compounds that inhibit mcl-1 protein

专利摘要:
Myeloid cell leukemia protein 1 (Mcl-1) inhibitors, methods for their preparation, related pharmaceutical compositions and methods of use are provided here. For example, compounds of Formula (I), or a stereoisomer thereof, are provided herein; and their pharmaceutically acceptable salts and pharmaceutical compositions containing the compounds. The compounds and compositions provided herein can be used, for example, in the treatment of diseases or conditions, such as cancer.
公开号:BR112019020459A2
申请号:R112019020459-8
申请日:2018-03-28
公开日:2020-07-21
发明作者:Paul E. Harrington；Ana Elena Minatti；Alexander J. Pickrell；Markian M. Stec；Joshua Taygerly；Kate Ashton；Sean P. Brown；Matthew R. Kaller；Todd J. Kohn；Brian Alan Lanman；Kexue Li；Yunxiao Li；Jonathan D. Low
申请人:Amgen Inc.；
IPC主号:

专利说明:

[0001] [0001] This application claims the benefit of US Provisional Application No. 62 / 479,171, filed on March 30, 2017, and US Provisional Application No. 62 / 479,230, filed on March, 2017, both of which are hereby incorporated. as a reference in its entirety and for all purposes as if they were presented here completely. FIELD OF THE INVENTION
[0002] [0002] The present invention relates to compounds that inhibit myeloid cell leukemia protein 1 (Mcl-1, also abbreviated as MCl-1, MCL-1 or MCL1); methods of treating diseases or conditions, such as cancer, using the compounds, and pharmaceutical compositions containing the compounds. BACKGROUND OF THE INVENTION
[0003] [0003] A common feature of human cancer is overexpression of Mcl-l. The overexpression of Mcl-l1 prevents cancer cells from undergoing programmed cell death (apoptosis), allowing cells to survive despite widespread genetic damage.
[0004] [0004] Mcl-1 is a member of the Bcl-2 protein family. The Bcl-2 family includes pro-apoptotic members (such as BAX and BAK) that, upon activation, form a homo-oligomer in the outer mitochondrial membrane that leads to the formation of pores and the escape of “mitochondrial content, a step in the onset of apoptosis. The anti-apoptotic members of the Bcl-2 family (such as Bcl-2, Bcel-XL and Mcl-1) block a stereoisomer, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt of their stereoisomer, where:
[0009] [0009] In another aspect, the compound of Formula I 'has Formula II'a:
[00012] [00012] Unless otherwise defined, all technical and scientific terms used here have the same meaning commonly understood by the person skilled in the art to which this disclosure belongs. Methods and materials are described here for use in the present disclosure; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references mentioned here are incorporated by reference in their entirety. In case of conflict, it will control this specification, including definitions.
[00013] [00013] Other characteristics and advantages of the disclosure will be clear from the following detailed description and figures, and from the Claims. BRIEF DESCRIPTION OF THE FIGURES
[00014] [00014] Figure 1 demonstrates the superior in vivo efficacy of Example 1 over Reference Compound 1 in a tumor PD model. Both compounds were dosed orally in nude athymic female mice inoculated with Luc OPM-2 cells.
[00015] [00015] Figure 2 demonstrates the superior in vivo efficacy of Example 2 and Example 3 over Reference Compound 1 in a tumor PD model. Both compounds were dosed orally in nude athymic female mice inoculated with Luc OPM-2 cells.
[00016] [00016] Figure 3 demonstrates the superior in vivo efficacy of Example 4 over Reference Compound 1 in a tumor PD model. Both compounds were dosed orally in nude athymic female mice inoculated with Luc OPM-2 cells.
[00017] [00017] Figure 4 demonstrates the superior in vivo efficacy of Example 10 over Reference Compound 1 in a tumor PD model. Both compounds were dosed orally in nude athymic female mice inoculated with Luc OPM-2 cells.
[00018] [00018] Figure 5 demonstrates the superior in vivo efficacy of Example 11 over Reference Compound 1 in a tumor PD model. Both compounds were dosed orally in nude athymic female mice inoculated with Luc OPM-2 cells.
[00019] [00019] Figure 6 demonstrates the superior in vivo efficacy of Example 13 and Example 14 over Reference Compound 1 in a tumor PD model. Both compounds were dosed orally in nude athymic female mice inoculated with Luc OPM-2 cells.
[00020] [00020] Figure 7 demonstrates the superior in vivo efficacy of Example 18 over Reference Compound 1 in a tumor PD model. Both compounds were dosed orally in nude athymic female mice inoculated with Luc OPM-2 cells.
[00021] [00021] Figure 8 demonstrates the in vivo efficacy of Example 1 in an OPM-2 xenograft efficacy model. Example 1 was dosed orally in nude athymic female mice with Luc OPM-2 cells.
[00022] [00022] Figure 9 demonstrates the in vivo efficacy of Example 4 in an OPM-2 xenograft efficacy model. Example 1 was dosed orally in nude athymic female mice with Luc OPM-2 cells.
[00023] [00023] Figure 10 demonstrates the in vivo efficacy of the Example in an OPM-2 xenograft efficacy model. Example 1 was dosed orally in nude athymic female mice with Luc OPM-2 cells.
[00024] [00024] Figure 11 demonstrates the in vivo efficacy of Example 11 in an OPM-2 xenograft efficacy model. Example 1 was dosed orally in nude athymic female mice with Luc OPM-2 cells.
[00025] [00025] Figure 12 demonstrates the in vivo efficacy of Example 13 in an OPM-2 xenograft efficacy model. Example 1 was dosed orally in nude athymic female mice with Luc OPM-2 cells.
[00026] [00026] Figure 13 demonstrates the in vivo efficacy of Example 18 in an OPM-2 xenograft efficacy model. The example
[00027] [00027] The symbol "-" represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol "-" is usually used to represent a methyl group in a molecule.
[00028] [00028] As used here, chemical structures that contain one or more illustrated stereocenters with dashed and bold links (i.e., “mm and -) are intended to indicate the absolute stereochemistry of the present stereocenter (s) in the chemical structure. As used here, links symbolized by a single line do not indicate a stereo preference. Unless otherwise stated, chemical structures that include one or more stereocent centers that are illustrated here without indicating absolute or relative stereochemistry encompass all possible stereoisomeric forms of the compound (for example, diastereomers, enantiomers) and mixtures thereof. Structures with a single bold or dashed line and at least one additional single line comprise a single enantiomeric series of all possible diastereomers.
[00029] [00029] As used here, the term "about" is intended to take into account variations due to experimental error. It is understood that all measurements reported here are modified by the term "about", whether or not the term is explicitly used, unless explicitly stated otherwise. As used here, the singular forms "one", "one", and "o / a" include plural referents unless the context clearly dictates otherwise.
[00030] [00030] The term "alkyl" means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl butyl, isobutyl, tert-butyl, sec-butyl, pentyl and hexyl. Typical alkyl groups are alkyl groups having from 1 to 8 carbon atoms, whose groups are usually represented as C1-g alkyl.
[00031] [00031] The term "compound", as used herein, is intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures represented. Compounds herein identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms, unless otherwise specified.
[00032] [00032] All compounds and their pharmaceutically acceptable salts can be present together with other substances, such as water and solvents (for example, hydrates and solvates).
[00033] [00033] The term "cycloalkyl" means a non-aromatic cyclic hydrocarbon. Representative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A cycloalkyl group can contain one or more double bonds. Representative examples of cycloalkyl groups containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl. Common cycloalkyl groups are C3-g cycloalkyl groups.
[00034] [00034] The term "excipient", as used here, means any additive, carrier, diluent, adjuvant or other pharmaceutically acceptable ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and / or administration to a patient . "Handbook of Pharmaceutical Excipients", 5th Edition, R.C. Rowe, P.J. Sheskey and S.C. Owen, editors, Pharmaceutical Press, 2005, Hardcover, 928, 0853696187.
[00035] [00035] For the terms "for example" and "such as" and their grammatical equivalences, it is understood that the phrase "and without limitation" is followed unless explicitly stated otherwise.
[00036] [00036] The term "halogen" or "halo" means F, Cl, Br or I.
[00037] [00037] The term "patient" means subjects including animals, such as dogs, cats, cows, horses, sheep and humans. Private patients are mammals. The term patient includes both male and female individuals.
[00038] [00038] The term "needy patient" means a patient having or at risk of having one or more diseases or conditions in which the Mcl-l1 protein is involved, such as cancers. The identification of a needy patient can consist of the evaluation of a subject or a healthcare professional, and can be subjective (for example, opinion) or objective (for example, measurable through a test or diagnostic method ).
[00039] [00039] The phrases “parenteral administration” and “administered parenterally”, as used here, mean different modes of administration from enteral and topical administration, usually by injection, and include without limitation, intravenous, intramuscular injection and infusion, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtraqueal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinatus and intrasternum.
[00040] [00040] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions and sterilized powders for reconstitution in sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, solvent diluents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol glycerol and the like), their suitable mixtures, vegetable oils (such as olive oil) and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by using a coating, such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.
[00041] [00041] The term "pharmaceutically acceptable" is used here to refer to those binders, materials, compositions and / or dosage forms that, within the scope of a reasoned medical assessment, are suitable for administration to a patient, proportionate to a benefit reason. / reasonable risk.
[00042] [00042] The phrase "pharmaceutically acceptable carrier", as used here, means a material,
[00043] [00043] The term "pharmaceutically acceptable salt" refers to the relatively non-toxic inorganic and organic acid addition salts of a compound provided herein. These salts can be prepared in situ during the final isolation and purification of a compound provided herein or by reacting separately from the compound in its free base form with a suitable organic or inorganic acid and isolating the salt formed in this way. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate salts , glucoheptonate, lactobionate, lauryl sulfonate and salts of amino acids and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).
[00044] [00044] The phrases "systemic administration", "systemically administered", "peripheral administration" and "administered peripherally", as used here, mean the administration of a ligand, drug or other material through a route that is not directly in the system central nervous system, so that it enters the patient's system and,
[00053] [00053] 6. The compound of any of Modalities 1-4 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where 2 is N.
[00054] [00054] 7. The compound of any of Modes 1-6 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Q is O.
[00055] [00055] 8. The compound of any of Modalities 1-6 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Q is S.
[00056] [00056] 9. The compound of any of Modalities 1-8 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where W is C = O.
[00057] [00057] 10. The compound of any of Modalities 1-8 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where W is CRWARHE,
[00058] [00058] 11. The compound of any of Modes 1-8 and 110 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R and RM are both H.
[00059] [00059] 12. The compound of any of Modalities 1-11 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R! it's halo.
[00060] [00060] 13. The compound of any of Modalities 1-12 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R! is Cl.
[00061] [00061] 14. The compound of any of Modalities 1-13 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[00062] [00062] 15. The compound of any one of Modalities 1-14 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H or -C1- «alkyl.
[00063] [00063] 16. The compound of any of Modalities 1- or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[00064] [00064] 17. The compound of any of Modalities 1-15 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[00065] [00065] 18. The compound of any of Modalities 1-17 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein D is independently selected from H, -Ci-salkyl, -Ci -salkyl-halo, -Ci-salkyl-O-Ci-salkyl or —- (CH2CH20) nRi, where -Ciçalkyl is not substituted or substituted with -OH, (= O), phenyl, -O-SiRºRPRº, -NRARP, a cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl with 3 to 12 members having 1, 2, 3 or 4 heteroatoms independently selected from O, N or Ss.
[00066] [00066] 19. The compound of any of Modalities 1-18 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[00067] [00067] 20. The compound of any of Modalities 1-18 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -Ci-salkyl.
[00068] [00068] 21 The compound of any of Modalities 1- 18 or 20 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[00069] [00069] 22. The compound of any of Modalities 1-18 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -Ci-salkyl-O-Ci-salkyl.
[00070] [00070] 23. The compound of any of Modes 1-18 or 22 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -CHxCH> OCH;:.
[00071] [00071] 24. The compound of any of Modalities 1-18 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -Ci-salkyl-OH.
[00072] [00072] 25. The compound of any of Modalities 1-18 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[00089] [00089] 42. The compound of any one of Modes 1-41 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, each of which R %% 5, R %%, R% , RA and R $ is independently selected from H, OH, halo or -Ci-salquila.
[00090] [00090] 43 The compound of Modality 42 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where each of R% º, R% º, R%, RA and R $ is H ,
[00091] [00091] 44, The compound of any of Modalities 1, 2 or 4-43 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº and Rºº are both H.
[00092] [00092] 45. The compound of any of Modalities 1-44 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R 'and Rº are both H.
[00093] [00093] 46. The compound of any of Modalities 1-45 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is independently selected from H, -Ci-salquila, -Cr -salkenyl or -Ci-salkyl-O-Ci-salkyl or -Ci-e «haloalkyl.
[00094] [00094] 47. The compound of any of Modes 1-46 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[00095] [00095] 48. The compound of any of Modes 1-46 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[00096] [00096] 49. The compound of any of Modes 1-46 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CHsCH ;.
[00097] [00097] 50. The compound of any of Modes 1-46 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH2CH (CH3) 2.
[00098] [00098] 51. The compound of any of Modes 1-46 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH> CH> OCH;:.
[00099] [00099] 52. The compound of any of Modes 1-46 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CF; 3.
[000100] [000100] 53. The compound of any of Modalities 1- 52 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is selected from EH, C1- ehaloalkyl, Cisalkyl, -Co -salkenyl - (CH2CH2O) nRº, -SO2Rº, -C (= O) Ri, -C (= 0) ORº, -C (= O) NRºRP, -NRºRP, -N = N = N, -Cisalkyl- O- Ci-salquila, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl groups, spiroheterocycloalkyl and heterocycloalkyl may include a C = O group and also in which the spiroheter groups ocycloalkyl and heterocycloalkyl may include an S = O or SO> ;.
[000101] [000101] 54. The compound of any of Modalities 1- 53 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº * º is -Cylcalkyl.
[000102] [000102] 55. The compound of any of Modalities 1- 53 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R *% is -C (= O) Rº.
[000103] [000103] 56. The compound of any of Modalities 1- 53 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R * is a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members , in which the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000104] [000104] 57. The compound of any of Modalities 1- 53 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R * is a monocyclic heterocycloalkyl group with 3 to 12 members, in that the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.
[000105] [000105] 58. The compound of any of Modalities 1- 53, 56 or 57 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein the monocyclic heterocycloalkyl group with 3 to 12 members R ** may not be substituted or substituted with 1, 2, 3 or 4 R! º substituents independently selected from OH, halo, -NRºRi, -Cigalquila, -Co-C «alkenyl, -Co-Kealquinyl, -OC1i- calkyl , -Ci-salkyl-OH, -Ci-salkyl-O-Ci-salkyl, C1- shaloalkyl, -O-haloCi-salkyl, -SO2Rº, -CN, -C (= O) NRºRI, - C (= O0) Re, -OC (= 0) Ri, -C (= 0) OR “, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocyclic group with 3 to 12 members, in which the heteroaryl, spiroheterocycloalkyl or heterocyclic groups oalkyl have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also in which the spiroheterocycloalkyl and heterocycloalkyl groups can include an S = O or SO>.
[000106] [000106] 59. The compound of any of Modes 1-58 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein the ol, 2, 3 or 4 R! º substituents are independently selected of -Ci «alkyl or a monocyclic heterocycloalkyl group with 3 to 12 members, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000107] [000107] 60. The compound of any of Modes 1-59 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R 1 is -Ci-salkyl.
[000108] [000108] 61. The compound of any one of Modes 1-59 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R! "º is a monocyclic heterocycloalkyl group with 3 to 12 members , in which the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000109] [000109] 62. The compound of any of Modes 1-53 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R * is a 5 to 12 membered bicyclic heterocycloalkyl group that the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.
[000110] [000110] 63. The compound of any of Modalities 1-52 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its
[000119] [000119] 72. The compound of any of Modalities 1, 2, 68-69 or 70 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -CH2CH2OCH; 3.
[000120] [000120] 73. The compound of any of Modalities 1, 2, 68-71 or 72 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H or -Ci-e alkyl.
[000121] [000121] 74. The compound of any of Modalities 1, 2, 68-71 or 72 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH;:.
[000122] [000122] 75. The compound of any of Modalities 1, 2, 68-71 or 72 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[000123] [000123] 76. The compound of any of Modalities 1, 2, 68-74 or 75 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H or -Ci-çe alkyl.
[000124] [000124] 77. The compound of any one of Modalities 1, 2, 68-75 or 76 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[000125] [000125] 578. The compound of any one of Modalities 1, 2, 68-75 or 76 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[000126] [000126] 79. The compound of any one of Modalities 1, 2, 68-77 or 78 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is independently selected from H, - Ci-haloalkyl, -C1- salkyl, -C7r-salkenyl, -Car-salquinyl, —- (CH2CH20) nRº, - C (= O) Ri, -C (= 0) ORº, -C (= O) NRºRb, -Ci-salkyl-O-Ci-salkyl, an aryl or heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl groups , spiroheterocycloalkyl and heterocycloalkyl may include a group C = O and also in which the groups spi ro-heterocycloalkyl and heterocycloalkyl can include an S = O or SO ;.
[000127] [000127] 80. The compound of any one of Modalities 1, 2, 68-78 or 79 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is -CH;:.
[000128] [000128] 81. The compound of any of Modalities 1, 2, 68-78 or 79 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -CH2CH; 3.
[000129] [000129] 82. The compound of any one of Modalities 1, 2, 68-80 or 81 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein RP is independently selected from H, Ci -haloalkyl, C1- salkyl, -Crystalkenyl, -Cresalquinyl - (CH2CH27O) nRêi, -SOJRº, -C (= O) Ri, -C (= 0) ORº, -C (= O) NRºRP, -NRºRº, -N = N = N, -Ci-salkyl- O-Ci-salkyl, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocyclical group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 hetero atoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a group C = O and also in which the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO> ;.
[000130] [000130] 83. The compound of any one of Modalities 1, 2, 68-81 or 82 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R * is -Ci-salkyl.
[000131] [000131] 84. The compound of any of Modalities 1, 2, 68-81 or 82 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -C (= O) Rº.
[000132] [000132] 85. The compound of any one of Modalities 1, 2, 68-81 or 82 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R * is a monocyclic or heterocycloalkyl group bicyclic with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000133] [000133] 86. The compound of any of Modalities 1, 2, 68-82 or 85 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ”is a monocyclic heterocycloalkyl group with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.
[000134] [000134] 87. The compound of any of Modalities 1, 2, 68-82 or 85-86 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein the monocyclic heterocycloalkyl group having 3 up to 12 Rº * º members may not be substituted or substituted with 1, 2, 3 or 4 R! º substituents independently selected from OH, halo, -NRºRi, -Ciealkyl, -Cr-salkenyl, -Corçalquinila, -OC1- salquila , -Ci-salkyl-oH, -Ci-salkyl-O-Ci-salkyl, C1r- 6ehaloalkyl, -O-haloCi-salkyl, -SO2Rº, -CN, -C (= O) NRºRI, - C (= O) Re, -OC (= O) Rº, -C (= 0) OR “, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocyclical group with 3 to 12 members, in which the heteroaryl, spiroheterocycloalkyl and heterocyclic groups cloalkyl have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also in which the spiroheterocycloalkyl and heterocycloalkyl groups can include an S = O or SO ;.
[000135] [000135] 88. The compound of any one of Modalities 1, 2, 68-82 or 85-86 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein the 1, 2, 3 or 4 R! º substituents are independently selected from -C1- salkyl or a monocyclic heterocycloalkyl group with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000136] [000136] 89. The compound of any of Modalities 1, 2, 68-82 or 85-88 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R "º is -Ci -salkyl.
[000137] [000137] 90. The compound of any one of Modalities 1, 2, 68-82 or 85-88 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R! º is a group monocyclic heterocycloalkyl with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000142] [000142] 95. The compound of any of Modalities 1, 2 or 93-94 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where D is independently selected from H, -Ci- salkyl, -Ci-salkyl-halo, -Ci-salkyl-O-Ci-salkyl or - (CH2CH2O) nRº, where -C-calkyl is not substituted or substituted with -OH, - (= 0), phenyl , -O-SiRºRPRºe, -NR6RP, a cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl with 3 to 12 members having 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000143] [000143] 96. The compound of any of Modalities 1, 2 or 93-95 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[000144] [000144] 97. The compound of any one of Modalities 1, 2 or 93-95 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where D is -CH> CH; OCH3.
[000145] [000145] 98. The compound of any of Modalities 1, 2 or 93-97 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H or -C1 salkyl.
[000146] [000146] 99. The compound of any one of Modalities 1, 2 or 93-98 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[000147] [000147] 100. The compound of any of Modalities 1, 2 or 93-98 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[000148] [000148] 101. The compound of any one of Modalities 1, 2 or 93-100 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H or -C1-salkyl.
[000149] [000149] 102. The compound of any one of Modalities 1, 2 or 93-101 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[000150] [000150] 103. The compound of any of Modalities 1, 2 or 93-101 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[000151] [000151] 104. The compound of any of Modalities 1, 2 or 9293-103 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is independently selected from H, -Ci- haloalkyl, -Ci- salkyl, -Co-salkenyl, -Co-salquinyl, - (CH2CH20) nRº, - C (= O0) Ri, -C (= 0) ORi, -C (= O) NRºRb, -Cisalquil- O-Cisalkyl, an aryl or heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or heterocycloalkyl group bicyclic with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups can include a C = O group and also where the h-spiro groups etherocycloalkyl and heterocycloalkyl may include an S = O or SO ;.
[000152] [000152] 105. A compound of any of Modalities 1, 2 or 93-104 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH;:.
[000153] [000153] 106. A compound of any one of Modalities 1, 2 or 93-104 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -CH2CH; 3.
[000154] [000154] 107. A compound of any one of Modalities 1, 2 or 93-104 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -H
[000155] [000155] 108. A compound of any of Modalities 1, 2 or 93-107 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R * is independently selected from H, Cighaloalkyl, C1 calkyl, -Crçalquenyl - (CH2CH20O) ninRi, -SO2Ri, -C (= O) R, - C (= 0) ORº, —C (= O) NRAR>, -NRºRP, -N = N = N, - Ci-salquil-o-C1- salquila, an aryl with 6 to 12 members, a heteroaryl with
[000156] [000156] 109. The compound of any one of Modalities 1, 2 or 93-108 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -Ci «alkyl.
[000157] [000157] 110. The compound of any one of Modalities 1, 2 or 93-108 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R * is -C (= O) Rº .
[000158] [000158] 111. The compound of any of Modalities 1, 2 or 93-108 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ”is a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000159] [000159] 112. The compound of any of Modalities 1, 2, 93-108 or 111 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R * is a monocyclic heterocycloalkyl group with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.
[000160] [000160] 113. The compound of any one of Modalities 1, 2, 93-108 or 112 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein the monocyclic heterocycloalkyl group having 3 to 12 R ** members may be unsubstituted or substituted with 1, 2, 3 or 4 R! º substituents independently selected from OH, halo, -NRºRi, c-Cigalquila, -Coçalquenila, -Co-salquinila, -OC1i- calquila, -Ci-salkyl-OH, -Ci-salkyl-O-Ci-salkyl, C1- shaloalkyl, -O-haloCi-salkyl, -SO2Rº, -CN, -C (= O) NRºRI, - C (= O0) Re , -OC (= 0) Ri, -C (= 0) OR “, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 up to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocyclical group with 3 to 12 members, in which the heteroaryl, spiroheterocycloalkyl and heterocyclic groups cloalkyl have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also in which the spiroheterocycloalkyl and heterocycloalkyl groups can include an S = O or SO>.
[000161] [000161] 114. The compound of any of Modalities 1, 2, 93-108 or 112-113 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein the 1, 2, 3 or 4 R! º substituents are independently selected from -C1- salkyl or a monocyclic heterocycloalkyl group with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000162] [000162] 115. The compound of any of Modalities 1, 2, 93-108 and 112-114 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is -Ci-salquila .
[000163] [000163] 116. The compound of any of Modalities 1, 2, 93-108 or 112-113 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R! | º is a monocyclic heterocycloalkyl group with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000164] [000164] 117. The compound of any one of Modalities 1, 2, 93-108 or 111 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ”is a bicyclic heterocycloalkyl group with 5 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.
[000165] [000165] 118. The compound of any one of Modalities 1, 2 or 93-108 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[000170] [000170] 123. The compound of any of Modalities 1, 2 or 119-121 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH> CH; OCH; 3 .
[000171] [000171] 124. The compound of any of Modalities 1, 2 or 119-123 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H or -Ci-e alkyl.
[000172] [000172] 125. The compound of any of Modalities 1, 2 or 119-124 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[000173] [000173] 126. The compound of any one of Modalities 1, 2 or 119-125 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[000174] [000174] 127. The compound of any of Modalities 1, 2 or 119-126 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H or -Ci-e alkyl.
[000175] [000175] 128. The compound of any one of Modalities 1, 2 or 119-127 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[000176] [000176] 129. The compound of any of Modalities 1, 2 or 119-127 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[000177] [000177] 130. The compound of any of Modalities 1, 2 or 119-129 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is independently selected from H, -Ci- haloalkyl, -C1- salkyl, -Crsalkenyl, - (CHXCH20) nRº, -C (= O) Rº, -C (= 0) OR, - C (= O) NRARP, -Cisalkyl-O-Ci-salquila, one 6 to 12 membered aryl or heteroaryl, 5 to 12 membered spirocycloalkyl or spiroheterocycloalkyl, 3 to 12 membered cycloalkenyl, 3 to 12 membered monocyclic or bicyclic cycloalkyl, or 3 to 12 monocyclic or bicyclic heterocycloalkyl group members, in which the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a group C = O and also in which the spiro-heterocycloalkyl and heterocycloalkyl may include an S = O or SO> ;.
[000178] [000178] 131. The compound of any one of Modalities 1, 2 or 119-130 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[000179] [000179] 132. The compound of any of Modalities 1, 2 or 119-130 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -CH2CH; 3.
[000180] [000180] 133. The compound of any one of Modalities 1, 2 or 119-132 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R * is independently selected from H, Cy- haloalkyl, C1- csalkyl, -Corçsalquenila - (CH2CH2O) níRºi, -SO2Rº, -C (= O) RA, - C (= 0) ORº, —C (= O) NRºR>, -NRºRP, -N = N = N, -Ci-salkyl-O-C1- salkyl, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, one monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocyclical group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S , in which the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a group C = O et also where the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO> ;.
[000181] [000181] 134. The compound of any of Modalities 1, 2 or 119-133 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -Ci «alkyl.
[000182] [000182] 135. The compound of any one of Modalities 1, 2 or 119-113 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is -C (= O) Rº.
[000183] [000183] 136. The compound of any of Modalities 1, 2 or 119-133 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R * º is a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 hetero atoms independently selected from O, N or S.
[000184] [000184] 137. The compound of any of Modalities 1, 2, 119-133 or 136 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ”is a monocyclic heterocycloalkyl group with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O or N.
[000185] [000185] 138. The compound of any of Modalities 1, 2, 119-133 or 136-137 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein the monocyclic heterocycloalkyl group having 3 up to 12 R ** members may be unsubstituted or substituted with 1, 2, 3 or 4 R! º substituents independently selected from OH, halo, -NRºRi, c-Ciçalquila, -Coçalquenila, -Corçalquinila, -OC1- salquila, -Ci-salkyl-OH, -Ci-salkyl-O-Ci-salkyl, Cir shaloalkyl, -O-haloCi-salkyl, -SO2Rº, -CN, -C (= O) NRºRI, - C (= O0) Re, -OC (= 0) Ri, -C (= 0) OR “, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocyclical group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and hetero groups rocycloalkyl have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also in which the spiroheterocycloalkyl and heterocycloalkyl groups can include an S = O or SO ;.
[000186] [000186] 139. The compound of any of Modalities 1, 2, 119-133 or 136-138 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein 1, 2, 3 or 4 R! º substituents are independently selected from -C1- salkyl or a monocyclic heterocycloalkyl group with 3 to 12 members, where the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.
[000187] [000187] 140. The compound of any of Modalities 1, 2, 119-133 or 136-139 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is -Ci-salquila .
[000188] [000188] 141. The compound of any one of Modalities 1, 2, 119-133 or 136-139 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R! | º is a monocyclic heterocycloalkyl group with 3 to 12 members, in which
[000199] [000199] 152. The Mode 149 method, in which cancer is multiple myeloma.
[000200] [000200] 153. The Mode 149 method, also comprising "administering to the needy patient a therapeutically effective amount of an additional pharmaceutically active compound.
[000201] [000201] 154. The Mode 153 method, wherein the additional pharmaceutically active compound is carfilzomib.
[000202] [000202] 155. The Mode 153 method, wherein the additional pharmaceutically active compound is venetoclax.
[000203] [000203] 156. The Mode 153 method, wherein the additional pharmaceutically active compound is cytarabine.
[000204] [000204] 157. Another embodiment of the present invention comprises the use of a compound according to any of Modalities 1-147 for the treatment of cancer in a subject.
[000205] [000205] 158. Another embodiment of the present invention comprises the compound according to any of Modes 1-147 in the preparation of a medicament for the treatment of cancer.
[000206] [000206] 159. The compound according to Modality 158, in which cancer is a hematological malignancy.
[000207] [000207] 160. The compound according to Modality 158, in which the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, cancer non-small cell lung, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia and acute myelogenous leukemia.
[000215] [000215] 4. The compound of any of the modalities 1-3 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Q is O, NRºNRP or S.
[000216] [000216] 5. The compound of any of modalities 1-4 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Q is O.
[000217] [000217] &. The compound of any of the modalities 1- or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where W is CRWRWB, -C = O or is absent.
[000218] [000218] 7. The compound of modality 5 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where W is CRWARVE,
[000219] [000219] & 8. The compound of modality 5 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where W is absent.
[000220] [000220] 9. The compound of any of the modalities 1-7 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº and RV are independently selected from H, (= O), -Ci-zalkyl, -Co-zalkenyl, -Co-r 3zalquinyl, halo, -OH or -O-Ci-zalkyl.
[000221] [000221] 10. The compound of modality 9 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where RM and R "P are both H.
[000222] [000222] 11. The compound of modality 9 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where RA is -CH3.
[000223] [000223] 12. The compound of modality 9 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R "P is -CH3.
[000224] [000224] 13. The compound of modality 9 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where RM is -OH and Rº is H.
[000225] [000225] 14. The compound of any of the modalities 1-13 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R 'is halo.
[000226] [000226] 15. The compound of modality 14 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R 'is Cl.
[000227] [000227] 16. The compound of any of the modalities 1- or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is selected from H and -Ci-salquila.
[000228] [000228] 17. The compound of modality 16 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R ° is -CH3.
[000234] [000234] 23. The compound of any of the modalities 1-22 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is selected from H or -Ci-salkyl.
[000235] [000235] 24. The compound of modality 23 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[000236] [000236] 25. The compound of any of the modalities 1-24 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein Rº is independently selected from H, -Cisalkyl, -Ci; haloalkyl , -Cisalkyl-O-Ci-salkyl, - Ci-salkyl- (5-6 membered heterocycloalkyl), where the heterocycloalkyl has one or two heteroatoms independently selected from N or O, or -Ci-salkyl-phenyl, where the phenyl of the -Ci-salkyl-phenyl of the groups Rº is not substituted or is substituted with 1 or 2 substituents R ! selected from halo or -Ci-salkyl-O-C1- salkyl.
[000237] [000237] 26. The compound of modality 25 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is independently selected from H, -CH3, -CH2CH3, -
[000267] [000267] 56. The compound of modality 55 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where W is CRWARKE,
[000268] [000268] 57. The compound of modality 55 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where W is absent.
[000269] [000269] 58. The compound of any of modalities 1 or 49-56 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein RM and R 'are independently selected from EH, -Ci -3alkyl, -C1- zalkenyl, -Ci-zalquinyl, halo, -OH or -O-Ci-zalkyl.
[000270] [000270] 59. The compound of modality 58 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rtº and RB are both H.
[000271] [000271] 60. The compound of modality 58 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where RW is -CH3.
[000272] [000272] 61. The compound of modality 58 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein at least one of RW and R "and is H,
[000273] [000273] 62. The compound of modality 58 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where RM is -OH and Rº is H.
[000274] [000274] 63. The compound of any one of modalities 1 or 49-62 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R! it's halo.
[000275] [000275] 64. The compound of modality 63 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R! is Cl.
[000276] [000276] 65. The compound of any of the modalities 1 or 49-64 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[000277] [000277] 66. The compound of any one of modalities 1 or 49-65 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R ° is independently selected from H or -Ci-salkyl.
[000278] [000278] 67. The compound of modality 66 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH; 3.
[000279] [000279] 68. The compound of any one of modalities 1 or 49-67 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R ° is selected from H or -Ci-salkyl.
[000280] [000280] 69. The compound of modality 68 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is -CH3.
[000281] [000281] 70. The compound of any of modalities 1 or 49-69 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[000282] [000282] 71. The compound of any of modalities 1 or 49-70 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R 'is selected from H or -NRºRb.
[000283] [000283] 72. The compound of modality 71 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R 'is H.
[000284] [000284] 73. The compound of any one of modalities 1 or 49-73 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein R ° is selected from H or -Ci-salkyl.
[000285] [000285] 74. The compound of modality 73 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where R is H.
[000286] [000286] 75. The compound of any one of modalities 1 or 49-70 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, in which, alternatively, R 'and Rº, together with the atoms to which they are attached, can form a ring with 3 to 12 members.
[000287] [000287] 76. The compound of any one of modalities 1, 49-70 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, in which, alternatively, R 'and Rº%, together with the atoms to which they are attached can form a ring with 3 to 12 members, where the ring can optionally contain at least one double bond.
[000288] [000288] 77. The compound of any one of modalities 1, 49-76 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, where Rº is independently selected from H, -OH, - ( = O), -Ci-alkyl, cyano, -C (= O) -Cylalkyl, -C (= 0) -phenyl, -Ci-salkyl-O-Ci-salkyl, -Ci-salkyl- (heterocycloalkyl mono- or 5-10 membered bicyclic), where the heterocycloalkyl may contain one, two, three or four heteroatoms independently selected from N or O.
