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WO2012006680A1 - 7, 9-nitrogen radical-4-oxo-4h-pyrido[l,2-a]pyrimidine-2-carboxylic acid benzylamide anti-virals - Google Patents

7, 9-nitrogen radical-4-oxo-4h-pyrido[l,2-a]pyrimidine-2-carboxylic acid benzylamide anti-virals Download PDF

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Publication number
WO2012006680A1
WO2012006680A1 PCT/AU2011/000894 AU2011000894W WO2012006680A1 WO 2012006680 A1 WO2012006680 A1 WO 2012006680A1 AU 2011000894 W AU2011000894 W AU 2011000894W WO 2012006680 A1 WO2012006680 A1 WO 2012006680A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
oxo
heterocyclic ring
compound
pyrido
Prior art date
Application number
PCT/AU2011/000894
Other languages
French (fr)
Inventor
David Ian Rhodes
John Joseph Deadman
Giang Thanh Le
Nicholas Andrew Van De Graff
Lu Long
Li Xinming
Feng Xiao
Yu Changjiang
Original Assignee
Avexa Limited
Shanghai Institute Of Organic Chemistry (Sioc)
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Publication date
Application filed by Avexa Limited, Shanghai Institute Of Organic Chemistry (Sioc) filed Critical Avexa Limited
Priority to CN2011800350758A priority Critical patent/CN103080113A/en
Priority to US13/807,420 priority patent/US20130178469A1/en
Priority to EP11806148.0A priority patent/EP2593460A4/en
Publication of WO2012006680A1 publication Critical patent/WO2012006680A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to novel bicyclic pyrimidinone compounds comprising nitrogen-containing substituents at the 7 and 9 positions for the treatment of viral infections, particularly HIV infections.
  • HIV human immunodeficiency virus
  • a feature of retrovirus replication includes the reverse transcription of the viral genome into proviral DNA and its integration into the host cell genome. These steps are required for HIV replication and are mediated by the virus encoded enzymes, reverse transcriptase and integrase respectively.
  • HIV infection follows a path of the virus particle binding to cell surface receptors and co-receptors resulting in fusion of the virus particle with the cell.
  • the contents of the virus are released into the cytoplasm where reverse transcription of the HIV genome occurs.
  • a double stranded proviral DNA copy is produced.
  • the proviral DNA is transported to the nucleus in a complex known as the pre integration complex (PIC) which contains integrase and other viral and possibly cellular proteins.
  • PIC pre integration complex
  • Once inside the nucleus the proviral DNA is integrated into the host cell genome via the action of integrase. Once integrated, transcription and translation of the viral genome can occur resulting in the production of viral proteins and a new viral R A genome.
  • the integration of the proviral genome into the host cell genome requires the action of an integrase which carries out this process in at least three steps, possibly four.
  • the first step involves the assembly of the viral genome into a stable nucleoprotein complex, secondly, processing of two nucleotides from the 3' termini of the genome to give staggered ends with free 3' OH residues and thirdly the transfer of these ends into the host cell genome.
  • the final step involves the gap filling and repair of the insertion site in the host genome. There is still some conjecture over whether the integrase performs this final step or whether it is carried out by cellular repair enzymes.
  • HIV infection can be treated with a number of inhibitors on the market which target reverse transcriptase, protease or entry into the cell. Treatment of HIV infection with these, or a combination of these, drugs is known to be an effective treatment for AIDS and similar diseases.
  • Shortcomings with the current inhibitors include the rapid emergence and increase incidence of resistance and numerous side effects and hence there is a need for new classes of inhibitors targeting proteins such as integrase.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkylC 3-6 cycloalkyl, C(0)Ci- 4 alkyl, C0 2 Ci -4 alkyl, -C(0)C(0)NR 6 R 7 , S0 2 C 1-4 alkyl, S0 2 NR 6 R 7 ; or R 1 and R 2 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0) 2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from C 1-4 alkyl, C 3 .
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, Ci -4 alkylC 3-6 cycloalkyl, C(0)C 1-4 alkyl, C0 2 C 1-4 alkyl, -C(0)C(0)NR 8 R 9 , S0 2 C alkyl, S0 2 NR 8 R 9 ; or R 3 and R 4 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0) 2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from C 3- 6cycloalkyl, halo, aryl, C(0)Ci -4 alkyl, S0 2 Ci -4 alkyl, S0 2 H, C0 2 H, C0 2 C 1-4 alkyl, NR 8 R 9 ; C ⁇ alkylNR ⁇ 9
  • R 5 is 0-3 substituents each of which is independently selected from the group consisting of halo, Cj.ioalkyl, C 2- i 0 alkenyl, -O-Cj.ioalkyl, C(0)C 1-4 alkyl C0 2 H, C0 2 Ci -4 alkyl, CN, NH 2 , N0 2 , CF 3; aryl, heteroaryl, alkylaryl, alkylheteroaryl, - O-alkylaryl.
  • the present inventors have further found that bicyclic pyrimidinones of Formula I in which the 9 position is substituted by a sulphonamide or cyclic sulphonamide show enhanced activity against the HIV virus. Accordingly, in a second aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof:
  • R and R are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkylC 3-6 cycloalkyl, C(0)C 1-4 alkyl, C0 2 Ci -4 alkyl, -C(0)C(0)NR 8 R 9 , S0 2 C alkyl, S0 2 NR 8 R 9 ; or R 1 and R 2 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0) 2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from C ⁇ alkyl, C 3-6 cycloalkyl, halo, aryl, C(0)Ci -4 alkyl, S0 2 C M alkyl, S0 2 H, C0 2 H, C0 2 Ci -4 alkyl, NR 6 R 7 , Ci -4
  • R and R are independently selected from the group consisting of
  • Y is selected from the group consisting of a bond, CH 2 , NH and NC 1-4 alkyl; and A is a bond or CH 2 ; wherein R 5 is 0-3 substituents each of which is independently selected from the group consisting of halo, C oalkyl, C 2-1 oalkenyl, -O-Q.ioalkyl, C(0)C 1-4 alkyl C0 2 H, C0 2 C alkyl, CN, NH 2 , N0 2 , CF 3, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -O-alkylaryl.
  • the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof.
  • the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, Cj. 4 alkyl, Ci -4 alkylC 3-6 cycloalkyl, C(0)C alkyl, C0 2 C 1-4 alkyl, -C(0)C(0)NR 6 R 7 , S0 2 C ]-4 alkyl, S0 2 NR 6 R 7 ; or R 1 and R 2 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0) 2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from Ci -4 alkyl, C 3-6 cycloalkyl, halo, aryl, C(0)C alkyl, S0 2 Ci -4 alkyl, S0 2 H, C0 2 H, C0 2 Ci -4 alkyl, NR 6 R 7 , C ⁇
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, C ⁇ alkyl, Ci -4 alkylC 3-6 cycloalkyl, C(0)C 1-4 alkyl, C0 2 C alkyl, -C(0)C(0)NR 8 R 9 , S0 2 Ci- alkyl, S0 2 NR 8 R 9 ; or R 3 and R 4 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0) 2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected f C 3-6 cycloalkyl, halo, aryl, C(0)C 1-4 alkyl, S0 2 C 1-4 alkyl, S0 2 H, C0 2 H, R 8 R 9 ; C 1-4 alkylNR 8 R 9 ; and further wherein one of the carbon
  • R 3 and R 4 when taken together with the attached nitrogen form a 4-7 membered heterocyclic ring and further wherein one of the carbon atoms in the heterocyclic ring is a carbonyl carbon, the carbonyl carbon is adjacent to the attached nitrogen.
  • R 3 and R 4 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0) 2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from C 1-4 alkyl; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon.
  • R 3 and R 4 are taken together with the attached nitrogen forms a 4-7 membered heterocyclic ring which contains at least one additional sulfur heteroatom in the S(0) 2 oxidation state adjacent to the attached nitrogen, and wherein the ring contains one additional nitrogen atom, wherein the additional nitrogen atom is optionally substituted with C 1-4 alkyl, preferably with methyl.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkylC 3-6 cycloalkyl, C(0)C 1-4 alkyl, C0 2 C 1-4 alkyl, -C(0)C(0)NR 6 R 7 , S0 2 Ci -4 alkyl, S0 2 NR 6 R 7 ; or R 1 and R 2 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0) 2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from Ci -4 alkyl, C3 -6 cycloalkyl, halo, aryl, C(0)C 1-4 alkyl, S0 2 C 1-4 alkyl, S0 2 H, C0 2 H, C0 2 C 1-4 alkyl, NR 6 R 7
  • R and R are independently selected from the group consisting of hydrogen and Ci ⁇ alkyl, and C 3-6 cycloalkyl; or R 6 and R 7 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N and O; wherein R 3 is C 1-4 alkyl and R 4 is S0 2 C M alkyl; or wherein NR 3 R 4 forms a cyclic sulphonamide of the formula II:
  • Y is selected from the group consisting of a bond, CH 2 , NH and NC]. 4 alkyl; and A is a bond or CH 2 ; wherein R 5 is 0-3 substituents each of which is independently selected from the group consisting of halo, Ct. ⁇ alkyl, C 2-10 alkenyl, -O-Ci-i 0 alkyl, C(0)Ci -4 alkyl C0 2 H, C0 2 C 1-4 alkyl, CN, NH 2 , N0 2 , CF 3, aryl, heteroaryl, alkylaryl, alkylheteroaryl, - O-alkylaryl.
  • R and R taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N or O, wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more Ci -4 alkyl substituents; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon.
  • R 1 and R 2 taken together with the attached nitrogen form morpholine.
  • R 1 and R 2 taken together with the attached nitrogen form piperazine
  • R 1 and R 2 taken together with the attached nitrogen form N-methyl piperazine.
  • R 5 is 1-3 substituents, more preferably R 5 is 1-2 substituents, even more preferably R 5 is 1 or 2 substituents.
  • R 5 is 1-2 substituents each independently selected from halo.
  • R 5 is 1-2 substituents each independently selected from CI or F.
  • R 5 is a fluorine substituent at the 4-position of the phenyl ring.
  • R 5 is two chlorine substituents at each of the 3 and 4-positions of the phenyl ring.
  • R 3 is and R 4 is S0 2 C 1 . 4 alkyl.
  • NR 3 R 4 forms a cyclic sulphonamide of the formula II:
  • Y is selected from the group consisting of a bond, C3 ⁇ 4, NH and NCj. 4 alkyl; and A is a bond or C3 ⁇ 4.
  • a and Y are each a bond the cyclic sulphonamide is a 4 membered ring.
  • the cyclic sulphonamide is a 5 membered ring.
  • the cyclic sulphonamide is a 6 membered ring.
  • NR'R 2 is selected from the group consisting of:
  • NR ⁇ 2 is selected from the group consisting of: even more preferably NR'R 2 is selected from the group consisting of:
  • NR 3 R 4 is selected from the consisting of:
  • NR 3 R 4 is selected from the group consisting of:
  • NR 3 R 4 forms a cyclic sulphonamide of the formula II:
  • Y is selected from the group consisting of a bond, CH 2 , NH and NCj.
  • NR 3 R 4 is selected from the group consisting of: more preferably NR 3 R 4 is:
  • 4-7 membered heterocyclic ring means a heterocyclic ring with 4, 5, 6 or 7 atoms or a range comprising any of two of those integers.
  • heterocyclic ring means a heterocyclic ring with 5, 6 or 7 atoms or a range comprising any of two of those integers.
  • a heterocyclic ring which contains zero to two additional heteroatoms means a heterocyclic ring that contains zero, one or two additional heteroatoms or a range comprising any of two of those integers.
  • halo refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).
  • alkyl either used alone or in compound terms such as NH(alkyl) or N(alkyl) 2 , refers to monovalent straight chain or branched hydrocarbon groups, having 1 to 3 (meaning 1, 2 or 3 carbon atoms or a range comprising any of two of those integers), 1 to 6 (meaning 1, 2, 3, 4, 5 or 6 carbon atoms or a range comprising any of two of those integers), or 1 to 10 carbon atoms (meaning 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or a range comprising any of two of those integers) as appropriate.
  • suitable alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3- methylbutyl, n-hexyl, 2-, 3- or 4-methylpentyl, 2-ethylbutyl, n-hexyl or 2-, 3-, 4-or 5- methylpentyl.
  • the term "Ci -4 alkyl” means an alkyl chain with 1, 2, 3 or 4 carbon atoms or a range comprising any of two of those integers.
  • Ci-ioalkyl means an alkyl chain with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or a range comprising any of two of those integers.
  • alkenyl refers to a straight chain or branched hydrocarbon groups having one or more double bonds between carbon atoms. Suitable alkenyl groups include, but are not limited to, ethenyl, allyl, propenyl, iso-propenyl, butenyl, pentenyl and hexenyl.
  • C 2- i 0 alkenyl means an alkenyl chain with 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or a range comprising any of two of those integers.
  • cycloalkyl refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 3-6 cycloalkyl means a cycloalkyl group with 3, 4, 5, or 6 carbon atoms or a range comprising any of two of those integers.
  • aryl refers to a C 6 -Cio aromatic hydrocarbon group, for example phenyl or naphthyl.
  • alkylaryl includes, for example, benzyl.
  • heterocycle when used alone or in compound words includes monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C 3-6 (which means 3, 4, 5, or 6 carbon atoms or a range comprising any of two of those integers), wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue.
  • bonds between atoms may be saturated or unsaturated.
  • Suitable heteroatoms include, O, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms.
  • heterocyclic groups may include pyrrolidinyl, piperidyl, piperazinyl, morpholino, quinolinyl, isoquinolinyl, thiomorpholino, dioxanyl, 2,2'-dimethyl-[l,3]-dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, cyclic sulfonamides such as sultams etc.
  • the term "sultam” is directed to cyclic sulfonamides in which the nitrogen and sulfur atoms of the sulfonamide group form part of the heterocyclic ring.
  • Preferred sultams include:
  • heteroaryl includes a 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S.
  • Suitable examples of heteroaryl groups include furanyl, thiophenyl, tetrazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, oxazolyl, oxadiazolyl, thioazolyl, thiodiazolyl etc.
  • the heteroaromatic ring may be fused to a 5- or 6-membered aromatic or heteroaromatic ring to form a bicyclic aromatic ring system eg benzofuran.
  • each alkyl, cycloalkyl, alkylaryl, aryl, heterocyclyl, or heteroaryl group may be optionally substituted with one or more of C Qalkyl, C 3 -C cycloalkyl, C 6 aryl, heterocyclyl, heteroaryl, Ci-C 3 alkylOH, alkylaryl, OH, OC,-C 3 alkyl, halo, CN, N0 2 , C0 2 H, C0 2 d-C 3 alkyl, CONH 2 , CONH(C !
  • an optionally substituted aryl group may be 4-methylphenyl or 4-hydroxyphenyl group, and an optionally substituted alkyl group may be 2-hydroxyethyl, trifluoromethyl, or difluoromethyl.
  • Each optional alkyl, cycloalkyl, alkylaryl, aryl, heterocyclyl, or heteroaryl substituent may also be optionally substituted.
  • Q-Csalkyl means an alkyl chain with 1, 2 or 3 carbon atoms or a range comprising any of two of those integers.
  • 0-3 substituents means 0, 1, 2 or 3 substituents or a range comprising any two of those integers.
  • optional substituents also include suitable nitrogen protecting groups (see “Protective Groups in Organic Synthesis” Theodora Greene and Peter Wuts, third edition, Wiley Interscience, 1999).
  • salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable derivative may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antibacterially active metabolite or residue thereof.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • Hydroxyl groups may be esterified with groups including lower alkyl carboxylic acids, such as acetic acid and 2,2-dimethylpropionic acid, or sulfonated with groups including alkyl sulfonic acids, such as methyl sulfonic acid.
  • This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I.
  • This invention also encompasses methods of treating or preventing a viral infection in a subject by administering prodrugs of compounds of the formula I.
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, hydroxy and carboxylic acid groups of compounds of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
  • Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I. It will also be recognised that the compounds of formula I may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form.
  • the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
  • the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof.
  • the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof, in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
  • the viral infection is a HIV or SIV infection.
  • the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • the compounds of the present invention may be administered by any suitable means, for example, parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non- aqueous solutions or suspensions).
  • parenterally such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non- aqueous solutions or suspensions).
  • compositions include those for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the compounds of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • a variety of other mammals can be treated according to the method of the present invention.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • the subjects treated in the above method are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female.
  • the term “effective amount” means the amount of the subject composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • treatment does not necessarily mean that the viral infection is completely cured.
  • treatment encompasses any reduction in the viral load and/or inhibition of replication in the subject being treated.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering a should be understood to mean providing a compound of the invention to the individual in need of treatment.
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles.
  • the combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0..5 to 5 or 5 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • Buffer A 100% water
  • Buffer B 100% acetonitrile
  • Buffer C 2% aqueous TFA
  • Buffer A 100% water
  • Buffer B 100% acetonitrile
  • Buffer C 2% aqueous TFA
  • Buffer A 100% water
  • Buffer B 100% acetonitrile
  • Buffer C 2% aqueous TFA
  • Buffer A 100% water
  • Buffer B 100% acetonitrile
  • Buffer C 2% aqueous TFA
  • Buffer A 100% water
  • Buffer B 100% acetonitrile
  • Buffer C 2% aqueous TFA
  • Buffer A 100% water
  • Buffer B 100% acetonitrile
  • Buffer C 2% aqueous TFA
  • Buffer A 100% acetonitrile
  • Buffer B 0.1 % aqueous TFA
  • Reagents and conditions (a) I 2 , HI0 4 .H 2 0, AcOH, H 2 S0 4 .H 2 0, 75°C, 7h, 70% (b) i) DAF, pTSOH, 100°C, 30h; ii) BnBr, K 2 C0 3 , DMF, 70°C, 16h, 16% 2-steps.
  • Step 1 Preparation of Preparation of 3-iodo-N 5 ,N 5 -dimethylpyridine -2, 5-diamine
  • Step 3 Preparation of methyl 7-(dimethylamino)-3-hydroxy-9-iodo-4- oxo-4H- pyrido[l,2-a]pyrimidine-2-carboxylate
  • This compound was prepared by adapting the procedure described in Example 1.2.
  • Example 3 The preparation of 3-Hydroxy-9-(5-methyl-l,l-dioxo-116- [l,2,5]thiadiazoIidin-2-yl)-7-(4-methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2- a]pyrimidine-2-carbox lic acid 4-fluoro-benzylamide
  • the cyclic sulfonamide starting material was prepared according to the literature: Eur. J. Med. Chem. 2007, 42 (9), 1176-1183.
  • the target compound was prepared by adapting the procedure described in Example 2.
  • the product from example 4.3 (100 mg, 0.15 mmol) was mixed in TFA (2 ml). The mixture was heated at 90°C for 3 hours. After cooling down to room temperature, the mixture was concentrated into dryness. The residue was sonicated in EA. The resulting solids were collected by filtration, washed with EA (2 ml x 2), dried in vacuo.
  • the crude TFA salt was mixed in methanol (2 ml) and then 4-fluorobenzylamine (100 mg, 0.80 mmol) was added. The mixture was heated at 50°C for 1 hour. After cooling down to room temperature, the solids were collected by filtration, washed with anhydrous methanol (2 ml x 3) and dried in vacuo to give the final target (44 mg. 61 %).
  • This target was prepared by adapting the procedure described in Example 4, except that TEA was used instead of 4-fluorobenzylamine in the de-salting step.
  • This compound was prepared by adapting the procedure described in example 4.1.
  • This compound was prepared by adapting the procedure described in example 4.2.
  • This compound was prepared by adapting the procedure described in example 4.3.
  • This compound was prepared by adapting the procedure described in example 4.4.
  • This compound was made by adapting the procedure described in Example 4, except that no de-salting was done.
  • This compound was prepared by adapting the procedure described in example 1.2.
  • This compound was prepared by adapting the procedure described in example 4.4, except that no de-salting was done.
  • the starting material 3-benzyloxy-7-dimethylamino-9-iodo-4-oxo-4H-pyrido[l,2- a]pyrimidine-2-carboxylic acid methyl ester was prepared by a similar method to the procedure described under the heading "Synthesis of the starting material 3-benzyloxy- 7-dimethylamino-9-iodo-4-oxo-4H-pyrido[l ,2-a]pyrimidine-2-carboxylic acid methyl ester" above.
  • This compound was prepared by adapting the procedure in Example 1.1, using the product of step 5 of the synthetic examples set out above.
  • Example 4.2 The product from Example 4.2 (60 mg, 0.1 1 mmol) was dissolved in TFA (5 ml) and heated at 70°C for 4h. TFA was removed in vacuo and then methanol (5 ml) was added. The solids were collected by filtration, washed with methanol and dried in vacuo to afford the desired compound (30 mg, 60%).
  • Example 8 Preparation of 7-(dimethylamino)-N-(4-fluorobenzyl)-3-hydroxy-4- oxo-9-(2-oxo-l,3-oxazinan-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
  • This compound was made by adapting the procedure described in example 7.3.
  • This target was made by adapting the procedure described in the Example 7, except that TEA was used for desalting of the deprotection product.
  • Example 9.1 Preparation of methyl 3-(benzyloxy)-9-(4-(tert-butoxycarbonyl)-2- oxopiperazin-l-yl)-7-(dimethylamino)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2- carboxylate
  • This compound was made by adapting the procedure described in example 7.3, except that TEA was used for desalting of the deprotection product.
