`So?a et a1.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,334,270 B2
`*Dec. 18, 2012
`
`US008334270B2
`
`(54)
`
`(75)
`
`NUCLEOSIDE PHOSPHORAMIDATE
`PRODRUGS
`
`Inventors: Michael Joseph So?a, Doylestown, PA
`(US); Jinfa Du, New Hope, PA (US);
`Peiyuan Wang, Glen Rock, N] (US);
`Dhanapalan Nagarathnam, Bethany,
`CT (US)
`
`2007/0265222 A1 11/2007 MacCoss
`2007/0275912 A1 11/2007 Bhat
`2009/0306007 A1 12/2009 Wagner
`2010/0022468 A1
`1/2010 Meppen
`2010/0035835 A1
`2/2010 Narjes
`2010/0152128 A1
`6/2010 Attenni
`2010/0173863 A1
`7/2010 Schinazi
`2010/0316594 A1 12/2010 Sommadossi
`2011/0124592 A1
`5/2011 McGuigan
`
`(73)
`
`Assignee:
`
`Gilead Pharmasset LLC, Foster City,
`CA (US)
`
`WO
`
`FOREIGN PATENT DOCUMENTS
`WO2006121820
`11/2006
`OTHER PUBLICATIONS
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is subject to a terminal dis
`claimer.
`
`(21)
`
`(22)
`
`(65)
`
`(63)
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`Appl. N0.: 13/099,671
`
`Filed:
`
`May 3, 2011
`
`Prior Publication Data
`
`US 2011/0257122 A1
`
`Oct. 20, 2011
`
`Related US. Application Data
`
`Continuation of application No. 12/053,015, ?led on
`Mar. 21, 2008, now Pat. No. 7,964,580.
`
`Provisional application No. 60/909,315, ?led on Mar.
`30, 2007, provisional application No. 60/982,309,
`?led on Oct. 24, 2007.
`
`Int. Cl.
`(2006.01)
`A01N 43/04
`(2006.01)
`A61K 31/70
`US. Cl. .............. .. 514/43; 514/45; 514/46; 514/47;
`514/48; 514/49; 514/50; 514/51
`Field of Classi?cation Search ...................... .. None
`See application ?le for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`6,348,587 B1
`2/2002 Schinazi
`6,455,513 B1
`9/2002 McGuigan
`6,777,395 B2
`8/2004 Bhat
`6,812,219 B2 11/2004 LaColla
`6,911,424 B2
`6/2005 Schinazi
`6,914,054 B2
`7/2005 Sommadossi
`7,018,989 B2
`3/2006 McGuigan
`7,105,493 B2
`9/2006 Sommadossi
`7,105,499 B2
`9/2006 Carroll
`7,125,855 B2 10/2006 Bhat
`7,202,224 B2
`4/2007 Eldrup
`7,307,065 B2 12/2007 Schinazi
`7,323,453 B2
`1/2008 Olsen
`7,390,791 B2
`6/2008 Becker
`7,429,572 B2
`9/2008 Clark
`7,608,597 B2 10/2009 Sommadossi
`7,608,600 B2 10/2009 Storer
`7,635,689 B2 12/2009 LaColla
`7,879,815 B2
`2/2011 MacCoss
`2006/0142238 A1
`6/2006 McGuigan
`2007/0042988 A1
`2/2007 Klumpp
`2007/0197463 A1
`8/2007 Chun
`
`US. Patent No. 7,964,580, which issued from US. Appl. No.
`12/053,0154Cover Page and Issued Claims.
`Selected Prosecution Documents from US. Appl. No. 12/053,015:
`(1) Jun. 15, 2010 Restriction Requirement; (2) Oct. 28, 2010 Amend
`ment; (3) Jan. 5, 2011 Notice of Allowance; and (4) Apr. 1, 2011
`Amendment.
`U.S. Appl. No. 12/783,680, ?led May 20, 2010iOriginally ?led
`claims.
`U.S. Appl. No. 13/076,552, ?led Mar. 31, 2011iOriginally ?led
`claims.
`U.S. Appl. No. 12/645,710, ?led Dec. 23, 2009iOriginally ?led
`claims.
`US. Patent No. 7,429,572, which issued from US. Appl. No.
`10/828,7534Cover Page and Issued Claims.
`Selected Prosecution Documents from US. Appl. No. 10/ 828,753:
`(1) Feb. 26, 2007 Amendment; (2) Mar. 30, 2007 Of?ce Action; (3)
`Jun. 19, 2007 Interview Summary; (4) Sep. 12,2007 Amendment; (5)
`Sep. 12, 2007 Declaration; (6) Sep. 24, 2007 Declaration; (7) Nov.
`28, 2007 Amendment; (8) Feb. 26, 2008 Of?ce Action; (9) Mar. 11,
`2008 Amendment; and (10) May 29, 2008 Notice ofAllowance.
`U.S. Appl. No. 11/854,218iPending Claims as of Jun. 28, 2011.
`Selected Prosecution Documents for US. Appl. No. 11/854,218: (1)
`Sep. 12, 2007 Amendment; (2) Oct. 1, 2009 Of?ce Action; (3) Mar.