[000289] [000289] 78. The compound of any of the modalities 1 or 49-75 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, in which, alternatively, Rº and R * º%, together with Q, W and the C to which Q and W are attached, they can form a monocyclic or bicyclic ring with 3 to 12 members, optionally containing a heteroatom in addition to Q selected from the atom of N, O or S, the ring can contain a double bond, the ring may optionally include a C = O group and the ring may be optionally substituted with 0, 1, 20 or 3 R1 substituents;
[000290] [000290] 79. The compound of any of modalities 1, 49-75 or 77 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, wherein RP is independently selected from H, -OH, -Cicalkyl, -Cao-6 alkenyl, -Corçalquinyl, -Cisalkyl, -C (= O), - (= O), - C (= O) Ra, cyano, -Ci-salquyl-O-Ci-salquila, - O-Ci-salquyl-O-C1i- csalkyl, -ORa, -CSRa, -CS (= O) Ra, -SORa, -NRaRb, - C (= O) NRaRb, phenyl, an aryl or heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members or a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, in which the heteroaryl groups and heterocycloalkyl have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S and the cycloalkyl and heterocycloalkyl groups may contain a double bond and in which the cycloalkyl groups are h etherocycloalkyl is one of embodiments 1-92 or a pharmaceutically acceptable salt thereof.
[000307] [000307] 95. The method of modality 94, in which cancer is a hematological malignancy.
[000308] [000308] 9. The method of modality 94, in which cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, lung cancer of non-small cells, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia and acute myelogenous leukemia.
[000309] [000309] 97. The method of modality 94, in which cancer is multiple myeloma.
[000310] [000310] 598. method of embodiment 94, also comprising "administering to the needy patient a therapeutically effective amount of an additional pharmaceutically active compound.
[000311] [000311] 99. The method of modality 98, wherein the additional pharmaceutically active compound is carfilzomib.
[000312] [000312] 100. The method of modality 98, wherein the additional pharmaceutically active compound is venetoclax.
[000313] [000313] 101. The method of modality 98, wherein the additional pharmaceutically active compound is cytarabine.
[000314] [000314] 102. Another embodiment of the present invention comprises a use of a compound according to any of Modalities 1-92 for the treatment of cancer in a subject.
[000315] [000315] 103. Another embodiment of the present invention comprises a compound according to any of the
[000316] [000316] 104. The compound according to Modality 103, in which cancer is a hematological malignancy.
[000317] [000317] 105. The compound according to modality 102, in which the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, cancer non-small cell lung, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia and acute myelogenous leukemia.
[000318] [000318] 106. The compound according to Mode 102, in which the cancer is multiple myeloma.
[000319] [000319] 107. The compound according to Mode 102, in which the cancer is acute myelogenous leukemia.
[000320] [000320] 108. The compound according to Mode 102, in which the cancer is non-Hodgkin's lymphoma.
[000321] [000321] Another embodiment of the present invention is directed to a method of inhibiting myeloid cell leukemia protein 1 (Mcl-1) of a cell, comprising contacting the cell with the compound of Formula I in an amount effective to inhibit Mcl -l, in conjunction with any of the above or below modalities. In one embodiment, contact is made in vitro. In another mode, contact is made in vivo. In one embodiment, contact comprises administering the compound to a subject. In one embodiment, administration is oral, parenteral, via injection, via inhalation, transdermal or transmucosal. In one embodiment, the subject suffers from cancer.
[000322] [000322] One embodiment of the present invention is directed to a method of treating cancer, comprising administering to a patient in need a therapeutically effective amount of the compound of Formula I or a pharmaceutical composition comprising the compound of Formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient, in conjunction with any of the above or below modalities. In one embodiment, cancer is a hematological malignancy. In one embodiment, cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-lymphoma Hodgkin, myeloma, multiple myeloma, leukemia and acute myelogenous leukemia. In one embodiment, cancer is multiple myeloma. In another embodiment, the method also comprises the step of administering to the needy patient a therapeutically effective amount of at least one additional pharmaceutically active compound. In one embodiment, the additional pharmaceutically active compound is carfilzomib, in conjunction with any of the above embodiments.
[000323] [000323] The methods provided here include the preparation and use of pharmaceutical compositions that include one or more of the compounds provided here. Also included are the pharmaceutical compositions themselves.
[000324] [000324] In some Claims, a compound provided herein may contain one or more acidic functional groups and, thus, is capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term
[000325] [000325] Wetting, emulsifying and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.
[000326] [000326] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gall,
[000327] [000327] A pharmaceutical composition can also contain adjuvants such as preservatives, agents - wet emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, sorbic acid phenol and the like. It may also be desirable to include tonicity adjusting agents, such as sugars and the like, in the compositions. In addition, the prolonged absorption of the injectable pharmaceutical form can be conferred by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.
[000328] [000328] In some cases, to prolong the effect of one or more compounds provided here, it is desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. For example, delayed absorption of a compound administered parenterally can be achieved by dissolving or suspending the compound in an oily vehicle.
[000329] [000329] The compounds of the present invention are administered to a patient in a therapeutically effective amount. the compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, compounds or compositions can be administered all at once, for example, by an injection of Dbolus,
[000330] [000330] The compounds of the present invention and, in some Claims, other additional pharmaceutically active compounds, can be administered to a patient orally, rectally, parenterally (e.g., intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesical, local (for example, powders, ointments or drops) or as a mouth or nasal spray. all methods that are used by those skilled in the art to administer a pharmaceutically active agent are contemplated.
[000331] [000331] Compositions prepared as described herein can be administered in various forms, depending on the disorder to be treated and the age, condition and weight of the patient's body, as is well known in the art. For example, when the compositions are to be administered orally, they can be formulated as tablets, capsules, granules, powders or syrups; or, for parenteral administration, they can be formulated as injections (intravenous, intramuscular or subcutaneous), drops infusion preparations or suppositories. For application via the ophthalmic mucous membrane, they can be formulated as eye drops or eye ointments. These formulations can be prepared by conventional means in conjunction with the methods described herein, and, if desired, the active ingredient can be mixed with any conventional additive or excipient, such as a binder, disintegrating agent, lubricant, corrector, solubilizing agent, suspending aid, emulsifying agent or coating agent.
[000332] [000332] Formulations suitable for oral administration can be in the form of capsules (for example, gelatin capsules), cachets (cachets), pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth) , powders, sucking tablets, granules or as a solution or a suspension in an aqueous or non-aqueous liquid or as a liquid oil-in-water or water-in-oil emulsion or as an elixir or syrup or as lozenges (using a inert matrix, such as gelatin and glycerin or sucrose and acacia) and / or as mouthwashes and the like, each containing a predetermined amount of a compound provided herein as an active ingredient. A composition can also be administered as a bolus, eletuary or paste. Oral compositions generally include an inert diluent or an edible carrier.
[000333] [000333] Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of an oral composition. In solid dosage forms for oral administration (capsules, tablets, pills, pills, powders, granules and the like), the active ingredient can be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, cyclodextrins, lactose, sucrose, saccharin, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, microcrystalline cellulose, tragacanth gum, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato starch, corn or tapioca, alginic acid, Primogel, certain silicates and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, Sterotes, solid polyethylene glycols sodium lauryl sulfate and mixtures thereof; (10) a sliding agent, such as colloidal silicon dioxide; (11) coloring agents, and (12) a flavoring agent such as peppermint, methyl salicylate or orange flavoring. In the case of capsules, tablets and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft or hard filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
[000334] [000334] A tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binder (for example, gelatin or hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active agent or dispersant. Molded tablets can be prepared by molding, in a suitable machine, a mixture of a powdered compound moistened with an inert liquid diluent.
[000335] [000335] Tablets and other solid dosage forms, such as pills, capsules, pills and granules, can optionally be grooved or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile, other polymeric matrices, liposomes, microspheres and / or nanoparticles. They can be sterilized, for example, by filtration through a filter that retains bacteria or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or other sterile injectable medium, immediately before use. These compositions may also optionally contain opacifying agents and may have a composition such that they release the active ingredient (s) only, or preferably, in a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the excipients described above.
[000336] [000336] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed oils, peanuts, corn, germ, olive oil, castor and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids and their mixtures.
[000337] [000337] In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring, coloring, perfuming and preservatives.
[000338] [000338] Suspensions, in addition to the active compound (s), may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum meta-hydroxide, bentonite , agar-agar, tragacanth and their mixtures.
[000339] [000339] Pharmaceutical compositions suitable for parenteral administration may include one or more compounds provided herein in combination with one or more sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or pharmaceutically acceptable powders that can be reconstituted in sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostatic agents, solutes that make the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
[000340] [000340] In a Claim, formulation IV consists of a composition containing hydroxypropyl-beta-cyclodextrin within a pH range between 8-10 as a buffered or non-buffered solution. Formulation IV can be formulated as a sterile solution ready for injection, a sterile solution ready for dilution in an IV mixture or a sterile solid for reconstitution. The API in formulation IV can exist as a free acid / base or a salt in situ.
[000341] [000341] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions provided herein include water for injection (e.g., sterile water for injection), bacteriostatic water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol such as liquid polyethylene glycol and the like), sterile buffer (such as citrate buffer) and their suitable mixtures, vegetable oils such as olive oil, injectable organic esters such as ethyl oleate, and Cremophor EL "(BASF, Parsippany, NJ). In all the cases, the composition must be sterilized and must be fluid so that there is an easy handling capacity with a syringe. The appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions and the use of surfactants.
[000342] [000342] The composition must be stable under the conditions of preparation and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In many cases it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, and sodium chloride in the composition. The prolonged absorption of the injectable compositions can be conferred by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
[000343] [000343] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients listed above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the other ingredients required from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are freeze-drying (freeze-drying), which gives rise to a powder of the active ingredient, plus any desired additional ingredient from a previously sterile filtered solution.
[000344] [000344] Injectable deposit forms can be produced by forming microencapsulated or nanoencapsulated matrices of a compound provided here in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug-to-polymer ratio and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by trapping the drug in liposomes, microemulsions or nanoemulsions that are compatible with body tissue.
[000345] [000345] For administration by inhalation, the compounds can be administered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant (for example, a gas such as carbon dioxide) or a nebulizer. Such methods include those described in U.S. Patent No. 6,468,798. In addition, intranasal administration can be performed as described, inter alia, in Hamajima et al., Clin. Immunol. Immunopathol., 88 (2), 205-10 (1998). Liposomes (for example, as described in U.S. Patent No. 6,472,375, which is incorporated herein by reference in its entirety),
[000346] [000346] Systemic administration of a therapeutic compound as described here can also be carried out by transmucosal or transdermal means. Dosage forms for topical or transdermal administration of a compound provided herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, dressings and inhalants. The active component can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts and fusidic acid derivatives. Transmucosal administration can be performed using nasal sprays or suppositories. For transdermal administration, the compounds are formulated in ointments, balms, gels or creams, as is generally known in the art.
[000347] [000347] Ointments, pastes, creams and gels may contain, in addition to one or more compounds provided here, excipients, such as animal and vegetable fats, oils,
[000348] [000348] Powders and sprays may contain, in addition to a compound provided here, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and powdered polyamide or mixtures of these substances. The sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
[000349] [000349] A compound provided herein can be administered by aerosol. This is achieved by preparing an aqueous aerosol, liposomal preparation or solid particles containing a compound or composition provided herein. A non-aqueous suspension (for example, fluorocarbon propellant) can be used. In some Claims, sonic nebulizers are used because they minimize the exposure of the agent to shear, which can result in degradation of the compound.
[000350] [000350] Usually, an aqueous aerosol can be prepared by formulating an aqueous solution or suspension of the agent, together with conventional pharmaceutically acceptable carriers and stabilizers. carriers and stabilizers vary with the requirements of the particular composition, but typically include non-ionic surfactants (TWEENº (polysorbates), PLURONICº (poloxamers), sorbitan esters, lecithin, CREMOPHORº (polyethoxylates)), pharmaceutically acceptable co-solvents such as polyethylene glycol, proteins innocuous such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.
[000351] [000351] Transdermal patches have the additional advantage of providing controlled delivery to the body of a compound provided here. Such dosage forms can be prepared by dissolving or dispersing the agent in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate of such flow can be controlled by providing a rate control membrane or by dispersing the compound in a polymeric matrix or gel.
[000352] [000352] Pharmaceutical compositions can also be prepared in the form of suppositories or retention enemas for rectal and / or vaginal administration. Formulations presented as a suppository can be prepared by mixing one or more compounds provided herein with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, glycerides, polyethylene glycol, a suppository wax or a salicylate, which is solid at room temperature, but liquid at body temperature and, consequently, will fuse in the rectum or vaginal cavity and release the active agent. Formulations that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers that are known in the art to be suitable.
[000353] [000353] In a claim, the active compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including microencapsulated implants and delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Such formulations can be prepared using standard techniques or obtained commercially (for example, from Alza Corporation and Nova Pharmaceuticals, Inc). Liposomal suspensions (including liposomes targeted to selected cells with monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811, which is incorporated herein by reference in its entirety for all purposes.
[000354] [000354] The compounds of the present invention are used in the treatment of diseases, disorders or symptoms mediated by inhibition of Mcl-1. Examples of diseases, disorders, or symptoms mediated by Mcl-1 inhibition include, but are not limited to, cancers. Non-limiting examples of cancers include breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma , leukemia and acute myelogenous leukemia.
[000355] [000355] Cancers can include carcinomas (originating in the outer layer of skin cells and internal membranes, for example, breasts, kidneys, lungs, skin); sarcomas (from connective tissue such as bone, muscle, cartilage and blood vessels), and haematological malignancies (for example, lymphomas and leukemias, which arise in the blood or blood-forming organs such as the spleen, lymph nodes and bone marrow). Cancer cells can include, for example, tumor cells, neoplastic cells, malignant cells, metastatic cells and hyperplastic cells.
[000356] [000356] In a Claim, the disease, disorder or symptom is a hyperproliferative disorder, for example, lymphoma, leukemia, carcinoma (e.g., renal, breast, lung, skin), multiple myeloma or a sarcoma. In a Claim, leukemia is acute myeloid leukemia. In a Claim, the hyperproliferative disorder is a relapsing or refractory cancer.
[000357] [000357] Actual dosage levels of the active ingredients in the pharmaceutical compositions provided here can be varied in order to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition and mode of administration without being toxic to the patient. the patient.
[000358] [000358] The specific dosage and dosage range depends on some factors, including the patient's requirements, the severity of the condition or disease being treated, the pharmacokinetic characteristics of the compound (s) employed and the route of administration. In some Claims, the compositions provided herein may be provided in an aqueous solution containing about 0.1-10% w / v of a compound disclosed herein, among other substances, for parenteral administration. Typical dose ranges may include from about 0.01 to about 50 mg / kg body weight per day, administered in 1-4 divided doses. Each divided dose can contain the same or different compounds. The dosage will be a therapeutically effective amount depending on several factors including the general health status of a patient and the formulation and route of administration of the selected compound (s).
[000359] [000359] Dosage forms or compositions containing a compound can be prepared as described herein in the range of 0.005% to 100% with the balance consisting of a non-toxic carrier. Methods for preparing these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001% -100% active ingredient, in one claim from about 0.1 to about 95%, in another claim from about 75 to about 85%. Although the dosage varies depending on the symptoms, age and weight of the patient's body, the nature and severity of the disorder to be treated or prevented, the route of administration and the form of the drug, in general, a daily dosage from about 0, 01 up to about 3,000 mg of the compound is recommended for an adult human patient and it can be administered in a single dose or in divided doses. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect.
[000360] [000360] The pharmaceutical composition can be administered at once or can be divided into a few smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and can be determined empirically using known test protocols or by extrapolating test data in vivo or in vitro. It should be noted that concentrations and dosage values can also vary with the severity of the condition being relieved. It should be further understood that, for any particular patient, the specific dosage regimens must be adjusted over time according to the individual need and the professional assessment of the person administering or supervising the administration of the compositions, and that the ranges of concentrations presented here they are merely exemplary and are not intended to limit the scope or practice of the Claimed compositions.
[000361] [000361] The precise timing of administration and / or amount of the composition that will give the most effective results in terms of treatment effectiveness in a given patient will depend on the activity, pharmacokinetics and bioavailability of a particular compound, the patient's physiological state (including age, sex, type and stage of the disease, general physical condition, responsiveness to a certain dosage and type of medication), route of administration, etc. However, the above guidelines can be used as a basis for fine-tuning treatment, for example, determining the optimal timing and / or amount of administration, which will require no more than routine experimentation consisting of patient monitoring and adjustment dosage and / or timing.
[000362] [000362] The compounds of the present invention can be administered alone, in combination with other compounds of the present invention or with other compounds or pharmaceutically active agents. the other pharmaceutically active compounds / agents may be used to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is intended to receive or is receiving multiple compounds or pharmaceutically active agents, the compounds can be administered simultaneously or sequentially.
[000363] [000363] The compounds of the present invention or their pharmaceutically acceptable salts can be used in combination with one or more additional pharmaceutically active compounds / agents.
[000364] [000364] One or more additional compounds or pharmaceutically active agents may be administered separately, as part of a multiple dose regimen, of the compound of Formula I (for example, sequentially, for example, in different overlapping schedules with the administration of one or more more compounds of Formula I (including any subgenera or specific compounds) In other Claims, the one or more additional compounds / agents may form part of a single dosage form, mixed together with the compound of Formula I in a single composition In yet another Claim, the one or more additional compounds / agents can be administered as a separate dose which is administered at approximately the same time as one or more compounds of Formula I are administered (for example, simultaneously with the administration of one or more plus Formula I compounds (including any subgenera or specific compounds). The Formula I compound and the one or more Additional compounds / agents can be present at dosage levels between about 1 and 100% and more preferably between about 5 and 95% of the dosage normally administered in a monotherapy regimen.
[000365] [000365] In a particular claim, the additional pharmaceutically active compound / agent is a compound or agent that can be used to treat cancer. For example, the additional pharmaceutically active compound / agent can be selected from antineoplastic agents, antiangiogenic agents, chemotherapeutic agents and peptide agents for cancer therapy. In another Claim, antineoplastic agents are selected from antibiotic type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon type agents, kinase inhibitors, proteasome inhibitors and combinations thereof. Note that the additional pharmaceutically active compound / agent can be a small organic chemical molecule or it can be a macromolecule such as a protein, antibody, peptibody, DNA, RNA or a fragment of such macromolecules.
[000366] [000366] Examples of additional pharmaceutically active compounds / agents that can be used in the treatment of cancers and that can be used in combination with one or more compounds of the present invention include: acemanan; aclarrubicin; aldesleukin; alitretinoin; amifostine; amrubicin; amsacrine; anagrelide; arglabine; arsenic trioxide; BAM 002 (Skeins); bicalutamide; broxuridine; cellmoleucine; cetrorelix; cladribine; clotrimazole; cytarabine; DA 3030 (Dong-A); daclizumab; diphthitox denileucin; deslorelin; dilazep; docosanol; doxercalciferol; doxifluridine; bromocriptine; cytarabine; HIT diclofenac; alpha interferon; tretinoin; edelfosine; edrecolomab; eflornithine; emitefur; epirubicin; beta epoetin; etoposide phosphate; exisulind; fadrozole; finasteride; fludarabine phosphate; formestane; fotemustine; gallium nitrate; gemtuzumab zogamycin; combination of gimeracil / oteracil / tegafur; glycopine; goserelin; heptaplatin; human chorionic gonadotropin; human fetal alpha fetoprotein; ibandronic acid; alpha interferon; natural alpha interferon; alpha-2 interferon; interferon alfa-2a; interferon alfa-2b; alpha-Nl1 interferon; alpha-n3 interferon; interferon alfacon-1; natural alpha interferon; beta interferon; interferon beta it; beta-lb interferon; natural gamma interferon; interferon gamma it; gamma-lb interferon; interleukin-1 beta; iobengguan; irsogladina; lanreotide; LC 9018 (Yakult); leflunomide; lenograstim; lentinan sulfate; letrozole; leukocyte alpha interferon; leuprorelin; levamisole + fluorouracil; liarozole; lobaplatin; lonidamine; lovastatin; masoprocol; melarsoprol; metoclopramide; mifepristone; miltefosine; mirimostim; Double-stranded RNA with faulty pairing; mitoguazone; mitolactol; mitoxantrone; molgramostim; nafarelin; naloxonatpentazocine; nartograstim; nedaplatin; nilutamide; noscapine; new erythropoiesis-stimulating protein; octreotide NSC 631570; oprelvecin; osaterone; Ppaclitaxel; pamidronic acid; peginterferon alfa-2b; 243 trimethyl sodium polysulfate; pentostatin; picibanil; pirarrubicin; polyclonal rabbit anti-thymocyte antibody; polyethylene glycol interferon alfa-2a; porfimer sodium; raltitrexed; rasburicase; rhenium ethydronate Re 186; retinamide RII; ruptured; samarium lexidronam (153 Sm); sargramostim; sizofuran; sobuzoxane; sonermine; strontium chloride-89; suramin; tasonermin; tazarotene; tegafur; temoporfin; teniposide; tetrachlorodecaoxide; timalfasin; thyrotropin alfa; toremifene; tositumomab-iodine 131; thosulfan; tretinoin; trilostane; trimetrexate; triptorelin; trametinib; tumor necrosis factor alpha natural; ubenimex; bladder cancer vaccine; Maruyama vaccine; melanoma lysate vaccine; valrubicin; venetoclax; verteporphine; virulizine; estimator of zinostatin; abarelix; AE 941 (Aeterna); ambamustine; antisense oligonucleotide; bcl-2 (Genta); APC 8015 (Dendreon); dexaminoglutetimide; diaziquone; EL 532 (Elan); EM 800 (Endorecherche); eniluracil; etanidazole; fenretinide; galocitabine; gastrin immunogen 17; gene therapy with HLA-B7 (Vical); macrophage granulocyte colony stimulating factor; histamine dihydrochloride; ibritumomab tiuxetan; ilomastat; IM 862 (Cytran); interleukin-2; iproxifene; LDI 200 (Milkhaus); leridistim; lintuzumab; monoclonal antibody (Mab) against CA 125 (Biomira); Cancer Mab (Japan Pharmaceutical Development); Mab against HER-2 and Fc (Medarex); Idiotypic Mab 105AD7 (CRC Technology); Mab against idiotypic CEA (Trilex); Mab against LYM-1-iodine 131 (Techniclone); Mab against polymorphic epithelial mucin-yttrium 90 (Antisoma); marimastat; menogaryl; mitumomab; gadolinium motexafin; MX 6 (Galderma); nolatrexed; protein P 30; pegvisomant; porphyromycin; prinomastat; RL 0903 (Shire); rubitecan; satraplatin; sodium phenylacetate; sparphosic acid; SRL 172 (SR Pharma); SU 5416 (SUGEN); TA 077 (Tanabe); tetrathiomolybdate; taliblastin; thrombopoietin; tin ethylethiopurpurin; tirapazamine; cancer vaccine (Biomira); melanoma vaccine; melanoma oncolisate vaccine; viral vaccine for melanoma cell lysates; valspodarl; fluorouracil; 5-fluorouracil; 244 trimethyl; imatinib; altretamine; cladibrin; cyclophosphamine; decarazine; irinotecan; mitosmycin; mitoxane; topotecan; Vvinorelbine; 244 trimethyl; miter; imiquimod; alemtuzmab; exemestane; bevacizumab; cetuximab; azacytidine; clofarabine; decitabine; desatinib; dexrazoxane; docetaxel; epirubicin; oxaliplatin; erlotinib; raloxifene; fulvestrant; letrozole; gefitinib; gemtuzumab; trastuzumab; gefitinib; ixabepilone; lapatinib; lenalidomide; aminolevulinic acid; temozolomide; nelarabine; sorafenib; nilotinib; pegaspargase; pemetrexed;
[000367] [000367] Additional pharmaceutically active compounds / agents that can be used in the treatment of cancers and that can be used in combination with one or more compounds of the present invention include: epoetin alfa; darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim; denosumab; ancestor; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951, and AMG 706 or a pharmaceutically acceptable salt thereof.
[000368] [000368] In certain claims, a composition provided herein is administered in conjunction with a chemotherapeutic agent. Suitable chemotherapeutic agents may include natural products such as vinca alkaloids (for example, vinblastine, vincristine and vinorelbine), paclitaxel, epidipodophyllotoxins (for example, etoposide and teniposide), antibiotics (for example, dactinomycin (actinomycin D), daunorubicin and dox idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mitramicin), mitomycin, enzymes (eg, L-asparaginase that systemically metabolizes L-asparagine and deprives cells that lack the ability to synthesize their own asparagine), antiplatelet agents, agents antiproliferative / antimitotic alkylants such as nitrogen mustards (eg, meclorethamine, cyclophosphamide and the like, melphalan and chlorambucil), ethylenimines and methylmelamines (eg, hexamethylmelamine and thiotepa)
[000369] [000369] The compounds of the present invention can also be used in combination with radiation therapy, hormonal therapy, surgery and immunotherapy, the therapies of which are well known to those skilled in the art.
[000370] [000370] In certain claims, a pharmaceutical composition provided herein is administered together with a steroid. Suitable steroids may include, but are not limited to, 21l-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, dexoxone, cortivazol, dehydrotoxone diflucortolone, difuprednate, enoxolone fluazacort, flucloronide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometolone, fluperolone acetate, flupredonone, flupredolone, flupredolone, flupredolone, flupredolone and flupredolone , hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, parametasone, prednicarbate, prednisolone, 25- prednisolone diethylaminoacetate, prednisolone, prednisone, prednisone, prednisone, prednisone, prednisone nolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide and its salts and / or derivatives. In a particular claim, the compounds of the present invention can also be used in combination with additional pharmaceutically active agents that treat nausea. Examples of agents that can be used to treat nausea include: dronabinol; granisetrone; metoclopramide; ondansetron, and prochlorperazine; or a pharmaceutically acceptable salt thereof.
[000371] [000371] Since an aspect of the present invention contemplates the treatment of diseases / conditions with a combination of pharmaceutically active compounds that can be administered separately, the invention also relates to the combination of separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions, such as a divided bottle or a divided foil package. Additional examples of containers include syringes, boxes and bags. In some Claims, the kit comprises guidelines for the use of separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (for example, oral and parenteral), are administered at different dosage intervals or when the titration of the individual components of the combination is desired by the care professional health professional who prescribes treatment.
[000372] [000372] The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodrugs. The term "salts" refers to inorganic and organic salts of compounds of the present invention. Salts can be prepared in situ during the final isolation and purification of a compound or by reacting separately from a purified compound in its base or free acid form with a suitable organic or inorganic base or acid and isolation of the salt formed in this way. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate salts,
[000373] [000373] The term "prodrug" means compounds that are transformed in vivo to give a compound of the present invention. Transformation can occur by several mechanisms, such as through hydrolysis in the blood. A discussion of the use of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Volume 14 of A.C.S. Symposium Series, and in “Bioreversible Carriers in Drug Design”, editor Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
[000374] [000374] For illustrative purposes, if the compound of the invention contains a carboxylic acid functional group, a prodrug can comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as (C1-Cg alkyl, (C2 -C12) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1- methyl-1- (alkanoyloxy) ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 - (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, l-methyl-l1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) aminomethyl having from 4 to carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N- (C1-C2) alkylamino (C2-C3) alkyl ( such as B-dimethylaminoethyl), carbamoyl- (C1-C:) alkyl, N, N-di (C1-C2) alkylcarbamoyl- (C1-C7) alkyl and piperidino-, pyrrolidine- or morphol no (Cr -;) alkyl.
[000375] [000375] Similarly, if a compound of the present invention comprises an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (C1- Ce) alkanoyloxymethyl, 1- ( (C1-Cs) alkanoyloxy) ethyl, 1-methyl- 1- ((C1-C6) alkanoyloxy) ethyl, (C1-C6) alkoxycarbonyloxymethyl, N- (C1-C6) alkoxycarbonylaminomethyl, succinyl, (Ci Cs) alkanoyl, a -amino (C1-C1a) alkanoyl, arylacyl and a-aminoacyl or a-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from naturally occurring L-amino acids, -P (O) (OH) x , -P (O) (O (C1-Cs) alkyl) ,; or glycosyl (the radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate).
[000376] [000376] The compounds of the present invention can contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as their mixtures, including racemic mixtures, form part of the present invention. Additionally, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both cis and trans forms (designated Z and E, respectively), as well as mixtures, are contemplated.
[000377] [000377] Mixtures of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components based on their physico-chemical differences by known methods such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (eg, an alcohol), separating the diastereomers and converting (eg, hydrolyzing) the individual diastereomers into the corresponding pure enantiomers.
[000378] [000378] The compounds of the present invention can exist in unsolvated forms, as well as solvated with pharmaceutically acceptable solvents, such as water (hydrate), ethanol and the like. The present invention contemplates and encompasses both solvated and unsolvated forms.
[000379] [000379] It is also possible that compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. Those skilled in the art will recognize that the names and structures of the compounds contained herein can be based on a particular compound's tautomer. Although the name or structure can be used for only one particular tautomer, it is intended that all tautomers are covered by the present invention, unless stated otherwise.
[000380] [000380] It is also intended that the present invention encompasses compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion and the like. It is also contemplated that the compounds of the present invention can be synthesized using a combination of in vitro and in vivo techniques.
[000381] [000381] The compounds of the present invention can exist in various solid states, including crystalline states and as an amorphous state. The different crystalline states, also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention. EXAMPLES
[000382] [000382] The examples presented below illustrate specific claims of the present invention. These examples are intended to be representative and are not intended to limit the scope of the Claims in any way.
[000383] [000383] The following abbreviations can be used here: v about AC acetate AC20 acetic anhydride ACOH acetic acid Al203 aluminum oxide broc Boc tert-butyloxycarbonyl
[000384] [000384] Note that when a percentage (%) is used in relation to a liquid, it is a percentage by volume in relation to the solution. When used with a solid, it is the percentage relative to the solid composition. GENERAL SUMMARY SCHEMES
[000385] [000385] Unless stated otherwise, starting materials and reagents used in the preparation of these compounds are available from commercial suppliers, such as Aldrich Chemical Co., (Milwaukee, Wis.), Or are prepared by methods known to those skilled in the art. technique following procedures presented in references such as "Fieser and Fieser's Reagents for Organic Synthesis", Volumes 1-17 (John Wiley and Sons, 1991); "Rodd's Chemistry of Carbon Compounds", Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); "Organic Reactions", Volumes 1-40 (John Wiley and Sons, 1991), "March's Advanced Organic Chemistry" (John Wiley and Sons, 4th Edition) and "Larock's Comprehensive Organic Transformations" (VCH Publishers Inc., 1989).
[000386] [000386] The starting materials for the following synthesis methods can be found in the General Methods and General Synthesis for Intermediates. The syntheses of some of the starting materials and intermediates are disclosed in U.S. Patent No. 9,562,061 and PCT / US17 / 19336, respectively, incorporated herein by reference in their entirety for all purposes. These methods of synthesis are merely illustrative of some methods by which the compounds of this invention can be synthesized and various modifications to these methods can be made and will be suggested to the person skilled in the art with reference to this disclosure. The starting materials and intermediates and end products of the reaction can be isolated and purified,
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide General Method 3 (Steps 1-3), General Method 7 (Step 1), General Method 8 (Step 4) "o Cc o õ ->» AN, SN 520 Step 1 No Step 2 S | No À no F ZD Ss oo H HOW OE! IN
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- oxiran] -15'-one 13 ', 13'-dioxide
[000389] [000389] A 250 mL 3-neck flask, equipped with a thermocouple, nitrogen intake and septum, was loaded with (18,3'R, 6'R, 8'E, 11'S, 12'R) -6- chlorine-11 ', 12'-dimethyl-3,4-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- oxiran] -15'-one 13 ', 13'-dioxide as a white solid. '! H NMR (400 MHz, Dichloromethane-ds) at ppm 8.08 (s, 1 H), 7.72 (d, J = 8.41 Hz, 1 H), 7.22 (d, J = 0 , 98 Hz, 1 H), 7.19 (dd, J = 8.41, 2.35
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000390] [000390] A 1 L 3-neck flask, equipped with a thermocouple, nitrogen adapter and septum, was loaded with (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R ) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-diespiro [naphthalene-l1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- oxiran] -15'-one 13 ', 13'-dioxide (10.22 g9, 16.72 mmol) and 2-methyltetrahydrofuran (300 ml). Triethyl borate (50 mL, 291 mmol was added via syringe and the reaction was placed in a thermal block preheated to 65 ° C. After 12 h, the reaction was cooled to room temperature overnight. The reaction mixture was quenched with saturated NaHCO3z (100 ml) and stirred for 10 min The aqueous layer was extracted with EtOAc (3 x 50 ml) and the combined organic layers were washed with brine (50 ml), dried over Na2SOs and filtered. on silica gel and purified by Flash chromatography (Bait (330 grams)) eluting with 0.3% ACOH in EtOAc: 0.3% AcCOH in heptane (0: 1 - 1: 1), giving 6.27 gq of (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-71'-ethoxy-7'- (hydroxymethyl) -11 ', 12'-dimethyl- 3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide. MS (EST, + ve ion) m / z 657.3 (M + 1) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide
[000391] [000391] A 250 mL 3-neck flask, equipped with a thermocouple, nitrogen adapter and septum, was loaded with (18,3'R, 6'R, 7'R, 8'E, 11'S, 12 ' R) -6-chloro-7'-ethoxy-7'- (hydroxymethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , Starting 13'-dioxide (6.27 g, 7.54 mmol), DCM (50 mL) and dimethyl sulfoxide (20 mL). The solution was cooled (0 ºC) in an ice bath and N, N-diisopropylethylamine was added (6.6 mL, 37.8 mmol) followed by sulfur trioxide pyridine complex (3.02 g, 18, 97 mmol), in portions over 15 min. The ice bath was removed and allowed to warm to room temperature for 2 h. The reaction mixture was poured into isopropyl acetate (200 ml) and the solution was washed with water (200 ml). The aqueous layer was extracted with EtOAc (1 x 100 ml) and the combined organic layers were washed with 50% saturated NH.Cl (2 x 100 ml), water (50 ml), brine (50 ml) and dried over Na; zSOs. The solution was filtered and the filtrate was concentrated under reduced pressure, giving a light yellow solid. The solid was dissolved in EtOAc, evaporated on silica gel and purified by Flash chromatography (Bait (220 grams)) eluting with 0.3% ACOH in EtOAc: 0.3% AcCOH in heptane (0: 1 - 1: 1), yielding 4.44 g of (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12'-dimethyl -15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide as a white solid. MS (ESI, + ve ion) m / z 655.3 (M + 1) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide
[000392] [000392] Preparation of the amine-free base: To a suspension at room temperature of (S) -coctahydropiperazine [2,1-c] morpholine dihydrochloride (7.04 g, 32.7 mmol; Synthonix, Wake Forest, NC) in DCM (100 ml) sodium methoxide (25 wt% methanol solution, 15 ml, 65.6 mmol) was added and the reaction was stirred for 2 h. The solvent was removed under reduced pressure and the residue was stirred over EtoOAc (100 ml) for 1 h. The solution was filtered and the filtrate was concentrated under reduced pressure, giving (S) coctahydropyrazine [2,1-c] [1,4] oxazine (4.33 g) as a light yellow oil. 1H NMR (400 MHz, DICLOROMETHANE-d; 7) at ppm 3.70 - 3.82 (m, 1 H), 3.61 -— 3.67 (m, 1 H), 3.52 - 3.60 (m, 1 H), 3.15 (t, J = 10.47 Hz, 1 HE), 2.79 - 2.93 (my, 2 H), 2.60 - 2.71 (my, 2 H ), 2.55 (d 1, J = 11.54 Hz, 1 H), 2.27 - 2.39 (my, 2 H), 2.05 - 2.21 (Mm, 2 H).
