US 20100048.559A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/004.8559 A1 Bondy et al. (43) Pub. Date: Feb. 25, 2010 (54) PYRIDO(3.2-D)PYRIDMIDINES USEFUL FOR Related U.S. Application Data TREATINGVIRAL INFECTIONS (60) Provisional application No. 60/871,916, filed on Dec. (75) Inventors: Steven S. Bondy, Danville, CA 26, 2006. (US); William J. Watkins, Saratoga, CA (US); Lee S. Chong, Newark, CA (US); Piet Andre Publication Classification Maurits Maria Herdewijn, (51) Int. Cl. Rotselaar/Wexemaal (BE); Steven A 6LX 3/59 (2006.01) Cesar Alfons De Jonghe, Brugge C07D 47L/04 (2006.01) (BE) A 6LX 3/5.377 (2006.01) Correspondence Address: A6IP3L/2 (2006.01) GLEAD SCIENCES INC 333 LAKESIDE DR (52) U.S. Cl. ...................... 514/234.2:544/279: 544/117; FOSTER CITY, CA 94.404 (US) 51.4/264.11 (73) Assignee: Gilead Science, Inc., Foster City, CA (US) (57) ABSTRACT (21) Appl. No.: 12/519,500 This invention provides pyrido(3,2-d)pyrimidine derivatives represented by the structural formula (I), wherein: R is (22) PCT Fled: Dec. 24, 2007 amino, R is hydrogen, and R. and Rs together provide a (86) PCT NO.: PCT/EP07/11495 specific Substitution pattern, pharmaceutical acceptable addi tion salts, Stereochemical isomeric forms, N-oxides, Solvates S371 (c)(1), and pro-drugs thereof, are useful in the treatment of hepatitis (2), (4) Date: Jun. 16, 2009 C. Patent Application Publication Feb. 25, 2010 Sheet 1 of 2 US 2010/0048.559 A1 Figure 1 O O NC. N. Cl a HN Ns C b E. N. C on-\41 HN1 Y1 HN1,N1\1 \ R2 O C ls.-ls.--( " . s1S . a . S1S a H.C. N. N HC3V N N HC3V N N R2 R2 N1 N. C 9 N1 PN. R HN S.N a HNN la Patent Application Publication Feb. 25, 2010 Sheet 2 of 2 US 2010/0048.559 A1 Figure 2 O S H3C-S HN 's C a t s Cl b - N1 S-Cl HNS 1 HN S.N 2 HNSN 2 C y R2 R2 Nan-Ns-R3 d N1 ins C J.-le s ls.- 2 US 2010/0048.559 A1 Feb. 25, 2010 PYRIDO(3.2-D)PYRIDMIDINES USEFUL FOR heteroaryl and on position 4 with monoarylamino or mono TREATINGVIRAL INFECTIONS heteroarylamino and which may further be substituted on positions 2 and/or 6, being useful as capsaicin receptor modu lators. WO 2006/069805 discloses pyrido(3,2-d)pyrimidine 0001. The present invention relates to a class of novel derivatives substituted on position 6 with aryl or heteroaryl trisubstituted pyrido(3,2-d)pyrimidine derivatives. This and on both positions 2 and 4 with monoalkylamino, mono invention also relates to pharmaceutical compositions com cycloalkylamino, monoarylamino or monoarylalkylamino, prising said trisubstituted pyrido(3,2-d)pyrimidine deriva and which may further be substituted on position 7, being tives and one or more pharmaceutically acceptable excipi useful in the treatment of a disease mediated by phosphodi ents. The present invention further relates to the use of said esterase-4 activity. WO 2006/135993 discloses 2,4,6-trisub trisubstituted pyrido(3,2-d)pyrimidine derivatives as biologi stituted pyrido(3,2-d)pyrimidine derivatives 2,4,6-trisubsti cally active ingredients for manufacturing medicaments for tuted useful in the treatment of hepatitis C. the prevention or treatment of infection by a virus of the 0004. However there is a continuous need in the art for Flaviridae family, more specifically for inhibiting replication specific and highly therapeutically active compounds for pre of hepatitis C virus. venting or treating infections due to Flaviridae and pathologic conditions associated therewith, especially hepatitis C. In BACKGROUND OF THE INVENTION particular, there is a need in the art to provide drugs which are 0002. A huge number of pyrido(3,2-d)pyrimidine deriva active against hepatitis C in a minor dose in order to replace tives is already known in the art. For instance pyrido(3,2-d) existing drugs having significant side effects and to decrease pyrimidine derivatives with various Substituents on positions treatment COStS. 2, 4 and 6 (using the standard atom numbering for the pyrido 0005 Hepatitis is an inflammation of the liver that is most (3.2-d)pyrimidine moiety) are known with biological activi often caused by infection with one of three viruses known as ties such as competitive inhibition of pteroylglutamic acid, hepatitis A, B or C. Hepatitis A virus (HAV) infection is the inhibition of thrombocyte aggregation and adhesiveness, most common cause of acute hepatitis, and usually resolves antineoplastic activity, inhibition of dihydrofolate reductase spontaneously after several weeks of acute symptoms. Hepa and thymidylate synthase, e.g. from U.S. Pat. No. 2.924,599, titis B virus (HBV) and hepatitis C virus (HCV) are the most U.S. Pat. No. 3,939,268, U.S. Pat. No. 4,460,591, U.S. Pat. common viral causes of chronic hepatitis, usually defined as No. 5,167,963 and U.S. Pat. No. 