  • This target was made by adapting the procedure described in the Example 7, except that TEA was used for desalting of the deprotection product.
  • This compound was made by adapting the procedure described in example 7.3, except that TEA was used for desalting of the deprotection product.
  • This target was made by adapting the procedure described in the Example 7, except that TEA was used for desalting of the deprotection product.
  • Example 11.2 Preparation of tert-butyl 4-(3-(benzyloxy)-2-(4-fluorobenzyl carbamoyl)-7-(3-methyImorpholino)-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)-3 oxopiperazine-l-carboxylate
  • This compound was made by adapting the procedure described in example 7.2.
  • Example 11.3 Preparation of N-(4-fluorobenzyl)-3-hydroxy-7-(3- methylmorpholino)-4-oxo-9-(2-oxopiperazin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2- carboxamide
  • This target was prepared by adapting the procedure described in Example 4.
  • This target was made by adapting the procedure described in Example 4, except that an extra step of reduction amination step was required.
  • Example 13.3 Preparation of 4-[3-Benzyloxy-7-(cyclopropyImethyl-methyl- amino)-2-(4-fluoro-benzylcarbamoyl)-4-oxo-4H-pyrido [1 ,2-a] pyrimidin-9-yl] -3- oxo-piperazine-l-carboxylic acid tert-butyl ester
  • Example 14.1 Preparation of 3-Benzyloxy-9-(4-tert-butoxycarbonyl-2-oxo piperazin-1 -yl)-7-(4-methyl-piperazin-l -yl)-4-oxo-4H-pyrido [ 1 ,2-a] py rimidine-2- carboxylic acid methyl ester
  • This target was prepared by adapting the procedure described in Example 4.
  • Example 15.2 Preparation of 4-[3-Benzyloxy-7-(4-tert-butoxycarbonyl- piperazin- l-yl)-2-(4-fluoro-benzylcarbamoyl)-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl]-3-oxo- piperazine-l-carboxylic acid tert-butyl ester
  • This compound was made by adapting the procedure described in example 4.3.
  • This target was made by adapting the procedure described in Example 7, except that TEA was used for desalting of the final target, and an extra step was required for the reductive animation.
  • This compound was made by adapting the procedure described in example 7.2.
  • This compound was made by adapting the procedure described in example 7.3, except that TEA was used for desalting.
  • This target was made by adapting the procedure described in the Example 4, except that TEA was used in the desalting step.
  • This compound was made by adapting the procedure described in example 4.3.
  • This compound was made by adapting the procedure described in example 4.4, except that TEA was used in desalting.
  • This target was made by adapting the procedure described in Example 4, except that TEA was used instead of 4-fluorobenzylamine in the desalting step.
  • This compound was made by adapting the procedure described in example 4.3.
  • This compound was made by adapting the procedure described in example 4.4, except that TEA was used instead of 4-fluorobenzylamine in the desalting step.
  • This target was made by adapting the procedure described in Example 4, except that TEA was used instead of 4-fluorobenzylamine in the desalting step.
  • This compound was made by adapting the procedure described in example 4.3.
  • This compound was made by adapting the procedure described in example 4.4, except that TEA was used instead of 4-fluorobenzylamine in the desalting step.
  • This compound was made by adapting the procedure described in example 2.3.
  • This compound was made by adapting the procedure described in example 2.4.
  • Example 21.3 The product from Example 21.3 (250 mg, 0.95 mmol), dimethyl 2,3-diacetoxyfumarate (369 mg, 1.42 mmol) and acetic acid (57 mg, 0.95 mmol) was dissolved in methanol (2 ml) and the mixture was heated at 70°C for 24h. After cooling down to room temperature, the solids were collected by filtration, washed with methanol and dried in vacuo to afford the desired compound (123 mg, 33%).
  • This compound was prepared by adapting the procedure in Example 21.5.
  • Example 24 Preparation of N-(4-fluorobenzyl)-9-(l, 3-propanesultam)-3- hydroxyl-7-morpholino-4-oxo-4H-py rido [1 ,2-a] pyrimidine-2-carboxamide.
  • Example 24.2 Preparation of 3-(l, 3-propanesultam)-5-morpholinopyridin amine.
  • Example 24.4 Preparation of N-(4-fluorobenzyI)-9-(l,3-propanesultam)-3- hydroxy-7-morpholino-4-oxo-4H-pyrido [ 1 ,2-a] py rimidine-2-carboxamide.
  • Example 27 Preparation of N-(4-fluorobenzyl)-9-(2-(dimethylamino)-2- oxoacetamido)-3-hydroxy-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2- carboxamide.
  • Example 27.1 Preparation of methyl 3-(benzyloxy)-9-(2-(dimethylamino)-2-oxo- acetamido)-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylate.
  • Example 27.2 Preparation of methyl 9-(2-(dimethylamino)-2- oxoacetamido)-3- hydroxy-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylate.
  • This compound was prepared by adapting the procedure described in Example 26.4.
  • Example 28.3 Preparation of N- (4-fluorobenzyl)-3-hydroxy-9- (N-methyl acetamido) -7-morpholino-4-oxo-4H-pyrido [1 , 2-a] pyrimidine-2-carboxamide
  • Example 29.1 Preparation of methyl 3-(benzyIoxy)-9-(3-methyl-2- oxoimidazolidin-l -yl)-7-morpholino-4-oxo-4H-py rido [ 1 ,2-a] pyrimidine-2- carboxylate
  • Example 29.1 The product from Example 29.1 (100 mg, 0.20 mmol) and aluminum trichloride (162 mg, 1.22 mmol) were mixed in dichloromethane (5 ml). The mixture was stirred at room temperature for 4h. Then water (10 ml) was added and the mixture was extracted with dichloromethane. The organic layers were washed with IN HCl three times, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue and (4-fluorophenyl)methanamine (33 mg, 0.26 mmol) were mixed in methanol (5 ml) and the mixture was heated at 70°C for 15h. After cooling down to room temperature, 6N HCl was added dropwise till the pH of the mixture was about 4. The solids were collected by filtration, washed with methanol and dried in vacuo to afford the desired compound (50 mg, 50%).
  • Example 31.3 Preparation of 7-Dimethylamino-3-hydroxy-9-(3-methyl-2-oxo- imidazolidin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
  • This compound was prepared by adapting the procedure described in example 2.1.
  • This compound was prepared by adapting the procedure described in example 2.2.
  • This compound was prepared by adapting the procedure described in example 2.4.
  • HuT-78 cells are seeded into 96 well microtitre plates at 50,000 cells per 50 ⁇ 1 per well in RF-10 containing 2 ⁇ g/mL polybrene (RF-10/2). Compounds are prepared to 4 x final concentration in RF-10/2, and 30 ⁇ , added to cells. Virus (40 in RF-10/2 containing 1600 pfu) is added to each well or 40 xL RF-10/2 for negative controls and for assaying compound cytotoxicity. After 24 hrs, an additional 90 ⁇ , of media or media containing 1 x compound is added to each well. At 4 days post infection, 100xL of media is removed from each well and replaced with 100 ⁇ of fresh media with or without compound.
  • RF-10/2 2 ⁇ g/mL polybrene
  • supematants Forty eight hours later supematants are harvested and levels of extracellular p24 determined. Supematants are diluted 1 in 10,000 and p24 levels assayed using the Vironostika p24 assay kit. EC50 is calculated as the concentration required to inhibit HIV p24 production to 50% that of no drug controls. In the tables below, this assay type is referred to as NL4-3.
  • Infectivity assays using reporter viruses derived from lentiviral vectors capable of a single round of infection were used to determine the activity (EC50) of compounds.
  • the DNA used to generate viruses for infection was the full-length HIV-1 genome which had been envelope-deleted.
  • a reporter gene (the firefly luciferase gene from Photinus pyralis) was cloned into the nef region of the HIV backbone for ease of assay readout.
  • Viruses were generated via liposomal transfection of the lentiviral-derived DNA backbone together with a vesicular stomatitis virus glycoprotein (VSV-G) expression plasmid into 293T cells. Culture supematants containing VSV-G pseudotyped virions were harvested 64h post transfection, clarified by centrifugation to remove cell debris, and frozen at -70°C until use.
  • Assay method :
  • 293FT cells were plated out at 12000 cells per well in CellView 96-well cell culture plates (Invitrogen) 16h prior to compound addition. Compounds were preincubated with cells for 4h at 37°C prior to the addition of virus sufficient to generate approximately 10000 Luciferase light units (as measured by the Victor Wallace luminometer) upon assaying using the Bright-GloTM reagent (Promega) according to the manufacturer's instructions at 48h post infection.
  • this assay is referred to as NLXLuc or HIV-Luc.
  • +++++ indicates value between 1 nM and 10 nM ++++ indicates value between 10 nM and 20 nM +++ indicates value between 20 nM and 100 nM ++ indicates value between 100 nM and 1 ⁇ + indicates value greater than 1 ⁇

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Abstract

The present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. Further provided is a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. A pharmaceutical composition or medicament comprising a compound of Formula I is also provided

Description

7, 9-nitrogen radical-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid benzylamide anti-virals FIELD OF THE INVENTION
The present invention relates to novel bicyclic pyrimidinone compounds comprising nitrogen-containing substituents at the 7 and 9 positions for the treatment of viral infections, particularly HIV infections.
BACKGROUND OF THE INVENTION
The retrovirus designated "human immunodeficiency virus" or "HIV" is the etiological agent of a complex disease that progressively destroys the immune system. This disease is known as acquired immune deficiency syndrome or AIDS. As at December 2005 an estimated 40 million people are living with HIV world wide and over 3 million deaths are occurring annually.
A feature of retrovirus replication includes the reverse transcription of the viral genome into proviral DNA and its integration into the host cell genome. These steps are required for HIV replication and are mediated by the virus encoded enzymes, reverse transcriptase and integrase respectively.
HIV infection follows a path of the virus particle binding to cell surface receptors and co-receptors resulting in fusion of the virus particle with the cell. The contents of the virus are released into the cytoplasm where reverse transcription of the HIV genome occurs. Through a series of steps a double stranded proviral DNA copy is produced. The proviral DNA is transported to the nucleus in a complex known as the pre integration complex (PIC) which contains integrase and other viral and possibly cellular proteins. Once inside the nucleus the proviral DNA is integrated into the host cell genome via the action of integrase. Once integrated, transcription and translation of the viral genome can occur resulting in the production of viral proteins and a new viral R A genome. These proteins and genome assemble at the cell surface and, depending on cell type, possibly other intracellular membranous compartments. Assembled particles then bud out from the cell and during, or soon after, this process mature into infectious HIV particles through the action of the viral protease.
The integration of the proviral genome into the host cell genome requires the action of an integrase which carries out this process in at least three steps, possibly four. The first step involves the assembly of the viral genome into a stable nucleoprotein complex, secondly, processing of two nucleotides from the 3' termini of the genome to give staggered ends with free 3' OH residues and thirdly the transfer of these ends into the host cell genome. The final step involves the gap filling and repair of the insertion site in the host genome. There is still some conjecture over whether the integrase performs this final step or whether it is carried out by cellular repair enzymes.
Currently HIV infection can be treated with a number of inhibitors on the market which target reverse transcriptase, protease or entry into the cell. Treatment of HIV infection with these, or a combination of these, drugs is known to be an effective treatment for AIDS and similar diseases. Shortcomings with the current inhibitors include the rapid emergence and increase incidence of resistance and numerous side effects and hence there is a need for new classes of inhibitors targeting proteins such as integrase.
We have previously described compounds for the treatment of viral infections, particularly HIV infections in WO 2008/077188, entitled "Bicyclic Pyrimidinones and Uses Thereof. We have now found a class of bicyclic pyrimidinones bearing two nitrogen-containing substituents that has not previously been exemplified. The compounds of this class show a significant and surprising advantage in activity over the compounds previously described.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000003_0001
I
R1 and R2 are each independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkylC3-6cycloalkyl, C(0)Ci-4alkyl, C02Ci-4alkyl, -C(0)C(0)NR6R7, S02C1-4alkyl, S02NR6R7; or R1 and R2 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from C1-4alkyl, C3.6cycloalkyl, halo, aryl, C(0)C1-4alkyl, S02C].4alkyl, S02H, C02H, C02C1-4alkyl, NR6R7 C1-4alkylNR6R7; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon; wherein R6 and R7 are independently selected from the group consisting of hydrogen and C]-4alkyl, and C3-6cycloalkyl; or R6 and R7 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N and O;
R3 and R4 are each independently selected from the group consisting of hydrogen, C1-4alkyl, Ci-4alkylC3-6cycloalkyl, C(0)C1-4alkyl, C02C1-4alkyl, -C(0)C(0)NR8R9, S02C alkyl, S02NR8R9; or R3 and R4 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from
Figure imgf000004_0001
C3-6cycloalkyl, halo, aryl, C(0)Ci-4alkyl, S02Ci-4alkyl, S02H, C02H, C02C1-4alkyl, NR8R9 ; C^alkylNR^9; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon; wherein R and R are each independently selected from the group consisting of hydrogen, C1-4alkyl and C3-6cycloalkyl; or R and R taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N and O;
R5 is 0-3 substituents each of which is independently selected from the group consisting of halo, Cj.ioalkyl, C2-i0alkenyl, -O-Cj.ioalkyl, C(0)C1-4alkyl C02H, C02Ci-4alkyl, CN, NH2, N02, CF3; aryl, heteroaryl, alkylaryl, alkylheteroaryl, - O-alkylaryl. The present inventors have further found that bicyclic pyrimidinones of Formula I in which the 9 position is substituted by a sulphonamide or cyclic sulphonamide show enhanced activity against the HIV virus. Accordingly, in a second aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof:
Figure imgf000005_0001
I wherein R and R are each independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkylC3-6cycloalkyl, C(0)C1-4alkyl, C02Ci-4alkyl, -C(0)C(0)NR8R9, S02C alkyl, S02NR8R9; or R1 and R2 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from C^alkyl, C3-6cycloalkyl, halo, aryl, C(0)Ci-4alkyl, S02CMalkyl, S02H, C02H, C02Ci-4alkyl, NR6R7 , Ci-4alkylNR6R7; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon;
f 1 * · wherein R and R are independently selected from the group consisting of
7
hydrogen and Ci-4alkyl, and C3-6cycloalkyl; or R and R taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N and O; wherein R3 is
Figure imgf000005_0002
and R4 is S02Ci-4alkyl; or wherein NR3R4 forms a cyclic sulphonamide of the formula II:
Figure imgf000006_0001
II wherein Y is selected from the group consisting of a bond, CH2, NH and NC1-4alkyl; and A is a bond or CH2; wherein R5 is 0-3 substituents each of which is independently selected from the group consisting of halo, C oalkyl, C2-1oalkenyl, -O-Q.ioalkyl, C(0)C1-4alkyl C02H, C02C alkyl, CN, NH2, N02, CF3, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -O-alkylaryl.
In a third aspect, the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof.
In a fourth aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
In a fifth aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof and a pharmaceutically acceptable carrier, diluent or excipient.
DETAILED DESCRIPTION OF THE INVENTION
In the specification below, where we refer to positions 7 and 9, this refers to the following sites on the compound of formula I:
Figure imgf000007_0001
I
In a first aspect the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000007_0002
I R1 and R2 are each independently selected from the group consisting of hydrogen, Cj. 4alkyl, Ci-4alkylC3-6cycloalkyl, C(0)C alkyl, C02C1-4alkyl, -C(0)C(0)NR6R7, S02C]-4alkyl, S02NR6R7; or R1 and R2 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from Ci-4alkyl, C3-6cycloalkyl, halo, aryl, C(0)C alkyl, S02Ci-4alkyl, S02H, C02H, C02Ci-4alkyl, NR6R7 , C^alkylNR^7; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon; wherein R6 and R7 are independently selected from the group consisting of hydrogen and C1-4alkyl, and C3-6cycloalkyl; or R6 and R7 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N and O;
R3 and R4 are each independently selected from the group consisting of hydrogen, C^alkyl, Ci-4alkylC3-6cycloalkyl, C(0)C1-4alkyl, C02C alkyl, -C(0)C(0)NR8R9, S02Ci- alkyl, S02NR8R9; or R3 and R4 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected f C3-6cycloalkyl, halo, aryl, C(0)C1-4alkyl, S02C1-4alkyl, S02H, C02H,
Figure imgf000008_0001
R8R9 ; C1-4alkylNR8R9; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon; wherein R and R are each independently selected from the group consisting of hydrogen, Ci-4alkyl and C3-6cycloalkyl; or R and R taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N and O; R5 is 0-3 substituents each of which is independently selected from the group consisting of halo, CMOalkyl, C2-i0alkenyl, -O-CM0alkyl, C(0)C1-4alkyl C02H, C02Ci-4alkyl, CN, NH2, N02, CF3> aryl, heteroaryl, alkylaryl, alkylheteroaryl, -O-alkylaryl.
In one embodiment, when R3 and R4 are taken together with the attached nitrogen form a 4-7 membered heterocyclic ring and further wherein one of the carbon atoms in the heterocyclic ring is a carbonyl carbon, the carbonyl carbon is adjacent to the attached nitrogen.
In one embodiment, R3 and R4 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from C1-4alkyl; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon.
In one embodiment, when R3 and R4 are taken together with the attached nitrogen form a 5-7 membered heterocyclic ring. The present inventors have further found that bicyclic pyrimidinones of Formula I in which the 9 position is substituted by a sulphonamide or cyclic sulphonamide show enhanced activity against the HIV virus. This is demonstrated in Tables 1 to 5 below which show biological activities for certain compounds of the present invention. Accordingly, in a preferred embodiment, R3 and R4 are taken together with the attached nitrogen forms a 4-7 membered heterocyclic ring which contains at least one additional sulfur heteroatom in the S(0)2 oxidation state adjacent to the attached nitrogen, and wherein the ring contains one additional nitrogen atom, wherein the additional nitrogen atom is optionally substituted with C1-4alkyl, preferably with methyl.
Further, in a second aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof:
Figure imgf000009_0001
wherein R1 and R2 are each independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkylC3-6cycloalkyl, C(0)C1-4alkyl, C02C1-4alkyl, -C(0)C(0)NR6R7, S02Ci-4alkyl, S02NR6R7; or R1 and R2 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from Ci-4alkyl, C3-6cycloalkyl, halo, aryl, C(0)C1-4alkyl, S02C1-4alkyl, S02H, C02H, C02C1-4alkyl, NR6R7 , Ci-4alkylNR6R7; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon;
7
wherein R and R are independently selected from the group consisting of hydrogen and Ci^alkyl, and C3-6cycloalkyl; or R6 and R7 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N and O; wherein R3 is C1-4alkyl and R4 is S02CMalkyl; or wherein NR3R4 forms a cyclic sulphonamide of the formula II:
Figure imgf000009_0002
II wherein Y is selected from the group consisting of a bond, CH2, NH and NC]. 4alkyl; and A is a bond or CH2; wherein R5 is 0-3 substituents each of which is independently selected from the group consisting of halo, Ct.^alkyl, C2-10alkenyl, -O-Ci-i0alkyl, C(0)Ci-4alkyl C02H, C02C1-4alkyl, CN, NH2, N02, CF3, aryl, heteroaryl, alkylaryl, alkylheteroaryl, - O-alkylaryl.
1 2
In one embodiment of the first and second aspects, when R and R are taken together with the attached nitrogen form a 4-7 membered heterocyclic ring and further wherein one of the carbon atoms in the heterocyclic ring is a carbonyl carbon, the carbonyl carbon is adjacent to the attached nitrogen.
In one embodiment of the first and second aspects, R and R taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N or O, wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more Ci-4alkyl substituents; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon.
In one embodiment of the first and second aspects, when R and R are taken together with the attached nitrogen form a 5-7 membered heterocyclic ring.
In one embodiment of the first and second aspects, R1 and R2 taken together with the attached nitrogen form morpholine.
In one embodiment of the first and second aspects, R1 and R2 taken together with the attached nitrogen form piperazine
In one embodiment of the first and second aspects, R1 and R2 taken together with the attached nitrogen form N-methyl piperazine. Preferably R5 is 1-3 substituents, more preferably R5 is 1-2 substituents, even more preferably R5 is 1 or 2 substituents.
In one embodiment of the first and second aspects, R5 is 1-2 substituents each independently selected from halo. Preferably, R5 is 1-2 substituents each independently selected from CI or F. In one embodiment, R5 is a fluorine substituent at the 4-position of the phenyl ring. In another embodiment, R5 is two chlorine substituents at each of the 3 and 4-positions of the phenyl ring.
In another embodiment of the second aspect, R3 is
Figure imgf000011_0001
and R4 is S02C1.4alkyl.
In one embodiment of the second aspect, NR3R4 forms a cyclic sulphonamide of the formula II:
Figure imgf000011_0002
II wherein Y is selected from the group consisting of a bond, C¾, NH and NCj. 4alkyl; and A is a bond or C¾. As understood by a person skilled in the art when A and Y are each a bond the cyclic sulphonamide is a 4 membered ring.
As understood by a person skilled in the art when A is a bond and Y is not a bond, or vice versa, the cyclic sulphonamide is a 5 membered ring.
As understood by a person skilled in the art when A is CH2 and Y is not a bond, the cyclic sulphonamide is a 6 membered ring.