[000393] [000393] To a solution at room temperature of (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12' - dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (4.44 g, 6.51 mmol) in 1,2-dichloroethane (40 mL) was added a solution of (S) coctahydropyrazine [2,1-c] [1,4] oxazine (2.91 9g, 18.01 mmol) in 1,2-dichloroethane (5 mL) and the reaction was stirred for 2 h. To the reaction, sodium triacetoxyborohydride (0.350 g, 1.651 mmol) was added as a solid. More sodium triacetoxyborohydride (0.350 g, 1.651 mmol) was added until the reaction was complete. The reaction was quenched with saturated NH «Cl (40 mL) and the layers were separated. The aqueous layer was extracted with DCM (2x) and the combined organic layers were washed with 1 M KH2POs (40 ml). The organic layer was dried over Na> zSO.s, filtered and the filtrate was concentrated under reduced pressure and stored in the freezer. The residual material was dissolved in DCM, evaporated on silica gel and purified by Flash chromatography (Bait (330 grams)) eluting with
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a white solid. MS (ESI, + ve ion) m / z 781.3 (M + 1) *. 1H NMR (400 MHz, DICLOROMETHANE-d :) 5 ppm 7.72 (d, J = 8.41 Hz, 1 H), 7.23 (s, 1 HE), 7.17 (dd, J = 8, 41, 1.96 Hz, 1 H), 7.09 (dy, J = 1.96 Hz, 1 H), 6.89 (s, 2 H), 5.58 - 5.75 (m, 1 É ) 5.43 (d 1, J = 15.85 Hz, 1 HH), 4.15 (q, J = 6.85 Hz, 1 H), 4.07 (s, 2 H), 4.01 ( d 1, J = 15.45 Hz, 1 H), 3.74 - 3.82 (my, 1 É), 3.71 (d 1, J = 14.08 Hz, 1 Hd), 3.54 - 3.66 (my, 3 H), 3.43 - 3.52 (my, 1 Hd), 3.27 (dy, J = 14.28 Hz, 1 À), 3.17 (t 1, J = 10.37 Hz, 1 H), 2.89 - 3.03 (m, 2 H), 2.72 - 2.85 (m, 2 H), 2.58 - 2.71 (my, 2 H) , 2.54 (my, 2 E), 2.48 (d 1, J = 14.28 Hz, 1 E), 2.20 - 2.40 (m, 5 H), 2.03 - 2.20 (my, 4 H), 1.65 - 2.00 (m, 6 H), 1.54 - 1.64 (my, 2 H), 1.41 (d, J = 7.24 Hz, 3 H ), 1.30 - 1.38 (m, 4 H), 1.01 (d 1, J = 5.67 Hz, 3 Å). Example 2 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12'- dimethyl-7' - (( 4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-di-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide oa O to ERA and NH oo - SS BASE Bos o * to Example 2
[000394] [000394] To a solution at room temperature of (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12' - dimethyl-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (0.050 g, 0.076 mmol) in 1,2-dichloroethane (1 mL) was added 1- (oxetan-3-yl) piperazine (0.100 mL, 0.823 mmol, Astatech, Inc., Bristol PA) via syringe and the reaction was stirred for 1 h. To the reaction, sodium triacetoxyborohydride (0.050 g, 0.236 mmol) was added as a solid and the reaction was stirred overnight. The reaction was quenched with pH 7 buffer and the layers were separated. The aqueous layer was extracted with DCM (3x) and the combined organic layers were concentrated under reduced pressure. The residue was dissolved in MeOH and purified by reverse phase HPLC (Gilson; Gemini-NX 10 m column C18 110 AXIA, 100 x 50 mm) eluting with 0.1% TFA-H2O: 0.1% CH; CN TFA (7: 3 - 5:95). Fractions containing the desired product were combined, treated with pH 7 buffer (1 M KH2POs / 1 M K2HPOs; 5 ml) and the layers were separated. The aqueous layer was extracted with
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (47 mg, 79%) as a white crystalline solid. MS (ESI, + ve ion) m / z 781.2 (M + 1) *. 'H NMR (400 MHz, DICLOROMETHANE) 5 ppm 8.07 (s 1, 1 H), 7.71 (d, J = 8.41 Hz, 1 H), 7.23 (s, 1 H) , 7.17 (dd, J = 8.51, 2.25 Hz, 1 H), 7.08 (d, J = 2.15 Hz, 1 H), 6.82 - 6.93 (my, 2 H), 5.61 - 5.78 (my, 1 H), 5.45 (d 1, J = 15.85 Hz, 1 H), 4.56 - 4.66 (my, 2 H), 4 , 44 - 4.54 (m, 2 H), 4.15 (d 1, J = 7.04 Hz, 1 H), 4.03 - 4.10 (my, 2 À), 3.99 (d 1, J = 14.67 Hz, 1 H), 3.70 (d 1, J = 14.28 Hz, 1 H) 3.61 (quin, J = 7.24 Hz, 1 Hd), 3.35 - 3.52 (m, 2 H), 3.26 (d, J = 14.28 Hz, 1 H), 2.95 (d ld, J = 14.87, 9.98 Hz, 1 H), 2.72 - 2.85 (m, 2 H), 2.59 - 2.71 (m, 2 H), 2.46 - 2.57 (my, 4 É), 2.24 - 2.41 ( m, 4 H), 2.02 - 2.19 (my, 4 H), 1.78 - 1.98 (m, 3 H), 1.70 (s 1, 1 H), 1.57 (d 1, J = 6.26 Hz, 4 H), 1.29 - 1.45 (my, 7 H), 1.00 (d 1, J = 5.09 Hz, 3 H) Example 3 (18.3 'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11', 12'- dimethyl-7 '- (((4- (3-oxetanil ) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide General Method 5 (Steps 1-3)
[6] [6] already N Se
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15'-ONA —13 ', 13'-DIOXIDE E (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-CHLORINE-7' - (1,3-DITIAN-2- IL) - 7 '-HIDROXI-11', 12'-DIMETHIL-3,4-DI-HYDRO-2H, 15'H-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24- PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE
[000395] [000395] To a 250 ml round bottom flask was added 1,3-dithian (4.79 g, 39.8 mmol) and THF (100 ml). The mixture was cooled to -78 ° C and n-butyllithium (1.6 M solution in hexane, 22.5 ml, 36.1 mmol) was added over 8 min. The solution was stirred in the bath at -78 ° C for 30 min. To a separate 100 mL flask was added (18.3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro -2H, 7'H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide and THF (5 ml). To this system was added a solution of lanthanum (III) chloride bis (lithium chloride (0.6 M in THF, 60.1 ml, 36.1 mmol) complex) and it was stirred for min at room temperature. it was then cooled to -78 "C and added via cannula to the dithian solution. After 2.5 ha at -78" * C, the solution was treated with NH «Cl sat and water. The pH of the solution was adjusted to pH = 4 with 10% aqueous citric acid and aqueous NaHCO; z The solution was extracted with EtOAc and the combined extracts were filtered through Celite. The filtrate was washed with water and brine and then dried (Na2S0s) and concentrated, giving a mixture of (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3-ditian-2- 11) -7' -hydroxy- 11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide in the form of a brown oil which was taken directly to the next step. MS (ESI, + ve ion) m / z 717.5 (M + H) *.
[20] [20] OXA [13] TIA [1.14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15'-ONA - 13 ', 13'-DIOXIDE E (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-CHLORINE-7' - (1,3-DITIAN-2- IL) -7 '-METOXI-11', 12'-DIMETHIL-3,4-DI-HYDRO-2H, 15'H- SPIRUS [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24- PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE
[000396] [000396] To a bottle capable of being resealed, the mixture of (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6- chlorine-7'- was added (1,3-dithian-2-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3-dithian-2-yl) -7 '-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (6.81 g, 9.49 mmol) and THF (100 mL). The mixture was cooled to O
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (1.66 g, 2.27 mmol, 24% yield). MS (ESI, + ve ion) m / z 731.5 (M + H) * e (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chlorine-7 '- (1,3-ditian-2-yl1) -7'-methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (4.69 g, 6.41 mmol, 68% yield). MS (ESI, + ve ion) m / z 731.5 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ' , 13'- dioxide
[000397] [000397] To a 250 mL round-bottom flask equipped with a reflux condenser was added (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro- 7 '- (1,3-dithian-2- 11) -7' -methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1.22' -
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (1.63 g, 2.23 mmol), acetonitrile (40 ml) and water (10 ml). The mixture was heated to 50 “* C and calcium carbonate (1.12 g, 11.1 mmol) and iodomethane (1.38 mL, 22.3 mmol) were added. After 23 h at 50 ºC, the solution was poured into NH. «Cl sat and water and then extracted with EtOAc. The combined extracts were washed with brine and then dried (Na; SOs) and concentrated on silica. Purification by chromatography on silica gel (0% to 40% EtOAc / heptane (both with 0.3% AcOH), Silicycle HP 120 g column) gave (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22 '-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (1.34 g, 2.09 mmol, 94% yield) as a white solid. MS (ESI, + ve ion) m / z 641.3 (MH + H) *.
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24- PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE
[000398] [000398] To a re-sealable flask was added (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-71'- methoxy-11 ', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (0.135 g, 0.211 mmol), 1,2-dichloroethane (2.0 mL) and 1- (oxetan-3-yl) piperazine (0.090 g, 0.632 mmol, AstaTech, Inc.). The solution was stirred at room temperature for 1 h. To this solution was added sodium triacetoxyborohydride (0.011 g, 0.053 mmol). After stirring overnight at room temperature, more portions of sodium triacetoxyborohydride (0.011 g, 0.053 mmol) were added until the reaction was complete. The reaction was carefully quenched with MeOH, stirred for 1 h and then filtered for purification by Prep-HPLC. The solution was purified by prep-HPLC (Column: Phenomenex Luna 5 1 C18, 100 À, 150 x 20 mm; Solvent: A = water (0.1% TFA), B = (R) (0.1% TFA) , 30 mL / min, 30% B to 100% B over 18 min, then 2 min to 100% B) and the product containing fractions were treated with aqueous buffer (based on KH> POs / K2HPOs) pH 7 and extracted with EtOAc. The combined extracts were washed with brine and then dried (Nas; SOs), filtered and concentrated, yielding (1S8,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6 -chloro-7'-methoxy-11 ', 12'-dimethyl-7' - (((4- (3-oxetanyl) -1-piperazinyl) methyl) - 3,4-dihydro-2H, 15'H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a white solid (0.101 gq, 0.132 mmol, 63% yield). '! H NMR (400 MHz, DICLOROMETHANE-d :) at ppm 7.72 (d, J = 9.8 Hz, 1 H), 7.25 (s 1, 1 H), 7.16 (d 1, J = 8.6 Hz, 1 H), 7.09 (s, 1 H), 6.89 (s, 2 H), 5.62 (s 1, 1 H), 5.37 (d 1, J = 14.9 Hz, 1 H), 4.56 - 4.66 (m, 2 H), 4.52 (t 1, J = 5.9 Hz, 2 H), 4.12 (d 1, J = 6.5 Hz, 1 H), 4.06 (s, 2 H), 3.98 (d 1, J = 14.9 Hz, 1 H), 3.70 (d 1, J = 14.1 Hz, 1 À), 3.40 - 3.52 (m, 1 H), 3.36 (s, 3 H), 3.19 - 3.30 (m, 1 H), 2.90 - 3, 03 (m, 1 H), 2.64 - 2.85 (my, 4 H), 2.45 - 2.63 (my, 5 HH), 2.26 - 2.41 (m, 4 H), 2.15 - 2.25 (m, 1 HE), 2.02 - 2.15 (1, 3 À), 1.78 -— 1.99 (m, 4 H), 1.66 - 1.76 (m, 1 H), 1.49 -— 1.64 (m, 2H), 1.40 (d 1, J = 7.2 Hz, 4 E), 1.01 (d 1, J = 5, 7 Hz, 3 E). MS (ESI, + ve ion) m / z 767.3 (M + H) *. Example 4 (18, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-CHLORINE-7 '- ((9AS) -HEXA- HYDROPIRAZINE [2,1-C] [1.4] OXAZIN-8 (1H) - ILMETHIL) -7 '-METOXI-11', 12'-DIMETHIL-3,4-DI-HYDRO-2H, 15'H-SPIRUS [NAFTALENE- 1,22 ' -
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24- PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13' , 13'-DIOXIDE General Method 9 OMe ONO OMe and RN OAONH o Z À = O TT, jo Ss SO Ss OO oo Example 4
[000399] [000399] To a 100 mL 3-neck flask was added (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'- methoxy-11 ', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (0.486 g, 0.758 mmol), DCM (20 mL) and ethanol (8.0 mL). To this solution was added (9aS) - octahydropiperazine [2,1-c] morpholine dihydrochloride (1.96 g, 9.10 mmol followed by N, N-diisopropylethylamine (4.0 mL, 22.7 To the solution, titanium (IV) isopropoxide (2.24 mL, 7.58 mmol) was added. The solution was stirred at room temperature for 17 h. To this solution was added sodium borohydride (0.143 gq, 3.79 mmol) in 3 portions The reaction mixture was stirred at room temperature After 18 h, more sodium borohydride (35 mg) was added and stirring was continued at room temperature for an additional 24 h. carefully quenched with NH. «Cl sat. and then diluted with aqueous pH 7 buffer (based on KH2POs / K2HPOs), filtered through Celite and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO1s), filtered and concentrated, giving rise to a white solid.The solid was purified by prep-HPLC (Column: Phenomenex Gemini C18 110 À, 100 x 50 mm; Solvent: A = water (0.1% TFA), B = (R) ( T FA 0.1%), 100 mL / min, 10% B to 100% B over 11 min, then 2 min to 100% B) and the product containing fractions were treated with pH 7 aqueous buffer ( based on KH2POs / K2HPOs), concentrated to remove acetonitrile and extracted with EtOAc. The combined extracts were washed with brine, dried (NazsSOs), filtered and concentrated, giving (1S8,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro- 7 '- ((9as) - hexahydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a white solid (0.478 g, 0.622 mmol, 82% yield). '! H NMR (400 MHz, DICLOROMETHANE-d,) at ppm 7.72 (dy, J = 8.6 Hz, 1 H), 7.26 (s, 1 H), 7.17 (dd, J = 8.5, 2.2 Hz, 1 H), 7.09 (d, J = 2.3 Hz, 1 H), 6.85 - 6.93 (my, 2 H), 5.57 - 5, 68 (m, 1 H), 5.35 (s, 1 H), 4.08 -— 4.17 (m, 1 Hd), 4.07 (s, 2 H), 3.96 - 4.04 (m, 1 H), 3.78 (d 1, J = 9.6 Hz, 1 H), 3.70 (d 1, J = 14.3 Hz, 1 H), 3.59 (d 1, J = 10.8 Hz, 2 H), 3.35 (s, 3 H), 3.25 (d, J = 14.3 Hz, 1 HE), 3.17 (s 1, 1 H), 2 , 88 - 3.06 (m, 2 H), 2.72 - 2.81 (my, 2 H), 2.58 - 2.67 (m, 2 H), 2.45 - 2.54 (m , 3 H), 2.30 - 2.37 (m, 2 H), 2.17 - 2.27 (my, 3 À), 2.07 - 2.14 (m, 2 H), 2.03 - 2.07 (m, 1 H), 1.90 - 1.99 (m, 2 H), 1.81 - 1.90 (my, 2 H), 1.66 - 1.75 (my, 1 H), 1.48 - 1.65 (my, 4 H), 1.36 - 1.44 (m, 4 HE), 1.02 (d, J = 6.1 Hz, 3 H) MS (ESI , + ve ion) m / z 767.7 (M + H) *.
[20] [20] OXA [13] TIA [1.14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15'-ONA 13 ', 13'-DIOXIDE
[000400] [000400] To a resealable flask was added (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-1'- methoxy-11 ', 12'-dimethyl-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (0.135 g, 0.211 mmol), 1,2-dichloroethane (2 mL) and 1-isopropylpiperazine (0.090 mL, 0.632 mmol, Across Organics). The solution was stirred at room temperature for 1 h. To this solution was added sodium triacetoxyborohydride (0.011 g, 0.053 mmol). After 2 h at room temperature, more portions of 0.25 eq. sodium triacetoxyborohydride (4 in total) was added until the reaction was complete. The reaction mixture was carefully quenched with MeOH, stirred for 1 h and then filtered for purification by Prep-HPLC. The solution was purified by prep-HPLC (Column: Phenomenex Luna C18, 100 À, 150 x 21.20 mm; Solvent: A = water (0.1% TFA), B = (R) (0.1% TFA) , 30 mL / min, 30% B to 100% B over 18 min, then 2 min to 100% B) and the fractions containing product were treated with aqueous buffer (based on KH2POs / K2HPO0 :) of pH 7 and extracted with EtOAc. The combined extracts were washed with brine and then dried (Na2SOs), filtered and concentrated, giving rise to
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a white solid (0.0855 9g, 0.113 mmol, 54% yield). 'H NMR (400 MHz, DICLOROMETHANE-d: z) 3 ppm 7.76 (dy, J = 8.6 Hz, 1 H), 7.30 (s, 1 H), 7.20 (d 1, J = 8.4 Hz, 1 H), 7.13 (s, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.92 (d, J = 9.0 Hz, 1 H), 5.63 - 5.74 (my, 1 H), 5.49 (d, J = 15.8 Hz, 1 H), 4.10 (s, 2 H), 3.96 - 4 , 05 (m, 2 H), 3.74 (dl, J = 14.3 Hz, 1H), 3.46 (s, 1 H), 3.38 - 3.43 (my, 1 HE), 3 , 37 (s, 3 HE), 3.30 (d 1, J = 14.3 Hz, 1 H), 2.96 - 3.04 (m, 2 H), 2.85 - 2.94 (m , 2 H), 2.77 - 2.84 (m, 2 H), 2.54 - 2.68 (Mm, 3 À), 2.36 -— 2.43 (m, 1 H), 2, 23 - 2.35 (my, 2 Hd), 2.14 - 2.23 (Mm, 2 H), 2.06 - 2.14 (my, 2 H), 1.83 - 2.03 (my, 4 H), 1.50 - 1.76 (m, 4 H), 1.35 - 1.47 (m, 10 H), 1.05 (d, J = 6.7 Hz, 3 H). MS (ESI, + ve ion) m / z 753.2 (M + H) *.
[20] [20] OXA [13] TIA [1.14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15'-ONA 13 ', 13'-DIOXIDE
[000401] [000401] To a re-sealable flask was added (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy- 11 ', 12'-dimethyl-l15'-ox0-3,4-dihydro-2H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13', 13'-dioxide (0.035 g, 0.053 mmol), 1,2-dichloroethane (0.7 mL) and Nt-butylpiperazine (0.026 mL, 0.160 mmol, Oakwood Products, Inc.). The solution was stirred at room temperature for min. To this solution was added sodium triacetoxyborohydride (2.83 mg, 0.013 mmol.). The reaction was stirred at room temperature. After 1 h, more portions of sodium triacetoxyborohydride (2.83 mg, 0.013 mmol) were added every 1 h until the reaction was complete. The reaction was carefully quenched with MeOH, stirred for 30 min and then concentrated. Purification by silica gel chromatography (0% to 10% MeOH / CH; Cl)) gave (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -7 '- (((4-tert-butyl-1-piperazinyl) methyl) -6-chloro-7'-ethoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [ naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a white solid (0.0284 g, 0.036 mmol, 68% yield). ! H NMR (400 MHz, Dichloromethane-d: s) at ppm 7.73 (dy, J = 8.6 Hz, 1 H), 7.31 (s, 1 H), 7.16 (dd, J = 8.5, 2.2 Hz, 1 H), 7.08 (d, J = 2.2 Hz, 1 H), 7.02 (d 1, J = 8.0 Hz, 1 H), 6, 84 (d, J = 8.2 Hz, 1 H), 5.55 - 5.74 (my, 2 H), 3.96 - 4.10 (m, 3 H), 3.79 (s 1, 1 H), 3.69 (d 1, J = 14.5 Hz, 1 HE), 3.50 - 3.65 (m, 1 H), 3.34 - 3.45 (m, 1 H), 3.30 (d, J = 14.3 Hz, 1 H), 2.94 - 3.04 (my, 1 H), 2.73 - 2.80 (my, 2 H), 2.58 - 2 , 68 (my, 3 H), 2.45 - 2.57 (my, 3 H), 2.29 -— 2.35 (mM, 1 H), 2.03 - 2.18 (my, 4 H ), 1.90 - 1.98 (m, 2 H), 1.81 - 1.90 (m, 2 H), 1.55 - 1.70 (my, 3 H), 1.45 - 1 , 53 (my, 1 HH), 1.34 - 1.44 (my, 1 HH), 1.24 - 1.31 (my, 9 E), 1.17 -— 1.24 (m, 9 E ), 1.00 (d, J = 6.8 Hz, 3 H). MS (ESI, + ve ion) m / z 781.3 (M + H) *. Example 7 (18, 3'R, 6'R, 7'S, 11'S, 12'R) -6-CHLORINE-7 '- ((9AS) -HEXA- HYDROPIRAZINE [2,1-C] [1,4] OXAZIN -8 (1H) -ILMETHIL) -7 '-HYDROXY- 11', 12'-DIMETHIL-3,4-DI-HYDRO-2H, 15'H-SPIRUS [NAFTALENE- 1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24-] PENTACOSA [16,18,24] TRIEN] -15'-ONA 13 ', 13 '-DIOXIDE General Method 6 (Steps 1-2) cl AA, e, So WITH RA CD Co COS ooo Example 7 Step 1: (18,3'R, 6'R, 11'S, 12'R) -6-chlorine -11 ', 12'- dimethyl-3,4-dihydro-2H, 15'H-diespiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[000402] [000402] To a stirred solution of (1S8,3'R, 6'R, 11'S, 12'R) - 6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7' H, 15'H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene] -7 ', 15'-diona 13 ', 13'-dioxide (100 mg, 0.167 mmol) and trimethylsulfoxonium iodide (38.6 mg, 0.175 mmol) in DMSO (1.5 mL) potassium hydroxide (33.0 mg, 0.501 mmol) was added at temperature environment. The resulting mixture was stirred at room temperature for a period of 18 h. The mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with EtOAc (2 X). The combined organic layers were dried over anhydrous sodium sulfate. The residue was subjected to Combi-Flash column chromatography on a 12 g ISCO Gold column eluting with 10% to 100% EtOAc / hexanes, yielding (18.3'R, 6'R, 11'S, 12'R ) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 2' '- oxiran] -15'-one 13 ', 13'-dioxide (72 mg, 0.117 mmol, 70% yield) as a mixture of diastereomers. MS (ESI, + ve ion) m / z 613.1 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide
[000403] [000403] A mixture of (18,3'R, 6'R, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H- diespiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 2' '- oxiran] -15'-one 13 ', 13'-dioxide (840 mg, 1.37 mmol), (S) -octahydropyrazine [2,1-c] [1,4] oxazine dihydrochloride (1.47 dg, 6.85 mmol) and triethylamine (3.00 mL, 21.6 mmol) in EtOH (6.0 mL) in a sealed microwave reactor was subjected to a microwave reaction condition (24 h, 90 ºC) . The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to Combi-Flash column chromatography on a 12 g ISCO Gold column eluting with 0% to 20% MeOH / DCM, giving rise to an impure mixture of two epimeric products of beta-hydroxylamine, which was subjected to separation by SFC (Column: MSA, Mobile Phase: 65:35 (A: B) isocratic, A: CO> Liquid, B: methanol (NH; 20 mM), Flow Rate: 70 g / min, Column / Oven temperature: 40 “ºC, Detection: UV at 240 nm). The epimer eluting first on both the reverse phase prep-HPLC and SFC columns was collected and subjected to Combi-Flash column chromatography on a 12 9g ISCO Gold column eluting with O to 20% MeOH / DCM, giving rise to (18,3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7 '- ((9aS) -hexa- hydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15'-ONA 13 ' , 13'-DIOXIDE
[000404] [000404] A mixture of (R) -l-boc-3-methyl-piperazine (630 mg, 3.15 mmol) and acetone (3.0 mL, 40.9 mmol) in DCM (4.0 mL) was stirred for 10 min before sodium triacetoxyborohydride (1333 mg, 6.29 mmol) was added in one portion as a solid. The resulting mixture was stirred at room temperature for 2.5 days. MeOH (0.5 mL) was added to the reaction and the mixture was stirred for min and then directly loaded onto a silica gel pre-column (25 g) and subjected to Combi- Flash column chromatography on a 24 g ISCO column Gold eluting with 2% to 20% MeOH / DCM, yielding tert-butyl (R) -4-isopropyl-3-methylpiperazine-1-carboxylate (0.72 g, 2.97 mmol, 94% yield ) as a colorless oil. 'H NMR (400 MHz, DICLOROMETHANE-d;) 3 3.54-3.90 (m, 2H), 3.25 (td, J = 6.41, 13.01 Hz, 1H), 3.02 ( bs, 1H), 2.64-2.84 (m, 2H), 2.52-2.63 (m, 1H), 2.19-2.34 (m, 1H), 1.43 (s, 9H), 1.10 (d,
[000405] [000405] To a stirred solution of tert-butyl (R) -4-isopropyl-3-methylpiperazine-1-carboxylate (670 mg, 2.76 mmol) in DCM (10 mL) was added trifluoroacetic acid (3.0 mL, 40 mmol) at room temperature. The resulting mixture was stirred at room temperature for 40 min. The volatiles were removed and the residue was subjected to high vacuum, giving rise to (R) -1-isopropyl-2-methylpiperazine bis-TFA salt as an almost white solid. ! H NMR (400 MHz, DICLOROMETHANE-dz) 3 11.33-12.07 (m, 2H), 10.45-11.02 (my, 1H), 3.88-4.10 (m, 3H) , 3.72-3.86 (m, 2H), 3.49-3.65 (m, 3H), 1.46 (dd, J = 6.46, 12.91 Hz, 6H), 1.31 (d, J = 6.65 Hz, 3H). MS (ESI, + ve ion) m / z 143.2 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000406] [000406] To a stirred mixture of (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl -15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (20 mg, 0.031 mmol) and bis-TFA salt of (R) -1-isopropyl-2-methylpiperazine (76.2 mg, 0.206 mmol) in DCM
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (17.6 mg, 0.020 mmol, 64% yield) as a TFA salt as a white solid. 'H NMR (400 MHz, DICLOROMETHANE) 3 8.08 (s 1, 1H), 7.71 (d, J = 8.61 Hz, 1H), 7.11 - 7.20 (m, 2H) , 7.09 (dy, J = 1.76 Hz, 1H), 6.90 (s, 2H), 5.78-5.96 (m, 1H), 5.47 (d 1, J = 15, 65 Hz, 1H), 4.13-4.26 (my, 18), 4.07 (s, 2H), 3.82-3.99 (m, 2H), 3.58-3.77 (m , 2H), 3.20-3.51 (m, 9H), 2.92-3.04 (m, 1H), 2.74-2.82 (m, 3H), 2.51-2.62 (m, 2H), 2.02-2.18 (m, 6H), 1.85-1.97 (m, 3H), 1.72-1.79 (m, 1H), 1.55-1 , 68 (m, 2H), 1.35-1.45 (m, 10H), 1.24 (d, J = 6.85 Hz, 3H), 1.02 (d, J = 6.65 Hz, 3H). MS (ESI, + ve ion) m / z 767.2 (M + H) *.
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24- PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13' , 13'-DIOXIDE General Method 10 THE
[000407] [000407] In a 3.75 mL vial (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ' , 12'-dimethyl-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (12 mg, 0.018 mmol) followed by a solution of (R) -1-isopropyl-2-methylpiperazine 2,2,2-trifluoroacetate (46.9 mg, 0.126 mmol) in DCM (1, 5 ml) and N, N-diisopropylethylamine (0.60 ml, 3.5 mmol). The resulting mixture was stirred at room temperature for 10 min before sodium triacetoxyborohydride (16 mg, 0.073 mmol) was added in one portion as a solid. The resulting mixture was stirred at room temperature for 58 h. The reaction mixture was concentrated in vacuo and the residue was dissolved and collected in MeOH and subjected to preparative reverse phase HPLC (Gemini * "column" Prep C18 10 µm; Phenomenex, Torrance, CA; elution with gradient of 20% to 90% of MeCN in water, in which both solvents contain 0.1% TFA, 15 min gradient in a 24 min method), resulting, after lyophilization, (18,3'R, 6'R, 7'R, 8 'E, 11'S, 12'R) -6-Chlorine-7'-ethoxy-11', 12'-dimethyl-7 '- (((3R) -3-methyl-4- (l-methylethyl) -l- piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (11.2 mg, 0.013 mmol, 70% yield) as a TFA salt as a white solid. 'H NMR (400 MHz, DICLOROMETHANE) 5 8.05 (s 1, 1H), 7.71 (d, J = 8.61 Hz, 1H), 7.17 (dd, J = 2.25, 8.51 Hz, 1H), 7.08-7.13 (m, 2H), 6.90 (s, 2H), 5.94- 6.08 (m, 1H), 5.55-5.64 (m, 1H), 4.20-4.29 (m, 1H), 4.08 (s, 2H), 3.85-3.92 (m, 2H), 3.70-3.83 (m , 2H), 3.62-3.68 (m, 1H), 3.46-3.58 (m, 3H), 3.33 (d 1, J = 4.50 Hz, 2H), 3.26 (d, J = 14.28 Hz, 1H), 2.99 (d ld, J = 10.07, 14.57 Hz, 2H), 2.73-2.87 (m, 3H), 2.57 (d ld, J = 7.92, 14.18 Hz, 2H), 2.11 - 2.18 (m, 3H), 2.06 (d 1, J = 13.89 Hz, 2H), 1, 86-1.98 (m, 4H), 1.79 (d 1, J = 8.02 Hz, 1H), 1.67 (d 1, J = 4.89 Hz, 2H), 1.37-1 , 45 (m, 13H), 1.24 (d, J = 6.65 Hz, 3H), 1.01 (d, J = 6.65 Hz, 3H). MS (ESI, + ve ion) m / z 781.2 (M + H) *. Example 10 (18, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-CHLORINE-7 '-METOXI-11', 12'- DIMETHIL-7 '- (( 9AR) -OCTA-HYDRO-2H-PIRID [1,2-A] PIRAZIN-2-ILMETHIL) -3,4-DI-HYDRO-2H, 15'H-SPIRUS [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13 ', 13'-DIOXIDE General Method 7 (Steps 1-2) “o
[20] [20] OXA [13] TIA [1.14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15'-ONA 13 ', 13'-DIOXIDE
[000408] [000408] Preparation of the amine free base: To a 150 mL round-bottom flask was added (R) - octahydro-1H-pyrido [1,2-a] lpyrazine dihydrochloride (5.0 g, 23, 5 mmol, WuXi) and methanol (30 ml). To the solution at room temperature, sodium methoxide (25% w / v methanol solution, 14.0 ml, 58.6 mmol) was added over 2 min. The solution was stirred at room temperature for 10 min and then concentrated. The material was treated with 2-methyltetrahydrofuran to form a suspension and then filtered. The filtrate was concentrated, forming a viscous brown oil. The oil was treated with 2-methyltetrahydrofuran and heptane, filtered through a syringe filter and then concentrated, yielding (R) -octahydro-1H-pyrido [1,2-a] lpyrazine (3,4 g) in the form of a brown semi-solid.
[000409] [000409] To a 250 mL 3-neck flask was added (18, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'- dimethyl-3,4-dihydro-2H, 15'H-diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- oxiran] -15'-one 13 ', 13'-dioxide (4.75 g, 7.77 mmol), sodium tert-butoxide (1.49 g, 15.5 mmol) and 2-methyltetrahydrofuran (40 mL). To the solution was added (R) coctahydro-1H-pyrido [1,2-alpyrazine (1.64 g, 11.7 mmol). The reaction mixture was then heated to 65 ° C for 1 d. The solution was allowed to cool to room temperature and treated with pH 7 buffer (based on K2HPOs / KH2POs). The solution was extracted with DCM (3x) and the combined extracts were washed with water and brine, dried over Naz2SOs and concentrated. the crude product, (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7'- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide, was conducted directly.