`31, 2010 Response; (4) Mar. 31, 2011 Declaration; (5) Jul. 22, 2010
`Of?ce Action; (6) Oct. 11, 2010 Amendment; (7) Oct. 11, 2010
`Declaration; (8) Dec. 23, 2010 Of?ce Action; (9) Jun. 28, 2011
`Amendment.
`U.S. Appl. No. 12/878,262iPending Claims as of Sep. 1, 2011.
`Selected Prosecution Documents for US. Appl. No. 12/ 878,262: (1)
`Sep. 9, 2010 Amendment; (2) Jun. 8,2011 Of?ce Action; and (3) Sep.
`1, 2011 Amendment.
`Aquaro et al., Antimicrobial Agents and Chemotherapy (2000) 1:
`173-177.
`
`(Continued)
`Primary Examiner * Patrick Lewis
`(74) Attorney, Agent, orFirm * Fitzpatrick, Cella, Harper &
`Scinto
`ABSTRACT
`(57)
`Disclosed herein are phosphoramidate prodrugs of nucleo
`side derivatives for the treatment of viral infections in mam
`mals, which is a compound, its stereoisomer, salt (acid or
`basic addition salt), hydrate, solvate, or crystalline form
`thereof, represented by the following structure:
`
`Also disclosed are methods of treatment, uses, and processes
`for preparing each of which utilize the compound represented
`by formula I.
`
`25 Claims, No Drawings
`
`IPR2018-00122
`
`Page 1 of 311
`
`I-MAK 1001
`
`
`
`US 8,334,270 B2
`Page 2
`
`OTHER PUBLICATIONS
`Chapman et al., Nucleotides, Nucleosides and Nucleic Acids (2001)
`20(4-7): 621-628.
`Chapman et al., Nucleotides, Nucleosides and Nucleic Acids (2001)
`20(4-7): 1085-1090.
`Clark et al., J. Med. Chem. (2005) 48(17): 5504-5508.
`Eisenberg et al., Nucleosides, Nucleotides & Nucleic Acids (2001)
`20(4-7): 1091-1098.
`Lee et al., Antimicrobial Agents and Chemotherapy (2005) 49(5):
`1898-1906.
`Ma et al., J. Biol. Chem. (2007) 282(41): 29812-29820.
`
`McGuigan et al., Antiviral Chemistry and Chemotherapy (1998) 9:
`473-479.
`Murakami et al., Antiviral Chemistry & Chemotherapy (2007) 51(2):
`503-509.
`Murakami et al., Antimicrobial Agents and Chemotherapy (2008)
`52(2): 458-464.
`Perrone et al., J. Med. Chem. (2007) 50(8): 1840-1849.
`Ray et al., Antimicrobial Agents and Chemotherapy (2008) 52(2):
`648-654.
`Stuyver et al., Antiviral Chemistry & Chemotherapy (2004) 48(2):
`651-654.
`
`IPR2018-00122
`
`Page 2 of 311
`
`I-MAK 1001
`
`
`
`US 8,334,270 B2
`
`1
`NUCLEOSIDE PHOSPHORAMIDATE
`PRODRUGS
`
`This application is a continuation of US. patent applica
`tion Ser. No. 12/053,015, ?led Mar. 21, 2008, Which issued as
`US. Pat. No. 7,964,580 on Jun. 21, 2011 and Which claims
`priority to US. Provisional Patent Application Nos. 60/909,
`315, ?led Mar. 30, 2007 and 60/982,309, ?led Oct. 24, 2007,
`all of Which are incorporated by reference in their entireties.
`
`FIELD OF INVENTION
`
`The present invention pertains to nucleo side pho sphorami
`dates and their use as agents for treating viral diseases. These
`compounds are inhibitors of RNA-dependent RNA viral rep
`lication and are useful as inhibitors of HCV NS5B poly
`merase, as inhibitors of HCV replication and for treatment of
`hepatitis C infection in mammals. The invention provides
`novel chemical compounds, and the use of these compounds
`alone or in combination With other antiviral agents for treat
`ing HCV infection.
`
`20
`
`BACKGROUND
`
`2
`HCV belongs to a much larger family of viruses that share
`many common features.
`Flaviviridae Viruses
`The Flaviviridae family of viruses comprises at least three
`distinct genera: pestiviruses, Which cause disease in cattle and
`pigs; ?aviviruses, Which are the primary cause of diseases
`such as dengue fever and yelloW fever; and hepaciviruses,
`Whose sole member is HCV. The ?avivirus genus includes
`more than 68 members separated into groups on the basis of
`serological relatedness (Calisher et al., .1. Gen. l/zrol, 1993,
`70, 37-43). Clinical symptoms vary and include fever,
`encephalitis and hemorrhagic fever (Fields Wrology, Editors:
`Fields, B. N., Knipe, D. M., and HoWley, P. M., Lippincott
`Raven Publishers, Philadelphia, Pa., 1996, Chapter 31, 931
`959). Flaviviruses of global concern that are associated With
`human disease include the Dengue Hemorrhagic Fever
`viruses (DHF), yelloW fever virus, shock syndrome and Japa
`nese encephalitis virus (Halstead, S. B., Rev. Infect. Dis.,
`1984, 6, 251-264; Halstead, S. B., Science, 239:476-481,
`1988; Monath, T. P., New Eng. J Med, 1988, 319, 64 1-643).
