Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives

{
  "publication_number": "US9763952B2",
  "country": "US",
  "kind": "B2",
  "title": "Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives",
  "abstract": "The invention relates to dihydro-benzo-oxazine and dihydro-pyrido-oxazine compounds of the formula (I) and/or pharmaceutically acceptable salts and/or solvates thereof, wherein Y, V, W, U, Q, R 1, R 5, R 7 and R 30 are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of the PI3K enzymes.",
  "claims": [
    "1. A method of inhibiting the activity of PI3Kδ isoform in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according Formula (I): or a pharmaceutically acceptable salt thereof, wherein Y is selected from O or NH; V is selected from CR 5 or N; W is selected from CH 2, or O; U is selected from N or CH; Q is selected from N or CR 6; wherein U and Q are not both N; R 1 is selected from phenyl, pyridyl, pyrimininyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, or - X - R 4 wherein X is selected from C(O), S(O) 2 or CH 2 and R 4 is selected from C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, cyano-C 1 -C 8 -alkyl, N,N-di-C 1 -C 4 -alkyl-amino-C 1 -C 8 -alkyl, C 1 -C 4 -alkyl-sulfonyl-C 1 -C 8 -alkyl, phenyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C 1 -C 8 -alkyl, C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkyl-oxy, C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C 1 -C 8 -alkyl, hydroxy, C 1 -C 8 -alkoxy, amino, N - C 1 -C 8 -alkyl-amino or N,N-di-C 1 -C 8 -alkyl-amino, wherein C 1 -C 8 -alkyl in N - C 1 -C 8 -alkyl-amino and in N,N-di-C 1 -C 8 -alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C 1 -C 4 -alkoxy, wherein C 3 -C 12 -cycloalkyl in C 3 -C 12 -cycloalkyl and in C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl may be unsubstituted or substituted by 1-5 substituents selected from halogen, hydroxy or C 1 -C 4 -alkoxy; wherein ‘heterocyclyl’ is a 3 to 7 membered saturated or partially unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, each of which is unsubstituted or substituted by 1-5 substituents selected from oxo, halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; wherein ‘heterocyclyl’ can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states, wherein ‘heteroaryl’ is a 3 to 7 membered fully unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, or pyrazolo[1,5-a]pyrimidine or imidazo[2,1-b]thiazole, each of which is unsubstituted or substituted by 1-5 substituents selected from halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; wherein ‘heteroaryl’ can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states; R 6 is selected from hydrogen, halogen, C 1 -C 4 -alkyl, halo-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl-sulfonyl, C 1 -C 4 -alkyl-sulfinyl, C 1 -C 4 -alkyl-sulfanyl, halo-C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino; R 7 is selected from hydrogen, halogen, cyano, nitro, C 1 -C 4 -alkyl, halo-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, N(R 8) 2 -sulfonyl, C 1 -C 4 -alkyl-sulfonyl, C 1 -C 4 -alkyl-sulfonyl-amino, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, or N,N-di-C 1 -C 8 -alkyl-amino; or R 6 and R 7, together are CH═CH - CH═CH, wherein R 8 is independently selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or two R 8 together with the nitrogen they are attached to form a 4 to 7 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O, S, which is unsubstituted or substituted by 1-3 substituents selected from C 1 -C 4 -alkyl; R 5 is independently selected from H, D, F or C 1 -C 2 -alkyl; R 30 is independently selected from H, D or F.",
    "2. A method of ameliorating a disorder or a disease selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis (MG), Sjögren's syndrome (SS) transplant rejection, lymphoctic leukemia, non-Hodgkin lymphoma, and lymphomas comprising administering to a subject suffering from the disease or disorder a therapeutically effective amount of a compound according Formula (I): or a pharmaceutically acceptable salt thereof, wherein Y is selected from O or NH; V is selected from CR 5 or N; W is selected from CH 2, or O; U is selected from N or CH; Q is selected from N or CR 6; wherein U and Q are not both N; R 1 is selected from phenyl, pyridyl, pyrimininyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, or - X - R 4 wherein X is selected from C(O), S(O) 2 or CH 2 and R 4 is selected from C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, cyano-C 1 -C 8 -alkyl, N,N-di-C 1 -C 4 -alkyl-amino-C 1 -C 8 -alkyl, C 1 -C 4 -alkyl-sulfonyl-C 1 -C 8 -alkyl, phenyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C 1 -C 8 -alkyl, C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkyl-oxy, C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C 1 -C 8 -alkyl, hydroxy, C 1 -C 8 -alkoxy, amino, N - C 1 -C 8 -alkyl-amino or N,N-di-C 1 -C 8 -alkyl-amino, wherein C 1 -C 8 -alkyl in N - C 1 -C 8 -alkyl-amino and in N,N-di-C 1 -C 8 -alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C 1 -C 4 -alkoxy, wherein C 3 -C 12 -cycloalkyl in C 3 -C 12 -cycloalkyl and in C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl may be unsubstituted or substituted by 1-5 substituents selected from halogen, hydroxy or C 1 -C 4 -alkoxy; wherein ‘heterocyclyl’ is a 3 to 7 membered saturated or partially unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, each of which is unsubstituted or substituted by 1-5 substituents selected from oxo, halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; wherein ‘heterocyclyl’ can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states, wherein ‘heteroaryl’ is a 3 to 7 membered fully unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, or pyrazolo[1,5-a]pyrimidine or imidazo[2,1-b]thiazole, each of which is unsubstituted or substituted by 1-5 substituents selected from halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; wherein ‘heteroaryl’ can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states; R 6 is selected from hydrogen, halogen, C 1 -C 4 -alkyl, halo-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl-sulfonyl, C 1 -C 4 -alkyl-sulfinyl, C 1 -C 4 -alkyl-sulfanyl, halo-C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino; R 7 is selected from hydrogen, halogen, cyano, nitro, C 1 -C 4 -alkyl, halo-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, N(R 8) 2 -sulfonyl, C 1 -C 4 -alkyl-sulfonyl, C 1 -C 4 -alkyl-sulfonyl-amino, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, or N,N-di-C 1 -C 8 -alkyl-amino; or R 6 and R 7, together are CH═CH - CH═CH, wherein R 8 is independently selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or two R 8 together with the nitrogen they are attached to form a 4 to 7 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O, S, which is unsubstituted or substituted by 1-3 substituents selected from C 1 -C 4 -alkyl; R 5 is independently selected from H, D, F or C 1 -C 2 -alkyl; R 30 is independently selected from H, D or F.",
    "3. The method of claim 2, wherein the compound of Formula I is a compound of formula (Ic′):",
    "4. The method of claim 2, wherein the compound of Formula I is a compound of formula (Id′)",
    "5. The method of claim 2, wherein the compound of Formula I is a compound of formula (Ie′)",
    "6. The method of claim 2, wherein the compound of Formula I is a compound of formula (If′)",
    "7. The method of claim 4, wherein the compound of Formula I is a compound of formula (If′)",
    "8. The method of claim 2, wherein the compound of Formula I is a compound in which R 1 is selected from phenyl, pyridyl, pyrimininyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, or - X - R 4, wherein R 4 is selected from C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, cyano-C 1 -C 8 -alkyl, N,N-di-C 1 -C 4 -alkyl-amino-C 1 -C 8 -alkyl, C 1 -C 4 -alkyl-sulfonyl-C 1 -C 8 -alkyl, phenyl, heterocyclyl, heterocyclyl-C 1 -C 8 -alkyl, C 3 -C 12 -cycloalkyl, heteroaryl, heteroaryl-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, wherein C 1 -C 8 -alkyl in N - C 1 -C 8 -alkyl-amino and in N,N-di-C 1 -C 8 -alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C 1 -C 4 -alkoxy, wherein C 3 -C 12 -cycloalkyl in C 3 -C 12 -cycloalkyl and in C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl may be unsubstituted or substituted by halogen, hydroxy or C 1 -C 4 -alkoxy; wherein ‘heterocyclyl’ is a 3 to 7 membered saturated or partially unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, which is unsubstituted or substituted by 1-5 substituents selected from oxo, halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; wherein ‘heterocyclyl’ can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states, wherein ‘heteroaryl’ is a 3 to 7 membered fully unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, or pyrazolo[1,5-a]pyrimidine or imidazo[2,1-b]thiazole, each of which is unsubstituted or substituted by 1-5 substituents selected from halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; wherein ‘heteroaryl’ can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states.",
    "9. The method of claim 2, wherein the compound of Formula I is a compound in which R 1 is selected from - X - R 4, wherein R 4 is selected from C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, cyano-C 1 -C 8 -alkyl, N,N-di-C 1 -C 4 -alkyl-amino-C 1 -C 8 -alkyl, C 1 -C 4 -alkyl-sulfonyl-C 1 -C 8 -alkyl, phenyl, heterocyclyl, heterocyclyl-C 1 -C 8 -alkyl, C 3 -C 12 -cycloalkyl, heteroaryl, heteroaryl-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, wherein C 1 -C 8 -alkyl in N - C 1 -C 8 -alkyl-amino and in N,N-di-C 1 -C 8 -alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C 1 -C 4 -alkoxy, wherein C 3 -C 12 -cycloalkyl in C 3 -C 12 -cycloalkyl and in C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl may be unsubstituted or substituted by halogen, hydroxy or C 1 -C 4 -alkoxy, wherein ‘heterocyclyl’ is a 3 to 7 membered saturated or partially unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, which is unsubstituted or substituted by 1-5 substituents selected from oxo, halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; wherein ‘heterocyclyl’ can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states, wherein ‘heteroaryl’ is a 3 to 7 membered fully unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, or pyrazolo[1,5-a]pyrimidine or imidazo[2,1-b]thiazole, each of which is unsubstituted or substituted by 1-5 substituents selected from halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N - C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl; wherein ‘heteroaryl’ can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states; R 6 is selected from halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl-sulfonyl or halo-C 1 -C 4 -alkoxy and R 7 is selected from hydrogen, halogen, cyano, C 1 -C 4 -alkyl, halo-C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy.",
    "10. The method of claim 2, wherein the compound of Formula I is a compound in crystalline form."