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24- PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE
[000410] [000410] To a 250 mL flask containing (18, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12' - dimethyl-7 '- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene- 1.22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (5.8 g, 7.7 mmol) was added 2-methyltetrahydrofuran (80 ml). The solution was cooled to () ºC and potassium bis (trimethylsilyl) amide (1 M in THF, 19.3 mL, 19.3 mmol) was added over 5 min. After stirring for 10 min at 0 ° C, iodomethane (1.44 mL, 23.2 mmol) was added in one portion. The solution was stirred at O “C for 2 h and then more potassium bis (trimethylsilyl) amide (4 ml) was added, stirred for 10 min and then more iodomethane (0.48 ml) was added. The solution was stirred for 1 h at 0 ° C and then aqueous pH 7 buffer (based on KH2POs / K2HPOs) was added and the reaction mixture was allowed to warm to room temperature. The solution was extracted with DCM (3x) and the combined extracts were washed with brine, dried in Nas; SOs and concentrated on silica. Purification by silica gel chromatography (10% to 60% EtOAc / heptane and then 5% to 10% MeOH / CHxCl2) gave (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7' - ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2- ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide General Method 1 (Steps 3-7) and General Method 11 (Step 11)
[000411] [000411] A 2 L three-neck dry flask with a thermocouple and magnetic stir bar, under nitrogen, was loaded with (S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-eno- 1-sulfonamide (54 g, 134 mmol) and 300 ml of dry toluene. The solution was cooled to -76 ºC internal temperature (acetone / dry ice bath). N-butyl lithium solution (1.6
[000412] [000412] At 0 "ºC, trifluoroacetic acid (164 mL, 2210 mmol) was added dropwise, via the addition funnel, to a solution of (3R, 48S) - 1-methoxy-N, N-bis (4- methoxybenzyl) -4-methyl-hept-6-ene-3-sulfonamide (20.4 g, 44.2 mmol) and anisole (48.0 mL, 442 mmol) in DCM (221 mL). The solution was allowed to reach room temperature and stirred overnight. The reaction was concentrated in vacuo. The remaining material was partitioned between DCM and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo, giving rise to the crude material. Purification by flash column chromatography on silica gel (eluted with 0% to 100% EtOAc in heptane) gave (3R, 4S) -1-methoxy-4-methyl-hept-6-ene-3-sulfonamide (9.85 g, 44.5 mmol, 101% yield) as a light yellow oil. MS (ESI, + ve ion) m / z 243.9 (M + Na) *.
[000413] [000413] To a 3-neck flask of 1 L rendered inert with nitrogen equipped with a thermometer and a magnetic stir bar, at room temperature, was added 4- (dimethylamino) pyridine (0.821 9, 6.72 mmol), 2 -methyltetrahydrofuran (80 ml), triethylamine (7.02 ml, 50.4 mmol), acetic anhydride (4.76 ml, 50.4 mmol), and a solution of (S) -6 '-chloro- 5- ((((1R, 2R) -2- ((S) -1- hydroxyaloyl) cyclobutyl) methyl) -3 ', 4.4', 5-tetrahydro-2H, 2'H-spiro [benzo [ b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic (15.72 gq, 33.6 mmol) in 2-methyltetrahydrofuran (80 mL) was added via cannula over 20 min (the internal temperature increased from 20 "C to 25" C during the addition). The reaction mixture was stirred at room temperature for 1.5 h. Water (40 mL) was added (the internal temperature increased from 23 ºC to 26 “C) followed by NaszHPO. 1 M (60 mL). Sodium hydroxide (1 M, 20 mL, 220 mmol) was added until the pH reached 9. The mixture was stirred at room temperature for 19 h and the pH was adjusted to 3 with 2 M HCl (80 mL). The mixture was diluted with PhMe (150 ml) and transferred to a separatory funnel. The aqueous layer was discarded and the organic phase was washed with water (75 ml), 20% brine (75 ml) and concentrated under reduced pressure. The concentrate was diluted with PhMe (100 ml) and the PhMe was removed under reduced pressure. This procedure was repeated three times, giving (S) -5- ((((1R, 2R) -2- ((S) -1- acetoxyalkyl) cyclobutyl) methyl) -6'-chloro-3 ', 4 , 4 ', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] - 7T-carboxylic in the form of an orange oil that was used without additional purification. MS (ESI, + ve ion) m / z 510.2 (M + H) *.
[000414] [000414] A 1 L 3-neck flask was loaded with (S) -5- ((((1R, 2R) -2- ((S) -1- acetoxyalkyl) cyclobutyl) methyl) -6'-chloro- 3 ', 4.4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] - 7T-carboxylic (28.73 g, 35.8 mmol) as a solution in toluene (228 mL). DMF (0.277 ml, 3.58 mmol) was added followed by slow addition of thionyl chloride (2.74 ml, 37.6 mmol) via syringe. The reaction was stirred at room temperature for 4 h and more thionyl chloride (0.50 ml) was added and the reaction was stirred for 1 h. In a separate flask, (3R, 4S) -1-methoxy-4-methyl-hept-6-ene-3-sulfonamide (9.85 g, 42.5 mmol) and 4- (dimethylamino) pyridine (0.437 g,
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-ila
[000415] [000415] A 5 L reactor equipped with a mechanical stirrer, thermocouple, nitrogen spray tube, condenser, was loaded with 3.6 L of toluene. The PhMe was heated to 79 ºC with nitrogen sparging through the solution. In a separate flask, (S) -1- ((1R, 2R) -2- ((((S) -6 '-chloro-7- (((((3R, 48S) -1-methoxy-4- methyl-hept-6-en-3-yl) sulfonyl) carbamoyl) -3 ', 4'-dihydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1' -naftalen] -5 (4H) -yl) methyl) cyclobutyl) ally (25.14 g, 32.0 mmol) was subjected to azeotropic treatment with 300 mL of toluene and then dissolved in 1.2 L of PhMe that was added via syringe pump over 2 h. Simultaneously, 4 charges of Umicore M73 SIMes (4 x 238 mg) (Umicore AG & Co. KG, Precious Metals Chemistry, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany) were added as a paste in 5 mL of PhMe. Each charge was added at 40 min intervals. After 4 h, the reaction was cooled to 30 ° C and di (ethylene glycol) vinyl ether (0.350 mL, 2.56 mmol) was added and the solution was stirred overnight with the sprinkler replaced with an admission of nitrogen. The reactor was drained and the reaction volume was reduced to 1 L. SilaMetS Thniol (70 g) (SiliCycle Inc. 2500, Parc-Technologique Blvd Quebec City, Quebec, Canada) was added and the mixture was stirred overnight. The mixture was filtered and SilaMetS Thiol was washed with EtOAc and the filtrate was concentrated. Purification by flash column chromatography on silica gel (330 g Gold Rf, eluting with 0% to 100% EtOAc in heptane) gave acetate (18.3'R, 6'R, 7'S, 8'E, 11'S, 12 'R) -6-chloro-12' - (2-methoxyethyl) -11'-methyl-13 ', 13'-dioxide-11'-ox0-3,4-dihydro-2H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-ila (19 , 76 9g, 28.8 mmol,
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000416] [000416] Sodium methoxide (25% methanol solution, 11.35 mL, 49.7 mmol) was added to an acetate solution of (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-12 '- (2-methoxyethyl) - 11'-methyl-13', 13'-dioxide-15'-ox0-3,4-dihydro-2H- spiro [naphthalene- 1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-ila (19 , 76 g, 24.83 mmol) in toluene (100 ml) and methanol (20.00 ml) at room temperature. After 45 min, the reaction was quenched with citric acid (2M aqueous solution, 37.2 ml, 74.5 mmol) and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with 2x water, saturated aqueous sodium chloride and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and dried overnight, yielding (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy- 12 '- (2-methoxyethyl) -111'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide in the form of an orange oil. MS (ESI, + ve ion) m / z 643.0 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- diona 13 ', 13'-dioxide
[000417] [000417] To a 1 L flask containing (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-12 '- (2-methoxyethyl ) -1'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (19.1 g, 29.7 mmol), prepared in the previous step, DCM (300 ml) was added. The solution was cooled in an ice bath for 20 min. Dess-Martin periodinane (15.11 gq, 35.6 mmol) was added in one portion and the reaction was stirred while being cooled in the ice bath for 40 min. The reaction was removed from the ice bath and stirred for 1.5 h at room temperature. Sodium thiosulfate was added followed by water and the mixture was stirred vigorously for min. The reaction was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc (3x). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by chromatography on silica gel (eluted with 0% to 60% EtOAc in heptane) gave (1S8,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-12 '- ( 2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- diona 13 ', 13'-dioxide
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000418] [000418] To a 100 ml round bottom flask was added 1,3-dithian (2.025 g, 16.84 mmol) in THF (42.1 ml). At -78 ºC, n-butyl lithium (2.5 M solution in hexane, 5.90 ml, 14.7 mmol) was added to the solution. The solution was stirred for 15 min and then (18,3'R, 6'R, 8'E, 11'S, 12'R) - 6-chloro-12 '- (2-methoxyethyl) -11'-methyl-3 , 4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide (2.70 g, 4.21 mmol) in 10 mL of THF was added slowly. The mixture was stirred for 1 h and 10 ml of saturated ammonium chloride was added to quench the reaction. The mixture was diluted with 1N HCl (20 ml) and extracted with EtoAc (3 x 40 ml). The organic extracts were washed with saturated NaCl (40 ml) and dried over MgSOs. The solution was filtered and concentrated in vacuo. The material was purified by chromatography through a pre-packaged silica gel column Redi-Sep (80 g), eluting with a gradient of 0% to 60% EtOAc (with 0.1% HOAc) in heptane, giving rise to (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3-ditian-2-yl) -7'-hydroxy- 12'- (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (1.6 g, 2.1 mmol, 50% yield). MS (ESI, + ve ion) m / z 761.1 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000419] [000419] To a 100 mL round bottom flask was added (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (1, 3- ditian-2-yl) -7'-hydroxy-12 '- (2-methoxyethyl) -111'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1.22' -
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (1.6 g, 2.1 mmol) and iodomethane (1.044 mL, 16.81 mmol) in THF (21 mL). At 0 ºC, sodium hydride (0.504 g, 21.0 mmol) was added in portions. The reaction was stirred at room temperature for 5 h. The reaction mixture was diluted with saturated NH2 Cl (20 ml) and extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with saturated NaCl (15 ml) and dried over MgSO4. The solution was filtered and concentrated in vacuo. Purification by chromatography through a pre-packaged silica gel column Redi-Sep (40 g), eluting with a gradient of 0% to 60% EtOAc (with 0.1% HOAc) in heptane, gave (18S, 3 ' R, 6'R, 7'R, 8'E, 11'S, 12'R) - 6-chloro-7 '- (1,3-ditian-2-11) -7'-methoxy-l12' - (2 -methoxyethyl) - 11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide
[000420] [000420] To a resealable flask was added (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (1, 3- ditian-2-1yl1) -7'-methoxy-12 '- (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' -
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.93 g, 1.2 mmol), acetonitrile (9.6 ml) and water (2.4 ml). To the mixture, calcium carbonate (0.600 g, 6.00 mmol) and iodomethane (0.745 mL, 12.0 mmol) were added. The mixture was heated to 45 ° C overnight. The solution was poured into saturated NH.Cl and water and then extracted with EtOAc. The combined extracts were washed with brine and then dried over NazSO. and concentrates. Purification by chromatography on silica gel (eluted with 0% to 60% EtOAc in heptane (with 0.1% AcCOH) gave (1S8.3'R, 6'R, 7'R, 8'E, 11'S, 12 ' R) -6-chloro-7'-methoxy- 12'- (2-methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ' , 13'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000421] [000421] To a 100 mL round bottom flask was added (18, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'- methoxy-12 '- (2-methoxyethyl) -111'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (450 mg, 0.657 mmol), HCl salt of (S) -octahydropyrazine [2,1-c] [1,4] oxazine (1130 mg, 5.25 mmol) and N, N - diisopropylethylamine (2,341 mL, 13.13 mmol) in DCM (13.1 mL). Titanium (IV) isopropoxide (0.770 mL, 2.63 mmol) was added to the solution slowly. The reaction was stirred at room temperature overnight. Sodium triacetoxyborohydride (278 mg, 1.31 mmol) was added to the reaction in portions and the mixture was stirred overnight. The reaction was diluted with saturated NaCl (20 ml). The white precipitate was removed by filtration over Celite. The filtrate was concentrated and diluted with 1 N HCl (20 ml) and extracted with EtOAc (3 x 50 ml). The combined organic extracts were washed with saturated NaCl (50 ml) and dried over MgSOs :. The solution was filtered and concentrated in vacuo. The concentrate was absorbed in a silica gel buffer and purified by chromatography through a pre-packaged Redi-Sep silica gel column (40 g, with a layer of sodium bicarbonate on top). Elution with a gradient of 0% to 10% methanol in DCM gave (18S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6- chloro-7 '- (( 9aS) -hexahydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-methoxy-12 '- (2-methoxyethyl) -11'-methyl-3,4 -di- hydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (420 mg, 0.518 mmol, 79% yield) as a white solid. MS (ESI, + ve ion) m / z 811.0 (M + H) '. 1H NMR (400 MHz, dichloromethane-d2) δ ppm 0.91 - 1.10 (m, 3 H), 1.33-1.72 (m, H, with residual water), 1.81-1.97 (m, 5 H), 2.03 - 2.39 (m, 10 H), 2.41 - 2.69 (m, 6 H), 2.71 - 2.83 (m, 2 H), 2 , 90 - 3.08 (m, 2 H), 3.12 - 3.27 (m, 2 H), 3.33 (s, 3 H), 3.37 (s, 3 H), 3.53 - 3.83 (m, 6 H), 3.95-4.09 (m, 3 H), 4.11 - 4.22 (my, 1 H), 5.23 - 5.29 (my, 1 H), 5.55 - 5.62 (my, 1 É), 6.80 - 6.93 (m, 2 H), 7.09 (s, 1 H), 7.13 - 7.22 (m , 1 H), 7.30 (s, 1 H), 7.72 (d, J = 8.41 Hz, 1 H). Example 12 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12 '- (2-methoxyethyl) -11'-methyl -7 '- ((((3R) -3-methyl-4- (l1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene- 1.22 '-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000422] [000422] To a 25 mL flask was added (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12 '- ( 2-methoxyethyl) -11'-methyl-1115'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (80 mg, 0.117 mmol), (R) -1-isopropyl-2-methylpiperazine bis (2,2,2-trifluoroacetate) (330 mg, 0.891 mmol), N, N-diisopropylethylamine (366 pL, 2.10 mmol) and titanium (IV) isopropoxide (137 µl, 0.477 mmol) in DCM (2335 µl). The solution was stirred at room temperature overnight. To this solution was added sodium triacetoxyborohydride (99 mg, 0.47 mmol). The reaction was stirred for 24 h. The reaction mixture was diluted with 1N HCl (10 ml) and extracted with DCM (2 x 20 ml). The organic solvent was concentrated. The residue was purified by prep-HPLC, giving (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12'- (2-methoxyethyl) -11'-methyl-7 '- ((((3R) -3-methyl-4- (11-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15 'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a TFA salt. MS (ESI, + ve ion) m / z 811.2 (M + H) '. 'H NMR (400 MHz, MeOH-da) at ppm 1.06 (d, J = 6.06 Hz, 3 H), 1.25-1.48 (m, 10 H), 1.49 - 2, 30 (m, 12 H), 2.42 - 2.84 (m, 8 H), 2.94 - 3.27 (m, 4 H), 3.35 (s, 3 H), 3.42 ( s, 4 H), 3.51-3.74 (m, H), 3.91 - 4.10 (my, 3 H), 4.14 - 4.25 (my, 1 HE), 5.35 (d, J = 16.04 Hz, 1 H), 5.69 - 5.82 (m, 1 H), 6.86 - 6.94 (m, 1 H), 7.01 (dd, J = 8.02, 1.76 Hz, 1 H), 7.10 (d, J = 1.96 Hz, 1 H), 7.16 (dd, J = 8.41, 2.15 Hz, 1 H) , 7.26 (d, J = 1.37 Hz, 1 H), 7.73 (d, J = 8.61 Hz, 1 H). Example 13 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '- ((9as) - hexahydropyrazine [2 , 1-c] [1,4] oxazin-8 (1H) -ylmethyl) -12 '- (2-methoxyethyl) -111'-methyl-3,4-dihydro-2H, 15'H-spiro [ naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide Cs Os OH DEt
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000423] [000423] To a 100 mL round bottom flask was added (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (1, 3- ditian-2-yl1) -7'-hydroxy-12 '- (2-methoxyethyl) -111'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' -
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.62 g, 0.814 mmol) and iodoethane (0.655 mL, 8.14 mmol) in N, N-dimethylformamide (8.14 mL). To 0 ºC, potassium bis (trimethylsilyl) amide (1 M in THF, 8.14 mL, 8.14 mmol) was added slowly. The reaction was stirred overnight. The reaction mixture was diluted with 1N HCl (15 ml) and extracted with EtoAc (3 x 15 ml). The organic extract was washed with saturated NaCl (15 ml) and dried over MgSOs :. The solution was filtered and concentrated in vacuo. The concentrate was absorbed in a silica gel buffer and purified by chromatography through a 24 g ISCO Gold column, eluted with a gradient of 0% to 40% EtOAc (with 0.1% HOAc) in heptane, giving rise to (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3-ditian-2- 11) -7' -ethoxy- 12 '- (2-methoxyethyl) -111'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.24 g, 0.304 mmol, 37% yield). MS (ESI, + ve ion) m / zZ 789.1 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide
[000424] [000424] To a re-sealable flask was added (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (1, 3- ditian-2-1i1) -7'-ethoxy-12 '- (2-methoxyethyl) -1''-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' -
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (510 mg, 0.646 mmol), acetonitrile (5168 À1uL) and water (1292 µl). To the mixture, calcium carbonate (323 mg, 3.23 mmol) and iodomethane (401 µL, 6.46 mmol) were added. The mixture was heated to 45 ° C overnight. The reaction was diluted with saturated NH.Cl (10 ml) and extracted with EtOAc (3 x 15 ml). The combined organic extracts were washed with saturated NaCl (20 ml) and dried over MgSOs. The solution was filtered and concentrated in vacuo. The concentrate was absorbed in a silica gel buffer and purified by chromatography through a pre-packaged silica gel column Redi-Sep (40 g), eluting with a gradient of 0% to 60% EtOAc (with HOAc 0.1 %), giving rise to (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6- chloro-7'-ethoxy-12 '- (2-methoxyethyl) - 11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ' , 13'-dioxide (230 mg, 0.329 mmol, 50.9% yield) as a white solid. MS (ESI, + ve ion) m / z 699.1 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000425] [000425] To a 50 mL round bottom flask was added (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '- (2-methoxyethyl) -111'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (150 mg, 0.215 mmol), HCl salt of (S) -octahydropyrazine [2,1-c] [1,4] oxazine (277 mg, 1.29 mmol) and N, N - diisopropylethylamine (574 n1uL, 3.22 mmol) in DCM (4290 uL). The reaction was stirred at room temperature overnight. Sodium triacetoxyborohydride (182 mg, 0.858 mmol) was added to the reaction mixture. The reaction was stirred for 8 h. The reaction mixture was diluted with 1 N HCl (20 ml) and extracted with DCM (2 x 20 ml). The organic layer was fully concentrated. The residue was further purified by prep-HPLC. The solution after prep-HPLC was washed with pH 7 solution and extracted with EtOAc (2 x 20 ml). The organic extract was washed with saturated NaCl (20 ml) and dried over MgSOs. The solution was filtered and concentrated in vacuo, yielding (1S8,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-71'- ethoxy-7'- ((9aS) -hexahydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -12 '- (2-methoxyethyl) -1'-methyl-3,4-di- hydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a white solid. MS (ESI, + ve ion) m / z 825.2 (M + H) *. 1H NMR (400 MHz, dichloromethane-d2) 5 ppm 1.01 (d, J = 6.26 Hz, 3 H), 1.35 (t, J = 6.85 Hz, 3 H), 1.44 - 1.74 (my, 7 HB), 1.77 - 2.01 (m, 5 H), 2.04 - 2.38 (m, 9 H), 2.41 - 2.65 (my, 5 É ), 2.70 - 2.83 (m, 2 H), 2.86 - 3.08 (m, 2 H), 3.27 (d, J = 14.28 Hz, 1 H), 3.35 (s, 3 H), 3.40 - 3.49 (m, 1 H), 3.52-3.83 (m, 7 H), 3.99-4.10 (m, 3 H), 4 , 12 -— 4.28 (m, 1 H), 5.35 - 5.42 (m, 1 H), 5.57 - 5.76 (my, 1 Hd), 6.85-6.92 ( m, 2 H), 7.09 (d, J = 2.15 Hz, 1 Hd), 7.13 - 7.20 (my, 1 Hd), 7.24 (s, 1 À), 7.72 (dy, J = 8.41 Hz, 1 H). Example 14 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-71'-ethoxy-12 '- (2-methoxyethyl) -11'-methyl -7 '- ((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide General Method 12 o
[000426] [000426] To a 25 ml flask was added (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '- ( 2-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (130 mg, 0.186 mmol) in DCM (3718 µl). To this solution was added 1- (oxetan-3-yl) piperazine (159 mg, 1.12 mmol) and a drop of acetic acid. The mixture was stirred for 8 h and sodium triacetoxyborohydride (158 mg, 0.744 mmol) was added. The reaction was stirred for 2 h and diluted with 1 N HCl (10 ml) and extracted with DCM (3 x 15 ml). The organic layer was concentrated. The concentrate was purified by prep-HPLC. The prep-HPLC solution was washed with pH 7 buffer and extracted with EtOAc. The organic layer was concentrated, yielding (1S8,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-71'- ethoxy-12 '- (2- methoxyethyl) -11'-methyl-7 '- (((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1.22' -
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a white solid. MS (ESI, + ve ion) m / z 825.2 (M + H) *. 'H NMR (400 MHz, dichloromethane-d2) 3 ppm 0.98 (s 1, 3 H), 1.29 - 1.43 (my, 4 H), 1.47 - 2.24 (my, 12 HE ), 2.24 - 2.41 (Mm, 4 H), 2.45 - 2.84 (my, 9 H), 2.87 - 3.07 (m, 1 H), 3.27 (d 1 , J = 14.09 Hz, 1 H), 3.34 (s, 3 H), 3.39 - 3.52 (m, 2 H), 3.57 - 3.76 (m, 4 H), 3.95-4.20 (m, 4 H), 4.45-4.55 (m, 2 E), 4.57- 4.65 (m, 2 H), 5.38 - 5.51 ( my, 1 HE), 5.59 - 5.74 (my, 1 É), 6.89 (s, 2 H), 7.09 (d, J = 1.96 Hz, 1 H), 7.13 - 7.19 (m, 1 H), 7.21 -— 7.28 (m, 1 Hd), 7.72 (d, J = 8.41 Hz, 1 H).
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000427] [000427] To a 25 mL flask was added (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '- ( 2-methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (60 mg, 0.086 mmol) and (9ar) -octahydro-2h-pyrido [1,2-a] pyrazine (120 mg, 0.858 mmol) in DCM (1716 µL). A drop of acetic acid was added. The solution was stirred at room temperature overnight. To this solution was added sodium triacetoxyborohydride (73 mg, 0.34 mmol). The reaction was stirred for 8 h and diluted with 1 N HCl (10 ml) and extracted with DCM (2 x 10 ml). The solvent was removed under reduced pressure. The concentrate was purified by prep-HPLC, giving (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12'- (2-methoxyethyl) -1l1'-methyl-7 '- ((9aR) -octahydro-2H-pyrido [1,2-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a TFA salt. MS (ESI, + ve ion) m / z 823.2 (M + H) *. 'H NMR (400 MHz, MeOH-ds.) 3d ppm 1.05 (d, J = 6.46 Hz, 3 H), 1.37 (t, J = 6.85 Hz, 3 H), 1, 41 - 2.02 (m, 14 H), 2.04 - 2.26 (Mm, 5 H), 2.30-2.51 (m, 2 H), 2.51 -— 2.87 (m , 6 H), 2.92 -— 3.08 (m, 3 H), 3.11-3.26 (my, 2 H), 3.35-3.54 (my, 7 HH), 3, 60 - 3.78 (my, 4 H), 3.94-4.11 (my, 3 H), 4.18 - 4.29 (Mm, 1 H), 5.43 (d, J = 16, 04 Hz, 1 HH), 5.67 - 5.89 (my, 1 H), 6.87 - 6.94 (my, 1 H), 6.95 - 7.03 (my 1 H), 7, 10 (dy, J = 1.96 Hz, 1 H), 7.14 -— 7.19 (my, 1 HH), 7.24 (dy, J = 1.56 Hz, 1 BE), 7.73 (d, J = 8.61 Hz, 1 H). Example 16 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-71'-ethoxy-12 '- (2-methoxyethyl) -11'-methyl -7 '- ((4- (l-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide “O
[000428] [000428] To a 10 mL flask was added 1-isopropylpiperazine (123 nL, 0.858 mmol) and (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6- chloro-71'-ethoxy-12 '- (2-methoxyethyl) -11'-methyl-1115'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (60 mg, 0.086 mmol) in DCM (1716 1pL). A drop of acetic acid was added and the reaction was stirred overnight. Sodium triacetoxyborohydride (72.7 mg, 0.343 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 8 h. The reaction mixture was diluted with 1N HCl (5 ml) and extracted with DCM (2x 10 ml). The organic layer was concentrated. The concentrate was purified by prep-HPLC, giving (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-71'-ethoxy-12'- (2-methoxyethyl) -11'-methyl-7 '- ((4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a TFA salt. MS (ESI, + ve ion) m / z 811.2 (M + H) *. 'H NMR (400 MHz, MeOH-d4) 5 ppm 1.05 (d, J = 6.46 Hz, 3 H), 1.29 - 1.47 (my, 10 H), 1.52 - 2, 30 (m, 12 H), 2.51-2.87 (my, 8 E), 2.93 - 3.11 (m, 2 H), 3.38 (s, 4 H), 3.45 - 3.57 (my, 3 É), 3.59 - 3.78 (m, 4 H), 3.95-4.11 (m, 3 H), 4.20 - 4.33 (mM, 1 H ), 5.45 (d, J = 15.85 Hz, 1 HH), 5.77 - 5.91 (m, 1 H), 6.84 - 6.94 (m, 1 H), 6.96 - 7.02 (m, 1 H), 7.10 (d, J = 1.96 Hz, 1
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000429] [000429] To a 25 mL flask was added (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '- ( 2-methoxyethyl) -1'-methyl-l15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (80 mg, 0.11 mmol), (R) -1-isopropyl-2-methylpiperazine bis (2,2,2-trifluoroacetate) (254 mg, 0.686 mmol), N, N-di -isopropylethylamine (408 pL, 2.29 mmol) and titanium (IV) isopropoxide (134 ul, 0.458 mmol) in DCM (2288 ul). The solution was stirred at room temperature for 8 h. To this solution was added sodium triacetoxyborohydride (97 mg, 0.46 mmol). The reaction was stirred overnight. The reaction mixture was diluted with 1N HCl (10 ml) and extracted with DCM (2 x 10 ml). The solvent was concentrated. The residue was purified by prep-HPLC, giving (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-71'-ethoxy-12'- (2-methoxyethyl) -11'-methyl-7 '- ((((3R) -3-methyl-4- (11-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15 'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a TFA salt. MS (ESI, + ve ion) m / z 825.4 (M + H) *. 'H NMR (400 MHz, MeOH-ds) at ppm 1.05 (d, J = 6.46 Hz, 3 H), 1.21 - 1.49 (m, 13 H), 1.51 - 2, 28 (m, 12 HE), 2.37 - 2.87 (my, 8 HE), 2.92 - 3.20 (my, 3 H), 3.36 - 3.57 (m, 7 H), 3.60 - 3.79 (m, 4 H), 3.97-4.07 (my, 3 H) 4.20 - 4.31 (my 1 H), 5.43 (d, J = 16, 04 Hz, 1 H), 5.75 - 5.90 (my, 1 H), 6.87 - 6.94 (m, 1 H), 6.98 - 7.01 (m, 1 H), 7 , 10 (d, J = 1.37 Hz, 1 H), 7.14-7.19 (m, 1 H), 7.24 (dy, J = 1.37 Hz, 1 H), 7.73 (dy, J = 8.61 Hz, 1 H). Example 18 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- ((9aS) -hexahydropyrazine [2,1-c] [1 , 4] oxazin-8 (1H) -ylmethyl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide General Method 2 (Steps 10-12) and General Method 4 (Steps 13-14)
[000430] [000430] To a stirred solution of (R) - (6-chloro-11-formyl-1,2,3,4-tetrahydronaphthalen-11-yl) 4-bromobenzoate in methyl (425 g, 1042 mmol) in DCM (5100 mL) and MeOH (5100 mL) under a nitrogen atmosphere was added pyridine (337 mL, 4170 mmol) followed by hydroxylamine hydrochloride (145 g,
[000431] [000431] (S, E) - (6-chloro-1- ((hydroxyimino) methyl) -1,2,3,4-tetrahydronaphthalen-l1-yl) methyl 4-bromobenzoate (425 g, 1005 mmol), prepared in the previous step, was dissolved in THF (5160 mL) under an atmosphere of nitrogen. The reaction mixture was cooled to 0 ° C and lithium and aluminum hydride (1.0 M in THF, 3519 ml, 3519 mmol) was added dropwise. The ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. The reaction was cooled to 0 ºC and water (160 ml) was added slowly, followed by 15% aqueous NaOH solution (160 ml) and water (500 ml). The mixture was allowed to stir for 10 min at room temperature and the reaction was filtered. The residual solids were washed with hot ethyl acetate (3 x 4.0 L). The combined filtrate was concentrated under reduced pressure, giving a yellow oil. The residue was dissolved in DCM (5160 ml) and the solution was cooled to 0 ºC. A solution of HCl (4.0 M in dioxane, 65 ml) was added dropwise and the mixture was allowed to stir for min at room temperature. The precipitate was collected by filtration. The solid was washed with ice-cold DCM (100 mL) and dried, yielding (S) - (1- (aminomethyl) -6-chloro-1,2,3,4-tetrahydronaphthalen-l1-yl) hydrochloride) methanol (192 g, 72.8% yield). H NMR (400 MHz, Methanol-da) 5 7.38 - 7.36 (dy, J = 8.2 Hz, 1H), 7.23 - 7.20 (m, 2H), 3.81 - 3.78 (m, 1H), 3.69 - 3.68 (dd, J = 10.9, 1.3 Hz, 1H), 3.48 - 3.45 (dy, J = 13.1 Hz, 1H), 3.23 - 3.20 (d, J = 13.2 Hz, 1H), 2.83 —- 2.81 (d, J = 6.3 Hz, 2H), 2.17 -— 2 , 11 (m, 1H), 1.91 - 1.85 (m, 2H), 1.83 - 1.74 (my, 1H); interchangeable protons not observed.
[000432] [000432] A stirred solution of (S) - (1- (aminomethyl) -6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl) methanol (150 g, 572 mmol) was dissolved in dry DMSO (2250 mL) under a nitrogen atmosphere at room temperature. The solution was treated with 6-bromo-5-fluoropicolinic acid (151 g, 687 mmol) and the resulting solution was treated with potassium 2-methylpropan-2-olate (218 9, 1945 mmol) at room temperature. The reaction mixture was stirred for 2 h at room temperature and quenched by the addition of acetic acid (-170 ml) at room temperature,
[000433] [000433] To a stirred solution of (S) -5 - ((1- (aminomethyl) - 6-chloro-1,2,3,4-tetrahydronaphthalen-11-yl) methoxy) -6-
[000434] [000434] A solution of 5 - (((S) -1- ((((((1R, 2R) -2- (acetoxymethyl) cyclobutyl) methyl) amino) methyl) -6-chloro-1,2,3, Methyl 4-tetrahydronaphthalen-11-yl) methoxy) -6-bromopicolinate (36 g, 62, 1 mmol) and N-ethyl-N-isopropylpropan-2-amine (161 mL, 933 mmol) in N-methyl -2-pyrrolidinone (360 mL) was stirred at 130 ºC under a nitrogen atmosphere for 16 h. The reaction was cooled to room temperature and diluted with ethyl acetate (1.0 L). The mixture was washed with water (5 x 400 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (60-120 mesh, 0% to 10% EtOAc in hexane) gave (S) - 5 '- ((((1R, 2R) -2- (acetoxymethyl) cyclobutyl) methyl) -6-chloro-3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] - Methyl 7 '-carboxylate (16 g, 51.7% yield) as a yellow liquid. MS (ESI, + ve ion) m / z 499.1 (M + 1). 'H NMR (400 MHz, Chloroform-d) at 7.72 - 7.70 (df, J = 8.5 Hz, 1H), 7.46 - 7.44 (dd, IJ = 7.9, 1, 1 Hz, 1H), 7.21 - 7.20 (dd, JIJ = 8.5, 2.2 Hz, 1H), 7.18 - 7.11 (m, 2H), 4.18 - 4.15 (dy, IJ = 12.2 Hz, 1H), 4.05 - 3.98 (m, 3H), 3.95 - 3.93 (d, J = 4.5 Hz, 1H), 3.91 - 3.89 (dy, JT = 1.0 Hz, 3H), 3.74 - 3.70 (d, J = 14.5 Hz, 1H), 3.42 - 3.32 (m, 2H), 2 , 79 - 2.76 (dt, J = 9.0, 5.1 Hz, 2H), 2.55 - 2.49 (dt, J = 15.5, 7.4 Hz, 2H), 1.98 - 1.85 (m, 8H), 1.76 - 1.74 (t, J = 9.4 Hz, 1H), 1.62 - 1.61 (dy, JIJ = 1.1 Hz, 1H), 1.50 - 1.49 (df, J = 1.1 Hz, 1H).
