WO2012058173A1 - Hiv integrase inhibitors - Google Patents

Hiv integrase inhibitors Download PDF

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Publication number
WO2012058173A1
WO2012058173A1 PCT/US2011/057557 US2011057557W WO2012058173A1 WO 2012058173 A1 WO2012058173 A1 WO 2012058173A1 US 2011057557 W US2011057557 W US 2011057557W WO 2012058173 A1 WO2012058173 A1 WO 2012058173A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
hydroxy
chloro
fluorobenzyl
trione
Prior art date
Application number
PCT/US2011/057557
Other languages
French (fr)
Inventor
Guillaume Barbe
Natalie N. M. Nguyen
Marc Blouin
Yves Gareau
David A. Powell
Bernard Cote
Guy Roland Humphrey
Jeffrey Thomas Kuethe
Karla Glaser Childers
Julie Farand
Vincent Hector Emile Trepanier
Alexandre Larivee
Vanessa Louise Rada
Mark W. Embrey
Thomas G. Steele
John T. Sisko
David Jonathan Bennett
Izzat Tiedje Raheem
John David Schreier
Timothy John Hartingh
William D. Shipe
Jaime Lynn Bunda
Original Assignee
Merck Sharp & Dohme Corp.
Merck Canada Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp & Dohme Corp., Merck Canada Inc. filed Critical Merck Sharp & Dohme Corp.
Priority to EP11836929.7A priority Critical patent/EP2632454A1/en
Priority to AU2011320651A priority patent/AU2011320651A1/en
Priority to CA2814703A priority patent/CA2814703A1/en
Publication of WO2012058173A1 publication Critical patent/WO2012058173A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 is directed to certain imidazolo[5,l-a]naphthyridine compounds and pharmaceutically acceptable salts thereof. These compounds are inhibitors of the HIV integrase enzyme.
  • the present invention is also directed to the use of the compounds and their salts in the prophylaxis or treatment of infection by HIV and in the prophylaxis, treatment, or delay in the onset or progression of AIDS.
  • HIV human immunodeficiency virus
  • HIV-1 virus HIV type-1 virus
  • HIV -2 virus HIV type-2 virus
  • retrovirus replication is the insertion by virally-encoded integrase of +pro viral DNA into the host cell genome, a required step in HIV replication in human T- lymphoid and monocytoid cells.
  • Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear pro viral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site.
  • the fourth step in the process, repair synthesis of the resultant gap may be accomplished by cellular enzymes.
  • Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)].
  • Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, .D. et al., Science, 231, 1567 (1 86); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
  • antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhibitors such as indinavir and nelfinavir.
  • the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication.
  • the inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIV infected cells.
  • the following references are of interest as background:
  • US 7598264 B2 discloses certain hydroxy polyhydro-2,6-naphthyridine dione compounds that are HIV integrase inhibitors.
  • US 721 1572 B2 discloses certain nitrogen-containing fused ring compounds and their use as HIV integrase inhibitors.
  • WO 2006/107478 A2 discloses a crystalline sodium salt of 6-(3-chloro-4- fluorobenzyl)-4-hydroxy-2-isopropyl-N 5 N-dimethyl-3,5-dioxo-2,3 5 5,6,7,8-hexahydro-2,6- naphthyridine- 1 -carboxamide, which is an HIV integrase inhibitor.
  • WO 2008/048538 Al discloses certain hexahydro-diazocinonaphthyridine trione compounds which are HIV integrase inhibitors.
  • WO 2009/154870 Al discloses hydroxy substituted
  • polyhydropyrimidopyridodiazocine trione compounds which are HIV integrase inhibitors.
  • the present invention is directed to certain certain imidazolo[5,l- ]naphthyridine compounds. These compounds (including hydrates and solvates thereof), opti onally in the form of pharmaceutically acceptable salts, are useful in the inhibition of retroviral integrases and for the prophylaxis or treatment of infections or other adverse diseases or conditions caused by retroviruses.
  • the compounds of the present invention are, for example, useful in: (a) the inhibition of HIV integrase (e.g., HIV-1 or HTV-2) and STV, (b) the prophylaxis or treatment of infection by HIV or SIV, and (c) the prophylaxis, treatment, and delay in the onset or progression of AIDS and or ARC.
  • the compounds are useful in: (a) the inhibition of XMRV, (b) the prophylaxis or treatment of infection by XMRV and (c) the prophylaxis, treatment or delay in the onset or progression of diseases or conditions caused by XMRV infection such as prostate cancer or chronic fatigue syndrome.
  • the compounds are useful in: (a) the inhibition of HTLV (e.g., type 1, type 2 or type 3), (b) the prophylaxis or treatment of infection by HTLV and (c) the prophylaxis, treatment or delay in the onset or progression of diseases or conditions caused by HTLV such as T-cell leukemia or T-cell lymphoma.
  • the compounds can be used per se but are typically employed with one or more other ingredients in pharmaceutical compositions and optionally in combination with other antiretroviral agents, anti-infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention includes compounds of Formula I and
  • RlA and RlB are each independently:
  • Rl a d RlB are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or etliylenedioxy;
  • R2A and R2B are each independently:
  • R2A an d R2B together form oxo
  • R3A and R3B are each independently:
  • Ci_8 alkyl optionally substituted with OH, O-Ci-8 alkyl, O-C] _8 haloalkyl, CN, N(RA)RB ? C(0)N(RA)RB, C(0)RA 5 CO2 A, C(0)-N(RA)-C2-8 alkylene -ORB, SRA, S(0)RA S SO2 A S02N(RA)RB F N(RA)C(0)RB ⁇ N( A)C02 B, N(RA)S02R B S N(RA)S02N(RA)RB ;
  • R4, R5 and R6 are defined as set forth in Part A, Part ⁇ or Part C below:
  • Ci-8 alkyl substituted with HetP Ci-8 hydroxyalkyl substituted with Ci-8 haloalkyl or CycA; or
  • R5 and R6 are each independently:
  • R4 and R5 together with the atoms to which they are attached form a 4- to 8- membered fused azacycloalkyi ring which is optionally substituted with from 1 to 4 substituents each of which is independently:
  • N(RA)S02N(RA)RB 5 N(RA)C(0)N(RA)RB, or 0C(0)N(RA)RB 5
  • R4 is:
  • N(RA)S02N(RA)RB F N(RA)C(0)N(RA)RB, or 0C(0)N(RA)RB,
  • R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 4- to 8-membered cycloalkyl, which can be optionally fused to a benzene ring or a 5 or 6-membered heteroaryl ring, (ii) a 6- to 10-membered fused or bridged bicycloalkyl, or (iii) a 5- to 8- membered heterocyclylalkyl in which the ring heteroatom is selected, from N, O and S where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted on a ring carbon with oxo and is optionally substituted with from 1 to 4 substituents each of which is independently:
  • N(RA)S02N(RA)RB S N(RA)C(0)N(RA)RB, or
  • Ci_8 alkyl substituted with AryB (8) Ci_8 alkyl substituted with AryB, .
  • AryA is an aryl which is optionally substituted with from 1 to 5 substituents, wherein:
  • each of the substituents is independently:
  • N02 N(RA)RB 5 C(0)N(RA)RB, C(0)RA CO2 A SRA S(0)RA SO2R S02N(RA)RB, N(RA)C(0)RB S N(RA)C02R B S
  • CycA is a 3- to 8-membered monocyclic or bicyclic cycloalkyl which is optionally
  • each CycB independently has the same definition as CycA;
  • HetA is a heteroaryl which is optionally substituted with from 1 to 5 substituents, each of which is independently:
  • each HetB independently has the same definition as HetA;
  • HetP is (i) a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2 or (ii) a 6- to 10- membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0) 2 ; and wherein the saturated or mono- unsaturated heterocyclic or heterobicyclic ring is optionally substituted with a total of from 1 to 4 substituents, each of which is independently halogen, Ci-g alkyl, haloalkyl, O-Ci-6 alkyl, O-Ci-6 haloalkyl, oxo, C(0)N(RA)RB,
  • each HetQ independently has the same definition as HetP;
  • each RA is independently H, C ⁇ -6 alkyl or haloalkyl
  • each RB is independently H, Ci-6 alkyl or 0 . haloalkyl
  • each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; and each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(0)2-
  • the present invention also includes pharmaceutical compositions containing a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present invention further includes methods involving compounds of Formula I for the treatment of AIDS, the delay in the onset or progression of AIDS, the prophylaxis of AIDS, the prophylaxis of infection by HIV, and the treatment of infection by HIV.
  • the present invention includes compounds of Formula I above (including hydrates and solvates thereof), and pharmaceutically acceptable salts thereof. These compounds are effective inhibitors of wild-type HIV integrase (e.g., HIV-l) and may be effective inhibitors of mutant strains of HIV integrase.
  • wild-type HIV integrase e.g., HIV-l
  • mutant strains of HIV integrase e.g., HIV-l
  • a first embodiment of the present invention is a compound of Formula I (alternatively and more simply referred to as “Compound I”), or a pharmaceutically acceptable salt thereof, wherein:
  • AryA is phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently:
  • each AryB independently has the same definition as AryA;
  • CycA is a 3- to 6-membered cycloalkyi which is optionally substituted with from 1 to 3 substituents each of which is independently OH, C ⁇ -6 alkyl, 0-Ci_6 alkyl, or Ci-g alkyl substituted with O-Ci-6 alkyl;
  • each CycB independently has the same definition as CycA;
  • HetA is a 5- or 6-membered .
  • heteroaromatic ring containing a total of from 1 to 3
  • heteroatoms independently selected from N, S and O, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently Ci-4 alkyl, OH, O-C1.4 alkyl, halogen, CN, C(0)N(RA)RB, C(0)RA C(0)ORA or SO2RA;
  • each HetB independently has the same definition as HetA;
  • HetP is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently C 1.4 alkyl, oxo, C(0)N(RA)RB ? C(0)RA, CO2R or SO2RA; and each HetQ independently has the same definition as HetP;
  • a second embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
  • Rl A and RIB are each independently:
  • RlA and R*B are respectively located on adjacent carbons in the phenyl and together form methylenedioxy or ethylenedioxy;
  • RlC is:
  • a third embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
  • R1 A and RlB are each independently:
  • a fourth embodiment of the present invention is compound of Formula I, or a pharmaceutically acceptable salt thereof, wherem: Rl A and RlB are each independently:
  • RlC is:
  • a fifth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
  • R! and R B are each independently:
  • RlC is:
  • Rl R B and R C are independently provided that at least one of Rl R B and R C is other than H;
  • a sixth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl A is F in the para position of the benzyl moiety; Rl B is H, CI, or Br in the ortho or meta position of the benzyl moiety; RlC is H; and all other variables are as originally defined or as defined in Embodiment E .
  • a seventh embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2A and R3A are each independently H, fluoro, or Ci_6 alkyl; R2B i s H; R3B 1S H; and all other variables are as originally defined or as defined in any one of the foregoing embodiments.
  • An eighth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2A 5 R2B ⁇ R3A 3 ⁇ 4 and R3B are each H; and all other variables are as originally defined or as defined in any one of the foregoing embodiments.
  • a ninth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4, R5 and R6 are defined as set forth in Part A, Part B or Part C below:
  • R5 and R6 is H or Ci_6 alkyl, and the other of R5 and R6 is:
  • haloalkyl CN, N(RA)RB, C(0)N(RA)RB, C(0)RA, CO2 A, SRA, S(0)RA or SO2R ,
  • R6 is:
  • Ci_8 alkyl (2) Ci_8 alkyl, (3) Ci-6 haloalkyl, or
  • haloalkyl CN ; N(RA)RB S C(0)N(RA)RB ? C(0)RA, C02R A , SRA, S(0)RA S02RA, or S02N(RA)RB;
  • spirocyclic ring which is (i) a 5- to 7-membered cycioalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl, or (iii) a 5- to 7-membered heterocyclylalkyl in which the ring atom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted on a ring carbon with oxo and is optionally substituted with from 1 to 3 substituents each of which is independently:
  • haloalkyl CN, N(RA)RB ; C(0)N(R A )RB ; C(0)RA CO2 A, SRA, S(0)RA, SO2RA or S02N(R A )RB,
  • CycA is a 3- to 6-membered cycioalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, Ci_6 alkyl, O-Ci-6 alkyl, or Ci-6 alkyl substituted with O-Ci-6 alkyl; and each CycB independently has the same definition as CycA.
  • a tenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4 5 R5 and R6 are defined as set forth in Part A, Part B or Part C below:
  • R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl which is optionally substituted on a ring carbon with oxo, or (iii) a 5- or 6-membered heterocyclylalkyl in which the ring atom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently:
  • CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently Ci-4 alkyl, O-C ⁇ .4 alkyl, or Cj-4 alkyl substituted with 0-Ci_4 alkyl; and CycB
  • An eleventh embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4, R5 and are defined as set forth in Part A, Part B or Part C below: R is:
  • R5 and R.6 is H or Ci-4 alkyl, and the other of R5 and R0 is:
  • R and R5 together with the atoms to which they are attached form a 5- or 6- membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently:
  • R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl which is optionally substituted on a ring carbon with oxo, or (iii) a 5- or 6-membered heterocyclylalkyl in which the ring atom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C ⁇ -4 alkyl,
  • CycA is a 3- to 6-membered cycloaikyl
  • CycB is a 3- to 6-membered cycloaikyl
  • a twelfth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4, R5 and 6 are defined as set forth in Part A, Part B or Part C below:
  • oalkyl ring is optionally substituted with 1 or 2 substituents each of which is independently methyl or ethyl; and each asterisk (*) denotes the point of attachment to the rest of the compound;
  • R4 is as defined in Part A;
  • CycA is cyclopropyl
  • CycB is cyclopropyl, cyclobutyl, or cyclopentyl.
  • a thirteenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4, R5 and R6 are as defined in Embodiment El 2, except that in part B of the definition of R4 s 5 and R6:
  • R4 and R5 together with the atoms to which they are attached form a fused azacycloalkyl ring which is:
  • R6 is (1 ) H, (2) CH3, or (3) CH2CH3 ;
  • R4 is (1) R (2) CH3, (3) CH 2 CH 3 , (4) CH2CH 2 CH 3 , (5) CH(CH 3 ) 2 ,
  • a fourteenth embodiment of the present invention is a compound of Formula I, or a phannaceutically acceptable salt thereof, wherein RA and RB are each independently H or C1-.4 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments.
  • a fifteenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RA and RB are each independently H or C 1.3 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments.
  • a sixteenth embodiment of the present invention is a compound of Formula i, or a pharmaceutically acceptable salt thereof, wherein RA and R are each independently H or CH3 ; and all other variables are as originally defined or as defined in any of the preceding embodiments.
  • a seventeenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
  • An eighteenth embodiment of the present invention is a compound of Formula I, or an individual enantiomer or diastereomer thereof, which is selected from Examples 1-177, as set forth in the Examples below.
  • An nineeenth embodiment of the present invention is a compound of Formula I, or an individual enantiomer or diastereomer thereof, which is selected from the group consisting of:
  • a twentieth embodiment of the present invention is a compound of Formula I, or an individual enantiomer or diastereomer thereof, which is selected from Examples 12, 14, 15, 17, 19, 26-29 or 150, as set forth in the Examples below.
  • variables R 1A , R 1B , R 1C , R 2A , R 2B , R 3A , R 3B , R 4 , R 5 and R 6 are selected independently of each other.
  • a first class of compounds of the present invention includes compounds of Formula II:
  • Ri A, IB and RlC are as defined in Embodiment E2;
  • R2A and R3A are each independently H, fluoro, or C 1-6 alkyl
  • R4, R5 and R0 are as defined in Embodiment E9;
  • CycA is a 3- to 6-membered cycloaikyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, Ci-6 alkyl, O-Ci-6 alkyl, or C ⁇ -(, alkyl substituted with O-Ci-6 alkyl;
  • each CycB independently has the same definition as CycA;
  • each R is independently H or Ci-6 alkyl
  • each RB is independently H or Ci-6 alkyl.
  • a first sub-class of the first class (alternatively referred to herein as "Subclass CI -SI”) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein R2A and R3A are each independently H, fluoro, or CH3; and all other variables are as originally defined in Class CI .
  • a second sub-class of the first class includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein each R is independently H or C1.4 alkyl; each RB is independently H or Cj.g alkyl; and all other variables are as originally defined in Class CI or as defined in Sub-class CI -S I .
  • a third sub-class of the first class includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein each R is independently H or CH3; each RB is independently H or CH3; and all other variables are as originally defined in Class CI or as defined in Sub-class CI -SI.
  • a second class of compounds of the present invention includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein:
  • R1 A S RIB a d RlC are as defined in Embodiment E3;
  • R2A and 3A are both H;
  • R4 ; R5 and R ⁇ 5 are as defined in Embodiment E10;
  • CycA is a 3- to 6-membered cycloaikyl which is optionally substituted with from 1 to 3 substituents each of which is independently C1 -.4 alkyl, O-C1-4 alkyl, or C1-.4 alkyl substituted with OC1-.4 alkyl; and
  • CycB independently has the same definition as CycA;
  • each RA is independently H or Ci _ alkyl
  • each RB is independently H or Ci_ alkyl.
  • a first sub-class of the second class includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein each R is independently H or Ci_4 alkyl; each RB is independently H or Ci-6 alkyl; and all other variables are as originally defined in Class C2.
  • a second sub-class of the second class includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein each RA is independently H or CH3; each RB is independently H or CH3; and all other variables are as originally defined in Class C2.
  • a third class of compounds of the present invention includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein:
  • RlA ⁇ RIB and RlC are as defined in Embodiment E4;
  • R2A and R3A are both H;
  • R4 s R5 and R6 are as defined in Embodiment El 1;
  • CycA is a 3- to 6-membered cycloalkyl
  • CycB is a 3- to 6-membered cycloalkyl.
  • a fourth class of compounds of the present invention includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein:
  • RlA, RlB and C are as defined in Embodiment E5;
  • R2A and R3A are both H;
  • R4, R5 and R0 are as defined in Embodiment El 2;
  • CycA is cyclopropyl
  • CycB is independently cyclopropyl, cyclobutyl, or cyclopentyl.
  • a first sub-class of the fourth class includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein RlA is F in the para position of the benzyl moiety; RlB is H, CI, or Br in the ortho or meta position of the benzyl moiety; and RlC is H; and all other variables are as originally defined in Class C4.
  • a second sub-class of the fourth class includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein all of the variables are as originally defined in Class C4, except that in part B of the definition of R4, R5 and 0;
  • R6 is (1) H, (2) CH3, or (3) CH2CH3; part C of the definition of R.4 R5 and Re;
  • R4 is (1) H, (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, (5) CH(CH3)2,
  • R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is:
  • a second sub-class of the fourth class includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein Rl A 1S F in the para position of the benzyl moiety; R B is H, CI, or Br in the ortho or meta position of the benzyl moiety; and Rl is H; and all other variables are as defined in Sub-class C4-S2.
  • variables R 1A Repeat r R> lB R 1C , R 2A , R 3A , R 4 , R s and R 6 are selected independently of each other.
  • R is halo
  • R 1B is H or halo
  • R 4 Is H, 3 to 8-membered cycloalkyl or C h alky!, wherein said 3 to 8- membered cycloalkyl group can be optionally substituted with -OH and wherein said Cj. galkyl group is substituted with ⁇ N(Ci -6 alkyI)-S02-(Ci. 6 alkyl), -0-(Ci- 6 alkyl) or 3 to 8- membered cycloalkyl, wherein said 3 to 8-membered cycloalkyl substituent can be optionally substituted with -OH;
  • R 5 is H; and
  • R 6 is cycloalkyl, or R 5 and R 6 , together with the common carbon atom to which they are attached, combine to form a spirocyclic ring which is: (i) a 4 to 8-membered cycloalkyl group or (ii) a 6 to 10-membered fused or bridged bicycloalkyl group, wherein said spirocyclic rings (i) and (ii) can be optionally substituted with a -0-(Ci- 6 alkyl) group.
  • R is F and R is H or CI.
  • R 4 is H, cyclopropyl
  • R 5 is H and R 6 is cyclopropyl.
  • R 5 is H and R 4 and 6 are each cyclopropyl.
  • R s and R 6 together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
  • R and R together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
  • R IA is F and R iB is H or CI;
  • R 4 is cyclopropyl or -CH 2 CH 2 N(CH 3 )S0 2 CH 3 ;R S is H; and
  • R 6 is cyclopropyl.
  • R 1A is F and R 1B is H or CI;
  • R 4 is H, -CH 2 CH 2 N(CH 3 )S0 2 CH 3> -CH 2 CH 2 OCH 3 or:
  • R 5 and R 6 together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
  • R IA is F and R 1B is H or CI;
  • R 4 is H, -CH 2 CH 2 N(CH 3 CH 3 or:
  • R s and R 6 together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
  • variables R 1A , R lB , R 4 , R 5 and R 6 are selected independently of each other.
  • substantially pure means suitably at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt.% (e.g., from about 90 wt.% to about 99 wt.%), even more preferably at least about 95 wt.% (e.g., from about 95 wt.% to about 99 wt.%, or from about 98 wt.% to 100 wt.%), and most preferably at least about 99 wt.% (e.g., 100 wt.%) of a product containing a compound of Formula I or its salt (e.g., the product isolated from a reaction mixture affording the compound or salt) consists of the compound or salt.
  • a product containing a compound of Formula I or its salt e.g., the product isolated from a reaction mixture affording the compound or salt
  • the level of purity of the compounds and salts can be determined using a standard method of analysis such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and/or mass spectrometry. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level of purity determined, then the method providing the highest purity level governs.
  • a compound or salt of 100% purity is one which is free of detectable impurities as determined by a standard method of analysis.
  • a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual
  • the present invention also includes prodrugs of the compounds of Formula I.
  • prodrug refers to a derivative of a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is converted in vivo into Compound I.
  • Prodrugs of compounds of Formula I can exhibit enhanced solubility, absorption, and/or lipophilicity compared to the compounds per se, thereby resulting in increased bioavailability and efficacy.
  • the in vivo conversion of the prodrug can be the result of an enzyme-catalyzed chemical reaction, a metabolic chemical reaction, and/or a spontaneous chemical reaction (e.g., solvolysis).
  • ester -OC(O-)R
  • carbonate ester - OC(O)OR
  • Other examples include the following:
  • the prodrug can be an ester or an amide, and when the compound of Formula I contains a primary amino group or another suitable nitrogen that can be derivatized, the prodrug can be an amide, carbamate, urea, imine, or a annich base.
  • One or more functional groups in Compound I can be derivatized to provide a prodrug thereof.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, edited by H. Bundgaard, Elsevier, 1985; J. J. Hale et al., J. Med. Chem. 2000, vol. 43, pp.1234-1241; C. S. Larsen and J. Ostergaard, "Design and application of prodrugs” in: Textbook of Drug Design and Discovery, 3 rd edition, edited by C. S. Larsen, 2002, pp. 410-458; and Beaumont et al., Current Drug Metabolism 2003, vol. 4, pp. 461- 458; the disclosures of each of which are incorporated herein by reference in their entireties.
  • a pharmaceutical composition comprising an effective amount of a compound of Formula I as defined above, or a prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of a compound of Formula I as defined above, or a prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • an anti-HIV agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents.
  • composition of (c), wherein the anti-HIV agent is an antiviral selected from the group consisting of HTV protease inhibitors, ⁇ reverse transcriptase inhibitors (nucleoside or non-nucleoside), HIV integrase inhibitors, HIV fusion inhibitors, and HIV entry inhibitors.
  • a combination which is (i) a compound of Formula I as defined above, or a prodrug or pharmaceutically acceptable salt thereof, and (ii) an anti-HIV agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti- infective agents; wherein Compound I and the anti-HIV agent are each employed in an amount that renders the combination effective for inhibition of HIV integrase, for treatment or prophylaxis of infection by HIV, or for treatment, prophylaxis of, or delay in the onset or progression of AIDS.
  • anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV reverse transcriptase inhibitors (nucleoside or non-nucleoside), HIV integrase inhibitors, HIV fusion inhibitors, and HIV entry inhibitors.
  • a method for the inhibition of HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof.
  • a method for the prophylaxis or treatment of infection by HIV e.g., HrV-1 in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof.
  • HIV antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, non- nucleoside HTV reverse transcriptase inhibitors, nucleoside HFV reverse transcriptase inhibitors, HIV fusion inhibitors, and HIV entry inhibitors.
  • HIV antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV fusion inhibitors, and HIV entry inhibitors.
  • a method for the inhibition of HTV integrase in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).
  • a method for the prophylaxis or treatment of infection by HIV e.g., HrV-1 in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).
  • HIV e.g., HrV-1
  • a method for the prophylaxis, treatment, or delay in the onset or progression of AIDS in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).
  • a method for the inhibition of X RV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier.
  • a method for the prophylaxis or treatment of infection by XMRV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier.
  • composition further comprising a pharmaceutically acceptable carrier.
  • a method for the inhibition of HTLV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier.
  • a method for the prophylaxis or treatment of infection by HTLV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier.
  • a method for the prophylaxis, treatment or delay in the onset or progression of a disease or condition caused by HTLV infection e.g., T-cell leukemia or T- cell lymphoma
  • a disease or condition caused by HTLV infection e.g., T-cell leukemia or T- cell lymphoma
  • administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier.
  • the present invention also includes a compound of Formula I, or a prodrug or pharmaceutically acceptable salt thereof, (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation of a medicament for: (a) therapy (e.g., of the human body), (b) medicine, (c) inhibition of HIV integrase, (d) treatment or prophylaxis of infection by HIV, (e) treatment, prophylaxis of, or delay in the onset or progression of AIDS, (f) inhibition of XMRV, (g) treatment or prophylaxis of infection by XMRV, (h) treatment or prophylaxis or delay in the onset or progression of a disease or condition caused by XMRV infection, (i) Inhibition of HTLV, (j) treatment or prophylaxis of infection by HTLV, (k) treatment or prophylaxis or delay in the onset or progression of a disease or condition caused by HTLV infection.
  • therapy
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(t) above and the uses (i)(a)-(k) through (iii)(a)-(k) set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, sub- embodiments, aspects, features, classes, or sub-classes described above. In all of these embodiments etc., the compound may optionally be used in the form of a prodrug or pharmaceutically acceptable salt.
  • Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein the compound of the present Invention or a salt or prodrug thereof employed therein is substantially pure.
  • a pharmaceutical composition comprising a compound of Formula I or its prodrug or salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it Is understood that the term "substantially pure" is in reference to a compound of Formula I or its prodrug or salt per se.
  • Still additional embodiments of the present invention include the
  • the compound of Formula I is employed in an amount effective against HIV-1 and the anti-HIV agent is an HIV-1 antiviral selected from the group consisting of HIV-1 protease inliibitors, HIV-1 reverse transcriptase inhibitors, HIV-1 integrase inhibitors, HIV-1 fusion inhibitors and HIV-1 entry inhibitors.
  • alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
  • Ci-6 alkyl (or “Cl-Cg alkyl”) refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso- propyl, ethyl and methyl.
  • Ci-4 alkyl refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • cycloalkyl refers to any monocyclic or bicyclic ring of an alkane having a number of carbon atoms in the specified range.
  • C3-8 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • azacycloalkyl refers to a cycloalkyl group as defined above in which one of the ring carbons has been replaced with a ring nitrogen.
  • a 4- to 8-membered fused azacycloalkyl refers to the following groups:
  • heterocycloalkyl refers to a cycloalkyl group as defined above in which one of the ring carbons has been replaced with a ring heteroatom which is N, O or S.
  • a spirocyclic ring which is a 5- to 8-membered
  • heterocyclylalkyl refers to the following groups:
  • L is the heteroatom and the asterisks (*) denote the points of attachment to the rest of the compound providing thereby a spirocycle.
  • alkylene refers to any divalent linear or branched chain aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
  • -C2-8 alkylene- refers to any of the C2 to C8 linear or branched alkylenes.
  • a class of alkylenes of interest with respect to the invention is -(CH2)2-4 ⁇ ; and sub-classes of particular interest include -CH2CH2- and -CH2CH2CH2-.
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, c loro, bromo, and iodo).
  • haloalkyl refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, CI, Br and/or I).
  • a halogen i.e., F, CI, Br and/or I.
  • Cj-6 haloalkyl or “Cj-Cg haloalkyl” refers to a C ⁇ to Cg linear or branched alkyl group as defined above with one or more halogen substituents.
  • fluoroalkyl has an analogous meaning except that the halogen substituents are restricted to fluoro.
  • Suitable fluoroalkyls include the series (CH2)0 ⁇ 4 F3 (i.e., trifluoromethyl, 2,2,2- trifluoroethyl, 3,3,3-trifmoro-n-propyl, etc.).
  • a fluoroalkyl of particular interest is CF3.
  • C(0) refers to carbonyl.
  • S(O) refers to sulfinyl.
  • aryl refers to (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic.
  • Suitable aryls include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, acenaphthenyl and fluorenyl.
  • a class of aryls suitable for use in the present invention is phenyl, naphthyl, and indenyl.
  • heteroaryl refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system which contains from 1 to 4 heteroatoms independently selected from N, 0 and S, and wherein in the fused ring system any one or more of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N in a ring is optionally in the form of an oxide, and each S is optionally S(O) or S(0)2- Suitable heteroaryls include, for example, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,
  • a class of heteroaryls suitable for use in the present invention consists of 5- and 6-membered heteroaromatic rings containing from ⁇ to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide.
  • Heteroaryls belonging to this class include pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl,, imidazolyl, pyrazolyl,
  • heteroaromatic rings containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom.
  • saturated or mono-unsaturated heterocyclic ring refers to (i) a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2 or (ii) a 6- to 10-membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2-
  • Suitable saturated heterocycles include, for example, azetidinyl, pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidii yl, morpholin
  • a class of suitable saturated or mono-unsaturated heterocyclic rings are the 4- to 7-membered rings containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2 (e.g., see HetZ).
  • Another suitable class consists of 5- or 6-membered saturated heterocyclic rings containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or S02-
  • Suitable mono-unsaturated heterocyclic rings include those corresponding to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond),
  • any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
  • a heteroaromatic ring described as containing from “1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range.
  • a heterocyclic ring described as containing from “1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms.
  • a phenyl or naphthyl (see, e.g., the definition of AryA) described as optionally substituted with "from 1 to 5 substituents" is intended to include as aspects thereof, a phenyl or naphthyl substituted with 1 to 5 substituents, 2 to 5 substituents, 3 to 5 substiuents, 4 to 5 substituents, 5 substituents,
  • any variable e.g., RA or R.B
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substitution by a named substituent is permitted on any atom in a ring provided such ring substitution is chemically allowed and results in a stable compound.
  • Compounds of the present invention having a hydroxy substituent on a carbon atom of a heteroaromatic ring are understood to include compounds in which only the hydroxy is present, compounds in which only the tautomeric keto form (i.e., an oxo substitutent) is present, and compounds in which the keto and enol forms are both present.
  • a “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic adrainistration to a subject).
  • the compounds of the present invention are limited to stable compounds embraced by Formula I.
  • compounds of the invention containing the group C(0)-N(RA)-C2-8 alkylene-ORB it is understood that the N(RA) moiety and the ORB moiety are typically not attached to the same carbon atom in the C2-8 alkylene moiety.
  • certain compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether individually or in mixtures, are within the scope of the present invention.
  • the atoms in a compound of Formula I may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (lH) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the
  • the methods of the present invention involve the use of compounds of Formula I in the inhibition of HIV integrase (e.g., wild type HIV-1 and/or mutant strains thereof), the prophylaxis or treatment of infection by human immunodeficiency virus (HIV) and the prophylaxis, treatment or delay in the onset or progression of consequent pathological conditions such as AIDS.
  • HIV integrase e.g., wild type HIV-1 and/or mutant strains thereof
  • HIV human immunodeficiency virus
  • prophylaxis treatment or delay in the onset or progression of consequent pathological conditions
  • Prophylaxis of AIDS, treating AIDS, delaying the onset or progression of AIDS, or treating or prophylaxis of infection by HIV is defined as including, but not limited to, treatment of a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
  • the present invention can be employed to treat infection by HIV after suspected past exposure to HIV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • the present invention can also be employed to prevent transmission of HIV from a pregnant female infected with HIV to her unborn child or from an HIV-infected female who is nursing (i.e., breast feeding) a child to the child via administration of an effective amount of Compound I or a prodrug or pharmaceutically acceptable salt thereof.
  • the compounds can be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof).
  • Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a
  • suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands such as quaternary ammonium salts.
  • pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • administration and variants thereof (e.g., “administering” a compound) in reference to a compound of Formula I mean providing the compound or a prodrug or salt of the compound to the individual in need of treatment or prophylaxis.
  • a compound or a prodrug or salt thereof is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating or prophylaxis of HIV infection or AIDS)
  • “administration” and its variants are each understood to include provision of the compound or prodrug or salt thereof and other agents at the same time or at different times.
  • the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately.
  • composition is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
  • pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
  • the terra "subject” as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the term "effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the effective amount is a "therapeutically effective amount” for the alleviation of the symptoms of the disease or condition being treated.
  • the effective amount is a "prophylactically effective amount” for prophylaxis of the symptoms of the disease or condition being prevented.
  • the term also includes herein the amount of active compound sufficient to inhibit HIV integrase (wild type and/or mutant strains thereof) and thereby elicit the response being sought (i.e., an "inhibition effective amount").
  • the active compound i.e., active ingredient
  • references to the amount of active ingredient are to the free form (i.e., the non-salt and non-prodrug form) of the compound.
  • the compounds of Formula I can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the compounds of the invention can, for example, be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenterally including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques
  • inhalation spray or rectally
  • a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • administration e.g., suspensions, syrups, elixirs and the like
  • Solid preparations suitable for oral administration e.g., powders, pills, capsules and tablets
  • Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid.
  • Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions for use in the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18 th edition, edited by A. R. Gennaro, Mack Publishing Co., 1990 and in Remington - The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005.
  • the compounds of Formula I can be administered orally in a dosage range of
  • compositions can be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • 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.
  • an anti-HIV agent is any agent which is directly or indirectly effective in the inhibition of HIV reverse transcriptase or another enzyme required for HIV replication or infection, the treatment or prophylaxis of HIV infection, and/or the treatment, prophylaxis or delay in the onset or progression of AIDS. It is understood that an anti-HIV agent is effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and/or diseases or conditions arising therefrom or associated therewith.
  • the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of one or more anti-HFV agents selected from HIV antiviral agents, imunomodulators, antiinfectives, or vaccines useful for treating HIV infection or AIDS.
  • anti-HFV agents selected from HIV antiviral agents, imunomodulators, antiinfectives, or vaccines useful for treating HIV infection or AIDS.
  • Suitable HIV antivirals for use in combination with the compounds of the present invention include, for example, those listed in Table A as follows:
  • nevirapine NVP
  • EI entry inhibitor
  • FI fusion inhibitor
  • Inl integrase inhibitor
  • PI protease inhibitor
  • nRTI nucleoside reverse transcriptase
  • nnRTI non-nucleoside reverse transcriptase inhibitor.
  • abacavir sulfate indinavir sulfate, atazanavir sulfate, nelfmavir
  • the one or more anti-HIV agents are selected from lamivudine, abacavir, ritonavir and lopinavir.
  • the compound of formula (I) is used in combination with a single anti-HIV agent which is lamivudine.
  • the compound of formula (I) is used in combination with two anti-HIV agent which are lamivudine and abacavir.
  • the compound of formula (I) is used in combination with two anti-HIV agent which are ritonavir and lopinavir.
  • the present invention provides pharmaceutical compositions comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable carrier; and (iii) one or more additional anti- HIV agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a
  • the present invention provides a method for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof, which comprises
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof and (ii) one or more additional anti-HIV agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a pharmaceutically acceptable salt thereof, wherein the amounts administered of components (i) and (ii) are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in .the onset or progression of AIDS in the subject in need thereof.
  • HIV antiviral agents and other agents will typically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in the Physicians' Desk Reference. Thomson PDR, Thomson PDR, 57* edition (2003), the 58 th edition (2004), the 59 th edition (2005), and the like.
  • the dosage ranges for a compound of the invention in these combinations are the same as those set forth above.
  • the compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds.
  • the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition.
  • the compounds of this invention are commercial products to be sold for these purposes.
  • the compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds.
  • the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition.
  • the compounds of this invention are commercial products to be sold for these purposes.
  • Alk alkyl
  • Boc reri-butoxycarbonyl
  • BOP benzotriazol-l-yloxytris(dimethylamino)- phosphonium
  • EDCI 1 -ethyl-3-(3 ' -dimethylaminopropyl)carbodiimide
  • HATU 2-(lH-7-Azabenzotriazol- 1 -yl)-l , 1 ,3,3-tetramethyl uronium hexafiuorophosphate
  • HOAt 1 -hydroxy-7 -azabenzotriazole
  • HOBt 1 -hydroxybenzotriazole
  • IP Ac zsopropyl acetate
  • NMP 1 -methyl 2-pyrrolidinone
  • the compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
  • Scheme A depicts a method for preparing compounds of the present invention, wherein benzyl halide 1 is reacted with amide 2 in the presence of a base.
  • the corresponding tertiary amide is deprotonated and reacted with phenyl methyl sulfone to generate sulfoxide 3.
  • the sulfoxide is then converted to the corresponding , ⁇ -unsaturated product via a Puminerer rearrangement and sulfide oxidation to compound 4.
  • Reaction with the anion of a protected amino ester and acid hydrolysis affords the alpha amino ester 5. Elimination of the sulfone under basic conditions affords the unsaturated ester 6.
  • Conversion of 6 to the pyridinone compound 7 can be accomplished in the presence of an ester oxalyl chloride followed by treatment with LiBr. Hydrolysis of ester 7 to the acid affords compound 8 which is then transformed to the tris-pivalate 9 using standard conditions.
  • Compounds 8 and 9 serve as valuable intermediates which can be transformed to HTV integrase inhibitors using the procedures and methods described in the following schemes.
  • Scheme B depicts a method for the conversion of bis ⁇ hydroxy carboxyiic acid compound 8 to bis-methoxy carboxyiic acid 11 utilizing a silver-catalyzed methylation and base-mediated ester hydrolysis.
  • Compound 11 serves as a valuable intermediate which can be transformed to HIV integrase inhibitors using the procedures and methods described in the following schemes.
  • Scheme C depicts a method for preparing compounds of the present invention, wherein carboxyiic acid 11 is reacted with primary amine 12 under standard amide coupling conditions (e.g. EDCI/HOAt/base/DMF) to yield secondary amide 13.
  • the methyl ethers of product 13 can be cleaved under acidic conditions (e.g. HBr in AcOH) to afford the hydroxyl pyridinone 14.
  • acidic conditions e.g. HBr in AcOH
  • Treatment of 14 with an aldehyde or ketone 15 under acidic conditions e.g. catalytic sulfuric acid or TFA
  • Scheme D provides a preparative sequence similar to that of Scheme C, except that an acetal or ketal (or hemi-acetal or -ketal) 17 is used in place of the aldehyde or ketone for the condensation reaction of the final Step in the presence of a protic acid.
  • R alkyl, e.g. Me, Et
  • Scheme E is a variation of Schemes C and D, wherein compounds of the invention can be prepared from activated mixed anhydride 9, which is reacted with primary amine 12 to yield secondary amide compound 18, Conversion of 18 to the desired product 16 can be conducted using either the procedure of Scheme C or Scheme D.
  • Scheme E is a variation of Schemes C and D, wherein compounds of the invention can be prepared from activated mixed anhydride 9, which is reacted with primary amine 12 to yield secondary amide compound 18, Conversion of 18 to the desired product 16 can be conducted using either the procedure of Scheme C or Scheme D.
  • Scheme F depicts another route to the desired compounds, wherein mixed anhydride 9, or a related carboxylic acid derivative, can be reacted with a source of ammonia (e.g. N3 ⁇ 4 (gas) or NH 4 OH) to afford the primary amide 19, which can be deprotonated to 20 and then alkylated with an electrophile to afford the product 16.
  • a source of ammonia e.g. N3 ⁇ 4 (gas) or NH 4 OH
  • X Leaving group such as I, Br, OMs
  • a strong acid e.g. HBr in AcOH
  • Compound 20 is dissolved in a suitable organic solvent (e.g. DMSO or DMF) is deprotonated by treatment with a strong base (e.g. KO-t-Bu) and then alkylated with benzyl halide 14 to provide desired product 16, which can be isolated and purified using conventional techniques such as silica gel chromatography or reverse-phase preparative HPLC.
  • a strong base e.g. KO-t-Bu
  • X Leaving group, e.g. Br, CI, OMs
  • Scheme H outlines a further procedure to prepare compounds- of the present invention where an R 4 alkyl alcohol 21 is converted to a leaving group (e.g. OMs, CI, Br) and this compound (22) is displaced with a nucleophile (e.g. an amine, sulfonamide, succinimide) under basic conditions to afford a further R 4 functionalized compound 23.
  • a nucleophile e.g. an amine, sulfonamide, succinimide
  • this amine compound 23 can also be further functionalized to a compound such as a sulfonamide or amide using standard conditions.
  • This transformation can be accomplished in the presence of a suitable oxidant (e.g. oxygen), base (e.g. NaH, KOi-Bu) and solvent (e.g. DMF, DMSO).
  • the secondary amide is treated with a benzylic halide (or other suitable leaving group) in the presence of a base (e.g. KOt-Bu) to afford 26.
  • Compound 26 can be transformed to inliibitors of the present invention using chemistry outlined in these general methods or specific examples.
  • Scheme J presents a further method to prepare compounds of the present invention.
  • a compound 16 is treated under oxidative conditions (oxygen, KOi-Bu, DMSO), affording alcohol compound 27.
  • Scheme depicts a method for the preparation of compounds of the invention wherein a secondary amide 27 is reacted with R 4 -X (e.g. an aryl or heteroaryl halide or cyclopropyl boronic acid) in the presence of a base (e.g. Cs 2 C0 3 , NaH) and/or a metal catalyst (e.g. Pd or Cu) to afford the compound 16, which can be isolated and purified using conventional techniques such as silica gel chromatography or reverse-phase preparative HPLC.
  • R 4 -X e.g. an aryl or heteroaryl halide or cyclopropyl boronic acid
  • a base e.g. Cs 2 C0 3 , NaH
  • a metal catalyst e.g. Pd or Cu
  • Scheme L outlines a method for the preparation of compounds of general structure 28.
  • An electron-deficient alkene 29 is treated with 27 under suitable conditions (e.g. Cul, NMP, heat) to afford the derivatives compound 28.
  • the protecting groups may be removed at a convenient subsequent stage using methods known in the art.
  • the interfering group can be introduced into the molecule subsequent to the reaction Step of concern.
  • Step 1 1 -(3 -Chloro-4-fluorobenzyl)-3-(phenylsulfinyl)piperidin'
  • the mixture was cooled to -30 to -20 °C and then the THF solution of LiHMDS which was prepared in advance was added at the rate of 100—150 L h at -30 to -20 °C.
  • the reaction mixture was maintained at this temperature for 6 h until the reaction was complete as monitored by HPLC analysis.
  • Methyl phenyl sulfone (45.7 kg, 228 mmol) was added into the reaction mixture at a rate of 5-10 kg h at -30 to -20 °C. After the addition, the reaction mixture was maintained at this temperature for 1 h until HPLC analysis revealed complete consumption of the sulfone starting material.
  • the filtrate was concentrated under reduced pressure (T ⁇ 30 °C, P ⁇ -0.08 MPa) until a volume of about 300-350 L of the mixture remained.
  • MTBE 340 kg
  • concentration was continued until 150-200 L volume of the mixture remained.
  • Petroleum ether 73 kg was added into the concentrated liquors under stirring, and then the mixture was cooled to 0 °C to induce crystallization.
  • the crystallized mixture was filtered by nutsche filter under the protection of nitrogen.
  • the filter cake was rinsed with the mixed solvent of MTBE (20 kg) and petroleum ether (24 kg) to afford the desired product as a white solid.