In a preferred embodiment of the first and second aspects, NR'R2 is selected from the group consisting of:
Figure imgf000011_0003
In a more preferred embodiment of the first and second aspects, NR^2 is selected from the group consisting of:
Figure imgf000012_0001
even more preferably NR'R2 is selected from the group consisting of:
Figure imgf000012_0002
In a preferred embodiment of the first aspect, NR3R4 is selected from the consisting of:
Figure imgf000012_0003
In a more preferred embodiment of the first aspect, NR3R4 is selected from the group consisting of:
Figure imgf000012_0004
. In a preferred embodiment of the second aspect, NR3R4 forms a cyclic sulphonamide of the formula II:
Figure imgf000013_0001
II wherein Y is selected from the group consisting of a bond, CH2, NH and NCj.
4alkyl; and A is a bond or CH2.
In another preferred embodiment of the second aspect, NR3R4 is selected from the group consisting of:
Figure imgf000013_0002
more preferably NR3R4 is:
Figure imgf000013_0003
In a preferred embodiment the present invention comprises a compound of formula I selected from the group consisting of:
Figure imgf000013_0004
As understood by a person skilled in the art 4-7 membered heterocyclic ring means a heterocyclic ring with 4, 5, 6 or 7 atoms or a range comprising any of two of those integers.
As understood by a person skilled in the art 5-7 membered heterocyclic ring means a heterocyclic ring with 5, 6 or 7 atoms or a range comprising any of two of those integers. As understood by a person skilled in the art a heterocyclic ring which contains zero to two additional heteroatoms means a heterocyclic ring that contains zero, one or two additional heteroatoms or a range comprising any of two of those integers.
As used herein, the term "halo" or "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo). As used herein, the term "alkyl" either used alone or in compound terms such as NH(alkyl) or N(alkyl)2, refers to monovalent straight chain or branched hydrocarbon groups, having 1 to 3 (meaning 1, 2 or 3 carbon atoms or a range comprising any of two of those integers), 1 to 6 (meaning 1, 2, 3, 4, 5 or 6 carbon atoms or a range comprising any of two of those integers), or 1 to 10 carbon atoms (meaning 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or a range comprising any of two of those integers) as appropriate. For example, suitable alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3- methylbutyl, n-hexyl, 2-, 3- or 4-methylpentyl, 2-ethylbutyl, n-hexyl or 2-, 3-, 4-or 5- methylpentyl. As understood by a person skilled in the art, the term "Ci-4alkyl" means an alkyl chain with 1, 2, 3 or 4 carbon atoms or a range comprising any of two of those integers.
As understood by a person skilled in the art, the term "Ci-ioalkyl" means an alkyl chain with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or a range comprising any of two of those integers. As used herein, the term "alkenyl" refers to a straight chain or branched hydrocarbon groups having one or more double bonds between carbon atoms. Suitable alkenyl groups include, but are not limited to, ethenyl, allyl, propenyl, iso-propenyl, butenyl, pentenyl and hexenyl. As understood by a person skilled in the art, the term "C2-i0alkenyl" means an alkenyl chain with 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or a range comprising any of two of those integers.
The term "cycloalkyl" as used herein, refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As understood by a person skilled in the art, the term "C3-6cycloalkyl" means a cycloalkyl group with 3, 4, 5, or 6 carbon atoms or a range comprising any of two of those integers. The term "aryl" as used herein, refers to a C6-Cio aromatic hydrocarbon group, for example phenyl or naphthyl.
The term "alkylaryl" includes, for example, benzyl.
The term "heterocycle" when used alone or in compound words includes monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C3-6 (which means 3, 4, 5, or 6 carbon atoms or a range comprising any of two of those integers), wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue. The bonds between atoms may be saturated or unsaturated. Suitable heteroatoms include, O, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. Suitable examples of heterocyclic groups may include pyrrolidinyl, piperidyl, piperazinyl, morpholino, quinolinyl, isoquinolinyl, thiomorpholino, dioxanyl, 2,2'-dimethyl-[l,3]-dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, cyclic sulfonamides such as sultams etc. The term "sultam" is directed to cyclic sulfonamides in which the nitrogen and sulfur atoms of the sulfonamide group form part of the heterocyclic ring. Preferred sultams include:
Figure imgf000016_0001
The term "heteroaryl" includes a 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S. Suitable examples of heteroaryl groups include furanyl, thiophenyl, tetrazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, oxazolyl, oxadiazolyl, thioazolyl, thiodiazolyl etc. The heteroaromatic ring may be fused to a 5- or 6-membered aromatic or heteroaromatic ring to form a bicyclic aromatic ring system eg benzofuran.
Unless otherwise stated, each alkyl, cycloalkyl, alkylaryl, aryl, heterocyclyl, or heteroaryl group may be optionally substituted with one or more of C Qalkyl, C3-C cycloalkyl, C6aryl, heterocyclyl, heteroaryl, Ci-C3alkylOH, alkylaryl, OH, OC,-C3alkyl, halo, CN, N02, C02H, C02d-C3alkyl, CONH2, CONH(C!.C3alkyl), CON(d-C3alkyl)2, trifluoromethyl, NH2, NH(C,-C3alkyl) or N(Ci.C3alkyl)2. For example, an optionally substituted aryl group may be 4-methylphenyl or 4-hydroxyphenyl group, and an optionally substituted alkyl group may be 2-hydroxyethyl, trifluoromethyl, or difluoromethyl. Each optional alkyl, cycloalkyl, alkylaryl, aryl, heterocyclyl, or heteroaryl substituent may also be optionally substituted.
"Q-Csalkyl" means an alkyl chain with 1, 2 or 3 carbon atoms or a range comprising any of two of those integers.
As understood by a person skilled in the art "0-3 substituents" means 0, 1, 2 or 3 substituents or a range comprising any two of those integers.
Examples of optional substituents also include suitable nitrogen protecting groups (see "Protective Groups in Organic Synthesis" Theodora Greene and Peter Wuts, third edition, Wiley Interscience, 1999).
The salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
The term "pharmaceutically acceptable derivative" may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antibacterially active metabolite or residue thereof.
Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine. General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as "Handbook of Pharmaceutical salts" P.H.Stahl, C.G.Wermuth, 1st edition, 2002, Wiley-VCH.
Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
Hydroxyl groups may be esterified with groups including lower alkyl carboxylic acids, such as acetic acid and 2,2-dimethylpropionic acid, or sulfonated with groups including alkyl sulfonic acids, such as methyl sulfonic acid.
This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I. This invention also encompasses methods of treating or preventing a viral infection in a subject by administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, hydroxy and carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain. Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I. It will also be recognised that the compounds of formula I may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
The present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof.
The present invention provides the use of a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof, in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
Preferably, the viral infection is a HIV or SIV infection. The present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable derivative, salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
The compounds of the present invention may be administered by any suitable means, for example, parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non- aqueous solutions or suspensions).
Pharmaceutical formulations include those for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention, together with a conventional adjuvant, carrier or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
The subjects treated in the above method are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female.
The term "effective amount" means the amount of the subject composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. As would be understood by those skilled in the art of treating viral infections, and particularly HIV infections, the term "treatment" does not necessarily mean that the viral infection is completely cured. The term "treatment" encompasses any reduction in the viral load and/or inhibition of replication in the subject being treated. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
In the treatment or prevention of conditions which require HIV inhibition or HIV integrase enzyme inhibition an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0..5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
In order that the nature of the present invention may be more clearly understood preferred forms thereof will now be described by reference to the following non-limiting Examples.
EXAMPLES
Methods
HPLC conditions
All HPLC measurements were performed on a Waters 2690 Alliance System.
Method 1
Column:
Waters Exterra C18 Column (Part # 186000410) at 30° C, flow rate 0.4 mL/min, spectra measured at 254 nM
Buffers:
Buffer A: 100% water, Buffer B: 100% acetonitrile, Buffer C: 2% aqueous TFA
Gradient: (linear gradient curve 6)
5 min 2 min 0.25 min 2.75 min 85%A:10%B:5%C *■ 0%A:95%B:5%C *■ 0%A:95%B:5%C »- 85%A:10%B:5%C »- 85%A:10%B:5%C
Method 2
Column:
Merck CI 8 Chromolith Column (Part # 1.02129.0001) at 30° C, flow rate 4 mL/min, spectra measured at 254 nM
Buffers:
Buffer A: 100% water, Buffer B: 100% acetonitrile, Buffer C: 2% aqueous TFA
Gradient: (linear gradient curve 6)
2 min 1 min 0.15 min 0.85 min
92%A:3%B:5%C - 80%A:15%B:5%C *- 80%A:15%B:5%C »- 92%A:3%B:5%C—— *- 92%A:3%B:5%C Method 3
Column:
Merck CI 8 Chromolith Column (Part # 1.02129.0001) at 30° C, flow rate 4 mL/min, spectra measured at 254 nM
Buffers:
Buffer A: 100% water, Buffer B: 100% acetonitrile, Buffer C: 2% aqueous TFA
Gradient: (linear gradient curve 6)
2.3 min 0.7 min 0.15 min 0.85 min 85%A:10%B:5%C » 45%A:50%B:5%C »- 45%A:50%B:5%C 85%A:10%B:5%C * 85%A:10%B:5%C Method 4
Column:
Merck CI 8 Chromolith Column (Part # 1.02129.0001) at 30° C, flow rate 4 mL/min, spectra measured at 254 nM
Buffers:
Buffer A: 100% water, Buffer B: 100% acetonitrile, Buffer C: 2% aqueous TFA
Gradient: (linear gradient curve 6)
2.3 min 0.7 min 0.15 min 0.85 min 70%A:25%B:5%C 20%A:75%B:5%C »- 20%A:75%B:5%C »- 70%A:25%B:5%C »- 70%A:25%B:5%C
Method 5
Column:
Phenomenex Gemini CI 8 Column (Part # 344382-3) at 30° C, flow rate 0.4 mL/min, spectra measured at 254 nM
Buffers:
Buffer A: 100% water, Buffer B: 100% acetonitrile, Buffer C: 2% aqueous TFA
Gradient: (linear gradient curve 6) Method 6
Column:
Phenomenex Gemini C18 Column (Part # 344382-3) at 30° C, flow rate 0.4 mL/min, spectra measured at 254 nM
Buffers:
Buffer A: 100% water, Buffer B: 100% acetonitrile, Buffer C: 2% aqueous TFA
Gradient: (linear gradient curve 6)
4 min 1 min 0.25 min 4.75 min 69%A:30%B: 1 %C 39%A:60%B: 1 %C »39%A:60%B: 1 %C «- 69%A:30%B: 1 %C »- 69%A:30%B: 1 %C
Method 7
Column:
Waters Symmetry® CI 8 Column (Part No WAT045905) at 25° C, flow rate 1 mL/min, spectra measured at 254 nM
Buffers:
Buffer A: 100% acetonitrile, Buffer B: 0.1 % aqueous TFA
Gradient: (linear gradient curve 6)
5 min 10 min l Omin
10%A:90%B 10%A:90%B 100%A:0%B 100%A:0%B
SYNTHETIC EXAMPLES
Synthesis of starting material -Synthetic Scheme 1
Figure imgf000025_0001
Reagents and conditions (a) I2, HI04.H20, AcOH, H2S04.H20, 75°C, 7h, 70% (b) i) DAF, pTSOH, 100°C, 30h; ii) BnBr, K2C03, DMF, 70°C, 16h, 16% 2-steps.
Synthesis of the starting material 3-benzyloxy-7-dimethylamino-9-iodo-4-oxo-4H- pyrido[l,2-a]pyrimidine-2-carboxyIic acid methyl ester.
Step 1: Preparation of Preparation of 3-iodo-N5,N5-dimethylpyridine -2, 5-diamine
Figure imgf000025_0002
Paraformaldehyde (1 g, 33.3 mmol) was suspended in MeOH (30 ml) and refluxed for 2 h, then cooled to room temperature. Then 3-iodopyridine-2, 5-diamine (2 g, 8.5 mmol) was added to the above mixture, followed by NaCNBH3 (4.7 g, 76mmol) in small portions. After TLC plate indicated that the reaction was over, most of the solvent was removed under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography to give the desired product (0.8 g, 35% yield).
1H NMR (300 MHz, DMSO-d6) δ 2.72 (s, 6 H), 5.32 (s, 2H), 7.48 (d, J= 2.6 Hz, 1H), 7.62 (d, J= 2.6 Hz, 1H)
MS (ESf) m/z 264 (M+l) Step 2: Preparation of 3-Acetoxy-7-dimethylamino-9-iodo-4-oxo-4H -pyrido[l,2- a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000026_0001
The product of example 227 (100 mg, 0.38 mmol), p-toluenesulfonic acid (10 mg, 0.52 mmol), DAF (400 mg, 1.53 mmol) were mixed in MeOH (0.5 ml). The mixture was stirred at 80°C for 8 h, after which the solvent was evaporated and acetic anhydride (400 mg, 4 mmol) in pyridine (5 ml) was added. The mixture was refluxed for 1 h. After cooling to the room temperature, the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the desired product (20 mg, 12% yield).
1H NMR (300 MHz, DMSO-cf6) δ 2.31 (s, 3H), 3.03 (s, 6H), 3.90 (s, 3H), 8.00 (d, J= 2.4 Hz, 1H), 8.56 (d, J= 2.7 Hz, 1H)
MS (ESf) m/z 454 (M+23)
Step 3: Preparation of methyl 7-(dimethylamino)-3-hydroxy-9-iodo-4- oxo-4H- pyrido[l,2-a]pyrimidine-2-carboxylate
Figure imgf000026_0002
To a solution of the product of example 228 (15 mg, 0.035 mmol) in MeOH (5 ml) was added K2C03 (30 mg, 0.217 mmol). The mixture was refluxed for 5h and then extracted with dichloromethane and water. Organic layer was concentrated into dryness to give the titled product (12 mg, yield 80%).
1H NMR (300 MHz, DMSO-d6) δ 2.97 (s, 6H), 3.89 (s, 3H), 7.84 (d, J 2.3 Hz, lH), 8.35 (d, J= 2.5 Hz, 1H), 10.18 (s, 1H) Step 4: Preparation of 3-Benzyloxy-7-dimethyIamino- 9-iodo-4-oxo-4H- pyrido [1, 2-a] pyrimidine-2-carboxylic acid methyl ester
Figure imgf000027_0001
The title compound was prepared by adapting methods described in example 8.1-8.2 of International Patent Application Publication No. WO2008/077188 to Avexa Limited using the product of example 65.
1H NM (300 MHz, DMSO-d6) δ 3.02 (s, 6H), 3.84 (s, 3H), 5.17 (s, 2H), 7.28-7.48 (m, 5H), 8.05 (d, J= 2.7 Hz, 1H), 8.49 (d, J- 2.7 Hz, 1H)
Example 1: Preparation of N-(4-fluorobenzyl)-3-hydroxy-7-(4-methylpiperazin-l- yl)-4-oxo-9-(2-oxo-l,3-oxazinan-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000027_0002
[l,3]Oxazinan-2-one was made according to the literature: Journal of Heterocyclic Chemistry, 1966, 3(1), 84-89, using starting material described in synthetic scheme 1. Example 1.1: Preparation of Methyl-3-(benzyloxy)-7-bromo-4-oxo-9-(2-oxo-l,3- oxazinan-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylate
Figure imgf000028_0001
The mixture of [l,3]Oxazinan-2-one (235 mg, 2.23 mmol), methyl 3- (benzyloxy)-7- bromo-9-iodo-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylate (1 g, 1.94 mmol), Pd2dba3 (179 mg, 0.19 mmol), xantphos (224 mg, 0.39 mmol) and Cs2C03 (950 mg, 2.9 mmol) were mixed in dioxane (10 ml). The mixture was heated under N2 atmosphere at 90°C for 6h. After cooling down to room temperature, dioxane was removed in vacuo. The residue was purified by column chromatography (EA/PE = 1/1) to give the desired product (350 mg, 40%).
1H NMR (300 M Hz, CDC13) δ 9.08 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.55- 7.45 (m, 2H), 7.44 - 7.31 (m, 3H), 5.34 (s, 2H), 4.53 (t, J = 5.1 Hz, 2H), 3.91 (s, 3H), 3.84-3.64 (m, 2H), 2.34-2.19 (m, 2H) .
MS (ESI+) m/z 488 (M[Br79]+l), 490 (M[Br81]+i) Example 1.2: Preparation of Methyl-3-(benzyloxy)-7-(4-methylpiperazin-l-yl) -4- oxo-9-(2-oxo-l,3-oxazinan-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylate
Figure imgf000028_0002
The product from example 1.1 (300 mg, 0.61 mmol), 1-methylpiperazine (123 mg, 1.23 mmol), Pd2dba3 (56 mg, 0.06 mmol), xantphos (69 mg, 0.12 mmol) and Cs2C03 (298 mg, 0.92 mmol) were mixed in dioxane (3 ml). The mixture was heated at 85°C under N2 atmosphere for 6h. After cooling down to room temperature, dioxane was removed in vacuo. The residue was purified by column chromatography (DCM/MeOH = 20/1) to give the desired product (120 mg, 33%) . 1H NMR (300 M Hz, CDC13) δ 9.08 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.59-7.49 (m, 2H), 7.44 - 7.31 (m, 3H), 5.30 (s, 2H), 4.53 (t, J = 4.8 Hz, 2H), 3.89 (s, 3H), 3.84-3.70 (m, 2H), 3.36-3.20 (m, 4H), 2.67-2.51 (m, 4H), 2.38 (s, 3H), 2.34-2.18 (m, 2H). MS (ESI+) m/z 508 (M+l)
Example 1.3: Preparation of MethyI-3-acetoxy-7-(4-methylpiperazin-l-yl)-4-oxo- 9-(2-oxo-l ,3-oxazinan -3-y 1) -4H-pyrido [1 ,2-a] pyrimidine-2-carboxylate
Figure imgf000029_0001
The solution of the product from example 1.2 (120 mg, 0.24 mmol) in TFA (2 ml) was heated at 65°C for 2h. After cooling down to room temperature, TFA was removed in vacuo to give the crude product methyl 3-hydroxy-7- (4-methylpiperazin-l-yl)-4-oxo- 9- (2-oxo-l,3-oxazinan-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylate, which was used directly in the acetylation step.
To the solution of the crude product from last step and TEA (119 mg, 1.18 mmol) in DCM (3 ml), was added AcCl (185 mg, 2.36 mmol) dropwise. The mixture was stirred at room temperature for 1 h, and then water was added, followed by EA. The organic phase was washed with water 3 times, dried over Na2S04, and concentrated in vacuo. The residue was purified by column chromatography (DCM / MeOH = 20 /1) to give the desired product (62 mg, two step total 60%) . Ή NMR (300 M Hz, CDC13) δ 8.30 (s, 1H), 8.79 (s, 1H), 4.56 (t, J = 4.8 Hz, 2H), 3.95 (s, 3H), 3.89-3.73 (m, 2H), 3.48-3.28 (m, 4H), 2.80-2.58 (m, 4H), 2.46 (s, 3H), 2.41 (s, 3H), 2.31 (t, J = 4.9, 2H) .
MS (ESI+) w/z 460 (M+l) Example 1.4: Preparation of N-(4-fluorobenzyI)-3-hydroxy-7-(4-methylpiperazin- l-y])-4-oxo-9-(2-oxo-l,3-oxazinan-3-yl)-4H-pyrido[l,2-a]pyrimidine-2- carboxamide
Figure imgf000030_0001
The solution of the product from example 1.3 (60 mg, 0.13 mmol) and (4- fluorophenyl)methan amine (84 mg, 0.67 mmol) in MeOH (1 ml) was heated at 65°C for 4 h. After cooling down to room temperature, MeOH was removed in vacuo to give the crude product, which was further purified on preparative HPLC using 0.1 % formic acid as eluent to give the desired product (20 mg, 30%). 1H NMR (300 M Hz, CDC13) δ 8.17 (m, 1H), 7.86 (m, 1H), 7.52 (m, 1H), 7.46-7.34 (m, 2H), 7.17-7.01 (m, 2H), 4.73-4.46 (m, 2H), 4.37-4.07 (m, 2H), 3.74-3.52 (m, 2H), 3.40- 3.17 (m, 4H), 2.78-2.59 (m, 4H), 2.43 (s, 3H), 2.15-1.89 (m, 2H) .
MS (ESI+) w/z 51 1 (M+l)
Example 2: Preparation of 3-Hydroxy-7-(4-methyl-piperazin-l-yl)-4-oxo-9-(2-oxo- pyrroIidin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000030_0002
Example 2.1: Preparation of 3-Benzyloxy-7-bromo-4-oxo-9-(2-oxo-pyrrolidin-l yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000031_0001
Compound prepared as set out in step 1 of the scheme for example 2, the crude product was used in the next step.
MS (ESI+) m/z 472 (M[Br79]+l), 474 (M[Br81]+l)
Example 2.2: Preparation of 3-Benzyloxy-7-(4-methyl-piperazin-l-yl)-4-oxo-9-(2- oxo-pyrrolidin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxyIic acid methyl ester
Figure imgf000031_0002
This compound was prepared by adapting the procedure described in Example 1.2.
Ή NMR (300 MHz, CDC13) δ 2.17-2.27 (m, 2H), 2.39 (s, 3H), 2.55-2.75 (m, 6H), 3.25-3.35 (m, 4H), 3.89 (s, 3H), 4.17 (t, J = 7.1 Hz, 2H), 5.30 (s, 2H), 7.30-7.42 (m, 3H), 7.46-7.56 (m, 2H), 7.78 (d, J= 2.5 Hz, 1H ), 8.29 ( d, J= 2.4 Hz, 1H).