[000435] [000435] To a stirred solution of (S) -5 '- ((((1R, 2R) -2- (acetoxymethyl) cyclobutyl) methyl) -6-chloro-3,4,4', 5'-tetrahydro -2H, 2'H-spiro [naphthalene-1,3-pyrido [3,2- b] [1,4] oxazepine] -7'-methyl carboxylate (68 g, 136 mmol) in THF (680 mL ) and water (680 ml) lithium hydroxide monohydrate (22.87 g, 545 mmol) was added at room temperature. The reaction was allowed to stir at room temperature for 12 h. The reaction was concentrated under reduced pressure and the residue was taken up in MTBE (1.0 L), 10% citric acid monohydrate solution (500 ml) was added and the solution was stirred for 10 min. The layers were separated and the organic layer was washed with brine (500 ml), dried over sodium sulfate and concentrated under reduced pressure. The concentrate was dissolved in dry methanol (600 ml) and cooled to 0 ºC. Thionyl chloride (14.92 mL, 204 mmol) was added and the reaction was heated to 60 ° C for 12 h. The reaction was cooled to 0 ºC and quenched by slowly adding 10% sodium bicarbonate solution (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with brine (300 ml), dried over sodium sulfate and concentrated under reduced pressure. The concentrate was suspended in acetonitrile (140 ml) and water (140 ml) was added. The mixture was stirred for 10 min. The solid was collected by filtration and dried, yielding (S) -6-chloro-5 '- ((((1R, 2R) -2- (hydroxymethyl) cyclobutyl) methyl) -
[000436] [000436] A 1 L 3-neck flask equipped with a mechanical stir bar and a temperature probe was loaded with DCM (220 mL, 5 V) followed by oxalyl chloride (10.16 mL, 116 mmol). The solution was cooled to -73 "C in a dry ice and acetone bath. DMSO (17.15 ml, 242 mmol) was added via syringe over 7 min (the internal temperature increased from -74 ºC to -60 ºC during the addition). The mixture was maintained for 14 min and a solution of (S) -6-chloro-5 '- ((((1R, 2R) -2- (hydroxymethyl) cyclobutyl) methyl) - 3,4,4', 5'- tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-methyl carboxylate (44.2 g, 97 mmol) in DCM (220 mL, 5 V), cooled in a dry ice and acetone bath, it was added via cannula over 12 min (the internal temperature increased from -75 * C to -72 “C during the addition). The solution was stirred for 17 min and triethylamine (67.4 ml, 484 mmol) was added over 7 min (the internal temperature increased from -76 ºC to -65 “* C during the addition). After adding Et3; N, the reaction was kept in the dry ice and acetone bath for 5 min, then heated to 7 ° C over 4 h and quenched with water (220 mL, 5 V) (the internal temperature increased from 7 “C to 15 ºC during extinction). The mixture was transferred to a separating funnel and the aqueous layer was discarded. The bottom layer was washed with NH. «Cl saturated (220 mL, 5 V), 1: 1 water: NaHCO; 3 saturated (220 mL, 5 V) and 1: 1 water: brine (220 mL, 5 V) . The bottom organic layer was dried over MgSO: s, filtered through a fine frit and concentrated under reduced pressure, giving an almost white foam. The foam was dissolved in 1: 1 EtoAC / DCM (100 ml) and filtered through a 2 cm silica pad (eluted with 400 ml 1: 1 EtOAc / DCM). The solution was concentrated under reduced pressure, diluted with PhMe (100 ml) and concentrated. This procedure was repeated two more times and the product (S) -6-chloro-5 '- ((((1R, 2R) -2-formylcyclobutyl) methyl) -3,4,4', 5'-tetrahydro- 2H, 2'H-spiro [naphthalene-1,3-pyrido [3,2-b] [1,4] oxazepine] -7'-methyl carboxylate was used without further purification. MS (ESI, + ve ion) m / z 454.9 (M + H) *.
[000437] [000437] A 2 L jacketed reactor was charged with (-) - cinchonidine (5.69 g, 19.34 mmol) followed by PhMe (220 mL, 5 V) and THF (220 mL, 5 V). The solution was cooled to -23 ºC (internal temperature) and zinc chloride (1.9 M in 2-methyltetrahydrofuran, 81 mL, 155 mmol) was added over 3 min (the internal temperature increased from -23 “ C to -19 ºC during the addition). The solution was stirred for min and vinylmagnesium chloride (1.6 M solution in THF, 206 mL, 329 mmol) was added via an addition funnel over 24 min (the internal temperature increased from -21 ºC to -13 ºC during the addition). The solution was stirred for 20 min (the internal temperature decreased to -22 ºC) and a solution of (S) -6-chloro-5 '- (((1R, 2R) -2-formylcyclobutyl) methyl) -3.4 Methyl 4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylate in the previous step, in PhMe (220 mL, 5 V) cooled in an ice water bath, it was added via cannula over 8 min (the internal temperature increased from -22 ºC to -16 ºC during the addition). The reaction was stirred at -20 ° C for 1 h and heated to 0 ° C. After 45 min, the reaction was cooled to -8 “ºC and quenched with saturated NH« Cl (350 mL, 8 V). Water (88 mL, 2 V) was added. Ammonium hydroxide (20 mL, 0.45 V) was added and the solids dissolved. The aqueous phase was discarded. The organic phase was washed with NH. «Cl saturated (220 ml, 5 V), 1 M citric acid (4 x 88 ml, 2 V), 1: 1 water: brine (440 ml, 10 V), dried over MgSO's , filtered and concentrated, yielding a yellow oil. MeOH (200 ml) was added and removed under reduced pressure. This procedure was repeated a second time and the product (1S) - 6-chloro-5 '- ((((1R, 2R) -2- (1-hydroxyaloyl) cyclobutyl) methyl) - 3,4,4', 5 ' -tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-methyl carboxylate was used without further purification as a mixture of diastereomers. MS (ESI, + ve ion) m / z 483.0 (M + H) *.
[000438] [000438] A 2 L jacketed reactor was charged with a solution of (18) -6-chloro-5 '- ((((1R, 2R) -2- (1-hydroxyalyl) cyclobutyl) methyl) -3,4, Methyl 4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylate, prepared in previous step, in MeOH (234 ml, 5 V) and THF (234 ml, 5 V). Lithium hydroxide monohydrate (16.23 g, 387 mmol) was added and the reaction was stirred at room temperature for 17 h. Citric acid (1 M in water, 180 ml) was added followed by water (187 ml, 4 V) and EtOAc (234 ml, 5 V). All the solids dissolved. The mixture was drained from the reactor into a 3 L flask and the mixture was concentrated to half the original volume. EtoOAc (234 mL, 5 V) was added and the mixture was transferred to a separatory funnel. The pH of the aqueous layer was 5. The aqueous layer was discarded. The organic layer was washed with 1: 1 water: brine (235 mL, 5 V), dried over MgSO:, filtered and concentrated, yielding 47.0 gq of a yellow solid which was 79% wt (1S) acid -6-chloro-5 '- ((((1R, 2R) -2- (1-hydroxyaloyl) cyclobutyl) methyl) -3,4,4', 5'-tetrahydro-2H, 2'H-spiro [ naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] - 7'-carboxylic (37.1 g, 79 mmol, 82% yield) and a mixture of diastereomers. MS (ESI, + ve ion) m / z 469.0 (M + H) *.
[000439] [000439] To a mixture of (18) -6-chloro-5 '- ((((1R, 2R) - 2- (1-hydroxyaloyl) cyclobutyl) methyl) -3,4,4', 5'-tetra -hydro- 2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] - 7'-carboxylic (34.7 gq, 58.5 mmol), 4- (dimethylamino) pyridine (21.42 g, 175 mmol) and (2R, 3S) - 3-methyl-hex-5-ene-2-sulfonamide (21.41 9g, 117 mmol) in a 1-necked flask 500 ml PhMe (100 ml) was added. The PhMe was removed under reduced pressure and the concentrate was diluted with DCM (347 mL, 10 V) and transferred to a 1 L 3-neck flask equipped with a temperature probe and a magnetic stirrer. Triethylamine (24.44 mL, 175 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl (22.41 g, 117 mmol) were added and the reaction was stirred at room temperature. After 43 h, the reaction was diluted with water (240 mL, 7 V) and transferred to a separating funnel. The pH of the aqueous phase was adjusted to 4 with 1 M citric acid (240 mL, 7 V) and the aqueous phase was discarded. The organic phase was washed with 1: 1 brine: water (240 ml, 7 V), dried over MgSOs, filtered and concentrated. Purification by flash column chromatography on silica gel (330 g silica, eluted with 50% to 100% DCM in heptane) gave (18S) -6-chloro-5 '- (((1R, 2R) -2- ( 1- hydroxyaloyl) cyclobutyl) methyl) -N - ((((2R, 3S) -3-methyl-hex-5-en-2-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro- 2H, 2'H-spiro [naphthalene-1,3-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxamide (24.7 g, 39.3 mmol, 67% yield ) in the form of a pale yellow foam and a mixture of diastereomers. MS (ESI, + ve ion) m / z 628.0 (M + H) *.
[000440] [000440] A solution of (18) -6-chloro-5 '- ((((1R, 2R) -2- (1-hydroxyaloyl) cyclobutyl) methyl) -N - ((((2R, 3S) -3-methyl -hex-5-en- 2-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b ] [1,4] oxazepine] -7'-carboxamide (2.82 g, 4.49 mmol) in DCM (28 mL, 10 V) in a 100 mL 1-neck flask, equipped with a temperature probe and magnetic stir bar, was cooled to 2 ºC in an ice water bath and Dess-Martin periodinane (2.094 g, 4.94 mmol) was added in one portion. The reaction was warmed to room temperature over 20 min and stirred at room temperature for 30 min. The solution was cooled to 2 ºC in an ice-water bath and quenched with a solution of sodium thiosulfate (2.4 g) in water (8.4 mL, 3 V) followed by NaHCO; saturated (20 mL, 7 V). The internal temperature increased from 2 "ºC to 7" ºC during extinction. The reaction was removed from the ice-water bath, warmed to room temperature and stirred for 30 min. The mixture was transferred to a separating funnel. The pH was adjusted to 7 with 1 M citric acid. The aqueous layer was discarded. The organic phase was washed with 1: 1 water: brine (28 ml, 10 V), dried over MgSOs, filtered and concentrated, yielding a yellow foam. The concentrate was dissolved in 10% EtOAc in DCM (-50 ml) and filtered through a 1 cm silica gel pad (eluted with -100 ml of 10% EtOAc in DCM). The filtrate was concentrated, yielding (S) -5'- ((((1R, 2R) -2-acryloylcyclobutyl) methyl) -6-chloro-N - ((((2R, 3S) -3-methyl-hex- 5-en-2-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1 , 4] oxazepine] -7'-carboxamide as a pale yellow foam that was used without further purification. MS (ESI, + ve ion) m / z 625.8 (M + H) *. ! H NMR (400 MHz, CHLOROPHORMUM-d) 3 ppm 1.14 (d, J = 6.85 Hz, 3H), 1.45 (d, J = 7.04 Hz, 3H), 1.48 - 1 , 56 (m, 1H), 1.81 —- 2.05 (m, 6H), 2.10 - 2.19 (m, 2H), 2.27 (q, J = 8.80 Hz, 1H) , 2.62 (qd, J = 7.14, 2.45 Hz, 1H), 2.73 - 2.87 (m, 2H), 3.04 - 3.17 (m, 1H), 3.30 (q, J = 8.80 Hz, 1H), 3.36 - 3.43 (m, 1H), 3.43 - 3.47 (m, 1H), 3.78 (d, J = 14, 48 Hz, 1H), 3.89 —- 4.07 (m, 3H), 4.20 (d, J = 12.32 Hz, 1H), 5.07 - 5.15 (m, 2H), 5 , 74 - 5.87 (my, 2H), 6.15 - 6.32 (my, 2H), 7.12 (d, J = 2.15 Hz, 1H), 7.18 - 7.22 (my , 2H), 7.58 (dy, J = 7.83 Hz, 1H), 7.69 (d, J = 8.41 Hz, 1H), 9.90 (s, 1H).
[20] [20] oxa [13] aunt [1,14,25] triazatetracycle [14.7.2.0-3,6-.0-19,
[000441] [000441] A 4-necked flask equipped with a magnetic stir bar, a temperature probe and an air-cooled condenser was charged with PhMe (1.8 L, 250 V). The solvent was heated to 80 “ºC and a gas dispersion tube was immersed in the solvent. Gaseous nitrogen was bubbled through the solvent via the gas dispersion tube. A solution of (S) -5 '- (((1R, 2R) -2-acryloylcyclobutyl) methyl) -6-chloro-N - ((((2R, 3S) -3-methyl-hex-5-en-2 -yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] Carboxamide (8.93 g, 80% w, 11.41 mmol) in PhMe (65 mL) was added via an addition funnel over 2 h. During the addition of the diene, Umicore M73 SIMes (Umicore AG & Co. KG, Precious Metals Chemistry, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany) was added in four equal portions (the total amount of catalyst was 0.346 g, 0.456 mmol ) as a suspension in PhMe (4 mL) via syringe a: t = O min, t = 30 min, t = 60 min and t = 90 min. After the addition of the diene was completed, the reaction was stirred for an additional 1 h at 80 ° C. The reaction was cooled to room temperature and 2- (2- (vinyloxy) ethoxy) ethanol (0.125 mL, 0.913 mmol) and SilaMetS Thiol (SiliCycle Inc. 2500, Parc- Technologique Blvd Quebec Cit, Quebec, Canada) (7, 71 g) were added. The mixture was stirred at room temperature for 18 h and the SilaMetS Thiol was removed by filtration and the system was washed with EtOAc and concentrated, giving a bronze-colored solid. MeOH (-50 mL) was added and removed under reduced pressure. MeOH (107 mL, 15 V) was added and the slurry was stirred at room temperature for 3 d and collected by filtration. The solid was washed with MeO0OH (1 x 40 mL) and dried on a frit under a vacuum with a positive nitrogen flow, giving 6.39 g of an almost white solid that was 66% P of (18.3 ' R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene -1.22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24> -] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13 ', 13'-dioxide (4.22 gq, 7.0 mmol, 62% yield). MS (ESI, + ve ion) m / z 598.1 (M + H) *.
[20] [20] oxa [13] tia [1, 14, 25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide
[000442] [000442] A 3-necked flask equipped with temperature probe, septum and nitrogen inlet was loaded with (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chlorine-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraene] -7 ', 15 '-dione 13', 13'-dioxide (6.33 q, 66% Pp, 6.98 mmol) and trimethylsulfonium iodide (2.138 g, 10.48 mmol). DMSO (35 ml) and THF (8.75 ml) were added and the mixture was stirred at room temperature for 20 min until the solids had dissolved. The solution was cooled in an ice water bath. When the internal temperature reached 6.5 ºC,
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19 24> -] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (2.93 g, 4.55 mmol, 65% yield). MS (ESI, + ve ion) m / z 644.0 (M + H) *.
[20] [20] oxa [13] aunt [1, 14, 25] triazathetracycle [14.7.2.0-3,6-.0-19,
[000443] [000443] To a solution of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7'- (hydroxymethyl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (79% w, 7.4 gq, 9.07 mmol) in DCM (60 ml) and DMSO (30 ml) was added N, N-diisopropylethylamine (7.92 ml, 45 , 4 mmol) The solution was cooled in an ice-water bath and a pyridine-sulfur trioxide complex (3.61 g, 22.69 mmol) was added. After 40 min, the reaction was quenched with saturated ammonium chloride and diluted with water and EtOAc. The organic phase was washed with water. The combined aqueous phase was extracted with EtOAc (2 x). The combined organic phase was washed with 50% saturated ammonium chloride (2 x), brine, dried over NazSOs, filtered and concentrated, yielding (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19 24> -] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide which was used without further purification. MS (ESI + ve ion) m / z 641.9 (M + H) *.
[20] [20] oxa [13] tia [1, 14, 25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24> -] pentacosa [8,16,18,24] tetraen] -15'- ona 13 ', 13'-dioxide
[000444] [000444] To a solution of (15,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7'-methoxy-11 ', 12'-dimethyl-15' -ox0-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14, 25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24> -] pentacosa [8,16,18,24] tetraene] -7'- carbaldehyde 13 ', 13'-dioxide (5.28 g, 8.22 mmol) and (S) -octahydropyrazine [2,1- c] l [1,4] oxazine (3.51 g, 24.67 mmol) in DCM (82 mL) at room temperature, acetic acid (0.475 mL, 8.22 mmol) was added. The mixture was stirred at room temperature for 1 h and sodium triacetoxyborohydride (2.091 g, 9.87 mmol) was added slowly over 1 min. After 1 h, more sodium triacetoxyborohydride (300 mg) was added. The reaction was stirred for 30 min and quenched with saturated NH.KCl. The aqueous phase was extracted with DCM (3 x). The combined organic extracts were washed with saturated NH.Cl (1 x), brine (1 x), dried over Na2SOs, filtered and concentrated. Purification by Flash column chromatography (330 g silica, eluted with 0% to 10% MeOH in DCM gave (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6- chloro-7 '- ((9aS) - hexahydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'- methoxy-11', 12'-dimethyl-3, 4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24> -] pentacosa [8,16,18,24] tetraen] -15'- 13 ', 13'-dioxide (6.02 q, 7.83 mmol, 95% yield) as an off-white solid. MS (ESI, + ve ion) m / z 768.2 (M + H) *. ! H NMR (400 MHz, CHLOROPHORMUM-d) 5 ppm 1.17 (d, J = 6.85 Hz, 3H), 1.46 (d, J = 7.04 Hz, 3H), 1.48 - 1 , 63 (m, 4H), 1.68 - 2.09 (m, 8H) 2.19 (d 1, J = 17.22 Hz, 1H), 2.49 (s 1, 3H), 2.33 (s 1, 3H),
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide General Method 13 oa OHC, oMe NO)> OoMe ci RR, QUNH AQ, o - o Ss o DZ Ss o ra Example 19
[000445] [000445] To a solution of (1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7'-methoxy-11 ', 12'-dimethyl-15' -oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24> -] pentacosa [8,16,18,24] tetraene] -7'- carbaldehyde 13 ', 13'-dioxide (12 mg, 0.019 mmol) and 1- (oxetan-3-yl) piperazine (26.6 mg, 0.187 mmol) in DCM (374 ul) at room temperature a few drops of isopropoxide were added titanium (IV). The mixture was stirred at room temperature for 8 h and sodium triacetoxyborohydride (15.84 mg, 0.075 mmol) was added slowly over 1 min. The reaction was stirred overnight and quenched with 5 ml of 1 N HCl solution. The aqueous phase was extracted with DCM (3 x). The combined organic extracts were concentrated. The residue was purified by prep-HPLC, giving (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12' - dimethyl-7 '- ((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24> -] pentacosa [8,16,18,24] tetraen] -15'- ona 13 ', 13'-dioxide as a TFA salt. MS (ESI, + ve ion) m / z 768.2 (M + H) *. 'H NMR (400 MHz, MeOH-ds) at ppm 1.11 (d, J = 6.65 Hz, 3 H), 1.39 (dy, J = 7.24 Hz, 3 H), 1.44 - 1.58 (m, 1 H,) 1.64 - 2.01 (m, 6 H), 2.03 - 2.27 (my, 2 H), 2.29 - 2.43 (my, 2 H,) 2.45 - 2.56 (m, 1 H), 2.32 -— 3.04 (my, 7 HH), 3.35 - 3.67 (m, 6 H), 3.35 - 3.65 (m, 6 H), 3.72 -— 3.93 (m, 4 H), 4.03 - 4.10 (Mm, 1 H), 4.12 -— 4.28 (m, 2 H), 4.61 (t, J = 6.16 Hz, 2 H), 4.69 - 4.77 (m, 2 H), 5.78-5.90 (my, 2 H), 7 , 12 (d, J = 1.96 Hz, 1 H), 7.15 -— 7.20 (my, 1 H), 7.21-7.26 (my, 2 HH), 7.70 (d , J = 8.41 Hz, 1 H). Example 20 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- ((9aS) -hexa-hydropyrazine [2,1-c] [1 , 4] oxazin-8 (1H) -ylmethyl) -7'-methoxy-12 '- (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene- 1.22'-
[20] [20] oxa [13] tia [1, 14, 25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24> -] pentacosa [8,16,18,24] tetraen] -15'- ona 13 ', 13'-dioxide
[6] [6] OMe CI oMe o - o - NOONÇA 252º Stage 5 NO ONÇA, 2520 Stage 6 X IL No X XX) No * o ”o o NA 1 name N CAN, ove and. Ow Ie fi OMe fe oo NON 80 Step 7 NON. $ Eo "O ONO VE ONO À | HO S (| HO Ss DZ S DZ o Oo Example 20 Step 1: (18) -6-chloro-5 '- (( (1R, 2R) -2- (1-hydroxyaloyl) cyclobutyl) methyl) -N - ((((3R, 4S) -1-methoxy-4-methyl-hept-6-en-3-yl) sulfonyl) -3 , 4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'- carboxamide
[000446] [000446] To a solution of (3R, 4S) -1-methoxy-4-methyl-hept-6-ene-3-sulfonamide (4.94 g, 22.34 mmol) in DCM (80 mL) was added acid (18) -6-chloro-5 '- ((((1R, 2R) -2- (1-hydroxyaloyl) cyclobutyl) methyl) -3,4,4', 5'-tetrahydro-2H, 2'H -
[000447] [000447] To a solution of (1S) -6-chloro-5 '- ((((1R, 2R) -2- (1-hydroxyaloyl) cyclobutyl) methyl) -N - ((((3R, 4S) -l- methoxy-4-methyl-hept-6-en-3-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [ 3,2-b] [1,4] oxazepine] -7'-carboxamide (6.1 g, 9.07 mmol) in DCM (70 mL) at 0 ºC Dess-Martin periodinane (4.5 g , 10.61 mmol). After the addition, the ice bath was removed and the resulting mixture was warmed to room temperature and stirred for 20 h. The reaction was quenched with 10% sodium thiosulfate (5 ml) and stirred for 30 min. The resulting mixture was washed with NaHCO; saturated (30 mL). The aqueous layer was extracted with DCM (2 x 50 ml). The combined organic layers were dried over MgSOs, filtered and concentrated. The crude product was purified by column chromatography (330 g silica, 0% to 40% acetone in heptane) to obtain (S) -5'- ((((1R, 2R) -2-acryloylcyclobutyl) methyl) -6 -chloro-N - ((((3R, 4S) - 1-methoxy-4-methyl-hept-6-en-3-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2- b] [1,4] oxazepine] -7'-carboxamide in the form of a light brown foam. ! H NMR (DICLOROMETHANE-ds;) 5 9.25-9.54 (m, 1H), 7.70-7.76 (m, 1H), 7.44-7.51 (my, 18), 7 , 14-7.21 (mM, 18), 7.03-7.13 (m, 2H), 5.85-6.03 (m, 2H), 4.13-4.22 (mM, 1H) , 4.01-4.12 (m, 2H), 3.85-3.99 (m, 1H), 3.72-3.81 (mM, 1H), 3.58-3.70 (m, 2H), 3.29-3.33 (my, 7H), 3.17-3.27 (m, 6H), 2.94-3.04 (m, 3H), 2.83-2.93 ( m, 4H), 2.73-2.80 (m, 2H),
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19 24> -] pentacosa [8,16,18,24] tetraene] -7 ', 15 '-dione 13', 13'- dioxide
[000448] [000448] To a solution of (S) -5 '- ((((1R, 2R) -2-acryloylcyclobutyl) methyl) -6-chloro-N - ((((3R, 4S) -l-methoxy-4-methyl -hept-6-en-3-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b ] [1,4] oxazepine] - 7'-carboxamide (2.2 g, 3.28 mmol) in 1,2-dichloroethane (1200 mL) under nitrogen, Hoveyda-Grubbs 2nd generation catalyst (0.206 g, 0.328 mmol). The resulting mixture was heated to 55 ° C for 20 h. The reaction was cooled to room temperature and concentrated. The crude product was purified by column chromatography (220 g silica, 0% to 30% acetone in heptane) to obtain (18.3'R, 6'R, 8'E, 11'S, 12'R) -6 -chloro-12 '- (2-methoxyethyl) -11'- methyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraene] -7 ', 15 '-dione 13', 13'-dioxide as a pale yellow solid (1.5 g). 'H NMR (DICLOROMETAN-ds;) 5 8.69 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H) 7.20 (dy, J = 8.4 Hz, 1H), 7.08-7.18 (m, 3H), 6.71-6.82 (mM,
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide
[000449] [000449] To a 50 ml 3-neck flask dried in the oven, which was equipped with a stir bar and temperature probe, was added 1,3-dithian (0.890 g, 7.40 mmol and THF (15 ml). The resulting mixture was cooled to -20 to -30 ºC and a solution of n-butyllithium (2.5 M in hexanes, 2.7 mL, 6.75 mmol) was added dropwise via syringe. stirred at -20 ºC for 30 min, cooled to less than -70 "* C and stirred for 20 min. To this reaction was added lanthanum (III) chloride and lithium chloride complex (0.6 Mem THF, 5, 6 mL, 3.36 mmol, Strem Chemical, Newbury Port, MA) drop by drop via syringe (the internal temperature was kept below -70 ° C). After 10 min, (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-12 '- (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 7'H, 15'H- spiro [naphthalene -1.22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraene] -7 ', 15 '-dione 13', 13'-dioxide (0.430 g, 0.670 mmol) in THF (5 mL) was added dropwise via syringe (the internal temperature was kept below -70 ° C). The reaction was stirred at -70 ° C for min after the addition. The reaction was quenched with saturated NH'Cl (3 ml), warmed to room temperature and partitioned between EtOAc (60 ml) and water (30 ml). The organic layer was dried over MgSO.s, filtered and concentrated. Purification by column chromatography (80 g silica, 0% to 30% acetone in heptane) gave (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro- 7 '- (1,3-dithian-2- 11) -7'-hydroxy-12' - (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [ naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14, 25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide as a white solid (0.350 g). 1H NMR (DICLOROMETHANE-d2) 5 9.24 (s 1, 1H), 7.65-7.73 (m, 1H), 7.35- 7.41 (my, 1H), 7.19 (df, J = 7.8 Hz, 2H), 7.11 (s, 1H), 5.767 5.87 (m, 1H), 5.60-5.71 (m, 1H), 4.61 (dd, J = 13.5, 4.9 Hz, 1H), 4.12-4.22 (m, 2H), 3.94-4.03 (m, 2H), 3.89 (d, J = 14.5 Hz , 1H), 3.53-3.63 (m, 2H), 3.44 (d, J = 14.5 Hz, 1H), 3.32 (s, 3H), 2.94-3.04 ( m, 2H), 2.85-2.93 (m, 4H), 2.73-2.84 (m, 3H), 2.54-2.70 (m, 2H), 2.17-2, 33 (my, 2H), 2.04-2.13 (mM, 4H), 1.87-2.00 (m, 3H), 1.71-1.83 (m, 3H), 1.64 ( dt, J = 18.6, 9.5 Hz, 1H), 1.47 (d, J = 14.9 Hz, 1H), 1.15 (dy, J = 6.8 Hz, 3H). MS (ESI, + ve ion) m / z 762.2 (M + H) *.
[20] [20] oxa [13] tia [1, 14.25] triazatetracycle [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide
[000450] [000450] To a 15 mL flask was added (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3-ditian-2 - yl) -7'-hydroxy-12'- (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24> -] pentacosa [8,16,18,24] tetraen] -15'- 13 ', 13'-dioxide (0.350 g, 0.459 mmol) and THF (15.0 mL). The mixture was cooled to 0 ° C and sodium hydride (60 weight percent in oil, 0.165 g, 4.13 mmol) was added. The ice bath was removed after the addition and the mixture was stirred at room temperature for 20 min, then iodomethane (0.520 ml, 8.37 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with water (5 ml). The resulting mixture was partitioned between EtOAc (50 ml) and water (20 ml). The organic layers were dried over MgSOs, filtered and concentrated. Purification by column chromatography (40 g silica, 0% to 30% acetone in heptane) gave (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro- 7 '- (1,3-dithian-2-yl) -7'-methoxy-12' - (2-methoxyethyl) - 11'-methyl-3,4-dihydro-2H, 15'H-spiro [ naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24> -] pentacosa [8,16,18,24] tetraen] -15'- ona 13 ', 13'-dioxide as a white solid. ! H NMR (DICLOROMETHANE-d2) at 9.20 (s 1, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H) , 7.16-7.22 (my, 2H), 7.11 (s, 1H), 5.73-5.86 (m, 1H), 5.49-5.60 (m, 1H), 4 , 82 (dd, J = 14.0, 5.0 Hz, 1H), 4.37 (s,
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'- dioxide
[000451] [000451] To a solution of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7 '- (1,3-ditian-2-11) - 7'-methoxy-12 '- (2-methoxyethyl) - 11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (0.250 g, 0.322 mmol) in acetonitrile (12.0 mL), calcium carbonate (0.161 g, 1.610 mmol), water (3.00 mL) and iodomethane (0.250 mL, 4, 02 mmol). The resulting mixture was heated at 40 ° C for 20 h. The reaction was partitioned between water (20 ml) and DCM (50 ml). The aqueous layer was extracted with DCM (30 ml). The combined organic layers were dried over MgSOs, filtered and concentrated. Purification by column chromatography (24 g silica, 0% to 30% acetone in heptane) gave (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chlorine -7'-methoxy-12 '- (2-
[20] [20] oxa [13] tia [1, 14, 25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13 ', 13'-dioxide as a white solid (0.130 g). 'H NMR (DICLOROMETHAN-ds) 3 9.74 (s, 1H), 9.50 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 2.2 Hz, 1H), 5.69 (d, J = 16 , 2 Hz, 1H), 5.38 - 5.47 (m, 1H), 4.42 (dd, J = 14.0, 8.5 Hz, 1H), 4.19 (d, J = 12, 3 Hz, 1H), 4.04 (d, J = 12.1 Hz, 1H), 3.87 (d, J = 14.7 Hz, 1H), 3.60 (td, J = 8.7, 4.9 Hz, 1H), 3.46-3.54 (m, 2H), 3.38-3.45 (m, 1H), 3.31 (s, 3H), 3.06 (s, 3H ), 2.96 (dd, J = 14.1, 5.9 Hz, 1H), 2.74-2.90 (m, 4H), 2.46 (ddd, J = 11.2, 7.1 , 3.7 Hz, 1H), 2.21 - 2.28 (my, 1H), 2.11 - 2.20 (my, 1H), 1.97-2.08 (m, 2H), 1, 81-1.96 (m, 5H), 1.67-1.79 (m, 1H), 1.55-1.66 (mM, 1H), 1.40-1.50 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H). MS (ESI, + ve ion) m / z 686.2 (M + H) *.