  • Step 2 l-(3-Chloro-4-fluorobenzyl)-3-( henylsulfinyl)-5 J 6-dihydropyridin-2(lH)- one
  • dichloromethane (2 ⁇ 455 kg). The combined organic layers were washed with 15% brine (378 kg), dried with anhydrous sodium sulfate (21 kg) and filtered by nutsche filtration. The filter cake was rinsed with dichloromethane (2 ⁇ 35 kg) and the mother liquors were concentrated under reduced pressure (T ⁇ 30 °C, P ⁇ -0.08 MPa) until the remaining mixture volume was about 200-250 L. Isopropyl alcohol (138 kg) was added and the mixture was concentrated continuously. After the remaining mixture volume was about 200-250 L, a mixture of isopropyl alcohol (35 kg) and petroleum ether (30 kg) was added, and then the mixture was concentrated for the third time.
  • Step 3 Ethyl amino [ 1 -(3-chloro-4-fluorobenzyl)-2-oxo-3-(phenylsulfinyl)piperidin- 4-yl] acetate
  • Step 4 Ethyl (2Z)-amino[ 1 -(3-chloro-4-fluorobenzyl)-2-oxopiperidin-4- ylidene]ethanoate
  • Step 5 Ethyl 6-(3 ⁇ chloro-4-fluoroben2yl) ⁇ 4-hydroxy-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridine- 1 -carboxylate
  • Step 2 6-(3-Chloro-4-fluorobenzyl)-3,4-dimethoxy-5-oxo-5 !l 6 5 7 5 8-tetrahydro-2,6-- naphthyridine-l-carboxylic acid
  • Step 1 4-Methoxy-6-(4-methoxybenzyl)-3,5-dioxo-2,3,5,6 5 7 i 8-hexahydro-2 i 6 ⁇
  • Ethyl 4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8,-tetrahydro-2,6- naphthyridine-l-carboxylate (14.0 g, 38.1 mmol, described in WO/2005/087768, Example 20, Step 2, page 117) and urea-hydrogen peroxide complex (7.5 g, 80 mmol, 2.1 equiv) were dissolved in CH 2 CI 2 (200 mL) and cooled to 0 °C. To the solution was added trifluoroacetic anhydride (10.8 mL, 76 mmol, 2 equiv) slowly over 20-30 minutes.
  • the reaction mixture was stirred at 0 °C for 30 minutes and allowed to warm to room temperature overnight.
  • Solid sodium bisulfite was added to quench the remaining oxidant and the mixture was poured into a separatory funnel containing water (200 mL) and extracted with CH 2 CI 2 (3 x 100 mL). The combined organic layers were washed with brine, dried over MgS0 4 , filtered and concentrated under reduced pressure.
  • the unpurified material from the previous Step was dissolved in 200 mL of toluene and acetic anhydride (33 mL, 348 mmol, 7.2 equiv) was added.
  • the reaction flask was fitted with a reflux condenser and the mixture was heated to 120 °C in an oil bath for 16 h.
  • the cooled reaction mixture was concentrated under reduced pressure.
  • This material was dissolved in ethanol (180 mL) and ⁇ 2 0 (7.0 g, 292 mmol, 6.9 equiv) was added together with 32 mL of water.
  • the reaction mixture was stirred at room temperature for 2 h, after which LCMS analysis reveals complete conversion of starting material.
  • the ethanol solvent was removed under reduced pressure and the crude reaction mixture was diluted with IM aqueous HCl solution to afford a yellow suspension.
  • the mixture was filtered through filter paper on a Hirsch funnel (under Hirsch funnel (under vacuum) and the yellow solid was washed with diethyl ether, and dried on the vacuum pump overnight to afford a white solid.
  • Step 2 4-Methoxy-6"(4-methoxybenzyl)-N-methyl-3 ? 5 ⁇ dioxo-2,3,5 ! 6,7,8-hexahydro- 2,6-naphthyridine- -carboxamide eO.
  • Step 3 6 , -Hydroxy-8 , -(4-methoxybenzyl)-2 , -methyl-9' J 10 , -dihydro-l'H- spiro[cyclopentane-l ,3'-imidazo[5,l -a] [2 J 6]naphthyridine]- ,5',7'(2'H,8'H)- trione
  • Step 4 6'-Hydroxy-2'-methyI-9', 10'-dihydro- 1 'H-spiro [cyclopentane- 1 ,3 ' ⁇
  • cyclohex-2-enone (96 g, 1.00 mol, 1.0 equiv) drop-wise with stirring over a 30 minute period.
  • the resulting solution was stirred for an additional 2 h while the temperature was maintained at 50 °C.
  • the reaction mixture was cooled to room temperature, then quenched by the addition of 1500 mL of H 2 0/ice.
  • the resulting solution was poured into a 4 L separatory funnel and extracted with diethyl ether (3 x 500 mL). The organic layers were combined, washed with saturated brine (3 x 150 mL), dried over MgS0 4 and concentrated under vacuum.
  • Step 2 2-(2-Methoxyethyl)cyclopentanone A solution of 2-cyclopentylidene-l,l-dimethylhydrazine (1.3 g, 10 nimol) in
  • Step 1 (2-Ethoxy-2 ⁇ oxoethyl)dimethylsulfonium
  • Step 2 ( ⁇ )-(U?,6 7i? Ethyl 2-oxobicyclo[4.1.0]heptane-7-carboxylate
  • Cyclohex-2-enone (60.8 g, 63 mmol) was added and the mixture was stirred at 13 °C for 18 h.
  • Step 1 (S)- 1 -Chlorohex-5-en-2-ol
  • Step 2 (IS, 2S, 5i?)-Bicyclo[3.1.0]hexan-2-oI oven-dried flask under an atmosphere of nitrogen was added (S)-l ⁇ chlorohex-5-en-2-ol (33.0 g, 245 mmol), anhydrous MTBE (900 mL), and 2,2,6,6- tetramethylpiperidine ( 107 mL, 635 mmol).
  • the solution was cooled to -78 °C in a dry ice/ acetone bath.
  • a solution of rc-butyl lithium (1.6 M in hexanes, 556 mL, 889 mmol) was added over 30 minutes to the reaction. The reaction was slowly warmed to room
  • tetrapropylammonium perruthenate (4.4 g, 12.5 mmol) was added, and the reaction was stirred at room temperature for 18 h.
  • the reaction was filtered through a pad of Celite, the filtrate was poured into a separatory funnel and washed successively with 2 M aqueous HCl solution (200 mL) and water (100 mL).
  • the combined aqueous layers were back-extracted with CH2CI2 (2 x 100 mL).
  • the combined organic layers were dried over Na 2 S0 4 , filtered through a plug of silica gel, rinsing with 25% diethyl ether/CH2Cl2, and concentrated under reduced pressure. The residue was then purified by vaccuum distillation.
  • (+)-8 -(3-C ⁇ oro-4-fluorober ⁇ l) ⁇ 6*-h dro y-2'-me l-9 10'-dihydro-2'H- spiro[bicyclo[2.2.1 ]heptane-2,3'-imidazo[5 5 l-a] P ⁇ jnaphthyridineJ-rjS'J S'i -iri 0116
  • Step 1 6-(3-Chloro-4-fluorobeiTzyI)-3 ? 4 ⁇ dimemoxy-N-methyl-5-oxo-5,6,7,8- tetrahydro-2,6-naphthyridine- 1 -carboxamide
  • Step 2 6-(3-ChlorO"4-fluorober ⁇ yl)-4-hydroxy-N-methyl-3 s 5-dioxo-2,3 J 5,6 ⁇ 7,8- hexahydro-2 , 6-naphthyridine- 1 -carboxamide
  • Step 3 (+)-8 , ⁇ (3-Chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9 , > 10'-dihydro-2 , H- spiro[bicyclo[2.2. ]heptane-2,3'-imidazo[5 s 1 -a] [2,6]naphthyridine]-
  • Step 1 6-(3-Chloro-4-fluorobenzyl)-3,4-dimethoxy-N-methyl-5-oxo-5,6 > 7,8- tetrahydro-2,6-naphthyridine- 1 -carboxamide
  • Step 2 ( ⁇ )-8-(3-Chloro-4-fIuorobenzyl)-6-hydroxy-23-dimethyl-2 ; 3,9,10- tetrahydroimidazo[5,l-a][2,63naphthyridine-l,5,7(8H)-trione
  • a solution of amide from Step 1 500 mg, 1.23 mmol
  • Step 1 6-(3-Chloro-4-fluorobenzyl)-iV-cyclopropyl-4-hydroxy-3,5-dioxo-2,3,5 5 6,7,8- hexahydro-2,6-naphthyridine- 1 -carboxamide
  • Step 2 (S)-8-(3-Chloro-4-fluorobenzyl)-2,3-dicyclopropyl-6-hydroxy-2,3 ,9, 10- telxahydroimidazofSjl-ajP ⁇ jna hthyridi e-ljS tS/ ⁇ -trione
  • Step 1 ( ⁇ )-8-(3 ⁇ ChJoiO-4-fluoiObenzyl)-3-cyclobutyl-6-hydroxy-2,3 ,9, 10- tetra ydroimidazotS -ajp ⁇ jnap th ridine-l ⁇ tSH ⁇ - ⁇ 01116
  • Step 2 ( ⁇ )-8-(3-Chloro-4-fluorobenzyl)-3-cyclobut l-6-hydroxy-2-(2-methoxyethyl)- 2,3,9,10-tetrahydroimidazo[5,l -a][2,6]naphthyridine-l ,5,7(8H)-trione
  • Step 1 6-(3-CWoro-4-fluoroberizyl)-N-(5-hydroxy-4,4-dimethylpentyl)-3 ? 4- dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naplithyridine-l-carboxamide
  • the title compound was prepared according to the procedure described in
  • Step 2 6-(3-Chloro-4-fluorobenzyI)-N-(4,4-dimemyl-5-oxopentyl)-3,4-dimethoxy-5- oxo-5,6,7 5 8-tetrahydro-2 J 6-naphthyridine- 1 -carboxamide
  • Dess-Martin periodinane (1.5 equiv) was added to a solution of alcohol (1.28 g, 2.52 mmol) in 03 ⁇ 4 ⁇ 2 (13 mL, 0.2 M). The reaction was stirred at room temperature for 2 h. Solid Na 2 S 2 0 3 (25 g) was added and the solution was diluted with saturated aqueous NaHC0 3 (100 mL) and EtOAc.
  • Step 3 ( ⁇ )-3-(3-Chloro-4-fluorobenzyi)-5-hydroxy-8,8-dimethyl-2,3 i 8 s 9, 10,11- hexahydro-7aH-pyrido[2', l':2 5 3]imidazo[5, 1 -a][2,6]naphthyridine- 4,6,13(lH)-trione
  • Step 1 6-(3-Chloro-4-fiuorobenzyl)-3 ! 4-dimethoxy-5-oxo-5,6,7 i 8-tetrahydro-2 : 6- naphthyridine-1 -carbonyl chloride
  • Step 3 ( ⁇ )-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,7a,8 ! 9 ) l 0- hexahydropyrrolo [2' , ⁇ : 2 , 3 ] imidazo [5 > 1 -a] [2,6] naphthyridine-4 ,6, 12( 1 )- trione
  • Step 1 2-(3-Chloro-4-fluorobenzyl)-7,8-dimethoxy-5-[(6 ⁇ methyl-3,4- dihydropyridin- 1 (2H) ⁇ yl)carbonyI]-3 s 4-dihydro-2 ,6-naphthyridin- 1 (2H)-one
  • a solution of amine (730 mg, 4.81 mmol), acid chloride (1.04 g, 2.52 mmol, prepared according to Example 6, Step 1) and N,iV-diisopropylethylamine (3 equiv) in THF (10 mL, 0.25 M) was stirred at room temperature for 18 h.
  • Step 2 6-(3 -Chioro-4-fluoroben2yl)-4-hydroxy-3 , 5 ⁇ dioxo-N-(5 -oxohexyl)-
  • Step 3 ( ⁇ )-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3 5 8 ? 9 ; l 0, 11- hexahydro-7aH-pyrido[2' 5 1 ':2,3]imidazo[5, ⁇ -a] [2,6]naphthyridine- 4,6,13(li7)-trione
  • Step 1 7 ⁇ Aminoheptan-3-one
  • the reaction was performed as outlined in J Org. Chem. 2006, 71, 4525-
  • Step 4 ( ⁇ )-3-(3-Chloro-4-fluorobenzyl)-7a-ethyl-5-hydroxy-2,3,8,9,10,l 1 - hexahydro-7aH-pyrido[2', :2,3]imidazo[5,l -a][2,6]naphthvridine-

Abstract

Tricyclic compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: (I), wherein R1A, R1B, R1C, R2A, R2B, R3A, R3B, R4, R5 and R6 are defined herein. The compounds are useful for the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment, or delay in the onset of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

Description

TITLE OF THE INVENTION
HIV INTEGRASE INHIBITORS
FIELD OF THE INVENTION
The present invention is directed to certain imidazolo[5,l-a]naphthyridine compounds and pharmaceutically acceptable salts thereof. These compounds are inhibitors of the HIV integrase enzyme. The present invention is also directed to the use of the compounds and their salts in the prophylaxis or treatment of infection by HIV and in the prophylaxis, treatment, or delay in the onset or progression of AIDS.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV), particularly the strains known as HIV type-1 (HIV-1) virus and type-2 (HIV -2) virus, is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of +pro viral DNA into the host cell genome, a required step in HIV replication in human T- lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear pro viral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, .D. et al., Science, 231, 1567 (1 86); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhibitors such as indinavir and nelfinavir. The compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIV infected cells. The following references are of interest as background:
US 7598264 B2 discloses certain hydroxy polyhydro-2,6-naphthyridine dione compounds that are HIV integrase inhibitors.
US 2009/0054399 Al discloses tricyclic analogs of hydroxy polyhydro-2,6- naphthyridine dione compounds which are HIV integrase inhibitors.
US 721 1572 B2 discloses certain nitrogen-containing fused ring compounds and their use as HIV integrase inhibitors.
WO 2006/107478 A2 discloses a crystalline sodium salt of 6-(3-chloro-4- fluorobenzyl)-4-hydroxy-2-isopropyl-N5N-dimethyl-3,5-dioxo-2,355,6,7,8-hexahydro-2,6- naphthyridine- 1 -carboxamide, which is an HIV integrase inhibitor.
WO 2008/048538 Al discloses certain hexahydro-diazocinonaphthyridine trione compounds which are HIV integrase inhibitors.
WO 2009/154870 Al discloses hydroxy substituted
polyhydropyridazinopyridodiazocine trione compounds and hydroxy substituted
polyhydropyrimidopyridodiazocine trione compounds which are HIV integrase inhibitors.
SUMMARY OF THE INVENTION
The present invention is directed to certain certain imidazolo[5,l- ]naphthyridine compounds. These compounds (including hydrates and solvates thereof), opti onally in the form of pharmaceutically acceptable salts, are useful in the inhibition of retroviral integrases and for the prophylaxis or treatment of infections or other adverse diseases or conditions caused by retroviruses. The compounds of the present invention are, for example, useful in: (a) the inhibition of HIV integrase (e.g., HIV-1 or HTV-2) and STV, (b) the prophylaxis or treatment of infection by HIV or SIV, and (c) the prophylaxis, treatment, and delay in the onset or progression of AIDS and or ARC. As another example, the compounds are useful in: (a) the inhibition of XMRV, (b) the prophylaxis or treatment of infection by XMRV and (c) the prophylaxis, treatment or delay in the onset or progression of diseases or conditions caused by XMRV infection such as prostate cancer or chronic fatigue syndrome. In still another example, the compounds are useful in: (a) the inhibition of HTLV (e.g., type 1, type 2 or type 3), (b) the prophylaxis or treatment of infection by HTLV and (c) the prophylaxis, treatment or delay in the onset or progression of diseases or conditions caused by HTLV such as T-cell leukemia or T-cell lymphoma. In the foregoing uses, the compounds can be used per se but are typically employed with one or more other ingredients in pharmaceutical compositions and optionally in combination with other antiretroviral agents, anti-infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention includes compounds of Formula I and
pharmaceutically acceptable salts thereof:
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein:
RlA and RlB are each independently:
0) H,
(2) Ci-6 alkyl,
(3) OH,
(4) O-Ci-6 alkyl,
(5) Ci-6 haloalkyl,
(6) 0-Ci_6 haloalkyl,
(7) halogen,
(8) CN,
(9) N(RA)RB,
(10) C(0)N(RA)RB;
(Π) C(0)RA
(12) C(0)0RA,
(13) SRA,
(14) S(0)RA
(15) SO2RA,
Figure imgf000005_0002
(18) N(RA)C(0)RB, or
(19) N(RA)C(0)C(0)N(RA)RB;
or alternatively Rl a d RlB are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or etliylenedioxy;
lC is:
(1) H,
(2) Ci_6 alkyl,
(3) O-Ci-6 alkyl,
(4) C i_6 haloalkyl,
(5) O-C 1-6 haloalkyl, or (6) halogen;
R2A and R2B are each independently:
(1) H,
(2) Ci -8 alkyl,
(3) Ci -8 haloalkyl, or
(4) C l -8 alkyl substituted with OH, C(0)N(RA)RB5 C(0)RAS CO2RA, or
C(0)-N(RA)-C2-8 alkylene-ORB; or
alternatively R2A and R2B together form oxo;
R3A and R3B are each independently:
(1) H,
(2) fSuoro,
(3) Ci_8 alkyl, optionally substituted with OH, O-Ci-8 alkyl, O-C] _8 haloalkyl, CN, N(RA)RB? C(0)N(RA)RB, C(0)RA5 CO2 A, C(0)-N(RA)-C2-8 alkylene -ORB, SRA, S(0)RAS SO2 A S02N(RA)RBF N(RA)C(0)RB} N( A)C02 B, N(RA)S02RB S N(RA)S02N(RA)RB;
N(RA)C(0)N(RA)RB, or OC(0)N(RA)RB;
(4) C 1- haloalkyl, or
(5) OH, O-C 1 - 8 alkyl, O-C 1 -8 haloalkyl, CN, N(RA)RB, C(0)N(RA)RB5
C(0)RA CO2RA, C(0)-N(RA)-C2-8 alkylene -ORB, SRA S(0)RAS SO2RA, S02N(RA)RB, N(RA)C(0)RB, N(RA)C02RB, N(RA)S02RB, N(RA)S02N(RA)RBS N(RA)C(0)N(RA)RB; or 0C(0)N(RA)RB;
alternatively 3 A and R3B together form oxo;
R4, R5 and R6 are defined as set forth in Part A, Part Β or Part C below:
(A) R4 is:
(1) H,
(2) Ci-8 alkyl,
(3) C 1-8 haloalkyl,
(4) Ci-8 alkyl substituted with OH, O-Ci-8 alkyl, O-Ci-8 haloalkyl, CN, N(RA)RB> C(0)N(RA)RB5 C(0)RA, C(0)-HetP, CO2 A,
C(0)-N(RA)-C2~8 alkylene-ORB, SRA, S(0)RA S02RA,
S02N(RA)RBS N(RA)C(0)RBS N( A)C02RB, N(RA)S02RB, N(RA)S02N(RA)RB? N(RA)C(0)N(RA)RB5 or OC(0)N(RA)RB,
(5) CycA,
(6) C i -8 alkyl substituted with CycA,
(7) C 1 - alkyl substituted with AryA,
(8) Ci-8 alkyl substituted with HetA,
(9) Ci-8 alkyl substituted with HetP; (10) Ci-8 hydroxyalkyl substituted with Ci-8 haloalkyl or CycA; or
(1 1) Het A
R5 and R6 are each independently:
(1) H,
(2) Ci-g alkyl,
(3) Ci_8 haloalkyl, or
(4) C i -8 alkyl substituted with OH, O-C l - 8 alkyl, O-C l -8 haloalkyl, CN, N(RA)RB? C(0)N(RA)RB, C(0)RA? C02RA, C(0)-N(RA)-C2-8 alkylene-ORB, SRA, S(0)RA, S02 A, S02N(RA)RBS
N(RA)C(0)RB, N(RA)C02RBF N(RA)S02 B,
N(RA)S02N(RA)RBJ N(RA)C(0)N(RA)RB5 or OC(0)N(RA)RB,
(5) CycB,
(6) AryB,
(7) HetB,
(8) C i -8 alkyl substituted with CycB,
(9) C 1 -8 alkyl substituted with AryB,
(10) Ct-g alkyl substituted with HetB, or
(11) C i - alkyl substituted with HetQ;
R4 and R5 together with the atoms to which they are attached form a 4- to 8- membered fused azacycloalkyi ring which is optionally substituted with from 1 to 4 substituents each of which is independently:
(1) Ci-8 alkyl,
(2) C 1-8 haloalkyl, or
(3) C i _8 alkyl substituted with OH, O-C l - 8 alkyl, O-C l -8 haloalkyl, CN, N(RA)RB, C(0)N(RA)RBJ C(0)RA CO2RA C(0)-N(RA)-C2-8 alkylene-ORB, SRA S(0)RA, SO2 A, S02N(RA)RB,
N(RA)C(0)RB, N(RA)C02RB, N(RA)S02RB,
N(RA)S02N(RA)RB, N(RA)C(0)N(RA)RB; or OC(0)N(RA)RB;
(4) CycB,
(5) AryB,
(6) HetB,
(7) C 1 -8 alkyl substituted with CycB,
(8) Ci- alkyl substituted with AryB,
(9) C - alkyl substituted with HetB, or
(10) Ci-8 alkyl substituted with HetQ; R6 is:
(1 ) H,
(2) C] -8 alkyl,
(3) Ci-8 haloalkyl, or
(4) Ci-8 alkyl substitated with OH, 0-Ci_8 alkyl, O-Ci-8 haloalkyl, CN5 N(RA)RB; C(0)N(RA)RB5 C(0)RA, C02RA, C(0)-N(RA)-C2-8 alkylene-ORB, SRA, S(0)RA, SO2R , S02 (RA)RB;
N(RA)C(0)RB, N(RA)C02RB, N(RA)S02RB,
N(RA)S02N(RA)RB5 N(RA)C(0)N(RA)RB, or 0C(0)N(RA)RB5
(5) CycB,
(6) AryB,
(7) HetB,
(8) C}-8 alkyl substituted with CycB,
(9) C i -8 alkyl substituted with AryB,
(10) Ci -8 alkyl substituted with HetB, or
(1 1) C-i -8 alkyl substituted with HetQ;
R4 is:
(1) H,
(2) Ci-8 alkyl,
(3) Ci-8 haloalkyl, or
(4) C 1 _8 alkyl substituted with OH, O-C 1 -8 alkyl, O-C 1 _8 haloalkyl, CN, N(RA)RB5 C(0)N(RA)RB5 C(0)RA} C02 A, -C(0)HetA, - C(0)N(RA)HetP, -C(0)N(RA)HetP, C(0)-N(RA)-C2-8
alkylene-ORB, SRA5 S(0)RA, S02 A, S02N(RA)RB5
N(RA)C(0)RB, N(RA)C02RB, N(RA)S02RB,
N(RA)S02N(RA)RBF N(RA)C(0)N(RA)RB, or 0C(0)N(RA)RB,
(5) CycA,
(6) C 1 _ alkyl substituted with CycA,
(7) C 1 -g alkyl substituted with AryA,
(8) Ci-8 alkyl substituted with HetA, or
(9) C 1 _8 alkyl substituted with HetP;
R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 4- to 8-membered cycloalkyl, which can be optionally fused to a benzene ring or a 5 or 6-membered heteroaryl ring, (ii) a 6- to 10-membered fused or bridged bicycloalkyl, or (iii) a 5- to 8- membered heterocyclylalkyl in which the ring heteroatom is selected, from N, O and S where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted on a ring carbon with oxo and is optionally substituted with from 1 to 4 substituents each of which is independently:
(1) Ci-8 alkyl,
(2) Ci-8 haloalkyl, or
(3) C l -8 alkyl substituted with OH, O-C l -8 alkyl, O-C l -8 haloalkyl, CN, N( A)RB, C(0)N(RA)RB; C(0)RA, C02Ra, C(0)~N(RA)-C2-8 alkylene-ORB, SRA, S(0)RA, S02RA, S02N(RA)RB,
N(RA)C(0)RB, N(RA)C02RB, N(RA)S02RB,
N(RA)S02N(RA)RBS N(RA)C(0)N(RA)RB, or
Figure imgf000009_0001
(4) CycB,
(5) AryB,
(6) HetB,
(7) Ci-8 alkyl substituted with CycB,
(8) Ci_8 alkyl substituted with AryB, .
(9) C i _8 alkyl substituted with HetB, or
(10) C 1-8 alkyl substituted with HetQ;
AryA is an aryl which is optionally substituted with from 1 to 5 substituents, wherein:
(A) each of the substituents is independently:
(1) Ci-6 alkyl,
(2) C i _6 alkyl substituted with OH, O-C i -6 alkyl, O-C i -6 haloalkyl, CN,
N02, N(RA)RB5 C(0)N(RA)RB, C(0)RA CO2 A SRA S(0)RA SO2R S02N(RA)RB, N(RA)C(0)RBS N(RA)C02RB S
N(RA)S02RB ? N(RA)S02N(RA)RB5 OC(0)N(RA)RBF
N(RA)C(0)N(RA)RBs or N(RA)C(0)C(0)N(RA)RBJ
(3) 0-Ci-6 alkyl,
(4) Ci_6 haloalkyl,
(5) O-C 1 -6 haloalkyl,
(6) OH,
(7) halogen,
(8) CN,
(9) N02,
(10) N(RA)RBS 0 1 ) C(0)N(RA)RB?
(12) C(0)RA
(13) C(0)-CI-6 haloalkyi.
(14) C(0)ORA
(15) 0C(0)N(RA)RB5
(16) SRA,
(17) S(0)RA,
(18) S02RA,
(19) S02N(RA)RB;
Figure imgf000010_0001
(22) N(RA)C(0)RB,
(23) N(RA)C(0)N(RA)RB,
(24) N(RA)C(0)C(0)N(RA)RB5 or
(25) N(RA)C02RB; or
(B) when there are two or more substituents on the aryl, two of the substituents are respectively located on adjacent carbons on the aryl ring and together form methylenedioxy or ethylenedioxy, and other substituents, if any, are each independently one of groups (1) to (25) as set forth in (A) above; each AryB independently has the same definition as AryA;
CycA is a 3- to 8-membered monocyclic or bicyclic cycloalkyl which is optionally
substituted with from 1 to 4 substituents each of which is independently halogen, OH, Ci-6 alkyl, O-Ci-g alkyl, Ci-6 alkyl substituted with -OH, O-Ci-6 alkyl, C j_6 haloalkyi, or O-C \ . haloalkyi;
each CycB independently has the same definition as CycA;
HetA is a heteroaryl which is optionally substituted with from 1 to 5 substituents, each of which is independently:
(1) C 1-6 alkyl,
(2) Ci-6 alkyl substituted with OH, 0-Ci„ alkyl, O-Ci-6 haloalkyi, CN, NO2, N(RA)RB; C(0)N(RA)RB, C(0)RA CO2RA SRA S(0)RA SO2RA S02N(RA)RBS N(RA)C(0)RB, N(RA)C02 B N(RA)S02RB,
N(RA)S02N(RA)RB? 0C(0)N(RA)RB; N(RA)C(0)N(RA)RBs or
N(RA)C(0)C(0)N(RA)RB,
(3) O-Ci-6 alkyl,
(4) Ci-6 haloalkyi,
(5) O-C 1-6 haloalkyi, (6) OH,
(7) halogen,
(8) CN,
(9) N02)
(10) N(RA)RBF
(Π) C(0)N(RA)RB,
(12) C(0)RA
(13) C(0)-Ci-6 haloalkyl,
(14) C(0)ORAJ
(15) OC(0)N(RA)RB5
(16) SRA
(17) S(0)RA
(18) S02RA,
(19) S02N(RA)RB;
Figure imgf000011_0001
(22) N(RA)C(0)RBS
(23) N(RA)C(0)N(RA)RBS
(24) N(RA)C(0)C(0)N(RA)RB5 or
(25) N(RA)C02RB;
each HetB independently has the same definition as HetA;
HetP is (i) a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2 or (ii) a 6- to 10- membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2; and wherein the saturated or mono- unsaturated heterocyclic or heterobicyclic ring is optionally substituted with a total of from 1 to 4 substituents, each of which is independently halogen, Ci-g alkyl, haloalkyl, O-Ci-6 alkyl, O-Ci-6 haloalkyl, oxo, C(0)N(RA)RB,
C(0)C(0)N(RA)RB; C(0)RA C02 A, BRA S(0)RA SO2R or S02N(RA)RB; each HetQ independently has the same definition as HetP;
each RA is independently H, C\-6 alkyl or haloalkyl;
each RB is independently H, Ci-6 alkyl or 0 . haloalkyl;
each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; and each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(0)2-
The present invention also includes pharmaceutical compositions containing a compound of Formula I or a pharmaceutically acceptable salt thereof. The present invention further includes methods involving compounds of Formula I for the treatment of AIDS, the delay in the onset or progression of AIDS, the prophylaxis of AIDS, the prophylaxis of infection by HIV, and the treatment of infection by HIV.
Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims .
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes compounds of Formula I above (including hydrates and solvates thereof), and pharmaceutically acceptable salts thereof. These compounds are effective inhibitors of wild-type HIV integrase (e.g., HIV-l) and may be effective inhibitors of mutant strains of HIV integrase.
A first embodiment of the present invention (alternatively referred to herein as "Embodiment El ") is a compound of Formula I (alternatively and more simply referred to as "Compound I"), or a pharmaceutically acceptable salt thereof, wherein:
AryA is phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) Ci-6 alkyl,
(2) O-Ci-6 alky
(3) Ci-6 haloalkyl,
(4) O-Cl-6 haloalkyl,
(5) OH,
(6) halogen,
(7) CN,
(8) N(RA)RBJ
(9) C(0)N(RA)RB)
(10) S(0)RA
(11) S02 A, (12) N(RA)S02RB,
(13) N(RA)S02N(RA)RB,
(14) N(RA)C(0)RB, or
(15) N(RA)C(0)C(0)N(RA)RB; and
each AryB independently has the same definition as AryA;
CycA is a 3- to 6-membered cycloalkyi which is optionally substituted with from 1 to 3 substituents each of which is independently OH, C\-6 alkyl, 0-Ci_6 alkyl, or Ci-g alkyl substituted with O-Ci-6 alkyl;
each CycB independently has the same definition as CycA;
HetA is a 5- or 6-membered. heteroaromatic ring containing a total of from 1 to 3
heteroatoms independently selected from N, S and O, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently Ci-4 alkyl, OH, O-C1.4 alkyl, halogen, CN, C(0)N(RA)RB, C(0)RA C(0)ORA or SO2RA;
each HetB independently has the same definition as HetA;
HetP is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently C 1.4 alkyl, oxo, C(0)N(RA)RB? C(0)RA, CO2R or SO2RA; and each HetQ independently has the same definition as HetP;
and all other variables are as originally defined (i.e., as defined in the Summary of the Invention).
A second embodiment of the present invention (Embodiment E2) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
Rl A and RIB are each independently:
(1) H,
(2) C 1 -6 alkyl,
(3) OH,
(4) O-Ci-6 alkyl,
(5) Ci-6 haloalkyl,
(6) O-Ci-6 haloalkyL
(7) halogen,
(8) CN,
(9) N(RA)RB,
(10) C(0)N(RA)RB5
(11) C(0)RA (12) C(0)0RA,
(13) SRA
(14) S(0)RA
(15) S02RA; or
or alternatively RlA and R*B are respectively located on adjacent carbons in the phenyl and together form methylenedioxy or ethylenedioxy;
RlC is:
0) H,
(2) Ci-6 alkyl,
(3) O-Ci-6 alkyl,
(4) Ci-6 haloalkyl,
(5) O-Cj-6 haloalkyl, or
(6) halogen;
and all other variables are as originally defined or as defined in Embodiment El.
A third embodiment of the present invention (Embodiment E3) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
R1 A and RlB are each independently:
G) H,
(2) Ci-4 alkyl,
(3) OH,
(4) O-C 1-4 alkyl,
(5) CF3j
(6) OCF3,
( ) CI,
(8) Br,
(9) F,
(10) C ,
(11) NH2,
(12) N(H)-Ci_4 alkyl,
(13) N(Ci-4 alkyl)2,
(14) C(0)NH2,
(15) C(0)N(H)-Ci-3 alkyl,
(16) C(0)N(Ci_3 alkyl)2,
(17) CH(0),
(18) C(0)-C 1-4 alkyl,
(19) C02H,
(20) CO2-C1-4 alkyl, (21) S02H, or
(22) S02-Ci-4 alkyl;
lC is:
(1) H
(2) Ci-4 alkyl,
(3) 0-Ci-4 alkyl,
(4) CF3,
(5) OCF3,
(6) CI,
(7) Br, or
(8) F;
and all other variables are as originally defined or as defined in Embodiment El .
A fourth embodiment of the present invention (Embodiment E4) is compound of Formula I, or a pharmaceutically acceptable salt thereof, wherem: Rl A and RlB are each independently:
(1) H,
(2)
(3) CH2CH3
(4) OH,
(5) OCH3,
(6) CF3>
(7) OCF3,
(8) CI,
(9) Br,
(10) F,
(1 1) CN,
(12) NH2,
(13) N(H)CH3,
(14) N(CH3)2,
(15) C(0)NH2,
(16) C(0)N(H)CH3,
(17) C(0)N(CH3)2,
(18) CH(0),
(19) C(0)CH3,
(20) CO2H,
(21) C02CH3,
(22) SO2H, or (23) SO2CH3;
RlC is:
(1) H,
(2) CH3>
(3) OCH3,
(4) CF3,
(5) OCF3,
(6) CI,
(7) Br, or
(8) F;
and all other variables are as originally defined or as defined in Embodiment EL
A fifth embodiment of the present invention (Embodiment E5) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
R! and R B are each independently:
(1) H,
(2) CH3,
(3) CI,
(4) Br, or
(5) F;
RlC is:
(1) H,
(2) CH3,
(3) CI,
(4) Br, or
(5) F;
and provided that at least one of Rl R B and R C is other than H;
and all other variables are as originally defined or as defined in Embodiment El.
A sixth embodiment of the present invention (Embodiment E6) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl A is F in the para position of the benzyl moiety; Rl B is H, CI, or Br in the ortho or meta position of the benzyl moiety; RlC is H; and all other variables are as originally defined or as defined in Embodiment E .
A seventh embodiment of the present invention (Embodiment E7) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2A and R3A are each independently H, fluoro, or Ci_6 alkyl; R2B is H; R3B1S H; and all other variables are as originally defined or as defined in any one of the foregoing embodiments. An eighth embodiment of the present invention (Embodiment E8) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2A5 R2B} R3A¾ and R3B are each H; and all other variables are as originally defined or as defined in any one of the foregoing embodiments.
A ninth embodiment of the present invention (Embodiment E9) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4, R5 and R6 are defined as set forth in Part A, Part B or Part C below:
(A) R is:
0) H,
(2) Ci-8 alkyl,
(3) Ci-6 haloalkyL
(4) Ci -6 alkyl substituted with O-Cj alkyl, C(0)N(RA)RB, C(0)RA CO2 A SRA S(0)RA SO2 A or S02N( A) B,
(5) CycA, or
(6) C 1 -6 alkyl substituted with CycA,
one of R5 and R6 is H or Ci_6 alkyl, and the other of R5 and R6 is:
(1) H,
(2) Ci-8 alkyl,
(3) Ci-6 haloalkyl,
(4) C l -6 alkyl substituted with O-C 1 -6 alkyl, C(0)N(RA)RB,
C(0)RA C02PA S(0) A, S02RA, or S02N( A)RB?
(5) CycB, or
(6) C 1 -6 alkyl substituted with CycB ;
or
(B) 4 and R5 together with the atoms to which they are attached form a 5- to 7- membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) C 1-6 alkyl,
(2) Ci-6 haloalkyl} or
(3) Ci_6 alkyl substituted with OH, O-Ci-6 alkyl, O-Ci-6
haloalkyl, CN, N(RA)RB, C(0)N(RA)RB, C(0)RA, CO2 A, SRA, S(0)RA or SO2R ,
(4) CycB, or
(5) Ci-6 alkyl substituted with CycB;
R6 is:
(1) H,
(2) Ci_8 alkyl, (3) Ci-6 haloalkyl, or
(4) Ci -6 alkyl substituted with OH, 0-Ci_6 alkyl, O-Cj-6
haloalkyl, CN; N(RA)RBS C(0)N(RA)RB? C(0)RA, C02RA, SRA, S(0)RA S02RA, or S02N(RA)RB;
or
(C) R4 is as defined in Part A;
5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycioalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl, or (iii) a 5- to 7-membered heterocyclylalkyl in which the ring atom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted on a ring carbon with oxo and is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) Ci-6 alkyl,
(2) Ci-6 haloalkyl, or
(3) Ci-6 alkyl substituted with OH, O-Ci-6 alkyl, O-Ci-6
haloalkyl, CN, N(RA)RB; C(0)N(RA)RB; C(0)RA CO2 A, SRA, S(0)RA, SO2RA or S02N(RA)RB,
(4) CycB, or
(5) C 1 _6 alkyl substituted with CycB ;
and all other variables are as originally defined or as defined in any one of the foregoing embodiments. In an aspect of this embodiment, CycA is a 3- to 6-membered cycioalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, Ci_6 alkyl, O-Ci-6 alkyl, or Ci-6 alkyl substituted with O-Ci-6 alkyl; and each CycB independently has the same definition as CycA.
A tenth embodiment of the present invention (Embodiment E 10) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R45 R5 and R6 are defined as set forth in Part A, Part B or Part C below:
(A) R is:
(1) H,
(2) C 1-4 alkyl,
(3 ) C i_4 fluoroalkyl,
(4) C 1 -4 alkyl substituted with O-C 1.4 alkyl, C(0)NH2,
C(0)NH(Ci-4 alkyl), C(0)N(Ci-4 alkyl)2, CO2H,
C(0)0-C l -4 alkyl, S-C 1.4 alkyl, or SO2-C 1.4 alkyl,
(5) CycA, or
(6) CH2-CycA; one of R5 and R0 is H or Q-4 alkyl, and the other of 5 and R is:
(1) H,
(2) Ci-8 alkyl,
(3) Ci_4 fluoroaikyl,
(4) C i _6 alkyl substituted with O-C l -6 alkyl,
(5) CycB, or
(6) CH2-CycB; 4 and R5 together with the atoms to which they are attached form a 5- or 6-membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) Ci-4 alkyl,
(2) C i_4 fluoroaikyl, or
(3) C i -4 alkyl substituted with O-C i .4 alkyl;
R6 IS
(1) H, or
(2) C alkyl;
or
(C) R4 is as defined in Part A:
R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl which is optionally substituted on a ring carbon with oxo, or (iii) a 5- or 6-membered heterocyclylalkyl in which the ring atom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) C 1 -4 alkyl,
(2) Ci-4 fluoroaikyl, or
(3) C 1 -4 alkyl substituted with O-C 1 _4 alkyl;
and all other variables are as originally defined or as defined in any one of the foregoing embodiments. In an aspect of this embodiment, CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently Ci-4 alkyl, O-C} .4 alkyl, or Cj-4 alkyl substituted with 0-Ci_4 alkyl; and CycB
independently has the same definition as CycA.
An eleventh embodiment of the present invention (Embodiment El 1 ) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4, R5 and are defined as set forth in Part A, Part B or Part C below: R is:
(1) H,
(2) C alkyl,
(3) CF3,
(4) CH2CF3,
(5) (CH2)l-3-T, wherein T is C(0)NH2, C(0)NH(CH3),
C(0)N(CH3)2, C02H, C(0)OCH3, or S02CH3,
(6) (CH2)2-3-U, wherein U is OCH3 or SCH3,
(7) CycA, or
(8) CH2-CycA;
one of R5 and R.6 is H or Ci-4 alkyl, and the other of R5 and R0 is:
(1) H,
(2) Ci-8 alkyl,
(3) CF3,
(4) CH2CF3,
(5) CycB, or
(6) CH2-CycB;
R and R5 together with the atoms to which they are attached form a 5- or 6- membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) C alkyl,
(2) CF3,
(3) CH2CF3,
(3 ) C 1.4 alkyl substituted with O-C 1.4 alkyl ;
R6 is
(1) H, or
(2) C 1-4 alkyl; (C) R4 is as defined in Part A:
R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl which is optionally substituted on a ring carbon with oxo, or (iii) a 5- or 6-membered heterocyclylalkyl in which the ring atom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C\-4 alkyl,
(2) CF3, or
(3) CH2CF3;
and all other variables are as originally defined or as defined in any one of the foregoing embodiments. In an aspect of this embodiment, CycA is a 3- to 6-membered cycloaikyl; and CycB is a 3- to 6-membered cycloaikyl.
A twelfth embodiment of the present invention (Embodiment El 2) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4, R5 and 6 are defined as set forth in Part A, Part B or Part C below:
(A) R4 is:
(I) H,
(3) CH2CH3,
(4) CH2CH2CH3,
(5) CH(CH3)2,
(6) CH2CH(CH3)2,
(7) CH2CF3,
(8) CH2C(0)OH,
(9) CH2C(0)OCH3,
(10) CH2C(0)OCH2CH3,
(I I) CH2CH20CH3,
(12) CH2CH2SCH3,
(13) CycA, or
(14) CH2~CycA;
(1) H,
(2) CH3,
(3) CH2CH3,
(4) CH2CH2CH3,
(5) CH(CH3)2,
(6) C(CH3)3,
(7) CH(CH2CH3)2,
(8) CH(CH3)CH2CH3, or
(9) C(CH2CH3)3,
(10) CH2CF3, or
(11) CycB;
H, CH3, or CH2CH3; or
(B) R.4 and R.5 together with the atoms to which they are attached form a 5- or 6-
Figure imgf000022_0001
oalkyl ring is optionally substituted with 1 or 2 substituents each of which is independently methyl or ethyl; and each asterisk (*) denotes the point of attachment to the rest of the compound;
R6 is
(1) H,
(2) CH3, or
(3) CH2CH3;
R4 is as defined in Part A;
R5 and 6 together with the carbon atom to which they are both attached
Figure imgf000022_0002
optionally substituted with 1 or 2 methyl groups; and each asterisk (*) denotes the point of attachment to the rest of the compound; and all other variables are as originally defined or as defined in any one of the foregoing embodiments. In an aspect of this embodiment, CycA is cyclopropyl; and CycB is cyclopropyl, cyclobutyl, or cyclopentyl.
A thirteenth embodiment of the present invention (Embodiment El 3) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4, R5 and R6 are as defined in Embodiment El 2, except that in part B of the definition of R4s 5 and R6:
R4 and R5 together with the atoms to which they are attached form a fused azacycloalkyl ring which is:
Figure imgf000023_0001
R6 is (1 ) H, (2) CH3, or (3) CH2CH3 ; and
in part C of the definition of R4, R5 and R6;
R4 is (1) R (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, (5) CH(CH3)2,
(6) CH2CH(CH3)2, (7) CH2C(0)OH, (8) cyclopropyl, or (9) CH2-cyclopropyl; and
R5 and 6 together with the carbon atom to which they are both attached form a
Figure imgf000023_0002
A fourteenth embodiment of the present invention (Embodiment El 4) is a compound of Formula I, or a phannaceutically acceptable salt thereof, wherein RA and RB are each independently H or C1-.4 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments.
A fifteenth embodiment of the present invention (Embodiment El 5) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RA and RB are each independently H or C 1.3 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments.
A sixteenth embodiment of the present invention (Embodiment El 6) is a compound of Formula i, or a pharmaceutically acceptable salt thereof, wherein RA and R are each independently H or CH3 ; and all other variables are as originally defined or as defined in any of the preceding embodiments.
A seventeenth embodiment of the present invention (Embodiment E 17) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R5 and R6, together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
Figure imgf000024_0001
An eighteenth embodiment of the present invention (Embodiment El 8) is a compound of Formula I, or an individual enantiomer or diastereomer thereof, which is selected from Examples 1-177, as set forth in the Examples below.