`The pestivirus genus includes bovine viral diarrhea virus
`(BVDV), classical sWine fever virus (CSFV, also called hog
`cholera virus) and border disease virus (BDV) of sheep
`(Moennig, V. et al. Adv. I/m Res. 1992, 41, 53-98). Pestivirus
`infections of domesticated livestock (cattle, pigs and sheep)
`cause signi?cant economic losses WorldWide. BVDV causes
`mucosal disease in cattle and is of signi?cant economic
`importance to the livestock industry (Meyers, G. and Thiel, H.
`1., Advances in Virus Research, 1996, 47, 53-118; Moennig
`V., et al, Adv. Vrr. Res. 1992, 41, 53-98). Human pestiviruses
`have not been as extensively characterized as the animal
`pestiviruses. However, serological surveys indicate consider
`able pestivirus exposure in humans.
`Pestiviruses and hepaciviruses are closely related virus
`groups Within the Flaviviridae family. Other closely related
`viruses in this family include the GB virus A, GB virus A-like
`agents, GB virus-B and GB virus-C (also called hepatitis G
`virus, HGV). The hepacivirus group (hepatitis C virus; HCV)
`consists of a number of closely related but genotypically
`distinguishable viruses that infect humans. There are at least
`6 HCV genotypes and more than 50 subtypes. Due to the
`similarities betWeen pestiviruses and hepaciviruses, com
`bined With the poor ability of hepaciviruses to groW e?i
`ciently in cell culture, bovine viral diarrhea virus (BVDV) is
`often used as a surrogate to study the HCV virus.
`The genetic organization of pestiviruses and hepaciviruses
`is very similar. These positive stranded RNA viruses possess
`a single large open reading frame (ORF) encoding all the viral
`proteins necessary for virus replication. These proteins are
`expressed as a polyprotein that is co- and post-translationally
`processed by both cellular and virus-encoded proteinases to
`yield the mature viral proteins. The viral proteins responsible
`for the replication of the viral genome RNA are located Within
`approximately the carboxy-terrninal. TWo-thirds of the ORF
`are termed nonstructural (NS) proteins. The genetic organi
`zation and polyprotein processing of the nonstructural protein
`portion of the ORF for pestiviruses and hepaciviruses is very
`similar. For both the pestiviruses and hepaciviruses, the
`mature nonstructural (NS) proteins, in sequential order from
`the amino-terminus of the nonstructural protein coding
`region to the carboxy-terrninus of the ORF, consist of p7,
`NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
`The NS proteins of pestiviruses and hepaciviruses share
`sequence domains that are characteristic of speci?c protein
`functions. For example, the NS3 proteins of viruses in both
`groups possess amino acid sequence motifs characteristic of
`serine proteinases and of helicases (Gorbalenya et al., Nature,
`
`25
`
`30
`
`35
`
`40
`
`45
`
`Hepatitis C virus (HCV) infection is a major health prob
`lem that leads to chronic liver disease, such as cirrhosis and
`hepatocellular carcinoma, in a substantial number of infected
`individuals, estimated to be 2-15% of the World’s population.
`There are an estimated 4.5 million infected people in the
`United States alone, according to the US. Center for Disease
`Control. According to the World Health Organization, there
`are more than 200 million infected individuals WorldWide,
`With at least 3 to 4 million people being infected each year.
`Once infected, about 20% of people clear the virus, but the
`rest can harbor HCV the rest of their lives. Ten to tWenty
`percent of chronically infected individuals eventually
`develop liver-destroying cirrhosis or cancer. The viral disease
`is transmitted parenterally by contaminated blood and blood
`products, contaminated needles, or sexually and vertically
`from infected mothers or carrier mothers to their offspring.
`Current treatments for HCV infection, Which are restricted to
`immunotherapy With recombinant interferon-0t alone or in
`combination With the nucleoside analog ribavirin, are of lim
`ited clinical bene?t. Moreover, there is no established vaccine
`for HCV. Consequently, there is an urgent need for improved
`therapeutic agents that effectively combat chronic HCV
`infection.
`The HCV virion is an enveloped positive-strand RNA virus
`With a single oligoribonucleotide genomic sequence of about
`9600 bases Which encodes a polyprotein of about 3,010
`amino acids. The protein products of the HCV gene consist of
`the structural proteins C, E1, and E2, and the non-structural
`proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B.
`The nonstructural (NS) proteins are believed to provide the
`catalytic machinery for viral replication. The NS3 protease
`releases NS5B, the RNA-dependent RNA polymerase from
`the polyprotein chain. HCV NS5B polymerase is required for
`the synthesis of a double-stranded RNA from a single
`stranded viral RNA that serves as a template in the replication
`cycle of HCV. Therefore, NS5B polymerase is considered to
`be an essential component in the HCV replication complex
`(K. Ishi, et al, Hepzology, 1999, 29: 1227-1235; V. Lohmann,
`et al., Wrology, 1998, 249: 108-118). Inhibition of HCV
`NS5B polymerase prevents formation of the double-stranded
`65
`HCV RNA and therefore constitutes an attractive approach to
`the development of HCV-speci?c antiviral therapies.