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide
[000452] [000452] To a solution of (15,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7'-methoxy-12 '- (2-methoxyethyl) -11 '-methyl-15'-ox0-3,4- dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14, 25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.080 g, 0.117 mmol) in DCM (4.0 mL) was added
[20] [20] oxa [13] tia [1, 14, 25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide as a white solid (0.066 g). 1H NMR (DICLOROMETHANE-d2) 5 7.70 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8, 4 Hz, 1H), 7.08-7.16 (m, 2H), 5.53- 5.66 (m, 2H), 4.13-4.19 (m, 1H), 4.02-4 , 12 (m, 2H), 3.74-3.83 (m, 2H), 3.65-3.73 (m, 1H), 3.53-3.63 (m, 3H), 3.46 (d, J = 14.7 Hz, 1H), 3.32 (s, 4H), 2.98-3.10 (m, 7H), 2.74-2.85 (m, 2H), 2, 72 (d, J = 6.1 Hz, 1H), 2.52-2.64 (m, 3H), 2.46 (d, J = 16.8 Hz, 3H), 2.23-2.37 (m, 2H), 2.06-2.15 (m, 1H), 1.96-2.03 (m, 2H), 1.85-1.94 (m, 4H), 1.72-1 , 81 (m, 2H), 1.45-1.63 (m, 6H), 1.08 (d, J = 6.8 Hz, 3H). An interchangeable proton was not observed. MS (ESI, + ve ion) m / z 812.4 (M + H) *. Example 21
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide o ma NA n4 ove Cm CON, oe' RA usa SO RA o - o BA ”Bote
[000453] [000453] To a solution of (1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7'-methoxy-12 '- (2-methoxyethyl) -11 '-methyl-15'-ox0-3,4- dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14,25] triazatetracyclo [14.7.2.0-3,6-.0-19 24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.140 g, 0.204 mmol) in DCM (5.0 mL) was added (R) coctahydro-1H-pyrido [1,2-a] pyrazine (0.160 g, 1.141 mmol) in DCM (1 mL) and ACOH (2 drops). The mixture was stirred at room temperature under nitrogen for 1 h, then treated with sodium triacetoxyborohydride (0.173 g, 0.816 mmol). The resulting mixture was stirred for 1 h, then partitioned between water (10 ml) and DCM (20 ml). The aqueous layer was extracted with DCM (20 ml). The combined organic layers were dried over MgSOs, filtered and concentrated. Purification by column chromatography (249g of silica, up to 10% MeOH in DCM) gave (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro- 7'-methoxy-12 '- (2-methoxyethyl) -11'-methyl-7' - ((9aR) -octahydro-2H-pyrido [1,2-
[20] [20] oxa [13] tia [1, 14, 25] triazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide as a white solid (0.120 g). 'H NMR (DICLOROMETHANE-d;) & 7.69-7.76 (m, 1H), 7.42-7.50 (m, 1H) 7.18 (dd, J = 8.5, 2.1 Hz, 1H), 7.04-7.14 (m, 2H), 5.77 (s 1, 2H), 4.17 (d, J = 12.9 Hz, 1H), 4.00-4, 13 (m, 2H), 3.77 (d, J = 14.5 Hz, 1H), 3.64-3.73 (m, 1H), 3.57 (d, J = 9.2 Hz, 2H ), 3.35-3.47 (my, 1H), 3.21-3.34 (m, 5H), 3.09 (s 1, 3H), 2.99 (s 1, 1H), 2, 83-2.95 (m, 2H), 2.65-2.82 (m, 5H), 2.55 (s 1, 2H), 2.25-2.44 (m, 3H), 2.09 -2.21 (m, 1H), 1.97-2.08 (m, 3H), 1.89 (d, J = 19.2 Hz, 4H), 1.61-1.73 (m, 4H ), 1.38-1.51 (m, 4H), 1.29-1.35 (m, 1H), 1.17 (s 1, 2H), 1.02 (d, J = 6.8 Hz , 4H). An interchangeable proton was not observed. MS (ESI, + ve ion) m / z 810.4 (M + H) *. Example 33 (18,3'R, 6'R, 7'R, 8'E, 12'R) -6-chloro-12'-ethyl-7'-methoxy-11'-methyl-7 '- (( 9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide Ç or q o7 CO or qf 620 Espa to qx O - Etapaz qx 80 Co CO CS º 9 Example 33 Step 1: (18,3'R, 6'R, 7'R, 8'E, 12'R) -6-chloro-12'-ethyl- 7T'-methoxy-14'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide
[000454] [000454] A 7.5 mL bottle was loaded with (18.3'R, 6'R, 7'R, 8'E, 12'R) -6-chloro-7 '- (1,3-ditian -2-11) -12'- ethyl-7'-methoxy-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (27 mg, 0.037 mmol; Accessed via General Methods 1 (R! '= H, using (S) -6' -chloro-5- ((((1R, 2R) -2- ((S ) -1- hydroxyaloyl) cyclobutyl) methyl) -3 ', 4.4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene ] -7-carboxylic and (R) -hept-6-ene-3-sulfonamide) and General Methods 5 (using MeIL)), a magnetic stir bar, acetonitrile (820 µl) and water (205 µl). To the resulting suspension, calcium carbonate (18.5 mg, 0.185 mmol) and iodomethane (23 µL, 0.37 mmol) were added. The flask was sealed and the mixture stirred at 45 ° C. More iodomethane (10 equiv) was added after 2.5 h, 19 h, 23 h and 27 h. After a reaction time of 51 h, the reaction was quenched by the addition of saturated aqueous ammonium chloride (1 ml) and water (1 ml). The mixture was extracted with EtOAc (3 x 2 mL) and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure, giving a mixture of (18.3'R, 6 ' R, 7'R, 8'E, 12'R) -6-chloro-12'-ethyl-7'-methoxy-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1, 22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ' , 13'- dioxide and (18,3'R, 6'R, 7'R, 8'E, 12'R) -6-chloro-12'-ethyl-7'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide in a 3: 1 ratio that was carried on to the next step without purification.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000455] [000455] A 1 ml bottle was loaded with a 3: 1 mixture of (18,3'R, 6'R, 7'R, 8'E, 12'R) -6-chloro-12'-ethyl- 71'- methoxy-l15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide and (18,3'R, 6'R, 7'R, 8'E, 12'R) -6-chloro-12'-ethyl-7'- methoxy-l14'-methyl-l15 '-ox0-3,4-dihydro-2H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (0.022 g, 0.034 mmol), (R) -octahydro-1H-pyrido [1,2-alpyrazine (26.5 mg, 0.189 mmol; Aurum Pharmatech, Franklin Park, NJ), one bar magnetic stirring and 1,2-dichloroethane (343 µL). The resulting mixture was stirred for 1 h before the addition of sodium triacetoxyborohydride (3.6 mg, 0.017 mmol). After 45 min, a second portion of sodium triacetoxyborohydride (3.6 mg, 0.017 mmol) was added and the reaction was continued for an additional 2 h before a third portion of sodium triacetoxyborohydride (3.6 mg, 0.017 mmol) has been added. After a further 3 h, the reaction was quenched by the addition of methanol. (1S8,3'R, 6'R, 7'R, 8'E, 12'R) -6-chloro-12'-ethyl-7'-methoxy-14'-methyl-7 '- ((9aR) -octa-hydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide was isolated as the corresponding TFA salt after purification via RP-HPLC (Column: Phenomenex Luna, C18, 150 x 21 mm; Solvent: A = water (0.1% TFA), B = (R) (0.1% TFA), 30 mL / min, 30% B to 100% B over 18 min, then 2 min to 100% B): 5.2 mg (0.006 mmol, 17% yield ); MS (ESI, + ve ion) m / z 779.3 (M + H) *. Example 34 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7' - ((((2 - (4-morpholinyl) ethyl) amino) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide General Method 13 o 2 Q (O) So
[000456] [000456] A solution of (1S5,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-15'-ox0o-7'- methoxy-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (52 mg, 0.081 mmol) and 2-morpholinoethanamine (106 µL, 0.811 mmol) in THF (810 µL) was stirred at room temperature for 90 min. Sodium cyanotrihydroborate (25.5 mg, 0.405 mmol) and acetic acid (93 nLuL, 1.6 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtoAc (2 ml) and washed with saturated aqueous sodium bicarbonate (5 ml); the layers were partitioned and the aqueous layer was washed with EtOAc (2 x 5 ml). The organic extracts were combined, dried over MgSO. anhydrous, filtered and concentrated in vacuo, giving an off-white solid. (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7' - ((((2- ( 4-morpholinyl) ethyl) amino) methyl) - 3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide was isolated as the corresponding TFA salt after purification via RP-HPLC (Column: Phenomenex Luna, C18, 150 x 21 mm; Solvent: A = water (0.1% TFA), B = (R) (0.1% TFA), 30 mL / min, 30% B to 100% B over 18 min, then 2 min to 100% B): 41.8 mg (0.048 mmol, 59% yield ); MS (ESI, + ve ion) m / z 755.2 (M + H) *. Example 99
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 3' '- [1,4] oxazino [3,4- c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide o. e, Cl, Cl, = HPH * H ooo Example 99 Step 1 : (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-1'- hydroxy-7 '- ((((3R) -3- (hydroxymethyl) -4 -morpholinyl) methyl) - 11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000457] [000457] To a mixture at room temperature of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl -15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (0.050 g, 0.080 mmol) and (R) -morpholin-3-ylmethanol hydrochloride (0.124 g, 0.807 mmol; J&W Pharmlab, Levittown, PA) N, N-diisopropylethylamine (0.230 mL) was added , 1.32 mmol) via syringe. After 30 min, 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.400 mL, 0.400 mmol) and acetic acid (0.100 mL, 1.73 mmol) were added and the reaction was allowed to stir at room temperature overnight .
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a white crystalline solid. (ESI, ion + ve) m / z 728.3 (M + 1) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 3' '- [1,4] oxazino [3,4- c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide
[000458] [000458] To a solution at room temperature of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'- ((((3R ) -3- (hydroxymethyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide in tetrahydrofuran (0.3 ml) was added 60% sodium hydride in mineral oil (0.011 g, 0.275 mmol) as a solid. After 30 min, the mixture was cooled (0 ° C) and treated with 1- (p-toluenesulfonyl) imidazole (0.064 g, 0.288 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated NH.Cl and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were evaporated on silica gel and purified by Flash chromatography (Isco, (HP 4 grams)) eluting with NH; 2 M in MeOH: CH3Cl7 (0: 1 - 1: 9) giving rise to (18,3'R, 6'R, 7'S, 8'E, 9a''S, 11'S, 12'R) -6- chlorine -11 ', 12'-dimethyl-3,4,6' ', 7' ', 9' ', 9a' '-hexa-hydro- 1''H, 2H, 15'H-diespiro [naphthalene-1, 22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 3' '- [1,4] oxazino [3,4- c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide (2.1 mg, 9%) as a bronze crystalline solid . MS (ESI, + ve ion) m / z 710.3 (M + 1) *. Example 100 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'- (((38) -3- (1H-imidazole -1-ylmethyl) -4-morpholinyl) methyl) - 11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide o. O.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000459] [000459] To a mixture at room temperature of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl -15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (0.052 g, 0.083 mmol) and 3 (S) -hydroxymethylmorpholine (0.099 g, 0.845 mmol; J&W Pharmlab, Levittown, PA) in tetrahydrofuran (2 mL) N, N-diisopropylethylamine was added (0.250 mL, 1.437 mmol). After 1 h, 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.450 mL, 0.450 mmol) and acetic acid (0.100 mL, 1.73 mmol) were added and the reaction was stirred overnight. The reaction mixture was quenched with pH 7 buffer and the aqueous layer was extracted with DCM (3x). The combined organic layers were evaporated on silica gel and purified by Flash chromatography (Bait (4 g)) eluting with 25% EtOoH / EtOAc: heptane (0: 1 = 1: 1), yielding (18S, 3'R , 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- (((38) -3- (hydroxymethyl) -4-morpholinyl) methyl) -11 ', 12'- dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (46 mg, 76%) as a white crystalline solid. (ESI, ion + ve) m / z 728.2 (M + 1) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000460] [000460] To a solution at room temperature of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'- (((38 ) -3- (hydroxymethyl) -4-morpholinyl) methyl) -11 ', 12'- dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide in tetrahydrofuran (1 ml) was added sodium hydride (0.020 g, 0.51 mmol) as a solid. After 30 min, the reaction was cooled (0 ° C) and treated with 1- (p-toluenesulfonyl) imidazole (0.112 gq, 0.550 mmol). After stirring overnight, the reaction mixture was quenched with pH 7 buffer and the aqueous layer was extracted with DCM (3x). The combined organic layers were evaporated on silica gel and purified by Flash chromatography (Isco (4 g)) eluting with 25% EtOoH / EtOAc: heptane (0: 1 - 1: 0), giving rise to (18S, 3'R , 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- (((38) -3- (1H-imidazol-1-ylmethyl) -4- morpholinyl) methyl) - 11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide (27 mg, 55%) as a white crystalline solid. (ESI, ion + ve) m / z 778.3 (M + 1) *. Example 105 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7'-ethoxy-7 '- ((9aS) -hexa-hydropyrazine [2,1-c] [ 1.4] oxazin-8 (1H) -ylmethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide O) O)
[000461] [000461] A mixture of (18S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '- (((9aS) -hexahydropyrazine [2,1- c] [1,4] oxazin-8 (1H) -ylmethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1, 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.010 g, 0.013 mmol) and palladium, 10% w (dry basis) on wet, activated carbon, Degussa-type (0.005 g, 2.3 umol) in EtOAc (1 ml) was stirred at room temperature under hydrogen (18 psig) overnight. The reaction was filtered on a pad of Celite and the pad was washed with EtOAc. The filtrate was concentrated under reduced pressure, diluted with MeOH and purified by reverse phase HPLC (Gilson; Gemini-NX C18 AXIA column, 100 x 50 mm) eluting with 0.1% TFA-H2O: 0.1% CH TFA; CN (9: 1 - 1: 9). The fractions containing the desired product were combined and partitioned between pH 7 buffer (1M K2HPOs / KH2POs) / EtOAC. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried over Na; SO. and filtered. The filtrate was concentrated under reduced pressure, giving rise to
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (6.5 mg, 68%) as a white crystalline solid. (ESI, ion + ve) m / z: 747.3 (M + 1) *. Example 124 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-4 '', 11 ', 12'-trimethyl-3,4-dihydro- 2H, 15'H-diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1,4] oxazinan] -15'-one 13 ', 13'-dioxide Ci OH oA OH OE OH [= S Ê Cl. Ê [= Is oo - oo E oo N -S = Egtapa1 N if N if "o" o "o“ NH “q L, on o fo) P fo Ê xono = -.) = O —Step3 = Step 2 V sn nº apê Ns nº * To * to Example 124 Step 1: (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-1'- hydroxy- 11 ', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ' , 13'- dioxide and (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-71'-hydroxy-11 ', 12'-dimethyl-15'- oxo-3,4-dihydro-2H-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide
[000462] [000462] Calcium carbonate (2.60 g, 18.5 mmol) and iodomethane (1 M in TBME; 18.5 mL, 37, 1 mmol) were sequentially added to a solution of (18.3'R, 6 'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7' - (1,3-dithian-2-yl) -7'-hydroxy-11 ', 12'-dimethyl- 3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3-ditian-2- 11) -7 '-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (2.66 g, 3.71 mmol) in acetonitrile (44 mL) / water (6.5 mL) at 50 ° C; the reaction mixture was stirred at 50 ° C for 16 h. The slurry was filtered to remove any excess calcium carbonate and the filtrate was concentrated. The solid was diluted with EtoOAc (150 ml); the milky mixture was discarded; the remaining solid was diluted with DCM / IPA (3: 2, 200 mL) and the combined organics were partitioned with NH «Cl aq. sat. (100ml). The organic layer was separated, solubilized with MeOH, dried over Na2SOs, filtered and concentrated in vacuo. The crude product was adsorbed on silica gel and purified via automated Flash chromatography (silica gel, 0% to 50% EtOAc / heptane with 0.3% AcOH), giving rise to
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (396 mg, 0.631 mmol, 17% yield) and (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy -11 ', 12'- dimethyl-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (0.810, 1.29 mmol, 35% yield), both in the form of white solids. MS (ESI, + ve) m / z 627.2 (M + 1) * for both.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000463] [000463] A mixture of (18S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'- oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (48 mg, 0.077 mmol), methanamine hydrochloride (91 mg, 1.3 mmol) and DIPEA (227 µL, 1.30 mmol) in DCM (383 µL) / MeOH (580 µL) was stirred at room temperature for 15 min; sodium cyanotrihydroborate (14 mg, 0.23 mmol) was then added. The slurry was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM (50 ml), added to a separating funnel and washed with water (50 ml); the organic layer was separated, dried over anhydrous NasSOs and concentrated in vacuo. The crude product was adsorbed on silica gel and purified via automated Flash chromatography (silica gel, 0% to 20% MeOH / DCM), yielding (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7' - ((methylamino) methyl) -3,4-dihydro-2H, 15'H-spiro [ naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (14 mg, 0.022 mmol, 29% yield) as a white film. MS (ESI, + ve) m / z 642.2 (M + 1) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1,4] oxazinan] -15'-one 13 ', 13'-dioxide
[000464] [000464] Cesium carbonate (85 mg, 0.26 mmol) was added to a solution of (1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7 '-hydroxy-11', 12'-dimethyl-7 '- ((methylamino) methyl) - 3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (14 mg, 0.022 mmol) and 1,2-dibromoethane (8 µL, 0.09 mmol) in DMF (0.22 mL) at room temperature. The reaction mixture was stirred at 70 ° C for 16 h. l-Tosyl-lH-imidazole (4.8 mg, 0.022 mmol) and sodium hydride (60% in mineral oil; 0.5 mg, 0.02 mmol) were added to the reaction mixture which was then stirred at room temperature for 20 min The reaction mixture was diluted with EtOAc (50 ml), added to a separating funnel and washed with saturated aqueous sodium bicarbonate (2 x 50 ml); the organic layer was separated, dried over anhydrous Naz2SOs and concentrated in vacuo. The crude product was adsorbed on silica gel and purified via automated Flash chromatography (silica gel, 0% to 10% MeOH / DCM) giving rise to (18.3'R, 6'R, 7'S, 8'E, 11'S , 12'R) -6-chloro-4 '', 11 ', 12'-trimethyl-3,4-dihydro-2H, 15'H-dispyro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1.4] oxazinan] -15'-one 13 ', 13'-dioxide (2 mg, 3 umol, 14% yield) as a light yellow oil. MS (ESI, + ve) m / z 668.3 (M + 1) *. Example 125 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7'- ((tert-butylamino) methyl) - 6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide du En, L. Pp Cc! [)
[000465] [000465] A solution of (18S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'- ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1.14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (53 mg, 0.077 mmol, 49% yield) as a white solid. MS (ESI, + ve) m / z 684.3 (M + 1) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000466] [000466] A solution of (18S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'- oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13', 13'-dioxide (68 mg, 0.11 mmol) and 2- (isopropylamino) ethanol (Enamine, Monmouth Jct, NJ; 112 mg, 1.08 mmol) in THF (1.1 mL) was stirred at room temperature for 2.5 h; sodium cyanotrihydroborate (34 mg, 0.54 mmol) and acetic acid (0.1 mL, 2.2 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (75 ml), added to a separating funnel and washed with saturated aqueous sodium bicarbonate (100 ml); the organic layer was separated, dried over anhydrous Na; zSOs and concentrated in vacuo. The crude product was adsorbed on silica gel and purified via automated Flash chromatography (silica gel, 0% to 8% MeOH / DCM), yielding (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- ((((2-hydroxyethyl) (1-methylethyl) amino) methyl) -11', 12'-dimethyl-3,4-di- hydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (20 mg, 0.028 mmol, 26% yield) as a white solid. MS (ESI, + ve) m / z 714.2 (M + 1) *. Example 127 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-4' '- (1-methylethyl) -3, 4-dihydro-2H, 15'H-diespiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1,4] oxazinan] -15'-one 13 ', 13'-dioxide Ago AL, or bo, cl cl RX NE O. NE oo Example 127
[000467] [000467] Sodium hydride (60% in mineral oil; 3 mg, 0.07 mmol) was added to a solution of (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- ((((2-hydroxyethyl) (1I-methylethyl) amino) methyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15 ' H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (17 mg, 0.024 mmol) and l-tosyl-1H-imidazole (6.9 mg, 0.031 mmol) in THF (0.24 mL) at 0 ° C; the reaction mixture was stirred at 0 ° C for 15 min. The reaction mixture was diluted with EtOAc (75 ml), added to a separating funnel and washed with saturated aqueous ammonium chloride (100 ml); the organic layer was separated, dried over Na; SO: anhydrous and concentrated in vacuo. A crude product solution in DCM was loaded onto the column and purified via automated Flash chromatography (silica gel, 0% to 6% MeOH / DCM), yielding (18.3'R, 6'R, 7'S, 8 'E, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-4 '' - (1-methylethyl) -3,4-dihydro-2H, 15'H-diespiro [naphthalene- 1.22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1.4] oxazinan] -15'-one 13 ', 13'-dioxide (6 mg, 9 umol, 36% yield) as a white solid. MS (ESI, + ve) m / z: 696.3 (M + 1) *. Example 128 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 2''H, 15'H-diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 5' '- [1.3] oxazolidine] - 2 '', 15'-dione 13 ', 13'-dioxide OR (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6- chlorine-11 ', 12'-dimethyl-3,4-dihydro-2H, 2' 'H, 15'H-diespirus [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 5' '- [1,3] oxazolidino] - 2 '', 15'-dione 13 ', 13'-dioxide —o Ho o oH oH Ci. It is [e] º Ê and º. o Step 1 9 Step 2 o N seo P N .8 = o N ns Y No Y No x No * Xo “* Xo o o o
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate methyl and ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-13', 13 ' -dioxide-l15'-ox0-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate of methyl
[000468] [000468] A solution of methyl acetate (0.172 mL, 2.17 mmol) in THF (1 mL) was added dropwise to a stirred solution of lithium diisopropylamide (1.0 M solution in hexanes / tetra- hydrofuran, 2.17 ml, 2.17 mmol) in THF (1 ml) at -78 ° C. The mixture was stirred at -78 ºC for 0.5 h before a solution of (18.3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'- dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide (216 mg, 0.362 mmol) in THF (2 mL) was added slowly via syringe. The reaction mixture was stirred at -78 ° C for 1.5 h before being allowed to warm to room temperature and quenched with water (15 ml). The mixture was extracted with EtOAc (25 ml). The organic layer was separated, washed with 1 M aqueous HCl (15 ml), washed with brine (15 ml), dried over MgSO4s, filtered and concentrated in vacuo, yielding a crude mixture of ((18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate methyl and ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-13', 13 ' -dioxide-l15'-ox0-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate methyl (246 mg, 0.366 mmol, 101% yield) as a yellow solid that was used directly in the next step. MS (ESI, + ve ion) m / z 671.3 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic and acid ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-13', 13'- dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic
[000469] [000469] Lithium hydroxide (2.0 M aqueous, 0.453 mL, 0.905 mmol) was added to a stirred solution of ((18.3'R, 6'R, 7'R, 8'E, 11'S, 12 ' R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxide-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate of methyl and
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate of methyl (243 mg, 0.362 mmol) in tetrahydrofuran (7 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NH «Cl (30 ml) and extracted three times with EtOAc (50 ml). The combined organic layers were washed with brine (50 ml), dried over MgSO.s, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc with 0.3% AcCOH as a modifier in heptane) gave the desired product contaminated with AcOH. The isolated product was subjected to azeotropic treatment with toluene, giving rise to a mixture of acid ((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-hydroxy-11', 12'-dimethyl-13 ', 13'-dioxide-11'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic and acid ((18,3'R, 6'R, 7'S8,8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-13', 13 '-dioxide-l15'-ox0-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic (66 mg, 0.100 mmol, 27.7% yield) as a white solid. MS (ESI, + ve ion) m / z 657.2 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 5' '- [1.3] oxazolidine] - 2 '', 15'-dione 13 ', 13'-dioxide or (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6- chlorine-11 ', 12'-dimethyl-3,4-dihydro-2H, 2''H, 15'H-diespirus [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 5' '- [1.3] oxazolidine] - 2 '', 15'-dione 13 ', 13'-dioxide
[000470] [000470] A mixture of acid ((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl -13 ', 13'-dioxide-15'-oxo-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic and acid ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-13', 13'- dioxide-l15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic (66 mg, 0.100 mmol), triethylamine (0.031 mL, 0.221 mmol) and diphenylphosphoryl azide (0.024 mL, 0.110 mmol) in tert-butanol (2 mL) refluxed for 2.5 h. The reaction mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc with 0.3% AcCcOH as a modifier in heptane) provided (18.3'R, 6'R, 7'R, 8'E, 11'S, 12 ' R) -6-chloro-11 ', 12'-dimethyl-3,4-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 5' '- [1.3] oxazolidine] - 2 '', 15'-dione 13 ', 13'-dioxide or (18, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6- chlorine-11 ', 12'-dimethyl-3,4-dihydro-2H, 2' 'H, 15'H-dispir (naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 5' '- [1.3] oxazolidine] - 2 '', 15'-dione 13 ', 13'-dioxide (30 mg, 0.046 mmol, 45.7% yield) as a white solid. MS (ESI, + ve ion) m / z 654.2 (M + H) *. Example 138 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -4 '' -benzyl-6-chloro-11 ', 12'- dimethyl-3,4- dihydro-2H, 15'H-diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1,4] oxazinan] -15'-one 13 ', 13'-dioxide
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000471] [000471] A mixture of (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15 '-oxo-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (199 mg, 0.317 mmol) and 2-aminoethanol (322 mg, 5.27 mmol) was stirred in dichloromethane (6 mL) for 20 min before acetic acid (0.366 mL, 6.35 mmol) and sodium cyanoborohydride (59.8 mg, 0.952 mmol) was added. The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was quenched with saturated aqueous NH.Cl (40 ml) and extracted with EtOAc (50 ml). The organic layer was separated, washed with brine (30 ml), dried over MgSOs, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 10% 2M ammonia in MeOH in DCM) provided (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6 -chloro-7'-hydroxy-7 '- ((((2-hydroxyethyl) amino) methyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (115 mg, 0.171 mmol, 53.9% yield) as a white solid. MS (ESI, + ve ion) m / z 672.2 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1,4] oxazinan] -15'-one 13 ', 13'-dioxide
[000472] [000472] Sodium hydride (60% dispersion in mineral oil, 20.5 mg, 0.513 mmol) was added to a stirred suspension of (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'- ((((2-hydroxyethyl) amino) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H -spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (115 mg, 0.171 mmol) in tetrahydrofuran (5 mL) at room temperature. The mixture was stirred for 20 min before being cooled to ºC, followed by the addition of 1- (p-toluenesulfonyl) imidazole (38.0 mg, 0.171 mmol). The reaction mixture was stirred at 0 ° C for 5 h. The reaction mixture was quenched with saturated aqueous NH.Cl (20 ml) and extracted with EtOAc (30 ml). The organic layer was separated, washed with brine (20 ml), dried over MgSOs, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 10% 2M ammonia in MeOH in DCM) provided (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6 -chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-diespiro
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1.4] oxazinan] -15'-one 13 ', 13'-dioxide (67 mg, 0.102 mmol, 60% yield) as a white solid. MS (ESI, + ve ion) m / z 654.2 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1,4] oxazinan] -15'-one 13 ', 13'-dioxide
[000473] [000473] (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chlorine-11 ', 12'-dimethyl-3,4-dihydro-2H , 15'H-diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1.4] oxazinan] -15'-one 13 ', 13'-dioxide (17 mg, 0.026 mmol), (bromomethyl) benzene (3.40 µL, 0.029 mmol) and triethylamine (7.95 pL, 0.057 mmol ) were mixed in acetonitrile (0.25 ml). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH «Cl (10 ml) and extracted with EtOAc (15 ml). The organic layer was separated, washed with brine (10 ml), dried over MgSO: z, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, O to 10% 2M ammonia in MeOH in DCM) provided (18.3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -4 ' '- benzyl-6-chloro-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-dispyro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2' '- [1.4] oxazinan] -15'-one 13 ', 13'-dioxide (9 mg, 0.012 mmol, 47% yield) as a white solid. MS (ESI, + ve ion) m / z 744.3 (M + H) *. Example 151 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'- (2-methoxyethoxy) - 11 ', 12'-dimethyl-7'- ((9aR) -octahydro-2H-pyrido [1,2-alpyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide Fe É sso CS fe Ç ç nd, «C), Ê f-) Ê and ÊP o, Elara 'o - Elapaz oo N, SE N. -S = N, If the" oo Boc É É CA Ss Du E) A) = DP CI, Cc! - - - Steps RR, Steps A Steps N. 28 = o N. 82 * o “oo
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000474] [000474] To a solution of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7 '- (1,3-ditian-2-11) - 7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (460 mg, 0.641 mmol) in tetrahydrofuran (8 mL) was added sodium hydride, 60% dispersion in mineral oil (679 mg, 19.24 mmol) in portions. After the addition, the mixture was then stirred at room temperature under nitrogen for 10 min, then 2-bromoethylmethyl ether (1.809 ml, 19.24 mmol) was added. The resulting mixture was stirred at room temperature for 14 h. The mixture was quenched with saturated NH.Cl (150 ml) and was extracted with EtOAc (2 x 200 ml). The combined organic extracts were dried over MgSO: and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) provided (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'- (1,3-dithian-2- 11) -7 '- (2-methoxyethoxy) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1.22 '-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (391 mg, 0.504 mmol, 79% yield) as a light yellow solid. MS (ESI, + ve ion) m / z 699.2, 755.3 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide
[000475] [000475] To a solution of (1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7 '- (1,3-ditian-2-1i1) - 7 '- (2-methoxyethoxy) -11', 12'- dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (391 mg, 0.50 mmol) in acetonitrile (10 mL) and water (2500 mL) was added methyl iodide (0.313 mL, 5.04 mmol) and calcium carbonate (252 mg, 2.52 mmol) ). The resulting mixture was then stirred at 50 ° C for 14 h. The mixture was quenched with saturated NH.Cl and was extracted with EtOAc (2 x 100 mL). The combined organic extracts were then dried over MgSO. and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) provided (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'- (2-methoxyethoxy) - 11 ', 12'-dimethyl-l15'-ox0-3,4-dihydro-2H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (233 mg, 0.340 mmol, 67.4% yield) as a light yellow solid. MS (ESI, + ve ion) m / z 685.3 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7 '-yl) methyl 2-methyl-2-propanyl) amino) methyl) -1-piperidinecarboxylate
[000476] [000476] A solution of (1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6- chloro-7 '- (2-methoxyethoxy) -11', 12'-dimethyl -15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (55 mg, 0.080 mmol) and tert-butyl (R) -2- (aminomethyl) piperidine-1-carboxylate (172 mg, 0.803 mmol) in 1,2-dichloroethane (0.8 mL) it was stirred at room temperature for 14 h. Sodium triacetoxyborohydride (0.059 ml, 0.401 mmol) was added to the mixture and the mixture was then stirred at room temperature for 1 h. The mixture was diluted with MeOH (5 ml) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was then purified by column chromatography on silica gel (solid charge, 0% to 100% EtOAc / heptane) providing (2R) -2 - ((((((18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6- chloro-7'- (2-methoxyethoxy) -11 ', 12'-dimethyl-13', 13'-dioxide- 15'-ox0-3,4 -di-hydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl ) 2-methyl-2-propanyl amino) methyl) -1-piperidinecarboxylate (64 mg, 0.072 mmol, 90% yield) as a light yellow solid. MS (ESI, + ve ion) m / z 883.5 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000477] [000477] To a solution of (2R) -2- ((((((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- - (2 - methoxyethoxy) -11 ', 12'-dimethyl-13', 13'-dioxide-15'-ox0-3,4- dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl ) 2-methyl-2-propanyl amino) methyl) -1-p1-1-piperidinecarboxylate (58 mg, 0.066 mmol) in dichloromethane (0.5 mL), trifluoroacetic acid (0.098 mL, 1.3 mmol) was added. The resulting mixture was then stirred at room temperature for 2 h. The mixture was cooled to O “ºC and iPr) Net (0.457 ml, 2.63 mmol) was added followed by 1,2-dibromoethane (0.023 ml, 0.263 mmol) and DMA (0.1 ml). The resulting mixture was then stirred at room temperature for 72 h and at 50 ° C for 1 h. The mixture was concentrated in vacuo and chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) provided (1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7 '- (2-methoxyethoxy) -11', 12'-dimethyl-7 '- (((((2R) -2-piperidinylmethyl) amino) methyl) -3,4-dihydro-2H, 15'H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a colorless oil, which was used in the next step. MS (ESI, + ve ion) m / z 783.3 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000478] [000478] To a solution of (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7 '- (2-methoxyethoxy) -11', 12'- dimethyl-7 '- (((((2R) -2-piperidinylmethyl) amino) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (51.4 mg, 0.066 mmol) in N, N-dimethylacetamide (0.4 mL) was added iPr »Net (0.057 mL, 0.328 mmol) and 1,2-dibromoethane (0.028 mL, 0.328 mmol) ). The resulting mixture was then stirred at room temperature for 14 h. Then 1,2-dibromoethane (0.2 ml) was added and the mixture was stirred at room temperature for 14 h, then at 55 ° C for 72 h. The mixture was purified by column chromatography on silica gel (0% to 10% MeOH / DCM) providing (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chlorine -7'- (2-methoxyethoxy) - 11 ', 12'-dimethyl-7' - ((9aR) -octahydro-2H-pyrido [1,2-alpyrazin-2-ylmethyl) -3,4-di -hydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (17 mg, 0.021 mmol, 32.0% yield) as a light yellow solid. MS (ESI, + ve ion) m / z 809.2 (M + H) *. Example 154 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7' - (( (9aR) -3-oxo-octahydro-2H-pyrido [1,2-alpyrazin-2-yl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and Be -B:
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7 '-yl) methyl 2-methyl-2-propanyl) amino) methyl) -1-piperidinecarboxylate
[000479] [000479] To a solution of (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) - 6-chloro-7'-methoxy-11 ', 12'-dimethyl- 15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (44 mag, 0.069 mmol) in 1,2-dichloroethane (1 mL) was added tert-butyl (R) -2- (aminomethyl) piperidine-1-carboxylate (147 mg, 0.686 mmol). The resulting mixture was then stirred at room temperature for 1 h. Then sodium triacetoxyborohydride (73 mg, 0.343 mmol) was added in portions. After the addition, the mixture was then stirred at room temperature for 3 d. The mixture was purified by column chromatography on silica gel (0% to 20% MeOH / DCM), yielding (2R) -2- ((((((18,3'R, 6'R, 7'R , 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxide-l15'-ox0-3,4-dihydro- 2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl ) 2-methyl-2-propanyl amino) methyl) -1-p1-1-piperidinecarboxylate (57.6 mg, 0.069 mmol, 100% yield) as a light yellow solid, which was used in the next step. MS (ESI, + ve ion) m / z 839.4 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7 '-yl) methyl 2-methyl-2-propanyl) amino) methyl) -1-piperidinecarboxylate
[000480] [000480] To a solution of (2R) -2- ((((((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'- methoxy- 11 ', 12'-dimethyl-13', 13'-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl ) 2-methyl-2-propanyl methyl) -1-piperidinecarboxylate (57.6 mg, 0.069 mmol) in dichloromethane (1.5 mL) at -78 ºC under nitrogen chloroacetyl chloride (10.92 nuL) , 0.137 mmol) followed by iPr.Net (0.036 mL, 0.206 mmol). After the addition, the mixture was then stirred at -78 ° C for 1.5 h. Chloroacetyl chloride (0.022 ml) was added and the mixture was stirred at -25 ° C for 1 h and placed in a freezer at -20 ° C for 16 h. The mixture was quenched with MeOH (2 ml) and concentrated in vacuo. Chromatographic purification (silica gel, 0% to 100% EtOAc / heptane) afforded (2R) -2- (((chloroacetyl) (((18,3'R, 6'R, 7'R, 8'E, 11'S , 12'R) -6-chloro-71'- methoxy-11 ', 12'-dimethyl-13', 13'-dioxide-15'-0ox0-3,4-dihydro-2H-spiro [naphthalene- 1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl ) amino) methyl) -1- 2-methyl-2-propanyl piperidinecarboxylate (62.8 mg, 0.069 mmol, 100% yield) as a light yellow solid. MS (ESI, + ve ion) m / z 937.3, 939.2 (M + Na) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000481] [000481] To a solution of (2R) -2- (((chloroacetyl) ((((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro- 7'- methoxy-11 ', 12'-dimethyl-13', 13'-dioxide-15'-0ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7 '-yl) methyl ) 2-methyl-2-propanyl amino) methyl) -1-p1-1-piperidinecarboxylate (61.8 mg, 0.067 mmol) in dichloromethane (1 mL) trifluoroacetic acid (0.251 mL, 3.37 mmol) was added. After the addition, the mixture was then stirred at room temperature for 17 min. The mixture was cooled to -78 ° C and iPrNEt (0.704 ml, 4.05 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature for 14 h. The mixture was purified by column chromatography on silica gel (0% to 20% MeOH / DCM) followed by preparative HPLC (Phenomenex Gemini C18 column, 150x30 mm, 10% to 100% TFA 0.1% in MeCN / H20 ) providing a desired product in a 0.1% MeCN / H2O TFA solution. The pH was adjusted to 7 with buffer (KH2PO «without K2HPOs) and the system was extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine, dried (Na; SOs :), concentrated and dried in vacuo,
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (33 mg, 0.042 mmol, 62.8% yield) as an off-white solid. MS (ESI, + ve ion) m / z 779.3 (M + H) *. Examples 176 and 177 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-methoxy- N, N, 11', 12'-tetramethyl-15 '-ox0-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carboxamide 13' , 13'- dioxide E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy- N, N, 11 ', 12' -tetramethyl-15'-ox0-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carboxamide 13' , 13'- oo dioxide | o— o— Z HO rá Cc! CC! o o N nºS = o Step 1 N São Step 2 Y no N No ”o” o O o WO », SÃO
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carboxylic 13' , 13'- dioxide
[000482] [000482] To a 15 mL round bottom flask was added (18.3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-15' -oxo- 7'-methoxy-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (18 mg, 0.028 mmol, a mixture of two epimers) and 2-methyl-2-butene (149 µL, 1.404 mmol) in tert-butanol (281 µl) and water (281 npL). Monobasic potassium phosphate (38.2 mg, 0.281 mmol) and sodium chlorite (25.4 mg, 0.281 mmol) were added to the solution. The solution was stirred at room temperature for 1 h. The reaction mixture was diluted with NaszSO0; saturated (5 mL) and extracted with DCM (3 x 10 mL). The organic extract was washed with saturated NaCl (10 ml) and dried over MgSOs. The solution was filtered and concentrated in vacuo, giving an off-white solid. The material was used in the next step without further purification. MS (ESI, + ve ion) m / z 657.2 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraene] -7 '-carboxamide 13', 13'- dioxide E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy- N, N, 11 ', 12'- tetramethyl-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carboxamide 13' , 13'- dioxide
[000483] [000483] To a 5 ml round bottom flask was added acid (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl- 15 '-oxo-7'-methoxy-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraene] -7 '-carboxylic 13', 13'-dioxide (13 mg, 0.020 mmol, a mixture of two epimers) and diethylamine (2 M in THF, 39.6 µl, 0.079 mmol) in DCM (396 µL). Cyclic anhydride of l-propanophosphonic acid (50% p solution in ethyl acetate, 62.9 µL, 0.099 mmol) was added at room temperature. The solution was stirred at room temperature for 2 h. The reaction mixture was diluted with NaHCO; saturated (5 ml) and extracted with EtOAc (2 x ml). The organic layer was concentrated. The crude material was further purified by prep-HPLC, giving rise to two products. The first peak collected was assigned to Example 176 and the second peak to Example 177. MS (ESI, + ve ion) m / z 684.2 (M + H) * for both isomers. Examples 193 and 213 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- ((9aS) -hexa-hydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' -
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (((9aS) -hexa-hydropyrazine [2, 1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene- 1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide Ho. OH OH Cc. Ê Cl, Ê Cc. Ê x O j o 3 o N. 5º Eta N 282º Stage N = SE pa ! A Ç A ”o" o "o
[20] [20] OXA [13] TIA [1.14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24-
[20] [20] OXA [13] TIA [1, 14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24 + PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE
[000484] [000484] To an ice-cold stirred solution of (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-di - hydro-2H, 7'H, 15'H-spiro [naphthalene- 1.22 '[20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19 24- ] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (1,015 g, 1,700 mmol) and trimethylsulfonium iodide (0.364 gg, 1.785 mmol) in dimethylsulfoxide (4 , 0 mL) was added dropwise potassium tert-butoxide, 1.0 M solution in tetrahydrofuran (4.25 mL, 4.25 mmol) under argon. The resulting mixture was stirred in the ice bath for 5 min and at room temperature for 30 min. The crude reaction mixture was directly loaded onto a silica gel pre-column (25 g) previously covered with an ammonium chloride layer and subjected to Combi- Flash column chromatography on a 24 g ISCO Gold column eluting with 0% until 100% EtOAc / Hexanes, followed by 5% to 20% MeOH / DCM, giving an approximately 3: 1 mixture of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12 ' R) -6-chloro-7'-hydroxy-71'- (hydroxymethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.82 g, 1.3 mmol, 79% yield) as a white solid. MS (ESI, + ve ion) m / z 629.2 (M + 1) *.