An nineeenth embodiment of the present invention (Embodiment El 9) is a compound of Formula I, or an individual enantiomer or diastereomer thereof, which is selected from the group consisting of:
8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9', 10'-dihydro-2'H- spiro[bicyclo[2.2. l]heptane-2,3'-imidazo[5, 1 -a] [2,6]naphthyridine]- 1 ',5',7'(8'H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3-djmethyl-2s3,9310- tetrahydroimidazo[5,l -a] [2,6]naphthyridme-l ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2-(2-methoxyethyl)-3- methyl-2,3 ,9, 10-tetrahydroimidazo [5 , 1 -a] [2,6]naphthyridine- 1 ,5 ,7(8H)-trione;
3-(3-chloro-4-fluorobenzyl)-5-hydroxy-8i8-dimethyl-253,8;9, 10,1 1- hexahydro-7aH-pyrido[2'5 V :2,3 ] imidazo [5, 1 -a] [2,6]naphthyridine-4,6, 13( 1 H)-trione;
3-(3-chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,7a,8?9s10- hexahydropyrrolo[2' ,V 2,3] imidazo [5 , 1 -a] [2,6] naphthyridine-4 ,6,12(1 H)-trione;
3-(3-cliloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2J3,8s9J10,l l-hexaliydro- 7aH-pyrido[2'3 :2,3 ] imidazo[5 , 1 -a] [2, ]naphthyridine-4,6 , 13 ( 1 H)-trione;
-3 -(3 -chloro-4-fluorobenzyl)-7a-ethyl- 5 -hydroxy -2,3 , 8,9,10,1 1 -hexahydro- 7aH-pyrido [2' , 1 ' :2 ,3 ] imidazo [ 551 -a] [2,6] naphthyridine-4,6, 13(1 H)-trione;
8-(4-fluorobenzyl)-6-hydroxy-2-methyl-3-( l-methylethyl)-2,3,9, 10- tetrahydroimidazo[5, 1-a] [2,6]naphthyridine-l ,5,7(8H)-trione;
8'-(2-bromo-4-fluorobenzyl)-6!-hydroxy-2'-methyl-9', 10'-dihydro-2!H- spiro[cyclopentane- 1 ,3'-imidazo 5, 1 -a] [2,6]naphthyridine]- 1
Figure imgf000024_0002
8 -(3 -chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3 -( 1 -methyl ethyl)-2 ,3,9,10- tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine-l,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3,3-trimethyl-2,3,9, 10- tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine-l ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methoxyethyl)-3-(l- methylethyl)-2,3 ,9,10-tetrahydroimidazo [5 , 1 -a] [2,6] naphthyri dine- 1 , 5 ,7(8H)-trione ;
3 -tert-butyl-S -(3 -chloro-4-fluorobenzyl)-6-hydroxy-2-methyl -2,3,9,10- tetrahydroimidazo [5 , 1 -a] [2 , 6]naphthyridine- 1 ,5 ,7(8H)-trione;
3-(3-chloro-4-fluorobenzyl)-5-hydroxy-2,3,8,9,10,l l-hexahydro-7aH- pyrido [2 V : 2,3] imidazo [ 5 , 1 -a] [2,6] naphthyridine-4 ,6,13(1 H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methoxyethyl)-3-methyl- 2,3 ,9,10-tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine-l ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-2,3-dicyclopropyI-6-hydroxy-2,3,9, 10- tetrahydroimidazo[ 5 , 1 -a] [2 , 6]naphthyridine- 1 , 5 ,7(8 H)-trione;
3 -tert-butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-2,3 ,9, 10- tetrahydroimidazo[5;l -a][2,6]naphthyridine-l ,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-ethyl-6-hydroxy-2-methyl-253,9,10- tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)-trione;
3-tert-butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3 ,9, 10- tetrahydroimidazo[5;l-a] [2,6]naphthyridine-l ,5,7(8H)-trxone;
8-(3 -chloro-4-fluorobenzyl)-3 -(1,1 -diethylpropyl)-6-hydroxy-2>3 ,9,10- tetxahydroimidazo[5,l-a][2,6]naplit] yridine-l ,5,7(8H)-trione;
8'-(3-chloro-4-fluoroberizyl)-6'-hydroxy-2'-methyl-9',10'-dihydro-2,H- spiro[cyclobutane- 1 ,3'-imidazo[5, 1 -a][2,6]naphthyridine]~ 1 'i5! }7'(8'H)-trione;
8-(3 -chloro-4-fluorobenzyl)-3-ethyl-6-hydroxy-3 -methyl -2,3,9,10- tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)-trione;
8,-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9',10<-dihydro-2'H- spiro[cyclopentane-lf3'-imidazo[5,l-a][2,6]naphthyridine]-l 5^7'(8'H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2J3,9, 10- tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine-l ,5,7(8H)-trione;
8,-(3~chloro-4-fluorobenzyl)-6'-hydiOxy-2,-methyl-9',10'-dihydro-2'H- spiro [cycl ohexane- 1 ,3 '-imidazo [5 , 1 -a] [2,6Jnaphthyridine] - V, 5 ', 7'(8 'H)-trione;
8<-(3-chloro-4-fluoroben2yl)-6,-hydroxy-2,-methyl-9',10'-dihydro-2,H- spiro[cycloheptane-l,3'-iinidazo[5,l-a][2,6]naphthyridine]-r55^7 8^-trione;
8-(3 -chloro-4-fluorobenzyl)- 3 -cyclobuty l-6-hydroxy-2 ,3 -dimethyl-2,3 , 9, 10- tetrahydroimidazo[5, 1-a] [2,6]naphthyridme-L5,7(8H)-trione;
8-(3 -chloro-4-fluorobenzyl)-3 -ethyl-6-hydroxy-2,3-dimethyl-2,3 ,9, 10- tetrahydroimidazo[5?l-a][2,6]naphthyridine-l55,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3-dimethyl-3-propyl-2,3,9,10- tetrahydroimidazo[5,l-a][2,6]naphthyridine-l,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-4',5',9i10-tetrahydro-2H- spiro [imidazo [5, 1 -a] [2,6]naphthyridine-3,3'-thiophene]-l ,5,7(8H)-trione;
8'-(3-chloro-4-fluorobenzyi)-6'-hydroxy-2',3~dimet yl-9,,10,-dihydro-2'H-
Figure imgf000025_0001
8-(3 -chloro-4-fluorobenzyl)-2-eihyl-6-hydroxy-3-meihy] -2,3 ,9, 10- tetrahydroimidazo[5,l-a][2,6]naphthyridine-l,5,7(8H)-trione;
8!-(3-chloro-4-fluoroberi2yl)-6,-hydroxy-2^4-dimethyl-9,,10,-dihydro-2'H- spiro[cyclohexane- 1 ,3 '-imidazo [5, 1 -a] [2J6]naphthyridine]- 1 ',5'?7'(8'H)-trione;
ethyl [8-(3-chloro-4-fluorobenzyl)-6-hydroxy-3~methyl-l ,5,7-trioxo- 1 ,5,7,8,9,10-hexahydroimidazo[5, 1 -a] 2,6]naphthyridin-2(3H)-yl]acetate
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3a',4,,6',6a',9,10-hexahydro- 1 'H,2H-spiro[imidazo[5, 1 -a] [2s6]naphthyridine-3,2'-pentaleneJ- 1 ,5,5',7(3'H,8H)-tetrone
8 -(3 -chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3 -(1 -methylpropyl)- 2,3,9,10-tetrahydroimidazo[5,l -a][2s6]naphthyridine-l ,5,7(8H)-trione;
8-(3-cWoro-4-fluorobenzyl)-3-(l-ethylpropyl)-6-hydroxy-2-methyl-2s3;9,10- tetrahydroimidazo[5, -a] [2,6]naphthyridine- 1 ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-cyclopentyl-6-hydroxy-2-methyl-2,359,10- tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine-l ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl~6-hydroxy-2-(2-methylpropyl)- 2,3,9, 10-tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-3-methyl-3-(2,2,2-trifluoroethyl)- 2,3,9,10-tetrahydroimidazo [5 , 1 -a] [2,6]naphthyridine- 1 , 5 ,7(8H)-trione;
8'-(3-chloro-4-fluorobenzyl)-2'-ethyl-6'-hydroxy-9', 10'-dihydro-2'H- spiro [cyclopentane- 1 ,3 '-imidazo [5, 1 -a] [2,6]naphthyridine] - 1 ',5',7'(8'H)-trione; 8,-(3-chloro-4-fluoroben2yl)-6,-hydroxy-9',10'-dihydro-2,H- spiro [cyclopentane- 1 ,3'-imidazo[5, 1 -a] [2,6]naphthyridine]- 1 ',5',7'(8'H)-trione;
3-to't-butyl-8-(3-chloro-4-fluoroben2yl)-6-hydroxy-2-(2-methylpi pyl)- 2,3,9, 10-tetrahydroimidazo [5, 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)-trione;
8'-(3-chloro-4-fluorobenzyl)-6,-hydroxy-2',3,3-trimethyl-9, >10'-dihydro-2,H- spiro[cyclohexane- 1 ,3'-imidazo[5, 1 -a] [2,6]naphthyridine]- ,5',7'(8'H)-trione;
methyl [8-(3 -chloro-4-fluorobenzyl)-3 -cyclopropyl-6-hydroxy- 1 ,5 ,7-trioxo- ,5,7,8,9, 10-hexahydroimidazo[5, 1 -a] [2,6]naphthyridin-2(3H)-yl]acetate
8'-(3-cnloro-4-fluoroberizyl)-6'-hydroxy-2'-(2-methylpropyl)-9,,10'-dihydro- 2'H-spiro [cyclopentane- 1 ,3 -imidazo [5, 1 -a] [2,6] naphthyri dine]- 1 ',5'57'(8'H)-trione;
8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2-methyl-9'510'-dihydro-2'H- spiro [cyclopentane- 1 , 3 '-imidazo [ 5 , 1 -a] [2,6] naphthyridine]- Γ, 5 ' , 7' ( 8'H)-trione ;
3-feri-butyl-8-(3-chloro-4-fiuorobenzyl)-6-hydroxy-2-[2- (methylsulfanyl)ethyl] -2,3,9,10-tetrahydroimidazo [5 , 1 -a] [2 , 6]naphthyridme- 1 , 5 , 7(8H)- trione;
8-(3 -chloro-4-fluorobenzyl)-3 -cyclopropyl-6-hydroxy-2- [2- (methylsulfanyl)ethyl] -2,3 ,9, 10-tetrahydroimidazo [5 , 1 -a] [2,6]naphthyridine~ 1 ,5 ,7(8H)- trione;
8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-2-(cyclopropylmethyl)-6-hydroxy- 3-methyl-2,3}9,10-tetrahydroimidazo[5,l-a][2,6]naphthyridine-l,5i7(8H)-trione;
8'-(3-chloro~4-fiuorobenzyl)-2'-cyclopropyl-6'-hydroxy-9',10'-dihydro-2'H- spiro [cyclopentane- 1 ,3'-imidazo [5 , 1 -a] [2,6]naphthyridine] - 1 ' ,5',7'(8Ή)-ΐποη€;
[S'-iS-chloro^-fluorobenzy - '-hydro y-l'^'J'-trio o-l'^'^'^'^' O'- hexahydro-2'H-spiro [cyclopentane- 1 ,3 '-imidazo [5, 1 -a] [2 , 6]naphthyridin] -2' -yl] acetic acid
8'-(S-chloro-4-fluorobenzyl)-2'-(c c^opropylmem ί)-6'-h drox -9,, 10'- dihydro-2'H-spiro [cyclopentane- 1 ,3'-imidazo[5, 1 -a][2,6]naphthyridine]-l ',5',7'(8'H)-trione;
and pharmaceutically acceptable salts thereof.
A twentieth embodiment of the present invention (Embodiment E20) is a compound of Formula I, or an individual enantiomer or diastereomer thereof, which is selected from Examples 12, 14, 15, 17, 19, 26-29 or 150, as set forth in the Examples below.
In one embodiment, for the compounds of formula (Γ), variables R1A, R1B, R1C, R2A, R2B, R3A, R3B, R4, R5 and R6 are selected independently of each other.
A first class of compounds of the present invention (alternatively referred to Class CI) includes compounds of Formula II:
Figure imgf000026_0001
and pharmaceutically acceptable salts thereof, wherein:
Ri A, IB and RlC are as defined in Embodiment E2;
R2A and R3A are each independently H, fluoro, or C 1-6 alkyl;
R4, R5 and R0 are as defined in Embodiment E9;
CycA is a 3- to 6-membered cycloaikyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, Ci-6 alkyl, O-Ci-6 alkyl, or C\-(, alkyl substituted with O-Ci-6 alkyl;
each CycB independently has the same definition as CycA;
each R is independently H or Ci-6 alkyl; and
each RB is independently H or Ci-6 alkyl.
A first sub-class of the first class (alternatively referred to herein as "Subclass CI -SI") includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein R2A and R3A are each independently H, fluoro, or CH3; and all other variables are as originally defined in Class CI .
A second sub-class of the first class (Sub-class C1-S2) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein each R is independently H or C1.4 alkyl; each RB is independently H or Cj.g alkyl; and all other variables are as originally defined in Class CI or as defined in Sub-class CI -S I .
A third sub-class of the first class (Sub-class CI -S3) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein each R is independently H or CH3; each RB is independently H or CH3; and all other variables are as originally defined in Class CI or as defined in Sub-class CI -SI.
A second class of compounds of the present invention (Class C2) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein:
R1 AS RIB a d RlC are as defined in Embodiment E3;
R2A and 3A are both H;
R4; R5 and R<5 are as defined in Embodiment E10;
CycA is a 3- to 6-membered cycloaikyl which is optionally substituted with from 1 to 3 substituents each of which is independently C1 -.4 alkyl, O-C1-4 alkyl, or C1-.4 alkyl substituted with OC1-.4 alkyl; and
CycB independently has the same definition as CycA;
each RA is independently H or Ci _ alkyl; and
each RB is independently H or Ci_ alkyl.
A first sub-class of the second class (Sub-class C2-S1) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein each R is independently H or Ci_4 alkyl; each RB is independently H or Ci-6 alkyl; and all other variables are as originally defined in Class C2. A second sub-class of the second class (Sub-class C2-S2) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein each RA is independently H or CH3; each RB is independently H or CH3; and all other variables are as originally defined in Class C2.
A third class of compounds of the present invention (Class C3) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein:
RlA} RIB and RlC are as defined in Embodiment E4;
R2A and R3A are both H;
R4s R5 and R6 are as defined in Embodiment El 1;
CycA is a 3- to 6-membered cycloalkyl; and
CycB is a 3- to 6-membered cycloalkyl.
A fourth class of compounds of the present invention (Class C4) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein:
RlA, RlB and C are as defined in Embodiment E5;
R2A and R3A are both H;
R4, R5 and R0 are as defined in Embodiment El 2;
CycA is cyclopropyl; and
• CycB is independently cyclopropyl, cyclobutyl, or cyclopentyl.
A first sub-class of the fourth class (Sub-class C4-S1) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein RlA is F in the para position of the benzyl moiety; RlB is H, CI, or Br in the ortho or meta position of the benzyl moiety; and RlC is H; and all other variables are as originally defined in Class C4.
A second sub-class of the fourth class (Sub-class C4-S2) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein all of the variables are as originally defined in Class C4, except that in part B of the definition of R4, R5 and 0;
R4 and 5 together with the atoms to which they are attached form a fused
Figure imgf000028_0001
R6 is (1) H, (2) CH3, or (3) CH2CH3; part C of the definition of R.4 R5 and Re;
R4 is (1) H, (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, (5) CH(CH3)2,
(6) CH2CH(CH3)2, (7) CH2C(0)OH, (8) cyclopropyl, or (9) CH2-cyclopropyl; and
R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is:
Figure imgf000029_0001
A second sub-class of the fourth class (Sub-class C4-S3) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein Rl A 1S F in the para position of the benzyl moiety; R B is H, CI, or Br in the ortho or meta position of the benzyl moiety; and Rl is H; and all other variables are as defined in Sub-class C4-S2.
Ifi one embodiment, for the compounds of formula (II), variables R 1A„ r R> lB R1C, R2A, R3A, R4, Rs and R6 are selected independently of each other.
Figure imgf000029_0002
and pharmaceutically acceptable salts thereof, wherein:
R is halo;
R1B is H or halo;
R4 Is H, 3 to 8-membered cycloalkyl or Chalky!, wherein said 3 to 8- membered cycloalkyl group can be optionally substituted with -OH and wherein said Cj. galkyl group is substituted with ~N(Ci-6alkyI)-S02-(Ci.6alkyl), -0-(Ci-6alkyl) or 3 to 8- membered cycloalkyl, wherein said 3 to 8-membered cycloalkyl substituent can be optionally substituted with -OH; R5 is H; and
6 is cycloalkyl, or R5 and R6, together with the common carbon atom to which they are attached, combine to form a spirocyclic ring which is: (i) a 4 to 8-membered cycloalkyl group or (ii) a 6 to 10-membered fused or bridged bicycloalkyl group, wherein said spirocyclic rings (i) and (ii) can be optionally substituted with a -0-(Ci-6alkyl) group.
In one embodiment, for the compounds of formula (III), R is F and R is H or CI.
embodiment, for the compounds of formula (III), R4 is H, cyclopropyl,
-CH2CH2N(CH3)S02CH3, -CH2CH2O
Figure imgf000030_0001
In one embodiment, for the compounds of formula (III), R5 is H and R6 is cyclopropyl.
In another embodiment, for the compounds of formula (III), R5 is H and R4 and 6 are each cyclopropyl.
In one embodiment, for the compounds of formula (HI), Rs and R6, together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
Figure imgf000030_0002
In another embodiment, for the compounds of formula (III), R and R , together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
Figure imgf000030_0003
In one embodiment, for the compounds of formula (III), RIA is F and RiB is H or CI; R4 is cyclopropyl or -CH2CH2N(CH3)S02CH3;RS is H; and R6 is cyclopropyl.
In another embodiment, for the compounds of formula (III), R1A is F and R1B is H or CI; R4 is H, -CH2CH2N(CH3)S02CH3> -CH2CH2OCH3 or:
Figure imgf000031_0001
R5 and R6, together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
Figure imgf000031_0002
In another embodiment, for the compounds of formula (HI), RIA is F and R1B is H or CI; R4 is H, -CH2CH2N(CH3 CH3 or:
Figure imgf000031_0003
Rs and R6, together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
Figure imgf000031_0004
In one embodiment, for the compounds of formula (III), variables R1A, RlB, R4, R5 and R6 are selected independently of each other.
Another embodiment of the present invention is
a compound of Formula I, or a pharmaceutically acceptable salt thereof, as originally defined or as defined in any of the foregoing embodiments, sub-embodiments, aspects, classes, or sub-classes, wherein the compound or its salt is in a substantially pure form. As used herein "substantially pure" means suitably at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt.% (e.g., from about 90 wt.% to about 99 wt.%), even more preferably at least about 95 wt.% (e.g., from about 95 wt.% to about 99 wt.%, or from about 98 wt.% to 100 wt.%), and most preferably at least about 99 wt.% (e.g., 100 wt.%) of a product containing a compound of Formula I or its salt (e.g., the product isolated from a reaction mixture affording the compound or salt) consists of the compound or salt. The level of purity of the compounds and salts can be determined using a standard method of analysis such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and/or mass spectrometry. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level of purity determined, then the method providing the highest purity level governs. A compound or salt of 100% purity is one which is free of detectable impurities as determined by a standard method of analysis. With respect to a compound of the invention which has one or more asymmetric centers and can occur as mixtures of stereoisomers, a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual
diastereomer or enantiomer.
The present invention also includes prodrugs of the compounds of Formula I.
The term "prodrug" refers to a derivative of a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is converted in vivo into Compound I. Prodrugs of compounds of Formula I can exhibit enhanced solubility, absorption, and/or lipophilicity compared to the compounds per se, thereby resulting in increased bioavailability and efficacy. The in vivo conversion of the prodrug can be the result of an enzyme-catalyzed chemical reaction, a metabolic chemical reaction, and/or a spontaneous chemical reaction (e.g., solvolysis). When the compound contains, for example, a hydroxy group, the prodrug can be a derivative of the hydroxy group such as an ester (-OC(O-)R), a carbonate ester (- OC(O)OR), a phosphate ester (-0-P(=0)(OH)2)5 or an ether (-OR). Other examples include the following: When the compound of Formula I contains a carboxylic acid group, the prodrug can be an ester or an amide, and when the compound of Formula I contains a primary amino group or another suitable nitrogen that can be derivatized, the prodrug can be an amide, carbamate, urea, imine, or a annich base. One or more functional groups in Compound I can be derivatized to provide a prodrug thereof. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, edited by H. Bundgaard, Elsevier, 1985; J. J. Hale et al., J. Med. Chem. 2000, vol. 43, pp.1234-1241; C. S. Larsen and J. Ostergaard, "Design and application of prodrugs" in: Textbook of Drug Design and Discovery, 3rd edition, edited by C. S. Larsen, 2002, pp. 410-458; and Beaumont et al., Current Drug Metabolism 2003, vol. 4, pp. 461- 458; the disclosures of each of which are incorporated herein by reference in their entireties.
Other embodiments of the present invention include the following:
(a) A pharmaceutical composition comprising an effective amount of a compound of Formula I as defined above, or a prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
(b) A pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of a compound of Formula I as defined above, or a prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
(c) The pharmaceutical composition of (a) or (b), further comprising an effective amount of an anti-HIV agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents.
(d) The pharmaceutical composition of (c), wherein the anti-HIV agent is an antiviral selected from the group consisting of HTV protease inhibitors, ΗΓΥ reverse transcriptase inhibitors (nucleoside or non-nucleoside), HIV integrase inhibitors, HIV fusion inhibitors, and HIV entry inhibitors.
(e) A combination which is (i) a compound of Formula I as defined above, or a prodrug or pharmaceutically acceptable salt thereof, and (ii) an anti-HIV agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti- infective agents; wherein Compound I and the anti-HIV agent are each employed in an amount that renders the combination effective for inhibition of HIV integrase, for treatment or prophylaxis of infection by HIV, or for treatment, prophylaxis of, or delay in the onset or progression of AIDS.
(f) The combination of (e), wherein the anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV reverse transcriptase inhibitors (nucleoside or non-nucleoside), HIV integrase inhibitors, HIV fusion inhibitors, and HIV entry inhibitors.
(g) A method for the inhibition of HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof.
(h) A method for the prophylaxis or treatment of infection by HIV (e.g., HrV-1) in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof.
(i) The method of (h), wherein the compound of Formula I is
administered in combination with an effective amount of at least one other HIV antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, non- nucleoside HTV reverse transcriptase inhibitors, nucleoside HFV reverse transcriptase inhibitors, HIV fusion inhibitors, and HIV entry inhibitors.
(j) A method for the prophylaxis, treatment or delay in the onset or progression of AIDS in a subject in need thereof which comprises administering to the subj ect an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof. (k) The method of (j), wherein the compound is administered in
-combination with an effective amount of at least one other HIV antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV fusion inhibitors, and HIV entry inhibitors.
(1) A method for the inhibition of HTV integrase in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).
(m) A method for the prophylaxis or treatment of infection by HIV (e.g., HrV-1) in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).
(n) A method for the prophylaxis, treatment, or delay in the onset or progression of AIDS in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).
(o) A method for the inhibition of X RV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier.
(p) A method for the prophylaxis or treatment of infection by XMRV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier.
(q) A method for the prophylaxis, treatment or delay in the onset or progression of a disease or condition caused by XMRV infection (e.g., prostate cancer or chronic fatigue syndrome) in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally
administered as a component in a composition further comprising a pharmaceutically acceptable carrier.
(r) A method for the inhibition of HTLV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier. (s) A method for the prophylaxis or treatment of infection by HTLV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier.
(t) A method for the prophylaxis, treatment or delay in the onset or progression of a disease or condition caused by HTLV infection (e.g., T-cell leukemia or T- cell lymphoma) in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier.
The present invention also includes a compound of Formula I, or a prodrug or pharmaceutically acceptable salt thereof, (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation of a medicament for: (a) therapy (e.g., of the human body), (b) medicine, (c) inhibition of HIV integrase, (d) treatment or prophylaxis of infection by HIV, (e) treatment, prophylaxis of, or delay in the onset or progression of AIDS, (f) inhibition of XMRV, (g) treatment or prophylaxis of infection by XMRV, (h) treatment or prophylaxis or delay in the onset or progression of a disease or condition caused by XMRV infection, (i) Inhibition of HTLV, (j) treatment or prophylaxis of infection by HTLV, (k) treatment or prophylaxis or delay in the onset or progression of a disease or condition caused by HTLV infection. In these uses, the compounds of the present invention can optionally be employed in combination with one or more anti-HIV agents selected from HIV antiviral agents, anti-infective agents, and immunomodulators.
Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(t) above and the uses (i)(a)-(k) through (iii)(a)-(k) set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, sub- embodiments, aspects, features, classes, or sub-classes described above. In all of these embodiments etc., the compound may optionally be used in the form of a prodrug or pharmaceutically acceptable salt.
Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein the compound of the present Invention or a salt or prodrug thereof employed therein is substantially pure. With respect to a pharmaceutical composition comprising a compound of Formula I or its prodrug or salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it Is understood that the term "substantially pure" is in reference to a compound of Formula I or its prodrug or salt per se. Still additional embodiments of the present invention include the
pharmaceutical compositions, combinations and methods set forth in (a)-(n) above and the uses (i)(a)-(e) through (iii)(a)-(e) set forth above, wherein the HFV of interest is HIV-1. Thus, for example, in the pharmaceutical composition (d), the compound of Formula I is employed in an amount effective against HIV-1 and the anti-HIV agent is an HIV-1 antiviral selected from the group consisting of HIV-1 protease inliibitors, HIV-1 reverse transcriptase inhibitors, HIV-1 integrase inhibitors, HIV-1 fusion inhibitors and HIV-1 entry inhibitors.
As used herein, the term "alkyl" refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "Ci-6 alkyl" (or "Cl-Cg alkyl") refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso- propyl, ethyl and methyl. As another example, "Ci-4 alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
The term "cycloalkyl" refers to any monocyclic or bicyclic ring of an alkane having a number of carbon atoms in the specified range. Thus, for example, "C3-8 cycloalkyl" (or "C3-C8 cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term "azacycloalkyl" refers to a cycloalkyl group as defined above in which one of the ring carbons has been replaced with a ring nitrogen. Thus, for example, the term "a 4- to 8-membered fused azacycloalkyl" refers to the following groups:
Figure imgf000036_0001
wherein the asterisks (*) denote the ring atoms that are attached to the rest of the compound, providing thereby a fused ring system.
The term "heterocycloalkyl" refers to a cycloalkyl group as defined above in which one of the ring carbons has been replaced with a ring heteroatom which is N, O or S. Thus, for example, the term "a spirocyclic ring which is a 5- to 8-membered
heterocyclylalkyl" refers to the following groups:
Figure imgf000037_0001
wherein L is the heteroatom and the asterisks (*) denote the points of attachment to the rest of the compound providing thereby a spirocycle.
The term "alkylene" refers to any divalent linear or branched chain aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "-C2-8 alkylene-" refers to any of the C2 to C8 linear or branched alkylenes. A class of alkylenes of interest with respect to the invention is -(CH2)2-4~; and sub-classes of particular interest include -CH2CH2- and -CH2CH2CH2-.
The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, c loro, bromo, and iodo).
The term "haloalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, CI, Br and/or I). Thus, for example, "Cj-6 haloalkyl" (or "Cj-Cg haloalkyl") refers to a C\ to Cg linear or branched alkyl group as defined above with one or more halogen substituents. The term "fluoroalkyl" has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)0~4 F3 (i.e., trifluoromethyl, 2,2,2- trifluoroethyl, 3,3,3-trifmoro-n-propyl, etc.). A fluoroalkyl of particular interest is CF3.
The term "C(0)" refers to carbonyl. The terms "S(0)2" and "SO2" each refer to sulfonyl. The term "S(O)" refers to sulfinyl.
An asterisk ("*") as the end of an open bond in a chemical group denotes the point of attachment of the group to the rest of the compound.
The term "aiyl" refers to (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic. Suitable aryls include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, acenaphthenyl and fluorenyl. A class of aryls suitable for use in the present invention is phenyl, naphthyl, and indenyl. Another class of suitable aryls is phenyl and naphthyl. A particularly suitable aryl is phenyl. The term "heteroaryl" refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system which contains from 1 to 4 heteroatoms independently selected from N, 0 and S, and wherein in the fused ring system any one or more of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N in a ring is optionally in the form of an oxide, and each S is optionally S(O) or S(0)2- Suitable heteroaryls include, for example, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, quinolinyl,
tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl,
benzodioxolyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, chromanyl, isocliromanyl, cinnolinyl, quinazolinyl, benzothienyl, benzofuranyl, imidazo[l,2- ajpyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl> indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzoforanyl, 2J3-dihydrobenzo-l,4- dioxinyl (i.e., o )5 benzo-l,3-dioxolyl (i.e., ), thiazolyl, and isothiazolyl.
A class of heteroaryls suitable for use in the present invention (e.g., suitable for use as HetA and/or HetB) consists of 5- and 6-membered heteroaromatic rings containing from ί to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide. Heteroaryls belonging to this class include pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl,, imidazolyl, pyrazolyl,
Figure imgf000038_0001
heteroaromatic rings containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom.
The term "saturated or mono-unsaturated heterocyclic ring" refers to (i) a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2 or (ii) a 6- to 10-membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2- Suitable saturated heterocycles include, for example, azetidinyl, pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidii yl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, thiazinanyl, azepanyl, diazepanyl, thiazepanyl and
thiadiazepanyl. A class of suitable saturated or mono-unsaturated heterocyclic rings (e.g., suitable as HetP and/or HetQ) are the 4- to 7-membered rings containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2 (e.g., see HetZ). Another suitable class consists of 5- or 6-membered saturated heterocyclic rings containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or S02- Suitable mono-unsaturated heterocyclic rings include those corresponding to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond),
It is understood that the specific rings and ring systems suitable for use in the present invention are not limited to those listed in the preceding paragraphs. These rings and ring systems are merely representative.
Unless it is expressly stated to the contrary or is otherwise clear from the context, any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
Unless expressly stated to the contrary, all ranges cited herein are inclusive.
For example, a heteroaromatic ring described as containing from "1 to 4 heteroatoms" means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from "1 to 4 heteroatoms" is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms. As another example, a phenyl or naphthyl (see, e.g., the definition of AryA) described as optionally substituted with "from 1 to 5 substituents" is intended to include as aspects thereof, a phenyl or naphthyl substituted with 1 to 5 substituents, 2 to 5 substituents, 3 to 5 substiuents, 4 to 5 substituents, 5 substituents,
1 to 4 substituents, 2 to 4 substituents, 3 to 4 substituents, 4 substituents, 1 to 3 substituents,
2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents, and 1 substituent.
When any variable (e.g., RA or R.B) occurs more than one time in any constituent or in Formula I or in any other formula depicting and describing compounds of the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring provided such ring substitution is chemically allowed and results in a stable compound.
As would be recognized by one of ordinary skill in the art, certain of the compounds of the present invention can exist as tautomers. All tautomeric forms of these compounds, whether isolated individually or in mixtures, are within the scope of the present invention. For example, in instances where a hydroxy (-OH) substituent is permitted on a heteroaromatic ring and keto-enol tautomerism is possible, it is understood that the substituent might in fact be present, in whole or in part, in the keto form, as exemplified here for a hydroxypyridinyl substituent:
Figure imgf000040_0001
Compounds of the present invention having a hydroxy substituent on a carbon atom of a heteroaromatic ring are understood to include compounds in which only the hydroxy is present, compounds in which only the tautomeric keto form (i.e., an oxo substitutent) is present, and compounds in which the keto and enol forms are both present.
A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic adrainistration to a subject). The compounds of the present invention are limited to stable compounds embraced by Formula I. Thus, for example, for compounds of the invention containing the group C(0)-N(RA)-C2-8 alkylene-ORB, it is understood that the N(RA) moiety and the ORB moiety are typically not attached to the same carbon atom in the C2-8 alkylene moiety.
As a result of the selection of substituents and substituent patterns, certain compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether individually or in mixtures, are within the scope of the present invention.
All solvates and hydrates of compounds of Formula I are within the scope of the present invention.
The atoms in a compound of Formula I may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (lH) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the
Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
The methods of the present invention involve the use of compounds of Formula I in the inhibition of HIV integrase (e.g., wild type HIV-1 and/or mutant strains thereof), the prophylaxis or treatment of infection by human immunodeficiency virus (HIV) and the prophylaxis, treatment or delay in the onset or progression of consequent pathological conditions such as AIDS. Prophylaxis of AIDS, treating AIDS, delaying the onset or progression of AIDS, or treating or prophylaxis of infection by HIV is defined as including, but not limited to, treatment of a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the present invention can be employed to treat infection by HIV after suspected past exposure to HIV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. As another example, the present invention can also be employed to prevent transmission of HIV from a pregnant female infected with HIV to her unborn child or from an HIV-infected female who is nursing (i.e., breast feeding) a child to the child via administration of an effective amount of Compound I or a prodrug or pharmaceutically acceptable salt thereof.
The compounds can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, or benzoic acid. When compounds employed in the present invention carry an acidic moiety (e.g., -COOH or a phenolic group), suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of Formula I mean providing the compound or a prodrug or salt of the compound to the individual in need of treatment or prophylaxis. When a compound or a prodrug or salt thereof is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating or prophylaxis of HIV infection or AIDS), "administration" and its variants are each understood to include provision of the compound or prodrug or salt thereof and other agents at the same time or at different times. When the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
The terra "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term "effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, the effective amount is a "therapeutically effective amount" for the alleviation of the symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for prophylaxis of the symptoms of the disease or condition being prevented. The term also includes herein the amount of active compound sufficient to inhibit HIV integrase (wild type and/or mutant strains thereof) and thereby elicit the response being sought (i.e., an "inhibition effective amount"). When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free form (i.e., the non-salt and non-prodrug form) of the compound.
In the method of the present invention (i.e., inhibiting HIV integrase, treating or prophylaxis of HIV infection or treating, prophylaxis of, or delaying the onset or progression of AIDS), the compounds of Formula I, optionally in the form of a salt or a prodrug, can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, for example, be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Liquid preparations suitable for oral
administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions for use in the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18th edition, edited by A. R. Gennaro, Mack Publishing Co., 1990 and in Remington - The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005. The compounds of Formula I can be administered orally in a dosage range of
0.001 to 1000 mg kg of mammal (e.g., human) body weight per day in a single dose or in divided doses. One preferred dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses. Another preferred dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses. For oral administration, the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. 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.
As noted above, the present invention is also directed to use of a compound of Formula I with one or more anti-HFV agents. An "anti-HIV agent" is any agent which is directly or indirectly effective in the inhibition of HIV reverse transcriptase or another enzyme required for HIV replication or infection, the treatment or prophylaxis of HIV infection, and/or the treatment, prophylaxis or delay in the onset or progression of AIDS. It is understood that an anti-HIV agent is effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and/or diseases or conditions arising therefrom or associated therewith. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of one or more anti-HFV agents selected from HIV antiviral agents, imunomodulators, antiinfectives, or vaccines useful for treating HIV infection or AIDS. Suitable HIV antivirals for use in combination with the compounds of the present invention include, for example, those listed in Table A as follows:
Table A
Figure imgf000044_0001
maraviroc, Selzentry® EI
nelfmavir, Viracept® PI
nevirapine, NVP, Viramune® nnRTI
raltegravir, MK-0518, Isentress® I l
rilpivirine, TMC-278 nnRTI
ritonavir, Norvir® PI
saquinavir, Invirase®, Fortovase® PI
stavudine, d4T,didehydrodeoxymymidine, Zerit® nRTI
tenofovir DF (DF = disoproxil furnarate), TDF, Viread® nRTI
tipranavir, Aptivus® PI
EI = entry inhibitor; FI = fusion inhibitor; Inl = integrase inhibitor;
PI = protease inhibitor; nRTI = nucleoside reverse transcriptase
inhibitor; nnRTI = non-nucleoside reverse transcriptase inhibitor. Some of the drugs listed in the table are used in a salt form; e.g.,
abacavir sulfate, indinavir sulfate, atazanavir sulfate, nelfmavir
mesylate.
In one embodiment, the one or more anti-HIV agents are selected from lamivudine, abacavir, ritonavir and lopinavir.
In another embodiment, the compound of formula (I) is used in combination with a single anti-HIV agent which is lamivudine.
In another embodiment, the compound of formula (I) is used in combination with two anti-HIV agent which are lamivudine and abacavir.
In still another embodiment, the compound of formula (I) is used in combination with two anti-HIV agent which are ritonavir and lopinavir.
In one embodiment, the present invention provides pharmaceutical compositions comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable carrier; and (iii) one or more additional anti- HIV agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a
pharmaceutically acceptable salt thereof, wherein the amounts present of components (i) and (iii) are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof.
In another embodiment, the present invention provides a method for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof, which comprises
administering to the subject (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (ii) one or more additional anti-HIV agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a pharmaceutically acceptable salt thereof, wherein the amounts administered of components (i) and (ii) are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in .the onset or progression of AIDS in the subject in need thereof.
It is understood that the scope of combinations of the compounds of this invention with anti-HIV agents is not limited to the HIV antivirals listed in Table A, but includes in principle any combination with any pharmaceutical composition useful for the treatment or prophylaxis of AIDS. The HIV antiviral agents and other agents will typically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in the Physicians' Desk Reference. Thomson PDR, Thomson PDR, 57* edition (2003), the 58th edition (2004), the 59th edition (2005), and the like. The dosage ranges for a compound of the invention in these combinations are the same as those set forth above.
The compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.
The compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.
List of Abbreviations ACN = acetonitrile
AcOH = acetic acid
Alk = alkyl
Ax = aryl
Boc = reri-butoxycarbonyl
BOP = benzotriazol-l-yloxytris(dimethylamino)- phosphonium
hexafluorophosphate
br = broad
d = doublet
DAB CO = l,4-diazabicyclo(2,2,2)octane DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
DCE 1 ,2-dichloroethane
DIPEA N, N-diisopropylethylamine
DMA = NjjV-dimethylacetamide
DMF dimethylformamide
DMSO dimethyl sulfoxide
EDCI = 1 -ethyl-3-(3 ' -dimethylaminopropyl)carbodiimide
hydrochloride
ESI = electrospray ionization
EtOAc = ethyl acetate
EtOH = ethanol
HATU = 2-(lH-7-Azabenzotriazol- 1 -yl)-l , 1 ,3,3-tetramethyl uronium hexafiuorophosphate
HOAc = acetic acid
HOAt = 1 -hydroxy-7 -azabenzotriazole
HOBt = 1 -hydroxybenzotriazole
HRMS = high resolution mass spectrometry
IP Ac = zsopropyl acetate
LCMS = liquid chromatography / mass sepectrometry m = multiplet
mCP&A = meta-cbloroperoxybenzoic acid
MeCN = acetonitrile
MeOH - methyl alcohol
MeTHF = 2-methyltetrahydrofuran
min = minutes
MS = mass spectroscopy
MTBE = methyl tert-butyl ether
NMP = 1 -methyl 2-pyrrolidinone
NMR = nuclear magnetic resonance spectroscopy
PG protecting group
Piv = pivalate, 2,2-dimethylpropanoyl
Ph phenyl
rt room temperature
s = singlet
SFC = supercritical fluid chromatography
t = triplet
TFA = trifluoroacetic acid
THF = tetrahydrofuran
wt% = weight percent
The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
Scheme A depicts a method for preparing compounds of the present invention, wherein benzyl halide 1 is reacted with amide 2 in the presence of a base. The corresponding tertiary amide is deprotonated and reacted with phenyl methyl sulfone to generate sulfoxide 3. The sulfoxide is then converted to the corresponding ,β-unsaturated product via a Puminerer rearrangement and sulfide oxidation to compound 4. Reaction with the anion of a protected amino ester and acid hydrolysis affords the alpha amino ester 5. Elimination of the sulfone under basic conditions affords the unsaturated ester 6. Conversion of 6 to the pyridinone compound 7 can be accomplished in the presence of an ester oxalyl chloride followed by treatment with LiBr. Hydrolysis of ester 7 to the acid affords compound 8 which is then transformed to the tris-pivalate 9 using standard conditions. Compounds 8 and 9 serve as valuable intermediates which can be transformed to HTV integrase inhibitors using the procedures and methods described in the following schemes.
Scheme A
Figure imgf000048_0001
Figure imgf000049_0001
Scheme B depicts a method for the conversion of bis~hydroxy carboxyiic acid compound 8 to bis-methoxy carboxyiic acid 11 utilizing a silver-catalyzed methylation and base-mediated ester hydrolysis. Compound 11 serves as a valuable intermediate which can be transformed to HIV integrase inhibitors using the procedures and methods described in the following schemes.
Scheme B
Figure imgf000049_0002
Scheme C depicts a method for preparing compounds of the present invention, wherein carboxyiic acid 11 is reacted with primary amine 12 under standard amide coupling conditions (e.g. EDCI/HOAt/base/DMF) to yield secondary amide 13. The methyl ethers of product 13 can be cleaved under acidic conditions (e.g. HBr in AcOH) to afford the hydroxyl pyridinone 14. Treatment of 14 with an aldehyde or ketone 15 under acidic conditions (e.g. catalytic sulfuric acid or TFA) will afford the product aminal 16.
Figure imgf000050_0001
Scheme D provides a preparative sequence similar to that of Scheme C, except that an acetal or ketal (or hemi-acetal or -ketal) 17 is used in place of the aldehyde or ketone for the condensation reaction of the final Step in the presence of a protic acid.
Scheme D
Figure imgf000050_0002
R = alkyl, e.g. Me, Et
Scheme E is a variation of Schemes C and D, wherein compounds of the invention can be prepared from activated mixed anhydride 9, which is reacted with primary amine 12 to yield secondary amide compound 18, Conversion of 18 to the desired product 16 can be conducted using either the procedure of Scheme C or Scheme D. Scheme E
Figure imgf000051_0001
Scheme F depicts another route to the desired compounds, wherein mixed anhydride 9, or a related carboxylic acid derivative, can be reacted with a source of ammonia (e.g. N¾ (gas) or NH4OH) to afford the primary amide 19, which can be deprotonated to 20 and then alkylated with an electrophile to afford the product 16.
Scheme F
Figure imgf000051_0002
X = Leaving group such as I, Br, OMs
Scheme G presents yet another procedure for preparing compounds of the invention, wherein a specific imidazolonaphthyridine trione 16a (where R1A = -OMe) is treated with a strong acid (e.g. HBr in AcOH) in order to cleave the benzyl group and afford 20. Compound 20 is dissolved in a suitable organic solvent (e.g. DMSO or DMF) is deprotonated by treatment with a strong base (e.g. KO-t-Bu) and then alkylated with benzyl halide 14 to provide desired product 16, which can be isolated and purified using conventional techniques such as silica gel chromatography or reverse-phase preparative HPLC.
Scheme G
Figure imgf000052_0001
X = Leaving group, e.g. Br, CI, OMs
Scheme H outlines a further procedure to prepare compounds- of the present invention where an R4 alkyl alcohol 21 is converted to a leaving group (e.g. OMs, CI, Br) and this compound (22) is displaced with a nucleophile (e.g. an amine, sulfonamide, succinimide) under basic conditions to afford a further R4 functionalized compound 23. In the case R or R are hydrogen, this amine compound 23 can also be further functionalized to a compound such as a sulfonamide or amide using standard conditions.
Scheme H
Figure imgf000053_0001
ving group (Br, C!, O s)
Figure imgf000053_0002
Scheme I describes a procedure for preparation of compounds of the present invention where a compound such as 24 (R is a protecting group, e.g. R = Me) is converted to a secondary amide 25. This transformation can be accomplished in the presence of a suitable oxidant (e.g. oxygen), base (e.g. NaH, KOi-Bu) and solvent (e.g. DMF, DMSO). The secondary amide is treated with a benzylic halide (or other suitable leaving group) in the presence of a base (e.g. KOt-Bu) to afford 26. Compound 26 can be transformed to inliibitors of the present invention using chemistry outlined in these general methods or specific examples.
Scheme I
Figure imgf000053_0003
Scheme J presents a further method to prepare compounds of the present invention. A compound 16 is treated under oxidative conditions (oxygen, KOi-Bu, DMSO), affording alcohol compound 27.