`
`50
`
`55
`
`60
`
`IPR2018-00122
`
`Page 3 of 311
`
`I-MAK 1001
`
`
`
`US 8,334,270 B2
`
`20
`
`25
`
`30
`
`35
`
`3
`1988, 333, 22; BaZan and Fletterick Virology, 1989, 171,
`637-639; Gorbalenya et al., Nucleic Acid Res., 1989, 17,
`3889-3897). Similarly, the NS5B proteins of pestiviruses and
`hepaciviruses have the motifs characteristic of RNA-directed
`RNA polymerases (Koonin, E. V. and Dolja, V. V., Crir. Rev.
`Biochem. Molec. Biol. 1993, 28, 375-430).
`The actual roles and functions of the NS proteins of pes
`tiviruses and hepaciviruses in the lifecycle of the viruses are
`directly analogous. In both cases, the NS3 serine proteinase is
`responsible for all proteolytic processing of polyprotein pre
`cursors downstream of its position in the ORF (Wiskerchen
`and Collett, Virology, 1991, 184, 341-350; Bartenschlager et
`al., J Vll’Ol. 1993, 67, 3835-3844; Eckart et al. Biochem.
`Biophys. Res. Comm. 1993, 192, 399-406; Grakoui et al., J.
`Vll’Ol. 1993, 67, 2832-2843; Grakoui et al., Proc. Natl. Acad.
`Sci. USA 1993, 90, 10583-10587; Hijikata et al., J Vll’Ol.
`1993, 67, 4665-4675; Tome et al., J. Virol, 1993, 67, 4017
`4026). The NS4A protein, in both cases, acts as a cofactor
`With the NS3 serine protease (Bartenschlager et al., J Vli’Ol.
`1994, 68, 5045-5055; Failla et al., J. Vll’Ol. 1994, 68, 3753
`3760; Xu et al., J Virol, 1997, 71:53 12-5322). The NS3
`protein of both viruses also functions as a helicase (Kim et al.,
`Biochem. Biophys. Res. Comm., 1995, 215, 160-166; Jin and
`Peterson, Arch. Biochem. Biophys, 1995, 323, 47-53; Warr
`ener and Collett, J Vli’Ol. 1995, 69, 1720-1726). Finally, the
`NS5B proteins of pestiviruses and hepaciviruses have the
`predicted RNA-directed RNA polymerases activity (Behrens
`et al., EMBO, 1996, 15, 12-22; Lechmann et al., J. I/irol,
`1997, 71, 8416-8428; Yuan et al., Biochem. Biophys. Res.
`Comm. 1997, 232, 231-235; Hagedorn, PCT WO 97/12033;
`Zhong et al, J. Virol, 1998, 72, 9365-9369).
`Currently, there are limited treatment options for individu
`als infected With hepatitis C virus. The current approved
`therapeutic option is the use of immunotherapy With recom
`binant interferon-0t alone or in combination With the nucleo
`side analog ribavirin. This therapy is limited in its clinical
`effectiveness and only 50% of treated patients respond to
`therapy. Therefore, there is signi?cant need for more effective
`and novel therapies to address the unmet medical need posed
`by HCV infection.
`A number of potential molecular targets for drug develop
`ment of direct acting antivirals as anti-HCV therapeutics have
`noW been identi?ed including, but not limited to, the NS2
`NS3 autoprotease, the N3 protease, the N3 helicase and the
`NS5B polymerase. The RNA-dependent RNA polymerase is
`absolutely essential for replication of the single-stranded,
`positive sense, RNA genome and this enzyme has elicited
`signi?cant interest among medicinal chemists.
`Inhibitors of HCV NS5B as potential therapies for HCV
`infection have been revieWed: Tan, S.-L., et al., Nature Rev.
`50
`Drug Discov., 2002, 1, 867-881; Walker, M. P. et al., Exp.
`Opin. Investigational Drugs, 2003, 12, 1269-1280; Ni, Z-.I.,
`et al., Current Opinion in Drug Discovery and Development,
`2004, 7, 446-459; Beaulieu, P. L., et al., Current Opinion in
`Investigational Drugs, 2004, 5, 838-850; Wu, 1., et al., Cur
`rent Drug Targets-Infectious Disorders, 2003, 3, 207-219;
`Gri?ith, R. C., et al, Annual Reports in Medicinal Chemistry,
`2004, 39, 223-237; Carrol, S., et al., Infectious Disorders
`Drug Targets, 2006, 6, 17-29. The potential for the emergence
`of resistant HCV strains and the need to identify agents With
`broad genotype coverage supports the need for continuing
`efforts to identify novel and more effective nucleosides as
`HCV NS5B inhibitors.