[20] [20] OXA [13] TIA [1, 14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24-] PENTACOSA [8,16,18,24] TETRAENO] -7 '-CARBALDEHYDE 13' , 13'- DIOXIDE E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-CHLORINE-7'- HYDROXY-11 ', 12'-DIMETHYL-15 '-OX0-3,4-DI-HYDRO-2H- SPIRUS [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24- PENTACOSA [8,16,18,24] TETRAENO] -7 '-CARBALDEHYDE 13', 13'- DIOXIDE
[000485] [000485] To an ice-cold stirred solution of a mixture of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'- hydroxy-7'- (hydroxymethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-71'- (hydroxymethyl) -11 ' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (180 mg, 0.286 mmol) in DCM (5.0 mL) was added, under argon,
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide and (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15 '-oxo-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide as an almost white solid. It was carried on to the next step without further purification. MS (ESI, + ve ion) m / z 627.2 (M + 1) *.
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13' , 13'-DIOXIDE E (18, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-CHLORINE-7 '- ((9AS) -HEXA- HYDROPIRAZINE [2, 1-C] [1,4] OXAZIN-8 (1H) -ILMETHIL) -7 '-HIDROXI- 11', 12'-DIMETHIL-3,4-DI-HYDRO-2H, 15'H-SPIRUS [NAFTALENO-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24- PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE
[000486] [000486] The title compounds were prepared from a mixture of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-71'-hydroxy-11 ' , 12'-dimethyl-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide and (18, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15 '-oxo-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide according to General Method 10. (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- ((9aS) -hexa - hydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H -spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 193) was the second epimer to elute from the silica gel column. MS (ESI, + ve ion) m / z 753.3 (M + 1) *. (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- ((9aS) -hexa-hydropyrazine [2,1-c] [1 , 4] oxazin-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15'-ONA 13 ' , 13'-DIOXIDE Ho. HO. HO, OH OH Lou the AL, female is it a It's o + o s not Pee! s no s in S no & Ho S HO "o“ o * o Second epimer to elute First epimer to elute | emma O) Op OH o OH Cc Ê CO CI Ê rn ojo “o Example 184 Step 1: (18 , 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-CHLORINE-7'- HYDROXY-7 '- (HYDROXIMETHIL) -11', 12'-DIMETHY-3,4- DI-HYDRO- 2H, 15'H-SPIRAL [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1, 14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24 + PENTACOSA [8,16,18,24] TETRAEN] -15'-ONA 13 ' , 13'-DIOXIDE
[000487] [000487] The title compound was obtained as a single stereoisomer from a column chromatography separation on silica gel of an epimeric mixture of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12 'R) -6-chloro-7'-hydroxy-7'- (hydroxymethyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 ' -
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'- (hydroxymethyl) -11 ' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide eluting with 1% to 20% MeOH / DCM. The title compound was the second epimer to elute from the silica gel column. MS (ESI, + ve ion) m / z 629.3 (M + 1) *.
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24- PENTACOSA [8,16,18,24] TETRAENO] -7 '-CARBALDEHYDE 13', 13'- DIOXIDE
[000488] [000488] The title compound was synthesized from (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'- (hydroxymethyl ) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24- + pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide according to the protocol of Example 193 (Step 2). MS (ESI, + ve ion) m / z 627.4 (M + 1) *.
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24- PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE
[000489] [000489] The title compound was synthesized from (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12' - dimethyl-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide according to General Method 10. MS (ESI, + ve ion) m / z 698.5 (M + 1) *. Example 270 ACID (4- ((((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-CHLORINE-7'- METOXI-11 ', 12'-DIMETHYL-13 ', 13'-DIOXIDE-15'-OX0-3,4-DI- HYDRO-2H-SPIRAL [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24-] PENTACOSA | [8,16,18,24] TETRAEN] -7 '-IL ) METHIL) -1- PIPERAZINIL) ACETIC A As o UN | the QN |
[000490] [000490] To a stirred solution of (4- ((((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12 '- dimethyl-13', 13'-dioxide-l15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl ) -l-piperazinyl) methyl acetate (Example 269) (15 mg, 0.019 mmol) in MeOH (1.5 ml) and water (0.5 ml) hydrated lithium hydroxide (8.0 mg, 0, 19 mmol). The resulting mixture was stirred at room temperature for 3 h. The residue was collected in MeOH and subjected to preparative reverse phase HPLC (Gemini column "” "" Prep C18 10 um; Phenomenex, Torrance, CA; elution with a gradient of 20 to 90% MeCN in water, in which both solvents contain 0.1% TFA, a 15 min gradient in a 24 min method, resulting, after lyophilization, 11 mg of acid (4- ((((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxide-15'-oxo-3,4-dihydro-2H-spiro [naphthalene -1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl ) -1-piperazinyl) acetic as a white solid. MS (ESI, + ve ion) m / z 769.7 (M + 1) *. Example 276 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7'- ((((9AS) -8-ACRILOILOCTA- HYDRO-2H-PIRAZINO [1,2-A ] PIRAZIN-2-IL) METHIL) -6-CHLORINE-7'- METOXI-11 ', 12'-DIMETHYL-3,4-DI-HYDRO-2H, 15'H- SPIRUS [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1, 14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24 + PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13 '-DIOXIDE OR (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7' - (((9AR) -8-ACRILOILOCTA- HYDRO-2H-PIRAZINO [1, 2-A] PIRAZIN-2-IL) METHIL) -6-CHLORINE-7'- METOXI-11 ', 12'-DIMETHIL-3,4-DI-HYDRO-2H, 15'H- SPIRUS [NAFTALENO-1, 22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24- PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE
[000491] [000491] A solution of (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'- ((((9asS) -8- (3- (phenylsulfonyl) propanoyl) octahydro-2H-pyrazino [1,2-alpyazin-2-yl) methyl) -3,4-dihydro-2H, 15'H - spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide OR (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7' - ( ((9aR) -8- (3- (phenylsulfonyl) propanoyl) octahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) methyl) -3,4-dihydro-2H, 15 ' H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (15 mg, 0.016 mmol) and 1,8-diazabicyclo- [5.4.0] undec-7-ene (0.15 mL, 1.0 mmol) in pyridine (0.30 mL) in a The microwave reactor was subjected to microwave irradiation for 50 min at 75 ºC. The crude mixture was collected in MeOH and subjected to preparative reverse phase HPLC (Gemini * ”column" "Prep Cig 10 um; Phenomenex, Torrance, CA; elution with gradient of 20 to 90% MeCN in water, in which both solvents contain 0.1% TFA, a 15 min gradient in a 24 min method giving, after lyophilization, 7.5 mg of (18.3'R, 6'R, 7'S, 8'E, 11'S, 12 ' R) -7'- ((((9AS) -8-ACRYLOILOCTA- HYDRO-2H-PIRAZINO [1,2-A] PIRAZIN-2-IL) METHIL) -6-CHLORINE-7'- METOXI-11 ', 12 '-DIMETHIL-3,4-DI-HYDRO-2H, 15'H- SPIRUS [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1, 14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24 + PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13 '-DIOXIDE OR (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7' - (((9AR) -8-ACRILOILOCTA- HYDRO-2H-PIRAZINO [1, 2-A] PIRAZIN-2-IL) METHIL) -6-CHLORINE-7'- METOXI-11 ', 12'-DIMETHIL-3,4-DI-HYDRO-2H, 15'H- SPIRUS [NAFTALENO-1, 22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24- PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE. MS (ESI, + ve ion) m / z 821.0 (M + 1) *. Example 345 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7' - (1H -1,2,3-triazol-1-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7'- (1H-1,2,3-triazol-1-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000492] [000492] A solution of methyltriphenylphosphonium bromide (1.80 g, 5.0 mmol) in THF (15 mL) was cooled to O “ºC. N-butyl lithium solution (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added dropwise and was stirred at 0 ° C for 10 min. The bromide solution was added dropwise to a solution of (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'- dimethyl-3,4 -di-hydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- diona 13 ', 13'-dioxide (0.30 g, 0.50 mmol) in THF (6.0 mL) (cooled in an ice bath) until the yellow color persists. O * C was stirred for
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (290 mg, 0.49 mmol, 97% yield). MS (ESI, + ve ion) m / z 595.2 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000493] [000493] The AD-Mix-alpha mixture (640 mg, 0.43 mmol) was dissolved in 20 mL of a 1: 1 mixture of tert-butanol (10.0 mL) and water (10.0 mL) and cooled for the ºC. o (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-7'-methylidene-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (255 mg, 0.428 mmol) was added and the reaction mixture was slowly warmed to room temperature overnight. An additional 5.0 mL of t-BuoH was added to homogenize the mixture. The reaction was stirred overnight. Another 320 mg of AD-Mix-alpha mixture was added and the reaction was stirred for another 3 d. The reaction was quenched by adding 575 mg of sodium sulfite at 0 ºC and stirring for 45 minutes. The mixture was then extracted with EtOAc (2 x 25 ml). The combined organic layers were washed with brine (1 x 20 ml) and dried over sodium sulfate. The crude product was then purified by medium pressure chromatography (silica, 0% to 100% EtOAc (+ 0.3% HOAc): heptanes), yielding (18.3'R, 6'R, 8'E , 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- (hydroxymethyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene- 1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (31 mg, 0.049 mmol, 12% yield). MS (ESI, + ve ion) m / z 629.2 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl
[000494] [000494] (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-Chlorine-7'-hydroxy-7'- (hydroxymethyl) -11 ', 12'-dimethyl-3 , 4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (25.0 mg, 0.040 mmol) was dissolved in DCM (800 µl) and cooled to O * C. Triethylamine (17 µL, 0.12 mmol) was added followed by the addition of mesyl chloride (6.50 µl, 0.083 mmol) and the reaction was stirred for 1.5 h. The reaction was then diluted with DCM (15 mL) and the mixture was washed with water (2 x 10 ml) and dried over sodium sulfate The crude product was then purified by medium pressure chromatography (silica, 0% to 70% EtOAc (+ 0.3% HOAc): heptanes ), giving rise to ((18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13' methanesulfonate, 13'-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl . MS (ESI, + ve ion) m / z 707.2 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000495] [000495] ((1S8,3'R, 6'R, 8'E, 11'S, 12'R) - 6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13 'methanesulfonate -dioxide-15'-oxo- 3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl (10 ma, 0.014 mmol) was dissolved in 0.36 mL of a 5: 1 mixture of DMF: water. To the solution, sodium azide (2.1 mg, 3.2 umol) was added. The mixture was heated to 70 ° C and stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and the crude product was purified by medium pressure chromatography (silica, 0% to 60% EtOAc (+ 0.3% HOAc): heptanes),
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (2.1 mg, 3.2 umol, 23% yield). MS (ESI, + ve ion) m / z 654.2 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000496] [000496] (1S8,3'R, 6'R, 8'E, 11'S, 12'R) -7 '- (Azidomethyl) -6-chloro-7'-hydroxy-11', 12'-dimethyl-3 , 4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (2.0 mg, 3.1 umol) was dissolved in 2-methyltetrahydrofuran (1.0 ml) and sodium hydride (60% dispersion) (0.73 mg, 0.031 mmol) was added followed by methyl iodide (0.956 pL, 0.015 mmol). The reaction was then stirred overnight until complete. The reaction was quenched with dropwise addition of water and extracted with EtOAc. The organic layers were then washed with brine and dried over magnesium sulfate, giving (18,3'R, 6'R, 8'E, 11'S, 12'R) -7'- (azidomethyl) -6-chlorine -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (3.0 mg) which was used directly in the next reaction without any further purification. MS (ESI, + ve ion) m / z 668.2 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7'- (1H-1,2,3-triazol-1-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000497] [000497] (18,3'R, 6'R, 8'E, 11'S, 12'R) -7 '- (Azidomethyl) -6-chloro-7'-methoxy-11', 12'-dimethyl-3 , 4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (20 mg, 0.030 mmol) was slurried in 3.0 mL of a 1: 1: 1 solution of t-BuOH: water: DMF. To the solution was added copper (II) sulfate (2.9 mg, 0.018 mmol), sodium (+) - l-ascorbate (12.0 mg, 0.061 mmol) and (trimethylsilyl) acetylene (65 µL, 0.46 mmol). The solution was then heated in a microwave reactor at 120 ºC for 2 h. The reaction was then diluted with water and EtOAc. The mixture was extracted with EtOAc (2 x 25 ml). The combined organic layers were washed with 1 N lithium chloride solution (1 x 15 ml) and brine (1 x 15 ml), then dried over magnesium sulfate. The residue was then purified by medium pressure chromatography (silica, 25% to 100% EtOAc (+ 0.3% HOAc): heptanes), giving rise to (1S8,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7' - (1H-1,2,3-triazol-11-ylmethyl) -3,4 -di- hydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7'- (1H-1,2,3-triazol-1-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide. MS (ESI, + ve ion) m / z 694.3 (M + H) *. Example 348 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-7'- (2-methylpropoxy) -7'- ((4- (3-oxetanyl) -1-piperazinyl) methyl) - 3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide ss À s À dz Ez OZ - - oa Ao a. O SE HO H Oo HO o o o
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000498] [000498] The reaction was carried out following the procedure for general method 5, step 2. MS (ESI, + ve ion) m / z 771.2 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000499] [000499] O (158,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3- ditian-2-yl) -11', 12'-dimethyl-7 '- (((2-methyl-2-propen-1-yl) oxy) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (200 mg, 0.26 mmol) was dissolved in EtOAc (5.0 mL) and platinum (IV) oxide (180 mg, 0.78 mmol) was added. The reactor was then pressurized to 40 psi with hydrogen and the system was stirred for 3.5 h until complete. The black paste was then filtered through a pad of Celite and washed with EtOAc. The filtrate was then concentrated, yielding (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3- ditian-2-yl ) -11 ', 12'-dimethyl-7' - (2-methylpropoxy) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (200 mg, 0.26 mmol, 100% yield). MS (ESI, + ve ion) m / z 773.2 (MHH) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide
[000500] [000500] The reaction was conducted following the procedure for general method 5, step 3. MS (ESI, + ve ion) m / z 683.3 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000501] [000501] The reaction was carried out following the procedure for general method 8. MS (ESI, + ve ion) m / z 809.2 (M + H) *. Examples 362 and 363 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '- ((28) -2-hydroxypropyl) -7'- methoxy-1111-methyl-7 '- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '- ((2R) -2-hydroxypropyl) -7 '-methoxy-1111'-methyl-7' - ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15 ' H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000502] [000502] ((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chlorine-71'- methoxy-11'-methyl-7 '- ((9aR ) -octa-hydro-2H-pyrido [1,2-alpyrazin-2-ylmethyl) -13 ', 13'-dioxide-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1, 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -12'-yl) acetaldehyde (Example 360) (32 mag, 0.040 mmol) was dissolved in THF (2.0 ml) and cooled to 0 ° C. Methylmagnesium bromide (3.4 M in 2-MeTHF, 0.12 mL, 0.40 mmol) was added dropwise and stirred for 45 min. The reaction was quenched with saturated ammonium chloride solution (15 mL) and the mixture was extracted with EtoAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 20 ml) and then dried over sodium sulfate. The mixture was then purified by preparative SFC chromatography (4FBSA column, 250 mm x 21 mm, Phenomenex, Torrance, CA; 28 g / minute MeOH (+ NH3; 20 mM) + 42 g / minute CO in SFC Thar 200; discharge pressure = 100 bar; temperature = 40 ºC; wavelength = 220 nm; used injections of 1.1 mL of 28 mg / 3 mL (9.3 mg / mL) sample solution of MeOH (3 mL ), giving rise to (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '- ((28) -2-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '- ((2R) -2-hydroxypropyl) -7 '-methoxy-1111'-methyl-7' - ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15 ' H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 362, first isomer to elute, tr = 3.19 minutes in analytical SFC; 4FBSA; 40% MeOH (+ 20 mM NH3 in CO;) with> 99.5%) (6, 2 mg, 7.7 umol, 19% yield). MS (ESI, + ve ion) m / z 809.4 (M + H) *. E (1S8,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '- ((2S) -2-hydroxypropyl) -7'-methoxy-l11 '-methyl-7'- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene -1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '- ((2R) -2-hydroxypropyl) -7 '-methoxy-1111'-methyl-7' - ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15 ' H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 363, according to isomer to elute, tr = 6.49 minutes in analytical SFC; 4FBSA; 40% MeOH (+ NH3; 20 mM in CO;) with de
[21] [21] oxa [27] tia [1, 15] diazapentacycle [15.7.2.1-12,15-.0-3,67-. 0-20,25-] heptacous [8,17,19,25] tetraen] -16 '-one 27', 27'- dioxide E (18,3'R, 6'R, 7'S, 8'E, 11'S , 12'R) -6-chloro-12 '- (2-chloroethyl) -7' - ((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazin- 8 (1H) -ylmethyl ) -7'-methoxy-11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide COD, COZ õ OH "OMs IESÃE - NE Space Example 346 NA | NA BeÃãe EE oo Example 364 Example 366 Step 1: methanesulfonate of 27 ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- ((9aS) -hexa-hydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7' -methoxy- 11'-methyl-13 ', 13'-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-l1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -12'-yl) ethyl
[000503] [000503] (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chlorine-7 '- ((9as) - hexahydropyrazine [2,1-c] [ 1.4] oxazin-8 (1H) -ylmethyl) -12 '- (2-hydroxyethyl) -7'-methoxy-11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene -1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 346) (15 mg, 0.018 mmol) was dissolved in DCM (1.0 mL) and Hunig's base (0.011 mL, 0.064 mmol) and mesyl chloride (3.7 µL, 0.048 mmol) ) have been added. The reaction mixture was stirred for 1.5 h almost until complete. The mixture was then diluted with DCM (20 ml) and water (15 ml). The layers were separated and the organic layer was dried over sodium sulfate. The filtrate was concentrated to dryness in vacuo, yielding 2- ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- methanesulfonate) ( (9aS) -hexa- hydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-methoxy- 11'-methyl-13 ', 13'-dioxide-15'- ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -12'-yl) ethyl (16 mg, 0.018 mmol, 100% yield) which was used directly in the next reaction. MS (ESI, + ve ion) m / z 875.3 (M + H) *.
[21] [21] oxa [27] tia [1, 15] diazapentacycle [15.7.2.1-12,15-.0-3,67-.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000504] [000504] 2- ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- ((9aS) -hexahydropyrazine methanesulfonate [2, 1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-methoxy-11'-methyl-13 ', 13'-dioxide-15'-oxo-3,4-dihydro- 2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -12'-yl) ethyl (16 mg, 0.018 mmol) was dissolved in acetonitrile (1.0 mL) and tetrabutylammonium difluoro triphenylsilicate (59 mg, 0.11 mmol) was added. The reaction was then heated to 75 ° C until completion. The reaction was then cooled to room temperature and then diluted with EtOAc (25 ml) and water (20 ml). The layers were separated and the organic layer was washed again with water (1 x 20 ml) and brine (1 x 20 ml) and dried over sodium sulfate. The crude product was then purified by medium pressure chromatography (silica, 0% to 100% (10% 2M ammonia in MeOH): DCM), giving rise to two products, (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- ((9aS) -hexa-hydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) - 7'-methoxy- 11'-methyl-3,4-dihydro-2H, 16'H-spiro [naphthalene-1,23'-
[21] [21] oxa [27] tia [1, 15] diazapentacycle [15.7.2.1-12,15-.0-3,67-. 0-20.25-] heptacous [8,17,19,25] tetraen] -16'-one 27,27 dioxide (Example 364) (4.9 mg, 6.3 umol, 34% yield), MS (ESI, ion + ve) m / z 779.3 (M + H) * E (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chlorine-12 '- ( 2-chloroethyl) - 7 '- ((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-methoxy-11'-methyl-3, 4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 366) (3.5 mg, 4.29 umol, 23% yield), MS (ESI, + ve ion) m / z 815.3 (M + H) *. Examples 358, 359, and 367 (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '- (2-hydroxyethyl) - 7'-methoxy -11'-methyl-7 '- ((9aR) -octahydro-2H-pyrido [1,2-alpyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene - 1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 358) E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'- methoxy-11'-methyl- 12 '- (2 - ((((2-methyl-2-propanyl) (diphenyl) silyl) oxy) ethyl) -7' - ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin -2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 359) E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12'- (2- (dimethylamino) ethyl ) -7'-methoxy-1111-methyl-7 '- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H , 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[000505] [000505] To a solution of (S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide (2.8 g, 6.9 mmol) in THF (15 mL) n-butyl lithium (2.5 M in hexanes, 3.1 mL, 7.6 mmol) was added at -78 ° C dropwise.
[000506] [000506] (3R, 48S) - 1-Hydroxy-N, N-bis (4-methoxybenzyl) -4-methyl-hept-6-ene-3-sulfonamide (6.4 g, 14 mmol) was dissolved in DMF (34 mL). Imidazole (1.7 g, 24 mmol) and tert-butyldiphenylsilyl chloride (6.3 mL, 24 mmol) were added and the mixture was stirred for 45 min. The reaction was then quenched with saturated ammonium chloride solution (150 ml) and extracted with EtOAc (1 x 300 ml). The layers were separated and the organic was washed (1 x 100 ml) with 1 N LiCcl solution (1 x 100 ml), 1 N HCl solution and (1 x 100 ml) brine and then dried over magnesium sulfate. The crude product was then purified by medium pressure chromatography (silica, 5% to 100% EtOAc: Heptanes), yielding (3R, 4S) -N, N-bis (4-methoxybenzyl) -4-methyl-1 - ((((2-methyl-2-propanyl) (diphenyl) silyl) oxy) -6-heptene-3-sulfonamide (9.70 g, 14.14 mmol, 98% yield). 'H NMR (400MHz, CHLOROPHORMUM-d) 5 7.67 (dt, J = 1.5, 7.3 Hz, 4H), 7.47 - 7.35 (m, 6H), 7.16 (d, J = 8.8 Hz, 4H), 6.79 -— 6.78 (m, 1H), 6.81 (dy, J = 8.6 Hz, 3H), 5.56 (tdd, J = 7, 0, 10.1, 17.0 Hz, 1H), 4.97 (dd, J = 1.8, 10.0 Hz, 1H), 4.91 (dd, J = 1.6, 17.0 Hz , 1H), 4.31 - 4.10 (m, 4H), 3.84 - 3.80 (m, 1H), 3.78 (s, 6H), 3.77 - 3.72 (m, 1H ), 3.09 (ddd, J = 1.6, 4.2, 7.4 Hz, 1H), 2.22 - 2.07 (m, 2H), 1.98 - 1.79 (m, 3H ), 1.07 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H). MS (ESI, + ve ion) m / z 708.3 (M + Na) *.
[000507] [000507] To a 1000 mL flask cooled to O “ºC was added (3R, 4S) -N, N-bis (4-methoxybenzyl) -4-methyl-l1 - ((((2-methyl-2-propanyl) (diphenyl) silyl) oxy) -6-heptene-3-sulfonamide (9.4 gq, 14 mmol), DCM (290 mL), anisole (7.5 mL, 69 mmol) and then trifluoroacetic acid (49 mL). The reaction was allowed to warm to room temperature overnight until completion. The reaction mixture was then concentrated on the rotovap to a volume of -25 ml. The crude product was then purified by medium pressure chromatography (silica, 10% to 50% EtOAc: heptanes), yielding (3R, 48S) -4-methyl-1 - ((((2-methyl-2-propanyl ) (diphenyl) silyl) oxy) -6-heptene-3-sulfonamide (2.7 g, 6.1 mmol, 44% yield). ! H NMR (400MHz, CHLOROPHOROMY- d) à 7.67 (ddd, J = 1.5, 5.8, 7.2 Hz, 4H), 7.49 - 7.37 (m, 6H), 5, 72 (tdd, J = 6.9, 10.1, 17.0 Hz, 1H), 5.06 - 4.94 (m, 2H), 4.41 (s 1, 2H), 3.93 - 3 , 80 (m, 2H), 3.23 - 3.16 (Mm, 1H), 2.46 (m, 1H), 2.13 - 2.06 (m, 1H), 2.05 - 2.01 (m, 1H), 1.91 (dtd, J = 3.7, 7.1, 14.7 Hz, 2H), 1.07 (s, 9H), 1.02 (d, J = 7.0 Hz, 3H). MS (ESI, + ve ion) m / z 468.2 (MiNa) *.
[000508] [000508] The reaction was conducted following the procedure for general method 1 (R '= H). MS (ESI, + ve ion) m / z 895.3 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000509] [000509] The reaction was conducted following the procedure for general method 1 (R! '= H). MS (ESI, + ve ion) m / z 867.3 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- diona 13 ', 13'-dioxide
[000510] [000510] The reaction was conducted following the procedure for general method 1 (R '= H). MS (ESI, + ve ion) m / z 865.3 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000511] [000511] The reaction was carried out following the procedure for general method 3 (Rº = Me). MS (ESI, + ve ion) m / z 911.4 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide
[000512] [000512] The reaction was carried out following the procedure for general method 3 (Rº = Me). MS (ESI, + ve ion) m / z 909.3 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide (Example 359)
[000513] [000513] The reaction was conducted following the procedure for general method 8. MS (ESI, + ve ion) m / z 1033.3 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 358)
[000514] [000514] (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chlorine-7'-methoxy- 11'-methyl-12 '- (2- ( ((2-methyl-2-propanyl) (diphenyl) silyl) oxy) ethyl) -7 '- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3 , 4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 359) (38 mg, 0.037 mmol) was dissolved in THF (1.0 ml). Tetrabutylammonium fluoride (1 O M in THF, 1.1 mL, 1.1 mmol) was then added and the reaction was stirred for 24 h until complete. The reaction mixture was then diluted with DCM and then loaded directly onto a column for purification by medium pressure chromatography (silica, 0% to 100% (maintain) (10% 2M ammonia in MeOH: DCM): DCM), giving origin of product that was contaminated with tetrabutylammonium fluoride. This material was then diluted with water (50 ml) and EtOAc (20 ml). The layers were then separated and the organic layer was then washed again with water (1 x 50 ml) to remove residual tetrabutylammonium fluoride. The organic layer was then extracted with brine (1x 15 ml) and dried over sodium sulfate. The paste was filtered and the filtrate was concentrated, giving (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '- (2-hydroxyethyl ) - 7'-methoxy-1111-methyl-7 '- ((9aR) -octahydro-2H-pyrido [1,2-alpyrazin-2-ylmethyl) -3,4-dihydro-2H, 15 'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (Example 358) (150 mg, 0.18 mmol, 61% yield). MS (ESI, + ve ion) m / z 795.3 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -12'-yl) ethyl
[000515] [000515] (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chlorine-12 '- (2-hydroxyethyl) -7'-methoxy-l1'- methyl-7 '- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 358) (50 mg, 0.063 mmol) was dissolved in DCM (3.0 mL) and Hunig's Base (66 n1uL, 0.38 mmol) and mesyl chloride (21 µL, 0, 26 mmol) were added. The reaction mixture was stirred for 1.5 h until complete. The mixture was then diluted with DCM (20 ml) and water (25 ml). The layers were separated and the organic layer was washed again with water (25 ml) and then dried over sodium sulfate. The filtrate was concentrated to dryness in vacuo, yielding 2 - ((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6- chloro-7 'methanesulfonate -methoxy-11'-methyl-7 '- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -13', 13'-dioxide-l15'-oxo- 3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -12'-yl) ethyl (63 mg). MS (ESI, + ve ion) m / z 873.3 (M + H) *.