Figure imgf000054_0001
Scheme depicts a method for the preparation of compounds of the invention wherein a secondary amide 27 is reacted with R4-X (e.g. an aryl or heteroaryl halide or cyclopropyl boronic acid) in the presence of a base (e.g. Cs2C03, NaH) and/or a metal catalyst (e.g. Pd or Cu) to afford the compound 16, which can be isolated and purified using conventional techniques such as silica gel chromatography or reverse-phase preparative HPLC. Scheme K
Figure imgf000054_0002
Scheme L outlines a method for the preparation of compounds of general structure 28. An electron-deficient alkene 29 is treated with 27 under suitable conditions (e.g. Cul, NMP, heat) to afford the derivatives compound 28.
Scheme L
Figure imgf000054_0003
In the methods for preparing compounds of the present invention set forth in the foregoing schemes, functional groups in various moieties and. substituents (in addition to those already explicitly noted in the foregoing schemes) may be sensitive or reactive under the reaction conditions employed and/or in the presence of the reagents employed. Such sensitivity/reactivity can interfere with the progress of the desired reaction to reduce the yield of the desired product, or possibly even preclude its formation. Accordingly, it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules concerned. Protection can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F. W. McOmie, Plenum Press, 1973 and in T.W. Greene & P.G.M Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999, and 2nd edition, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art. Alternatively the interfering group can be introduced into the molecule subsequent to the reaction Step of concern.
The following examples serve only to illustrate the invention and its practice.
The examples are not to be construed as limitations on the scope or spirit of the invention. In these examples, all temperatures are degrees Celsius unless otherwise noted, and "room temperature" refers to a temperature in a range of from about 20°C to about 25°C. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). lH NMR spectra were recorded on Varian or Bruker instruments at 400-500 MHz. Compounds described herein were synthesized as a racemic mixture unless otherwise stated in the experimental procedures. Preparation of Key Intermediates
EXAMPLE INT-A
6-(3 -Chloro-4-fluorobenzyl)-3 ,4-bis [(2,2-dimethylpropanoyl)oxy] -5 -oxo-5 ,6 ,7, 8-tetrahydro- 2,6-naphthyridine-l-carboxylic 2,2-dimethylpropanoic anhydride (Intermediate A)
Step 1 : 1 -(3 -Chloro-4-fluorobenzyl)-3-(phenylsulfinyl)piperidin'
Figure imgf000055_0001
To a 2000 L glass-lined reactor, under the protection of nitrogen, MTBE (633 kg) and valerolactam (34.9 kg, 350 mol) were charged by vacuum. After initiating stirring, a 33% aqueous solution of tetrabutylammonium hydrogen sulfate (8.35 kg) was added. The mixture was cooled to 20-30 °C and then a 50% aqueous solution of sodium hydroxide (270 kg) was added to the mixture at a rate of 10-15 L/minute at this temperature. After the addition, the mixture was maintained at the same temperature for 30 minutes followed by the addition of 3-chloro-4-fluoro-benzylbromide (62.9 kg, 280 mol) at a rate of 2-3 kg/minute at 20-30 °C. After 5-10 h, water (283 kg) was added to the reaction mixture at a rate of 30-40 kg/minute at 20-30 °C to quench the reaction. The mixture was stirred for 30 minutes and then the water phase was separated out. The organic phase was washed with 25% aqueous brine solution (226 kg), and the organic phase was dried with anhydrous sodium sulfate (30 kg) under stirring. The dried mixture was filtered by nutsche filter and the filter cake was rinsed with MTBE (50 kg). The combined filtrate was concentrated under reduced pressure (T < 35 °C, P< -0.08 MPa) until the mixture volume remained at about 350-500 L. Petroleum ether was added (138.4 kg) to the mixture and concentrated continuously. After the mixture volume remained at about 350-500 L, another 138 Kg of petroleum ether was added to the mixture and then concentrated. The mixture was cooled to 0-5 °C, stirred for 2-3 h, and then filtered. The filter cake was dried by rotary conical dryer below 35 °C to afford 67.7 kg of l-(3-chloro-4-fluorobenzyl)piperidin-2-one (99% yield).
To a 1500 L low temperature reactor, THF (117.5 kg) and hexamethyl disilylamine (73.5 kg, 455 mol) were charged. The mixture was cooled down to -30 to -20 °C. To the solution was added n-BuLi (130.6 kg, 455 mol) at a rate of 50-60 kg h at -30 to - 20 °C. After the addition, the reaction mixture was maintained at the same temperature for 30 minutes. Under the protection of nitrogen, to another 1500 L low temperature reactor, THF (222.5 kg) was charged, followed by the benzyl lactam from the above Step (50 kg, 207 mol). The mixture was cooled to -30 to -20 °C and then the THF solution of LiHMDS which was prepared in advance was added at the rate of 100—150 L h at -30 to -20 °C. The reaction mixture was maintained at this temperature for 6 h until the reaction was complete as monitored by HPLC analysis. Methyl phenyl sulfone (45.7 kg, 228 mmol) was added into the reaction mixture at a rate of 5-10 kg h at -30 to -20 °C. After the addition, the reaction mixture was maintained at this temperature for 1 h until HPLC analysis revealed complete consumption of the sulfone starting material. Under the protection of nitrogen, 4 N aqueous HC1 solution was added to quench the reaction at a temperature of -5 to 5 °C. Ethyl acetate (424 kg) was added into the mixture and the water phase was separated out (repeated 2x). The combined organic phases were washed twice with water (170 kg) and 25% brine (2 x 204 kg), dried for 8 h with anhydrous sodium sulfate (50 kg) and filtered by nutsche filter. The filter cake was rinsed with ethyl acetate (50 kg) for 30 minutes, and then combined with the filtrate. The filtrate was concentrated under reduced pressure (T < 30 °C, P < -0.08 MPa) until a volume of about 300-350 L of the mixture remained. MTBE (340 kg) was added into the concentrated liquor and then concentration was continued until 150-200 L volume of the mixture remained. Petroleum ether (73 kg) was added into the concentrated liquors under stirring, and then the mixture was cooled to 0 °C to induce crystallization. The crystallized mixture was filtered by nutsche filter under the protection of nitrogen. The filter cake was rinsed with the mixed solvent of MTBE (20 kg) and petroleum ether (24 kg) to afford the desired product as a white solid.
Step 2: l-(3-Chloro-4-fluorobenzyl)-3-( henylsulfinyl)-5J6-dihydropyridin-2(lH)- one
Figure imgf000057_0001
Under the protection of nitrogen, to a clean and dry 1000 L glass-lined reactor, was charged acetonitrile (340 kg), followed by l-(3-chloro-4-fluorobenzyl)-3- (phenylsulfmyl)piperidin-2-one (70 kg, 190 mol). Under stirring, acetic anhydride (39.1 kg, 380 mol) was added to the mixture at the rate of 10 kg/minute, and then methanesulfonic acid (9.2 kg, 100 mol) was added at the rate of 1 kg/minute at 18 to 28 °C. After the addition, the mixture was stirred at this temperature for 10-15 h until complete as determined by HPLC analysis. The mixture was then concentrated under reduced pressure (T < 30 °C, P < -0.08 MPa). Under the protection of nitrogen, deoxygenated ethyl acetate (315 kg) was added, the mixture was washed with 5% brine (3 χ 315 kg) and then water phase was separated out. The organic phase was concentrated under reduced pressure (T < 30 °C, P < -0.08 MPa) after which deoxygenated methanol (486 kg), deoxygenated purified water (124.6 kg) and sodium periodate (102.2 kg, 480 mol) were added to the mixture and the mixture stirred at 18 to 28 °C for 26 h. The mixture was filtered by nutsche filtration and the filter cake was rinsed with dichloromethane (2 x 133 kg), and then the filtrates were combined. The filtrate was diluted with water (700 kg) and then extracted with
dichloromethane (2 χ 455 kg). The combined organic layers were washed with 15% brine (378 kg), dried with anhydrous sodium sulfate (21 kg) and filtered by nutsche filtration. The filter cake was rinsed with dichloromethane (2 χ 35 kg) and the mother liquors were concentrated under reduced pressure (T < 30 °C, P < -0.08 MPa) until the remaining mixture volume was about 200-250 L. Isopropyl alcohol (138 kg) was added and the mixture was concentrated continuously. After the remaining mixture volume was about 200-250 L, a mixture of isopropyl alcohol (35 kg) and petroleum ether (30 kg) was added, and then the mixture was concentrated for the third time. After the concentration was completed, petroleum ether (168 kg) was added. Then mixture was cooled to -5 to 0 °C to induce crystallization. The mixture was filtered by centrifuge and the filter cake was dried to afford the title product (59.4 kg, 85% yield).
Step 3 : Ethyl amino [ 1 -(3-chloro-4-fluorobenzyl)-2-oxo-3-(phenylsulfinyl)piperidin- 4-yl] acetate
Figure imgf000058_0001
To a 100 L flask was added THF (40 L), followed by the unsaturated sulfoxide (5.0 kg, 13.7 mol) and the commercially available ethyl 2- (diphenylmethyleneamino)acetate (4.0 kg, 15.1 mol). The batch was stirred at room temperature to dissolve the solids and then cooled to 0 °C in an ice/water bath. Lithium tert- butoxide (1.4 L, 1 M in THF) was then added drop- wise, maintaining the temperature below 15 °C. The batch was stirred at 0 °C for 1 h until full conversion is evidenced by HPLC analysis. To the cooled batch was added 2M aqueous HC1 solution (35 L) at a rate that allows the batch to warm gradually to room temperature (15 minutes). The hazy yellow solution was then stirred at room temperature for 30-45 minutes. The solution was charged to a 200 L extractor, and MTBE (25 L) was added. Layers were separated, and the organic layer was extracted with 2 M aqueous HC1 solution (5 L). The combined aqueous layers were washed with MTBE (2 χ 25 L) to remove residual benzophenone. The acidic aqueous layer was recharged to a 100 L flask, along with IP Ac (25 L) and the batch was cooled to 0 °C. Aqueous 5M NaOH solution (-25 L) was added drop-wise, keeping the temperature below 5 °C, until the pH was 8.5. Layers were then separated, and the aqueous layer was re- extracted with IP Ac (8 L).
Step 4: Ethyl (2Z)-amino[ 1 -(3-chloro-4-fluorobenzyl)-2-oxopiperidin-4- ylidene]ethanoate
Figure imgf000058_0002
To a 100 L flask was added the sulfoxide from the previous Step (6.4 kg, 13.7 mol) as a solution in IP Ac. The batch was solvent switched to toluene then adjusted to a total volume of 65 L (KF = 200 ppm). Hunig's base (2.4 L, 13.8 mol) was added, along with a water-cooled condenser and the slurry was heated to 90 °C. After 30 minutes at 90 °C, the batch was assayed for conversion and then cooled slightly. Batch concentration commenced at -70 °C and the volume was reduced to 18 L, upon which a slurry formed. Once the appropriate volume is reached, IPAc (2 L) was added in a single addition, and the slurry was slowly cooled to room temperature, and stirred until the supernatant
concentration was below 16 mg/mL. The slurry was filtered, rinsed with 5:1 heptane:TPAc (12 L), and dried overnight- on the filter pot with vacuum and nitrogen sweep to give a fluffy white solid (3.0 Kg, 65% isolated, yield).
Step 5: Ethyl 6-(3~chloro-4-fluoroben2yl)~4-hydroxy-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridine- 1 -carboxylate
Figure imgf000059_0001
In a 100 L flask was charged the starting Imine (3.50 kg, 8.80 mol) and THF (45 L). The batch was cooled to 0 °C and DIPEA was added (1.70 L, 1.4 mol). To the resulting solution was added drop-wise the monoethyl oxalyl chloride (1.2 L, 9.24 mol) at such a rate that the temperature is maintained below 3.5 °C (45 minutes to 1 h). After stirring the reaction mixture for 30 minutes below 3.5 °C, the reaction was monitored for completion by HPLC analysis. To the batch was added directly, as a solid, LiBr (3.06 kg, 35.2 mol) followed by DABCO (1.97 kg, 17.6 mol). The batch was allowed to warm to room temperature and stirred overnight (16 h) at room temperature. The reaction mixture was quenched with 2 M aqueous HC1 solution (35 L) and stirred at room temperature for 30 minutes. Approximately half to three quarters of the total THF was then removed under reduced pressure, and the resulting slurry was diluted to the original quench volume with water. The approximate amount of TFTF removed was 36-38 L. The slurry was stirred at room temperature for 30 minutes and filtered. The wet cake was washed with water (2 x 12 L) and then with MTBE (3 χ 12 L) and dried under vacuum/N2 sweep until dry, affording the title product. Step 6: 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,657,8-hexahydro-2,6- naphthyridine-l-carboxylic acid
Figure imgf000060_0001
A 100 L flask was charged with the ester from the previous Step (3.08 kg, 7.80 mol) and 37 L of a 1 :1 mixture of EtOH THF. To the resulting slurry was added 9.4 L of a 5 M aqueous NaOH solution and the batch was warmed to 50-53 °C for 45 minutes. The slurry was then diluted with 10 L of water (-3.33 L/Kg) and stirred for an additional 1 h at 50-53 °C. Upon completion of the hydrolysis, the batch was cooled to 15 °C and acidified with 6 L of concentrated HC1 and stirred at room temperature for 12 h until the reaction was complete as monitored by HPLC analysis. The slurry was then filtered, washed with water (3 x 12 L) and dried under vacuum/N2 sweep at 35 °C until dry to give the title acid as a colorless solid.
6-(3-Chloro-4-fiuorobenzyl)-3,4-bis[(2,2-dimethylpropanoyl)oxy]-5-oxo- 5,6,7,8-tetrahydro-2,6-naphthyridine-l-carboxylic 2,2-dimethylpropanoic anhydride
Figure imgf000060_0002
Intermediate A
A 100 mL flask was charged with 15 mL of THF (KF < 300 ppm) and the acid (2.73 mmol, 1.0 g). Triethylamine (1.90 mL, 13.65 mmol) was then added under nitrogen at 20 °C. The slurry was cooled to 10 °C and trimethylacetyl chloride (1.18 mL, 9.56 mmol) added. The slurry was then stirred at 20 °C for 5 h until HPLC analysis revealed complete conversion. The slurry was filtered (to remove Et3N/HCl salt) and the solid washed with 5 mL of dry THF. The solid was discarded and the filtrate then solvent switch under reduced pressure to heptane with a final volume of 15 mL. The resultant slurry was stirred at 20 °C for 1 h, filtered, washed with one bed of heptane and dried in oven at 40 °C with a nitrogen stream for 12 h to give Intermediate A. MS (+ESI) m/z = 619.
EXAMPLE INT-B
6-(3-CWoro-4-fluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-l- carboxylic acid (Intermediate B) Methyl 6-(3-chloro-4-fluorobenzyl)-3,4-dimethoxy-5-oxo-5;657s8-tetrahydro 2,6-naphthyridine- 1 -carboxylate
Figure imgf000061_0001
A round bottom flask equipped with a mechanical stirrer was charged with 6-
(3-chloro-4-fiuoroben2yl)-3,4-dihydroxy-5-oxo-5,6?7,8-tetrahydro-2,6-naphthyridine-l- carboxylic acid from Example INT-A , Step 6 (180 g, 491 mmol) and DCE (1.8 L, 0.2 M). Silver carbonate (4 equiv) was added, followed by the addition of methyl iodide (8 equiv). The mixture was stirred at room temperature for 20 h. The mixture was then heated between 35-39 °C for 6 days which resulted in >99% conversion to the fully tris-methylated product. The solids were filtered on Solka Floe and rinsed with MeOH. The filtrate was concentrated to dryness to yield a yellow solid. The product was triturated from MeOH. The residue was suspended in MeOH (1 L, 5 mL/g) and stirred at room temperature for 20 minutes. The mixture was cooled to 0 °C and stirred for 1 h. The solid was filtered on a Buchner funnel and rinsed with cold MeOH (300 mL, 1 x 1.5 mL/g). The solid was dried on a sintered glass funnel for 2 h to afford the title product.
Step 2: 6-(3-Chloro-4-fluorobenzyl)-3,4-dimethoxy-5-oxo-5!l65758-tetrahydro-2,6-- naphthyridine-l-carboxylic acid
Figure imgf000061_0002
Intermediate B
A round bottom flask equipped with a mechanical stirrer was charged with methyl ester (132 g, 324 mmol) from Step 1 and 1 : 1 THF/MeOH ( 1.2 L total, 0.27 M). Aqueous lithium hydroxide (2 M, 2 equiv) was added and the reaction was heated to 40 °C for 15 minutes (>99% conversion to the acid). The solution was cooled to 0 °C and acidified to pH = 2 using 6 M aqueous HC1. The product was extracted with CH2C12 (3 x 10 mL/g), dried over MgS04, filtered and concentrated. The product was triturated from MTBE. The residue was suspended in MTBE (1 L, 6 mL/g)/hexanes (1 L, 6 mL/g) and stirred at room temperature for 90 minutes. The mixture was filtered on a Buchner funnel and rinsed with hexanes (1 χ 1.5 mL/g). The solid was dried on a sintered glass funnel for 2 h to afford the title compound. MS (+ESI) m/z = 395.
EXAMPLE INT-C
6'-Hydroxy-2'-methyl-9's 10'-dihydro- 1 'H-spirojcyclopentane- 1 ,3'-imidazo[5, 1 - a][2,6]naphthyridme]-r,5,,7,(2fH,8,H)-trione (Intermediate C)
Step 1 : 4-Methoxy-6-(4-methoxybenzyl)-3,5-dioxo-2,3,5,657i8-hexahydro-2i6~
naphmyridine-l-carboxylic acid
Figure imgf000062_0001
WO/2005/087768
Example 20, step 2
Ethyl 4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8,-tetrahydro-2,6- naphthyridine-l-carboxylate (14.0 g, 38.1 mmol, described in WO/2005/087768, Example 20, Step 2, page 117) and urea-hydrogen peroxide complex (7.5 g, 80 mmol, 2.1 equiv) were dissolved in CH2CI2 (200 mL) and cooled to 0 °C. To the solution was added trifluoroacetic anhydride (10.8 mL, 76 mmol, 2 equiv) slowly over 20-30 minutes. The reaction mixture was stirred at 0 °C for 30 minutes and allowed to warm to room temperature overnight. The reaction mixture was cooled to 0 °C and neutralized to pH = 7 with aqueous K2HP04 solution. Solid sodium bisulfite was added to quench the remaining oxidant and the mixture was poured into a separatory funnel containing water (200 mL) and extracted with CH2CI2 (3 x 100 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The unpurified material from the previous Step was dissolved in 200 mL of toluene and acetic anhydride (33 mL, 348 mmol, 7.2 equiv) was added. The reaction flask was fitted with a reflux condenser and the mixture was heated to 120 °C in an oil bath for 16 h. The cooled reaction mixture was concentrated under reduced pressure. This material was dissolved in ethanol (180 mL) and ίϊΟΗ·Η20 (7.0 g, 292 mmol, 6.9 equiv) was added together with 32 mL of water. The reaction mixture was stirred at room temperature for 2 h, after which LCMS analysis reveals complete conversion of starting material. The ethanol solvent was removed under reduced pressure and the crude reaction mixture was diluted with IM aqueous HCl solution to afford a yellow suspension. The mixture was filtered through filter paper on a Hirsch funnel (under Hirsch funnel (under vacuum) and the yellow solid was washed with diethyl ether, and dried on the vacuum pump overnight to afford a white solid.
Step 2: 4-Methoxy-6"(4-methoxybenzyl)-N-methyl-3?5~dioxo-2,3,5!6,7,8-hexahydro- 2,6-naphthyridine- -carboxamide eO.
Figure imgf000063_0001
A three-necked, round-bottom flask fitted with a N2 inlet, magnetic stir bar and addition funnel was charged with the carboxylic acid from the previous Step (11.9 g, 33.2 mmol) and DMF (120 mL). The solution was cooled to 4 °C and then HATU (31.6 g, 83 mmol, 2.5 equiv) was added followed by methylamine hydrochloride (11.2 g, 166 mmol, 5 equiv) and DIPEA (46.4 mL, 266 mmol, 8 equiv). The reaction mixture was stirred for 16 h at room temperature. The clear solution was cooled to 0 °C and diluted with water (150 mL) and acidified with 2M HCl aqueous solution. The resulting solution was extracted with CH2CI2 (2x) and the combined organic layers were washed with 1M aqueous HCl solution (2 x 100 mL), dried over MgS04, filtered and concentrated. MS (+ESI) m/z = 372.
Step 3: 6,-Hydroxy-8,-(4-methoxybenzyl)-2,-methyl-9'J10,-dihydro-l'H- spiro[cyclopentane-l ,3'-imidazo[5,l -a] [2J6]naphthyridine]- ,5',7'(2'H,8'H)- trione
Figure imgf000063_0002
O OMe dioxane, 110 , 64 § H
A round-bottom flask fitted with a reflux condenser, a N2 inlet and a magnetic stir bar was charged with the secondary amide from the previous Step (14.5 g, 26.9 mmol), 1,4-dioxane (300 mL), cyclopentanone (24.2 mL, 270 mmol, 10 equiv) and concentration sulfuric acid (4.32 mL, 81 mmol, 3 equiv). The reaction mixture was heated to 1 10 °C in an oil bath for 64 h. The cooled reaction mixture was diluted with water (300 mL) and basified with M aqueous NaOH solution. The aqueous layer was washed with MTBE (2x), acidified with 2M aqueous HCl solution and extracted with CH2C12 (2x). The combined dichloromethane layers were washed with brine, dried over Na2S04, filtered and concentrated. The yellow solid was triturated in MTBE and filtered to afford a pale yellow solid (9.2 g, 73% yield).
Step 4: 6'-Hydroxy-2'-methyI-9', 10'-dihydro- 1 'H-spiro [cyclopentane- 1 ,3 '■
imidazo[5ίl~β][2ί6]na hthyridine]-1^5 7'(2,H,8'H)-tΓione
Figure imgf000064_0001
Intermed ate
A round-bottom flask fitted with a nitrogen inlet, a magnetic stir bar and a reflux condenser was charged with aminal reagent from the previous Step (9.2 g, 19.6 mmol) and HBr (48% in acetic acid, 90 mL). The reaction mixture was heated to 80 °C for 16 h. The brown slurry was cooled to room temperature and diluted with water (100 mL). Concentration under reduced pressure afforded a dark colored oil which was purified by preparative reverse-phase column chromatography through a Cjg-column, eluting with 5% MeCN in H20 (+0.1% TFA) to 95% MeCN in H20 (+0.1% TFA) as a gradient to provide the title compound as an off-white solid. 1H NM (500 MHz, DMSO-fife) 6 8.90 (s, 1 H), 3.43-3.36 (m, 2H), 3.25-3.17 (m, 2H), 2.96 (s, 3H), 2.56-2.51 (m, 2H), 2.20-2.11 (m, 2H), 1.98-1.91 (m, 2H), 1.90-1.82 (m, 2H).
EXAMPLE INT-D
6-(3-Chloro-4-fluorobenzyl)-4~hydroxy-3,5-dioxo-2, 3,5,6,7, 8-hexahydro-2,6-naphthyridi
1 carboxamide (Intermediate D)
Figure imgf000064_0002
Intermediate A
A solution of Intermediate A (16.2 mmol, 10.0 g) and ammonium hydroxide (10 equiv, 28 wt %) in ethanol (65 mL, 0.25 M) was stirred at room temperature for 1 h. The reaction was acidified with concentrated HC1 to pH = 2 - 3. The resulting solid was filtered and washed with water, then hexanes, to afford the primary amide as an off-white solid. MS (+ESI) w/z = 366.
Preparation of Non-Commercial Reagents
2-Methoxycyclopentanone
Figure imgf000065_0001
oven-dried flask under an atmosphere of nitrogen was added 2- chlorocyclopentanone (10.0 mL, 100 mmol), anhydrous methanol (100 mL) and anhydrous triethylamine (15.3 mL, 110 mmol). The reaction was stirred at room temperature for 65 h. The reaction was concentrated gently under reduced pressure and the residue was purified by coloumn chromatography through silica gel (120 g), eluting with 0-30% EtOAc in hexanes as a gradient, to afford the title compound (8.6 g, 75% yield). 1H NMR (400 MHz, CDC13)
5 3.68 (m, 1H), 3.50 (s} 3H), 2.35-2.15 (m, 3H), 2.09-2.00 (m, 1H), 1.82-1.73 (m, 2H).
)-2-Aminocyclopropyl]methanol hydrochloride
Figure imgf000065_0002
To a solution of ¾rt-butyl[(cz5)-2-(hydroxymethyl)cyclopropyl]carbamate (1.0 g, 5.3 mmol) in THF (11 mL) was added aqueous 6 M HCI (2.0 mL, 12.3 mmol). The resulting mixture was heated to 45 °C for 3 h. The mixture was concentrated and azeotroped three times with toluene to afford the title compound (650 mg, 98% yield) as a dark oil !H NMR (499 MHz, <¾~DMSO) δ 8.40 (s, 3H), 3.71 (dd, J= 12.1, 5.1 Hz, 2H), 2.54 (s, 1H), 1.22-1.15 (m, 1H), 0.86-0.79 (m, 1H), 0.64 (dd, J- 1 1.0, 5.5 Hz, 1H).
(±)-N-(ieri-Butyl)-2-oxocycIopentanecarboxamide
Figure imgf000065_0003
A dry flask was charged with cyclopentanone (0.526 ml, 5.94 mmol) and THF (30 mL) and the solution was cooled to -78 °C in a dry ice/acetone bath. Lithium bis(trimethylsilyl)amide (1.0 M in THF, 6.54 ml, 6.54 mmol) was added and the reaction contents were stirred for 1 h at -78 °C. After this time, ferf-butyl isocyanate (0.768 ml, 6.54 mmol) was added via syringe and the reaction contents were allowed to warm slowly to room temperature and stirred at this temperature for 48 h. The reaction mixture was quenched with saturated NH4CI (10 mL), poured into a separatory funnel and extracted with C¾C12 (2 x 50 mL), dried over Na2S04, filtered and evaporated to afford a residue. This residue was purified via column chromatography through silica gel, eluting with 100% hexanes to 100% EtOAc as a gradient to afford the title compound (0.634 g, 58% yield). MS (+ESI) m/z = 184. !H NMR (400 MHz, <¾-DMSO) δ 7.51 (s, 1H), 3.02 (t, J= 8.9 Hz, 1H), 2.15-2.09 (m, 4H), 1.95-1.91 (m, 1H), 1.73-1.71 (m, 1H), 1.22 (s, 9H).
Meth l 2-oxobic clo |3.1.0] hexane- 1-carb oxylate
Figure imgf000066_0001
This compound was prepared following the procedure described in J. Org. Chem. 2002, 67, 6535 - 6538.
Methyl 2-(2-oxocyclopentyl)propanoate
Figure imgf000066_0002
A solution of l-(trimethylsilyloxy)cyclopentene (0.31 g, 2.00 mmol) and methyl 2-bromopropionate (0.33 ml, 3.00 mmol) in THF (10 ml) was cooled to -78 °C under a nitrogen atmosphere. After 15 minutes, tetrabutylammonium difluorotxiphenylstannate (1.4 g, 2.20 mmol) was added. The dry-ice/acetone bath was removed and the reaction allowed to warm to room temperature with stirring for 12 h. The reaction was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The ketone was purified by column chromatography through silica gel (24 g), eluting with 30% EtOAc in hexanes to afford the title compound (0.15 g, 44% yield).
Bicycio [4,1.0] he tan-2-one
Figure imgf000066_0003
Into a 2 L, 3 -necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen was placed NaH (60 wt%, 44.0 g, 1.10 mol, 1.10 equiv - washed four times with 500 ml of hexane). To this was added anhydrous DMSO (1200 mL), followed by the addition of trimethyl sulfoxoniura iodide (242 g, 1.10 mol, 1.10 equiv) in several batches to control hydrogen evolution and exotherm. The resulting solution was stirred for 15 minutes at room temperature. To the above was added cyclohex-2-enone (96 g, 1.00 mol, 1.0 equiv) drop-wise with stirring over a 30 minute period. The resulting solution was stirred for an additional 2 h while the temperature was maintained at 50 °C. The reaction mixture was cooled to room temperature, then quenched by the addition of 1500 mL of H20/ice. The resulting solution was poured into a 4 L separatory funnel and extracted with diethyl ether (3 x 500 mL). The organic layers were combined, washed with saturated brine (3 x 150 mL), dried over MgS04 and concentrated under vacuum. The residue was dissolved in MeOH (500 mL) and 2-aminoethanol (200 g, 3.00 mol, 3.0 equiv) was added. The resulting solution was stirred for 16 h at room temperature. The reaction mixture was poured into a 2 L separatory funnel containing water (1 L) and extracted with CH2C12 (3 χ 500 mL). The organic layers were combined, washed with 10% aqueous HQ solution (3 χ 150 mL), dried over MgS04 and concentrated under vacuum. The oil was purified by distillation under reduced pressure (10 mm Hg) and the desired fractions collected at 90 °C> affording the desired bicyclo[4.1.0]heptan-2-one as colorless liquid (30 g, 26% yield). 1H NMR (300 MHz, CDC13) δ 2.29-2.24 (m, 1H), 1.93-1.90 (m, 3H), 1.73-1.70 (m, 4H), 1.23- 1.20 (m, 1H), 1.15-1.10 (m5 1H).
2-(2-Methoxyethyl)cyciopeiitanone
Figure imgf000067_0001
Stepl : 2-Cyclopentylidene-l,l-dimethylhydrazine
To a solution of cyclopentanone (16.8 ml, 200 mmol) in toluene (100 mL) was added dimethylhydrazine (15.3 ml, 200 mmol) and TFA (0.2 ml, 2.60 mmol). The solution was stirred at 90 °C for 12 h. The mixture was cooled to room temperature and washed with water. The organic layers were combined, dried over Na2S04, filtered and concentrated under reduced pressure affording 21.1 g of a brown liquid.
Step 2: 2-(2-Methoxyethyl)cyclopentanone A solution of 2-cyclopentylidene-l,l-dimethylhydrazine (1.3 g, 10 nimol) in
THF (20 mL) was cooled to - 30 °C in a bath. To this was added a solution of n- butyllithium (6.6 mL, 11 mmol, 1.8 M in hexanes) and the mixture was stirred at -30 °C for
1 h. The solution was warmed to 0 °C and 1 -bromo-2-methoxyethane was added (0.94 ml, 10 mmol). The solution was warmed to room temperature and stirred for an additional 2 h followed by the addition of potassium phosphate (2.1 g, 10 mmol), phosphorous acid (1.6 g, 20 mmol) and water (10 mL). After stirring for 14 h, the mixture was poured into a separatory funnel containing water (50 mL) and the aqueous layer was extracted with diethyl ether (2 x 50 mL). The organic layers were dried over Na2S04f filtered and concentrated under reduced pressure. The ketone was purified by column chromatography through silica gel (100 g), eluting with 25% EtOAc in hexanes to affording the title compound (0.42 g,
30% yield).
(±)~(lR,6S,7J?)-ethyl 2-oxobicycIo[4.1.0|heptane-7-carboxylate
Figure imgf000068_0001
Step 1 : (2-Ethoxy-2~oxoethyl)dimethylsulfonium
A solution of ethyl bromoacetate (167 g, 100 mmol) and dimethyl sulfide (62 g, 100 mmol) in acetone (3 L) was stirred at 15 °C under at atmosphere of N2 for 24 h. The mixture was filtered and the solid was washed with acetone (2 x 500 mL) to afford the title compound (165 g, 72% yield).
Step 2: (±)-(U?,6 7i? Ethyl 2-oxobicyclo[4.1.0]heptane-7-carboxylate A solution of (2~ethoxy-2-oxoethyl)dimethylsulfom'um (183.4 g, 80 mmol) and DBU (123 g, 80 mmol) in CHC13 (1.4 L) was stirred under an atmosphere of nitrogen at room temperature for 1 h. Cyclohex-2-enone (60.8 g, 63 mmol) was added and the mixture was stirred at 13 °C for 18 h. The reaction mixture was poured into a 3 L separatory funnel, washed with water (3 x 500 mL) and the organic layer was removed, dried over MgS04, filtered and concentrated. The mixture was purified by recrystallization from Et20 to afford the title compound as a white solid (40 g, 34% yield). MS (+ESI) m/z = 183. 1H NMR (300 MHz, -DMSO) 5 4.12-3.32 (m, 2H), 2.53-2.49 (m, 1H), 2.26-2.17 (m, 1H), 2.08-1.85 (ra, 5H), 1.66-1.56 (m, 2H), 1.22-1.17 (t, J= 7.2 Hz, 3H). (iS,5R)-Bieyclo[3.1.0]hexan
Figure imgf000069_0001
Step 1 : (S)- 1 -Chlorohex-5-en-2-ol
To an oven-dried flask under an atmosphere of nitrogen was added (S)-2-
(chloromethyl)oxirane (25.0 g, 270 mmol), anhydrous THF (270 mL) and copper (I) iodide (5.15 g, 27.0 mmol). The mixture was cooled to -78 °C in a dry ice/ acetone bath. A solution of allyl magnesium chloride (2.0 M in THF, 149 mL, 298 mmol) was added over 25 minutes to the reaction. The reaction was slowly warmed to -10 °C over 2 h and the cooling bath was then removed. The reaction was stirred further for 3 h at room temperature.
Aqueous NH4CI was added to quench the reaction, the reaction was poured into a separatory funnel and extracted with diethyl ether (3 x 200 mL). The combined organic layers were dried over Na2S04, filtered through a plug of silica gel, and concentrated under reduced pressure to afford the title compound (33 g, 91% yield). 1H NMR (400 MHz, CDC13) δ 5.82 (ddt, J= 17.2, 10.2, 6.6 Hz, 1H), 5.07 (dq, J= 17.2, 1.7 Hz, 1H), 5.01 (dq, J= 10.2, .7 Hz, 1H), 3.85-3.80 (m, 1H), 3.64 (dd, J= 11.1, 3.5 Hz, 1H), 3.49 (dd, J = 1 1.1, 7.0 Hz, 1H), 2.27-2.15 (m, 3H), 1.67-1.61 (m, 2H).
Step 2: (IS, 2S, 5i?)-Bicyclo[3.1.0]hexan-2-oI oven-dried flask under an atmosphere of nitrogen was added (S)-l~ chlorohex-5-en-2-ol (33.0 g, 245 mmol), anhydrous MTBE (900 mL), and 2,2,6,6- tetramethylpiperidine ( 107 mL, 635 mmol). The solution was cooled to -78 °C in a dry ice/ acetone bath. A solution of rc-butyl lithium (1.6 M in hexanes, 556 mL, 889 mmol) was added over 30 minutes to the reaction. The reaction was slowly warmed to room
temperature over 16 h. The reaction was re-cooled to -20 °C and methanol (50 mL) was added portion- wise. The reaction was warmed to room temperature and diluted with MTBE (300 mL). The reaction was poured into a separatory funnel and the organic layer was washed successively with 2 M aqueous HC1 solution (2 x 400 mL) and then water. The combined aqueous layers were back-extracted with MTBE (2 χ 100 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound which was used without further purification. 1H NMR (400 MHz,
CDCI3) δ 4.23 (d, J= 4.8 Hz, 1H), 2.00-1.88 (m, 1H), 1.68 (dd, J= 12.5, 8.1, 1H), 1.55 (dd, J= 14.5, 8.4, 1H), 1.45-1.28 (ra, 3H), 0.48-0.41 (m, 1H), 0.05-0.01 (m, 1H). Step 3: (IS, 5i?)~Bicyclo[3.1.0]hexan-2~one
To a solution of (AS £5i?)-bicyclo [3.1.0] hexan-2-ol (24.0 g, 245 mmol) in anhydrous C¾C12 (1500 mL), was added 4-methylmorpholine-N-oxide (45.8 g, 391 mmol) and 50 g of 3A molecular sieves. The reaction was placed in a water bath,
tetrapropylammonium perruthenate (4.4 g, 12.5 mmol) was added, and the reaction was stirred at room temperature for 18 h. The reaction was filtered through a pad of Celite, the filtrate was poured into a separatory funnel and washed successively with 2 M aqueous HCl solution (200 mL) and water (100 mL). The combined aqueous layers were back-extracted with CH2CI2 (2 x 100 mL). The combined organic layers were dried over Na2S04, filtered through a plug of silica gel, rinsing with 25% diethyl ether/CH2Cl2, and concentrated under reduced pressure. The residue was then purified by vaccuum distillation. The title compound distilled at 60-65 °C at a vacuum of 10 mm Hg (9.36 g, 44% yield). Ή NMR (400 MHz, CDCI3) δ 2.18-1.98 (m, 5H), 1.80-1.74 (m, 1H), 1.23-1.16 (m, 1H), 0.93 (q, J= 4.0 Hz, 1H).
(/R,55)-Bicydo (3.1.0] hexan-2-one
Figure imgf000070_0001
(7i?,5S)-bicyclo[3.1.0]hexan-2-one was prepared as using the same procedure described for ( 5)5if)-bicyclo[3.1.0]hexan-2-one, replacing (1S)-2-(chloromethyl)oxirane with (i?)-2-(chloromethyl)oxirane in Step 1. The 1H NMR is identical to (1S,5R)- bicyclo[3J.0]hexan-2-one. Preparation of Examples
EXAMPLE 1
(+)-8,-(3-Cωoro-4-fluorober^l)~6*-h dro y-2'-me l-9 10'-dihydro-2'H- spiro[bicyclo[2.2.1 ]heptane-2,3'-imidazo[55l-a] P^jnaphthyridineJ-rjS'J S'i -iri0116
Figure imgf000071_0001
Figure imgf000071_0002
Step 1 : 6-(3-Chloro-4-fluorobeiTzyI)-3?4~dimemoxy-N-methyl-5-oxo-5,6,7,8- tetrahydro-2,6-naphthyridine- 1 -carboxamide
A mixture of Intermediate B (5.0 g, 12.7 mmol), methylamine hydrochloride (1.5 equiv), EDCI (1.5 equiv), HO At (1.5 equiv) and N,N-diisopropylethylaraine (2.5 equiv) in DMF (0.2 M) was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NH^Cl and extracted with EtOAc. The organic layer was washed with water (2*), brine, dried over Na2S04 and filtered. The solution was concentrated under reduced pressure. Trituration with EtOAc afforded a beige solid. MS (+ESI) m/z - 408. Step 2: 6-(3-ChlorO"4-fluorober^yl)-4-hydroxy-N-methyl-3s5-dioxo-2,3J5,6}7,8- hexahydro-2 , 6-naphthyridine- 1 -carboxamide
A solution of the amide from Step 1 (4.11 g, 10.0 mmol) in HBr (33% in AcOH, 0.2 M) was heated at 50 °C for 30 minutes. The reaction was cooled to room temperature, diluted with EtOAc and concentrated under reduced pressure. The resulting solid was triturated with EtOH, filtered and washed with a mixture of EtOH and hexanes to afford a beige solid (3.62 g, 95% yield). MS (+ESI) m/z = 380
Step 3: (+)-8,~(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9, >10'-dihydro-2,H- spiro[bicyclo[2.2. ]heptane-2,3'-imidazo[5s 1 -a] [2,6]naphthyridine]-
1',5',7'(8Ή)-ΐποηβ A mixture of amide from Step 2 (200 mg, 0.53 rnmol), (±)-norcamphor (30 equiv) and sulfuric acid (catalytic, 0.05 equiv) in 1,4-dioxane (0.1 M) was heated at 100 °C for 18 h (note: the reaction mixture became homogeneous at 100 °C). The reaction was cooled to room temperature, diluted with saturated aqueous NaHC03 and extracted with CH2C12 (3x). The combined organic layers were dried over Na2S04, filtered and
concentrated under reduced pressure. The crude product was purified by reverse phase chromatography using a Cjg column, eluting with 10% MeCN in H20 (+0.1% formic acid) to 90% MeCN in H20 (+0.1% formic acid) as a gradient to afford a yellow solid as a 2: 1 mixture of diastereomers (52 mg, 21% yield). MS (+ESI) m/z = 472 for both diastereomers.
EXAMPLE 2
(±)- 8-(3 -Chloro -4-fluorobenzy l)-6-hydroxy-2,3 -dimethyl-2,3 ,9,10-tetrahydroimidazo [5,1- a] [2,6]naphthyridine-l ,5,7(8H)-trione
Figure imgf000072_0001
intermediate B
Figure imgf000072_0002
Step 1 : 6-(3-Chloro-4-fluorobenzyl)-3,4-dimethoxy-N-methyl-5-oxo-5,6>7,8- tetrahydro-2,6-naphthyridine- 1 -carboxamide
The title compound was prepared according to the procedure described Step 1 of Example 1.
Step 2: (±)-8-(3-Chloro-4-fIuorobenzyl)-6-hydroxy-23-dimethyl-2;3,9,10- tetrahydroimidazo[5,l-a][2,63naphthyridine-l,5,7(8H)-trione A solution of amide from Step 1 (500 mg, 1.23 mmol) and acetaldehyde diethyl acetal (5 equiv) in HBr (33% in AcOH, 0.2 M) was heated, at 50 °C for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative reverse phase chromatography through a Cjs column, eluting with 10% MeCN in H20 (+0.1% formic acid) to 90% MeCN in H20 (+0.1 % formic acid) as a gradient. The solid was triturated with EtOH/hexanes to afford a gray/green solid (275 mg, 55% yield). MS (+ESI) m/z = 406. Ή NMR (400 MHz. DMSO- d6) 5 13.57 (s, 1H), 7.60 (d, J= 7.2 Hz, 1H), 7.45-7.35 (m, 2H), 5.68-5.61 (m, 1H), 4.80- 4.64 (m, 2 H), 3.60-3.53 (m, 2H), 3.36-3.14 (m, 2H), 2.96 (s, 3H), 1.62 (d, J= 5.7 Hz, 3H).
EXAMPLE 3
(5 -8-(3-Chloro-4-fiuorobenzyl)-2,3-dicyclopropyl-6-hydroxy-2s3;9s10- tetrahydroimidazo [5 , 1 -a] [2,6]naphthyridine- 1 , 5 ,7(8H)-trione
Figure imgf000073_0001
Step 1 : 6-(3-Chloro-4-fluorobenzyl)-iV-cyclopropyl-4-hydroxy-3,5-dioxo-2,3,556,7,8- hexahydro-2,6-naphthyridine- 1 -carboxamide
A 3.0 L flask was charged with dry THF (1.5 L) and Intermediate A (124 g, 200 mmol). Cyclopropylamine (1 14 g, 2000 mmol) was then added under nitrogen at 0 °C and the resulting slurry was then stirred at 20 °C for 18 h. The slurry was cooled in an ice bath and concentrated aqueous HC1 was added until the pH of the suspension was 1. Water was added and a white precipitate formed. The suspension was stirred at room temperature for 2 h, then filtered with successive rinses of water, ethanol and ethyl acetate. The resulting solid was dried under vaccum to afford the title compound (75 g, 92% yield). MS (+ESI) m/z = 406. Step 2: (S)-8-(3-Chloro-4-fluorobenzyl)-2,3-dicyclopropyl-6-hydroxy-2,3 ,9, 10- telxahydroimidazofSjl-ajP^jna hthyridi e-ljS tS/^-trione
A mixture of the amide from Step 1 (60 g, 150 mmol) in 1,4-dioxane (2000 mL) was added cyclopropanecarbaldehyde (115 g, 1500 mmol) and concentrated sulfuric acid (1 mL) under nitrogen at 0 °C, then the mixture was heated to 100 °C for 18 h. After cooling, a solution of NaHC03 in water was added, and the resulting mixture was extracted with CH2C12 (3 x 500 mL), the combined organics were washed with water and brine, dried over Na2S04j filtered and concentrated under reduced pressure. The residue was
recrystallized. with MeOH to afford the racemic compound (48 g, 69% yield). The racemic mixture (32 g) was separated by chirai SFC to afford the enantiopuie example 3 (12.0 g, first eluting enantiomer, >99% ee). Preparative chirai separation of the enantiomers was achieved using a ChiralPak AD-H column (250 χ 30 mm ID. 20 urn), eluting with C02 plus methanol :acetonitrUe (2 : 2 : 1 + 0.05% Et2NH) at a flow rate of 80 mL/minute and a column temperature of 38 °C. MS (+ESI) m/z = 458. H NM (400 MHz, CDC13) δ 13.58
(s, 1H), 7.41-7.37 (m, 1H), 7.30-7.12 (m, 2H), 4.98-4.93 (m, 1H), 4.77 (d, J- 15 Hz, 1H), 4.64 (d, J= 15 Hz, 1H), 3.55-3.43 (m, 3H), 3.31-3.20 (m, 1H), 2.77-2.70 (m, 1H), 1.28- 1.14 (m, 2H)S 1.08-1.00 (m, 1H), 0.97-0.85 (m, 1H), 0.86-0.69 (m, 4H), 0.65-0.57 (m, 1H).