`Nucleoside inhibitors of NS5B polymerase can act either
`as a non-natural substrate that results in chain termination or
`as a competitive inhibitor Which competes With nucleotide
`binding to the polymerase. To function as a chain terminator
`
`40
`
`45
`
`55
`
`60
`
`65
`
`4
`the nucleoside analog must be taken up by the cell and con
`ver‘ted in vivo to a triphosphate to compete for the polymerase
`nucleotide binding site. This conversion to the triphosphate is
`commonly mediated by cellular kinases Which imparts addi
`tional structural requirements on a potential nucleoside poly
`merase inhibitor. Unfortunately, this limits the direct evalua
`tion of nucleosides as inhibitors of HCV replication to cell
`based assays capable of in situ phosphorylation.
`In some cases, the biological activity of a nucleoside is
`hampered by its poor substrate characteristics for one or more
`of the kinases needed to convert it to the active triphosphate
`form. Formation of the monophosphate by a nucleoside
`kinase is generally vieWed as the rate limiting step of the three
`pho sphorylation events. To circumvent the need for the initial
`phosphorylation step in the metabolism of a nucleoside to the
`active triphosphate analog, the preparation of stable phos
`phate prodrugs has been reported. Nucleoside phosphorami
`date prodrugs have been shoWn to be precursors of the active
`nucleoside triphosphate and to inhibit viral replication When
`administered to viral infected Whole cells (McGuigan, C., et
`al., J Med. Chem., 1996,39, 1748-1753; Valette, G., et al., J.
`Med. Chem., 1996, 39, 1981-1990; BalZarini, J., et al., Proc.
`National Acad Sci USA, 1996, 93, 7295-7299; Siddiqui, A.
`Q, et al., J. Med. Chem., 1999, 42, 4122-4128; Eisenberg, E.
`1., et al., Nucleosides, Nucleotides and Nucleic Acids, 2001,
`20, 1091-1098; Lee, W. A., et al., Antimicrobial Agents and
`Chemotherapy, 2005, 49, 1898); US 2006/0241064; and WO
`2007/095269.
`Also limiting the utility of nucleosides as viable therapeu
`tic agents is their sometimes poor physicochemical and phar
`macokinetic properties. These poor properties can limit the
`intestinal absorption of an agent and limit uptake into the
`target tissue or cell. To improve on their properties prodrugs
`of nucleosides have been employed. It has been demonstrated
`that preparation of nucleoside phosphoramidates improves
`the systemic absorption of a nucleoside and furthermore, the
`pho sphoramidate moiety of these “pronucleotides” is masked
`With neutral lipophilic groups to obtain a suitable partition
`coe?icient to optimiZe uptake and transport into the cell dra
`matically enhancing the intracellular concentration of the
`nucleoside monophosphate analog relative to administering
`the parent nucleoside alone. EnZyme-mediated hydrolysis of
`the phosphate ester moiety produces a nucleoside monophos
`phate Wherein the rate limiting initial pho sphorylation is
`unnecessary.
`
`SUMMARY OF THE INVENTION
`
`The present invention is directed toWard novel pho sphora
`midate prodrugs ofnucleoside derivatives for the treatment of
`viral infections in mammals, Which is a compound, its stere
`oisomers, salts (acid or basic addition salts), hydrates, sol
`vates, or crystalline forms thereof, represented by the folloW
`ing structure:
`
`(a) R1 is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or
`aryl, Which includes, but is not limited to, phenyl or naphthyl,
`
`IPR2018-00122
`
`Page 4 of 311
`
`I-MAK 1001
`
`
`
`US 8,334,270 B2
`
`5
`where phenyl or naphthyl are optionally substituted with at
`least one ofC 1-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C1_6 alkoxy,
`F, Cl, Br, l, nitro, cyano, C1_6 haloalkyl, 7N(Rlv)2, C1_6
`acylamino, iNHSOZCL6 alkyl, isOZN(R1')2, COR“, and
`istCp6 alkyl; (RF is independently hydrogen or alkyl,
`which includes, but is not limited to, C1_20 alkyl, C1_10 alkyl,
`or C1_6 alkyl, R1” is iOR' or 7N(Rlv)2);