  ],
  "description_excerpt": "This application claims priority to U.S. Provisional Application No. 61/579,231 filed Dec. 22, 2011, the contents of which are incorporated herein by reference in their entirety.\n\nThe invention relates to the preparation and use of new dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives as drug candidates in free form or in pharmaceutically acceptable salt form with valuable druglike properties, such as e.g. metabolic stability and suitable pharmacokinetics, form for the modulation, notably the inhibition of the activity or function of the phosphoinositide 3′ OH kinase family (hereinafter PI3K).\n\nMembers of the phosphoinositide-3 kinase (PI3K) family are involved in cell growth, differentiation, survival, cytoskeletal remodeling and the trafficking of intracellular organelles in many different types of cells (Okkenhaug and Wymann, Nature Rev. Immunol. 3:317 (2003).\n\nTo date, eight mammalian PI3Ks have been identified, divided into three main classes (I, II and III) on the basis of their genetic sequence, structure, adapter molecules, expression, mode of activation, and preferred substrate.\n\nPI3Kδ is a lipid kinase belonging to the class I PI3K family (PI3K α, β, γ and δ) that generates second messenger signals downstream of tyrosine kinase-linked receptors. PI3Kδ is a heterodimer composed of an adaptor protein and a p110δ catalytic subunit which converts phosphatidylinositol-4,5-bis-phosphate (PtdlnsP2) to phosphatidylinositol-3,4,5-tri-phosphate (PtdlnsP3). Effector proteins interact with PtdlnsP3 and trigger specific signaling pathways involved in cell activation, differentiation, migration, and cell survival.",
  "cpc": [
    "A61K 31/5383",
    "A61K 31/538",
    "A61P 11/02",
    "A61P 17/04",
    "A61P 17/10",
    "A61P 19/00",
    "A61P 19/02",
    "A61P 21/04",
    "A61P 25/00",
    "A61P 27/02",
    "A61P 29/00",
    "A61P 33/00",
    "A61P 33/02",
    "A61P 33/06",
    "A61P 35/00",
    "A61P 35/02",
    "A61P 37/00",
    "A61P 37/02",
    "A61P 37/06",
    "A61P 37/08",
    "A61P 43/00",
    "A61P 7/00",
    "A61P 7/06",
    "C07D 413/12",
    "C07D 413/14",
    "C07D 487/04",
    "C07D 498/04",
    "C07D 519/00",
    "C12N 9/12",
    "C12Q 1/25",
    "C12Q 1/686",
    "Y02A 50/30"
  ],
  "ipc": [
    "A61K 31/538",
    "A61K 31/5383"
  ],
  "assignees": [
    "Novartis AG"
  ],
  "inventors": [
    "Giorgio Caravatti",
    "Sylvie Chamoin",
    "Pascal Furet",
    "Klemens Hogenauer",
    "Konstanze Hurth",
    "Karen KAMMERTOENS",
    "Ian Lewis",
    "Henrik Moebitz",
    "Alexander Baxter Smith",
    "Nicolas Soldermann",
    "Romain Wolf",
    "Frederic Zecri"
  ],
  "filing_date": "2015-12-21",
  "publication_date": "2017-09-19",
  "grant_date": "2017-09-19",
  "priority_date": "2011-12-22",
  "application_number": "US-201514976998-A",
  "family_id": "47678928",
  "cited_by_count": 9,
  "citations": [
    "EP0432893A2",
    "WO1994026739A1",
    "WO2000039103A1",
    "WO2001023389A2",
    "WO2001057003A1",
    "WO2002072049A1",
    "US20040121996A1",
    "WO2004056820A1",
    "WO2004087646A2",
    "WO2005040355A2",
    "EP1777225A1",
    "WO2006032342A2",
    "WO2006034769A1",
    "US20090042773A1",
    "WO2006050054A2",
    "US20060161001A1",
    "WO2007089034A1",
    "WO2008001076A1",
    "US20100137302A1",
    "WO2008044022A1",
    "WO2008051493A2",
    "WO2008098058A1",
    "US20080221091A1",
    "US20080306093A1",
    "WO2009026444A1",
    "WO2009071895A1",
    "EP2298731A1",
    "WO2009157196A1",
    "WO2010027002A1",
    "US20110172217A1",
    "EP2341052A1",
    "US20100152160A1",
    "WO2010111626A2",
    "WO2010117425A1",
    "WO2010151737A2",
    "WO2011143495A1",
    "WO2012004299A1",
    "KR20120018236A",
    "WO2012068106A2",
    "WO2012068096A2",
    "WO2012136080A1",
    "WO2013093849A1",
    "WO2014102630A1"
  ]
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