EXAMPLE 4
(+)~8 -(3 -Chloro-4-fiuorobenzyl)-3 -cyclobuty l-6-hydroxy-2-(2-methoxyethyl)-2 ,3,9,10- tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)-trione
Figure imgf000074_0001
intermediate D
Figure imgf000074_0002
Step 1 : (±)-8-(3~ChJoiO-4-fluoiObenzyl)-3-cyclobutyl-6-hydroxy-2,3 ,9, 10- tetra ydroimidazotS -ajp^jnap th ridine-l^^tSH}-^01116
A mixture of Intermediate D (2.50 g, 5.13 mmol), cyclobutyl methyl ketone (5 equiv) and concentrated sulfuric acid (catalytic, 0.05 equiv) in 1,4-dioxane (25 mL, 0.2 M) was heated at 100 °C for 18 h (note: the reaction mixture became homogeneous at 100 °C). The reaction was cooled to room temperature, diluted with EtOAc and the resulting solid was filtered to afford the desired aminal as a light yellow solid (2.68 g, 85% yield). Step 2: (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclobut l-6-hydroxy-2-(2-methoxyethyl)- 2,3,9,10-tetrahydroimidazo[5,l -a][2,6]naphthyridine-l ,5,7(8H)-trione
A solution of aminal from Step 1 (200 mg, 0.45 mmol), 2-bromoethyl methyl ether (5 equiv) and sodium hydride (60 wt% in oil, 5 equiv) in DMF (1.8 mL, 0.25 M) was stirred at room temperature for 18 h. The solution was directly loaded onto a preparative reverse phase C18 column and eluted with 10% MeCN in H20 (+ 0.1% formic acid) to 90% MeCN in ¾0 (+ 0.1% formic acid) as a gradient. The resulting solid was further purified by trituration using EtOAc/hexanes to afford a beige solid. MS (+ESI) m/z = 504.
EXAMPLE 5
(±)-3-(3-Chloro-4-fluorober^l)-5-hydroxy-8,8-dime l-2,3,8,9,10,l l-hexahydro-7aH- pyrido [2',1 ' :2 ,3 ] imidazo[5 , 1 -a] [256]naphthyridine~4,6, 13( 1 H)-trione
Figure imgf000075_0001
Dess-Martin
periodinane
Figure imgf000076_0001
Figure imgf000076_0002
O OH
Step 1 : 6-(3-CWoro-4-fluoroberizyl)-N-(5-hydroxy-4,4-dimethylpentyl)-3?4- dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naplithyridine-l-carboxamide The title compound was prepared according to the procedure described in
Step 1 of Example 1 using 5-amino-2,2-dimethylpentanol (1.5 equiv) as the source of amine. The reaction was quenched with 10% aqueous HQ and extracted with EtOAc (3*). The organic layer was washed with saturated "aqueous NaHC03, dried over Na2S04, filtered and concentrated under reduced pressure to afford a yellow oil. The product was used unpurified in the subsequent reaction. MS (+ESI) mJz ^ 508.
Step 2: 6-(3-Chloro-4-fluorobenzyI)-N-(4,4-dimemyl-5-oxopentyl)-3,4-dimethoxy-5- oxo-5,6,758-tetrahydro-2J6-naphthyridine- 1 -carboxamide Dess-Martin periodinane (1.5 equiv) was added to a solution of alcohol (1.28 g, 2.52 mmol) in 0¾Ο2 (13 mL, 0.2 M). The reaction was stirred at room temperature for 2 h. Solid Na2S203 (25 g) was added and the solution was diluted with saturated aqueous NaHC03 (100 mL) and EtOAc. The solution was stirred until solid materials were dissolved (10 minutes). The layers were separated and the organic layer was washed with saturated aqueous NaHCC>3. The aqueous layer was extracted with EtOAc (2χ). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to afford a colorless foam. The product was used unpurified in the next reaction. MS (+ESI) m/z = 506. Step 3 : (±)-3-(3-Chloro-4-fluorobenzyi)-5-hydroxy-8,8-dimethyl-2,3i8s9, 10,11- hexahydro-7aH-pyrido[2', l':253]imidazo[5, 1 -a][2,6]naphthyridine- 4,6,13(lH)-trione The title compound was prepared according to the procedure described in Step 2 of Example 2. Trituration from EtOH afforded the desired product as a yellow solid (604 mg, 52% yield over 2 steps). MS (+ESI) m/z = 460. Ή NMR (400 MHz, d6~DMSO) δ 13.62 (s, 1H), 7.64-7.59 (m, 1H), 7.45-7.37 (m, 2H), 5.64 (s, 1H), 4.76 (d, J= 15 Hz, 1H), 4.67 (d, J= 15 Hz, 1H), 4.19-4.11 (m, 1H)5 3.60-3.53 (m, 2H), 3.43-3.30 (m, 1H), 3.20-3.10 (m, 1H), 3.00-2.90 (m, 1H), 1.80-1.69 (m, 1H), 1.58-1.42 (m, 3H), 1.24 (s, 3H), 0.51 (s, 3H).
EXAMPLE 6
(±)-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,7a,8,9,10- hexahydropyrrolo[2', :2,3]imidazo[5f 1 -a] [2,6]naphthyridine-4,6, 12( lH)-trione
Figure imgf000077_0001
Figure imgf000077_0002
Step 1 : 6-(3-Chloro-4-fiuorobenzyl)-3!4-dimethoxy-5-oxo-5,6,7i8-tetrahydro-2:6- naphthyridine-1 -carbonyl chloride
Oxalyl chloride (1.1 equiv) was added to a solution of Intermediate B (1.00 g, 2.53 mmol) in THF (10 mL, 0.25 M). DMF (catalytic, 0.05 equiv) was added (note:
reaction began to bubble) and the solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and the acid chloride was used unpurified in the subsequent reaction. An aliquot was diluted with MeOH to form the methyl ester in order to confirm the presence of the acid chloride. MS (+ESI) of the corresponding methyl ester m/z = 409. Step 2: (3-Chloro-4-fluorobenzyl)-3J4-dimethoxy-5-oxo-N-(4-oxopentyl)-5,6,7,8- tetrahydro-2,6-naphthyridine- 1 -carboxamide
The reaction was performed as outlined, in J Org. Chem. 1984, 49, 4067- 4070. Unpurified acid chloride (1.04 g, 2.52 mmol) was added to a solution of 2-methyl- 1 - pyrroline (10 equiv) and 10% aqueous OH (7 mL, 5 equiv) and THF (10 mL, 0.25 M). The reaction was stirred at room temperature for 2 h. The reaction was then diluted with CH2CI2 and water. The layers were separated and the organic layer was washed with 10% aqueous HCl, dried over Na2S04, filtered and concentrated under reduced pressure to afford an orange oil. The resulting ketone was used unpurified in the next reaction. MS (+ESI) m = 478.
Step 3 : (±)-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,7a,8!9)l 0- hexahydropyrrolo [2' , Γ : 2 , 3 ] imidazo [5 > 1 -a] [2,6] naphthyridine-4 ,6, 12( 1 )- trione
The title compound was prepared according to the procedure described in Step 2 of Example 2 using the ketone from Step 2 above (1.20 g, 2,52 mmol). - After concentrating the reaction under reduced pressure, the resulting oil was placed in the freezer for 18 h. The product became a mixture of solid and oil. After the addition of EtOAc, a solid precipitated from the solution. The solid was filtered and washed with EtOAc and then with EtOH to afford a brown solid. MS (+ESI) m/z = 432. lH NMR (400 MHz, CDCI3) δ 13.60 (s, 1H), 7.41-7.37 (m, 1H), 7.27-7.14 (m, 2H), 4.78-4.64 (m, 2H), 3.87-3.78 (m, 1H), 3.54-3.45 (m, 2H), 3.40-3.31 (m, 3H), 2.75-2.67 (m, 1H), 2.36-2.26 (m, 2H), 1.88- 1.75 (m, 4H).
EXAMPLE 7
(±)-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3 ,8,9, 10, 1 1 -hexahydro'
pyrido [2 1 ' : 2 , 3 ] imidazo [5, 1 -a] [2,6] naphthyridine-4,6513(1 H)-trione
Figure imgf000078_0001
Figure imgf000079_0001
Step 1 : 2-(3-Chloro-4-fluorobenzyl)-7,8-dimethoxy-5-[(6~methyl-3,4- dihydropyridin- 1 (2H)~yl)carbonyI]-3 s4-dihydro-2 ,6-naphthyridin- 1 (2H)-one A solution of amine (730 mg, 4.81 mmol), acid chloride (1.04 g, 2.52 mmol, prepared according to Example 6, Step 1) and N,iV-diisopropylethylamine (3 equiv) in THF (10 mL, 0.25 M) was stirred at room temperature for 18 h. The reaction was diluted with 10% aqueous HC1 and was extracted with dichloromethane (3 x 25 mL). The organic layer was washed with saturated aqueous NaHCC dried over Na2S0 , filtered and concentrated under reduced pressure to afford a yellow oil. The enamine was used unpurified in the next reaction. MS (+ESI) m/z = 474.
Step 2 : 6-(3 -Chioro-4-fluoroben2yl)-4-hydroxy-3 , 5 ~dioxo-N-(5 -oxohexyl)-
2,355,6!7,8-hexahydro-2,6-naphthyridine- 1 -carboxamide
The reaction was performed as outlined in Advanced Synthesis and Catalysis, 1990, 351, 2081-2085. A large spatula of silica gel («1 g) was added to a solution of enamine (1.19 g , 2.51 mmol) in CH2C12 (10 mL, 0.25 M). The reaction was stirred at room temperature for 18 h. The silica gel was filtered off and was washed with 50% MeOH in CH2O2. The crude product was purified by preparative reverse phase chromatography through a CI 8 column, eluting with 10% MeCN in H20 (+0.1% formic acid) to 90% MeCN in H20 (+0.1% formic acid) to afford a yellow oil. MS (+ESI) m/z = 492.
Step 3 : (±)-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,358?9;l 0, 11- hexahydro-7aH-pyrido[2'51 ':2,3]imidazo[5, \-a] [2,6]naphthyridine- 4,6,13(li7)-trione
The title compound was prepared according to the procedure described in Step 2 of Example 2 using the ketone described in the previous step (329 mg, 0.67 mmol). Trituration with EtOAc and then EtOH afforded a yellow solid. MS (+ESI) m/z = 446. EXAMPLE 8
(±)-3-(3-Chloro-4-fluorober^l)-7a-ethyl-5-hydroxy-2s358;9,105l l-hexahydro-7aH- pyrido [2', Γ :2,3 ] imidazo [5 , 1 ~a] [2 , 6]naphtbyridine-4 ,6,13(1 H)-trione
Figure imgf000080_0001
Step 1 : 7~Aminoheptan-3-one The reaction was performed as outlined in J Org. Chem. 2006, 71, 4525-
4529. To a solution of N-tert-butylcarboxycarbamoyl-piperidin-2-one (260 mg, 1.31 mmol) in THF (2.6 mL, 0.5 M) at -78 °C was added ethylmagnesium bromide (1.2 mL, 3.59 mmol). The reaction was stirred for 2 h during which the reaction slowly warmed up to room temperature. The reaction was quenched with saturated aqueous NaHC03 and extracted with EtOAc (3 x 25 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to afford a colorless oil. The ketone was used unpurified in the next reaction. MS (+ESI) m/z = 252 (M + Na)+
Step 2: 6-Ethyl-2,3J4,5-tetrahydropyridine
The reaction was performed as outlined in J. Org. Chem. 2006, 71 f 4525- 4529. A solution of ketone (300 mg, 1.31 mmol) in CH2C12/TFA (4:1, 0.5 M) was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to afford a yellow oil. The enamine was used unpurified in the next reaction. MS (+ESI) m/z - 112. Step 3 : 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-3 ,5-dioxo-jV-(5-oxoheptyl)~
2 , 3 ,5 ,6, 7, 8 -hexahydro-2,6-naphthyridi ne- 1 -carboxamide
To a solution of acid chloride (539 mg, 1 ,30 mmol, prepared according to
Example 6, Step 1) and N,N-diisopropylethylamine (3 equiv) in THF (5.2 mL, 0.25 M) was added 6-ethyl-2,3,4,5-tetrahydropyridine (1 equiv). The reaction was stirred at room temperature for 18 h. LCMS indicated a mixture of carboxylic acid and desired ketone. The reaction was diluted with 10% aqueous HC1 and extracted with CH2CI2 (3 χ 25 mL). The organic layer was washed with saturated aqueous NaHC03, dried over Na2S04, filtered and concentrated under reduced pressure to afford a yellow oil. The ketone was used unpurified in the next reaction. MS (+ESI) m/z = 506.
Step 4: (±)-3-(3-Chloro-4-fluorobenzyl)-7a-ethyl-5-hydroxy-2,3,8,9,10,l 1 - hexahydro-7aH-pyrido[2', :2,3]imidazo[5,l -a][2,6]naphthvridine-
4,6,13(lHRrione
The title compound was prepared according to the procedure described in Step 2 of Example 2 using the ketone described in the previous step (660 mg, 1.30 mmol). Trituration with EtOAc and then EtOH afforded a yellow solid. MS (+ESI) m/z = 460.
EXAMPLE 9
(±)-8-(4-Fluorobenzyl)-6-hydroxy-2-methyl-3-(propan-2-yl)-2,3,9s10- tetrahydroimidazo[5, 1 -a] [2>6]naphthyridine-l ,5,7(8H)-trione
Figure imgf000081_0001
A 200 mL Parr vessel equipped with a stir bar was charged with the aryl chloride (prepared according to general procedure in Example 1, 200 mg, 0.46 mmol), Pearlman's catalyst (20 wt% on carbon, 2 equiv), AcOH (16 equiv) and EtOH/CH2Cl2 (5:1 , 0.03 M). The vessel was purged with nitrogen then placed under vacuum (repeat 3 *). The vessel was then filled with hydrogen (40-50 psi) and was vigorously shaken at room temperature for 5 h. The reaction was diluted with CH2CI2, filtered over a pad of Celite and was washed with CH2C12 and MeOH to afford a gray/green foam. MS (+ESI) m/z = 400. 1H NMR (400 MHz, CDC13) δ 13.70 (s, 1H), 7.36-7.29 (m, 2H), 7.1 1-7.02 (m, 2H), 5.57 (bs, 1H), 4.78 (d, J = 14.5 Hz, 1H), 4.69 (d, J = 14.5 Hz, 1H), 3.52-3.38 (m, 3H), 3.35-3.23 (m, 1H), 3.21-3.05 (m, 4H), 1.21 (d, J= 7.0 Hz, 3H), 0.71 (d, J= 6.5 Hz, 3H). EXAMPLE 10
8H2-Bromo-4-fluorobenzyl)-6'-hydroxy-2'-m
l,3,-irrddazo[5,l- ][2,6]naphthyridine]-r,5',7,(8'H)-trione
Figure imgf000082_0001
Intermediate C (100 mg, 0.33 mmol), 2~bromo-4-fluorobenzyi bromide (3 equiv) and potassium fert-butoxide (5 equiv) were dissolved in DMSO (1 mL, 0.3 M) and stirred at room temperature for 2.5 h. The reaction was quenched with AcOH/H20 and extracted with CH2CI2. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography through silica gel, eluting with 0 to 10% MeOH in CH2CI2 as a gradient to afford the title compound as a yellow solid. MS (+ESI) m z = 490. 1H NMR (500 MHz, t¾-DMSO) δ 13.44 (s, 1H), 7.69- 7.65 (m, 1H), 7.45-7.40 (m, 1H), 7.29-7.24 (m, 1H), 4.74 (s, 2H), 3.61-3.55 (m, 2H), 2.97 (s, 3H), 2.58-2.50 (m, 2H), 2.20-2.11 (m, 3H), 2.00-1.93 (m, 2H), 1.90-1.83 (m, 3H).
EXAMPLE 11
(+)-8-(3-Chloro-4-fluorobenzyl)-2-cyclopropyl-6-hydroxy-3-(2-(methylsulfonyl)ethyl)- 2,3,9,10-tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine-l ,5,7(8H)-trione
Figure imgf000083_0001
Step 1 : (±)-8-(3-Chloro-4-fluorobenzyi)-2-cyclopropyl-6-hydroxy-3-(2- (methylthio)ethyl)-2,3 ,9, 10-tefr
l,5,7(8H)-trione
A solution of cyclopropylamide (from Example 3, Step 1) (1.14 g , 2.81 mmol) in 1,4-dioxane (14 mL) was treated with 3-(methylthio)propionaldehyde (2.81 mL, 28.1 mmol) and concentrated sulfuric acid (0.03 mL, 0.562 mmol, 20 mol%). The solution was heated at 100 °C for 6 h and then cooled to room temperature. The mixture was poured into a 250 mL separatory funnel, diluted with saturated aqueous NaHC03 solution (100 mL) and extracted with CH2C12 (2 χ 50 mL). The combined organics were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 10% MeOH in CH2CI2 afforded the title compound as a yellow oil (1.23 g, 89% yield). MS (+ESI) m/z - 492.
Step 2 : (±)- 8-(3 -Chloro-4-fluorobenzyl)-2-cyclopropyl-6~hydroxy-3 -(2-
(methylsulfonyl)ethyl)-2,3,9,l 0-tetrahydroimidazo[5,l -a] [2,6]naphthyridine- l,5,7(8H)-trione
A solution of the sulfide from Step 1 (1.5 g, 3.05 mmol) in CH2CI2 (15 mL) was cooled to 0 °C in an ice bath. The solution was treated with w-CPBA (3.16 g? 9.15 mmol) and the resulting mixture warmed to room temperature and stirred for 16 h. The reaction mixture was poured into a 250 mL separatory funnel containing saturated aqueous NaHC03 (100 mL) and extracted with CH2CI2 (2 x 50 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. Purification by reverse-phase CI 8 column chromatography, eluting with 20% MeCN in water (+0.1% TFA) to 90% MeCN in water (+0.1% TFA) afforded the title compound (130 mg, 8% yield). MS (+ESI) mfz = 524.
EXAMPLE 12
(5)-2,3-Dicyclopropyl-8-(4-fluorobenzyl)-6-hydroxy-2,3 ,9, 10-tetrahydroimidazo[5, 1 -
Figure imgf000084_0001
The first eluting enantiomer from Example 3 (12 g, 26 mmol) was placed in dry MeOH (150 mL) and 3.5 g of 10 wt% palladium on carbon was added under nitrogen. The mixture was stirred under a balloon of ¾ for 24 h at room temperature. The mixture was filtered through a syringe filter, and the filtrate was concentrated under reduced pressure. Purification by column chromotography through silica gel, eluting with dichloromethane, afforded the title compound (6.5 g, 60% yield) as light yellow solid. MS (+ESI) m/z = 424. 1H NMR (400 MHz, CDC13) δ 13.71 (s, 1H), 7.34-7.30 (m, 2H), 7.09- 7.05 (m, 2H), 4.96 (d, J- 8.0 Hz, 1H), 4.78-4.69 (m, 2H), 3.27-3.20 (m, 4H , 2.75-2.73 (m, 1H), 1.22-1.21 (m, 2H), 1.05-1.03 (m, 2H), 0.79-0.60 (m, 5H).
EXAMPLE 13
(S)-253-dicyclopropyl-8-(4-fluorobenzyl)-l,5,7-trioxo-l,23,5,7,8,9,10-
Figure imgf000084_0002
Example 12 Into a 250 mL round-bottom flask equipped with a magnetic stirbar was added Example 12 (2,00 g, 4.72 mmol) and acetonitrile (15 mL). The solution was treated with a 1.0 M aqueous NaOH solution (4.96 mL, 4.96 mmol) and stirred at room temperature for 30 minutes. The reaction was transfered to a lyophilizer jar using water (5 mL), frozen with dry-ice/acetone to the sides and placed on the lyophilizer for 16 h. The title compound was isolated as a slight greenish-white solid (1.94 g, 92% yield). MS (+ESI) m/z = 424.
EXAMPLE 14
8l-(3-Chloro-4-fluoroben2yl)-6,-hydroxy-2-methoxy-9 0'-dihydro~rH~spiro[cyclopentane- 1 ,3'-imidazo[5, [2;6]naphthyridine]-l,,5'57'(2,H8'H)-trione
Figure imgf000085_0001
Intermediate D
To a mixture of Intermediate D (344 mg, 3.65 mmol) in anhydrous DMA (15 mL) was added 2-methoxycyclopentanone (4.1 g, 35.9 mmol) and concentrated sulfuric acid (0.194 mL, 3.65 mmol). The reaction vial was sealed and stirred at 105 °C for 18 h. After cooling, the reaction was poured into a separatory funnel, diluted with ethyl acetate (50 mL) and washed with water (3 15 mL). The organic layer was dried over Na2S0 i filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunPire CI 8 10 μΜ 50 χ 250 mm column. The compound was loaded with DMSO and methanol, and eluted with 25% MeCN in ¾0 (+ 0.1% TFA) to 70% MeCN in H20 (+ 0.1% TFA) over 35 minutes to afford the racemic title compound (530 mg, 32% yield). The racemic mixture was separated by chiral SFC to afford the enantiopure title compound, Example 14 (fourth eluting enantiomer). Preparative chiral separation of the enantiomers was achieved using a ChiralPak OD-H, 250 χ 30 mm I.D. 5 μπι column, eluting with C02 plus methano acetonitrile (70:20:10 + 0.1% Et2NH) at a flow rate of 80 mL/min. The purified material was partitioned between daqueous 1M HC1 and ethyl acetate and extracted with ethyl acetate (3 χ 20 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound. MS (+ESI) m/z - 462. !H NMR (400 MHz, afe-DMSO) δ 13.49 (s, 1H), 9.77 (s, 1H), 7.61 (d, J - 7.2 Hz, 1H), 7.42-737 (m, 2H), 4.75-4.65 (m, 2H)5 3.76 (dd, J= 11.1, 7.0 Hz, 1H), 3.55 (t, J= 6.6 Hz, 2H)S 3.28-3.22 (m, 2H), 3.14 (s, 3H), 2.96-2.88 (m, 1H), 2.37-2.28 (m, 1H), 2.15-2.06 (m, 1H), 1.98-1.90 (m, 1H), 1.88-1.80 (m, 1H), 1.68-1.57 (m, 1H).
EXAMPLES 15 AND 16
(IS, 5i?)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-9'J 10'-di ydro- 1 Ή- spiro[bicyclo[3.1.0]hexane-2,3'~imidazo[5,l~ ][2,^^
Figure imgf000086_0001
Intermediate D
Figure imgf000086_0002
Example 15 Example 16 first eluting diastereomer second eluting diastereomer
To a mixture of intermediate D (500 mg, 1.37 mrnol) in anhydrous DMA (4 mL) was added (IS, J#)-bicyclo[3.1.0]hexan-2~one (526 mg, 5.47 mmol) and sulfuric acid (73 μί,, 1.37 mmol). The reaction vial was sealed and stirred at 105 °C for 18 h. After cooling to room temperature, the reaction was poured into a separatory funnel, diluted with ethyl acetate (50 mL) and washed with water (2 x 15 mL) and brine (20 mL). The organic layer was dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 50 x 250 mm column. The compound was loaded with DMSO, methanol, and water and eluted with 25% MeCN in H20 (+ 0.1% TFA) to 65% MeCN in H20 (+ 0.1% TFA) over 35 minutes to afford the separated diastereomers of the title compound.
Example 15 is the first eluting diastereomer (102 mg, 17% yield). MS (+ESI) m/z = 444. 1H NMR (400 MHz, <¾-D SO) δ 13.48 (s, 1H), 9.55 (s, 1H), 7.59 (dd, J= 7.2, 2.0 Hz, 1H), 7.44-7.35 (m, 2H), 4.75-4.67 (m, 2H), 3.55 (t, J- 6.4 Hz, 2H), 3.26 (t, J- 6.4 Hz, 2 H), 2.68-2.56 (m, 1H), 2.18-2.1 1 (m, 1H)5 1.88-1.71 (m, 2H), 1.69-1.63 (m, 1H), 1.53-1.47 (m5 1H), 0.65-0.57 (m, 1H), 0.51 (q, J- 4.5 Hz, IE).
Example 16 is the second eluting diastereomer (135 mg, 22% yield). MS (+ESI) m/z = 444. Ή NMR (400 MHz, rf6-DMSO) δ 13.46 (s, 1H), 9.95 (s, 1H), 7.59 (dd, J= 7.2, 2.0 Hz, 1H), 7.43-7.35 (m, 2H), 4.75-4.67 (m, 2H), 3.55 (t, J- 6.5 Hz, 2H), 3.35-3.21 (m, 2H), 2.80 (td, J- 12.4, 8.0 Hz, 1H), 2.14-2.02 (ra, 1H), 1.80 (dd, J= 12.4, 7.9 Hz, 1H), 1.51-1.43 (m, 2H), 1.34 (dd, J = 13.0, 7.9 Hz, 1H), 1.25-1.19 (m, 1H), 0.78-0.70 (m, 1H). EXAMPLES 17 AND 18
(1R, 55')-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-9', 10'-dihydro-l'H- spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,l -a) [2;6]naphthyridine]-r,5'37'(2'H,8'H)-trione
Figure imgf000087_0001
Intermediate D
Figure imgf000087_0002
Example 17 Example 18 first eluting diastereomer second eluting diastereomer
The separated diastereomers of the title compound were prepared as described for (7¾5i?)-8'-(3-cMoro-4-fluorobertzyl)-6!-hydroxy-9';l O'-dihydro-rH- spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5;l - ] [2,6]naphthyridine]- 1 'J5',7,(2'H,8,H)-trione (Examples 15 & 16) replacing (iS,5i?)-bicyclo[3.1,0]hexan~2-one with (1R,5S)- bicyclo[3.1.0]hexan-2-one. Example 17 is the first eluting diastereomer and the !H NMR is identical to Example 15. Example 18 is the second eluting diastereomer and the 1H NMR is identical to Example 16.
EXAMPLE 19
8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2'-[(l-hydroxycyclopropyl)methyl]-9'f10'-dihydro- 2'H-spiro[cyclopentane- 1 ,3'-imidazo[5, 1 -a] [2,6]naphthyridine]- 1 ^5',7 8'H)-trione
Figure imgf000088_0001
Figure imgf000088_0002
Step 1 : 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N-[(l-hydroxycyclopropyl)methyl]- S^-dio o^ jS^ jS-hexahydro-l^-na hth ridi e- 1 -carboxamide
A 250 mL flask was charged with dry THF (54 mL) and Intermediate A (5.0 g, 8.1 mmol). l-(Aminomethyl)cyclopropanol (0.9 g, 10.5 mmol) was then added and the resulting mixture was stirred at room temperature for 10 minutes. Methylamine (33% in EtOH; 5.4 mL, 40.4 mmol) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with EtOAc (500 mL), washed with a saturated solution of NaHC03 in water (200 mL) and then aqueous 1 N HQ (2 χ 200 mL). The organic layer containing a suspension was separated and filtered, and the solid was dried under vacuum to afford the title compound (2.9 g, 83% yield) as a white solid. MS (+ESI) m/z = 436.
Step 2: 8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2'-[(l-hydroxycyclopropyl)metliyl]- 9' , 10'-dihydro-2'H-spiro [cyclopentane- 1,3' -imidazo [5,1- a] [2,6]naphthyridine]- 1 '55'57'(8'H)-trione A mixture of the amide from Step 1 (420 mg, 1.0 mmol) in 1,4-dioxane (2.4 mL) was added cyclopentanone (810 mg, 10.0 mmol) and concentrated sulfuric acid (0.1 mL) under nitrogen at room temperature, then the mixture was heated to 100 °C for 18 h. After cooling, the reaction mixture was diluted with EtOAc (100 mL) and washed with a saturated aqueous solution of NaHC03 (20 mL) and water (20 mL), and the organic layer was separated. The organic layer was dried over MgS04, filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire C18 5 μπι 30 x 150 mm column, eluting with 35-75% MeCN in ¾0 with (+0.1% TFA) as a gradient over 20 minutes to afford the title compound. HRMS (+ESI) m/z = 502.1551 found, 502.1540 required. Ή NMR (500 MHz, acetone) δ 13.65 (s, 1H)S 7.62 (d, J- 7.0 Hz, 1H), 7.47 (d, J= 7.4 Hz, 1H), 7.33 (t, J= 8.9 Hz, 1H), 4.83 (s, 2H), 4.42 (s, 2H), 3.68 (t, J= 6.4 Hz, 2H), 3.35 (t, J= 6.4 Hz, 2H), 2.71-2.61 (m, 4H), 2.22 (m, 2H), 2.02 (m, 2H), 1.83 (m, 2H), 1.07 (t, J= 7.2 Hz, 2H).
EXAMPLE 20
(+) or (9-8-(3~Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(2-{methyl[(l -methyl- lH-pyrazol-4-yl)methyl] amino) ethyl)-2,3,9, 10-tetrahydroimidazo[5, 1 -a][2,6]naphthyridine- l,5,7(8H)-trione
Figure imgf000089_0001
Figure imgf000090_0001
chiral - second etuting enantiomer
Step 1 : 6-(3-Chloro-4-fluorobenzyl)-3,4-dihydroxy-N-(2-hydroxyethyl)-5-oxo- 5,6,7,8 -tetrahydro-2,6-naphthyridine- -carboxamide
Into a 300-mL flask was added Intermediate A (8.00 g, 12.92 mmol) and THF (100 mL). The solution was treated with ethanolamine (4.74 gf 78 mmol) then stirred at room temperature for 2 h. There was a thick, white precipitate present after 1 h. The solid was filtered and washed with THF and dried under vacuum. The solid was then suspended in methanol (60 mL)/water (80 mL) and acidified with concentrated HC1 to pH = 1. This suspension was stirred for 1 h and then the solid was filtered through Whatman #1 filter paper on a Buchner funnel under vacuum. The solid was washed with water (2 x 80 mL), methanol (20 mL) and ethyl ether (2 x 30 mL) then dried under vacuum to afford the title compound (4.89 g, 92% yield). MS (+ESI) m/z = 410.
Step 2 : (±)- 8-(3 ~C oro-4-fiuorobenzyl)-3 -cyclopropyl-6-hydroxy-2-(2~
hydroxyethyl)-2,3 ,9,10-tetrahydroimidazo [ 551 -a] [2 ,6] naphthyridine- l,5,7(8H)-trione The solid amido alcohol from Step 1 (2.86 g, 6.98 mmol) was suspended in
1,4-dioxane (30 mL) in a 100 mL round-bottom flask equipped with a reflux condenser. To this suspension was added cyclopropanecarboxaldehyde (1.96 g, 27.9 mmol) and concentrated sulfuric acid (0.05 ml, 0.7 mmol). A stir bar was added and the suspension was stirred at 100 °C under reflux for 3 h. The light green colored suspension was cooled to room temperature and the solid was filtered, washed with 1 ,4-dioxane followed by methanol. The resulting solid was dried under vacuum, affording the title compound. (2.58 g, 80% yield). MS (+ESI) m/z = 462. Step 3 : (±)-2-[8-(3-Chloro-4-fiuorobenzyl)-3-cyclopropyI-6-hydroxy-l ,5,7-trioxo-
1 ,5,7,8,9, 10-hexahydroimidazo[5 , 1 -a] [2,6]naphthyridin-2(3H)-yl]ethyl methanesulfonate The alcohol from Step 2 (500 mg, 1.08 rnmol) was suspended in CH2CI2 (10 mL) and triethylamine (0.15 ml, 1.08 mmol) was added. Methanesulfonyl chloride (0.08 mL, 1.08 mmol) was added drop-wise via syringe over 15 minutes and the resulting suspension was stirred at room temperature for 4 h. This reaction was used directly
(unpurified) in the next Step. MS (+ESI) m/z = 540.
Step 4: (+) or (-)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(2-
{methyl [( 1 -methyl- 1 H-pyrazol-4-yl)methyl] amino } ethy l)-2 ,3 ,9, 10- tetrahydroimidazo[5,l -a][2,6]naphthyridine-l ,5,7(8H)~trione To the unpurified material from Step 3 (585 mg, 1.08 mmol) was further added triethylamine (0.76 ml, 5.42 mmol). N-Methyl-l-(l-methyl-7H-pyrazol-4- yl)methanamine (542 mg, 4.33 mmol) was added and the mixture stirred at room
temperature for 2 h. The reaction mixture was concentrated and purified by preparative reverse phase chromatography through a SunPire CI 8 10 μΜ 30 x 150 mm column. The compound was loaded with DMSO/methanol, and eluted with 40% MeCN in H20 (+0.1 % TFA) to 90% MeCN in ¾0 (+0.1% TFA) over 30 minutes at a flow rate of 35 mL/min. The title compound was recovered after concentration as a racemic, TFA salt (190 mg, 26% yield). MS (+ESI) m/z = 569.2094. The racemic mixture (190 mg) was separated by chiral SFC to afford the enantiopure Example 20 (36 mg, second eluting enantiomer). Preparative chiral separation of the enantiomer s was achieved using a ChiralPak AD-H column (250 χ 30 mm LD), eluting with C02 plus methanol :acetonitrile (49:35:16 + 0.1% Et2NH) at a flow rate of 50 mL/min. MS (+ESI) m/z = 569. 1H NMR (400 MHz, CD3OD) δ 7.84 (m, 1H), 7.75 (m, 1H), 7.50 (dd, J= 7.0, 6.5 Hz, 1H), 7.36 (m, 1H), 7.27 (t, J= 6.5 Hz, 1H), 7.40 (d, J= 8.0 Hz, 1H), 4.85-4.82 (m, 1H), 4.50 (m, 4H), 3.91 (m, 5H), 3.54 (m, 4H), 2.94 (s, 3H), 1.15 (m, 1H), 0.83 (m, 4H).
EXAMPLE 21
(±)-N-{2-[8-(3-Chloro-4-fluorobenzyl)-3-cyciopropyl-6-hydroxy-l,5,7-trioxo-i,5,7,8 hexahydroimidazo[5 , 1 -a] [2,63naphmyridin-2(3H)-yl]ethyl}-N-methylethanesulfonamide
Figure imgf000092_0001
Step 1 : tert-Butyl [2-( { [6-(3 -chloro-4-fluorobenzyI)-4-hydroxy-3 ,5-dioxo- 2,3,5,6, 7,8-hexahydro-2,6-naphthyridin- 1 - yl] carbonyl } amino)ethyl] methylcarbamate
A solution of Intermediate A (2.50 g, 4.04 mmol) in tetrahydrofuran (27 mL) was treated with fert-butyl (2-aminoethyl)methylcarbamate (0.844 g, 4.85 mmol) and stirred at room temperature for 20 minutes. Methylamine (33 % wt. solution in methanol, 3.26 mL, 24.2 mmol) was added and the mixture stirred at room temperature for 16 h. The mixture was acidified to pH ~8 with 1 N aqueous HC1 and partitioned between water (40 mL) and EtOAc (400 mL). The organic phase was dried over Na2S0 , filtered and concentrated to afford the title compound, which was used in subsequent steps without purification. MS (+ESI) m z = 523.
Step 2: 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N-[2-(methylamino)ethyl]-3,5-dioxo- 2,3,5, 6,7, 8-hexahydro-2,6-naphthyridine-l -carboxamide trifluoroacetate
A solution of secondary amide from Step 1 (2.23 g, 4.26 mmol) in dichloromethane (28 mL) was treated with trifluoroacetic acid (3.29 mL, 42.6 mmol) and stirred at room temperature for 2 h. The mixture was concentrated to afford the title compound, which was used in subsequent steps without purification. MS (+ESI) m/z - 423.
Step 3: Benzyl [2-({[6-(3-chloro-4-fiuorobenzyl)-4-hydroxy-3,5-dioxo-2i355s6J,8- hexahydro-2,6-naphthyridin-l-yl]carbonyl}amino)ethyi]methylcarbamate
A solution of the secondary amine from Step 2 (1.95 g, 3.63 mmol) in dichloromethane (18.2 mL) was treated with benzyl chloroformate (0.52 mL, 3.63 mmol) and triethylamine (2.53 mL, 18.2 mmol). After stirring at room temperature for 16 h, the mixture was poured into a 250 mL separatory funnel and partitioned between water (100 mL) and EtOAc (300 mL). The organic phase was hazy and was concentrated without drying over MgS0 or filtration. The residue was suspended in 50 mL of 10: 1
CH2Cl2 MeOH and filtered through a fine fritted sintered glass funnel. The filtrate was concentrated to afford the title compound (1.53 g, 76% yield). MS (+ESI) m/z - 557. Step 4: (±)-Benzyl {2-[8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-l,5,7- trioxo- 1 ,5,7,8,9, 10-hexahydroimidazo[5, 1 -a] [2,6]naphthyridin-2(3H)- yl] ethyl } methyl carbamate
A solution of CBz-protected amine from Step 3 (2.00 g, 3.59 mmol) and cyclopropanecarboxaldehyde (2.52 g, 35.9 mmol) in 1 ,4-dioxane (12 mL) was treated with concentrated sulfuric acid (0.29 mL, 5.4 mmol) and heated to 70 °C for 40 minutes. The residue was purified by preparative reverse phase chromatography through a SunFire C18 5 μιη 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 30% MeCN in ¾0 (+0.1% TFA) to 90% MeCN in H20 (+0.1% TFA) as a gradient over 30 minutes at a flow rate of 35 mL/min. The purified material was poured into a 250 mL separatory funnel and partitioned between water (50 mL) and EtOAc (200 mL). The organic phase was dried over Na2S04, filtered and concentrated to afford the title compound (400 mg, 18 % yield). MS (+ESI) m/z = 609.
Step 5 : (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[2- (methylamino)ethyl]~2,3,9, 10-tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine-
1,5 J(8H)-trione hydrochloride
A solution of compound from Step 4 (400 mg, 0.66 mmol) in EtOAc (6.5 mL) was treated with 20 mol% Pd(OH)2 on carbon (92 mg, 0. ί 3 mmol). The flask was evacuated and backfilled with ¾ (gas) three times and stirred under a ¾ atmosphere (~ 1 atm) at room temperature overnight. During the reaction, MeOH and a few drops of concentrated HC1 solution were added to the reaction mixture to enable solubility. The mixture was filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated to afford the title compound (309 mg, 99% yield). MS (+ESI) m/z - 475.
Step 6: (+)-N-{2-[8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-l ,5,7- trioxo-l>5,7,8,9,10-hexaliydroimidazo[5,l-a][2,6]naphthyridin-2(3H)- yl]ethyl}-N-methylethanesulfonamide
A suspension of compound from Step 5 (21 mg, 0.044 mmol) in dichloromethane (442 μΤ) was treated with triethylamine (18 μΐ,, 0.133 mmol) and ethane sulfonyl chloride (8.5 mg, 0.066 mmol). The mixture was stirred at room temperature for 10 minutes. The residue was purified by preparative reverse phase chromatography through a SunPire CI 8 5 μιη 50 x 250 mm column. The compound was loaded with
DMSO/methanol, and eluted with 50% MeCN in ¾0 (+0.1% TFA) to 90% MeCN in H20 (+0.1% TFA) as a gradient over 30 minutes at a flow rate of 35 mL/min. Pure fractions were concentrated to afford the title compound (7.7 mg, 31% yield). MS (+ESI) m/z - 567. Ή NMR (500 MHz, ^-acetone) 13.71 (s, 1H), 7.63 (dd, J= 7.1, 2.3 Hz, 1H), 7.50-7.46 (m, 1H), 7.33 (t, J= 8.9 Hz, 1H), 5.27 (d, J = 8.7 Hz, 1H), 4.83 (d, J = 2.8 Hz, 2H), 4.18-4.1 1 (m, 1H), 3.70-3.61 (m, 4H), 3.48-3.41 (m, 2H), 3.30 (dt, J- 16.3, 7.1 Hz, 1H), 3.05 (d, J= 7.4 Hz, 2H), 2.97 (s, 3 H), 1.25 (t, J= 7.4 Hz, 3H), 1.20-1.15 (m, 1H), 0.96-0.89 (m, 1H), 0.80-0.70 (m, 3H). EXAMPLES 22 AND 23
(2R) or (2S)-(1S, 5/?)-8'-(3,4-difluorobenzyl)-6'-hydroxy-9!,l O'-dihydro-l'H- spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5 , 1 -a] [2,6]naphthyridine]- 1 ',5!,7'(2'Hs8,H)-trione
Figure imgf000095_0001
Figure imgf000095_0002
Example 22 Example 23
first eluting diastereomer second eluting diastereomer
Step 1 : S^-Dimethoxy-S-oxo-S^^jS-tetrahydro^^-naphthyridine-l-carboxylic acid
Into an oven dried flask under an atmosphere of nitrogen was added sodium hydride (95 wt%, 102 mg, 4.05 mmol) and anhydrous DMSO (20 mL). The suspension was stirred at room temperature for 10 minutes. To this was added Intermediate B (1.0 g, 2.53 mmol) and the reaction was stirred at room temperature for 30 minutes. Oxygen was then bubbled into the reaction via a gas dispersion tube, followed by addition of potassium tert- butoxide (568 mg, 5.07 mmol). As the reaction stirred at room temperature, oxygen was continually bubbled into the suspension in the flask. After 15 minutes, additional potassium fert-butoxide (568 mg, 5.07 mmol) was added to drive the reaction to completion. The reaction was quenched with 2 M aqueous HC1 solution (7.5 mL), diluted with brine, poured into a separatory funnel and extracted with CH2CI2 (3 x 30 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 50 x 250 mm column. The compound, was loaded with DMSO/methanol, and eluted with 5% MeCN in ¾0 (+ 0.1% TFA) to 50% MeCN in ¾0 (+ 0.1% TFA) over 30 minutes to afford the title compound (450 mg, 70% yield). MS (+ESI) m/z = 253.
Step 2: 6-(3,4-Difluorobenzyl)-3,4-dimethoxy-5-oxo-5,6J7,8-tetrahydro-2,6- naphthyridine-l-carboxyHc acid
Into a 10 mL vial equipped with a magnetic stirbar was added the secondary amide from Step 1 (50 mg, 0.198 mmol) and ½rt-butanol (2 mL). The solution was treated with 2.4 equiv of potassium iert-butoxide (53 mg, 0.476 mmol). The resulting yellow suspension was stirred at room temperature for 10 minutes and then treated with 3,4- difiuorobenzyl chloride (65 mg, 0.396 mmol). The mixture was stirred for 10 minutes at room temperature and then heated to 60 °C for 1 h. The cooled reaction mixture was diluted with aqueous 1 M HCl solution until the pH of the solution was 2. The aqueous mixture was poured into a phase separator cartridge and extracted with dichloromethane (3 5 mL). The combined organics were concentrated under reduced pressure. The compound was purified by column chromatography through silica gel (12 g), eluting with 25% EtOAc in hexanes to 100% EtOAc in hexanes as a gradient. The title product was isolated as a light yellow foam (51 mg, 68% yield). MS (+ESI) m/z = 379.