MS (ESI+) m/z 492 (M+l)
Example 2.3: Preparation of Trifluoro-acetate4-[3-hydroxy-2-methoxycarbonyl - 4-oxo-9-(2-oxo-py rrolidin-1 -yI)-4H-py rido [1 ,2-a] pyrimidin-7-yl] -1 -methyl- piperazin-l-iiim
Figure imgf000032_0001
The mixture of the product from example 2.2 (300 mg, 0.611 mmol) in TFA (5 ml) was heated to reflux for 5 h. After cooling down to room temperature, the mixture was concentrated in vacuo. The resulting residue was recrystallized from a mixed solvent of PE/EA/MeOH (10/3/1) to give the title compound (200 mg, 81.6%).
1H NMR (300 MHz, DMSO-d6) δ 2.08-2.22 (m, 2H), 2.45-2.60 (m, 2H, overlap), 2.87 (s, 3H), 2.95-3.95 (m, 8H), 3.88 (s, 3H), 3.97 (t, J = 7.0 Hz, 2H), 7.86 (d, J = 2.5 Hz, 1H), 8.04 (d, J= 2.3 Hz, 1H), 9.80-10.02 (brs, 1H), 10.30 (s, 1H)
MS (ESI+) m/z 402 (M-TFA+1)
Example 2.4: Preparation of 3-Hydroxy-7-(4-methyl-piperazin-l-yl)-4-oxo-9-(2- oxo-pyrrolidin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzy lamide
Figure imgf000032_0002
The product from example 2.3 (100 mg, 0.25 mmol) was suspended in MeOH (5 ml) under N2 atmosphere, and then 4-fluorobenzylamine (lOOmg, 1.00 mmol) was added. The mixture was heated at 75°C for 15hours. After cooling down to room temperature, the mixture was concentrated in vacuo. The residue was sonicated in MeOH (2 ml). The resulting solids were collected by filtration, washed with cold methanol and dried in vacuo to afford the desired product as yellow solids (70mg, 57%). 1H NMR (300 MHz, CDC13) δ 2.00-2.15 (m, 2H), 2.37 (s, 3Η), 2.47 (t, J- 8.2 Hz, 2H), 2.54-2.65 (m, 4H), 3.18-3.30 (m, 4H), 3.85 (t, J= 6.9 Hz, 2H), 4.60 (d, J= 5.9 Hz, 2H), 7.08 (t, J= 8.9 Hz, 2H), 7.30-7.40 (m, 2H), 7.51 (d, J= 2.6 Hz, 1H), 7.82 (t, J= 5.4 Hz, 1H), 8.15 (d, J= 2.6 Hz, 1H), 11.65-11.90 (brs, 1H). MS (ESI+) w/z 495 (M+l)
HPLC 98.4 %
Example 3: The preparation of 3-Hydroxy-9-(5-methyl-l,l-dioxo-116- [l,2,5]thiadiazoIidin-2-yl)-7-(4-methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2- a]pyrimidine-2-carbox lic acid 4-fluoro-benzylamide
Figure imgf000033_0001
Figure imgf000033_0002
The cyclic sulfonamide starting material was prepared according to the literature: Eur. J. Med. Chem. 2007, 42 (9), 1176-1183. The target compound was prepared by adapting the procedure described in Example 2.
Example 3.1: Preparation of 3-Benzyloxy-7-bromo-9-(5-methyI-l,l-dioxo-116- [l,2,5]thiadiazolidin-2-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000034_0001
Compound prepared as set out in step 1 of the scheme for example 3.
1H NMR (300 MHz, CDC13) δ 2.89 (s, 3H), 3.57(t, J= 6.6Hz, 2H), 3.89 (s, 3H), 4.37 (t, J = 6.3 Hz, 2H,), 5.34 (s, 2H), 7.32-7.42 (m, 3H), 7.48 (dd, J - 8.4,1.8 Hz, 2H), 7.97(d, J= 2.3 Hz, 1H), 8.98 (d, J= 1.8Hz, 1H)
MS (ESI+) m/z 523 (M[Br79]+l), 525 (M[Br81]+l) Example 3.2: Preparation of 3-Benzyloxy-9-(5-methyl-l,l-dioxo-116-
[l,2,5]thiadiazolidin-2-yl)-7-(4-methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2- a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000034_0002
Compound prepared as set out in step 2 of the scheme for example 3. 1H NMR (300 MHz, CDCI3) δ 2.38 (s, 3H), 2.55-2.65 (m, 4H), 2.89 (s, 3H), 3.24-3.35 (m, 4H), 3.59 (t, J = 6.4Hz, 2H), 3.88 (s, 3H), 4.39 (t, J = 6.7 Hz, 2H), 5.30(s, 2H), 7.30-7.45 (m, 3H), 7.47-7.57 (m, 2H), 7.92 ( d, J= 2.3Hz, 1H), 8.25 (d, J= 2.1Hz, 1H).
MS (ESr1") m/z 543 (M+l) Example 3.3: Preparation of Trifluoro-acetate4-[3-hydroxy-2-methoxycarbonyl-9-
(5-methyl-l,l-dioxo-116-[l,2,5]thiadiazolidin-2-yI)-4-oxo-4H-pyrido[l,2- a] py rimidin-7-y I] - 1 -methy 1-piperazin- 1 -ium ;
Figure imgf000035_0001
Compound prepared as set out in step 3 of the scheme for example 3, and the crude product was used in the next step.
MS (ESI+) m/z 453 (M-TFA+1).
Example 3.4: Preparation of 3-Hydroxy-9-(5-methyl-l,l-dioxo-116-[l,2,5] thiadiazolidin-2-yl)-7-(4-methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2- a]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide
Figure imgf000035_0002
Compound prepared as set out in step 4 of the scheme for example 3, using the product of example 3.3.
1H NMR (300 MHz, CDC13) δ 2.38 (s, 3Η), 2.53-2.67 (m, 4H), 2.76 (s, 3H), 3.18-3.30 (m, 4H), 3.50 (t, J = 5.8 Hz 2H,), 3.94 (t, J = 5.8 Hz, 2H), 4.59 (t, J = 5.4 Hz, 2H), 6.95-7.11 (m, 3H), 7.32-7.44 (m, 2H), 8.06 (d, J = 1.6 Hz, 1H), 9.38-9.50 (brs ,1H), 12.15-12.35 (brs, 1H).
MS (ESI+) w/z 546 (M+l)
HPLC=96.7% Example 4: Preparation of 3-Hydroxy-4-oxo-9-(2-oxo-piperazin-l-yl)-7- pyrroIidin-l-yl-4H-py rido [ 1 ,2-a] py rimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000036_0001
Example 4.1: Preparation of 3-Benzyloxy-7-bromo-9-(4-tert-butoxycarbonyl-2- oxo-piperazin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000036_0002
boc
This compound was prepared as set out in step 1 of the scheme for example 4. Ή NMR (300 MHz, CDC13) δ 9.09 (d, J= 2.1 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.53- 7.43 (m, 2H), 7.42-7.31 (m, 3H), 5.33 (s, 2H), 4.30 (s, 2H), 3.93-3.72(m, 7H), 1.51 (s, 9H)
MS (ESI+) m/z 587 (M[Br79]+l), 589 (M[Br81]+l) Example 4.2: Preparation of 3-Benzyloxy-9-(4-tert-butoxycarbonyl-2-oxo- piperazin-l-yI)-4-oxo-7-pyrrolidin-l-yl-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000037_0001
oc This compound was prepared by adapting the procedure described in Example 1.2.
Ή- NMR (300 MHz, CDC13) δ 8.06 (d, J = 2.0 Hz, 1H), 7.48-7.56 (m, 2H), 7.43 (d, J =2.0 Hz, 1H), 7.30-7.41 (m, 3H), 5.29 (s, 2H), 4.32 (s, 2H), 3.70-3.96 (m, 7H), 3.31- 3.49 (m, 4H), 2.01-2.15 (m, 4H), 1.51 (s, 9H)).
MS (ESI+) m/z 578 (M+l) Example 4.3: Preparation of 4-[3-Benzyloxy-2-(4-fluoro-benzylcarbamoyl)-4-oxo- 7-pyrroIidin-l -yl-4H-py rido [1 ,2-a] pyrimidin-9-yl] -3-oxo-piperazine- 1 -carboxylic acid tert-butyl ester
Figure imgf000037_0002
boc F
The product from Example 4.2 (224 mg, 0.39 mmol) 4-fluorobenzylamine (3.50 g, 28.00 mmol) were mixed in methanol (4 ml). The mixture was heated at 50°C for 20 hours. After cooling down to room temperature, the mixture was diluted with DCM (20 ml), washed with 0.5 N HC1 (10 ml x 2) and water (20 ml x 3) successively, dried over Na2S04 and concentrated in vacuo. The residue was purified on column chromatography using a mixed solvent EA/PE (1 : 1) as eluent to give the desired product (202 mg, 77 %). 1H NMR (300 MHz, CDC13) δ 8.02 (d, J = 2.2 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.50-7.44 (m, 2H), 7.42 (d, J = 2.7 Hz, 1H), 7.38-7.30 (m, 3H), 7.24 - 7.20 (m, 2H), 7.05 (t, J = 8.7 Hz, 2H), 5.30 (s, 2H), 4.52 (d, J = 5.9 Hz, 2H), 4.23 (s, 2H), 3.85-3.75 (m, 4H), 3.50-3.30 (m, 4H), 2.15-2.05 (m, 4H), 1.51 (s, 9H). MS (ESI+) w/z 671 (M+l)
Example 4.4: Preparation of 3-Hydroxy-4-oxo-9-(2-oxo-piperazin-l-yl)-7- pyrrolidin-l-yl-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000038_0001
The product from example 4.3 (100 mg, 0.15 mmol) was mixed in TFA (2 ml). The mixture was heated at 90°C for 3 hours. After cooling down to room temperature, the mixture was concentrated into dryness. The residue was sonicated in EA. The resulting solids were collected by filtration, washed with EA (2 ml x 2), dried in vacuo. The crude TFA salt was mixed in methanol (2 ml) and then 4-fluorobenzylamine (100 mg, 0.80 mmol) was added. The mixture was heated at 50°C for 1 hour. After cooling down to room temperature, the solids were collected by filtration, washed with anhydrous methanol (2 ml x 3) and dried in vacuo to give the final target (44 mg. 61 %).
1H NMR (300 MHz, CDC13) δ 1 1.75-1 1.40 (brs, 1H), 8.13 (t, J = 5.1 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.41-7.32 (m, 2H), 7.30 (d, J = 2.6 Hz, 1H), 7.08 (t, J - 8.6 Hz, 2H), 4.59 (d, J = 5.4 Hz, 2H), 3. 83-3.45 (m, 4H), 3.43-3.29 (m, 4H), 3.18-2.97 (brs, 2H), 2.15-1.94 (m, 4H).
MS (ESf) m/z 481 (M+l), 503(M+23)
HPLC 97.48 % Example 5: Preparation of 3-Hydroxy-9-(methanesulfonyl-methyl-amino)-7-(4- methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2-a)pyrimidine-2-carboxylic acid 4- fluoro-benzylamide
Figure imgf000039_0001
This target was prepared by adapting the procedure described in Example 4, except that TEA was used instead of 4-fluorobenzylamine in the de-salting step.
Example 5.1: Preparation of 3-Benzyloxy-7-bromo-9-(methanesulfonyI-methyl- amino)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000039_0002
This compound was prepared by adapting the procedure described in example 4.1.
Ή NMR (300 MHz, CDC13) δ 9.07 (d, J=2.1 Hz, IH), 7.84 (d, J=2.1 Hz, IH), 7.52 - 7.45 (m, 2H), 7.42 - 7.33 (m, 3H), 5.35 (s, 2H), 3.89 (s, 3H), 3.39 (s, 3H), 3.22 (s, 3H).
MS (ESI+) m/z 496 (M[Br79]+l), 498 (M[Br81]+l) Example 5.2: Preparation of 3-Benzyloxy-9-(methanesulfonyl-methyl-amino)-7-(4- methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000040_0001
This compound was prepared by adapting the procedure described in example 4.2.
Ή NMR (300 MHz, CDC13) δ 8.30 (d, J=2.4 Hz, IH), 7.77 (d, J=2.4 Hz, IH), 7.49- 7.56 (m, 2H), 7.41 - 7.31 (m, 3H), 5.31 (s, 2H), 3.88 (s, 3H), 3.41 (s, 3H), 3.30-3.26 (m, 4H), 3.20 (s, 3H), 2.67-2.63 (m, 4H), 2.41 (s, 3H).
MS (ESI+) m/z 516(M+l) Example 5.3: Preparation of 3-BenzyIoxy-9-(methanesulfonyl-methyl-amino)-7-(4- methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4- fluoro-benzylamide
Figure imgf000040_0002
This compound was prepared by adapting the procedure described in example 4.3.
]H NMR (300 MHz, CDC13) δ 8.24 (d, J=2.4 Hz, IH), 8.10 (t, J=5.4 Hz, IH), 7.75 (d, J=2.4 Hz, IH), 7.39 - 7.27 (m, 5H), 7.16-7.20 (m, 2H), 7.09 - 6.96 (m, 2H), 5.30 (s, 2H), 4.48 (d, J=5.7 Hz, 2H), 3.43 (s, 3H), 3.37 (s, 3H), 3.33 - 3.24 (m, 4H), 2.63-2.59 (s, 4H), 2.38 (s, 3H).
MS (ESI+) m/z 609(M+l) Example 5.4: Preparation of 3-Hydroxy-9-(methanesulfonyl-methyl-amino)-7-(4- methyl-piperazin-1 -y l)-4-oxo-4H-pyrido [1 ,2-a] pyrimidine-2-carboxylic acid 4- fluoro-benzylamide
Figure imgf000041_0001
This compound was prepared by adapting the procedure described in example 4.4.
1H NMR (300 MHz, CDC13) δ 8.44 (t, J=6.3 Hz, IH), 8.15 (d, J=2.4 Hz, IH), 7.53 (d, J=2.4 Hz, IH), 7.37 - 7.29 (m, 2H), 7.05 (t, J=8.7 Hz, 2H), 4.61 (d, J=6.3 Hz, 2H), 3.26 (s, 7H), 2.99 (s, 3H), 2.62 (s, 4H), 2.39 (s, 3H).
MS (ESI+) w/z 519(M+l) Example 6: Preparation of Trifluoro-acetate 4-[2-(4-fluoro-benzylcarbamoyl)-3- hydroxy-9-(methanesulfonyl-methyl-amino)-4-oxo-4H-pyrido[l,2-a]pyrimidin-7- yl]-l-isopropyl-piperazin-l-ium;
This compound was made by adapting the procedure described in Example 4, except that no de-salting was done.
Figure imgf000041_0002
Figure imgf000041_0003
Example 6.1: Preparation of 3-Benzyloxy-7-(4-isopropyl-piperazin-l-yI)-9- (methanesulfonyl-methyl-amino)-4-oxo-4H-pyrido[l,2-a]pyriinidine-2-carboxyIic acid methyl ester
Figure imgf000042_0001
This compound was prepared by adapting the procedure described in example 1.2.
1H NMR (300 MHz, CDC13) δ 8.29 (d, J=2.2 Hz, IH), 7.77 (d, J=2.4 Hz, IH), 7.52 (d, J=6.6 Hz, 2H), 7.37 (dd, J=15.0, 7.4 Hz, 3H), 5.31 (s, 2H), 3.88 (s, 3H), 3.41 (s, 3H), 3.30 (s, 4H), 3.21 (s, 3H), 2.72 (s, 5H), 1.12 (s, 6H).
MS (ESI+) /z 544 (M+l) Example 6.2: Preparation of 3-BenzyIoxy-7-(4-isopropyI-piperazin-l-yl)-9- (methanesulfonyl-methyl-amino)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide
Figure imgf000042_0002
This compound was prepared by adapting the procedure described in example 4.3. 1H NMR (300 MHz, CDC13) δ 8.23 (d, J=2.7 Hz, IH), 8.1 1 (m, IH), 7.76 (d, J=2.4 Hz, IH), 7.33 (s, 5H), 7.21 - 7.13 (m, 2H), 6.98 (t, J=8.7 Hz, 2H), 5.29 (s, 2H), 4.48 (d, J=5.4 Hz, 2H), 3.43 (s, 3H), 3.38 (s, 3H), 3.37-3.30 (m, 4H), 2.75-2.70 (m, 5H), 1.14- 1.08 (s, 6H).
MS (ESI+) w/z 637 (M+l) Example 6.3: Preparation of Trifluoro-acetate4-[2-(4-fluoro-benzylcarbamoyl) -3- hydroxy-9-(methanesulfonyl-methyI-amino)-4-oxo-4H-pyrido [1 ,2-a] py rimidin-7- yl]-l -isopropyl-piperazin-1 -ium ;
Figure imgf000043_0001
This compound was prepared by adapting the procedure described in example 4.4, except that no de-salting was done.
1H NMR (300 MHz, CDC13) δ 8.49 (m, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.04 (t, J=8.7 Hz, 2H), 4.60 (d, J=6 Hz, 2H), 3.28-3.22 (m, 7H), 3.01 (s, 3H), 2.76-2.70 (m, 5H), 1.09 (d, J=6.6 Hz, 6H). MS (ESI+) m/z 547 (M-TFA+1)
Example 7: Preparation of 7-(dimethylamino)-N-(4-fluorobenzyl)-3-hydroxy-4- oxo-9-(2-oxooxazolidin-3-yl)-4H-py rido [ 1 ,2-a] pyrimidine-2-carboxamide
Figure imgf000043_0002
The starting material 3-benzyloxy-7-dimethylamino-9-iodo-4-oxo-4H-pyrido[l,2- a]pyrimidine-2-carboxylic acid methyl ester was prepared by a similar method to the procedure described under the heading "Synthesis of the starting material 3-benzyloxy- 7-dimethylamino-9-iodo-4-oxo-4H-pyrido[l ,2-a]pyrimidine-2-carboxylic acid methyl ester" above.
As can be seen from the synthetic scheme, the substituent at the 7-position was fixed at the core stage and the substituent at the 9-position was introduced by coupling reaction. Amide reaction followed by deprotection of Bn gave the desired product.
Example 7.1: Preparation of methyl 3-(benzyloxy)-7-(dimethylamino)-4-oxo- 9-(2- oxooxazolidin-3-yI)-4H-pyrido[l,2-a]pyrimidine-2-carboxylate
Figure imgf000044_0001
48%
This compound was prepared by adapting the procedure in Example 1.1, using the product of step 5 of the synthetic examples set out above.
1H NMR (300 MHz, CDC13) δ 8.15 (d, J = 2.7 Hz, 1H), 7.86 (d, J= 2.7 Hz, 1H), 7.56- 7.50 (m, 2H), 7.43-7.32 (m, 3H), 5.31 (s, 2H), 4.60-4.50 (m, 4H), 3.90 (s, 3H), 3.08 (s, 6H).
MS (ESI+) m/z 439 (M+l), 461 (M+23) Example 7.2: Preparation of 3-(benzyloxy)-7-(dimethylamino)-N-(4-fluorobenzyl)- 4-oxo-9-(2-oxooxazolidin-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000044_0002
This compound was prepared by adapting the procedure in Example 4.3. Ή NMR (300 MHz, CDC13) δ 8.09 (d, J = 3.0 Hz, 1H), 7.98-7.87 (m, 2H), 7.42-7.36 (m, 2H), 7.36-7.30 (m, 3H), 7.27-7.21 (m, 2H), 6.99 (t, J = 8.8 Hz, 2H), 5.32 (s, 2H), 4.64-4.44 (m, 6H), 3.08 (s, 6H).
MS (ESI+) m/z 532 (M+l), 554 (M+23) Example 7.3: Preparation of 7-(dimethylamino)-N-(4-fluorobenzyl)-3-hydroxy-4- oxo-9-(2-oxooxazolidin-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000045_0001
The product from Example 4.2 (60 mg, 0.1 1 mmol) was dissolved in TFA (5 ml) and heated at 70°C for 4h. TFA was removed in vacuo and then methanol (5 ml) was added. The solids were collected by filtration, washed with methanol and dried in vacuo to afford the desired compound (30 mg, 60%).
1H NMR (300 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.31 (t, J = 3.0 Hz, 1H), 7.90 (d, J = 2.7 Hz, 1H), 7.81 (d, J= 2.4 Hz, 1H), 7.45-7.33 (m, 2H), 7.17 (t, J= 8.7 Hz, 2H), 4.59- 4.51 (m, 4H), 4.19 (t, J- 8.0 Hz, 2H), 2.98 (s, 6H). MS (EST) m/z 440 (M-l)
Example 8: Preparation of 7-(dimethylamino)-N-(4-fluorobenzyl)-3-hydroxy-4- oxo-9-(2-oxo-l,3-oxazinan-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000046_0001
This target was made by adapting the procedure described in Example 7. Example 8.1: Preparation of methyl 3-(benzyloxy)-7-(dimethylamino)-4-oxo-9-(2- oxo-l,3-oxazinan-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylate
Figure imgf000046_0002
This compound was made by adapting the procedure described in example 7.1.
Ή NMR (300 MHz, CDC13) δ 8.15 (d, J = 2.7 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.57- 7.51 (m, 2H), 7.43-7.31 (m, 3H), 5.29 (s, 2H), 4.53 (t, J = 2.7 Hz, 2H), 3.89 (s, 3H), 3.84-3.71 (m, 2H), 3.07 (s, 6H), 2.35-2.24 (m, 2H).
