acceptable salt thereof.