Step 3: 6-(3,4-Difluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetraliydro-2,6- naphthyridine- 1 -carboxamide Into a 100 mL round-bottom flask equipped with a magnetic stirbar was added the carboxylic acid from Step 2 (401 mg, 1.06 mmol), HATU (564 mg, 1.48 mmol), and DMF (5 mL). The solution was treated with EtN(zPr)2 (0.37 mL, 2.12 mmol) and concentrated aqueous ammonium hydroxide solution (0.13 mL, 3.18 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was poured into a 125 mL separatory funnel containing 1 M aqueous HCl (75 mL) and the mixture extracted with ethyl acetate (3 30 mL). The combined organic layers were washed with brine, dried over MgS0 , filtered and the solvent was evaporated under reduced pressure. The compound was purified by column chromatography through silica gel (40 g), eluting with 75% EtOAc in hexanes to 100% EtOAc in hexanes as a gradient. The title compound was isolated as a light yellow solid (406 mg, >99% yield). MS (+ESI) m/z = 378. Step 4 : 6-(3 ,4-Difluorobenzyl)-4-hydroxy-3 , 5 -dioxo-2,3 ,5 ,6,7, 8-hexahydro-2,6 - naphthyridine- 1 -carboxamide
Into a 100 mL round-bottom flask equipped with a magnetic stirbar was added the carboxamide from Step 3 (400 mg, .060 mmol). The solid was treated with a solution of 25% HBr in acetic acid (4 mL, 73.7 mmol). The red-orange solution was heated to 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure, using toluene as a co-solvent to remove all the AcOH and HBr. The resulting red solid was purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 20% MeCN in H20 (+0.1% TFA) to 90% MeCN in H20 (+0.1% TFA) over 30 minutes at a flow rate of 85 mL/min. The desired product was collected and concentrated under reduced pressure to afford a white solid (192 mg, 52% yield). MS (+ESI) m/z = 350. Step 5: (2R) or ^-(/^J^-S'-tS^-ditoorober^ -e'-hych-o y- O'-dihydro-l'H- spiro[bicyclo[3.1.0]hexane-2,3,-imidazo[5,l-i3][2!6]naphthyridine]- l',5',7(2'H,8'H trione
Into a 25 mL sealable pressure vial equipped with a magnetic stir-bar was added the carboxamide from Step 4 (190 mg, 0.544 mmol), (2S,5i?)-bicyclo[3.1.0]hexan-2- one (209 mg, 2.17 mmol), DMA (4 mL) and concentrated sulfuric acid (0.14 mL). The vial was sealed and heated in an oil bath at 105 °C for 16 h. The reaction mixture was concentrated and purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 25% MeCN in ¾0 (+0.1% TFA) to 70% MeCN in H20 (+0.1% TFA) over 30 minutes at a flow rate of 85 mL/min. The desired products were collected and concentrated under reduced pressure.
The first eluting diastereomer (Example 22) was isolated as an off-white solid (43 mg, 18% yield). MS (+ESI) m/z = 428. Ή NMR (400 MHz, CDC13) δ 7.86 (bs, IH), 7.17-7.15 (m, 2H), 7.07-7.05 (bs, IH), 4.74-4.70 (m, 2H), 3.50-3.37 (m, 4H), 2.89 (m, IH), 2.36-2.32 (m, IH), 1.92-1.90 (m, 3H), 1.58-1.57 (m, IH), 0.78-0.77 (m, IH), 0.38-0.36 (m, IH).
The second eluting diastereomer (Example 23) was isolated as a light yellow solid (56 mg, 24% yield). MS (+ESI) m/z = 428. 1H NMR (400 MHz, CDC13) δ 8.21 (bs, IH), 7.15-7.07 (m, 3H), 4.73 (d, J- 15 Hz, IH), 4.67 (d, J=15 Hz, IH), 3.49-3.39 (m, 4H), 3.05 (q, J- 6.0 Hz, IH), 2.03-2.01 (m, 2H), 1.72-1.70 (m, IH), 1.60-1.58 (m, IH), 1.47-1.44 (m, IH), 1.25- 1.20 (ra, IH), 0.90-0.87 (m, IH). EXAMPLES 24 AND 25
(lS,5£)-8X2,4-difluoro^^
Figure imgf000098_0001
Figure imgf000099_0001
Step 1 : l-(2,4-Difluoroben2yl)piperidin-2-one To a solution of valerolactam (15.0 g, 150 mmol) in DMF (750 niL) at 0 °C was added sodium hydride (60 wt%, 6.6 g, 165 mmol). The solution was stirred at 0 °C for
30 minutes and then 2,4-difiuorobenzyl chloride (25 g, 152 mmol) in DMF (50 mL) was added drop-wise. The ice bath was removed and the solution stirred for 16 h at room temperature. The reaction was quenched with water (5000 mL), poured into a separatory funnel and extracted with EtOAc (3 x 500 mL). The combined organics were washed with water and the combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure, affording 31 g of the unpurified desired product. MS (+ESI) m/z = 226. Step 2: l-(2,4-Difluorobenzyl)-3-(phenylsulfmyl)piperidin-2-one l-(2,4-Difluorobenzyl)piperidm-2-one (31 g, 140 mmol) in THF (300 mL) was cooled to -10 °C and a solution of lithium bis(trimethylsilyl)amide (300 ml, 300 mmol, 1.0 M in THF) was added drop-wise. After the addition was complete the solution was stirred for 40 minutes at -10 °C. Methyl benzenesulfmate (22 ml, 170 mmol) was added drop-wise at -10 °C. After 1 h, the reaction was quenched with an aqueous solution of saturated NH4CI (200 mL) and brine (200 mL). The aqueous layer was poured into a separatory funnel and extracted with EtOAc (2 x 100 mL). The combined organics were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The crude product (obtained in quantitative yield) was not purified at this stage. MS (+ESI) m/z - 350.
Step 3 : 1 -(2,4-Difiuorobenzyl)-5 ,6-dihydropyridin-2( 1 H)-one
A solution of l-(2,4-Difluoroberrzyl)-3-( henylsulfinyl)piperidin-2-one (64 g, 183 mmol) in toluene (425 mL) was treated with sodium carbonate (85 g, 806 mmol) and stirred at 95 °C for 12 h. After cooling to room temperature the solution was poured into a separatory funnel, quenched with water (250 mL) and extracted with EtOAc (3 x 300 mL). The combined organics were dried over Na2S04, filtered and concentrated under reduced pressure. The dihydropyridinone was purified by column chromatography through silica gel (330 g), eluting with 50% EtOAc in hexanes to afford the title compound (20.4 g, 50% yield). MS (+ESI) m/z = 224. Step 4; Ethyl 6-(2J4-difluorobenzyl)-4-hydroxy-5-oxo-556,7,8-tetrahydro-256- naphthyridine- 1 -carboxylate
A solution of l-(2,4-difluorobenzyl)-556-dihydropyridin-2(lH)-°ne (20.4 g, 91 mmol) and ethyl 5-butoxy-l,3-oxazole-2 -carboxylate (27.3 g, 128 mmol, procedure described in patent WO 2005/087768 Al ) in water (2.5 mL, 137 mmol) was stirred at 150 °C for 6 days. After cooling to room temperature, methanol (20 mL) was added. The yellow solid was filtered and the resulting solid was triturated in hot C1¾CL; (100 mL). Filtration afforded 17 g of the desired product. The combined filtrates were concentrated under reduced pressure. Purification of the filtrate by column chromatography through silica gel (220 g), eluting with 5% MeOH in CH2CI2 provided an additional 10 g of desired compound (combined yield: 27 g, 82% yield). MS (+ESI) m/z - 363.
Step 5: Ethyl 6-(2,4-difluorobenzyl)-4-methoxy-5-oxo-5,6J7,8-tetrahydro-256- naphthyridine- 1 -carboxylate
To a solution of ethyl 6-(2J4-difluorobenzyl)-4-hydroxy-5-oxo-5}6,7,8- tetrahydro-2,6-naphthyridine-l -carboxylate (17 g, 47 mmol) in MeOH (100 mL) and CH2CI2 (200 mL) at 0 °C was added trimethylsilyl-diazomethane (35 mL, 70 mmol. 2.0 M solution in diethyl ether). The ice bath was removed and the solution stirred at room temperature for 14 h. Concentration under reduced pressure afforded an oil, which was purified by column chromatography on silica gel (220 g), eluting with 5% MeOH in CH2CI2 to afford the desired methyl phenol ether (16.8 g, 95% yield). MS (+ESI) m/z = 377. Step 6: Ethyl 6-(2i4-difluorobenzyl)-4-methoxy~5-oxo-5,6,7,8-tetrahydro-2,6- naphthyridine- 1 -carboxylate 2-oxide To a solution of ethyl ester from Step 5 (10.5 g, 27.9 mmol) in CH2CI2 (175 mL) at 0 °C was added urea hydrogen peroxide (5.25 g, 55.8 mmol) followed by drop-wise addition of trifluoroacetic anhydride (8.28 mLf 58.6 mmol). The ice bath was removed and the solution stirred for 14 h at room temperature. Saturated aqueous K2HP04 solution was added to the mixture until the pH was 7. The solution was cooled to 0 °C and solid sodium bisulfite (5 g) was added. After stirring at room temperature for 1 h, water (250 mL) was added. The mixture was poured into a separatory funnel, and the aqueous layer was extracted with C¾C12 (250 mL). The organic layer was washed with brine, dried over Na2S0 , filtered and concentrated under reduced pressure. The crude TV-oxide 10.9 g was used directly in the next step without purification. MS (+ESI) m/z = 393.
Step 7: Ethyl 3-(acetyloxy)-6-(2s4-difluorobenzyl)-4-methoxy-5-oxo-556,758- tetrahydro-2,6-naphthyridine- 1 -carboxylate
To a solution of JV-oxide from Step 6 (10.9 g, 27.8 mmol) in toluene (125 mL) was added acetic anhydride (18.0 mL, 200 mmol). The resulting mixture was refluxed for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Additional toluene (25 mL) was added and the solution was concentrated twice more to remove any residual acetic anhydride. The resulting acylated product (12.4 g) was used directly in the next step without further purification. MS (+ESI) m/z = 435.
Step 8 : 6-(2,4-Difluorobenzyl)-3 -hydroxy-4-methoxy-5 -oxo-5 ,6,7, 8-tetrahydro-2s6- naphthyridine-l-carboxylic acid
To a solution of ethyl ester from Step 7 (12.3 g, 28.3 mmol) in ethanol (125 mL) was added a solution of lithium hydroxide (4.47 g, 187 mmol) in water (25 ml). The resulting solution was stirred at room temperature for 12 h. The solution was concentrated under reduced pressure and then acidified with aqueous 1 M HC1. The resulting yellow product was filtered through filter paper on a Hirsch funnel under vacuum, affording the title compound (9.6 g, 93% yield). MS (+ESI) m/z = 365.
Step 9 : 6-(2?4-DifluorobenzyI)- 3 -hydroxy-4-methoxy- 5 -oxo-5 ,6 ,7,8 -tetrahydro-2,6- naphthyridine- 1 -carboxamide A solution of carboxylic acid from Step 8 (3.6 g, 10 mmol) in DMF (100 mL) was treated with HA.TU (5.3 g, 14 mmol), N,JV'~diisopropylethylamine (3.5 mL, 20 mmol), and concentrated ammonium hydroxide (1.2 mL, 30 mmol). Progess of the reaction was checked by LCMS and additional equivalent of reagents were added as necessary (approx 3- times). After 12 h, the reaction was quenched with a saturated aqueous solution of NH4CI (1 0 mL) and the mixture was poured into a separatory funnel The aqueous layer was extracted with EtOAc (3 x xl50 mL) and the combined organics layers were dried over MgS04, filtered and concentrated under reduced pressure affording 1.5 g of the primary amide. MS (+ESI) m/z = 364.
Step 10: (15! }5i?)-8'-(2,4-Difluorobenzyl)-6'-methoxy-9M0'-dihydro-2'H- spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,l -a] [2s6]naphthyridine]- l',5',7'(8!H)-trione
To a solution of amide from Step 9 (0.72 g, 2.0 mmol) in DMA (5.0 mL) was added (25, )5i?)-bicyclo[3.1.0]hexan-2-one (0.58 g, 6.0 mmol) and concentrated sulfuric acid (0.10 ml, 2.0 mmol). The mixture was heated to 100 °C for 4 h. After cooling to room temperature, a saturated solution of NaHC03 in water was added, the resulting mixture was poured into a separatory funnel and extracted with CH2C12 (3 x 25 mL). The combined organic layers were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The title compound (0.66 g) was used directly in the next step without purification. MS (+ESI) m/z = 442. Step 1 1 : (l^S^i-S'^^-Difluoroben -e'-hydro - 'JO'-dihydro- 'H- spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5, 1 -a) [2,6]naphthyridine]~
Figure imgf000102_0001
To a solution of compound from Step 10 (0.66 g,
1.5 mmol) in DMF (15 mL) was added lithium chloride (0.19 g, 4.5 mmol) and the solution heated at 100 °C for 2 h. After cooling to room temperature the reaction mixture was diluted with water (15 mL), poured into a separatory funnel and extracted with EtOAc (3 x 10 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. Purification by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 30 χ 150 πιτη column, eluting with 25% MeCN in H20 (+0.1 % TFA) to 95% MeCN in H20 (+0.1% TFA) over 12 minutes at a flow rate of 25 ml/min, afforded Example 24 (0.156 g, the first eluting diastereomer) and Example 25 (0.172 g, the second eluting diastereomer).
Example 24 (first eluting diastereomer): MS (+ESI) m/z = 428. 1H NMR (400 MHz, d6- DMSO) δ 13.45 (s, IH), 9.53 (s, IH), 7.50-7.43 (m, 1H), 7.31-7.22 (m, IH), 7.13- 7.04 (m, IH), 4.73 (s, 2H), 3.61-3.54 (m, 2H), 3.29-3.22 (m, 2H), 2.68-2.57 (m, IH), 2.19-2.12 (m, IH), 1.87-1.71 (m, 2H), 1.69-1.63 (m, IH), 1.54-1.47 (m, IH), 0.63-0.48 (m, 2H).
Example 25 (second eluting diastereomer): MS (+ESI) m/z - 428. ]H NMR (400 MHz, d6- DMSO) δ 13.43 (s, IH), 9.94 (s, IH), 7.57-7.43 (m, IH), 7.27-7.22 (m, H), 7.11- 7.06 (m, IH), 4.73 (s, 2H), 3.60-3.52 (m, 2H), 3.32-3.24 (m, 2H), 2.83-2.75 (m, IH), 2.18-2.05 (m5 IH), 1.82-1.76 (m, IH), 1.53-1.42 (m, 2H), 1.39-1.33 (m, IH), 1.24-1.19 (m, IH), 0.80- 0.71 (ms IH).
EXAMPLE 26
(+) or (-)-TV- {2-[8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy- 1 ,5,7-trioxo- l,5,7,8,9,10-hexahydroimidazo[5,l-a][2,6]naphthyridin-2(3H)-yl]ethyl} -N- methylmethanesulfonamide
Figure imgf000103_0001
first eluting enantiomer
Figure imgf000104_0001
chiral
Step 1 : fert-Butyl [2-({[6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-
2,3 ,5,6,7,8-hexahydro-2,6-naphthyridin- 1 - yl] carbonyl } amino)ethyl]methylcarbamate
A solution of Intermediate A (11.0 g, 17.8 mmol) in THF (118 ml) was treated with benzyl (2-aminoethyl)methylcarbamate (4.81 g, 23.1 mmol), triethylamine (4.95 mL, 35.5 mmol) and sti ed at room temperature for 20 minutes. Methylamine (33 wt% solution in methanol, 9.56 mL, 71.1 mmol) was added and the mixture stirred at room temperature for 16 h. The mixture was acidified to pH -8 with 1 M aqueqous HCl solution, poured into a 1 L separatory funnel and partitioned between water (200 mL) and EtOAc (800 mL). The organic phase was dried over Na2S04, filtered and concentrated to afford the title compound which was used in subsequent steps without purification. MS (+ESI) m/z = 557.
Step 2: (R) or (S)-Benzyl {2-[8-(3-chloro-4-fiuorobenzyl)-3-cyclopropyl-6-hydroxy-
1 ,5,7-trioxo- 1 ,5,7,8,9, 10-hexahydroimidazo[5, 1 -a] [2,6]naphthyridin-2(3H)- yljethyl } methylcarbamate
A solution of secondary amide from Step 1 (9.9 g, 17.8 mmol) and cyclopropanecarboxaldehyde (7.47 g, 107 mmol) in 1,4-dioxane (59 mL) was treated with concentrated sulfuric acid (1.42 mL, 26.7 mmol) and heated to 70 °C for 3 h. The reaction mixture was concentrated and purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 50 x 250 mm column. The compound was loaded with
DMSO/methanol, and eluted with 50% MeCN in H20 (+0.1% TFA) to 90% MeCN in H20 (+0.1 % TFA) over 30 minutes at a flow rate of 85 mL/min. The desired product fractions were partitioned between water (100 mL) and EtOAc (500 mL). The organic phase removed, dried over Na2S04, filtered and concentrated to afford the racemic compound (5.5 g, 51 % yield). The racemic mixture (5.5 g) was separated by chiral SFC to afford enantiopure title compound (2.15 g, first eluting enantiomer, >95% ee). Preparative chiral separation of the enantiomers was achieved using a ChiralPak OD-H, 250 χ 30 mm I.D. 20 μηι column, eluting with C02 plus methanol: acetonitrile (60 : 26.7 : 13.3 + 0.1% Et2NH) at a flow rate of 80 mL/min. MS (+ESI) m/z = 609. Step 3: (R) or (5 -8-(3-chloro-4~ftuorobenzyl)-3-cyclopropyl-6-hydroxy-2-[2-
(methylamino)ethyl]-2,3,9, 10-tetrahydroimidazo[5, 1 -a] [2,6]naphthyridme- l,5,7(8H)-trione hydrochloride
A solution of chiral CBz-protected amide from Step 2 (1.00 g, 1.64 mmol) in EtOAc (16.4 mL) was treated with 20 wt% Pd(OH)2 on carbon (231 mg, 0.131 mmol). The flask was evacuated and backfilled with H2 (gas) three times and stirred under a ¾ atmosphere (» 1 atm) at 50 °C for 2 h. At this time, an additional 20 wt% Pd(OH)2 on carbon was added (165 mg, 0.065 mmol). The flask was evacuated and backfilled with ¾ (gas) three times and stirred under a H2 atmosphere (« 1 atm) at 50 °C for an additional 4 h. Methanol and a few drops of concentrated HCl solution were added to the suspension to aid in solubility of the compound. The mixture was filtered through a pad of Celite and the filter cake was washed with MeOH. The Filtrate was concentrated to afford the title compound (700 mg, 83% yield). MS (+ESI) m/z = 475. Step 4: (R) or 5)-iV-{2-[8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-l,5,7- trioxo- 1 ,5,7,8,9 ,10-hexahydroimidazo[5, 1 -a] [2,6]naphthyridin-2(3H)- yl] ethyl } -N-methylmethanesulfonamide
A suspension of secondary amine from Step 3 (488 mg, 1.03 mmol) in dichloromethane (10 mL) was cooled to 0 °C and treated with triethylamine (0.86 mL, 6.17 mmol) followed by methane sulfonyl chloride (0.20 mL, 2.57 mmol). The mixture was stirred and warmed to room temperature over 25 minutes. The mixture was concentrated, diluted with tetrahydroftiran (10 mL) and treated with 4 N aqueous LiOH solution (2.57 mL, 10.3 mmol). The resulting mixture was stirred at room temperature for 1 h. The mixture was poured into a 250 mL separatory funnel and partitioned between 1 M aqueous HCl (50 mL) and EtOAc (200 mL). The organic phase was removed and concentrated under reduced pressure. The reaction mixture was purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 5% MeCN in ¾0 (+0.1% TFA) to 95% MeCN in H20 (+0.1% TFA) over 30 minutes at a flow rate of 85 mL/min. Pure fractions were partitioned between water (50 mL) and EtOAc (200 mL). The organic phase was removed, dried over Na2S04, filtered and concentrated to yield the desired material of 90 % ee (287 mg, 50% yield). This material was further purified by chiral SFC to afford enantiopure Example 26 (189 mg, second eluting enantiomer, >99% ee). Preparative chiral separation of the enantiomers was achieved using a ChiralPak OD-H, 20 χ 250 mm I.D. column, eluting with C02 plus methanol :acetonitrile (65:23.5: 11.5 + 0.1% Et2NH) at flow rate of 50 mL/min. MS (+ESI) m/z = 553. Ή NMR (400 MHz, CDC13) δ 7.34 (dd, J- 6.8, 2.2 Hz, 1H), 7.18 (ddd, J= 8.5, 4.5, 2.2 Hz, 1H), 7.10 (t, J= 8.6 Hz, 1H), 5.14-5.10 (m, 1H), 4.66 (d, J= 4.3 Hz, 2 H)s 4.11-4.01 (m, 1H), 3.62 (dt, J= 14.4, 5.7 Hz, 1 H), 3.48-3.37 (m, 3H), 3.36 (t, J = 5.8 Hz, 1H), 3.28 (ddd, J- 14.9, 8.0, 5.9 Hz, 2H), 2.91 (s, 3H), 2.76 (s, 3H), 1.28 (dd, J= 9.6, 5.0 Hz, 1H), 0.80-0.73 (m, 3H), 0.61-0.55 (m, 1H).
EXAMPLES 27 AND 28
(+) and (-) - N-{2-[8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-l,,5',7,-trioxo-r,5,,7, 58';9,,10'- hexahydro-2'H-spiro[bicycio[3.1.0]hexane-2,3'-imidazo[5, 1 -a) [2,6]naphthyridin]-2'- yljethy 1 } -N-methy 1 methanesulfonamide
Figure imgf000106_0001
Intermediate D
Figure imgf000106_0002
Example 27 Example 28 First eluting diastereomer First eluting diastereomer First eluting enantiomer Second eluting enantiomer Step 1 : (±)-8'-(3-Chloro-4-fluorobenzyl)-6!-hydroxy-9'! 10'-dihydro~2'H- spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5, 1 -a] [2,6]naphthyridine]- l\5\7 87¾4rione A 250 mL flask was charged with dry DMA (65 mL), Intermediate D (6.00 g,
16.3 mmol), racemic bicyclo[3.1.0jhexan-2-one (6.23 g, 65.2 mmol) and concentrated sulfuric acid (1.9 mL). The resulting mixture was heated to 105 °C under an atmosphere of N2 for 6 h. After cooling, the reaction mixture was poured into a 1 L separatory funnel, diluted with EtOAc (500 mL), washed with water (2 χ 200 mL) and brine (200 mL), and the organic layer was separated. The organic layer was dried over MgS04, filtered and concentrated to afford the title compound. MS (+ESI) m/z = 444.
Step 2: (±)-2'-(2~Chloroethyl)-8'-(3-chloro»4-fluorobenzyl)-6,-hydroxy-9',l 0'- dihydro-2'H -spiro[bicyclo [3.1.0]hexane-2, 3 '-imidazo [5,1- a] [2,6]naphthyridine]- 1 ',5',7'(8Ή)-ΐποηε
A 250 mL flask was charged with dry DMF (45 mL) and the compound from Step 1 (4.0 g, 9.0 mmol). Sodium hydride (95 wt%, 1.1 g, 45 mmol) was added to the mixture portion- wise at room temperature, followed by the addition of l-bromo-2- chloroethane (6.5 g, 45 mmol) and the resulting mixture was stirred at room temperature. After 1 h, the reaction was recharged with 1 -bromo-2-chloroethane (6.5 g, 45 mmol) and sodium hydride (95 wt%, 1.1 g, 45 mmol). The same process was repeated 2-times until the alkylation was complete by LCMS analysis. The reaction mixture was poured into a 1 L separatory funnel, diluted with EtOAc (500 mL), washed with aqueous 1 N HC1 (100 mL), a saturated solution of NaHC03 in water (100 mL) and water (8 x 100 mL). The organic layer was separated, dried over MgS04i filtered and concentrated to afford the title compound (4.3 g, 95% yield) as a yellow solid. MS (+ESI) m/z = 506.
Step 3: (+) and (-)-N-{2-[8'-(3-Chloro-4-fiuoroben2yl)-6,-hydroxy-l',5',7'-trioxo- 1^5^7^8^9^10'-hexahydro-2'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,l- ] [2}6]naphthyridin]-2'-yl]ethyl} -N-methylmethanesulfonamide
To a solution of N-methylmethanesulfonamide (1.3 g, 11.9 mmol) in dry THF (5 mL) was added sodium hydride (60 wt%, 415 mg, 10.4 mmol) at room temperature. The resulting suspension was stirred at room temperature for 30 minutes, at which point a solution of the chloroethyl-compound from Step 2 (750 mg, 1.5 mmol) in dry THF (5 mL) was added in a single portion. The resulting mixture was heated to 100 °C for 16 h. After cooling, the reaction mixture was poured into a 500 mL separatory funnel, diluted with EtOAc (200 mL) and washed with 1M aqueous HC1 solution (50 mL) and water (50 mL). The organic layer was separated, dried over MgSC>4, filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire CI 8 5 μτη 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 30% MeCN in ¾0 (+0.1% TFA) to 70% MeCN in H20 (+0.1% TFA) as a gradient over 30 minutes at a flow rate of 35 mL/min.
First eluting diastereomer (240 mg, 28% yield), yellow solid. HRMS (+ESI) m/z = 579.1452 found, 579.1452 required. Ή NMR (500 MHz, acetone) δ 13.69 (s, 1H), 7.62 (dd, J= 7.1, 2.3 Hz, IH), 7.47 (ddd, J= 8.5, 4.6, 2.2 Hz, 1H), 7.33 (t, J= 8.9 Hz, 1H), 4.83 (s, 2H), 3.99-3.92 (m, IH), 3.67 (t, J= 6.4 Hz, 2H), 3.55-3.47 (m, 4H), 3.43-3.38 (m, 2H), 2.99 (s, 3H), 2.88 (s, 3H), 2.86-2.78 (m, 1H), 2.21 (dt, J- 15.4, 9.3 Hz, IH), 1.90-1.80 (m, 2H), 1.50 (q, J= 6.0 Hz, IH), 0.94-0.88 (m, 2H).
Second eluting diastereomer (198 mg, 23% yield), yellow solid. HRMS (+ESI) m/z = 579.1452 found, 579.1452 required. Ή NMR (500 MHz, acetone) δ 13.69 (s, IH), 7.62 (dd, J= 7.1, 23 Hz, 1 H), 7.47 (ddd, J= 8.6, 4.7, 2.2 Hz, IH), 7.33 (t, J = 8.9 Hz, IH), 4.83 (s, 2H), 3.85-3.77 (m, 2H), 3.68 (t, J= 6.4 Hz, 2H), 3.53-3.42 (m, 3H), 3.41-3.32 (m, 2H), 3.00 (s, 3H), 2.89 <s, 3H>, 2.35 (m, IH), 2.04 (m, IH), 1.92 (t, J- 4.6 Hz, IH), 1.85 (s, IH), 1.76 (ra, IH), 1.39 (dt, J= 8.7, 4.5 Hz, IH), 0.90-0.79 (m, IH).
The racemic mixture of the first eluting diastereomer (240 mg) was separated by chiral SFC to afford enantiopure Example 27 (83 mg, first eluting enantiomer, >99% ee) and Example 28 (89 mg, second eluting enantiomer). Preparative chiral separation of the enantiomers was achieved using a ChiralPak OD-H, 20 x 250 mm I.D. column, eluting with C02 plus ethanol (60:40 + 0.1% Et2NH) at a flow rate of 50 mL/min. HRMS (+ESI) m/z - 579.1454 found, 579.1452 required. Ή NMR (399 MHz, CDC13) 6 7.37 (dd, J= 8.7, 2.4 Hz, IH), 7.21 (ddd, J= 9.9, 4.9, 2.3 Hz, IH), 7.14 (t, J= 8.5 Hz, 1 H), 4.69 (s, 2H), 3.98 (t, J= 9.6 Hz, IH), 3.55-3.46 (m, 4H), 3.39 (t, J= 9.3 Hz, 4H), 3.00 (s, 3H), 2.83 (s, 3H), 2.05 (m, 4H), 1.92- 1.84 (m, IH), 0.96 (q, J= 7.4 Hz, IH), 0.76 (q, J- 4.8 Hz, IH). EXAMPLE 29
(IS, 5R)-8'-Q -Chloro-4-fluorobenzyl)-6'-hydroxy-2'-(2-methoxyethyl)-9', 10'-dihydro- 1 Ή- spiro[bicyclo[3.1 ,0]hexane-2,3'-imidazo[5,l -i2][2,6]naphthyridine]-l ,,5',7,(21H,8'H)-trione
Figure imgf000109_0001
(3-chloro-4-fiuorobenzyl)-6,-hydroxy-9',l 0'-dihydro- H-spiro[bicyclo[3.1.0]hexane-2,3'- imidazo[5il-a][2,6]naphthyridine]-l,,5',7*(2,H,8'H)-trione (Example 15) (102 mg, 0.23 mmol) and anhydrous DMF (4 mL). To this solution was added sodium hydride (95 wt%, 29 mg, 1.15 mmol) and the reaction was stirred at room temperature for 45 minutes. 1- Bromo-2-methoxyethane (86 μ]ϋ, 0.92 mmol) was then added and the reaction was stirred at room temperature for 18 h. The reaction was quenched with 1 M aqueous HC1 solution (1.5 mL) and stirred at room temperature for 90 minutes. This solution was purified by preparative reverse phase chromatography through a SunFire C18 10 μΜ 50 x 250 mm column, eluting with 35% MeCN in H20 (+ 0.1% TFA) to 85% MeCN in H20 (+ 0.1% TFA) over 25 minutes to afford the title compound (37 mg, 32 % yield). MS (+ESI) m/z = 502. Ή NMR (499 MHz, i¼-DMSO) 6 13.45 (s, 1H), 7.58 (d, J= 7.1 Hz, 1H), 7.43-7.34 (m, 2H), 4.75-4.67 (m, 2H), 3.81-3.73 (m, 1H), 3.61-3.47 (m, 5H), 3.32-3.26 (m, 5H), 2.68- 2.60 (m, 1H), 2.22-2.11 (m, 1H), 1.97-1.88 (m, 1H), 1.80-1.71 (m, 2H), 1.39 (m, 1H), 0.85- 0.77 (ra, 2H).
EXAMPLE 30
(+) or (-)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(3-methoxy-3- methylbutyl)-2,3,9, 10-tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)-trione
Figure imgf000110_0001
Step 1 : 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N-(3-hydroxy-3-methylbutyl)-355- dioxo-2 ,3,5,6,7,8 -hexahydro-2 ,6-naphthyridine- 1 -carboxamide
4-amino-2-methylbutan-2-ol (0.372 g, 2.42 mmol) was added to a stirring solution of Intermediate A (1.50 g, 2.42 mmol) in THF (16 mL). Triethylamine (1.35 mL, 9.69 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. Next, a 33 wt% EtOH solution of methylamine (1.96 mL, 14.54 mmol) was added, and the reaction ixdxture was stirred for an additional 1 h. The reaction mixture was poured into a 500 mL separatory funnel, diluted with EtOAc (150 mL) and washed sequentially with saturated aqueous NaHC03 solution (150 mL) and brine (150 mL). The combined organics layers were dried over MgS04, filtered, and concentrated under reduced pressure to afford the title compound as a light yellow semi-solid. The overall yield was not determined, and the isolated material was used in the subsequent step without further purification assuming quantitative conversion. MS (+ESI) m/z - 452. Step 2: (±)~8-(3-Chloro-4-fluorobenzyI)-3-cyclopropyl-6-hydroxy-2-(3--methylbut-2- en-l-yl)-2,3,9, 10-tetrahydroiraidazo[5, 1 -a] [256]naphthyridine- 1 S5,7(8H)- trione Concentrated sulfuric acid (0.34 mL, 6.09 mmol) was added drop-wise to a stirring suspension of the amide compound from Step 1 (1.10 g, 2.42 mmol) and
cyclopropane-carboxaldehyde (1.71 g, 24.34 mmol) in 1,4-dioxane (12 mL) in a 25 m.L pressure vessel. The vessel was sealed, and the reaction mixture was heated to 85 °C for 1 h. The reaction mixture was diluted with EtOAc (120 mL) and washed sequentially with saturated aqueous NaHCOs solution (120 mL) and brine (120 mL). The combined organics were dried over MgS04, filtered, and concentrated under reduced pressure to afford the crude title compound as a light yellow semi-solid. The resulting gum was purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 30 x 150 mm column. The compound was loaded with DMSO/methanol, and eluted with 5% MeCN in H20 (+ 0.1 % TF A) to 95% MeCN in ¾0 (+ 0.1 % TFA) to afford the racemic compound as a light yellow gum (398 mg, 34% over 2 Steps). MS (+ESI) m/z = 486.
Step 3: (+) or (-)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(3- methoxy-3 - methylbutyl)-2,3 ,9, 10-tetrahydroimidazo [5 , 1 -a] [2, 6]naphthyridine- 1 ,5,7(8H)- trione
The alkene from Step 2 (0.398 g, 0.82 mmol) was treated with 3M HC1 in MeOH (13.7 mL) in a 25-mL pressure vessel. The vessel was sealed, and the reaction mixture was heated to 75 °C for 16 h. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The resulting brown gum was purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 30 x 150 mm column. The compound was loaded with DMSO, and eluted with 5% MeCN in ¾0 (+ 0.1% TFA) to 95% MeCN in H20 (+ 0.1% TFA) to afford the racemic title compound as a light yellow gum (250 mg, 59% yield). The racemic mixture (250 mg) was separated by chiral SFC to afford the enantiopure title compound (99 mg, first eluting enantiomer, >99% ee). Preparative chiral separation of the enantiomers was achieved using a ChiralCel OD-H, 250 x 30 mm I.D. 5 μιη column, eluting with C02 plus methanol (1 :1 + 0.1% Et2NH) at a flow rate of 80 mL/min., column temperature - 38 °C. MS (+-ESI) m/z - 518. 1H NMR (500 MHz, CDC13) δ 13.68 (s, 1H), 7.61 (d, J= 7.1 Hz, 1H), 7.49-7.45 (m, 1H), 7.33 (t, J- 8.9 Hz, 1H), 5.16 (d, J = 8.8 Hz, 1H), 4.83 (td, J= 14.9, 12.7 Hz, 2H), 3.91 (ddd, J = 13.9, 11.5, 5.13 Hz, 1H), 3.72-3.65 (m, 2H), 3.56-3.41 (m, 2H), 3.33-3.27 (m, 1H), 3.20 (ss 3H)} 1.99 (ddd, J= 13.9, 7.1, 4.4 Hz, 1H), 1.80 (ddd, J= 13.9, 8.1, 5.6, 1H), 1.21 (s, 6H), 1.20-1.15 1.21 (s, 6H)> 1.20-1.15 (m, 1H), 0.92-0.87 (ra, 1H), 0.80-0.71 (rn, 3H).
EXAMPLE 31
(+) or (-)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyi-6-hydroxy-2-[(d5')-2- (methoxymethyi)cyclopropyl]-2,3,9, 10-tetrahydroimidazo[5.1 -a) [2,6]naphthyridine- l,5,7(8H)-trione
Figure imgf000112_0001
Intermediate A
separate enantiomers
Figure imgf000112_0002
first eluting diastereomer
first eluting enantiomer
6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N-[(cz5')-2-
(hydroxymethyl)cyclopropyl]-355-dioxo-2,3,5,6,7s8-hexahydro-2,6- naphthyridine- 1 -carboxamide
A 100 mL flask was charged with dry THF (27 mL) and Intermediate A (2.5 g5 4.0 mmol). [(Cis)-2~aminocyclopropyl]methanol hydrochloride (0.7 g, 5.3 mrnol) and triethylamine (1.1 mL, 8.1 mmol) were then added and the resulting mixture was stirred at room temperature for 30 minutes. Methylamine (33 wt% in EtOH, 2.7 mL, 20.2 mmol) was added and the mixture was stirred at room temperature for 20 mmutes. The reaction mixture was poured into a 500 mL separatory funnel, diluted with EtOAc (200 mL), washed with a with a saturated solution NaHC03 in water (50 mL) and 1 M aqueous HC1 solution (2 x 50 mL). The organic layer containing a suspension was separated and filtered, and the solid was dried under vacuum to afford the title compound (1.6 g, 91% yield) as a white solid. M.S (+ESI) m/z = 436.
Step 2: (±)"8~(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[(cis)-2- (hydroxymethyl)cyclopropyl]-2,3,9310-tetrahydroimidazo[5, 1 - a] [2,6]naphthyridine-l ,5,7(8H)-trione To a mixture of the amide from Step 1 (1.2 g, 2.7 mmol) in 1,4-dioxane (9.1 mL) was added cyclopropanecarboxaldehyde (1.9 g, 27 mmol) and concentrated sulfuric acid (0.3 mL) under nitrogen at room temperature. The resulting mixture was heated to 80 °C for 30 minutes. After cooling, the reaction mixture was poured into a 250 mL separatory funnel, diluted with EtOAc (200 mL) and washed with a saturated solution of NaHC03 in water (50 mL), water (50 mL), and the organic layer was separated. The organic layer was dried over MgS04, filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire CI 8 5μηι 50 x 250 mm column. The compound was loaded with DMSO/methanol and eluted with 30% MeCN in ¾0 (+0.1% TFA) to 75% MeCN in H20 (+0.1% TFA) as a gradient over 30 minutes to afford the title compound. MS (+ESI) mJz - 488.
Step 3: (+)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[(cw)-2- (methoxymethyl)cyclopropyl] -2,3 ,9, 10-tetrahydroimidazo[5 , 1 - a] [2}6]naphthyridine- 1 ,5 ,7(8H)-trione
To a stirring solution of the alcohol from Step 2 (280 mg, 0.6 mmol) in dry DMF (2.9 mL) was added sodium hydride (60 wt%, 69 mg, 1.7 mmol) at room temperature followed by the addition of iodomethane (244 mg, 1.7 mmol) and the resulting mixture was stin-ed at room temperature for 10 minutes. The reaction mixture was poured into a 250 mL separatory funnel and diluted with EtOAc (100 mL), washed with 1 M aqueous HC1 (20 mL), a saturated solution of NaHC03 in water (20 mL) and water (2 x 20 mL). The organic layer was separated, dried over MgS04, filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire CI 8 5 μηι 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 35% MeCN in ¾0 (+0.1% TFA) to 85% MeCN in H20 (+0.1% TFA) as a gradient over 30 minutes to afford both diastereomers of the title compound. First eluting diastereomer (204 mg, 71% yield), yellow solid, HRMS (+ESI) m/z =
502.1543 found, 502.1540 required. 'H NM (500 MHz, <¾-acetone) δ 13.71 (s, 1H), 7.62 (dd, J= 7.1, 2.1 Hz, 1H), 7.49-7.45 (m, 1H), 7.33 (t, J= 8.9 Hz, 1H), 5.14 (d, J= 7.8 Hz, 1H), 4.90-4.75 (m, 2H)f 3.81 (dd, J= 10.5, 4.7 Hz, 1H), 3.68 (t, J= 6.3 Hz, 2H), 3.45 (dts J - 16.4, 5.8 Hz, 1H), 3.30-3.21 (m, 1H), 3.20 (s, 3H), 2.98 (t, J= 9.7 Hz, 1H), 2.86 (td, J=
7.4, 4.7 Hz, 1 H), 1.63-1.57 (m, 1H), 1.16-0.95 (m, 4H), 0.77-0.64 (m, 3H).
Second eluting diastereomer (28 mg, 10% yield), yellow solid. HRMS (+ESI) m/z = 502.1536 found, 502.1540 required. Ή NMR (500 MHz, i¾-acetone) δ 13.71 (s, 1H), 7.61 (dd, J= 7.1, 2.2 Hz, 1H), 7.47 (ddd, J - 8.5, 4.6, 2.2 Hz, 1H), 7.33 (t, J- 8.9 Hz, 1H), 5.10 (d, J= 8.7 Hz, 1H), 4.89-4.77 (m, 2H), 3.70-3.64 (m, 3H), 3.47 (dt, J- 16.4, 5.8 Hz, 1H), 3.27 (s; 3H), 3.27-3.21 (m, 1H), 2.95-2.83 (m, 2H), 1.47-1.39 (m, 1H), 1.31 (ddd, J= 9.2,
7.5, 6.1 Hz, 1H), 1.11-1.06 (m, 1H); 1.04-0.96 (m, 2H), 0.91-0.83 (m, 1H), 0.74-0.65 (m, 2H). Step 4: (+) or (-)-8-(3-Chloro-4-fiuorobenzyl)-3-cyclopropyl-6-hydroxy-2-[(cw)-2-
(methoxymethyl)cyclopropyl]-2s3,9510-tetrahydroimidazo[5,l- a] [2,6]naphthyridine-l ,5,7(8H)-trione
The racemic mixture of the first eluting diastereomer (150 mg) was separated by chiral SFC to afford enantiopure Example 31 (43 mg, first eluting enantiomer, >99% ee) and enantiomer B (42 mg, second eluting enantiomer, >99% ee). Preparative chiral separation of the enantiomers was achieved using a ChiralPak OD-H, 20 x 250 mm I.D. column, eluting with C02 plus methanol (55:45 + 0.1% Et2NH) at a flow rate of 50 mL/min., detection at 254 nm. HRMS (+ESI) m/z = 502.1550 found, 502.1540 required. 1H NMR analysis was identical to racemic material in Step 3.
EXAMPLE 32
(5) or (J?)-8-(3-Chloro-4-fluorobenzy3)-3-cyclopropyl-6-hydroxy-2-[(li?,2ii)-2- methoxycyclohexyl] -2,3,9,10-tetrahydroimidazo [5 , 1 -a] [2,6] naphthyridine- 1 ,5 ,7(8H)-trione
Figure imgf000115_0001
Figure imgf000115_0002
Step 1 : e-tS-CUoro^-fluorobe zy^^-hydroxy-N-tCl^^^^-hydroxycyclohe yl]- 3,5-dioxo-25355f6,7f8-hexahydro~2,6-naphthyridine- -carboxamide
A 50 mL flask was charged with dry THF (5.4 mL) and Intermediate A (500 mg, 0.8 mmol). (lii,2J?)-2-aminocyclohexanol hydrochloride (0.2 g, 1.1 mmol) and triethylamine (0.2 mL, 1.6 mmol) were then added and the resulting mixture was stirred at room temperature for 10 minutes. Methylamine (33 wt% in EtOH, 0.5 mL, 4.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into a 250 mL separatory funnel, diluted with EtOAc (100 mL), washed with a saturated solution NaHC03 in water (20 mL) followed by aqueous 1M HCl solution (2 x 20 mL). The organic layer containing a suspension was separated and filtered, and the solid was dried under vacuum to afford the title compound (303 mg, 81% yield) as a white solid. MS (+ESI) m/z = 464.
Step 2: (5) and (i?)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-
[(lii,2JR)-2-hydroxycyclohexyl]-2,3;,9,l 0-tetrahydroimidazo[5, 1 - a] [2,6]naphthyridine-l 55,7(8H)-trione
A mixture of the amide from Step 1 (200 mg, 0.4 mmol) in 1,4-dioxane (1.4 mL) was added cyclopropanecaxboxaldehyde (300 mg, 4.3 mmol) and concentrated sulfuric acid (0.07 mL) under nitrogen at room temperature, then the mixture was heated to 100 °C for 45 minutes. After cooling, the reaction mixture was poured into a 125 mL separatory funnel, diluted with EtOAc (50 mL) and washed with a saturated solution of NaHC03 in water (10 mL), water (10 mL), and the organic layer was separated. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire CI 8 5 μηι 30 x 150 mm column. The compound was loaded with DMSO/methanol, and eluted with 35% MeCN in ¾0 (+0.1% TFA) to 75% MeCN in ¾0 (+0.1% TFA) as a gradient over 25 minutes to separate the diastereomers of the title compound.
First eluting diastereromer (33 mg, 15% yield): HRMS (+ESI) m/z = 516.1693 found, 516.1696 required. Ή NMR (500 MHz, ^-acetone) δ 13.68 (s, 1H), 7.62 (dd, J= 7.1 , 2.2 Hz, 1H), 7.49-7.45 (m, 1H), 7.33 (t, J= 8.9 Hz, 1H), 5.40 (d, J= 8.2 Hz, 1H), 4.90-4.76 (m, 2H), 4.21-4.14 (m, 1H), 3.79 (td, J= 10.6, 5.5 Hz, 1 H), 3.68 (t, J= 6.4 Hz, 2 H), 3.45 (dt, J = 16.4, 5.6 Hz, 1 H), 3.31-3.22 (m, 1H), 2.12 (d, J= 8.0 Hz, 1H), 1.95 (s, 2H), 1.75 (s, 2H)S 1.37-1.26 (m, 4H), 1.08-1.02 (m, 1H), 0.76-0.63 (m, 3H).
Second eluting diastereomer (37 mg, 17% yield): HRMS (+ESI) m/z - 516.1703 found, 516.1696 required.