`(b) R2 is hydrogen, C1_10 alkyl, R3“ or R3b and R2 together
`are (CH2)n so as to form a cyclic ring that includes the adjoin-
`ing N and C atoms, C(O)CR3“R3Z’NHR1, where n is 2 to 4 and
`R1, R3“, and R3b;
`(c) R3“ and R3b are (i) independently selected from hydro-
`gen, C1_10 alkyl, cycloalkyl, 7(CH2)C(NR3 )2, C1_6 hydroxy-
`alkyl, %HZSH, 7(CH2)2S(O)dMe, 7(CH2)3NHC(:NH)
`NHZ,
`(lH-indol-3 -yl)methyl,
`(lH-imidazol-4-yl)methyl,
`7(CH2)9COR3”, aryl and aryl C1.3 alkyl, said aryl groups
`optionally substituted with a group selected from hydroxyl,
`C1_10 alkyl, C1_6 alkoxy, halogen, nitro and cyano; (ii) R3“ and
`R3b both are C1_6 alkyl; (iii) R3“ and R3b together are (CH2)fso
`as to form a spiro ring; (iV) R3“ is hydrogen and R3b and R2
`together are (CH2)n so as to form a cyclic ring that includes
`the adjoining N and C atoms (V) R3b is hydrogen and R3“ and
`R2 together are (CH2)n so as to form a cyclic ring that includes
`the adjoining N and C atoms, where c is l to 6, d is 0 to 2, e is
`0 to 3, fis 2 to 5, n is 2 to 4, and where R3' is independently
`hydrogen or C1_6 alkyl and R3” is 40R' or 7N(R3')2); (Vi)
`R3“ is H and R3b is H, CH3, CHZCH3, CH(CH3)2, CHZCH
`(CH3)2,
`CH(CH3)CH2CH3,
`CHzPh,
`CHZ-indol-3-yl,
`iCHzCstCH3,
`CHZCOZH,
`CH2C(O)NH2,
`CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2,
`iCHZCHZCHZNHC(NH)NH2,
`CH2-imidazol-4-yl,
`CHZOH, CH(OH)CH3, CH2((4'-OH)-Ph), CH28H, or lower
`cycloalkyl; or (Viii) R3“ is CH3, iCHZCH3, CH(CH3)2,
`CHZCH(CH3)2, CH(CH3)CH2CH3, CHzPh, CHZ-indol-3-yl,
`7CH2CHZSCH3,
`CHZCOZH,
`CH2C(O)NH2,
`CH2CH2COOH, CHZCH2C(O)NH2, CHZCH2CH2CH2NH2,
`iCHZCH2CH2NHC(NH)NH2,
`CH2-imidazol-4-yl,
`CHZOH, CH(OH)CH3, CH2((4'-OH)-Ph), CH28H, or lower
`cycloalkyl and R3 b is H, where R3 V is independently hydrogen
`or alkyl, which includes, but is not limited to, C1_20 alkyl,
`C1_10 alkyl, or C1_6 alkyl, R3” is iOR' or 7N(R3')2);
`(d) R4 is hydrogen, C1_10 alkyl, C1_10 alkyl optionally sub-
`stituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or
`halogen, C1_ 10 haloalkyl, C3_10 cycloalkyl, cycloalkyl alkyl,
`cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl,
`such as, pyridinyl, substituted aryl, or substituted heteroaryl,
`(e) R5 is H, a lower alkyl, CN, Vinyl, O-(lower alkyl),
`hydroxyl lower alkyl,
`i.e., 7(CH2)POH, where p is 1-6,
`including hydroxyl methyl (CHZOH), CHZF, N3, CHZCN,
`CHZNHz, CHZNHCH3, CH2N(CH3)2, alkyne (optionally
`substituted), or halogen, including F, Cl, Br, or I, with the
`provisos that when X is OH, base is cytosine and R6 is H, R5
`cannot be N3 and when X is OH, R6 is CH3 or CHZF and B is
`a purine base, R5 cannot be H;
`(i) R6 is H, CH3, CHZF, CHFZ, CF3, F, or CN;
`(g) X is H, OH, F, OMe, halogen, NHZ, or N3;
`(h)Y is OH, H, C1_4 alkyl, C2_4 alkenyl, C2_4 alkynyl, Vinyl,
`N3, CN, Cl, Br, F, 1, N02, OC(O)O(C1_4 alkyl), OC(O)O(C1_4
`alkyl), OC(O)O(C2_4 alkynyl), OC(O)O(C2_4 alkenyl),
`OC1_10 haloalkyl, O(aminoacyl), O(C1_10 acyl), O(C1_4
`alkyl), O(C2_4 alkenyl), S(Cl_4 acyl), S(Cl_4 alkyl), S(C2_4
`alkynyl), S(C2_4 alkenyl), SO(C1_4 acyl), SO(C1_4 alkyl),
`SO(C2_4 alkynyl), SO(C2_4 alkenyl), SOZ(C1_4 acyl), SO2
`(C1_4 alkyl), SOZ(C2_4 alkynyl), SOZ(C2_4 alkenyl), OS(O)2
`(Cl-4 acyl), OS(O)2(C1—4 alkyl), OS(O)2(C2—4 alkenyl), Nst
`NH(C1_4 alkyl), NH(C2_4 alkenyl), NH(C2_4 alkynyl),
`NH(C1_4 acyl), N(C1_4 alkyl)2, N(C1_18 acyl)2, wherein alkyl,
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`alkynyl, alkenyl and Vinyl are optionally substituted by N3,
`CN, one to three halogen (Cl, Br, F, 1), N02, C(O)O(C1_4
`alkyl), C(0)0(C1.4 alkyl), C(O)O(C2.4 alkynyl), C(0)0(C2.4
`alkenyl), O(C1_4 acyl), O(C1_4 alkyl), O(C2_4 alkenyl), S(C1_4
`acyl), S(Cl_4 alkyl), S(C2_4 alkynyl), S(C2_4 alkenyl), SO(C1_4
`acyl), SO(C1_4 alkyl), SO(C2_4 alkynyl), SO(C2_4 alkenyl),
`S02(C1—4 acyl), S02(C1—4 alkyl), S02(C2—4 alkynyl), S02(C2—4
`alkenyl), OS(O)2(C1_4 acyl), OS(O)2(C1_4 alkyl), OS(O)2