MS (ESI+) m/z 453 (M+l), 475 (M+23) Example 8.2: Preparation of 3-(benzyloxy)-7-(dimethylamino)-N-(4-fluorobenzyl)- 4-oxo-9-(2-oxo-l,3-oxazinan-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000047_0001
This compound was made by adapting the procedure described in example 7.2. 1H NMR (300 MHz, CDC13) δ 8.11 (d, J = 2.7 Hz, 1H), 7.63-7.55 (m, 2H), 7.54-7.48 (m, 2H), 7.38-7.27 (m, 5H), 7.01 (t, J = 8.7 Hz, 2H), 5.31 (s, 2H), 4.54 (d, J = 5.1 Hz, 2H), 4.32 (t, J= 4.8 Hz, 2H), 3.78-3.66 (m, 2H), 3.06 (s, 6H), 2.18-2.07 (m, 2H).
MS (ESI+) m/z 546 (M+l ), 568 (M+23)
Example 8.3: Preparation of 7-(dimethylamino)-N-(4-fluorobenzyl)-3-hydroxy-4- oxo-9-(2-oxo-l ,3-oxazinan-3-yl)-4H-pyrido [ 1 ,2-a] pyrimidine-2-carboxamide
Figure imgf000047_0002
This compound was made by adapting the procedure described in example 7.3.
Ή NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.89 (t, J = 6.6 Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.81 (d, J = 2.7 Hz, 1H), 7.47-7.33 (m, 2H), 7.19 (t, J = 8.7 Hz, 2H), 4.57 (d, J = 6.6 Hz, 2H), 4.40 (t, J= 4.5 Hz, 2H), 3.94-3.47 (m, 2H), 2.99 (s, 6H), 2.22-2.07 (m, 2H).
MS (ESI+) m/z 456 (M+l), 478 (M+23) Example 9: Preparation of 7-(dimethylamino)-N-(4-fluorobenzyl)-3-hydroxy-4- oxo-9-(2-oxopiperazin-l -y l)-4H-py rido [1 ,2-a] py rimidine-2-carboxamide
Figure imgf000048_0001
boc
This target was made by adapting the procedure described in the Example 7, except that TEA was used for desalting of the deprotection product.
Example 9.1: Preparation of methyl 3-(benzyloxy)-9-(4-(tert-butoxycarbonyl)-2- oxopiperazin-l-yl)-7-(dimethylamino)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2- carboxylate
Figure imgf000048_0002
This compound was made by adapting the procedure described in example 7.1.
1H NMR (300 MHz, CDC13) δ 8.17 (d, J = 2.7 Hz, 1H), 7.60-7.50 (m, 3H), 7.42-7.36 (m, 3H), 5.29 (s, 2H), 4.32 (s, 2H), 3.92-3.80 (m, 7H), 3.07 (s, 6H), 1.50 (s, 9H).
MS (ESI+) m/z 552 (M+l), 574 (M+23) Example 9.2: Preparation of tert-butyl 4-(3-(benzyloxy)-7-(dimethylamino)-2-(4- fluorobenzylcarbamoyl)-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)-3-oxopiperazine-
1-carboxylate
Figure imgf000049_0001
boc This compound was made by adapting the procedure described in example 7.2.
1H NMR (300 MHz, CDC13) δ 8.14 (d, J = 2.7 Hz, 1H), 7.63 (t, J = 4.8 Hz, 1H), 7.56 (d, J= 2.7 Hz, 1H), 7.49-7.46 (m, 2H), 7.34-7.30 (m, 3H), 7.27-7.22 (m, 2H), 7.00 (t, J = 8.7 Hz, 2H), 5.30 (s, 2H), 4.51 (d, J = 5.4 Hz, 2H), 4.23 (s, 2H), 3.84-3.73 (m, 4H), 3.08 (s, 6H), 1.50 (s, 9H).
MS (ESI+) m/z 645 (M+l), 667 (M+23)
Example 9.3: Preparation of 7-(dimethylamino)-N-(4-fluorobenzyl)-3-hydroxy-4- oxo-9-(2-oxopiperazin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000049_0002
This compound was made by adapting the procedure described in example 7.3, except that TEA was used for desalting of the deprotection product.
1H NMR (300 MHz, DMSO-d6) δ 8.84 (t, J= 4.8 Hz, 1H), 7.80 (m, 2H), 7.40 (m, 2H), 7.19 (t, J = 8.7 Hz, 2H), 4.58 (d, J = 6 Hz, 2H), 3.78-3.50 (m, 2H), 3.41 (s, 2H), 3.09- 3.01 (m, 2H), 2.98 (s, 6H).
MS (ESI+) m/z 455 (M+l) Example 10: Preparation of N-(4-fluorobenzyl)-3-hydroxy-7-morphoIino-
(
Figure imgf000050_0001
boc
This target was made by adapting the procedure described in the Example 7, except that TEA was used for desalting of the deprotection product.
Example 10.1: Preparation of 3-Benzyloxy-9-(4-tert-butoxycarbonyl-2-oxo- piperazin-l-yl)-7-morpholin-4-yl-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxyIic acid methyl ester
Figure imgf000050_0002
oc
This compound was made by adapting the procedure described in example 7.1.
1H NMR (300 MHz, CDC13) δ 8.32 (d, J = 2.6 Hz, 1H), 7.62 (d, J = 2.6 Hz, 1H), 7.56 7.47 (m, 2H), 7.42-7.32 (m, 3H), 5.30 (s, 2H), 4.31 (s, 2H), 3.96-3.74 (m, 1 1H), 3.30 3.18 (m, 4H), 1.51 (s, 9H).
MS (ESI+) m/z 594 (M+l) Example 10.2: Preparation of tert-butyl 4-(2-(4-fluorobenzylcarbamoyl)-3- hydroxy-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)-3-oxopiperazine-l- carboxylate
Figure imgf000051_0001
boc This compound was made by adapting the procedure described in example 7.2.
Ή NMR (300 MHz, CDC13) δ 8.28 (d, J = 2.4 Hz, 1H), 7.64-7.56 (m, 2H), 7.48-7.44 (m, 2H), 7.36-7.31 (m, 3H), 7.28-7.22 (m, 2H), 7.00 (t, J = 8.7 Hz, 2H), 5.30 (s, 2H), 4.51 (d, J= 5.4 Hz, 2H), 4.22 (s, 2H), 3.93-3.74 (m, 8H), 3.23 (t, J= 4.3 Hz, 4H), 1.50 (s, 9H). MS (ESI+) m/z 687 (M+l), 709 (M+23)
Example 10.3: Preparation of N-(4-fluorobenzyl)-3-hydroxy-7-morpholino -4-oxo- 9-(2-oxopiperazin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000051_0002
This compound was made by adapting the procedure described in example 7.3, except that TEA was used for desalting of the deprotection product.
Ή NMR (300 MHz, DMSO-d6) δ 8.90 (t, J = 6.0 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.91 (d, J= 1.8 Hz, 1H), 7.46-7.34 (m, 2H), 7.19 (t, J= 8.7 Hz, 2H), 4.58 (d, J= 6 Hz, 2H), 3.76 (t, J = 4.3 Hz, 4H), 3.67-3.53 (m, 2H), 3.42 (s, 2H), 3.18 (t, J = 4.3 Hz, 4H), 3.09-2.99 (m, 2H). MS (ESf) m/z 497 (M+l), 519 (M+23) Example 11: Preparation of N-(4-fluorobenzyI)-3-hydroxy-7-(3- methylmorpholino)-4-oxo-9-(2-oxopiperazin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2- carboxamide
Figure imgf000052_0001
This target was made by adapting the procedure described in the Example 7, except that TEA was used for desalting of the deprotection product.
The starting material 7-(3-methylmorpholino)-9-Br core was made in a similar method to its morpholine derivative. 3-Methylmorpholine was made according to US2005/38032 Al. Example 11.1: Preparation of methyl 3-(benzyloxy)-9-(4-(tert-butoxycarbonyl)-2- oxopiperazin-l-yl)-7-(3-methylmorpholino)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2- carboxylate
Figure imgf000052_0002
This compound was made by adapting the procedure described in example 7.1. Ή NMR (300 MHz, CDC13) δ 8.28 (d, J = 2.7 Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H), 7.56- 7.52 (m, 2H), 7.43-7.30 (m, 3H), 5.30 (s, 2H), 4.31 (s, 2H), 4.04 (d, J = 10.2 Hz, 1H), 3.92-3.63 (m, 11H), 3.38-3.26 (m, 1H), 3.22-3.14 (m, 1H), 1.51 (s, 9H), 1.22 (d, J Hz, 3H).
MS (ESI+) m/z 608 (M+l), 630 (M+23)
Example 11.2: Preparation of tert-butyl 4-(3-(benzyloxy)-2-(4-fluorobenzyl carbamoyl)-7-(3-methyImorpholino)-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)-3 oxopiperazine-l-carboxylate
Figure imgf000053_0001
boc
This compound was made by adapting the procedure described in example 7.2.
Ή NMR (300 MHz, CDC13) δ 8.23 (d, J = 2.4 Hz, 1H), 7.63-7.55 (m, 2H), 7.50-7.44 (m, 2H), 7.37-7.30 (m, 3H), 7.30-7.22 (m, 2H), 7.00 (t, J = 8.7 Hz, 2H), 5.30 (s, 2H), 4.51 (d, J = 6 Hz, 2H), 4.22 (s, 2H), 4.02 (d, J = 9.9 Hz, 1H), 3.65-3.90 (m, 8H), 3.37- 3.25 (m, 1H), 3.21-3.13 (m, 1H), 1.50 (s, 9H), 1.22 (d, J= 6.6 Hz, 3H).
MS (ESI+) m/z 701 (M+l), 723 (M+23)
Example 11.3: Preparation of N-(4-fluorobenzyl)-3-hydroxy-7-(3- methylmorpholino)-4-oxo-9-(2-oxopiperazin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2- carboxamide
Figure imgf000053_0002
This compound was made by adapting the procedure described in example 7.3, except that TEA was used for desalting of the deprotection product. 1H NMR (300 MHz, DMSO-d6) δ 8.89 (t, J = 6.0 Hz, 1H), 7.93-7.91 (m, 2H), 7.46- 7.33 (m, 2H), 7.19 (t, J = 8.7 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 3.96 (d, J = 8.8 Hz, 2H), 3.72 (s, 2H), 3.65-3.51 (m, 3H), 3.44-3.40 (m, 2H), 3.24-2.96 (m, 4H), 1.06 (d, J= 6.5 Hz, 3H). MS (ESI+) m/z 51 1 (M+l)
Example 12: Preparation of 3-Hydroxy-4-oxo-9-(2-oxo-piperazin-l-yi)-7- piperidin-l-yl-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide
Figure imgf000054_0001
This target was prepared by adapting the procedure described in Example 4.
Example 12.1: Preparation of 3-BenzyIoxy-9-(4-tert-butoxycarbonyl-2-oxo- piperazin-l-yl)-4-oxo-7-piperidin-l-yl-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000054_0002
This compound was made by adapting the procedure described in example 4.2. 1H NMR (300 MHz, CDC13) δ 8.31 (d, J= 2.7 Hz, 1H), 7.65 (d, J= 2.7 Hz, 1H), 7.57- 7.47 (m, 2H), 7.45-7.30 (m, 3H), 5.32 (s, 2H), 4.32 (s, 2H), 3.94-3.72 (m, 7H), 3.28- 3.18 (m, 4H), 1.82-1.54 (m, 6H) , 1.52 (s, 9H).
MS (ESI+) m/z 614 (M+23) Example 12.2: Preparation of 4-[3-BenzyIoxy-2-(4-fluoro-benzylcarbamoyl)-4-oxo- 7-piperidin-l-yl-4H-pyrido[l,2-a]pyrimidin-9-yl]-3-oxo-piperazine-l-carboxylic acid tert-butyl ester
Figure imgf000055_0001
boc
This compound was made by adapting the procedure described in example 4.3. Ή NMR (300 MHz, CDC13) δ 8.27 (d, J - 2.6 Hz, 1H), 7.65-7.54 (m, 2H), 7.52-7.42 (m, 2H), 7.36-7.28 (m, 3H), 7.26-7.20 (m, 2H), 7.00 (t , J = 8.6 Hz, 2H), 5.32 (s, 2H), 4.52 (d, J= 6.0 Hz, 2H), 4.23 (s, 2H) , 3.85-3.65 (m, 4H), 3.28-3.18 (m ,4H), 1.80-1.60 (m, 6H), 1.51 (s, 9H).
MS (ESI+) m/z 685 (M+l) Example 12.3: Preparation of 3-Hydroxy-4-oxo-9-(2-oxo-piperazin-l-yl)-7- piperidin-l-yl-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide
Figure imgf000055_0002
This compound was made by adapting the procedure described in example 4.4. Ή NMR (300 MHz, CDC13) δ 8.25-8.10 (m, 2H), 7.46 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 6.0, 8.5 Hz, 2H), 7.06 (t, J= 8.1 Hz, 2H), 4.56 (d, J= 5.1Hz, 2H), 3.78-3.40 (m ,4H), 3.25-2.90 (m, 6H), 1.85-1.50 (m, 6H).
MS (ESI+) m/z 495 (M+l) Example 13: Preparation of 7-(CyclopropyImethyl-methyI-amino)-3-hydroxy-4- oxo-9-(2-oxo-piperazin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4- fluoro-benzylamide
This target was made by adapting the procedure described in Example 4, except that an extra step of reduction amination step was required.
Figure imgf000056_0001
Figure imgf000056_0002
Example 13.1: Preparation of 3-Benzyloxy-9-(4-tert-butoxycarbonyl-2-oxo- piperazin-l-yl)-7-(cyclopropyImethyl-amino)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2- carboxylic acid methyl ester
Figure imgf000057_0001
oc This compound was made by adapting the procedure described in example 4.2.
1H NMR (300 MHz, CDC13) δ 8.06 (d, J = 2.0 Hz, 1H), 7.58-7.48 (m, 2H), 7.42-7.28 (m, 5H), 5.32 (s, 2H), 4.32 (s, 2H), 3.95-3.70 (m, 7H), 2.95 (s, 2H), 1.50 (s, 9H), 1.25- 1.15 (m, 1H), 0.68-0.54 (m, 2H), 0.32-0.22 (m, 2H).
MS (ESI+) m/z 578 (M+l)
Example 13.2: Preparation of 3-Benzyloxy-9-(4-tert-butoxycarbonyl-2- piperazin-l-yl)-7-(cyclopropylmethyl-methyl-amino)-4-oxo-4H-pyrido[l,2- a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000057_0002
boc boc
The product from example 13.1 (450 mg, 0.781 mmol) was suspended in a mixed solvent of DCM (2 ml) and MeOH (2 ml). To the above stirred mixture was added HCHO (100 mg, 3.30 mmol), HOAc (20μ1), NaBH3CN (200 mg 3.2 mmol) successively. The mixture was stirred at room temperature for 30 minutes, after which it was concentrated in vacuo. The residue was purified on column chromatography (PE/EtOAc = 1/1) to give the crude product, which was further purified on preparative TLC to afford the desired product (130 mg, 30%). 1H NMR (300 MHz, CDC13) δ 8.21 (d, J= 2.6 Hz, 1H), 7.60 (d, J= 2.6 Hz, 1H), 7.56- 7.48 (m, 2H), 7.41-7.30 (m, 3H), 5.32 (s, 2H), 4.32 (s, 2H), 3.93-3.77 (m, 7H), 3.29 (d, J= 6.8 Hz, 2H), 3.10 (s, 3H), 1.50 (s, 9H), 1.25-1.15 (m, 1H), 0.75-0.65 (m, 2H), 0.33- 0.23 (m ,2H). MS (ESI+) m/z 592 (M+l)
Example 13.3: Preparation of 4-[3-Benzyloxy-7-(cyclopropyImethyl-methyl- amino)-2-(4-fluoro-benzylcarbamoyl)-4-oxo-4H-pyrido [1 ,2-a] pyrimidin-9-yl] -3- oxo-piperazine-l-carboxylic acid tert-butyl ester
Figure imgf000058_0001
boc F This compound was made by adapting the procedure described in example 4.3.
1H NMR (300 MHz, CDC13) δ 8.17 (d, J = 2.6 Hz, 1H), 7.67-7.55 (m, 2H), 7.54-7.42 (m, 2H), 7.38-7.29 (m, 3H), 7.26-7.18 (m, 2H), 7.00 (t, J = 8.5 Hz, 2H), 5.32 (s, 2H), 4.52 (d, J= 5.4 Hz, 2H), 4.22 (s, 2H), 3.85-3.70 (m, 4H), 3.29 (d, J= 6.6 Hz, 2H), 3.08 (s, 3H), 1.50 (s, 9H), 1.10-1.00 (m, 1H), 0.69-0.55 (m ,2H), 0.30-0.20 (m ,2H). MS (ESI+) w/z 685 (M+l)
Example 13.4: Preparation of 7-(Cyclopropylmethyl-methyl-amino)-3-hydroxy-4- oxo-9-(2-oxo-piperazin-l-yI)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4- fluoro-benzylamide
Figure imgf000058_0002
This compound was made by adapting the procedure described in example 4.4. Ή NMR (300 MHz, CDC13) δ 8.14 (t, J= 4.8 Hz, 1H), 8.03 (d, J= 2.4 Hz, 1H), 7.46(d, J= 2.4 Hz, 1H), 7.33 (dd, J= 5.9, 8.2 Hz, 2H), 7.07 (t, J= 8.2 Hz, 2H), 4.60 (d, J= 5.1 Hz, 2H), 3.80-3.35 (m, 4H), 3.24 (d, J - 6.3 Hz, 2H), 3.15-2.95 (m, 5H), 1.10-0.95 (m, 1H), 0.65-0.50 (m, 2H), 0.30-0.18 (m, 2H). MS (ESI+) w/z 495 (M+l)
Example 14: Preparation of 3-Hydroxy-7-(4-methyl-piperazin-l-yl)-4-oxo-9- (2- oxo-piperazin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000059_0001
boc boc
Figure imgf000059_0002
This target was made by adapting the procedure described in Example 4.
Example 14.1: Preparation of 3-Benzyloxy-9-(4-tert-butoxycarbonyl-2-oxo piperazin-1 -yl)-7-(4-methyl-piperazin-l -yl)-4-oxo-4H-pyrido [ 1 ,2-a] py rimidine-2- carboxylic acid methyl ester
Figure imgf000059_0003
oc This compound was made by adapting the procedure described in example 4.2. 1H NMR (300 MHz, CDC13) δ 8.33 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Ηζ,ΙΗ), 7.58- 7.48 (m, 2H), 7.47-7.37 (m, 3H), 5.32(s, 2H), 4.31 (s, 2H), 3.95-3.75 (m, 7H), 3.36- 3.24 (m, 4H), 2.68-2.57 (m, 4H), 2.38 ( s, 3H), 1.53 (s, 9H).
MS (ESI+) m/z 607 (M+l) Example 14.2: Preparation of 4-[3-Benzyloxy-2-(4-fluoro-benzylcarbamoyl)-7- (4- methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl]-3-oxo-piperazine-l- carboxylic acid tert-butyl ester
Figure imgf000060_0001
This compound was made by adapting the procedure described in example 4.3 and the crude product was used in the next step.
MS (ESI+) /n/z 700 (M+l).
Example 14.3: Preparation of 3-Hydroxy-7-(4-methyI-piperazin-l-yl)-4-oxo-9-(2- oxo-piperazin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000060_0002
This compound was made by adapting the procedure described in example 4.4.
1H NMR (300 MHz, CDC13) δ 8.20-8.02 (m, 2H), 7.48 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 4.9, 8.1 Hz, 2H), 7.07 (t, J= 8.5 Hz, 2H), 4.59 (d, J =5.1 Hz, 2H), 3.80-3.40 (m, 4H), 3.30-3.16 (m, 4H), 3.08 (s, 2H), 2.68-2.50 (m, 4H), 2.36 (s, 3H). MS (ESI+) m/z 510 (M+l) Example 15: Preparation of 3-Hydroxy-4-oxo-9-(2-oxo-piperazin-l-yl)-7- piperazin-l-yI-4H-pyrido [1 ,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000061_0001
oc oc
Figure imgf000061_0002
This target was prepared by adapting the procedure described in Example 4.
Example 15.1: Preparation of 3-Benzyloxy-9-(4-tert-butoxycarbonyl-2-oxo- piperazin-l-yl)-7-(4-tert-butoxycarbonyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2- a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000061_0003
This compound was made by adapting the procedure described in example 4.2.
1H NMR (300 MHz, CDC13) δ 8.34 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.55- 7.47 (m, 2H), 7.43-7.30 (m, 3H), 5.32 (s, 2H), 4.32 (s, 2H), 3.92-3.75 (m, 7H), 3.67- 3.55 (m, 4H), 3.26-3.16 (m, 4H), 1.50 (d, J= 4.2 Hz, 18H). MS (ESI+) m/z 693 (M+l)
Example 15.2: Preparation of 4-[3-Benzyloxy-7-(4-tert-butoxycarbonyl- piperazin- l-yl)-2-(4-fluoro-benzylcarbamoyl)-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl]-3-oxo- piperazine-l-carboxylic acid tert-butyl ester
Figure imgf000062_0001
This compound was made by adapting the procedure described in example 4.3.