Step 3 : (5) or ( f)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[(cw)-2-
(methoxymethyl)cyclopropyl]-2,3,9, 10-tetrahydroimidazo[5, 1 - a] [2,6]naphthyridine- 1 ,5,7(8H)-trione
To a stirring solution of the first eluting diastereomer from Step 2 (10 mg, 0.02 mmol) in dry DMF (0.2 mL) was added sodium hydride (60 wt%, 3.1 mg, 0.08 mmol) at room temperature. This was followed by the addition of iodomethane (11.0 mg, 0.08 mmol) and the resulting mixture was stirred at room temperature for 0 minutes. The reaction mixture was poured into a 50 mL separatory furuiel, diluted with EtOAc (10 mL), washed with aqueous 1 M HCI (1 mL) and a saturated solution of NaHC03 in water (1 mL). The organic layer was separated, dried over MgS04, filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire CI 8 5 μιη 30 x 150 mm column. The compound was loaded with DMSO/methanol and eluted with 35% MeCN in ¾0 (+0.1 % TFA) to 90% MeCN in ¾0 (+0.1 % TFA) as a gradient over 15 minutes to afford the title compound, Example 32. HRMS (+ESI) m/z = 530.1853 found, 530.1853 required. Ή NMR (500 MHz, <¾-acetone) δ 13.70 (s, 1H), 7.62 (dd, J= 7.1, 2.1 Hz, 1H), 7.50-7.46 (m, 1H), 7.33 (t, J= 8.9 Hz, 1H), 5.25 (d, J= 8.1 Hz, 1H), 4.83 (d, J - 7.0 Hz, 2H), 3.95 (s, 1H), 3.82-3.75 (m, 1H), 3.69 (t, J= 6.4 Hz, 2H), 3.45 (dt, J- 16.4, 5.7 Hz, 1H), 3.30 (s, 4H), 2.35 (d, J= 12.5 Hz, 1H), 1.97-1.92 (m, 2H), 1.80-1.76 (m, 2H), 1.37-1.25 (m, 3H), 1.15 (q, J= 1 1.7 Hz, 1H), 1.07-1.00 (m, 1H), 0.74-0.62 (m, 3H). EXAMPLE 33
(15i5i?)-2,-CycIopropyl-8'-(4-fluorober^l)-6,-hydroxy-9'i10'-dihydro-2,H-
Figure imgf000117_0001
Step 1 : (l1?,5i?)-8,~(3-Chloro-4-fluorobenzyl)-2'-cyclopropyl-6,-hydroxy-9'310'- dihydro-2'H- spiro [bicyclo [3.1.0]hexane-2 , 3 '-imidazo [5,1- ] [2,6]naphthyridine]~ 1 ';5',7'(8'H)-trione To a suspension of Example 15 (0.18 g, 0.40 mmol), cyclopropylboronic acid
(0.07 g, 0.80 mmol), and sodium carbonate (0.08 g, 0.80 mmol) in 1 ,2-dichloroethane (4.0 mL) was added a suspension of copper (II) acetate (0.07 g, 0.40 mmol) and 2,2'-bipyridine (0.06 g, 0.40 mmol) in hot 1 ,2-dichloroethane (2 mL). The mixture was heated at 70 °C for
2 h, open to air. The reaction was incomplete and another equivalent of reagents (Cu, ligand and cyclopropyl boronic acid) were added. After 2 h the solution was cooled to room temperature and an aqueous saturated N¾C1 solution was added (5 mL). The mixture was poured into a separatory funnel and the aqueous layer was extracted with CH2C12 (3 10 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The reaction mixture was purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 30 x 150 mm column. The compound was loaded onto the column with DMSO, and eluted with 25% MeCN in ¾0 (+ 0.1% TFA) to 95% MeCN in ¾0 (+ 0.1% TFA) over 12 minutes at a flow rate of 25 rruL/rriin. The title compound was isolated after concentration (0.03 g, 1 % yield). MS (+ESI) m/z = 484. 1H NMR (400 MHz, CDC13) δ 13.58 (s5 1H), 7.41-7.37 (m, 1H), 7.30-7.12 (m, 2H), 4.98-4.93 (m, 1H), 4.77 (d, J = 15 Hz, 1H), 4.64 (d, J= 15 Hz, 1H), 3.55-3.43 (m; 3H), 3.31-3.20 (m, 1H), 2.77-2.70 (m, 1H), 1.28-1.14 (m, 2H), 1.08-1.00 (m, 1H), 0.97-0.85 (m, 1H), 0.86- 0.69 (ms 4H)} 0.65-0.57 (m, 1H). Step 2: (lίS, s5 ^)-2,-cyclopropyl-8,-(4-Iluorobenzyl)-6,-hydro y-9,, 10'-dihydro-2'H- spiro[bicyclo[3.1.0]hexane-2}3'-imidazo[5, 1 -a] [2,6]naphthyridine]- ^5\7\8*H)-trione
To a solution of compound from Step 1 (25 mg, 0.052 mmol) in methanol (10 mL) under nitrogen was added 20 wt% Pd(OH)2 on carbon (19 mg, 0.027 mmol) and the suspension was hydrogenated on a Parr apparatus at 50 psi for 12 h. The resulting mixture was filtered through a pad of Celite and washed with methanol. The filtrate was
concentrated under reduced pressure and purified by preparative reverse phase
chromatography through a SunFire C18 10 μΜ 30 x 150 mm column. The compound was loaded onto the column with DMSO/methanol, and eluted with 25% MeCN in H20 (+ 0.1% TFA) to 95% MeCN in H20 (+ 0.1% TFA) over 12 minutes at a flow rate of 25 mL/min. The title compound was isolated after concentration (7 mg, 30% yield). MS (+ESI) mJz = 450. lE NMR (400 MHz, CDCI3) δ 13.58 (s, 1H), 7.41-7.37 (m, 1H), 7.30-7.12 (m, 2H), 4.98-4.93 (m, 1H), 4.77 (d, J- 15 Hz, 1H), 4.64 (d, J= 15 Hz, 1H), 3.55-3.43 (m, 3H), 3.31-3.20 (m, 1H), 2.77-2.70 (m, 1H), 1.28-1.14 (m, 2H), 1.08-1.00 (m, 1H), 0.97-0.85 (m, 1H), 0.86-0.69 (m, 4H), 0.65-0.57 (m, 1H). EXAMPLE 34
(+)-or (-)-(! S, 5i?)-8'-(4-Fluorobenzyl)-6'f 10'-dihydroxy-2'-(2-methoxyethyl)-9' , 10'-dihydro- 1 'H-spiro[bicyclo[3.1.03hexane-2,3'-imidazo[5, 1 -a] [2,6]naphthyridine]- 1 , 55')7'(2'H,8'H)- trione
Figure imgf000119_0001
second eluting diastereomer
single enantiomer
Step 1 : (IS, 57?)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2*-(2-methoxyethyl)-9', 10'- dihydro- 1 'H-spiro [bicyclo [3.1.0] hexane-2, 3 '-imidazo [5,1- a] [2,6]naphthyridine]- 1 '!5';7,(2'H8'H)-trione
The title compound was prepared as in Example 29 replacing (i5,5J?)-8'-(3- cMoro-4-fiuorobenzyl)-6'-hydroxy-9^10'-dihydro-rH-spiro[bicyclo[3.1.0]hexane-2f3'- imidazo[5Jl-a][256]naphmyridme] ',5\7 2,H '-^)-trione - Example 15 with Example 16. MS (+ESI) m/z - 502.
Step 2: (IS, Ji?)-8'-(4-Fluorobenzyl)-6'-hydroxy-2,-(2-methoxyethyl 9, 510*-dihydro~
1 Tf-spiro [bicyclo [3.1.0]hexane-2,3'-imidazo[5f l-a] [2f6]naphthyridkie]- r,5'J7,(2'Hi8,H)-trione To a solution of compound from Step 1 (80 mg, 0.16 mmol) in methanol (20 mL) sparged with nitrogen gas, was added palladium hydroxide catalyst (15-20 wt% on carbon, 20 mg). The reaction was fitted with a balloon filled with hydrogen and stirred at room temperature. After 3 h, the reaction was filtered through a 0.45 micron filter and concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 30 x 150 mm column. The compound was loaded with DMSO, and eluted with 30% MeCN in H20 (+ 0.1% TFA) to 80% MeCN in H20 (+ 0.1% TFA) over 14 minutes to afford the title compound. MS (+ESI) m/z = 468. Step 3: (+)-or (-)-(iS,,5i?)-8'-(4-Fluorobenz>d)-6',10,-dihydi xy-2,-(2-methoxyethyl)-
9 10!-dihydro- 1 'H-spiro[bicyclo [3.1.0]hexane-2,3 '-imidazo[5 , 1 - a][2,6]naphthyridine]-r,5',7,(2'H,8,H)-trione
In an oven dried flask under an atmosphere of nitrogen was added the compound from Step 2 (30 mg, 0.064 mmol) and anhydrous DMSO (3 mL). To this was added sodium hydride (95 wt%, 3 mg, 0.12 mmol) and the reaction was stirred at room temperature for 10 minutes. Oxygen was then bubbled into the reaction via a pipette, followed by addition of solid potassium tert-butoxide (29 mg, 0.26 mmol). As the reaction stirred at room temperature, oxygen was continually bubbled into the suspension. After 45 minutes, more potassium ferf-butoxide (50 mg, 0.41 mmol) was added to drive the reaction to completion. The reaction was quenched with 1M aqueous HC1 solution (3 mL), diluted with water (5 mL), and extracted with ethyl acetate (3 30 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 30 x 150 mm column. The compound was loaded with DMSO, and eluted with 35% MeCN in H20 (+ 0.1% TFA) to 70% MeCN in ¾0 (+ 0.1% TFA) over 20 minutes to afford the separated diastereomers. The later eluting diastereomer is the title compound (5 mg, 16% yield). MS (+ESI) m/z - 484. 1H NMR (400 MHz, i%-DMSO) δ 13.6 (s, 1H), 7.42 (dd, J= 8.4, 5.5 Hz, 2 H), 7.18 (t, J- 8.8 Hz, 2H), 5.67 (s, 1H), 5.43 (bs, 1H), 4.76- 4.65 (m, 2H), 3.76-3.50 (m, 6H), 3.29 (s, 3H), 3.17-3.08 (m, 1H), 2.25-2.14 (m, 1H), 1.96- 1.89 (m, 1H), 1.81-1.75 (m, 2H), 1.74-1.67 (m, 1H), 1.29-1.22 (m, 1H), 0.87-0.81 (m, 1H).
EXAMPLES 35 AND 36
(R) or (5)-(li??55')-8,-(3-Chloro-4-fluorobenzyl)-6,-hydroxy-l-methyl-9',10,-dihydro-2'H- spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5, l-a] [2,6]naphthyridine]- 1 ',5'?7'(8'H)-trione
Figure imgf000121_0001
Figure imgf000121_0002
first eluting diastereomer
Step 1 : (2S53S 6-Methyl-2,3-diphenyl-l ,4-dioxaspiro[4.4]non-6~ene
A solution of 2-methyl-2-cyclopenten-l-one (11.49 mL, 117 mmol) in toluene (600 mL) was added (5i5 -(-)-hydrobenzoin (25 g, 117 mmol) and pyridinium p- toluenesulfonate (2.94 g, 11.70 mmol). The mixture was refluxed under nitrogen for 4 days azeotropically removing water with a Dean-Stark trap. The solution was cooled to room temperature, diluted with diethyl ether and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over Na2S04s filtered and concentrated under reduced pressure. The resulting ketal was purified by column chromatography through silica gel (330 g), eluting with 10% EtOAc in hexanes (16.2 g, 47% yield). Step 2: (1R,4 5S,5'S)-1 -Methyl-4'55'-diphenylspiro[bicyclo[3.1.0]hexane-2,2'-
[l,3]dioxolane]
A solution of (25',55)-6-methyl-2,3-diphenyl-l,4-dioxaspiro[4.4]non-6-ene (16.23 g, 55.5 mmol) in CH2CI2 (56 mL) was cooled to 0 °C and then diethylzinc (117 mL, 117 mmol) was added drop-wise. To the resulting mixture was added diiodomethane (9.40 mL, 117 mmol) drop- wise over 30 minutes. The ice bath was removed and the slurry stirred for 16 h at room temperature. The reaction was carefully quenched with 1 M aqueous HCl solution (100 mL), poured into a separatory funnel and diluted with EtOAc (500 mL). The organic layer was separated, washed with brine, dried over Na2SC> s and concentrated under reduced pressure. The product was purified by column chromatography through silica gel (330 g), eluting with 20% EtOAc in hexanes, The enriched diastereomeric mixture (15 g) was further purified by chiral SFC to afford the enantiopure title compound (10.1 g, first eluting diastereomer, >99% ee). Preparative chiral separation of the diastereomers was achieved using a ChiralPak AD-H, 250 χ 30 mm I.D.20 μιη column. The compound was eluted with C02 plus methanol (85:15 + 0.1% Et2NH) at a flow rate of 80 mL/minute and column temperature of 38 °C.
Step 3: (R) or (5)-(li?,5S)-8,-(3-chloro-4-fluorobenzyl)-6'-hydroxy- l-methyl-9', 10*- dihydro-2'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5, 1 - fl][2,63naphthyridine]-l,,5,,7,(8,/i)-trione
A solution of Intermediate D (4.0 g, 11 mmol) in DMA (28 mL) was added (li?,4 55^5,5)-l-methyl-4, s5'-diphenylspiro[bicyclo[3.1.0]hexane-2i2'-[ls3]dioxolane] (10.0 g, 33 mmol) and concentrated sulfuric acid (0.58 mL). The mixture was heated to 100 °C for 18 h. After cooling, a solution of saturated NaHC03 in water (150 mL) was added, and the resulting mixture was poured into a separatory funnel and extracted with CH2C12 (3 x 200 mL). The combined organic layers were washed with water and brine, dried over Na2S0 , filtered and concentrated under reduced pressure. The diastereomers were resolved by preparative reverse phase chromatography using a SunFire C18 50 x 250 mm, eluting with 30% MeCN in H20 (+0.1% TFA) to 75% MeCN in ¾0 (+0.1% TFA) at a flow rate of 85 mL/min. The desired compound ws obtained as a solid (0.22 g, 4% yield, first eluting diastereomer). MS (+ESI) m/z = 458. 1H NMR (400 MHz, CDC13) δ 13.58 (s, 1H), 7.42- 7.37 (m, 1H), 7.24-7.20 (m, 1H), 7.18-7.10 (m, 1H), 6.53 (s, 1H), 4.75-4.63 (m, 2H), 3.53- 3.46 (m, 2H), 3.41-3.35 (m, 2H), 2.94-2.86 (m, 1H), 2.39-2.32 (m, 1H), 1.95-1.87 (m, 1H), 1.84-1.74 (m, 2H), 0.94 (s, 3H), 0.60-0.54 (m, 1H), 0.45-0.40 (m, 1H).
EXAMPLE 36
(i?) or (¾-(1^5J?)-8'-(3-chloro-4-fluorobenzyl)-6,-hydroxy-l-methyl-9^10'-dihy&o-2'H- spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5, -a] [2,i 6]naphthyridine]-l',5'J7,(8,H)-trione
Figure imgf000122_0001
Intermediate D second eluting diastereomer Step 1 : (R) or (5)-(15;5i?)-8,-(3-Chloro-4-rluorobenz>'l)-6'-hydroxy-l-methyl-9, i10'- dihydro-2'H- spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,l - a] [2J6]naphthyridine]-r,5, J7'(8,H)-trione A solution of Intermediate D (4.0 g, 11 mmol) in DMA (31 mL) was added
(lS,4S,5.R,5^-l-methyM\5^ (11 g, 33 mmol) (prepared in an identical manner to Example 35 beginning with (#, )-(+)- hydrobenzoin) and concentrated sulfuric acid (0.66 mL). The mixture was heated to 100 °C for 18 h. After cooling to room temperature, a solution of NaHC03 in water was added, the mixture was. poured into a separatory runnel and extracted with C¾C12 (3 x 200 mL). The combined organic layers were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The diastereomers were resolved by preparative reverse phase chromatography using a SunFire CI 8 50 x 250 mm, eluting with 30% MeCN in H20 (+0.1% TFA) to 75% MeCN in ¾0 (+0.1% TFA) at a flow rate of 85 ml/min. The desired compound ws obtained as a solid (0.21 g, 4% yield, second eluting diastereomer). MS (+ESI) mfz = 458. 1H NMR (400 MHz, CDC13) δ 13.58 (s, 1H), 7.40-7.36 (m, IK), 7.24-7.20 (m, 1H), 7.18-7.1 1 (m, 1H), 6.40 (s, 1H), 4.73-4.68 (m5 2H), 3.53-3.46 (m, 2H), 3.41-3.35 (m, 2H), 3.16-3.05 (m, 1H), 1.98-1.90 (m, 3H), 1.53-1.47 (m, 1H), 1.37-1.32(m, 1H), 1.03 (s, 3H), 0.84-0.79 (m9 1H).
EXAMPLE 37
(±)-Methyl 2- {2-[8 -(3 -chloro-4-fluorobenzyl)-3 -cyclopropyl-6-hydroxy- 1 ,5 ,7-trioxo- 1 ,5,7,8,9, 10-hexahydroimidazo[5,l - ][236]naphthyridin-2(3H)-yl]ethyl}pyridine-3- carboxylate trifluoroacetate
Figure imgf000123_0001
Step 1 : Methyl 2-[2-({[6-(3-chloro-4-iluorobenzyl)-4-hydroxy-3J5-dioxo-2J3,556J7i8- hexahydro-2,6-naphthyridin-l -yl]carbonyl} amino)ethyl]pyridine-3- carboxylate A 50 mL flask was charged with dry THF (5.4 mL) and Intermediate A (500 mg, 0.8 mmol). Methyl 2-(2-aminoethyI)pyridine-3-carboxylate ethanedioate (280 mg, 1.1 mmol) and triethylamine (0.2 mL, 1.6 mmol) were then added and the resulting mixture was stirred at room temperature for 10 minutes. Methylamine (33% in EtOH; 0.5 mL, 4.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into a 125 mL separatory funnel and diluted with EtOAc (100 mL), washed with a saturated solution NaHC03 in water (20 mL) and aqueous 1 M HC1 solution (2 x 20 mL). The organic layer containing a suspension was separated and filtered, and the solid was dried under vacuum to afford the title compound (366 mg, 86% yield) as a white solid. MS (+ESI) m/z = 529.
Step 2: (±)-Methyl 2-{2-[8-(3-chloro-4-fiuorobenzyl)"3-cyclopropyl-6-hydroxy-
1 ,5,7-trioxo- 1 ,5,7,8,9, 10-hexahydroimidazo[5, \-a] [2,6]naphthyridin-2(3H)- yl]ethyl}pyridine-3-carboxylate trifluoroacetate A mixture of the amide from Step 1 (300 mg, 0.6 mmol) in 1,4-dioxane (1.9 mL) was added cyclopropanecarboxaldehyde (400 mg, 5.7 mmol) and concentrated sulfuric acid (0.06 mL) under nitrogen at room temperature. The mixture was heated to 100 °C for 45 minutes. After cooling, the reaction mixture was poured into a 125 mL separatory funnel, diluted with EtOAc (50 mL) and washed with a solution of NaHC03 in water (10 mL), water (10 mL), and the organic layer was separated. The organic layer was dried over MgS04, filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire Prep CI 8 5 μηι 30 χ 150 mm column. The compound was loaded with DMSO or methanol and eluted with 20% MeCN in H20 (+0.1% TFA) to 70% MeCN in ¾0 (+0.1 % TFA) as a gradient over over 25 minutes to afford the title compound (103 mg, 26% yield). H MS (+ESI) m/z = 581.1600 found, 581.1598 required. Ή NMR (500 MHz, <f6-acetone) δ 13.72 (s, 1H), 8.77 (d, J- 5.0 Hz, 1H), 8.43 (d, J= 7.9 Hz, 1H), 7.63-7.55 (m, 2H), 7.47-7.44 (m, 1H), 7.32 (t, J= 8.8 Hz, 1H), 5.30 (d, J= 8.7 Hz, 1H), 4.89-4.74 (m, 2H), 4.35 (dt, J= 14.2, 7.2 Hz, 1H), 3.94 (s, 3H), 3.76-3.69 (m, 1H), 3.66 (t, J- 6.4 Hz, 3H), 3.57-3.50 (m, 1H), 3.38 (dt, J= 16.4, 5.7 Hz, 1H), 3.25-3.15 (m, 1H), 1.15-1.09 (m, 1H), 1.04-0.96 (m, 1H), 0.78-0.68 (m, 3H). EXAMPLE 38
(±)-8-(3-Chloro-4-fluoroberizyl)-3-c^
Figure imgf000125_0001
Step 1 : (±)-8-(3-Chloro-4-fluorobenzyI)-3-cyclopropyl-6-hydroxy-2}3,9,10- tetrahydroimidazo[5, 1 -a][2,6]naphthyridine- 1 ,5,7(8H)-trione
This compound was prepared from Intermediate D and
cyclopropylcarboxaldehyde using the procedure described in Example 4, Step 1.
(±)- 8 -(3 -Chloro-4-fluorobenzyl)-3 -cyclopropyl-6-hydroxy-2-(pyridin- 3 -yl )- 2,3,9, 10-tetrahydroimidazo[5, 1 -a][2,6]naphthyridine-l ,5,7(8H)-trione
A 2 mL microwave vial was charged with compound from Step 1 (40 mg, 0.1 mmol), 3-iodopyridine (39 mg, 0.2 mmol), anhydrous potassium carbonate (53 mg, 0.4 mmol), and copper(I) iodide (18 mg, 0.1 mmol) in NMP (0.7 mL). The mixture was degassed, purged with nitrogen, and the resulting mixture was heated in a microwave reactor at 180 °C for 20 minutes. The reaction mixture was poured into a 50 mL separatory funnel, diluted with EtOAc (20 mL) and washed with water (5 mL), and the organic layer was separated. The organic layer was dried over MgS04, filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire Prep CI 8 5 μπι 30 x 150 mm column. The compound was loaded with DMSO or methanol and eluted with 20% MeCN in H30 (+0.1% TFA) to 75% MeCN in H20 (+0.1% TFA) as a gradient over 20 minutes to afford title compound (1 mg, 35% yield). HRMS (+ESI) m/z =
495.1242 found, 495.1230 required. Ή NMR (499 MHz, c¼-DMSO) δ 8.86 (s, 1H), 8.51- 8.48 (m, 1H), 8.07 (d, J= 8.2 Hz, 1H), 7.66-7.18 (m, 4H), 6.25-6.19 (m, 1H), 4.80-4.67 (m, IH), 4.62-4.47 (ro, IH), 1.23 (s, 2H), 0.76-0.69 (m, IH), 0.56-0.54 (m, IH), 0.40 (s, IH), 0.23 (s, 2H), 0.10 (s, 2H).
EXAMPLE 39
(+) and (-)-8'-(3-Chloro-4-fluorober^^
hexahydro-2'H-spiro [cyclopentane- 1 ,3 '-imidazo [5 , 1 -a] [2,6]naphthyridine] -2-carboxarnide
Figure imgf000126_0001
Step 1 : (±)-Methyl 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-r,5',7'-trioxo-
1 ',5',7',8',9', 10'-hexahydro-2'H-spiro [cyclopentane- 1 ,3'-imidazo[5,l - a] [2,6]naphthyridine] -2-carboxylate
A solution of Intermediate D (2.2 g, 6.0 mmol) in 1 ,4-dioxane (30 mL) was treated with methyl cycIopentanone-2-carboxylate (2.2 mL, 18 mmol) and concentrated sulfuric acid (0.06 mL, 1.2 mmol). The mixture was heated to 100 °C for 18 h. After cooling, an aqueous solution of NaHC03 in water was added, and the resulting mixture was poured into a separatory funnel and extracted with CH2C12 (3 x 200 mL). The combined organic layers were washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The ester was purified by preparative reverse phase chromatography through a SunFire Prep Ο18 5 μηι 30 χ 250 mm column. The compound was loaded with DMSO or methanol and eluted with 30% MeCN in H20 (+0.1% TFA) to 75% MeCN in H20 (+0.1% TFA) at a flow rate of 85 mL/min. over 35 minutes to afford the desired product (290 mg, 10% yield). MS (+ESI) m/z - 490.
(±)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-l,,5'J7'-trioxo-rs5'J, }8, f9'i10!- hexahydro-2'H- spiro [cyclopentane- 1 , 3 '-imidazo[ 5 , 1 -a] [2,6] naphthyridine] -: carboxylic acid
The ester from Step 1 (0.13 g, 0.25 mmol) in a mixture of THF (1.5 mL)/MeOH (0.5 mL)/water (0.5 mL) was treated with 2 M aqueous sodium hydroxide solution (0.25 mL, 0.5 mmol). The solution was stirred at room temperature for 2 h and then neutralized with an aqueous solution of 2 N HC1 (0.25 mL, 0.5 mmol). The resulting carboxylic acid was concentrated under reduced pressure, dissolved in CH2CI2/MeOH
(90/10) and filtered. The acid was concentrated again and used directly without purification. MS (+ESI) m/z = 476.
Step 3 : (±)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-N-methyl- 1 ',5',7'-trioxo- l',5',7, !8'J9'f10'-hexahydro-2'H-spiro[cyclopentane-l,3*-imidazo[5,l- a] [2,6]naphthyridine]-2-carboxamide
To a solution of the acid from Step 2 (35 mg, 0.074 mmol) in CH2C12 (7 mL) was added BOP (36 mg, 0.081 mmol) followed by methylamine hydrochloride (6 mg, 0.088 mmol) and NfN-diisopropylethylarnine (0.064 mL, 0.368 mmol). The solution was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by preparative reverse phase chromatography through a SunFire Prep CI 8 5 μηι 30 x 150 mm column. The compound was loaded with DMSO or methanol and eluted with 25% MeCN in H20 (+0.1% TFA) to 95% MeCN in H20 (+0.1% TFA) at a flow rate of 25 mL/min over 12 minutes to afford the desired product as a mixture of diastereomers (10 mg, 28% yield). MS (+ESI) m/z - 489. EXAMPLE 40
(±)-2-[8' 3-Chloro-4-fluorobenzyl)-6!-hydroxy-1^5^7,-trioxo-l 5^7^8 9 10'-hexahydro-2'H- spiro[cyclopentane-l ,3'-imidazo[5, 1 -a] [2,6]naphthyridin]-2-yl]-7Y-methylacetamide
Figure imgf000128_0001
Step 1 : (±)-Ethyi [8,-(3-chloro-4-fluorobenzyl)-6,-hydroxy-r,5',7'-trioxo- ^' '^'^' O'-hexahydro- 'H-spirotcyclopentane-l^'-irnidazofS,!- a] [2,6]naphthyridmj-2~yl]acetate
A solution of Intermediate D (1.1 g, 3.0 mmol) in DMA (7.5 mL) was treated with ethyl (2-oxocyclopentyl)acetate (2.0 g, 12 mmol) and concentrated sulfuric acid (0.16 mL, 3.0 mmol). The mixture was heated to 100 °C for 18 h. After cooling, an aqueous solution of NaHC03 was added, the mixture poured into a separatory funnel, and the resulting mixture extracted with C¾C12 (3 x 200 mL). The combined organic layers were washed with water and brine, dried over a2S04, filtered and concentrated under reduced pressure. The diastereomers were resolved by preparative reverse phase chromatography through a SunFire Prep CI 8 5 μιη 30 x 250 mm column. The compound was loaded with DMSO or methanol and eluted with 30% MeCN in H20 (+0.1% TFA) to 75% MeCN in ¾0 (+0.1% TFA) at a flow rate of 85 raL/min over 35 minutes. The diastereomerically enriched fractions were concentrated to afford the first eluting diastereomer (100 mg) and the second eluting diastereomer (60 mg). MS (+ESI) m/z = 518 (both diastereomers). Step 2: (±)-[8'-(3-chloro-4-fluoroben2yl)-6,-hydroxy-r,5,,7'-trioxo-r,5',7'?8, J9,,10'- hexahydro-2'H-spiro [cy clopentane- 1 , 3 '-i midazo [ 5 , 1 -a] [2,6] naphthyridin] -2- yl] acetic acid
A solution of first eluting diastereomeric ethyl ester from Step 1 (50 mg, 0.096 mmol) in a mixture of THF (0.15 mL)/MeOH (0.5 mL)/water (0.5 mL) was treated with 2 M aqueous sodium hydroxide solution (0.10 mL, 0.19 mmol). The solution was stirred at room temperature for 2 h and then neutralized with aqueous 2 M HC1 solution (0.10 mL, 0.19 mmol). The crude acid was concentrated under reduced pressure, dissolved in CH2Cl2/MeOH (90/10) and filtered. The acid was concentrated again and used directly without further purification. MS (+ESI) m/z = 490.
Step 3: (±)-2-[8,-(3-Chloro-4-fluoroberzyl)-6,-hydroxy-l,,5'f7,-trioxo-Γ,5',7',8'59, ϊ10,- hexahydro-2!H-spiro [cyclopentane- 1 , 3 '-imidazo [5 , 1 -a] [2,6] naphthyridin] -2- yl] -N-methylacetamide
To a solution of carboxylic acid from Step 2 (20 mg, 0.041 mmol) in CH2CI2 (0.4 mL) was added BOP (20 mg, 0.045 mmol) followed by methylamine (0.022 mL, 0.045 mmol) and N,N'-diisopropylethylamine (0.037 ml, 0.20 mmol). The solution was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by preparative reverse phase chromatography through a SunFire Prep C 8 5 μπι 30 χ 150 mm column. The compound was loaded with DMSO or methanol and eluted with 25% MeCN in ¾0 (+0.1% TFA) to 95% MeCN in H20 (+0.1% TFA) at a flow rate of 25 mL/min over 12 minutes. The title compound was obtained as an oil (9 mg, 44% yield). MS (+ESI) m/z = 503.
EXAMPLE 41
(+)-2-(8'-(3~Chloro-4-fluorober^l)-6'-hyta
spiro [cyclohexane- 1,3' -imidazo [5 , 1 -a] [2,6] naphthyridin] -2-yl)-N-isopropylacetamlde
Figure imgf000130_0001
Intermediate D
Figure imgf000130_0002
Ste l : (±)-E 1 2-(8'-(3-chloro-4-fluorobenzyl)-6,-hydroxy-r,5',7,-trioxo- 2'55',7,,8'59'510'-hexahydro-l'H-spirofcyclohexane-l ?3'-imidazo[5, 1 - a] [2,6]naphthyridin}-2-yl)acetate
Intermediate D (1.0 g, 2.73 mmol) was suspended in acetonitrile (20 mL) and treated with ethyl 2-cyclohexanoneacetate (2.02 g, 10.94 mmol) followed by ferric (III) chloride (0.443 g, 2.73 mmol). The mixture was heated to 90 °C for 48 h under stirring. The reaction mixture was diluted with 1M aqueous HCl (8 mL) and the mixture was stirred at room temperature for 90 min. The mixture was diluted with dichloromethane (30 mL) and washed with aqueous 1M HCl solution (2 x 20 mL), dried over Na2S04, filtered and evaporated to give a light brown solid. This was tritterated with hexanes and filtered to give the title compound (1.33 g, 91% yield). MS (+ESI) m/z = 532.
Step 2: (+)-2-(8'-(3-Chloro-4-fluoroben2yl)-6'"hydroxy-l',5',7,-trioxo-2,,5,,7',8,,9'J10'- hexahydro- 1 'H-spiro[cyclohexane- 1 ,3'-imidazo[5,l -a] [2,6]naphthyridin]-2- yl)acetic acid The ester from Step 1 (1.03 g, 1.94 mmol) was suspended in ethanol (9.7 ml) and treated with 1 M aqueous NaOH solution (7.76 mL, 7.76 mmol) and stirred at room temperature for 18 h. The reaction contents were evaporated under vacuum to give a residue which was suspended in 1M aqueous HC1 (10 mL) and filtered to give the title compound as a yellow solid (0.861 g, 88% yield). MS (+ESI) m/z - 504.
Step 3: (±)-2-(8,-(3-Cmoro-4-fiuorobenzyl)-6'-hydroxy-r,5's7,-trioxo-2'f5',7'J8's9,,10'- hexahydro-1 'H-spiro[cyclohexane-l ,3'-imidazo[5, l-a] [2,6]naphthyridin]~2- yl)acetic acid
The acid from Step 2 (0.30 g, 0.595 mmol) was suspended in dichloromethane (3 ml) and treated with oxalyl chloride (0.146 mL, 1.67 mmol) followed by DMF (14 uL). The reaction mixture was stirred at room temperature for 30 min. The reaction contents were evaporated in vacuo to afford the the title compound (0.311 g).
Step 4: (±)-2-(8,-(3-Chloro-4-fluoroben2yl)-6'-hydroxy-l, ?5'57, rioxo-2, 55, J7',8',9'J10'- hexahydro- 1 Ή- spiro [cycl ohexane- 1 ,3'-imidazo [5 , 1 -a) [2 , 6]naphthyridin] -2- yI)-N-isopropylacetamide The acid chloride from Step 3 (50 mg, 0.096 mmol) was dissolved in dichloromethane (480 μΐ) and treated with isopropylamine (49.2 μΐ, 0.574 mmol) followed by A^N-diisopropylethylamine (50.2 μΐ, 0.287 mmol) and stirred at room temperature for 18 h. The reaction contents were diluted with CH2C12 (1 mL), washed with with aqueous 1 M HC1 solution (1 mL), dried by filtering through a hydrophobic frit and evaporating to afford a residue. This residue was purified by preparative reverse phase chromatography through a SunFire CI 8 10 μΜ 30 χ 150 mm column. The compound was loaded with DMSO or methanol, and eluted with 10% MeCN in H20 (+ 0.1% TFA) to 95% MeCN in H20 (+ 0.1% TFA) to afford the racemic title compound as a light yellow solid (16 mg, 31 % yield). MS (+ESI) m/z - 545. 1H NMR (400 MHz, £¾-DMSO) δ 13.50 (s, 1H), 9.93 (s, 1H), 7.60 (m, 2H), 7.41 (m, 2H), 4.77 (d, J = 15 Hz, 1H), 4.66 (d, J- 15 Hz, 1H), 3.70 (m, 2H), 3.55 (m, 2H), 3.35 (m, 1H), 3.27 (m, 2H), 3.00 (m, 2H), 1.66 (m, 4H), 1.48 (d, J= 13 Hz, 1H), 1.27 (m, 2H), 0.97 (d, J- 6.5 Hz, 3H), 0.91 (d, J= 6.5 Hz, 3H).
EXAMPLE 42
(+) or (-)-8'-(3-Chloro-4-fluorobenzyl)-6<-hydroxy-2,2-dimethyl-9', 10!-dihydro- 1 Ή- spiro[cyclopentane-l,3'-imidazo[5,l-a][2,6]naphthyridine]-1^5 7 2 ,8'H) rione
Figure imgf000132_0001
Intermediate D second eluting enantiomer
To a sealable reaction vial, was added Intermediate D (2.0 g5 5.47 mmol), anhydrous acetonitrile (40 mL), 2,2-dimethylcyclopentanone (3.43 mL, 27.3 mmol) and iron(III) choride (890 mg, 5.47 mmol). The vial was sealed and heated at 90 °C for 18 h. The reaction was diluted with ethyl acetate (10 mL) and treated with 0.1 M aqueous disodium EDTA solution (8.5 mmol) and concentrated HC1 (2 mL). The mixture was stirred at room temperature for 2 h and the grey precipitate was filtered through a pad of Celite. The filtrate was washed sucessively with acidified aqueous disodium EDTA, water, and brine. The combined organic layers were dried over Na2S0 , filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase
chromatography through a SunFire CI 8 10 μΜ 50 x 250 mm column. The compound was loaded with DMSO or methanol, and eluted with 25% MeCN in H20 (+ 0.1% TFA) to 80% MeCN in H20 (+ 0.1% TFA) over 30 minutes to afford the racemic title compound. The racemic mixture was separated by preparative chiral SFC to afford enantiopure title compound (second eluting enantiomer). Preparative chiral separation of the enantiomers was achieved using a Chiralcel OD, 250 x 20 mm I.D column, eluting with 75 % C02 : 25% methanolracetonitrile (2:1 + 0.1% Et2NH) at a flow rate of 50 mL/min. The purified material was partitioned between 1 M aqueous HC1 and ethyl acetate and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na2S04, filtered, and
concentrated under reduced pressure to afford the title compound. MS (+ESI) m/z = 460. 1H NMR (400 MHz, <¾-DMSO) δ 13.47 (s, 1H), 9.56 (s, 1H), 7.60 (d, J= 7.2 Hz, 1H), 7.43- 7.37 (m, 2H), 4.74 (d, J- 15.1 Hzs 1H), 4.68 (d, J= 15.1 Hz, 1H), 3.55 (t, J= 6.4 Hz, 2H), 3.34-3.20 (m, 2H), 2.99-2.90 (m, 1H), 2.41-2.31 (m, 1H), 2.05-1.90 (m, 2H), 1.89-1.77 (m, 1H), 1.64-1.56 (m, 1H), 0.98 (s, 3 H), 0.75 (s, 3H).
EXAMPLES 43 TO 177
The compounds of Examples 43 to 177 were prepared in accordance with the procedures described above for the compounds of Examples 1 to 42. Table B below provides the structure, name, preparative method, and [M+l]+ value for each of the compounds of the present invention, numbered 1-177. Diastereomers were purified using reverse phase HPLC through a CI 8 column, and the final compounds are described according to their relative retention times on the C18 column (e.g. , first eluting or second eluting diastereomer). In all cases enantiomers were purified using normal phase SFC chromatography through an AD, AS or OD-based column, and the final compounds are described according to their relative retention times (e.g. first eluting or second eluting enantiomer). In cases where starting materials required for the synthesis of these examples are not commercially available, the synthesis of the ketone or amine building blocks is described above herein.
Table B
Figure imgf000133_0001
chiral - (S)
Example 4
Figure imgf000133_0002
racemic
Figure imgf000134_0001
Example 12 424
Figure imgf000135_0001
O OH
chiral - (S)
Example 13 424
Example 14 462
Figure imgf000135_0002
chiral - fourth eluting enantiomer by SFC
Example 15 444
Figure imgf000135_0003
chiral - first eluting diastereomer
Example 1 444
Figure imgf000135_0004
chiral - second eiuting diastereomer
Example 17 444
Figure imgf000135_0005
chiral - first eluting diastereomer Example 18 444
Figure imgf000136_0001
chiral - second eluting diastereomer
Example 19 502
Example 20 569
Figure imgf000136_0002
chiral - second eluting enantiomer
Example 21 567
Example 22 428
Figure imgf000136_0003
chiral ~ first eluting diastereomer Example 23 428
Figure imgf000137_0001
- second eluting diastereomer
Example 24 428
Example 25 428
Figure imgf000137_0002
- second eluting diastereomer
Example 26 553
Figure imgf000137_0003
- second eluting enantiomer
Example 27 579
Figure imgf000137_0004
chiral
first eluting diastereomer
first eluting enantiomer Example 28 579
Figure imgf000138_0001
O OH
chiral
first eluting diastereomer
second eluting enantiomer
Example 29 502
Figure imgf000138_0002
first eluting diastereomer
Example 30 518
Figure imgf000138_0003
chiral - first eluting enantiomer
Example 31 502
Figure imgf000138_0004
chiral
first eluting diastereomer
first eluting enantiomer Example 32 530
Example 33 450
Figure imgf000139_0001
chiral - first eluting diastereomer
Example 34 484
Figure imgf000139_0002
chiral
second eluting diastereomer
Example 35 458
Figure imgf000139_0003
chiral - first eluting diastereomer
Example 36 458
Figure imgf000139_0004
chiral - second eluting diastereomer Example 37 581
Example 38 495
Figure imgf000140_0001
racemic
Example 39 489
Example 40 503
Figure imgf000140_0002
racemic
second eluting diastereomer
Example 41 545
Figure imgf000140_0003
racemic - mixture Example 42 460
Figure imgf000141_0001
chirat - second eluting enantiomer
434
420
478
448
432
Figure imgf000141_0002
Example 1, Step 1,
wherein the bis-hydroxy acid resulting from the
hydrolysis of
Intermediate A was used 450 as starting material for the coupling reaction,
Figure imgf000142_0001
then Example 2, Step 2
racemic with sulfuric acid/ 1,4- dioxane 1 &2, teps 2 448
1 & 2, teps 2 448
Figure imgf000142_0002
chiral - second eluting enantiomer
Example 2 420
Figure imgf000142_0003
Example 4, Step 1 434
Example 4, Step 1 476
Figure imgf000142_0004
racemic
Figure imgf000143_0001
ı42
Figure imgf000144_0001
Figure imgf000145_0001
racemic
Example 1 , Steps 1 & 2, then Example 3, Step 2
Example 1, Steps 1 & 2, 460 then Example 3, Step 2
Example 1, Steps 1 & 2, 474 then Example 3, Step 2
Figure imgf000145_0002
73
74
75
76
Figure imgf000146_0001
77 Example 1 488
Figure imgf000146_0002
O OH
e
Example 1, Steps 1 & 2, 490
78 then Example 3, Step 2
Figure imgf000146_0003
racemic 79
80
81
Figure imgf000147_0001
racemic
82
83
84
Figure imgf000147_0002
Figure imgf000148_0001
Example 3 545
Example 3 488
Example 3 516
Example 3 516
Figure imgf000149_0001
chiral, first eluting diastereomer
Example 3 553
Figure imgf000149_0002
racemic
Figure imgf000150_0001
chiral - second eluting enantiomer
Figure imgf000150_0002
Figure imgf000150_0003
chiral - second eluting enantiomer
Figure imgf000151_0001
Figure imgf000152_0001
151
Figure imgf000153_0001
Example 4 484
Figure imgf000154_0001
0 OH
chiral - second eluting enantiomer
Example 4 490
Figure imgf000154_0002
racemic, mixture of diastereomers
Example 4 488
Figure imgf000154_0003
racemic,- mixture of diastereomers
Example 4 518
Figure imgf000154_0004
chiral, first eluting diastereomer
first eluting enantiomer
Example 4 518
Figure imgf000154_0005
chiral, second eluting diastereomer
first eluting enantiomer 119 Example 4 518
Figure imgf000155_0001
chiral, second eluting diastereomer
second eluting enantiomer
120 Example 4 532
Figure imgf000155_0002
racemic, first eluting diastereomer
121 Example 4 532
122 Example 4 502
Figure imgf000155_0003
racemic, mixture of diastereomers
123 Example 4 531
Figure imgf000155_0004
racemic, single diastereomer Example 4 486
Figure imgf000156_0001
chiral, first eluting diastereomer
Example 4 518
Figure imgf000156_0002
racemio, mixture
Example 4 530
Figure imgf000156_0003
racemic - first eluting diastereomer
Example 4 458
Figure imgf000156_0004
racemic - first eluting diastereomer
Example 4 490
Figure imgf000156_0005
racemic, first eluting diastereomer Example 4 481
Example 4 571
Figure imgf000157_0001
racemic, first eluting diastereomer
Example 4 571
Example 4 557
Figure imgf000157_0002
racemic, first eluting diastereomer
Figure imgf000158_0001
racemic first eluting diastereomer
135 Example 4
Figure imgf000158_0002
racemic, second eluting diastereomer
Figure imgf000158_0003
c iral - second eluting enantiomer Example 4 (second
eluting product from
137 chiral SFC used for 412
Figure imgf000159_0001
subsequent reduction)
followed by Example 12 chiral - derived from second eluting product
Example 4 (third eluting product from chiral SFC
138 used for subsequent 412
Figure imgf000159_0002
reduction) followed by
Example 12
chiral - derived from third eluting product
Example 4 (fourth eluting product from
139 chiral SFC used for 412 subsequent reduction)
Figure imgf000159_0003
followed by Example 12 chiral - derived from fourth eluting product
Figure imgf000159_0004
racemic, mixture
Figure imgf000159_0005
chiral - second eluting enantiomer Example 42 then
143 Example 4, Step 2 484 followed by Example 12
Figure imgf000160_0001
- first eluting enantiomer
Example 42 then
144 Example 4, Step 2 484 followed by Example 12
Figure imgf000160_0002
chiral - second eluting enantiomer
Figure imgf000160_0003
racemic
Figure imgf000160_0004
chiral - first eluting diasfereomer
Figure imgf000161_0001
Figure imgf000161_0002
Figure imgf000161_0003
chiral - first elutin diastereomer
Figure imgf000161_0004
chiral - second elutin diastereomer
Figure imgf000161_0005
- second eluting diastereomer Example 14 (using the
154 third eluting enantiomer) 428 followed by Example 12
155 Example 20 475
Figure imgf000162_0001
racemic
89
156 Example 20 4
Figure imgf000162_0002
racemic
157 Example 20 525
Figure imgf000162_0003
racemic © TFA
158 Example 20 551
0 OH
159 Example 20 551
Figure imgf000163_0001
racemic
160 Example 21 545
Figure imgf000163_0002
racemic
33
161 Example 21 5
Figure imgf000163_0003
racemic Example 21 517
Figure imgf000164_0001
racemic
Example 21 560
Figure imgf000164_0002
racemic
Example 22 428
Figure imgf000164_0003
chiral - first elutin diastereomer
Example 23 428
Figure imgf000164_0004
- second eluting diastereomer
Example 27 569
Figure imgf000164_0005
- first eluting diastereomer 167 Example 27 569
Figure imgf000165_0001
- second eluting diastereomer
168 Example 27 584
Figure imgf000165_0002
- first eluting diastereomer
169 Example 27 584
Figure imgf000165_0003
racemic - second eluting diastereomer
owed
170 ep 2 to 595
Figure imgf000165_0004
racemic d
171 to 585
Figure imgf000166_0001
racemic
172 o 607
Figure imgf000166_0002
racemic
Figure imgf000166_0003
chiral - first eluting diastereomer
Figure imgf000166_0004
c/?/ra/ - first eluting diastereromer
Figure imgf000167_0001
racemic, mixture of diastereomers
EXAMPLE 178
Assay for inhibition of HIV replication
Assays for the inhibition of acute HIV-1 infection of T-Iymphoid cells (i.e., MT4 cells) were conducted in accordance with Vacca, LP. et aL, Proc. Natl. Acad. Set USA 1 94, 91 : 4096. MT-4 cells (250,000 cells/mL) were bulk-infected with HIV (Η9ΙΠΒ strain) at low multiplicity of infection (MOI) in + 10% FBS for 24 hours. Cells were then washed twice in serum free Roswell Park Memorial Institute medium (RPMI) and resuspended in RPMI + 10 or 50% normal human serum (NHS). Test compounds were serial-diluted in DMSO and then diluted in 10 or 50% NHS. MT-4 cells and compounds were added to a 384-well TC-treated polystyrene plate (12,000 cells and 0.25% DMSO final) using an automated liquid handler (Agilent Bravo). After 72 hours of incubation, the cell/virus suspension was mixed and samples were lysed. Viral growth was determined by HIV-1 p24- gag AlphaLISA assay (384-well Bravo automated format, Z-0.5-0.9). Percent viral growth inhibition was calculated by [ 1 -(Signal-Min)/(Max-Min)] * 100, where Min is complete inhibition by an HIV anti- viral compound and Max is viral growth in DMSO. Compound IC95 or IC50 was determined by a 4-pararmeter dose response curve analysis. Representative compounds of the present invention exhibit inhibition of HIV replication in this assay (also referred to herein as the "spread assay"). For example, the compounds of Examples 1 to 9 and 11 to 177were tested in this assay in 50% NHS and found to have the IC95 values in Table C. The compound of Example 10 was tested in 10% NHS and its IC50 value is provided in Table C.
