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Isoindoline Derivatives for Use in The (19) TZZ¥_ _T (11) EP 3 166 925 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 209/44 (2006.01) A61K 31/4035 (2006.01) 14.03.2018 Bulletin 2018/11 A61K 31/454 (2006.01) C07D 407/10 (2006.01) C07D 401/06 (2006.01) C07D 407/06 (2006.01) (21) Application number: 15742106.6 (86) International application number: (22) Date of filing: 06.07.2015 PCT/IB2015/055095 (87) International publication number: WO 2016/005878 (14.01.2016 Gazette 2016/02) (54) ISOINDOLINE DERIVATIVES FOR USE IN THE TREATMENT OF A VIRAL INFECTION ISOINDOLINDERIVATE ZUR VERWENDUNG BEI DER BEHANDLUNG VON VIRUSINFEKTIONEN DÉRIVÉS D’ISOINDOLINE À UTILISER DANS LE TRAITEMENT D’UNE INFECTION VIRALE (84) Designated Contracting States: • VELTHUISEN, Emile, Johann AL AT BE BG CH CY CZ DE DK EE ES FI FR GB North Carolina 27709 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • WEATHERHEAD, Jason, Gordon PL PT RO RS SE SI SK SM TR North Carolina 27709 (US) Designated Extension States: • SUWANDI, Lita BA ME North Carolina 27709 (US) Designated Validation States: • TEMELKOFF, David MA North Carolina 27709 (US) (30) Priority: 08.07.2014 US 201462021844 P (74) Representative: Gladwin, Amanda Rachel 16.10.2014 US 201462064615 P GlaxoSmithKline 18.03.2015 US 201562134616 P Global Patents (CN925.1) 980 Great West Road (43) Date of publication of application: Brentford, Middlesex TW8 9GS (GB) 17.05.2017 Bulletin 2017/20 (56) References cited: (73) Proprietor: VIIV Healthcare UK Limited WO-A1-2008/155001 WO-A1-2009/030316 Brentford, Middlesex TW8 9GS (GB) WO-A1-2013/012649 WO-A1-2013/103738 WO-A1-2013/134142 WO-A1-2014/009794 (72) Inventors: • JOHNS, Brian, Alvin North Carolina 27709 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 3 166 925 B1 Printed by Jouve, 75001 PARIS (FR) EP 3 166 925 B1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to substituted isoindoline compounds, pharmaceutical compositions, and uses thereof for (i) inhibiting HIV replication in a subject infected with HIV, or (ii) treating a subject infected with HIV, by administering such compounds. BACKGROUND OF THE INVENTION 10 [0002] Human immunodeficiency virus type 1 (HIV-1) leads to the contraction of acquired immune deficiency disease (AIDS). The number of cases of HIV continues to rise, and currently over twenty-five million individuals worldwide suffer from the virus. Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. Indeed, the U.S. Food and Drug Administration has approved twenty-five drugs over six different inhibitor 15 classes, which have been shown to greatly increase patient survival and quality of life. However, additional therapies are still required because of undesirable drug-drug interactions; drug-food interactions; non-adherence to therapy; and drug resistance due to mutation of the enzyme target. [0003] Currently, almost all HIV positive patients are treated with therapeutic regimens of antiretroviral drug combina- tions termed, highly active antiretroviral therapy ("HAART"). However, HAART therapies are often complex because a 20 combination of different drugs must be administered often daily to the patient to avoid the rapid emergence of drug- resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur. The emergence of multidrug-resistant HIV-1 isolates has serious clinical consequences and must be suppressed with a new drug regimen, known as salvage therapy. [0004] Current guidelines recommend that salvage therapy includes at least two, and preferably three, fully active 25 drugs. Typically, first-line therapies combine three to four drugs targeting the viral enzymes reverse transcriptase and protease. One option for salvage therapy is to administer different combinations of drugs from the same mechanistic class that remain active against the resistant isolates. However, the options for this approach are often limited, as resistant mutations frequently confer broad cross-resistance to different drugs in the same class. Alternative therapeutic strategies have recently become available with the development of fusion, entry, and integrase inhibitors. However, 30 resistance to all three new drug classes has already been reported both in the lab and in patients. Sustained successful treatment of HIV-1-infected patients with antiretroviral drugs will therefore require the continued development of new and improved drugs with new targets and mechanisms of action. [0005] For example, over the last decade HIV inhibitors have been reported to target the protein-protein interaction between HIV-1 integrase and Lens Epithelium Derived Growth Factor/p75 ("LEDGF"). LEDGF is a cellular transcriptional 35 cofactor of HIV-1 integrase that promotes viral integration of reverse transcribed viral cDNA into the host cell’s genome by tethering the preintegration complex to the chromatin. Because of its crucial role in the early steps of HIV replication, the interaction between LEDGF and integrase represents another attractive target for HIV drug therapy. Inhibitors of HIV replication have been disclosed, for example, in WO 2014/009794 and WO 2013/134142. 