Ή NMR (300 MHz, CDC13) δ 8.27 (d, J = 2.4 Hz, 1H), 7.67-7.52 (m, 2H), 7.50-7.38 (m, 2H), 7.37-7.28 (m, 3H), 7.27-7.17 (m, 2H), 7.00 (t, J = 8.7 Hz, 2H), 5.32 (s, 2H), 4.52 (d, J = 5.1 Hz ,2H), 4.23 (s, 2H) , 3.84-3.70 (m, 4H), 3.66-3.54 (m, 4H), 3.28-3.14 (m, 4H), 1.49 (d, J= 3.1 Hz, 18H)
MS (ESf ) m/z 786 (M+l)
Example 15.3: Preparation of 3-Hydroxy-4-oxo-9-(2-oxo-piperazin-l-yl)-7- piperazin-l-yl-4H-pyrido[l,2-a]pyrimidine-2-carboxyIic acid 4-fluoro- benzylamide
Figure imgf000062_0002
This compound was made by adapting the procedure described in example 4.4.
1H NMR (300 MHz, CDC13) δ 8.23-8.07 (m, 2H), 7.45 (d, J = 2.7 Hz ,1H), 7.40-7.30 (m, 2H), 7.07 (t, J= 8.3 Hz, 2H), 4.59 (d, J= 5.5 Hz, 2H), 3.80-3.40 (m, 4H), 3.25-3.12 (m, 4H), 3.12-2.95 (m, 6H). MS (ESI+) m/z 496 (M+l) Example 16: Preparation of 3-Hydroxy-9-(4-methyl-2-oxo-piperazin-l-yl)-7- morpholin-4-yl-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000063_0001
Figure imgf000063_0002
This target was made by adapting the procedure described in Example 7, except that TEA was used for desalting of the final target, and an extra step was required for the reductive animation.
Example 16.1: Preparation of 3-Benzyloxy-7-morphoIin-4-yl-4-oxo-9-(2-oxo- piperazin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000063_0003
This compound was made by adapting the procedure described in example 7.1.
1H NMR (300 MHz, CDC13) δ 8.32 (d, J= 2.5 Hz, 1H), 7.64 (d, J= 2.5 Hz, 1H), 7.56- 7.47 (m, 2H), 7.42-7.30 (m, 3H), 5.29 (s, 2H), 3.96-3.74(m, 1 1H), 3.34 (t, J = 5.1 Hz, 2H), 3.28-3.16 (m, 4H). MS (ESI+) m/z 494 (M+ 1 ) Example 16.2: Preparation of 3-Benzyloxy-9-(4-methyl-2-oxo-piperazin-l-yl)-7- morpholin-4-yl-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000064_0001
This compound was made by adapting the procedure described in example 13.2. 1H NMR (300 MHz, CDC13) δ 8.32 (d, J= 2.4 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.56- 7.45 (m, 2H), 7.43 - 7.31 (m, 3H), 5.43 - 5.15 (m, 2H), 4.35 (s, 2H), 4.01 - 3.41 (m, 1 1H), 3.26 (t, J= 4.5 Hz, 4H), 3.14 (s, 3H).
MS (ESI+) m/z 508 (M+l)
Example 16.3: Preparation of 3-Benzyloxy-9-(4-methyl-2-oxo-piperazin-l-yl)-7- morpholin-4-yl-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000064_0002
This compound was made by adapting the procedure described in example 7.2.
!H NMR (300 MHz, CDC13) δ 8.27 (d, J = 2.8 Hz, 1H), 7.80-7.68 (m, 1H), 7.64-7.50 (m, 3H), 7.42-7.31 (m, 5H), 7.03 (t, J = 8.7 Hz, 2H), 5.31 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H), 3.88 (t, J = 4.6 Hz, 4H), 3.80-3.66 (brs, 2H), 3.30-3.10 (m, 6H), 2.77-2.60 (brs, 2H), 2.31 (s, 3H).
MS (ESI+) m/z 601 (M+l) Example 16.4: Preparation of 3-Hydroxy-9-(4-methyl-2-oxo-piperazin-l-yI)-7- morpholin-4-yI-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000065_0001
This compound was made by adapting the procedure described in example 7.3, except that TEA was used for desalting.
Ή NMR (300 MHz, DMSO-d6) δ 11.80-11.60 (brs, 1H), 8.54 (t, J= 5.6 Hz, 1H), 8.02- 7.94 (m, 2H), 7.44 (dd, J = 5.8, 8.2 Hz, 2H), 7.22 (t, J = 8.8 Hz, 2H), 4.57 (d, J = 5.6 Hz, 2H), 3.82-3.70 (m, 4H), 3.66-3.50 (m, 2H), 3.25-3.14 (m, 4H), 3.09 (s, 2H), 2.76- 2.62 (m, 2H), 2.22 (s, 3H).
MS (ESI+) w/z 511 (M+l)
HPLC: 98.9 %
Example 17: Preparation of 3-Hydroxy-9-(3-isopropyI-2-oxo-imidazolidin-l-yl)-7- (4-methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4- fluoro-benzylamide
Figure imgf000066_0001
Figure imgf000066_0002
This target was made by adapting the procedure described in the Example 4, except that TEA was used in the desalting step.
Example 17.1: Preparation of 3-Benzyloxy-7-bromo-9-(3-isopropyl-2-oxo- imidazolidin-l-yI)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000066_0003
This compound was made by adapting the procedure described in example 4.1.
1H NMR (300 MHz, CDC13) δ 8.95 (d, J = 1.9 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.44- 7.54 (m, 2H), 7.30-7.42 (m, 3H), 5.34 (s, 2H), 4.20-4.40 (m, 3H), 3.90 (s, 3H), 3.48 (t, J= 7.9 Hz, 2H), 1.21 (d, J= 6.8 Hz, 6H). MS (ESf) m/z 537 (M[Br79]+23), 539 (M[Br81]+23)
Example 17.2: Preparation of 3-Benzyloxy-9-(3-isopropyl-2-oxo-imidazoIidin-l- yl)-7-(4-methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000067_0001
This compound was made by adapting the procedure described in example 4.2.
1H NMR (300 MHz, CDC13) δ 8.24 (d, J= 2.5 Hz, 1H), 8.01 (d, J= 2.5 Hz, 1H), 7.48- 7.58 (m, 2H), 7.28-7.42 (m, 3H), 5.31 (s, 2H), 4.39 - 4.16 (m, 3H), 3.89 (s, 3H), 3.48 (t, J = 8.1 Hz, 2H), 3.24-3.36 (m, 4H), 2.54-2.68 (m, 4H), 2.38 (s, 3H), 1.21 (d, J= 6.7 Hz, 6H).
MS (ESf) m/z 535 (M+l)
Example 17.3: Preparation of 3-Benzyloxy-9-(3-isopropyl-2-oxo-imidazolidin-l- yl)-7-(4-methyl-piperazin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide
Figure imgf000067_0002
This compound was made by adapting the procedure described in example 4.3.
1H NMR (300 MHz, DMSO-d6) δ 8.93 (t, J - 6.1 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.52-7.42 (m, 2H), 7.41 - 7.30 (m, 5H), 7.07 (t, J = 8.8 Hz, 2H), 5.14 (s, 2H), 4.45 (d, J = 5.9 Hz, 2H), 4.16 - 3.93 (m, 3H), 3.42 (t, J = 7.8 Hz, 2H), 3.30-3.12 (m, 4H), 2.58-2.41 (m, 4H), 2.24 (s, 3H), 1.13 (d, J= 6.7 Hz, 6H). MS (ESI+) m/z 650 (M+23)
Example 17.4: Preparation of 3-Hydroxy-9-(3-isopropyI-2-oxo-imidazolidin-l-yl)- 7-(4-methyl-piperazin-l-yI)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide
Figure imgf000068_0001
This compound was made by adapting the procedure described in example 4.4, except that TEA was used in desalting.
Ή NMR (300 MHz, CDC13) δ 1 1.83 - 1 1.65 (m, 1H), 8.13 (d, J = 2.5 Hz, 1H), 7.94 (t, J = 5.6 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.38-7.29 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H), 4.62 (d, J = 5.7 Hz, 2H), 4.24-4.08 (m, 1H), 3.85 (t, J = 7.8 Hz, 2H), 3.33 (m, J = 7.8 Hz, 2H), 3.29-3.19 (m, 4H), 2.66-2.50 (m, 4H), 2.36 (s, 3H), 1.1 1 (d, J= 6.8 Hz, 6H).
MS (ESI+) m/z 560 (M+23)
HPLC: 99.1%
Example 18: Preparation of 3-Hydroxy-7-(4-methyl-piperazin-l-yl)-4-oxo-9-(2- oxo-piperidin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000069_0001
This target was made by adapting the procedure described in Example 4, except that TEA was used instead of 4-fluorobenzylamine in the desalting step.
Example 18.1: Preparation of 3-Benzyloxy-7-bromo-4-oxo-9-(2-oxo-piperidin-l- yl)-4H-Pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000069_0002
This compound was made by adapting the procedure described in example 4.1.
Ή NMR (300 MHz, CDC13) δ 9.06 (d, J= 1.8 Hz, 1H), 7.67 (d, J= 2.1 Hz, 1H), 7.53 7.45 (m, 2H), 7.41-7.31 (m, 3H), 5.31 (s, 2H), 3.88 (s, 3H), 3.75-3.60 (brs, 2H), 2.64 2.53 (m, 2H),2.06-1.93 (m, 4H)
MS (ESI+) m/z 486(M+1), 508(M+23) Example 18.2: Preparation of 3-Benzyloxy-7-(4-methyI-piperazin-l-yI)-4-oxo-9-(2- oxo-piperidin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxyIic acid methyl ester
Figure imgf000070_0001
This compound was made by adapting the procedure described in example 4.2. Ή NMR (300 MHz, CDC13 ) δ 8.30 (d, J = 2.1Hz, 1H), 7.59 (d, J = 2.4Hz, 1H), 7.53- 7.49 (m, 2H), 7.41-7.30 (m, 3H), 5.28 (s, 2H), 3.87 (s, 3H), 3.79-3.61 (m, 2H), 3.33- 3.24 (m, 4H), 2.65-2.54 (m, 6H), 2.37 (s, 3H), 2.06-1.93 (m, 4H)
MS (ESI+) m/z 506(M+1), 528(M+23)
Example 18.3: Preparation of 3-Benzyloxy-7-(4-methyl-piperazin-l-yl)-4-oxo-9-(2- oxo-piperidin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000070_0002
This compound was made by adapting the procedure described in example 4.3.
Ή NMR (300 MHz, DMSO-d6 ) 8 8.26 (d, J = 2.7 Hz, 1H), 7.49-7.43 (m, 4H), 7.40- 7.31 (m, 5H), 7.13-7.04 (m, 2H), 5.13 (s, 2H), 4.48-4.41 (m, 2H), 3.74-3.46 (m, 2H), 3.37-3.41 (m, 4H), 2.50-2.70 (m, 4H), 2.30-2.50 (m, 5H), 1.89-1.77 (m, 4H)
MS (ESI+) w/z 599(M+l) Example 18.4: Preparation of 3-Hydroxy-7-(4-methyl-piperazin-l-yl)-4-oxo-9-(2- oxo-piperidin-l-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000071_0001
This compound was made by adapting the procedure described in example 4.4, except that TEA was used instead of 4-fluorobenzylamine in the desalting step.
1H NMR (300 MHz, CDC13 ) δ 1 1.79 (s, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.83 (m, 1H), 7.42 (d, J =1.8 , 1H), 7.39-7.30 (m, 2H), 7.13-7.03 (m, 2H), 4.68-4.47 (m, 2H), 3.70- 3.80 (m, 2H), 3.29-3.18 (m, 4H), 2.64-2.52 (m, 4H), 2.50-2.30 (m, 5H), 1.94-1.51 (m, 4H)
MS (ESI+) m/z 509(M+l)
Example 19: Preparation of 3-Hydroxy-4-oxo-9-(2-oxo-oxazolidin-3-yl)-7- piperazin-l-yl-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000071_0002
This target was made by adapting the procedure described in Example 4, except that TEA was used instead of 4-fluorobenzylamine in the desalting step.
Example 19.1: Preparation of 3-Benzyloxy-7-bromo-4-oxo-9-(2-oxo-oxazolidin-3- yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000072_0001
This compound was made by adapting the procedure described in example 4.1.
1H NMR (300 MHz, CDC13 ) δ 9.07 (d, J = 1.8 Hz, 1H), 7.67 (d, J= 2.4 Hz, 1H), 7.53- 7.45 (m, 2H), 7.41-7.31 (m, 3H), 5.31 (s, 2H), 3.88 (s, 3H), 3.75-3.62 (m, 2H), 2.63- 2.55 (m, 2H) MS (ESI+) w/z 474 (M+l)
Example 19.2: Preparation of 3-Benzyloxy-7-(4-tert-butoxycarbonyl- piperazin-1- yl)-4-oxo-9-(2-oxo-oxazolidin-3-yI)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl este
Figure imgf000072_0002
This compound was made by adapting the procedure described in example 4.2.
1H NMR (300 MHz, CDC13 ) δ 8.28 (d, J = 2.7 Hz, 1H), 7.91 (d, J= 2.4 Hz, 1H), 7.52- 7.47 (m, 2H), 7.40-7.31 (m, 3H), 5.31 (s, 2H), 4.57-4.50 (m, 4H), 3.89 (s, 3H),3.65- 3.57 (m, 4H), 3.25-3.17 (m, 4H), 1.49 (s, 9H)
MS (ESI+) m/z 580 (M+l), 602 (M+23) Example 19.3: Preparation of 4-[3-Benzyloxy-2-(4-fluoro-benzylcarbamoyl)-4-oxo- 9-(2-oxo-oxazolidin-3-yl)-4H-pyrido[l,2-a]pyrimidin-7-yl]-piperazine-l-carboxylic acid tert-butyl ester
Figure imgf000073_0001
This compound was made by adapting the procedure described in example 4.3.
1H NMR (300 MHz, DMSO-d6 ) δ 8.99 (t, J = 6.0 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.49-7.41 (m, 2H), 7.41-7.32 (m, 5H), 7.07 (t, J= 8.7Hz, 2H), 5.14 (s, 2H), 4.56-4.42 (m, 4H), 4.26-4.16 (m, 2H), 3.56-3.47 (m, 4H), 3.27-3.19 (m, 4H), 1.45(s, 9H) MS (ESI+) m/z 673(M+l), 695 (M+23)
Example 19.4: Preparation of 3-Hydroxy-4-oxo-9-(2-oxo-oxazolidin-3-yl)-7- piperazin-l-yI-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000073_0002
This compound was made by adapting the procedure described in example 4.4, except that TEA was used instead of 4-fluorobenzylamine in the desalting step.
Ή NMR (300 MHz, CDC13 ) δ 8.15 (m, 1H), 7.91-7.81 (m, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.39-7.31 (m, 2H), 7.08 (t, J= 8.7 Hz, 2H), 4.65-4.59 (m, 2H), 4.44-4.35 (m, 2H), 4.10-4.02 (m, 2H), 3.22-3.14 (m, 4H), 3.09-3.01 (m, 4H) MS (ESI+) w/z 483 (M+l) Example 20: Preparation of 3-Hydroxy-7-(4-methyI-piperazin-l-yI)-4-oxo-9-(2- oxo-oxazolidin-3-yI)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000074_0001
This target was made by adapting the procedure described in Example 2.
Example 20.1: Preparation of 3-Benzyloxy-7-bromo-4-oxo-9-(2-oxo-oxazolidin-3- yl)-4H-pyrido[l,2-a] pyrimidine-2-carboxylic acid methyl ester
Figure imgf000074_0002
This compound was made by adapting the procedure described in example 2.1. Ή NMR (300 MHz, CDC13 ) δ 9.07 (d, J = 1.8 Hz, 1H), 8.05 (d, J= 2.4 Hz, 1H), 7.53- 7.45 (m, 2H), 7.41-7.31 (m, 3H), 5.31 (s, 2H), 4.43-4.62 (m, 4H), 3.88 (s, 3H)
MS (ESI+) no ionisation Example 20.2: Preparation of 3-Benzyloxy-7-(4-methyl-piperazin-l-yl)-4-oxo-9-(2- oxo-OxazoIidin-3-yl)-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000075_0001
This compound was made by adapting the procedure described in example 2.2. 1H NMR (300 MHz, CDC13 ) δ 8.28 (d, J = 2.7 Hz, 1H), 7.93 (d, J= 2.7 Hz, 1H), 7.54- 7.47 (m, 2H), 7.41-7.31 (m, 3H), 5.31 (s, 2H), 4.60-4.46 (m, 4H), 3.89 (s, 3H), 3.33- 3.25 (m, 4H), 2.63-2.55 (m, 4H), 2.37 (s, 3H)
MS (ESI+) m/z 494 (M+l), 516(M+23)
Example 20.3: Preparation of Trifluoro-acetate4-[3-hydroxy-2-methoxy carbonyl- 4-oxo-9-(2-oxo-oxazolidin-3-yl)-4H-pyrido [1 ,2-a] pyrimidin-7-yl] -1 -methyl- piperazin-l-ium
CF3CO
Figure imgf000075_0002
This compound was made by adapting the procedure described in example 2.3.
1H NMR (300 MHz, DMSO-d6 ) δ 10.37-10.30 (brs, 1H), 10.05-9.92 (brs, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 4.55-4.47 (t, J = 7.8 Hz, 2H), 4.28-4.20 (t, J = 8.1 Hz, 2H), 3.77-3.98 (m, 5H), 3.69-3.46 (m, 2H), 3.33-2.96 (m, 4H), 2.88 (s, 3H)
MS (ESI+) m/z 404 (M-TFA+1) Example 20.4: Preparation of 3-Hydroxy-7-(4-methyI-piperazin-l-yl)-4-oxo- 9-(2- oxo-oxazolidin-3-yl)-4H-py rido [ 1 ,2-a] pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000076_0001
This compound was made by adapting the procedure described in example 2.4.
1H NMR (300 MHz, DMSO-c*6 ) 6 12.12-11.69 (brs, 1H), 9.45-9.29 (brs, 1H), 7.98- 7.91 (m, 2H), 7.42-7.35 (m, 2H), 7.21-7.1 1 (m, 2H), 4.58-4.47 (m, 4H), 4.22-4.13 (m, 2H), 3.21-3.14 (m, 4H), 2.60-2.40 (m, 4H), 2.25 (s, 3H)
MS (ESI+) m/z 497 (M+l) Example 21: Preparation of N-(4-fluorobenzyl)-3-hydroxy-7,9-dimorpholino-4- oxo-4H-pyrido [1 ,2-a] pyrimidine-2-carboxamide
Figure imgf000076_0002
70%
Figure imgf000076_0003
Example 21.1: Preparation of 4-(5-iodo-6-nitropyridin-3-yl)morphoIine
Figure imgf000077_0001
X=Br
X=l
Reagents and conditions: (a) i) CICOOEt, Py 93% ii) HN03, H2S04, 30°C, 20h, 68% iii) KOH/EtOH/H20, 75% (b) morpholine, 140°C, 10 h, 85 % (c) NaN02, H2S04, H20, 0°C, 2h then 80°C 2h, 75% for X=OH or CuBr, X=Br 80% or Cul for X=I, 30%.
Example 21.2: Preparation of 4,4,-(2-nitropyridine-3,5-diyl)dimorpholine
Figure imgf000077_0002
The mixture of 4-(5-iodo-6-nitropyridin-3-yl)morpholine (1.0 g, 3 mmol) and morpholine (10 ml) were heated at 60°C for 24h. After cooling down to room temperature, ethyl ether (20 ml) was added. The solids were collected by filtration, washed with water three times and dried in vacuo to afford the desired compound (790 mg, 90%).
Ή NMR (300 MHz, CDC13) δ 7.78 (d, J = 1.5 Hz, 1H), 6.88 (d, J = 1.5 Hz, 1H), 3.96- 3.84 (m, 8H), 3.36 (t, J= 4.5 Hz, 4H), 3.10 (t, J = 4.5 Hz, 4H).
MS (ESI+) m/z 295 (M+l)
Example 21.3: Preparation of 3,5-dimorpholinopyridin-2-amine
Figure imgf000077_0003
70% Tin(II) chloride (4.3 g, 18.8 mmol) was added into the solution of the product from Example 21.2 (791 mg, 2.7 mmol) in ethanol (30 ml). The mixture was heated to reflux under nitrogen atmosphere for 15hours. Then most of ethanol was removed in vacuo and water (30 ml) was added. Aqueous sodium hydroxide (4N) solution was added dropwise to make the pH to ~9. Then the mixture was extracted with dichloromethane three times. The organic layers were combined, washed with water, dried and evaporated under reduced pressure to afford the desired compound (500 mg, 70%).
Ή NMR (300 MHz, CDC13) δ 7.49 (d, J = 1.5 Hz, 1H), 6.93 (d, J = 1.5 Hz, 1H), 4.60 (s, 2H), 3.91-3.79 (m, 8H), 3.02 (t, J= 4.5 Hz, 4H), 2.92 (t, J- 4.5 Hz, 4H).
Figure imgf000078_0001
Example 21.4: Preparation of methyl 3-hydroxy-7,9-dimorpholino-4-oxo-4H- pyrido [1,2-a] pyrimidine-2-carboxylate
Figure imgf000078_0002
The product from Example 21.3 (250 mg, 0.95 mmol), dimethyl 2,3-diacetoxyfumarate (369 mg, 1.42 mmol) and acetic acid (57 mg, 0.95 mmol) was dissolved in methanol (2 ml) and the mixture was heated at 70°C for 24h. After cooling down to room temperature, the solids were collected by filtration, washed with methanol and dried in vacuo to afford the desired compound (123 mg, 33%).