Table C Cell Assay
Example No. (wild type)
IC95 (nM)
1 1530
2 9768
3 1070
4 227
5 1487
6 5624
7 613
8 1312
9 4463
10 c50 = 80 (10
11 226
12 83
13 57
14 90
15 124
16 239
17 233
18 241
19 270
20 80
21 162
93
23 163
24 42
25 199
26 100
27 85
28 21
29 100
30 141 31 42
32 67
33 89
34 44
35 126
36 83
37 261
38 1807
39 181
40 148
41 217
42 207
43 3818
44 990
45 783
46 4701
47 3477
48 4516
49 1599
50 7793
51 6834
3946
52
966
53
1051
54
431
55
1234
56
8339
57
1406
58
8599
59
294
60
313
61
432
62 1252
63
9995
64
7852
65
3411
66
3175
67
1016
68
2982
69
1853
70
7726
71
506
72
1537
73
2044
74
1623
75
550
76
601
77
507
78
1295
79
175
80
467
81
340
82
738
83
1448
84
6958
85
786
86
153
87
229
88
183
89
165
90
61
91
45
92
76
93
140
94 78
95
38
96
106
97
103
98
236
99
195
100
182
101
204
102
219
103
233
104
244
105
247
106
57
107
1 16
108
212
109
243
110
214
111
141
112
249
113
186
114
137
115
236
116
216
117
127
118
90
119
197
120
208
121
122 81
123 243
124 169
125 102
126 155 127 212
128 34
129 20
130 26
131 54
132 85
133 100
134 54
135 67
136 190
137 206
138 151
139 109
140 228
141 209
142 48
143 71
144 74
145 143
146 183
147 41
148 56
149 31
150 56
151 92
152 164
153 172
154 198
155 170
156 141
157 117
158 213 159 168
160 201
161 246
162 220
163 177
164 137
165 214
166 32
167 74
168 45
169 57
170 58
171 49
172 69
173 42
174 70
175 23
176 63
177 178
EXAMPLE 179
Cytotoxicity
Cytotoxicity was determined by microscopic examination of the cells in each well in the spread assay, wherein a trained analyst observed each culture for any of the following morphological changes as compared to the control cultures: pH imbalance, cell abnormality, cytostatic, cytopathic, or crystallization (i.e., the compound is not soluble or forms crystals in the well). The toxicity value assigned to a given compound is the lowest concentration of the compound at which one of the above changes is observed.
Representative compounds of the present invention that were tested in the spread assay (see Table C of Example 178) were examined for cytotoxicity up to a concentration of 10 micromolar, and no cytotoxicity was exhibited.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I:
Figure imgf000175_0001
or a^ pharmaceutically acceptable salt thereof, wherein: Rl and R.1 B are each independently:
0) H,
(2) Ci-6 alkyl,
(3) OH,
(4) O-Cl-6 alkyl,
(5) Ci-6 haloalkyL
(6) O-Ci-6 haloalkyl,
(7) halogen,
(8) CN,
(9) N(RA)RB,
(10) C(0)N(RA)RB?
(1 1) C(0)RA
(12) C(0)0RA
(13) SRA,
Figure imgf000175_0002
(16) N(RA)S02RB,
(17) N(RA)S02N(RA)RB5
(1.8) N(RA)C(0)RB, or
(19) N(RA)C(0)C(0)N(RA)RB;
or alternatively R* A and RlB are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy;
RlC is:
(1) H,
(2) Ci-6 alkyl, (3) O-C 1-6 alkyl,
(4) C 1 -6 haloalkyl,
(5) O-C 1-6 haloalkyl, or
(6) halogen;
R2A and R2B are each independently:
(1) H,
(2) Ci-8 alkyl,
(3) Ci-8 haloalkyl, or
(4) C i .8 alkyl substituted with OH, C(0)N(RA)RB5 C(0)RA CO2 A, or
C(0)-N(RA)-C2-8 alkylene-ORB; or
alternatively R2A and R2B together form oxo;
R3A and R3B are each independently:
(1) H,
(2) fluoro,
(3) Ci_8 alkyl, optionally substituted with OH, O-Ci-8 alkyl, O-Ci-g haloalkyl, CN, N(RA)RB; C(0)N(RA)RB, C(0)RA, CO2 A, C(0)-N(RA)-C2-8 alkylene -ORB, BRA, S(0)RA, SO2RA, S02N(RA)RB, N(RA)C(0)RB, N(RA)C02 BS N(RA)S02RB, N(RA)S02N(RA)RB,
N(RA)C(0)N(RA)RB; or 0C(0)N(RA)RB;
(4) Ci - haloalkyl, or
(5) OH, O-C 1 -8 alkyl, O-C 1„8 haloalkyl, CN, N(RA)RB, C(0)N(RA)RB T
C(0)RA, CO2 A, C(0)-N(RA)-C2-8 alkylene -ORB, SRA S(0)RA, SO2RA, S02N(RA)RB, N(RA)C(0)RB, N(RA)C02RB, N(RA)S02RB, N(RA)S02N(RA)RB5 N(RA)C(0)N(RA)RB, or OC(0)N(RA)RB;
alternatively R3A and R3B together form oxo;
R4, R5 and R0 are defined as set forth in Part A, Part B or Part C below:
(A) R4 is:
(1) H,
(2) Ci-8 alkyl,
(3) C 1-8 haloalkyl,
(4) C 1 -g alkyl substituted with OH, O-C 1-8 alkyl, O-C 1 -8 haloalkyl, CN, N(RA)RB, C(0)N(RA)RB, C(0)RA C(0)-HetP, CO2 A
C(0)-N(RA)-C2-8 alkylene-ORB, SRA, S(0)RAS SO2RA,
S02N(RA)RB5 N(RA)C(0)RB, N(RA)C02RB, N(RA)S02 BS N(RA)S02N(RA)RB; N(RA)C(0)N(RA)RB5 or OC(0)N(RA)RBS
(5) CycA,
(6) C 1 _8 alkyl substituted with CycA, (7) Ci-8 alkyl substituted with AryA,
(8) Ci_8 alkyl substituted with HetA,
(9) C i _8 alkyl substituted with HetP;
(10) Ci_ hydroxyalkyl substituted with C i -8 haloalkyl or CycA; or
(1 1) Het A 5 and R6 are each independently:
(1) H,
(2) Ci _8 alkyl,
(3) Ci-8 haloalkyl, or
(4) C i -8 alkyl substituted with OH, O-C l -8 alkyl, O-C l -8 haloalkyl, CN, N(RA)RB? C(0)N(RA)RB} C(0)RA5 C02RA f C(0)-N(RA)-C2-8 alkylene-ORB, SRA, S(0)RA, S02 A, S02N(RA)RB,
N(RA)C(0)RB, N(RA)C02 B, N(RA)S02RB,
N(RA)S02N(RA)RB, N(RA)C(0)N(RA)RBs or OC(0)N(RA)RB;
(5) CycB,
(6) AryB,
(7) HetB, -
(8) C i -8 alkyl substituted with CycB,
(9) C i -8 alkyl substituted with AryB,
(10) C 1 -8 alkyl substituted with HetB, or
(11) C -8 alkyl substituted with HetQ;
R4 and R5 together with the atoms to which they are attached form a 4- to 8- membered fused azacycloalkyl ring which is optionally substituted with from 1 to 4 substituents each of which is independently:
(1) Ci-8 alkyl,
(2) C] -8 haloalkyl, or
(3) Ci-8 alkyl substituted with OH, OC-i -8 alkyl, O-Ci _8 haloalkyl, CN, N(RA)RB, C(0)N(RA)RB; C(0)RA5 C02 A, C(0 N(RA)-C2-8 alkylene-ORB, SRA S(0)RA S02 A, S02 (RA)RB?
N(RA)C(0)RB, N(RA)C02RB, N(RA)S02RB,
N(RA)S02N(RA)RBS N(RA)C(0)N(RA)RB, or OC(0)N(RA)RB,
(4) CycB,
(5) AryB,
(6) HetB,
(7) C i _8 alkyl substituted with CycB, (8) C l -8 alkyl substituted with AryB,
(9) Ci-8 alkyl substituted with HetB, or
(10) C 1-8 alkyl substituted with HetQ;
R6 is:
(1) ¾
(2) Ci-g alkyl,
(3) Ci_8 haloalkyl, or
(4) C i .8 alkyl substituted with OH, O-C l - 8 alkyl, O-C l -8 haloalkyl, CN, N(RA)RB, C(0)N(RA)RB, C(0)RA, C02RA, C(0)-N(RA)-C2-8 alkylene-ORB, SRA S(0)RA, S02 A, S02N(RA)RB,
N(RA)C(0)RB, N(RA)C02RB, N(RA)S02RB,
N(RA)S02N(RA)RBS N(RA)C(0)N(RA)RBs or OC(0)N(RA)RBs
(5) CycB,
(6) AryB,
(7) HetB,
(8) C i _8 alkyl substituted with CycB,
(9) C i _8 alkyl substituted with AryB,
(10) Ci-8 alkyl substituted with HetB, or
(11) C l -8 alkyl substituted with HetQ;
(C) R is:
(1) H,
(2) Ci-8 alkyl,
(3) Ci-8 haloalkyl, or
(4) C i -8 alkyl substituted with OH, O-C\ _8 alkyl, O-C l - 8 haloalkyl, CN, N(RA)RB; C(0)N(RA)RB? C(0)RA CO2 A, -C(0)HetA, - C(0)N(RA)HetP, -C(0)N(RA)HetP, C(0)-N(RA)-C2-8 alkylene-ORB, SRA S(0)RA, SO2RA, S02N(RA)RB, N(RA)C(0)RB, N(RA)C02RB, N(RA)S02RB,
N(RA)S02N(RA)RBS N(RA)C(0)N(RA)RB} or OC(0)N(RA)RB,
(5) CycA,
(6) Ci-8 alkyl substituted with CycA,
(7) Ci-8 alkyl substituted with AryA,
(8) Cl- alkyl substituted with HetA, or
(9) C 1 -8 alkyl substituted with HetP ; R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 4- to 8 -membered cycloalkyl, which can be optionally fused to a benzene ring or a 5 or 6-membered heteroaryl ring, (ii) a 6- to 10-membered fused or bridged bicycloalkyl, or (iii) a 5- to 8~ membered heterocyclylalkyl in which the ring heteroatom is selected from N, O and S where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted on a ring carbon with oxo and is optionally substituted with from 1 to 4 substituents each of which is independently:
(1) Ci-8 alkyl,
(2) Ci-8 haloalkyl, or
(3) Ci -8 alkyl substituted with OH, O-C i _8 alkyl, O-C l -8 haloalkyl, CN, N RAjRB, C(0)N(RA)RB5 C(0)RAS C02 A, C(0)-N(RA)-C2-8 alkylene-ORB, SRA, S(0)RA, S02RA } S02N( A) B}
N(RA)C(0)RB, N(RA)C02RB, N(RA)S02RB,
N(RA)S02N(RA)RB, N(RA)C(0)N(RA)RB} or 0C(0)N(RA)RB,
(4) CycB,
(5) AryB,
(6) HetB,
(7) Ci_8 alkyl substituted with CycB,
(8) C i _8 alkyl substituted with AryB,
(9) Ci-8 alkyl substituted with HetB, or
(10) C 1 _8 alkyl substituted with HetQ ;
AxyA is an aryl which is optionally substituted with from 1 to 5 substituents, wherein:
(A) each of the substituents is independently:
(1) Ci-6 alkyl,
(2) C i -6 alkyl substituted with OH, O-C i -6 alkyl, O-C I -6 haloalkyl, CN, N02, N(RA)RB, C(0)N(RA)RB, C(0)RA CO2R SRA S(0)RA, SO2RA, S02N(RA)RB5 N(RA)C(0)RB, N(RA)C02RB,
N(RA)S02Rb, N(RA)S02N(RA)RB5 OC(0)N(RA)RBF
N(RA)C(0)N(RA)RBs or N(RA)C(0)C(0)N(RA)RB,
(3) 0-Ci_6 alkyl,
(4) C 1-6 hak kyl,
(5) O-C] _6 haloalkyl,
(6) OH,
(7) halogen, (8) CN,
(9) N02,
(10) N(RA)RB,
(Π) C(0)N(RA)RBJ
(12) C(0)RA
(13) C(0)-CI-6 haloalk l,
(14) C(0)ORA
(15) OC(0)N(RA)RB,
(16) SRA,
(17) S(0)RA,
Figure imgf000180_0001
(19) S02N(RA)RB,
(20) N(RA)S02RB,
Figure imgf000180_0002
(22) N(RA)C(0)RB,
(23) N(RA)C(0)N(RA)RB5
(24) N(RA)C(0)C(0)N(RA)RBj or
(25) N(RA)C02RB; or
(B) when there are two or more substituents on the aryl, two of the substituents are respectively located on adjacent carbons on the aryl ring and together form methyl enedioxy or ethylenedioxy, and other substituents, if any, are each independently one of groups (1) to (25) as set forth in (A) above; each AryB independently has the same definition as AryA;
CycA is a 3- to 8-membered monocyclic or bicyclic cycloalkyl which is optionally
substituted with from 1 to 4 substituents each of which is independently halogen, OH, Ci-6 alkyl, O-Ci-6 alkyl, C] _6 alkyl substituted with -OH, O-Ci-6 alkyl, Ci .g haloalkyl, or O-Ci-6 haloalkyl;
each CycB independently has the same definition as CycA;
HetA is a heteroaryl which is optionally substituted with from 1 to 5 substituents, each of which is independently:
(1) Ci-6 alkyl,
(2) C i -6 alkyl substituted with OH, O-C i - 6 alkyl, O-C i _ haloalkyl, CN, NO2, N(RA)RB5 C(0)N(RA)RBF C(0)RA C02 , SRA S(0)RA, S02 A, S02N(RA)RB; N(RA)C(0)RB, N(RA)C02RB > N(RA)S02RB >
N(RA)S02N(RA)RB5 OC(0)N(RA)RB? N(RA)C(0)N(RA)RB5 or
N(RA)C(0)C(0)N(RA)RB5
(3) 0-Ci_6 alkyl, (4) Ci~<5 haloalkyl,
(5) O-Ci-6 haloalkyl,
(6) OH,
(7) halogen,
(8) CN,
(9) N02;
(10) N(RA) B;
(1 1) C(0)N(RA)RB;
(12) C(0)RA,
(13) C(0)-Ci„6 haloalkyl,
(14) C(0)ORA,
(15) OC(0)N(RA)RB5
(16) SRA,
(17) S(0)RA
(18) SO2RA,
(19) S02N(RA)RBf
(20) N(RA)S02RB,
Figure imgf000181_0001
(22) N(RA)C(0)RB,
(23) N(RA)C(0)N(RA)RBJ
(24) N(RA)C(0)C(0)N(RA)RBj or
(25) N(RA)C02RB;
each HetB i ndependently has the same defmiti
HetP is (i) a 4- to 7-membered,, saturated or mono-unsatuxated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(0) or S(0)2 or (ii) a 6- to 10- membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms mdependently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2; and wherein the saturated or mono- unsaturated heterocyclic or heterobicyclic ring is optionally substituted with a total of from 1 to 4 substituents, each of which is mdependently halogen, 0\. alkyl, Ci-6 haloalkyl, O-Ci-6 alkyl, O-Ci-6 haloalkyl, oxo, C(0)N(RA)RB,
C(0)C(0)N(RA)RB, C(0)RA C'02RA SRA, S(0)RA S02RA, or S02N(RA)RB; each HetQ independently has the same definition as HetP;
each RA is independently H, Ci_6 alkyl or C 1-6 haloalkyl;
each RB is independently H, Ci-6 alkyl or Ci_6 haloalkyl; each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyciic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyciic ring system in which at least one ring is aromatic; and each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(0)2-
2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
AryA is phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently:
(1 ) C 1-6 alkyl,
(2) O-C 1.6 alkyl,
(3) Cl- haloalky],
(4) O-C 1- haloalkyl,
(5) 0¾
(6) halogen,
(7) CN,
(8) N(RA)RB,
(9) C(0)N(RA)RB5
(10) S(0)RA
(11) S02
Figure imgf000182_0001
(14) N(RA)C(0)RB, or
(15) N(RA)C(0)C(0)N(RA)RB; and each AryB independently has the same definition as AryA;
CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, Ci- alkyl, O-Ci-6 alkyl, or C 1-6 alkyl substituted with 0-Ci_6 alkyl; each CycB independently has the same definition as CycA;
HetA is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from N, S and O, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently Ci-4 alkyl, OH, O-Ci-4 alkyl, halogen, CN, C(O)N(JRA)RB, C(0)RA C(O)ORA, 0r SO2RA; each HetB independently has the same definition as HetA;
HetP is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently Ci-4 alkyl, oxo, C(0)N(RA)RB5 C(0)RA CO2 A, or SO2RA; and each HetQ independently has the same definition as HetP.
3. A compound according to claim I , or a pharmaceutically acceptable salt thereof, which is a compound of Formula II:
Figure imgf000183_0001
RlA and lB are each independently:
(1 ) H,
(2) C 1 -6 alkyl,
(3) OH,
(4) O-C 1 -6 alkyl,
(5) Ci- haloalkyl,
(6) O-C 1 - haloalkyl,
(7) halogen,
(8) CN,
(9) N(RA)RB,
(10) C(0)N(RA)RB5 (11) C(0)RA
(12) C(0)0RA
(13) SRA
(14) S(0)RA
(15) S02RA; or or alternatively l a d RlB are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy;
RlC is:
(1) H,
(2) C 1-6 alkyl,
(3) O-C 1-6 alkyl,
(4) Ci -6 haloalkyl,
(5) O-C 1-6 haloalkyl, or
(6) halogen;
R2A and R3A are each independently H, fiuoro, or Ci-6 alkyl;
R4, R5 and R0 are defined as set forth in Part A, Part B or Part C below:
(A) R4 is:
(1) H,
(2) Ci -8 alkyl,
(3) C 1 - haloalkyl,
(4) Ci -6 alkyl substituted with O-Ci-6 alkyl, C(0)N(RA)RBj C(0)RA, CO2 A, SRA S(0)RA, SO2 A or S02N(RA)RB,
(5) CycA, or
(6) C l -6 alkyl substituted with CycA, one of R5 and R6 is H or CI_6 alkyl, and the other of 5 and R6 is:
(1) H,
(2) Ci-8 alkyl,
(3) Ci -6 haloalkyl,
(4) Ci -6 alkyl substituted with O-C 1 -6 alkyl, C(0)N(RA)RB, C(0)RA CO2 A S(0)RA SO2RA or S02N(RA)RB,
(5) CycB, or
(6) Ci -6 alkyl substituted with CycB; or
(B) R4 and R5 together with the atoms to which they are attached form a 5- to 7- membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) Ci-6 alkyl,
(2) Ci-6 haloalkyl, or
(3) Ci-6 alkyl substituted with OH, O-Ci-6 alkyl, O-Ci-6 haloalkyl, CN5 N(RA)RB5 C(0)N(RA)RBS C(0)RA5 CO2RA SRA, S(0)RA5 or
Figure imgf000185_0001
(4) CycB, or
(5) Ci-6 alkyl substituted with CycB;
R6 is:
(1) H,
(2) Ci-8 alkyl,
(3) C 1 _6 haloalkyl, or
(4) Ci-6 alkyl substituted with OH, O-Ci-6 alkyl, O-Ci-6 haloalkyl, CN, N(RA)RBF C(0)N(RA)RB5 C(0)RAS CO2 A, SRA S(0)RA,
Figure imgf000185_0002
or
(C) R4 is as defined in Part A:
R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered. fused or bridged bicyclo alkyl, or (iii) a 5- to 7-membered heterocyclylalkyl in which the ring atom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted on a ring carbon with oxo and is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) Cl-6 alkyl,
(2) C 1 -6 haloalkyl , or
(3) C 1 _6 alkyl substituted with OH, O-C 1 ~6 alkyl, O-C l -6 haloalkyl, CN, N(RA)RB, C(0)N(RA)RBs C(0)RA CO2RA, SRA S(0)RA
Figure imgf000185_0003
(4) CycB, or
(5) C 1 -6 alkyl substituted with CycB ; CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, Ci-6 alkyl, O-Ci-6 alkyl, or Ci_6 alkyl substituted with O-Ci-6 alkyl; and each CycB independently has the same defimtion as CycA;
4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein:
Rl A a d RlB are each independently:
(1) ri,
(2) C 1-4 alkyl,
(3) OH,
(4) O-Ci-4 alkyl,
(5) CF3,
(6) OCF3,
(7) CI,
(8) Br,
(9) F,
(10) CN,
(1 1) N¾,
(12) N(H)-Cj-4 alkyl,
(13) N(Cj-4 alkyl)2,
(14) C(0)NH2,
(15) C(0)N(H)-Ci-3 alkyl,
(16) ■ C(0)N(Ci-3 alkyl)2,
(17) CH(O),
(18) C(0)-Ci-4 alkyl,
(19) C02H,
(20) CO2-C 1-4 alkyl,
(21) SO2H, or
(22) SO2-C1-4 alkyl;
RlC js
(1) H,
(2) Ci-4 alkyl,
(3) O-Ci-4 alkyl,
(4) CF3) (5) OCF3,
(6) CI,
(7) Br, or
(8) F;
R2A and R3A ^ both H;
R4} R5 and R6 are defined as set forth in Part A, Part B or Part C below:
(A) R4 is:
(1) H,
(2) Ci-4 alkyl,
(3) Ci-4 fluoroalkyl,
(4) C 1 -4 alkyl substituted with O-C 1 -4 alkyl, C(0)NH2, C(0)NH(C 1 -4 alkyl), C(0)N(Ci-4 alkyl)2, CO2H, C(0)0-CM alkyl, S-CM alkyl, or S02-Cl-4 alkyl,
(5) CycA, or
(6) C¾-CycA; one of R5 and 6 is H or C\-4 alkyl, and the other of R5 and R6 is:
(1) H,
(2) Ci-8 alkyl,
(3 ) C i -4 fluoroalkyl,
(4) C 1 -6 alkyl substituted with O-C 1 -6 alkyl,
(5) CycB, or
(6) CH2-CycB;
or
(B) R4 and R5 together with the atoms to which they are attached form a 5- or 6-membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) C alkyl,
(2) C 1-4 fluoroalkyl, or
(3 ) C \ -4 alkyl substituted with O-C 1.4 alkyl;
R6 is
(1) H, or
(2) C alkyl; (C) R4 is as defined in Part A;
R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl which is optionally substituted on a ring carbon with oxo, or (iii) a 5- or 6-membered heterocyclylalkyl in which the ring atom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) Ci-4 alkyL
(2) Ci-4 fluoroalkyl, or
(3) C i _4 alkyl substituted with O-C i -.4 alkyl;
CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently Q_4 alkyl, 0-Ci-4 alkyl, or C 1-4 alkyl substituted with O-C 1-4 alkyl; and
CycB independently has the same definition as CycA.
5. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein:
RI A and RlB are each independently:
(1) H,
(2) CH3>
(3) CH2CH3
(4) OH,
(5) OCH3,
(6) CF3,
(7) OCF3s
(8) CI,
(9) Br,
(10) F,
(1 1) CN,
(12) NH2>
(13) N(H)CH3:
(14) N(CH3)2, (15) C(0)NH2,
(16) C(0)N(H)CH3,
(17) C(0)N(CH3)2,
(18) CH(0),
(19) C(0)CH3,
(20) C02H,
(21) C02CH3,
(22) SO2H, or
(23) SO2CH3;
(1) H,
(2) CH3,
(3) OCH3,
(4) CF3,
(5) OCF3,
(6) CI,
(7) Br, or
(8) F;
R4, R5 and R6 are defined as set forth in Part A, Part B or Part C below:
(A) 4 is:
(1) ¾
(2) C 1-4 alkyl,
(3) CF3s
(4) CH2CF3,
(5) (CH2)l-3-T, wherein T is C(0)NH2, C(0)NH(CH3), C(0)N(CH3)2, CO2H, C(0)OCH3, or SO2CH3,
(6) (CH2)2-3-U, wherein U is OCH3 or SCH3,
(7) CycA, or
(8) CH2-CycA; one of R5 and R6 is H or Ci-4 alkyl, and the other of R5 and R6 is:
(1) H,
(2) C1-8 alkyl,
(3) CF3 ;
(4) CH2CF3, (5) CycB, or
(6) CH2-CycB; 4 and R.5 together with the atoms to which they are attached form a 5- or 6- membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) Ci -4 alkyl,
(2) CF3s
(3) CH2CF3,
(3) C 1 _4 alkyl substituted with O-C \ _4 alkyl ;
IIS is
(1) H, or
(2) C alkyl;
R4 is as defined in Part
R5 and R6 together with the carbon atom to- which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl which is optionally substituted on a ring carbon with oxo, or (iii) a 5- or 6-membered heterocyclylalkyl in which the ring atom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently:
(1) Ci_4 alkyl,
(2) CF3, or
(3) CH2CF3;
CycA is a 3- to 6-membered cycloalkyl; and
CycB is a 3- to 6-membered cycloalkyl.
6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein:
RlA and RlB are each independently:
(1) H,
(2) CH3, (3) CI,
(4) Br, or
(5) F;
RlC is:
(1) H,
(2) CH3,
(3) CI,
(4) Br, or
(5) F;
and provided that at least one of Rl RlB and Rl is other than H;
R4, R5 and R6 are defined as set forth in Part A, Part B or Part C below:
(A) R4 is:
(1) H>
(2) CH3,
(3) CH2CH3,
(4) CH2CH2CH35
(5) CH(CH3)2,
(6) CH2CH(CH3)2,
(7) CH2CF3,
(8) CH2C(0)OH,
(9) CH2C(0)OCH3,
(10) CH2C(0)OCH2CH3,
(1 1) CH2CH2OCH3>
(12) CH2CH2SCH3,
(13) CycA, or
(14) CH2-CycA;
(1) H,
(2) CH3,
(3) CH2CH3,
(4) CH2CH2CH3,
(5) CH(CH3)2,
(6) CiCHsiS,
(7) CH(CH2CH3)2,
(8) CH(CH3)CH2CH3, or (9) C(CH2CH3)3,
(10) CH2CF3, or
(1 1) CycB;
R6 is H, CH3, or CH2CH3;
or
(B) 4 and R5 together with the atoms to which they are attached form a 5- or 6- membered fused azacycloalkyl ring which is:
Figure imgf000192_0001
; wherein the azacycloalkyl ring is optionally substituted with 1 or 2 substituents each of which is independently methyl or ethyl; and each asterisk (*) denotes the point of attachment to the rest of the compound;
R6 is
(1) H,
(2) CH3, or
(3) CH2CH3;
or
R4 is as defined in Part A:
R5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is: . ,
Figure imgf000192_0002
optionally substituted with 1 or 2 methyl groups; and each asterisk (*) denotes the point of attachment to the rest of the compound;
CycA is cyclopropyl; and
CycB is independently cyclopropyl, cyclobutyl, or cyclopentyl.
7. A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein:
Rl is F in the para position of the benzyl moiety;
RlB is H, CI, or Br in the ortho or meta position of the benzyl moiety; and
RlC is H.
8. A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein: in part B of the definition of R , R5 and R6;
R4 and R5 together with the atoms to which they are attached form a fused azacycloalkyl ring which is:
Figure imgf000193_0001
R6 is (1) H} (2) CH3S or (3) CH2CH3; and in part C of the definition of R45 R5 and R0;
R4 is (1) H, (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, (5) CH(CH3)2,
(6) CH2CH(CH3)2, (7) CH2C(0)OH, (8) cyclopropyl, or (9) CH2-cyclopropyl; and
R5 and R6 together with the carbon atom to which they are both attached form a spiiocyclic ring which is:
Figure imgf000193_0002
9. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound of Formula III:
Figure imgf000194_0001
R1A is halo;
R1B is H or halo;
R4 is H} 3 to 8-membered cycloalkyl or Chalky!, wherein said 3 to 8- membered cycloalkyl group can be optionally substituted with -OH and wherein said Cj. salkyl group is substituted with
Figure imgf000194_0002
-0-(C1-6alkyl) or 3 to 8- membered cycloalkyl, wherein said 3 to 8-membered cycloalkyl substituent can be optionally substituted with -OH;
R5 is H; and
R6 is cycloalkyl, or R5 and R6, together with the common carbon atom to which they are attached, combine to form a spirocyclic ring which is: (i) a 4 to 8- membered cycloalkyl group or (ii) a 6 to 10-membered fused or bridged bicycloalkyl group, wherein said spirocyclic rings (i) and (ii) can be optionally substituted with a -0-(C1-6alkyl) group.
10. The compound according to claim 9, wherein R1A is F and RiB is H or
CI; R4 is cyclopropyl or -CH2CH2N(CH3)S02CH3; R5 is H; and R6 is cyclopropyl.
11. The compound according to claim 9, wherein R is F and R is H or CI; R4 is H, ~CH2CH2N(CH3)S02C or:
Figure imgf000194_0003
R5 and R6, together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:
Figure imgf000195_0001
12. A compound according to claim 1, or an individual enantiomer or diastereomer thereof, which is selected from the group consisting of:
8,-(3-c oro-4-fluorobenzyl)-6'-hydroxy-2,-methyl-9'i10'-dihydro-2,H- spiro[bicyclo[2.2J]heptane-2f3!~imidazo[5,l-a][2s6]naphthyridine]- ,5^7 8'H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2s3--dimethyi-2!3;.9,10- tetrahydroimidazo[5,l-a][2,6]naphthyridine-l,557(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2-(2-methoxyethyl)-3- methyl-2,3 ,9, 10-tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)-trione;
3-(3-chloro-4-fiuorobenzyl)-5-hydroxy-8,8-dimethyl-2,358,9J10,l l- hexahydro-7aH-pyrido [2'; 1 ' :2,3] imidazo [5 , 1 -a] [2,6]naphthyridine-4,6, 13(1 H)-trione;
3-(3-chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-253?7a,8,9510- hexahydropyrrolo[2', :2!3]imidazo[5, 1 -a] [2,6]naphthyridine-4,6, 12(1 H)-trione;
3-(3-cMoro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,358;9, 10,1 l~hexahydro- 7aH-pyrido[2'f :2 ,3 ] imidazo [5 , 1 -a] [2, 6]naphthyridine-4, , 13 ( 1 H)-trione ;
-3-(3-chloro-4-fluorobenzyl)-7a-ethyl-5-hydroxy-2,3,8,9, 10, 11 -hexahydro- 7aH-pyrido[2', : 2,3] imidazo [5, 1 -a] [2,6]naphmyridine-4,6, 13(lH)-trione;
8-(4-fluorobenzyl)-6-hydroxy-2-methyl-3-(l-methylethyl)-2,3,9,10- tetrahydro imidazo [5, 1 -a] [256]naphthyridine- 1 ,5,7(8H)-trione;
8'-(2-bromo-4-fluorobenzyl)--6'-hydroxy-2'-methyl-9',10,-dihydro-2'H" spiro[cyclopentane-l53'-imidazo[5,l-a3[2,6]naphmyridine]-1^5\7 8'H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3-(l-methylethyl)-2,3,9,10- tetrahydroimidazo[5,l-a][2,6]naphthyridine-l,5,7(8H)-trione;
8-(3-chloiO-4-fluorobenzyl)-6-hydroxy-2,3,3-trimethyl-2,3,9,10- tetrahydroimidazo[5, 1 -a] [2,63naphthyridine- 1 ,5,7(8H)-trione;
8-(3 -chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methoxyethyl)-3 -( 1 - methylethyl)-2,3,9,l 0-tetrahydroimidazo[5,l -a] [2,6]naphthyridine-l ,5,7(8H)-trione;
3-te^bufyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-2!3,9,10-- tetrahydroimidazo [5 , 1 -a] [2,6]naphthyridine~ 1 ,5 ,7(8H)-trione;
3 -(3-chloro-4-fluorobenzyl)-5 -hydroxy-2,3 ,8,9, 10, 1 1 -hexahydro-7aH~ pyrido [2' , Γ: 2,3 ] imidazo[5 , 1 -a] [2,6] naphthyridine-4 ,6,13(1 H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methoxyethyl)-3-methyi- 2,3,9,10-tetrahydroimidazo [5 , 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-2,3-dicyclopropyl-6-hydroxy-2,3,9, 10- tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine-l ,5,7(8H)-trione;
3-iert-butyl-8-(3-chloro-4-fluoroberizyl)-6-hydroxy-2-methyl-2,3s9J10- tetrahydroimidazo[551 -a][2,6]naphthyridine- 1 ,5,7(8H)-trione;
8-(3-chloro-4-fiuorobenzyi)-3-ethyl-6-hydroxy-2-methyl-253,9s10~ tetrahydroimidazo[5,l-a][2,6]naphthyridine-l ,5,7(8H)-trione;
3-ter/-butyl-8-(3 -chloro-4-fluorobenzyl)-6-hydroxy-2,3 ,9,10- tetrahydroimidazo[5,l -a][2,6]naphthyrjdine-l ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-(l , 1 -diethylpropyl)-6-hydroxy-2,3 ,9, 10- tetrahydroimidazo[5,l-a] [2,6]naphthyridine-l,5,7(8H)-trione; 8'-(3~cWoro-4-fluoroberLzyl)-6,-hydroxy-2'-methyl-9',10,-dihydro-2'H- spiro [cyclobutane- 1 , 3 '-imidazo [5 , 1 -a] [2,6] naphthyridine] - Γ, 5 ' , 7'(8 'H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-ethyl-6-hydiOxy-3-methyl-2,3;9,10~ tetrahydroimidazo[5,l-a][2,6]naphthyridine-l,5,7(8H)-trione;
8'-(3 -chloro-4-fluorobenz l)-6'-h droxy-2'-metllyl-9,, 10'-dihydro~2'H- spiro[cyclopentane~l,3'-imidazo[55l-a][2J6]naphthyridine]- ,5^7 81-l)-trione;
8~(3-chloro-4~fluorobenzyl)-3-cyclobutyl-6-hydroxy-2,3;9;10- tetrahydroimidazo[5fl-a][2f6]naphthyridine-l35,7(8H)-trione;
8<-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'- ro-2'H- spiro[cyclohexane- 1 ,3 '-imidazo [5, 1 -a] [2,6]naphthyridine]- 1
Figure imgf000196_0001
8,-(3-chloro-4-fluorobenzyl)-6,-hydroxy-2'-me l-9'510'-dihydro-2'H- spiro[cycloheptane-l,3'-imidazo[5,l-a][2,6]naphthyridine]-1^5 7 8'H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2J3~dimethyl-2f3?9f10- tetrahydroimidazo [5 , 1 -a] [2,6]naphthyridine- 1 ,5 ,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-ethyl-6- ydroxy-2,3-dimethyl-2,3,9,10- tetrahydroimidazo[5, 1 -a] [2,6] naphthyridine- 1 ,5 ,7(8H)-trione;
8 -(3 -cMoro-4-fluorobenzyl)-6-hydroxy-2, 3 -dimethyl- 3 -propyl-2 ,3,9,10- tetrahydroimidazo[5,l-a][2,6]naphthyridine-l,557(8H)-trione;
8-(3 -chloro-4-fluoroben2yi)-6-hydroxy-2-methyl-4, !5 9, 10-tetrahydro-2H- spiro [imidazo [5 , 1 -a] [2 , 6] naphthyridine-3 ,3 '-thiophene]- 1 , 5 ,7(8H)~trione:
8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2',3-dimethyl-9'si0'-dihydro-2!H- spiro [cyclopentane- 1 ,3 '-imidazo [5 , 1 -a] [2,6]naphthyridin.e] - 1 '.5',7'(8Ή)-ΐΓίοηβ;
8-(3-chloro-4-fluorobenzyl)-2-ethyl-6-hydroxy-3-methyl-2,3,9,10- tetrahydroimidazolSJ-aJp^lnaphthyridine-ljS fS^-trione;
8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2,,4-dimethyl-9',10'-dihydro-2'H- spiro[cyclohexane-l ,3 '-imidazo [5, 1 -a] [2,6)naphmyridine]- ,5',7'(8'H)-trione;
ethyl [8-(3-chloro-4-fluorobenzyl)-6-hydroxy-3 -methyl- 1 ,5 ,7-trioxo- 1 ,5,7,8,9,10-hexahydroimidazo[5, 1 -a][2,6]naphthyridin-2(3H)-yl]acetate
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3a',4',6',6a',9,10-hexahydro- l¾,2H-spiro[imidazo[5,l-a][2,6]naphthyridine-3,2'-pentalene]-l,5,5',7(3'H,8H)-tetrone
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3-(l-methylpropyl)- 2,3,9,10-tetrahydroimidazo[5,l-a][256]naphthyridme-l!5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-(l-ethylpropyl)-6-hydroxy-2-methyl-2,3,9,10- tetrahydroimidazo[5, 1 -a] [2,6] naphthyridine- 1 ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-cyclopentyl-6-hydroxy-2-meihyl-2,3,9,10- tetrahydro imidazo [5, 1 -a] [2,6]naphthyridine-l ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(2-methylpropyl)- 2,3 ,9, 10-tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)-trione;
8-(3-chloro-4-fluorobenzyl)-6-hydroxy-3-methyl-3-(2,2,2-trifluoroethyl)- 2,3,9, 10-tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine-l ,5,7(8H)-trione;
8'-(3-chloro-4-fluorobenzyl)-2'-ethyI-6,-hydroxy-9,,10'-dihydro-2'H- spiro[cyclopentane- 1 ,3'-imidazo[5 , 1 -a] [2;6]naphthyridine] - 1 ',5',7'(8'H)-trione;
8'-(3-chloro-4-fluorobenzyl)-6,-hydroxy-9', 10'-dihydro-2'H- spiro[cyclopentane-l,3'-imida2o[5sl-a][2;6]naphthyridine]- ,5\7'(8H)-trione;
3-¾r -butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methylpropyl)- 2,3,9,10-tetrahydxoimidazo [ 5 , 1 -a] [2 ,6) naphthyridine- 1 , 5 ,7(8H)-trione ;
8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2',3,3-trimethyl-9',10'-dihydro-2!H- spirofeyclohexane- 1 ,3'-imidazo[5, 1 -a][2,6]naphthyridine]-l 5',7'(8Ή)-ίήθΏ^; methyl [8 -(3 -chloro-4-fiuorobenzyl)-3 -cyclopropyl-6-hydroxy- 1 , 5 ,7-tri oxo- l^ jS^JO-he ahydroimidazofS^-aJJ ^Jna hthyridin- tS^- lJacetate
8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2,-(2-metnylpropyl)-9'J10'-dihydro- 2,H-spiro[cyclopentane~ 1 ,3'-iniida2o[5 , 1 -a] [2,6]naphthyridine]- 1 ',5',7'(8'H)-trione;
8!-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2-methyl-9'J10,-dihydro-2'H- spiro[cyclopentaiie-l,3'-imidazo[5,l~a][2,6]naphmyridine]- ,5'?7'(8'H)-trione;
3-ieri-butyl-8~(3-chloro-4-fiuorobenzyl)-6-hydroxy-2-[2- (methylsulfanyl)ethyl]-2,3.9, 10~tetrahydroimidazo[5, 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)- trione;
8-(3 -chloro-4-fluorobenzyl)- 3 ~cyclopropyl-6-hydroxy-2- [2- (methylsulfanyl)ethyl]-2,3,9, 10-tetraliydroimidazo[5, 1 -a] [2,6]naphthyridine- 1 ,5,7(8H)- trione;
8-(3-cUoro-4-fluorobenzyl)-3-cyclobutyl-2-(cyclopropylmethyl)-6-hydroxy- 3-methyl-2f3,9,10-tetrahydroimidazo[5fl-a][2,6]naphthyridine-l,557(8H)-trione;
8'-(3-chloro-4-fluorobenzyl)-2'-cyclopropyl-6'-hydroxy-9',10'-dihydro-2,H- spiro[cyclopentane-l ,3'-imidazo[5 , 1-a] [2,6]naphthyridine]- 1 ',5',7'(8'H)-trione;
[S'-tS-chloro^-fluoroberi y -e'-hydroxy-r^' '-trioxo-r^' '^'^ O'- hexahydro-2'H-spiro[cyclopentane-l,3'-imidazo[55l-a3[2,6]naphthyridin3-2'-yl]acetic acid
8'-(3-chloro-4-fluorobenzyl)-2'-(cyclopropylmethyl)-6,-hydroxy-9'510'- dihydro-2¾-spiro [cyclopentane- 1 ,3Mmid^
and pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method for the treatment or prophylaxis of infection by HTV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.
15. The method according to claim 14, wherein the HTV is HIV-1.
16. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the inhibition of HTV integrase, for the treatment or prophylaxis of infection by HTV, or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof.
17. The use according to claim 12, wherein the HIV is ITTV-1.
18. The pharmaceutical composition according to claim 13, further comprising one or more additional therapeutic agents selected from lamivudine, abacavir, ritonavir and lopinavir, wherein the amounts present of: (i) the compound according to any one of claims 1-10 and (ii) the one or more additional therapeutic agents are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof.
19. The method according to claim 14 or 15, further comprising administering to the patient one or more additional therapeutic agents selected from lamivudine, abacavir, ritonavir and lopinavir, wherein the amounts administered of: (i) the compound according to any one of claims 1-10 and (ii) the one or more additional therapeutic agents are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof.
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