`(C2_4 alkenyl), NHZ, NH(C1_4 alkyl), NH(C2_4 alkenyl),
`NH(C2—4 alkynyl), NH(C1—4 acyl), N(C1—4 alkyl)2, N(C1—4
`acy1)2;
`the base is a naturally occurring or modified purine or
`pyrimidine base represented by the following structures:
`
`R9
`
`I
`
`\N
`N/KO
`
`0
`
`NH
`
`R8
`R7
`
`R8
`
`| kR7
`
`N
`
`0
`
`R10
`
`<2 I1
`
`N
`W‘NL‘NV‘
`
`N/
`
`R“
`
`b
`
`0
`
`d
`
`wherein
`
`Z is N or CRIZ;
`R7, R8, R9, R10, and R11 are independently H, F, Cl, Br, I,
`OH, OR', SH, SR', NHZ, NHR', NR'Z, lower alkyl of C1-C6,
`halogenated (F, Cl, Br, 1) lower alkyl of C1-C6, lower alkenyl
`of C2-C6, halogenated (F, Cl, Br, 1) lower alkenyl of C2-C6,
`lower alkynyl of C2-C6 such as CECH, halogenated (F, Cl,
`Br, 1) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halo-
`genated (F, Cl, Br, 1) lower alkoxy of C1-C6, COZH, COzR',
`CONH2,
`CONHR',
`CONR'Z,
`CH:CHCOzH,
`or
`CH:CHCOZR',
`wherein R'
`is an optionally substituted alkyl, which
`includes, but is not limited to, an optionally substituted C1_20
`alkyl, an optionally substituted C1_10 alkyl, an optionally sub-
`stituted lower alkyl; an optionally substituted cycloalkyl; an
`optionally substituted alkynyl of C2-C6, an optionally substi-
`
`IPR2018-00122
`
`Page 5 of311
`
`I-MAK 100 l
`
`IPR2018-00122
`
`Page 5 of 311
`
`I-MAK 1001
`
`
`
`US 8,334,270 B2
`
`7
`tuted lower alkenyl of C2-C6, or optionally substituted acyl,
`Which includes but is not limited to C(O) alkyl, C(O)(Cl_2O
`alkyl), C(O)(Cl_l0 alkyl), or C(O)(loWer alkyl) or alterna
`tively, in the instance of NR'2, each R' comprise at least one C
`atom that are joined to form a heterocycle comprising at least
`tWo carbon atoms; and
`R12 is H, halogen (including F, Cl, Br, I), OH, OR', SH, SR',
`NH2, NHR', NR'2, NO2 loWer alkyl of C l-C6, halogenated (F,
`Cl, Br, 1) lower alkyl of C1-C6, loWer alkenyl of C2-C6,
`halogenated (F, Cl, Br, 1) lower alkenyl of C2-C6, loWer alky
`nyl of C2-C6, halogenated (F, Cl, Br, 1) lower alkynyl of
`C2-C6, loWer alkoxy of C l-C6, halogenated (F, Cl, Br, 1) lower
`alkoxy of C l-C6, CO2H, CO2R', CONH2, CONHR', CONR'2,
`CH:CHCO2H, or CH:CHCO2R'; With the proviso that
`When base is represented by the structure c with R11 being
`hydrogen, R12 is not a: (i) iCECiH, (ii) iC:CH2, or
`(iii) iNOz.
`
`De?nitions
`
`The phrase “a” or “an” entity as used herein refers to one or
`more of that entity; for example, a compound refers to one or
`more compounds or at least one compound. As such, the
`terms “a” (or “an”), “one or more”, and “at least one” can be
`used interchangeably herein.
`The phrase “as de?ned herein above” refers to the ?rst
`de?nition provided in the SUMMARY OF THE INVEN
`TION
`The terms “optional” or “optionally” as used herein means
`that a subsequently described event or circumstance may but
`need not occur, and that the description includes instances
`Where the event or circumstance occurs and instances in
`Which it does not. For example, “optional bond” means that
`the bond may or may not be present, and that the description
`includes single, double, or triple bonds.
`The term “independently” is used herein to indicate that a
`variable is applied in any one instance Without regard to the
`presence or absence of a variable having that same or a dif
`ferent de?nition Within the same compound. Thus, in a com
`pound in Which R appears tWice and is de?ned as “indepen
`dently carbon or nitrogen”, both R’s can be carbon, both R’s
`can be nitrogen, or one R' can be carbon and the other nitro
`gen.
`The term “alkenyl” refers to an unsubstituted hydrocarbon
`chain radical having from 2 to 10 carbon atoms having one or
`tWo ole?nic double bonds, preferably one ole?nic double
`bond. The term “C2_N alkenyl” refers to an alkenyl comprising
`2 to N carbon atoms, Where N is an integer having the fol
`loWing values: 3, 4, 5, 6, 7, 8, 9, or 10. The term “C2_l0
`alkenyl” refers to an alkenyl comprising 2 to 10 carbon atoms.