1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.76 (d, J = 1.5 Hz, 1H), 6.96 (d, J = 1.5 Hz, 1H), 3.86 (s, 3H), 3.82-3.73 (m, 8H), 3.34 (t, J = 4.8 Hz, 4H), 3.17 (t, J = 4.8 Hz, 4H).
MS (ESI+) m/z 391 (M+l), 413 (M+23), 445 (M+55) Example 21.5: Preparation of N-(4-fluorobenzyI)-3-hydroxy-7,9-dimorpholino-4- oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000079_0001
(4-Fluorophenyl)niethanamine (64 mg, 0.5 mmol) was added into the solution of the product from Example 21.4 (80 mg, 0.2 mmol) in methanol (5 ml) and the mixture was heated at 70°C for 15h. After cooling down to room temperature, the solids were collected by filtration, washed with methanol three times and dried in vacuo to afford the desired compound (33 mg, 33%).
Ή NMR (300 MHz, DMSO-d6) δ 1 1.71 (s, 1H), 8.66 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.46-7.37 (m, 2H), 7.20 (t, J = 8.7 Hz, 2H), 7.02 (d, J = 1.5 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 3.82-3.71 (m, 8H), 3.24 (t, J = 4.2 Hz, 4H), 3.16 (t, J = 4.2 Hz, 4H).
MS (ESI") w/z 482 (M-l)
Example 22: Preparation of N-(3,4-dichlorobenzyI)-3-hydroxy-7,9-dimorphoIino- 4-oxo-4H-pyrido [ 1 ,2-a] py rimidine-2-carboxamide
Figure imgf000079_0002
This compound was prepared by adapting the procedure in Example 21.5.
Ή NMR (300 MHz, DMSO-d6) δ 1 1.60 (s, 1H), 8.80 (t, J = 6.0 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.67-7.61 (m, 2H), 7.39-7.33 (m, 1H), 7.03 (d, J = 1.5 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 3.81 (t, J = 4.5 Hz, 4H), 3.77 (t, J = 4.5 Hz, 4H), 3.26 (t, J = 4.5 Hz, 4H), 3.16 (t, J= 4.5 Hz, 4H). MS (ESI+) m/z 534 (M+l), 556 (M+23)
Example 23: Preparation of ethyl 2- (4-fIuorobenzylcarbamoyl)-3-hydroxy-7- morpholino-4-oxo-4, 9a-dihydro-3H-pyrido[l, 2-a]pyrimidin-9-yIcarbamate
Figure imgf000080_0001
5-Morpholino-2-nitropyridin-3-amine was prepared as described in example 21.1. Example 23.1: Preparation of ethyl 5-morpholino-2-nitropyridin-3-yl carbamate
Figure imgf000080_0002
To the solution of 5-morpholino-2-nitropyridin-3-amine (2 g, 8.8 mmol ) in pyridine (30 ml ) was added ethyl carbonochloridate (1.1 ml, 11 mmol ) at 0°C. After stirring at room temperature for 3 days, EA was added. The organic phase was washed with saturated aqueous NaCl three times, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography (EA / PE = 1 /l) to give the desired product (1.2 g, 50 %)
1H NMR (300 M Hz, CDC13) δ 10.06 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 4.26 (q, J i= 14.1 Hz, J 2= 7.2 Hz, 2H), 3.87 (t, J = 5.4 Hz, 4H), 3.45 (t, J = 5.4 Hz, 4H), 1.35 (t, J= 6.6 Hz, 3H)
MS (ESI+) w/z 351 (M+55) Example 23.2: Preparation of ethyl 2-amino-5-morpholinopyridin-3-yl carbamate
Figure imgf000081_0001
The mixture of the product from example 23.1 (900 mg, 3 mmol) and Pd/C (90 mg) in EtOH (10 ml) was stirred at room temperature under H2 atmosphere for 18 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give titled compound (730mg, 90%).
1H NMR (300 M Hz, CDC13) δ 7.57 (s, 2H), 6.61 (s, 1H), 4.24 (q, J i= 14.1 Hz, J2= 6.9 Hz, 2H), 3.84 (t, J= 4.8 Hz, 4H), 3.05 (t, J= 4.8 Hz, 4H), 1.32 (t, J= 6.9 Hz, 3H)
Example 23.3: Preparation of methyl 9-(ethoxycarbonylamino)-3-hydroxy-7- morpholino-4-oxo-4,9a-dihydro-3H-pyrido[l,2-a]pyrimidine-2-carboxylate
Figure imgf000081_0002
The mixture of the product from example 23.2 (120 mg, 0.45 mmol), DAF (176 mg, 0.67 mmol) and AcOH (13 mg, 0.23 mmol) in MeOH (0.5 ml) was heated at 80°C for 18 hours. After cooling down to room temperature, the solids were collected by filtration, washed with MeOH and dried in vacuo to give the desired product (20 mg, 1 1.5%).
Ή NMR (300 M Hz, DMSO-c/ 6) δ 8.64 (s, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 4.21 (q, J ,= 14.1 Hz, J 2= 6.9 Hz, 2H), 3.90 (s, 3H), 3.84-3.72 (m, 4H), 3.17-3.06 (m, 4H), 1.27 (t, J= 6.9 Hz, 3H) MS (ESI") m/z 393 (M-l) Example 23.4: Preparation of ethyl 2- (4-fluorobenzyIcarbamoyl)-3-hydroxy-7- morpholino- 4-oxo-4, 9a-dihydro-3H-pyrido[l,2-a]pyrimidin-9-yl carbamate
Figure imgf000082_0001
The solution of the product from example 23.3 (100 mg, 0.25 mmol) and (4- fluorophenyl) methan amine (158 mg, 1.27 mmol) in MeOH (2 ml) was heated at reflux for 3 h. After cooling down to room temperature, MeOH was concentrated in vacuo. The solids were collected by filtration, washed with MeOH and dried in vacuo to give the desired product (30 mg, 25%).
1H NMR (300 M Hz, DMSO- 6) δ 12.41 (s, 1H), 10.41 (t, J = 6.3 Hz, 1H), 9.90 (s, 1H), 8.32 (d, J = 2.1 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.38 (dd, J ,= 8.7 Hz, J 2= 5.7 Hz, 2H), 7.19 (t, J = 8.7 Hz, 2H), 4.60 (d, J = 6.0 Hz, 2H), 4.25 (m, 2H), 3.84-3.72 (m, 4H), 3.17-3.06 (m, 4H), 1.29 (t, J= 7.2 Hz, 3H)
MS (EST) w/z: 486 (M-l)
Example 24: Preparation of N-(4-fluorobenzyl)-9-(l, 3-propanesultam)-3- hydroxyl-7-morpholino-4-oxo-4H-py rido [1 ,2-a] pyrimidine-2-carboxamide.
Figure imgf000082_0002
4-(5-Bromo-6-nitropyridin-3-yl)morpholine was prepared as described in example 21.1 Isothiazolidine 1,1 -dioxide was made according to the literature: J. Org. Chem., 52, 11, 1987, 2162-2166. Example 24.1: Preparation of 4-[5-(l,3-propanesultam)-6-nitropyridin-3- yljmorpholine
Figure imgf000083_0001
To the mixture of 4-(5-bromo-6-nitropyridin-3-yl)morpholine (1.00 g, 3.47 mmol) in toluene (20 ml), isothiazolidine 1,1-dioxide (0.63 g, 5.21 mmol), Cul (0.17 g, 0.87 mmol), DMEDA (0.15 g, 1.74 mmol) and K2C03 (0.96 g, 6.94 mmol) were added successively. The mixture was heated at 80°C for 5 h under nitrogen atmosphere. After cooling down to room temperature, the mixture was filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH= 100/1 ) to give the desired product (0.49 g, 43.1 %).
Ή NMR (300 MHz, -DMSO) δ 8.16 (d, J = 2.7 Hz, 1H), 7.51 (d, J = 2.7 Hz, 1H), 3.79-3.72 (m, 6H), 3.43-3.34 (m, 6H), 2.43 (m, 2H ).
MS (ESI+) m/z 329 (M+l)
Example 24.2: Preparation of 3-(l, 3-propanesultam)-5-morpholinopyridin amine.
Figure imgf000083_0002
To the solution of the product from example 24.1 (1.20 g, 3.66 mmol) in EtOH (20 ml), SnCl22H20 (2.48g, 10.98 mmol) was added. The mixture was heated at 80°C for 5 h. After cooling down to room temperature, the mixture was adjusted pH to 9-10 with KOH (20%) and then filtrated. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=50/l) to afford the product as a brown solid (0.82 g, 75.3%).
1H NMR (300 MHz, d-DMSO) δ 7.67 (d, J = 3.0 Hz, 1H), 7.23 (d, J = 3.0 Hz, 1H), 5.52 (s, 2H), 3.71-3.67 (m, 4H), 3.53 (t, J = 6.9 Hz, 2H), 3.40 (t, J= 7.5 Hz, 2H), 2.94- 2.89 (m, 4H), 2.41 -2.35 (m, 2H). MS (ESI+) m/z 299 (M+l)
Example 24.3: Preparation of methyl 9-(l,3-propanesultam)-3-hydroxy-7- morpholino-4-oxo-4H-py rido [ 1 ,2-a] pyrimidine-2-carboxy late
Figure imgf000084_0001
The product from example 24.2 (0.55 g, 1.85 mmol), DAF (0.96 g, 3.69 mmol) and HO Ac (0.02 g 0.37mmol) were mixed in MeOH (1.2 ml). The mixture was heated at 90°C for 20 h. This mixture was used directly in the next step.
Example 24.4: Preparation of N-(4-fluorobenzyI)-9-(l,3-propanesultam)-3- hydroxy-7-morpholino-4-oxo-4H-pyrido [ 1 ,2-a] py rimidine-2-carboxamide.
Figure imgf000084_0002
The mixture from example 24.3 was diluted with MeOH (20 ml) and then (4- fluorophenyl)methan-amine (0.23 g, 1.84 mmol) was added. The mixture was heated at reflux for 3 h. After cooling down to room temperature, the resulting precipitates were collected by filtration, washed with MeOH and dried in vacuo to afford the product as a yellow solid (0.14 g, two steps yield 15.2%).
Ή NMR (300 MHz, d-DMSO) δ 11.89 (s, 1H), 9.70 (t, J = 6.3 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.35 (m, 2H), 7.16 (t, J = 8.7 Hz, 2H), 4.53 (d, J = 6.6 Hz, 2H), 3.98 (t, J = 6.3 Hz, 2H), 3.77-3.74 (m, 4H), 3.47 (t, J = 6.9 Hz, 2H), 3.21-3.18 (m, 4H), 2.47-2.44 (m, 2H).
MS (EST) m/z 516 (M-l)
Example 25: Preparation of N-(3,4-dichlorobenzyI)-9-(l,3-pr panesultam)-3- hydroxy-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000085_0001
This target was made in a similar way to Example 24.
1H NMR (300 MHz, -DMSO) δ 11.74 (s, 1H), 9.71 (t, J = 6.3 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.62-7.57 (m, 2H), 7.53 (d, J = 1.8 Hz, 1H), 7.33-7.28 (m, 1H), 4.57 (d, J = 6.0 Hz, 2H), 3.99 (t, J = 6.3 Hz, 2H), 3.78-3.74 (m, 4H), 3.48 (t, J = 6.9 Hz, 2H), 3.20-3.14 (m, 4H), 2.47-2.42 (m, 2H).
MS (ESI") m/z 566 (M-l)
Example 26: Preparation of preparation of 9-acetamido-N-(4-fluorobenzyl)-3- hydroxy-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000085_0002
yield:64%
Example 26.1: Preparation of 9-acetamido-N-(4-fluorobenzyI)-3-hydroxy-7- morpholino-4-oxo-4H-pyrido[l, 2-a]pyrimidine-2-carboxamide
Figure imgf000085_0003
Methyl-3-(benzyloxy)-9-bromo-7-morpholino-4-oxo-4H-pyrido[l ,2-a]pyrimidine-2- carboxylate (471 mg, 1.0 mmol), diphenylmethanimine (0.2 ml, 1.2 mmol), Pd2dba3 (46 mg, 0.05 mmol), xantphos (58 mg, 0.1 mmol) and Cs2C03 (489 mg, 1.5 mmol) were mixed in toluene (10 ml) . The mixture was heated under N2 atmosphere at 80°C for 18h. After cooling down to room temperature, toluene was removed in vacuo. The residue was purified by column chromatography (DCM / MeOH = 50 / 1) to give the desired product (470 mg, 82 %) .
Ή NMR (300 M Hz, CDC1) δ 7.91 (d, J = 2.4 Hz, 1H), 7.75-7.65 (m, 2H), 7.63-7.20 (m, 3H ), 7.41-7.31 (m, 6H), 7.31-7.20 (m, 3H), 7.19-7.09 (m, 2H), 5.12 (s, 2H), 3.76 (s, 3H), 3.73-3.62 (m, 4H), 3.16-3.02 (m, 4H)
MS (ESI+) m/z 597 (M+23) Example 26.2: Preparation of methyl 9-amino-3-(benzyloxy)-7-morpholino-4-oxo- 4H-pyrido [l,2-a]pyrimidine-2-carboxylate
Figure imgf000086_0001
To the solution of the product from 26.1 (100 mg, 0.17 mmol) in THF (2 ml), IN HCl (0.068 ml) was added. After stirring at room temperature for 5 minutes, aqueous NaHC03 solution was added. The mixture was extracted with DCM three times. The organic phase were combined, washed with water, dried and concentrated in vacuo. The residue was purified by gel column chromatography (PE / EA =1 / 1) to give the title compound (68 mg, 95%).
1H NMR (300 M Hz, DMSO-i/ 6) δ 7.71 (d, J = 2.4 Hz, 1H), 7.42-7.30 (m, 5H), 6.91 (d, J = 2.4 Hz, 1H), 6.11 (s, 2H), 5.13 (s, 2H), 3.79 (s, 3H), 3.76 (t, J = 4.5Hz, 4H), 3.13 (t, J= 4.5Hz, 4H) Example 26.3: Preparation of methyl 9-acetamido-3-(benzyIoxy)-7-morphoIino-4- oxo-4H-p rido [1 , 2-a] py rimidine-2-carboxylate
Figure imgf000087_0001
To the solution of the product from example 26.2 (350 mg, 0.9 mmol) in DCM (10 ml), TEA (370 mg, 3.66 mmol) and AcCl (143 mg, 1.83 mmol) were added successively at 0°C. After stirring at room temperature for 6 hours, water was added. The organic phase was washed with saturated brine three times, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography (EA / PE = 1 II) to give the desired product (250 mg, 64 %) . 1H NMR (300 M Hz, CDC1) δ 9.26 (s, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.51-7.45 (m, 2H), 7.39-7.33 (m, 3H), 5.30 (s, 2H), 4.02-3.83 (m, 7H), 3.34- 3.19 (m, 4H), 2.31 (s, 3H)
Example 26.4: Preparation of methyl 9-acetamido-3-hydroxy-7-morpholino-4-oxo- 4H-pyrido[l,2-a]pyrimidine-2-carboxylate
Figure imgf000087_0002
The product from example 26.3 (300 mg, 0.66 mmol) and FeCl3 (535 mg, 3.3 mmol) were mixed in DCM (5 ml). After stirring at room temperature for 4hours, dilute HC1 was added. The organic phase was washed with saturated brine three times, dried over Na2S04 and concentrated in vacuo. The residue was washed with EA to give the desired product (50 mg, 17 %).
Ή NMR (300 M Hz, DMSO-G? 6) δ 10.24 (s, 1H), 9.66-9.58 (m , 1H), 8.49 (d, J = 1.5 Hz, 1H), 7.78 (d, J = 1.5 Hz, 1H), 3.88 (s, 3H), 3.82-3.71 (m, 4H), 3.19-3.06 (m, 4H), 2.25 (s, 3H) Example 26.5: Preparation of 9-acetamido-N- (4-fluorobenzyl)-3-hydroxy-7- morpholino -4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000088_0001
The solution of the product from example 26.4 (40 mg, 0.1 1 mmol) and (4- fluorophenyl) methan amine (69 mg, 0.55 mmol) in MeOH (3 ml) was heated at reflux for 3 h. After cooling down to room temperature, MeOH was concentrated in vacuo. The solids were collected by filtration, washed with MeOH and dried in vacuo to give the desired product (1 1 mg, 22%).
1H NMR (300 M Hz, CDC1) δ 12.19-11.09 (m, 1H), 8.91-8.76 (m, 1H), 8.67 (d, J= 1.8 Hz, 1H), 8.02 (s, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.41-7.29 (m, 2H), 7.03 (t, J = 8.1Hz, 2H), 4.67 (s, 2H), 3.96-3.75 (m, 4H), 3.29-3.06 (m, 4H), 2.27 (s, 3H)
MS (ESI+) m/z 478 (M+23)
Example 27: Preparation of N-(4-fluorobenzyl)-9-(2-(dimethylamino)-2- oxoacetamido)-3-hydroxy-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2- carboxamide.
Figure imgf000088_0002
Example 27.1: Preparation of methyl 3-(benzyloxy)-9-(2-(dimethylamino)-2-oxo- acetamido)-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylate.
Figure imgf000089_0001
To the solution of the product from example 26.2 (0.12 g, 0.29 mmol) and TEA (0.1 1 g, 0.88 mmol) in DCM (5 ml), 2-(dimethylamino)-2-oxoacetyl chloride (49 mg, 0.35 mmol) was added. The mixture was heated at 40°C for 3 h. After cooling down to room temperature, the mixture was concentrated under reduced pressure and EA (20 ml) was added. The mixture was washed with H20 (3x20 ml) and brine successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=4/1) to give the crude product (0.1 1 g, crude yield 73.3%).
MS (ESf) w/z 510 (M+l)
Example 27.2: Preparation of methyl 9-(2-(dimethylamino)-2- oxoacetamido)-3- hydroxy-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylate.
Figure imgf000089_0002
This compound was prepared by adapting the procedure described in Example 26.4.
Ή NMR (300 MHz, d-DMSO) δ 10.66 (s, 1H), 10.33 (s, 1H), 8.47 (d, J= 2.7 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H), 3.80-3.75 (m, 4H), 3.26 (s, 3H), 3.17-3.13 (m, 4H), 2.97 (s, 3H). MS (ESr) w z 418 (M-l) Example 27.3: Preparation of N-(4-fluorobenzyl)-9-(2-(dimethylamino)-2- oxoacetamido)-3-hydroxy-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2- carboxamide.
Figure imgf000090_0001
This product was made by adapting the procedure described in Example 26.5.
1H NMR (300 MHz, </-DMSO) δ 12.23 (s, 1H), 10.82 (s, 1H), 10.08 (t, J= 6.3 Hz, 1H), 8.45 (d, J= 1.8 Hz 1H), 7.82 (d, J= 2.4 Hz, 1H), 7.42-7.37 (m, 2H), 7.23-7.16 (m, 3H), 4.60 (d, J = 6.3 Hz, 2H ), 3.80-3.74 (m, 4H), 3.15-3.12 (m, 4H), 2.92(s, 3H), 2.91 (s, 3H). MS (ESI") m/z 511 (M-l)
Example 28: Preparation of N-(4-fluorobenzyl)-3-hydroxy-9-(N-methyl acetamido)-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxamide
Figure imgf000090_0002
Example 28.1: Preparation of methyl 3- (benzyloxy)-9- (N-methylacetamido)-7- morpholino -4-oxo-4H-pyrido[l, 2-a]pyrimidine-2-carboxylate
Figure imgf000091_0001
The product from example 26.3 (500 mg, 0.1 mmol), Mel (669 mg, 4.71 mmol), and K2C03 (976 mg, 7.07 mmol) were mixed in DMF (10 ml). After stirring at 80°C for 18 hours, water was added. The reaction mixture was extracted with EA three times. The organic layers were combined, dried and concentrated in vacuo. The residue was purified by gel column chromatography (DCM / MeOH =30 / 1) to give the title compound (380 mg, 68%). 1H NMR (300 M Hz, CDC1) δ 8.36 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.55- 7.47 (m, 2H), 7.43-7.29 (m, 3H), 5.32 (s, 2H), 3.95-3.84 (m, 7H), 3.32 (s, 3H), 3.29- 3.18 (m, 4H), 1.97 (s, 3H)
MS (ESf) m/z 489 (M+23)
Example 28.2: Preparation of methyl 3-hydroxy-9- ( -methylacetamido) -7- morpholino -4-oxo-4H-pyrido [ 1 , 2-a] pyrimidine-2-carboxy late
Figure imgf000091_0002
The crude product was made by adapting the procedure described in Example 26.4, which was used for the next step directly. Example 28.3: Preparation of N- (4-fluorobenzyl)-3-hydroxy-9- (N-methyl acetamido) -7-morpholino-4-oxo-4H-pyrido [1 , 2-a] pyrimidine-2-carboxamide
Figure imgf000092_0001
This target was made by adapting the procedure described in the Example 26.5. 1H NMR (300 M Hz, DMSO- 6) 5 12.1 1 (s, 1H), 8.99 (t, J = 1.8 Hz, 1H), 8.10-7.99 (m, 2H), 7.43-7.36 (m, 2H), 7.17 (t, J = 8.7Hz, 2H), 4.56 (d, J= 6.0 Hz, 2H), 3.81-3.72 (m, 4H), 3.25-3.04 (m, 7H), 1.81 (s, 3H)
Example 29: Preparation of N-(4-fluorobenzyl)-3-hydroxy-9-(3- methyl-2- oxoimidazolidin-l-yl)-7-morphoIino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2- carboxamide
o
HN N""
Figure imgf000092_0002
Example 29.1: Preparation of methyl 3-(benzyIoxy)-9-(3-methyl-2- oxoimidazolidin-l -yl)-7-morpholino-4-oxo-4H-py rido [ 1 ,2-a] pyrimidine-2- carboxylate
Figure imgf000093_0001
This compound was prepared by adapting the procedure described in Example 2.1
1H NMR (300 MHz, CDC13) δ 8.24 (d, J= 1.8 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.53- 7.48 (m, 2H), 7.41-7.30 (m, 3H), 5.31 (s, 2H), 4.33 (t, J = 8.1 Hz, 2H), 3.91-3.84 (m, 7H), 3.54 (t, J= 8.1 Hz, 3H), 3.24 (t, J= 4.2 Hz, 4H), 2.93 (s, 3H).