40 SUMMARY OF THE INVENTION [0006] Briefly, in one aspect, the present invention discloses compounds of Formula I: 45 50 55 wherein: 1 R is C1-6alkyl; 2 EP 3 166 925 B1 2 2 R is C5-14aryl, C3-7cycloalkyl, C3-7cycloalkenyl, C2-9heterocycle, or C2-9heteroaryl, wherein each R group is op- tionally substituted by one to four substituents selected from halo, C1-6alkyl, C1-6hetereoalkyl, or C1-6alkylene or C1-6hetereoalklylene wherein said C1-6alkylene or C1-6hetereoalklylene are bonded to adjacent carbon atoms on said C5-14aryl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-9heterocycle, or C5-9heteroaryl to form a fused ring; 5 L is a bond, -CH2(CO)-, -C1-3alkylene-, -SO2-, -C(O)-, -C(S)-, -C(NH)-, -C(O)NH-, - C(O)NHCH2-,-C(O)N-, -C(O)OCH2-, -C(O)O-, -C(O)C(O)-, -SO2-NH- , or -CH2C(O)-; 3 R is H, CN,1-6 alkyl,C C5-14aryl, CH2C5-14aryl, CH2C3-7cyloalkyl, C3-7cycloalkyl, C3-7spirocycloalkyl, 3 C3-7cycloalkenyl, C2-9heterocycle, or C2-9heteroaryl, wherein each R group is optionally substituted by one to four substituents selected from halo, 1-6C alkyl, C2-8bridgedheterocycle, C3-7cycloalkyl, C1-3fluoroalkyl, -OC1-6alkyl, 10 4 4 4 -C(O)R , -C(O)NR, -C(O)NHR, C5-14aryl, 1-6C hetereoalkyl, -B(OH)2, C2-9heterocycle, C1-6heteroaryl, -C(O)OC1-6alkyl, or two substituents bonded to adjacent atoms may bond together to form a fused ring and that fused ring may optionally be substituted with R4; 4 R is CN, halo, -OC1-6alkyl, C1-6alkyl, C3-7cycloalkyl, C2-9heterocycle, or C5-14aryl; and wherein each heterocycle, heteroaryl, heteroalkyl, and heteroalkylene comprises 15 one to three heteroatoms selected from S, N, B, or O. [0007] In another aspect the present invention discloses pharmaceutically acceptable salts of the compounds of Formula I. [0008] In another aspect, the present invention discloses pharmaceutical compositions comprising a compound of 20 Formula I or a pharmaceutically acceptable salt thereof. [0009] In another aspect, the present disclosure relates to a method for treating a viral infection in a patient mediated at least in part by a virus in theretrovirus family of viruses, comprising administering to said patient a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the viral infection is mediated by the HIV virus. 25 [0010] In another aspect, a particular embodiment of the present disclosure provides a method of treating a subject infected with HIV comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. [0011] In yet another aspect, a particular embodiment of the present disclosure provides a method of inhibiting pro- gression of HIV infection in a subject at risk for infection with HIV comprising administering to the subject a therapeutically 30 effective amountof a compoundof Formula I, or apharmaceutically acceptable salt thereof. Those and otherembodiments are further described in the text that follows. [0012] In accordance with another embodiment of the present disclosure there is provided a method for preventing or treating a viral infection in a mammal mediated at least in part by a virus in theretrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing 35 said viral infection, a compound as defined in Formula I, wherein said virus is an HIV virus and further comprising administration of a therapeutically effective amount of one or more agents active against an HIV virus, wherein said agent active against the HIV virus is selected from the group consisting of Nucleotide reverse transcriptase inhibitors; Non-nucleotide reverse transcriptase inhibitors; Protease inhibitors; Entry, attachment and fusion inhibitors; Integrase inhibitors; Maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors. 40 DETAILED DESCRIPTION OF THE INVENTION 1 1 [0013] Preferably R is C1-6alkyl. Most preferably, R is t-butyl. [0014] Preferably R2 is optionally substituted phenyl. Most preferably, R 2 is phenyl substituted by one to four substit- 45 uents selected from fluorine, methyl, -CH 2CH2CH2O- wherein said - CH 2CH2CH2O- is bonded to adjacent carbon atoms on said phenyl to form a bicyclic ring, or - NHCH2CH2O- wherein said -NHCH2CH2O- is bonded to adjacent carbon atoms on said phenyl to form a bicyclic ring.
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