5,508,281. Pyrido(3,2-d) liver inflammation persisting for more than six months. HCV pyrimidine derivatives with various substituents on positions is the second most common cause of viral hepatitis in general 2, 4, 6 and 7 (using the standard atom numbering for the and most common cause of chronic hepatitis. The World pyrido(3.2-d)pyrimidine moiety). Some of them with biologi Health Organization estimates that worldwide 170 million cal activities, are also known e.g. from U.S. Pat. No. 5,521, people (3% of the world's population) are chronically 190, U.S. patent application publication No. 2002/0049207, infected with HCV. These chronic carriers are at risk of devel U.S. patent application publication No. 2003/0186987, U.S. oping cirrhosis and/or liver cancer. In studies with a 10 to 20 patent application publication No. 2003/0199526, U.S. year follow-up, cirrhosis developed in 20-30% of the patients, patent application publication No. 2004/0039000, U.S. 1-5% of whom may develop liver cancer during the next ten patent application publication No. 2004/0106616, U.S. Pat. years. The 15% to 45% of persons with acute hepatitis C who No. 6,713,484, U.S. Pat. No. 6,730,682 and U.S. Pat. No. do recover are not subject to long-term complications and do 6,723,726. not need treatment. Since HCV and pestiviruses belong to the 0003 U.S. Pat. No. 5,654,307 discloses pyrido(3,2-d)py same virus family and share many similarities (such as, but rimidine derivatives substituted on position 4 with monoary not limited to, organisation of the genome, analogous gene lamino or monobenzylamino, and on positions 6 and 7 with products and replication cycle), pestiviruses may be adopted Substituents each independently selected from the group con as a model virus and surrogate for HCV. For example the sisting of lower alkyl, amino, lower alkoxy, mono- or dialky Bovine Viral Diarrhea Virus (BVDV) is closely related to lamino, halogen and hydroxy. WO 01/083456 discloses hepatitis C virus (HCV) and may be used as a surrogate virus pyrido(3,2-d)pyrimidine derivatives substituted on position 4 in drug development for HCV infection. with morpholinyl and on position 2 with hydroxyphenyl or 0006 HCV is a representative and highly significant morpholinoethoxyphenyl, having PI3K and cancer inhibiting member of the Flaviviridae family, a family of positive-strand activity. U.S. Pat. No. 6,476,031 discloses substituted RNA viruses. This family includes the following genera: quinazoline derivatives, including (in reaction scheme 5) a Genus Flavivirus (type species Yellow fever virus; others series of pyrido(3,2-d)pyrimidine derivatives which are sub include West Nile virus and Dengue Fever), Genus Hepacivi stituted on position 4 with hydroxy, chloro or an aryl, het rus (type species Hepatitis C virus), and Genus Pestivirus eroaryl (including pyridyl, pyrimidyl, indolyl, benzimida (type species Bovine viral diarrhea virus (BVDV); others Zolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, include classical Swine fever or hog cholera). Contrary to benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, other families of positive strand RNA viruses such as human imidazolyl), cycloaliphatic or cycloheteroaliphatic group immunodeficiency virus (HIV), HCV seems incapable of being optionally spaced from the pyrido(3,2-d)pyrimidine integrating into the host's genome. The primary immune ring by a linker such as NH.WO 02/22602 and WO 02/22607 response to HCV is mounted by cytotoxic T lymphocytes. disclose pyrazole and triazole compounds, including 2-(1- Unfortunately, this process fails to eradicate infection in most trifluoromethylphenyl)-4-fluorobenzopyrazolyl-pyrido(3,2- people; in fact, it may contribute to liver inflammation and, d)pyrimidine and 2-(1-tri-fluoromethylphenyl)-4-methyl ultimately, tissue necrosis. The ability of HCV to escape triazolyl-pyrido(3.2-d)pyrimidine being useful as protein immune Surveillance is the Subject of much speculation. One kinase inhibitors. WO 03/062209 discloses pyrido(3,2-d)py likely means of viral persistence relies on the presence of rimidine derivatives substituted on position 7 with aryl or closely related but heterogeneous populations of viral US 2010/0048.559 A1 Feb. 25, 2010 genomes. Further studies of these quasi-species enable clas those with genotype 1 within 48 weeks of treatment and 65% sification of several genotypes and Subtypes, which have for those with genotype 4 within 48 weeks of treatment. clinical implications. About 80% of hepatitis C patients in the United States exhibit 0007. The diagnosis of hepatitis C is rarely made during genotype 1, whereas genotype 4 is more common in the the acute phase of the disease because the majority of people Middle East and Africa.