MS (ESI+) m/z 494 (M+l), 516 (M+23) Example 29.2: Preparation of N-(4-fluorobenzyl)-3-hydroxy-9-(3-methyl-2- oxoimidazolidin-1 -yl)-7-morpholino-4-oxo-4H-py rido [1 ,2-a] pyrimidine-2- carboxamide
Figure imgf000093_0002
The product from Example 29.1 (100 mg, 0.20 mmol) and aluminum trichloride (162 mg, 1.22 mmol) were mixed in dichloromethane (5 ml). The mixture was stirred at room temperature for 4h. Then water (10 ml) was added and the mixture was extracted with dichloromethane. The organic layers were washed with IN HCl three times, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue and (4-fluorophenyl)methanamine (33 mg, 0.26 mmol) were mixed in methanol (5 ml) and the mixture was heated at 70°C for 15h. After cooling down to room temperature, 6N HCl was added dropwise till the pH of the mixture was about 4. The solids were collected by filtration, washed with methanol and dried in vacuo to afford the desired compound (50 mg, 50%).
1H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 9.14 (t, J = 6.0 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.78 (d, J - 2.1 Hz, 1H), 7.45-7.36 (m, 2H), 7.19 (t, J= 8.7 Hz, 2H), 4.55 (d, J = 6.0 Hz, 2H), 3.99 (t, J = 8.7 Hz, 2H), 3.76 (t, J = 4.5 Hz, 4H), 3.49 (t, J = 8.7 Hz, 2H), 3.15 (t, J= 4.5 Hz, 4H), 2.77 (s, 3H).
MS (ESI+) m/z 497 (M+l), 519 (M+23), 551 (M+55)
Example 30: Preparation of N-(3,4-dichlorobenzyl)-3-hydroxy-9-(3-methyl -2- oxoimidazolidin-l-yI)-7-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidine-2- carboxamide
Figure imgf000094_0001
This compound was prepared by adapting the procedure described in Example 29.2
1H NMR (300 MHz, DMSO-d6) δ 1 1.87 (s, 1H), 9.23 (t, J = 6.0 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.66-7.60 (m, 2H), 7.38-7.33 (m, 1H), 4.57 (d, J = 6.0 Hz, 2H), 4.03 (t, J = 8.1 Hz, 2H), 3.76 (t, J = 4.2 Hz, 4H), 3.53 (t, J = 8.1 Hz, 2H), 3.15 (t, J = 4.2 Hz, 4H), 2.79 (s, 3H).
MS (ESI+) m/z 547 (M+l), 569 (M+23)
Example 31: Preparation of 7-DimethyIamino-3-hydroxy-9-(3-methyl-2-oxo- imidazolidin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro - benzylamide
Figure imgf000095_0001
This target was made by adapting the procedure described in Example 7.
Example 31.1: Preparation of 3-Benzyloxy-7-dimethylamino-9-(3-methyl imidazoIidin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid ester
Figure imgf000095_0002
Ή NMR (300 MHz, DMSO-d6) δ 7.99 (d, J = 2.2 Hz, 1H), 7.89 (d, J =2.2 Hz, 1H), 7.50-7.30 (m, 5H), 4.07 (t, J = 7.5 Hz, 2H), 3.82 (s, 3H), 3.47 (t, J = 8.1 Hz, 2H), 3.02 (s, 6H), 2.80 (s, 3H).
MS (ESI+) m/z 452 (M+l)
Example 31.2: Preparation of 3-Benzyloxy-7-dimethylamino-9-(3-methyl-2-oxo - imidazolidin-l-yI)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000096_0001
The crude product was used in the next step. MS (ESI+) w/z 545 (M+l)
Example 31.3: Preparation of 7-Dimethylamino-3-hydroxy-9-(3-methyl-2-oxo- imidazolidin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro- benzylamide
Figure imgf000096_0002
Ή NMR (300 MHz, DMSO-d6) δ 1 1.89 (s, 1H), 9.07 (t, J = 6.2 Hz, 1H), 7.78 (d, J = 2.6 Hz, 1H), 7.72 (d, J= 2.6 Hz, 1H), 7.41 (dd, J= 5.9, 8.2 Hz, 2H), 7.19 (t, J= 8.6 Hz, 2H), 4.56 (d, J= 6.2 Hz, 2H), 4.01 (t, J= 7.0 Hz, 2H), 3.49 (t, J= 7.9 Hz, 2H), 2.96 (s, 6H), 2.77 (s, 3H).
MS (ESI+) m/z 455 (M+l)
Example 32: Preparation of 3-Hydroxy-7-(4-isopropyl-piperazin-l-yI)-9-(3- methyI-2-oxo-imidazolidin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide
Figure imgf000097_0001
This target was made by adapting the procedure described in Example 2.
Example 32.1: Preparation of 3-BenzyIoxy-7-bromo-9-(3-methyl-2-oxo- imidazolidin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxyIic acid methyl ester
Figure imgf000097_0002
This compound was prepared by adapting the procedure described in example 2.1.
Ή NMR (300 MHz, CDC13) δ 8.96 (s, 1H), 8.09 (s, 1H), 7.52-7.43 (m, 2H), 7.41-7.31 (m, 3H), 5.34 (s, 2H), 4.31 (t, J = 8.0 Hz, 2H), 3.89 (s, 3H), 3.54 (t, J = 8.0 Hz, 2H), 2.93 (s, 3H).
MS (ESI+) m/z 487 (M[Br79]+l), 489 (M[Br81]+i) Example 32.2: Preparation of 3-Benzyloxy-7-(4-isopropyl-piperazin-l-yI)-9-(3- methyl-2-oxo-imidazolidin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid methyl ester
Figure imgf000098_0001
This compound was prepared by adapting the procedure described in example 2.2.
1H NMR (300 MHz, CDC13) δ 8.23 (s, IH), 7.95 (s, IH), 7.52-7.43 (m, 2H), 7.41-7.31 (m, 3H), 5.30 (s, 2H), 4.31 (t, J = 8.0 Hz, 2H), 3.89 (s, 3H), 3.54 (t, J = 7.7 Hz, 2H), 3.29 (s, 4H), 2.93 (s, 3H), 2.68 (s, 5H), 1.09 (s, 6H).
MS (ESI+) w/z 535 (M+l) Example 32.3: Preparation of 3-Hydroxy-7-(4-isopropyl-piperazin-l-yl)-9-(3- methyl-2-oxo-imidazolidin- 1 -yl)-4-oxo-4H-py rido [ 1 ,2-a] pyrimidine-2-carboxy lie acid methyl ester
Figure imgf000098_0002
This compound was prepared by adapting the procedure described in example 2.3. Ή NMR (300 MHz, DMSO- ) δ 10.26 (s, IH), 9.50 (s, IH), 7.98 (d, J = 2.5 Hz, IH), 7.81 (d, J= 2.5 Hz, IH), 4.18 - 4.08 (m, 2H), 3.94 - 3.85 (m, 5H), 3.64 - 3.45 (m, 5H), 3.29 - 3.16 (m, 2H), 3.1 1 - 2.98 (m, 2H), 2.81 (s, 3H), 1.30 (d, J= 6.6 Hz, 6H).
MS (ESI+) m/z 445 (M-TFA+1) Example 32.4: Preparation of 3-Hydroxy-7-(4-isopropyl-piperazin-l-yl)-9-(3- methyl-2-oxo-imidazolidin-l-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide
Figure imgf000099_0001
This compound was prepared by adapting the procedure described in example 2.4.
Ή NMR (300 MHz, DMSO-d*) δ 11.95 (s, 1H), 9.25-9.10 (brs, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.40 (dd, J = 5.8, 8.8 Hz, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.55 (d, J = 6.3 Hz, 2H), 4.00 (t, J = 8.0 Hz, 2H), 3.49 (t, J = 8.0 Hz, 2H), 3.20 - 3.08 (m, 4H), 2.77 (s, 3H), 2.74 - 2.67 (m, 1H), 2.65 - 2.56 (m, 4H), 1.01 (d, J = 6.5 Hz, 6H).
MS (ESf) m/z 538 (M+l)
Example 33: Preparation of 3-Hydroxy-4-oxo-9-(l,3-pn>panesultam)-7-piperazin- l-yl-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide
Figure imgf000099_0002
This compound was prepared by adapting the procedures described in examples 15 and example 24. ACTIVITY ASSAYS
Compounds of the present invention were tested for biological activity using the assay techniques below:
Inhibition of HIV replication
HuT-78 cells are seeded into 96 well microtitre plates at 50,000 cells per 50μ1 per well in RF-10 containing 2μg/mL polybrene (RF-10/2). Compounds are prepared to 4 x final concentration in RF-10/2, and 30 μΐ, added to cells. Virus (40 in RF-10/2 containing 1600 pfu) is added to each well or 40 xL RF-10/2 for negative controls and for assaying compound cytotoxicity. After 24 hrs, an additional 90 μΐ, of media or media containing 1 x compound is added to each well. At 4 days post infection, 100xL of media is removed from each well and replaced with 100 μΐ of fresh media with or without compound. Forty eight hours later supematants are harvested and levels of extracellular p24 determined. Supematants are diluted 1 in 10,000 and p24 levels assayed using the Vironostika p24 assay kit. EC50 is calculated as the concentration required to inhibit HIV p24 production to 50% that of no drug controls. In the tables below, this assay type is referred to as NL4-3.
Luciferase assay
Reporter Viruses:
Infectivity assays using reporter viruses derived from lentiviral vectors capable of a single round of infection were used to determine the activity (EC50) of compounds. The DNA used to generate viruses for infection was the full-length HIV-1 genome which had been envelope-deleted. In addition, a reporter gene (the firefly luciferase gene from Photinus pyralis) was cloned into the nef region of the HIV backbone for ease of assay readout. Viruses were generated via liposomal transfection of the lentiviral-derived DNA backbone together with a vesicular stomatitis virus glycoprotein (VSV-G) expression plasmid into 293T cells. Culture supematants containing VSV-G pseudotyped virions were harvested 64h post transfection, clarified by centrifugation to remove cell debris, and frozen at -70°C until use. Assay method:
293FT cells were plated out at 12000 cells per well in CellView 96-well cell culture plates (Invitrogen) 16h prior to compound addition. Compounds were preincubated with cells for 4h at 37°C prior to the addition of virus sufficient to generate approximately 10000 Luciferase light units (as measured by the Victor Wallace luminometer) upon assaying using the Bright-Glo™ reagent (Promega) according to the manufacturer's instructions at 48h post infection.
In the tables below, this assay is referred to as NLXLuc or HIV-Luc.
Table 1
Figure imgf000101_0001
Figure imgf000102_0001
^+++++indicates value less than 1 nM
+++++ indicates value between 1 nM and 10 nM ++++ indicates value between 10 nM and 20 nM +++ indicates value between 20 nM and 100 nM ++ indicates value between 100 nM and 1 μΜ + indicates value greater than 1 μΜ
Table 2
Example Structure Assay Type Cell type EC50
24.4 NL4-3 HuT-78 ++++++
Figure imgf000103_0001
28.3 NL4-3 HuT-78
23.4 NL4-3 HuT-78 +++++
26.5 NL4-3 HuT-78 +++
comparative NL4-3 HuT-78 ++ example comparative NL4-3 HuT-78 ++ example
0 Table 3
Figure imgf000104_0001
Table 4
Figure imgf000104_0002
As can be seen from Tables 1 to 4, the compounds of the present invention show surprisingly enhanced activity against the HIV virus when compared to compounds which have previously been exemplified. Table 5
Figure imgf000105_0001
Table 6
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Evaluation of Bioavailability and Pharmacokinetic Profiles of the Compound of Example 3.4 in Male Sprague Dawley Rats Following Intravenous and Oral Administration Method: For IV infusion over 10 minutes the compound of Example 3.4 was dissolved in 20% DMSO, 30% PEG400 and 50% Water. For oral (PO) dosing AVX62738 was dissolved in 0.5%benzyl alcohol and 0.4% Tween 80 and 99.1% 0.5% hydroxypropylmethylcellulose. Compounds were dosed IV and then after a one week washout, orally in the same rats.( Body weight: Rat 1 : 254.7 g; Rat 2: 253.4 g). Ex-vivo plasma samples were assayed for AVX62738 using an LC-ms method of Lower limit of quantitation. (LLOQ)=2.5ng/mL.
Results:
Table 7: Plasma Concentrations of Compound 3.4 in Male Sprague Dawley Rats following Intravenous and Oral Administration
Sample Plasma Concentration (ng/mL)
Collection Animal Number
Time AVX62738 (IV-5 mg/kg) AVX62738 (PO-10 mg/kg)
Point (hr) Rat i Rat 2 Mean Rat i Rat 2 Mean
Pre-dose BLQ BLQ NA BLQ BLQ NA
0.083 2713.49 3352.49 3032.99 42.37 28.06 35.21
0.25 1994.77 2133.03 2063.90 66.22 78.08 72.15
0.5 1211.86 1064.57 1138.21 35.66 91.60 63.63
1 547.66 506.38 527.02 20.94 58.11 39.52
2 122.82 103.78 113.30 13.83 14.31 14.07
4 19.34 18.73 19.03 5.62 4.96 5.29
6 5.44 6.97 6.21 2.62 BLQ 1.31
8 2.64 2.19 2.41 148.29* BLQ NA
24 BLQ BLQ NA 4.66* BLQ NA
*The concentrations of these timepoints were not kept for calculation.
Lower limit of quantitation. (LLOQ)=2.5ng/mL
BLQ: Below limit of quantitation
SD: Standard deviation
NA: Not applicable, or failed to collect samples Table 8. Selected Pharmacokinetics Parameters of Compound 3.4 in Male Sprague Dawley Rats following Intravenous and Oral Administration
AUC(o-t) AUC(o-oo) MRTi0-oo) /2z Tmax Vz CLz max F ug/L*hr ug/L*hr hr hr hr L/kg L/hr/kg ίϊ/L %
IV (5 m ka)
701 1856.72 1862.02 0.68 1.39 0.08 5.39 2.69 2713.49
702 1852.06 1856.14 0.63 1.29 0.08 5.02 2.69 3352.49
Mean 1854.39 1859.08 0.66 1.34 0.08 5.21 2.69 3032.99
PO (10 mg/ke
801 82.79 89.04 2.03 1.65 0.25 NA NA 66.22 2.39
802 124.14 130.06 1.22 0.83 0.50 NA NA 91.60 3.50
Mean 103.47 109.55 1.63 1.24 0.38 NA NA 78.91 2.95 Table 9. Clinical Observation
Clinical Observation
Following intravenous administration, no obvious abnormalities were observed..
Following oral administration, no obvious abnormalities were observed.
It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

CLAIMS:
A compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000111_0001
I
R1 and R2 are each independently selected from the group consisting of hydrogen,
Figure imgf000111_0002
Ci-4alkylC3-6cycloalkyl, C(0)Ci-4alkyl, C02C1-4alkyl, -C(0)C(0)NR6R7, S02C1-4alkyl, S02NR6R7; or R1 and R2 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from Ci^alkyl, C3-6cycloalkyl, halo, aryl, C(0)Ci-4alkyl, S02C1-4alkyl, S02H, C02H, C02C1-4alkyl, NR6R7 C,.4alkylNR6R7; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon; wherein R6 and R7 are independently selected from the group consisting of hydrogen and C1-4alkyl, and C3-6cycloalkyl; or R6 and R7 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N and O;
R3 and R4 are each independently selected from the group consisting of hydrogen, C^alkyl, Ci-4alkylC3-6cycloalkyl, C(0)Ci-4alkyl, C02C1-4alkyl, -C(0)C(0)NR8R9, S02C1-4alkyl, S02NR8R9; or R3 and R4 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from C3- cycloalkyl, halo, aryl, C(0)C1-4alkyl, S02C1-4alkyl, S02H, C02H, C02Ci.4alkyl, NR8R9 ; C1-4alkylNR8R9; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon; wherein R8 and R9 are each independently selected from the group consisting of hydrogen, C1-4alkyl and C3-6cycloalkyl; or R and R taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N and O;
R5 is 0-3 substituents each of which is independently selected from the group consisting of halo, Ci-10alkyl, C2-i0alkenyl, -O-Ci-ioalkyl, C(0)Ci-4alkyl C02H, C02Ci-4alkyl, CN, NH2, N02, CF3, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -O-alkylaryl.
A compound according to claim 1 wherein R3 and R4 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from C1-4alkyl.
A compound according any one of claims 1 or 2, wherein R3 and R4 taken together with the attached nitrogen forms a 4-7 membered heterocyclic ring which contains at least one additional sulfur heteroatom in the S(0)2 oxidation state adjacent to the attached nitrogen, and wherein the ring contains one additional nitrogen atom, wherein the additional nitrogen atom is optionally substituted with Ci-4alkyl.
A compound according to claim 3, wherein the additional nitrogen is substituted with methyl.
A compound according to claim 1, wherein NR3R4 is selected from the group consisting of:
Figure imgf000113_0001
I wherein R1 and R2 are each independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4alkylC3-6cycloalkyl, C(0)Ci-4alkyl, C02C1-4alkyl, -C(0)C(0)NR6R7, S02C alkyl, S02NR6R7; or R1 and R2 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N, O or S where S can be at the S, S(O) or S(0)2 oxidation state and wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more substituents selected from C1-4alkyl, C3-6cycloalkyl, halo, aryl, C(0)C1-4alkyl, S02C alkyl, S02H, C02H, C02C1-4alkyl, NR6R7 ,
7
C1-4alkylNR R ; and further wherein one of the carbon atoms in the heterocyclic ring is optionally a carbonyl carbon; wherein R6 and R7 are independently selected from the group consisting of hydrogen and Ci-4alkyl, and C3-6cycloalkyl; or R6 and R7 taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N and O; wherein R3 is C1-4alkyl and R4 is S02Ci-4alkyl; or wherein NR3R4 forms a cyclic sulphonamide of the formula II:
Figure imgf000114_0001
II wherein Y is selected from the group consisting of a bond, CH2, NH and NCi- 4alkyl; and A is a bond or CH2; wherein R5 is 0-3 substituents each of which is independently selected from the group consisting of halo, Ci-i0alkyl, C2-i0alkenyl, -O-Ci.ioalkyl,
C(0)C alkyl C02H, C02C alk l, CN, NH2, N02, CF3> aryl, heteroaryl, alkylaryl, alkylheteroaryl, -O-alkylaryl.
1
7. A compound according to any one of claims 1 to 6, wherein R and R taken together with the attached nitrogen form a 4-7 membered heterocyclic ring which contains zero to two additional heteroatoms selected from N or O, wherein said heterocyclic ring is optionally substituted at the carbon or nitrogen atoms with one or more
Figure imgf000114_0002
substituents.
1 ")
8. A compound according to any one of claims 1 to 7, wherein R and R taken together with the attached nitrogen form morpholine.
1 2
9. A compound according to any one of claims 1 to 7, wherein R and R are taken together with the attached nitrogen form piperazine
10. A compound according to any one of claims 1 to 7, wherein R and R are taken together with the attached nitrogen form N-methyl piperazine.
11. A compound according to any one of claims 1 to 6, wherein NR R is selected from the group consisting of:
Figure imgf000115_0001
12. A compound according to any one of claims 1 to 9, wherein R5 is 1-2 substituents each independently selected from halo.
13. A compound according to any one of claims 1 to 10, wherein R5 is 1-2 substituents each independently selected from CI or F.
14. A compound according to any one of claims 1 to 11, wherein R5 is a fluorine substituent at the 4-position of the phenyl ring.
15. A compound according to any one of claims 1 to 11, wherein R5 is two chlorine substituents at the 3 and 4-position of the phenyl ring. 16. A compound selected from the group consisting of:
Figure imgf000115_0002
17. A method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of any one of claims 1 to 16 or a pharmaceutically acceptable derivative, salt or prodrug thereof.
18. The use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject. 19. A method according to claim 17 or a use according to claim 18, wherein the viral infection is a HIV or SIV infection.
20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier, diluent or excipient.
PCT/AU2011/000894 2010-07-16 2011-07-15 7, 9-nitrogen radical-4-oxo-4h-pyrido[l,2-a]pyrimidine-2-carboxylic acid benzylamide anti-virals WO2012006680A1 (en)

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