`The term “C2_4 alkenyl” refers to an alkenyl comprising 2 to
`4 carbon atoms. Examples include, but are not limited to,
`vinyl, l-propenyl, 2-propenyl (allyl) or 2-butenyl (crotyl).
`The term “halogenated alkenyl” refers to an alkenyl com
`prising at least one of F, Cl, Br, and I.
`The term “alkyl” refers to an unbranched or branched
`chain, saturated, monovalent hydrocarbon residue containing
`1 to 30 carbon atoms. The term “C 1_ M alkyl” refers to an alkyl
`comprising 1 to M carbon atoms, Where M is an integer
`having the folloWing values: 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, l2, l3,
`l4, l5, l6, l7, l8, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or
`30. The term “C l_4 alkyl” refers to an alkyl containing 1 to 4
`carbon atoms. The term “loWer alkyl” denotes a straight or
`branched chain hydrocarbon residue comprising 1 to 6 carbon
`atoms. “Cl_2O alkyl” as used herein refers to an alkyl com
`prising l to 20 carbon atoms. “Cl_l0 alkyl” as used herein
`refers to an alkyl comprising 1 to 10 carbons. Examples of
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`alkyl groups include, but are not limited to, loWer alkyl groups
`include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-bu
`tyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
`The term (ar)alkyl or (heteroaryl)alkyl indicate the alkyl
`group is optionally substituted by an aryl or a heteroaryl
`group respectively.
`The term “cycloalkyl” refers to an unsubstituted or substi
`tuted carbocycle, in Which the carbocycle contains 3 to 10
`carbon atoms; preferably 3 to 8 carbon atoms; more prefer
`ably 3 to 6 carbon atoms (i.e., loWer cycloalkyls). Examples
`of cycloalkyl groups include, but are not limited to, cyclopro
`pyl, 2-methyl-cyclopropyl, cyclobutyl, cyclopentyl, and
`cyclohexyl.
`The term “cycloalkyl alkyl” refers to an additionally
`unsubstituted or substituted alkyl substituted by a loWer
`cycloalkyl. Examples of cycloalkyl alkyls include, but are not
`limited to, any one of methyl, ethyl, propyl, i-propyl, n-butyl,
`i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl,
`and octyl that is substituted With cyclopropyl, 2-methyl-cy
`clopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
`The term “cycloheteroalkyl” refers to an unsubstituted or
`substituted heterocycle, in Which the heterocycle contains 2
`to 9 carbon atoms; preferably 2 to 7 carbon atoms; more
`preferably 2 to 5 carbon atoms. Examples of cyclohet
`eroalkyls include, but are not limited to, aZiridin-2-yl, N-Cl_3
`alkyl-aZiridin-2-yl, aZetidinyl, N-Cl_3-alkyl-aZetidin-m'-yl,
`pyrrolidin-m'-yl, N-C1_3-alkyl-pyrrolidin-m'-yl, piperidin
`m'-yl, and N-Cl_3 -alkyl-piperidin-m'-yl, Where m' is 2, 3, or 4
`depending on the cycloheteroalkyl. Speci?c examples of
`N-Cl_3-alkyl-cycloheteroalkyls include, but are not limited
`to, N-methyl-aZiridin-2-yl, N-methyl-aZetidin-3-yl, N-me
`thyl-pyrrolidin-3 -yl, N-methyl-pyrrolidin-4-yl, N-methyl-pi
`peridin-2-yl, N-methyl-piperidin-3-yl, and N-methyl-piperi
`din-4-yl. In the instance of R4, the point of attachment
`betWeen the cycloheteroalkyl ring carbon and the oxygen
`occurs at any one of m'
`The term “heterocycle” refers to an unsubstituted or sub
`stituted heterocycle containing carbon, hydrogen, and at least
`one of N, O, and S, Where the C and N can be trivalent or
`tetravalent, i.e., sp2- or sp3-hybridiZed. Examples of hetero
`cycles include, but are not limited to, aZiridine, aZetidine,
`pyrrolidine, piperidine, imidaZole, oxaZole, piperaZine, etc.
`In the instance of piperaZine, as related to R10 for NR'2, the
`corresponding opposite nitrogen atom of the piperaZinyl is
`substituted by a loWer alkyl represented by the folloWing
`structure:
`
`loWer alkyl—N
`
`N—
`
`Preferably, the opposite nitrogen of the piperaZinyl is substi
`tuted by a methyl group.
`The term “halogenated alkyl” (or “haloalkyl”) refers to an
`unbranched or branched chain alkyl comprising at least one of
`F, Cl, Br, and I. The term “C 1_ M haloalkyl” refers to an alkyl
`comprising 1 to M carbon atoms that comprises at least one of
`F, Cl, Br, and I, Where M is an integer having the folloWing
`values: 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, l2, l3, l4, l5, l6, l7, l8,
`19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. “Cl_3
`haloalkyl” refers to a haloalkyl comprising 1 to 3 carbons and
`at least one of F, Cl, Br, and I. The term “halo