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[000516] [000516] 2- ((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11'-methyl-7 'methanesulfonate - (((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -13 ', 13'-dioxide-l15'-ox0-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -12'-yl) ethyl (30 mg, 0.34 mmol), dimethylamine (2 M in THF, 0.17 mL, 0.34 mmol) potassium carbonate (95 mg, 0.69 mmol) and a catalytic amount of potassium iodide were dissolved in acetonitrile (1.0 mL) in a vial that was sealed with a pressure cap. The reaction mixture was then heated to 65 * C for 40 min until complete. The reaction was then diluted with DCM and filtered through a glass frit. The filtrate was then concentrated and the residue was then purified by preparative SFC chromatography (Kromasil Cyan 250 mm x 21 mm column; 17.5 g / minute MeOH (+ 20 mM tampon) + 52.5 g / minute CO, in SFC Thar 200; discharge pressure = 100 bar; temperature = 22 ºC; wavelength = 215 nm; used injections of 1.0 ml of 31 mg / 4 ml (7.8 mg / ml) sample solution of MeOH ( 4 mL) giving (1S8,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12'- (2- (dimethylamino) ethyl) -7 ' -methoxy-11'-methyl-7 '- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H -spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 3' '- [1 , 4] oxazino [3,4- c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide E (18,3'R, 6'R, 7'S, 9a'! 'S, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl- 3,4,6' ', 7' ', 9' ', 9a' '-hexa-hydro-1''H, 2H, 15'H- diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 3' '- [1 , 4] oxazino [3,4-c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide o. O. oo Cor .. $ oo - so + e N NO Step N FE N. (E s H IS MSH o õ “So o. po. Sm Q o Nu 2 fe RS 1 ER oo zo £ Oo Espa2” N Ao N ooo Example 399 Example 400
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide E (18,3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-7' - ((((3R) -3- (hydroxymethyl) -4- morpholinyl) methyl) -111 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [16,18,24] trien] -15'-one 13 ', 13' -dioxide
[000517] [000517] A microwave glass reactor was charged with (1S8,3'R, 6'R, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-di- hydro-2H, 15'H-diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 2' '- oxiran] -15'-one 13 ', 13'-dioxide (0.300 g, 0.489 mmol) and 3 (R) -hydroxymethylmorpholine (0.650 g, 5.55 mmol; Matrix Sci., Elgin, SC). Ethanol (3 ml) and triethylamine (1.8 ml, 12.9 mmol) were added, the reaction mixture was sealed under argon and heated in an Initiator microwave reactor at 90 ºC for a total of 27 h. The reaction was heated to 90 ºC in the microwave for an additional 16 h. The reaction mixture was purified by reversed phase HPLC (Gilson; Gemini-NX 10 um column, C18, AXIA, 100 x 50 mm) eluting with 0.1% TFA-H2O: 0.1% CH3 TNC; CN (9: 1> 1: 9). The fractions containing the desired product were combined and partitioned between pH 7 buffer (1M K2HPOs / KH2POs) / EtOAcC. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried over NasSOs and filtered. The filtrate was concentrated under reduced pressure, giving a mixture of
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide and (18,3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-7' - ((((3R) -3- (hydroxymethyl) -4- morpholinyl) methyl) -111 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide (177 mg, 50%) as a white crystalline solid.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 3' '- [1 , 4] oxazino [3,4- c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide E (18,3'R, 6'R, 7'S, 9a''S, 11'S , 12'R) -6-chloro-11 ', 12'-dimethyl- 3,4,6' ', 7' ', 9' ', 9a' '-hexa-hydro-1''H, 2H, 15 'H- diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trieno-7 ', 3' '- [1 , 4] oxazino [3,4- c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide
[000518] [000518] To a mixture at room temperature of (18,3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- ((((3R) - 3- (hydroxymethyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide and
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide (0.136 g, 0.186 mmol) in tetrahydrofuran (4 ml) was added sodium hydride, 60% dispersion in mineral oil (0.050 g, 1.250 mmol), and the reaction was stirred for 30 min. To the reaction, p-toluenesulfonic anhydride (0.250 g, 0.766 mmol) was added and the reaction was stirred for 5.5 h. To the reaction, sodium hydride, 60% dispersion in mineral oil (0.050 g, 1.250 mmol) was added, and the reaction was stirred overnight. To the reaction, p-toluenesulfonic anhydride (0.180 g) was added and the reaction was stirred for 24 h. To the reaction, sodium hydride, 60% dispersion in mineral oil (0.050 g, 1.25 mmol) was added, and the reaction was stirred for an additional 24 h. The reaction was quenched with pH 7 buffer (1M K2HPOs / KH2POs) and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine and the filtrate was purified by reverse phase HPLC (Gilson; Gemini-NX 10 um column, C18, AXIA, 100 x 50 mm) eluting with 0.1% TFA-H2O0: TFA 0, 1% CH; CN (9: 1 = »1: 9). The fractions containing the desired product were combined and partitioned between pH 7 buffer (1 M K2HPOs / KH2PO0s) / EtOAc. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried over NazsSO :. and filtered. The filtrate was concentrated under reduced pressure, giving 118 mg (89%) of a white solid. The material was purified by achiral SFC chromatography, yielding (18,3'R, 6'R, 7'R, 9a''S, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl - 3,4,6 '', 7 '', 9 '', 9a '' -hexa-hydro-1''H, 2H, 15'H- diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 3' '- [1 , 4] oxazino [3,4- c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide OU (18,3'R, 6'R, 7'S, 9a''S, 11'S , 12'R) -6-chloro-11 ', 12'-dimethyl- 3,4,6' ', 7' ', 9' ', 9a' '-hexa-hydro-1''H, 2H, 15 'H- diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trieno-7 ', 3' '- [1 , 4] oxazino [3,4-c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide (10 mg, 8%, first peak to elute) as a white crystalline solid. m / z (EST, ion + ve) 712.7 (M + 1) *. A second compound to be eluted was isolated as (18,3'R, 6'R, 7'R, 9a''S, 11 'S, 12'R) -6-chloro-11', 12'-dimethyl-3 , 4,6 '', 7 '', 9 '', 9a '' - hexahydro- 1''H, 2H, 15'H-diespiro [naphthalene-l1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 3' '- [1 , 4] oxazino [3,4- c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide OU (18,3'R, 6'R, 7'S, 9a''S, 11'S , 12'R) -6-chloro-11 ', 12'-dimethyl- 3,4,6' ', 7' ', 9' ', 9a' '-hexa-hydro-1''H, 2H, 15 'H- diespiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 3' '- [1 , 4] oxazino [3,4-c] [1,4] oxazin] -15'-one 13 ', 13'-dioxide (12 mg, 9%, second peak to elute) as a white crystalline solid. (ESI, ion + ve) m / z 712.6 (M + 1) *. Example 405
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide 20H 20H fe AN> Cc! AX í o o (o o o Example 405
[000519] [000519] One flask was loaded with (18,3'R, 6'R, 7'S, 8'E, 10'S, 11'S) -6-chloro-7 '- ((9aS) -hexa-hydropyrazine [2,1- c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-hydroxy-10 ', 11'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1, 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.012 g, 0.016 mmol) and platinum (IV) oxide (0.4 mg, 1.6 umol). Ethanol (2 ml) and methanol (0.3 ml) were added. The reaction was flushed with nitrogen for 5 min, then evacuated / refilled with hydrogen three times. The reaction was stirred under 20 psi of hydrogen at room temperature overnight. The reaction was flushed with nitrogen. Methanol (5 ml) and DCM (5 ml) were added. The reaction was flushed with nitrogen, then evacuated / refilled with hydrogen three times. The reaction was stirred under 20 psi of hydrogen at room temperature for 24 h. The reaction was washed under pressure with nitrogen and filtered through Celite rinsing with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel using a gradient of 0% to 10% MeOH in DCM, giving the title compound (0.007 g, 9 umol, 58% yield). MS (ESI, + ve ion) m / z 755.2 (M + H) *. Example 466 (18,3'R, 6'R, 7'R, 11'S, 12'R) -6-CHLORINE-11 ', 12'-DIMETHYL-4' '- (METHYLSULFONIL) -3,4-DI- HYDRO-2H, 15'H-DIESPIRO [NAFTALENO- 1,22'-
[20] [20] OXA [13] TIA [1.14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24-] PENTACOSA [16,18,24] TRIENO-7 ', 2' '- [ 1.4] OXAZINAN] -15 '-ONA 13', 13 '-DIOXIDE E (18, 3'R, 6'R, 7'S, 11'S, 12'R) -6-CHLORINE- 11', 12 '-DIMETHYL -4 '' - (METHILSULFONIL) -3,4-DI-HYDRO-2H, 15'H- DIESPIRO [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24- PENTACOSA [16,18,24] TRIENO-7 ', 2' '- [1 , 4] OXAZINAN] -15'-ONA 13 ', 13' -DIOXIDE iW: EX OH o Lo o —— o E o
[000520] [000520] To a stirred solution of (18,3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- (((2-hydroxyethyl) amino ) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide (Example 452) (34 mo, 0.043 mmol) in THF (1.5 mL) in a microwave reactor was added at room temperature diisopropylethylamine (0.075 mL, 0.431 mmol) under argon followed by methanesulfonic anhydride (37.6 mg, 0.216 mmol). The resulting mixture was stirred at room temperature for 5 min, during which time the color of the mixture changed from colorless to light greenish yellow. The reactor was covered and subjected to microwave reaction irradiation (3 h at 70 ºC). 4- (Dimethylamino) pyridine (15.81 mg, 0.129 mmol) was then added followed by more methanesulfonic anhydride (18 mg, 0.11 mmol). The reactor was sealed and again subjected to microwave irradiation (4 h at 70 ºC). The volatiles were removed and the concentrate was dissolved in DMSO and purified by preparative reverse phase HPLC (Gemini column ”Prep c18 5 um; Phenomenex, Torrance, CA; elution with a gradient of 30% to 95% MeCN in water, where both solvents contain 0.1% TFA, 25 min method) giving rise, after lyophilization, to 4.0 mg of (18.3'R, 6'R, 7'R, 11'S, 12'R) -6 -chloro-11 ', 12'- dimethyl-4' '- (methylsulfonyl) -3,4-dihydro-2H, 15'H-dispiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 2' '- [1 , 4] oxazinan] -15'-one 13 ', 13'-dioxide E (18,3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-7 ', 2' '- [1 , 4] oxazinan] -15'-one 13 ', 13'-dioxide as a white solid. MS (ESI, + ve ion) m / z 734.2 (M + 1) *. Examples 499 and 500 3- ((9AR) -8- ((((18,3'R, 6'R, 7'R, 11'S, 12'R) -6-CHLORINE-7 '-HYDROXY- 11', 12 '-DIMETHYL-13', 13'-DIOXIDE-15'-OX0-3,4-DI-HYDRO-2H- SPIRUS [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24-] PENTACOSA | [16,18,24] TRIEN] -7 '-IL) METHYL ) OCTA-HYDRO-2H- PIRAZINO [1,2-A] PIRAZIN-2-IL) METHIL PROPANOATE E 3 - (((9AR) - 8- ((((18,3'R, 6'R, 7'S, 11'S , 12'R) -6-CHLORINE-7 '-HYDROXY-11', 12'- DIMETHYL-13 ', 13'-DIOXIDE-15'-OX0-3,4-DI-HYDRO-2H- SPIRUS [NAFTALENO- 1.22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24- PENTACOSA | [16,18,24] TRIEN] -7 '-IL) METHIL) OCTA-HYDRO-2H- PIRAZINO [1,2-A] PIRAZIN-2-IL) METHYL PROPANOATE E 3 - ((9AS) - 8 - ((((18,3'R, 6'R, 7'R, 11'S, 12'R) -6-CHLORINE-7'-HYDROXY-11 ', 12'- DIMETHYL-13', 13'-DIOXIDE-15'-OX0-3,4-DI-HYDRO-2H- SPIRUS [NAFTALENE -1.22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24-] PENTACOSA | [16,18,24] TRIEN] -7 '-IL) METHYL ) OCTA-HYDRO-2H- PIRAZINO [1,2-A] PIRAZIN-2-IL) METHYL PROPANOATE E 3 - (((9AS) - 8- ((((18,3'R, 6'R, 7'S, 11'S , 12'R) -6-CHLORINE-7 '-HYDROXY-11', 12'- DIMETHYL-13 ', 13'-DIOXIDE-15'-OX0-3,4-DI-HYDRO-2H- SPIRUS [NAFTALENO- 1.22'-
[20] [20] OXA [13] TIA [1, 14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24 +
[20] [20] OXA [13] TIA [1.14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24-] PENTACOSA [16,18,24] TRIEN] -15 '-ONA 13', 13'-DIOXIDE E (18,3'R, 6'R, 7'R, 11'S, 12'R) -7 '- ((((9AS) -8-ACRYLOILOCTA-HYDRO-2H-PIRAZINE [1,2- A] PIRAZIN-2-IL) METHIL) -6-CHLORINE-7'-HYDROXY-11 ', 12' -DIMETHYL-3,4-DI-HYDRO-2H, 15'H-SPIRUS [NAFTALENE- 1,22 ' -
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24> + PENTACOSA [16,18,24] TRIEN] -15 '-ONA 13', 13 '-DIÓXIDO E (18,3'R, 6'R, 7'S, 11'S, 12'R) -7'- ((((9AR) -8-ACRILOILOCTA-HIDRO- 2H-PIRAZINO [1,2-A] PIRAZIN -2-IL) METHYL) -6-CHLORINE-7'-HYDROXY- 11 ', 12'-DIMETHYL-3,4-DI-HYDRO-2H, 15'H-SPIRUS
[20] [20] OXA [13] TIA [1.14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24-] PENTACOSA [16,18,24] TRIEN] -15 '-ONA 13', 13'-DIOXIDE E (18,3'R, 6'R, 7'S, 11'S, 12'R) -7 '- ((((9AS) -8-ACRYLOILOCTA-HYDRO-2H-PIRAZINO [1,2-A] PIRAZIN-2-IL) METHIL) -6-CHLORINE-7'-HYDROXY- 11 ', 12' -DIMETHYL-3,4-DI-HYDRO-2H, 15'H-SPIRAL [NAFTALENE- 1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24> + PENTACOSA [16,18,24] TRIEN] -15'-ONA 13 ', 13 '-DIOXIDE (Example 500) N
[000521] [000521] To a stirred solution of (18,3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7'- ((9aR) -octahydro-2H-pyrazino [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide, (18,3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'- dimethyl-7 '- ((9aS) -octa-hydro-2H-pyrazine [1,2-a] lpyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide, (18,3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'- dimethyl-7 '- ((9aR) -octa -hydro-2H-pyrazine [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide, (18,3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'- dimethyl-7 '- ((9aS) -octa -hydro-2H-pyrazine [1,2-a] lpyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide (Example 479) (0.15 g, 0.199 mmol) and diisopropylethylamine (1.5 mL, 8.62 mmol) in DCM (10 mL) was added at room temperature acrylic acid n-hydroxysuccinimide ester (0.303 g, 1.789 mmol) in one portion as a solid. The resulting mixture was stirred at room temperature for 3 h. MeOH (8 ml) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 20 min before being concentrated in vacuo. The crude residue was directly loaded onto a silica gel pre-column (25 g) and subjected to Combi-Flash column chromatography on a 12 g ISCO Gold column eluting with 1% to 20% MeOH / DCM, giving rise to 30 mg of impure product mixture, which was subjected to preparative reverse phase HPLC (Gemini "" column Prep C18 10 um; Phenomenex, Torrance, CA; elution with gradient of 20% to 90% MeCN in water, in which both the solvents contain 0.1% TFA, a 15 min gradient in a 24 min method), resulting, after lyophilization, 18.5 mg of 3- ((9AR) -8- (((18,3'R, 6'R, 7'R, 11'S, 12'R) -6-CHLORINE-7 '-HYDROXY- 11', / 12 '-DIMETHYL-13', 13'-DIOXIDE-15'-O0X0-3,4- DI-HYDRO-2H- SPIRUS [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24-] PENTACOSA [16,18,24] TRIEN] -7 '-IL) METHIL) OCTA-HIDRO-2H- PIRAZINO [1,2-A] PIRAZIN-2-IL) METHYL PROPANOATE E 3 - ((9AR) - 8- ((((18,3'R, 6'R, 7'S, 11'S, 12'R) -6-CHLORINE-7 '-HYDROXY-11', 12'- DIMETHYL-13 ', 13'-DIOXIDE-15'-OX0-3,4-DI-HYDRO-2H- SPIRUS [NAFTALENE-1 , 22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24- PENTACOSA [16,18,24] TRIEN] -7 '-IL) METHIL) OCTA -HYDRO-2H- PIRAZINO [1,2-A] PIRAZIN-2-IL) METHYL PROPANOATE E 3 - ((9AS) - 8 - (((18,3'R, 6'R, 7'R, 11'S , 12'R) -6-CHLORINE-7'-HYDROXY-11 ', 12'- DIMETHYL-13', 13'-DIOXIDE-15'-OX0-3,4-DI-HYDRO-2H- SPIRUS [NAFTALENO- 1.22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24-] PENTACOSA [16,18,24] TRIEN] -7 '-IL) METHIL) OCTA -HYDRO-2H- PIRAZINO [1,2-A] PIRAZIN-2-IL) METHYL PROPANOATE E 3 - ((9AS) - 8- (((18,3'R, 6'R, 7'S, 11'S, 12 'R) -6-CHLORINE-7' -HYDROXY-11 ', 12'- DIMETHYL-13', 13'-DIOXIDE-15'-OX0-3,4-DI-HYDRO-2H-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24-] PENTACOSA [16,18,24] TRIEN] -7 '-IL) METHIL) OCTA -HYDRO-2H- PIRAZINO [1,2-A] PIRAZIN-2-IL) METHYL PROPANOATE (EXAMPLE 499) IN an approximately 1-to-1-to-1-to-1 epimeric mixture. MS (ESI, + ve ion) m / z 841.0 (M + 1) *. Additionally, (18, 3'R, 6'R, 7'R, 11'S, 12'R) -7'- (((9AR) -8-ACRILOILOCTA-HYDRO- 2Z2H-PIRAZINO [1,2-A] PIRAZIN -2-IL) METHYL) -6-CHLORINE-7'-HYDROXY- 11 ', 12' -DIMETHYL-3,4-DI-HYDRO-2H, 15'H-SPIRUS [NAFTALENE- 1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24 + PENTACOSA [16,18,24] TRIEN] -15 '-ONA 13', 13 ' -DIOXIDE E (18,3'R, 6'R, 7'R, 11'S, 12'R) -7 '- ((((9AS) -8-ACRYLOILOCTA-HYDRO-2H-PIRAZINO [1,2-A] PIRAZIN-2-IL) METHIL) -6-CHLORINE-7 '-HYDROXY-11', 12'-DIMETHYL-3,4-DI-HYDRO-2H, 15'H-SPIRUS [NAFTALENE- 1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24-] PENTACOSA [16,18,24] TRIEN] -15 '-ONA 13', 13 '-DIÓXIDO E (18,3'R, 6'R, 7'S, 11'S, 12'R) -7'- ((((9AR) -8-ACRILOILOCTA-HIDRO- 2Z2H-PIRAZINO [1,2-A] PIRAZIN -2-IL) METHYL) -6-CHLORINE-7'-HYDROXY- 11 ', 12' -DIMETHYL-3,4-DI-HYDRO-2H, 15'H-SPIRUS [NAFTALENE- 1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24 + PENTACOSA [16,18,24] TRIEN] -15 '-ONA 13', 13 ' -DIOXIDE E (18,3'R, 6'R, 7'S, 11'S, 12'R) -7 '- ((((9AS) -8-ACRYLOILOCTA-HYDRO- 2H-PIRAZINO [1,2-A] PIRAZIN- 2-IL) METHYL) -6-CHLORINE-7 '-HYDROXY- 11', 12'-DIMETHYL-3,4-DI-HYDRO-2H, 15'H-SPIRUS [NAFTALENE- 1,22'-
[20] [20] OXA [13] TIA [1, 14] DIAZATETRACYCLE [14.7.2.0-3,6-.0-19,24 +
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide OR (18,3'R, 6'R, 7'S, 11'S, 12'R) -7'- (aminomethyl) -6-chloro-7'- hydroxy-11', 12'-dimethyl-3, 4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 'Ni-dioxide, OH Now OH CI Á (e) to RA or NAS - OO POA) Example 506 o HAN, oH HaN OH ax Lo "ax 2S = O0
[000522] [000522] (18,3'R, 6'R, 7'S, 11'S, 12'R) -7 '- (Azidomethyl) -6-chloro-7'-hydroxy-11', 12'-dimethyl-3,4 -di-hydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6.0-19,24] nachos [16,18,24] trien] -15'-one 13 ', 13'-dioxide OR
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6.0-19,24] pentacosa [16,18,24] trien] -15'-one 13 ', 13'-dioxide ( Example 506) (36.0 mg, 0.055 mmol) was dissolved in ethyl acetate (5.0 ml) and platinum (IV) oxide (2.49 mg, 11.0 umol) was added. The reactor was filled with hydrogen to 15 psi and stirred vigorously for 2.5 h. MeOH (1.5 mL) was added and the reactor was refilled with hydrogen (15 psi) and stirred overnight. The slurry was filtered and the precipitate was washed with DMSO to ensure that no product remained in the catalyst. the filtrate was concentrated. The crude material was purified by preparative reverse phase HPLC using a Phenomenex Gemini column, 10 um, C18, 100 À, 150 x 30 mm, 0.1% TFA in CH3CN / H20O, gradient 20% to 85% over 30 min, giving rise to (18,3'R, 6'R, 7'S, 11'S, 12'R) -7'- (aminomethyl) -6-chloro-7'- hydroxy-11 ', 12'-dimethyl-3 , 4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide OR (18,3'R, 6'R, 7'S, 11'S, 12'R) -7'- (aminomethyl) -6-chloro-7'- hydroxy-11', 12'-dimethyl-3, 4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide (32 mg, 0.037 mmol, 68% yield) as the di-TFA salt. MS (ESI, + ve ion) m / z 630.2 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide E (18,3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-7' - ((9aS) -hexahydropyrazine [2,1 -c] [1,4] oxazin-8 (1H) -ylmethyl) -12 '- (2-methoxyethyl) -1'-methyl-3,4-dihydro-2H, 15'H- spiro [naphthalene- 1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide Es NO NA q À to - = - R À 2620 + q À 2,620 va: À O v O o "oo Example 517 Example 518
[000523] [000523] A reactor was charged with platinum (IV) oxide (18.6 mg, 0.082 mmol), then placed in a Biotage Endeavor and treated with a solution of (18.3'R, 6'R, 7'R , 8'E, 11'S, 12'R) - 6-chloro-7'-ethoxy-7 '- ((9aS) -hexahydropyrazine [2,1- c] [1,4] oxazin-8 (1H) -ylmethyl) -12 '- (2-methoxyethyl) -1'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (128 mg) in EtOAc (3 ml). The reactor was purged with Argon (3X), then pressurized to 200 psi with H> and stirred (250 RPM) at 80 ºC for 20 h. The reactor was cooled to room temperature and purged with Argon (3X), then filtered through a Celite pad that was liberally rinsed with EtOAc. The filtrate was concentrated in vacuo and purified by preparative reverse phase HPLC (Shimadzu) on a Phenomenex Luna column (5 µm, C18, 110 À, Axia, 150 mm X 21.2 mm) eluting at 30 mL / min with a gradient 25% to 100% MeCN (0.1% TFA) in water (0.1% TFA) over 20 min. The desired fractions were poured into 10% Naz2CO3 and extracted with DCM (2 X 5 mL). The combined organic layers were dried over MgSO: and concentrated in vacuo, yielding (18.3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-7 ' - (((9aS) -hexa-hydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -12 '- (2-methoxyethyl) -11'-methyl-3,4-di -hydro-2H, 15'H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide (Example 518) (32.8 mg, 0.040 mmol, 13% yield) as a white solid. MS (ESI, + ve ion) m / z 827.2 (M + H) *. Additionally, (18,3'R, 6'R, 7'R, 11'S, 12'R) -7'-ethoxy-7'- ((9aS) -hexahydropyrazine [2,1-c] [1, 4] oxazin-8 (1H) -ylmethyl) - 12'- (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide (Example 517) was isolated as a peak eluting earlier (12.9 mg, 0.016 mmol, 6% yield) as a white solid. MS (ESI, + ve ion) m / z 793.3 (M + H) *. Example 519 (18,3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-71'-ethoxy-12 '- (2-methoxyethyl) -11'-methyl-7'- ((((3R) -3-methyl-4- (2-propanyl) -l-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide / EA EA HONO Cl. o e fo o »o o N no Step 1 N If Step 2 D HO 3 N o” = o ”o
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide
[000524] [000524] A reactor was charged with carbon sulfated Pt (5% w, 54.2 mg, 0.295 mmol), then placed in the Biotage Endeavor and treated with a solution of (18.3'R, 6'R, 7 ' R, 8'E, 11'S, 12'R) -6-chloro-71'-ethoxy-7'- (hydroxymethyl) -12 '- (2-methoxyethyl) -11'-methyl-3,4-dihydro - 2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide] (207 mg, 0.295 mmol) in EtOAc (3.25 mL). The reactor was purged with Argon (3X), then pressurized to 200 psi with H; and stirred (250 RPM) at 80 ° C for 20 h. The reactor was cooled to room temperature and purged with Argon (3X), then filtered through a Celite pad that was liberally rinsed with EtOAc. The filtrate was concentrated in vacuo, yielding (18.3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-71'- (hydroxymethyl) -12 ' - (2-methoxyethyl) -111'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide (196 mg, 0.279 mmol, 94% yield) as a white solid. MS (ESI, + ve ion) m / z 703.3 (MHH) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene] -7 '-carbaldehyde 13', 13 '-dioxide
[000525] [000525] To a solution cooled in an ice bath of (18,3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-71'- (hydroxymethyl) -12 '- (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 Dioxide (161 mg, 0.229 mmol) in DCM (10 mL) 0.3 M Dess-Martin periodinane in DCM (1.0 mL, 0.300 mmol) was added dropwise over 2 min. After 1.5 h, LC-MS suggests about 60% conversion, the reaction was treated with an additional 0.9 mL of 0.3 M Dess-Martin Periodinane in DCM dropwise over 1 min. After another 2.5 h, LC-MS suggests complete conversion. The reaction was treated with 5 ml of saturated sodium bisulfite and stirred for 20 min. The reaction was poured into water (15 ml) and the organic layer was separated. The aqueous layer was extracted with DCM (1 X 5 ml). The combined "organic layers" were concentrated in vacuo Ee adsorbed on a silica gel buffer and chromatographed through a pre-packaged silica gel column Redi-SepG6 (Gold, 12 g), eluting with 0% to 25% EtOAc in heptanes , giving rise to (1S8,3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '- (2-methoxyethyl) -11'-methyl-l15 '-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene] -7 '-carbaldehyde 13', 13 '-dioxide (105 mg, 0.150 mmol, 65.4% yield) as a white solid. MS (ESI, + ve ion) m / z 701.2 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide
[000526] [000526] A round bottom flask was loaded with the TFA salt of (R) -1-isopropyl-2-methylpiperazine (68.2 mg, 0.285 mmol) and (18.3'R, 6'R, 7 ' R, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '- (2-methoxyethyl) -11'-methyl-l15'-oxo-3,4-dihydro-2H-spiro [naphthalene -1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene] -7 '-carbaldehyde 13', 13 '-dioxide (50 mg, 0.071 mmol) in DCE (2 mL) and N, N-diisopropylethylamine (0.1 mL, 0.574 mmol). After 1.5 h, the solution was treated with sodium triacetoxyborohydride (6 mg). After an additional 3 h, the reaction was treated with more sodium triacetoxyborohydride (7 mg). After an additional 16 h, the reaction was again treated with sodium triacetoxyborohydride (6 mg). The reaction was monitored by LC-MS and sodium triacetoxyborohydride was added in 5-10 mg portions until the reaction was considered complete. After an additional 24 h, the reaction was diluted with DCE (3 ml). After 4 d, the reaction was treated with acetic acid (12 µL, 0.208 mmol). After an additional 24 h, more acetic acid (18 µL) was added. After an additional 24 h, the reaction was treated with an additional 30 mg of amine. After an additional 96 h, the reaction was treated with larger portions of sodium triacetoxyborohydride to drive the reaction to the desired product or the resulting reduced aldehyde alcohol. LC-MS suggests no further progression, the reaction was quenched with water and the aqueous layer was extracted with DCM (2 X 10 mL). The combined DCM layers were concentrated in vacuo and adsorbed to a silica gel buffer and chromatographed through a pre-packaged silica gel column Redi-Sep6 (Gold, 12 g), eluting with 0% to 80% EtOAc: EtoH (3: 1) in heptanes, giving rise to one 13 ', 13'-dioxide
[20] [20] oxa [13] tia / 11,14]) diaz atetracycle [1 4.7.2.0-3.67. 0-19,24-] pentacosa [8.1 6,18,24] tetraen]) - 15'-
[20] [20] oxa [13] tia [1,14] diaz atetracycle [1
[20] [20] oxa [13] tia [1,14] diaz atetracycle [1
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide ss
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3-dithian-2-yl) -7 '-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000528] [000528] To a 250 ml round bottom flask was added 1,3-dithian (4.79 g, 39.8 mmol) and THF (100 ml). The mixture was cooled to -78 * C and n-butyl- lithium (1.6 M solution in hexane, 22.5 mL, 36.1 mmol) was added over 8 min. The solution was stirred in the bath at -78 ° C for 30 min. To a separate 100 mL flask was added (18.3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro -2H, 7'H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide and THF (5 ml). To this system, lanthanum (III) chloride bis lithium chloride complex solution (0.6 M in THF, 60.1 ml, 36.1 mmol) was added and this was stirred for min at room temperature. The solution was then cooled to -78 “C and added via cannula to the dithian solution. After 2.5 h at -78 ºC, the solution was treated with NH «Cl sat and water. The pH of the solution was adjusted to pH = 4 with 10% aqueous citric acid and NaHCO3; aqueous. The solution was extracted with EtOAc and the combined extracts were filtered through Celite. The extracts were washed with water and brine and then dried (Na2SO0s :) and concentrated, resulting in a mixture of
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3-dithian-2-yl) -7 '-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide in the form of a brown oil which was taken directly to the next step. MS (ESI, + ve ion) m / z 717.5 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3-dithian-2-yl) -7 '-methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000529] [000529] To a flask capable of being resealed the mixture of (1S8,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6- chloro-7'- was added (1,3-dithian-2-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (1,3-ditian-2-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (6.81 g, 9.49 mmol) and THF (100 mL). The mixture was cooled to 0 ºC and potassium bis (trimethylsilyl) amide (1 M in THF, 38.0 ml, 38.0 mmol) was added over 10 min. The solution was stirred at 0 ° C for 5 min and then iodomethane (2.36 mL, 38.0 mmol) was added over 3 min. After 2.5 h at 0 C, the solution was poured into saturated NH'Cl and the pH was adjusted to 4 with 1 M citric acid. The solution was extracted with EtOAc and the combined extracts were washed with brine, dried (Na2SO0s :) and concentrated on silica. Purification by chromatography on silica gel (0% to 35% EtOAc / heptane, with 0.3% AcCOH, 330 g Redi-Sep Gold column) gave (18.3'R, 6'R, 7'R , 8'E, 11'S, 12'R) -6-chloro-71'- (1,3-ditian-2-1i11) -7'-methoxy-11 ', 12'-dimethyl-3,4-di- hydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (1.66 g, 2.27 mmol, 24% yield). MS (ESI, ion + ve) m / z 731.5 (M + H) * e (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chlorine-7 '- (1,3-ditian-2-1yl1) -7'-methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (4.69 g, 6.41 mmol, 68% yield). MS (ESI, + ve ion) m / z 731.5 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'- dioxide
[000530] [000530] To a 250 mL round-bottom flask equipped with a reflux condenser was added (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 ' - (1,3-dithian-2-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (1.63 g, 2.23 mmol), acetonitrile (40 ml) and water (10 ml). The mixture was heated to 50 ° C and calcium carbonate (1.12 g, 11.1 mmol) and iodomethane (1.38 mL, 22.3 mmol) were added. After 23 h at 50 ° C, the solution was poured into NH. «Cl saturated and water and then extracted with EtOAc. The combined extracts were washed with brine and then dried (Na2SO1) and concentrated on silica. Purification by silica gel chromatography (0 to 40% EtOAc / heptane (both with 0.3% AcCOH), HP 120 g Silicycle column) gave rise to (18.3'R, 6'R, 7'S, 8'E , 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ' , 13'-dioxide (1.34 g, 2.09 mmol, 94% yield) as a white solid. MS (ESI, + ve ion) m / z 641.3 (M + H) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000531] [000531] To a solution at room temperature of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl -15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 '-carbaldehyde 13' , 13'-dioxide (30 mg, 0.047 mmol) in MeOH (2 mL) and THF (0.5 mL) was added sodium borohydride (17 mg, 0.47 mmol). was poured into saturated NaCl and then extracted with EtOAc. The combined extracts were dried (NaszSO :) and concentrated. Purification by chromatography on silica gel (0% to 60% EtOAc (0.3% AcCOH) in heptane (4 g column)) gave (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'- (hydroxymethyl) - 7T'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (10 mg, 0.016 mmol, 50% yield) as a white solid. ! H NMR (400 MHz, CHLOROPHORMUM-d) 5 7.95-8.01 (m, 1H), 7.68 (d, J = 8.61 Hz, 1H), 7.16-7.20 (my , 1H), 7.10 (dd, J = 1.86, 13.99 Hz, 2H), 6.85-6.95 (m, 2H), 5.71 - 5.80 (my, 1H), 5.67 (d, J = 0.98 Hz, 1H), 4.29-4.41 (m, 1H), 4.07 (d, J = 4.89 Hz, 3H), 3.87-3 , 97 (m, 2H), 3.72 (d 1, J = 14.48 Hz, 1H), 3.26 (d, J = 14.28 Hz, 1H), 3.10 (s, 3H), 2.96-3.04 (m, 1H), 2.72-2.80
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N, N-dimethylacetamide e.g. > ”HO AZ or RD CI, Cc
[000532] [000532] Acid ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-1'- methoxy-11 ', 12'-dimethyl-13', 13 '-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic (60 mg, 0.089 mmol) was collected in THF (1.8 mL) and lithium hydroxide (2.0 M in water, 0.18 mL, 0.36 mmol) was added. The mixture was stirred at room temperature for 10 min before being concentrated in vacuo, yielding the lithium carboxylate of the starting material as an off-white solid that was used in the amide coupling. HATU (51.0 mg, 0.134 mmol and dimethylamine (2.0 M in THF, 0.134 mL, 0.268 mmol) were added to a stirred suspension of the lithium carboxylate previously prepared in N, N-dimethylformamide (1.8 mL). The reaction mixture was stirred at room temperature for minutes The reaction mixture was diluted with water and EtOAc and transferred to a separating funnel 1.0 M HCl was added and the phases were mixed The organic layer was separated and washed sequentially with LiCl 1.0 M and brine, then dried over magnesium sulfate and concentrated under reduced pressure Purification via Flash chromatography on silica gel using a gradient of 50% to 100% EtOAc + 0.3% ACOH in heptane gave rise to 2- 7 ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-13', 13'-dioxide -15'-ox0-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N, N-dimethylacetamide (38 mg, 0.054 mmol, 61% yield) as a white solid. ! H NMR (300 MHz, CHLOROPHORMUM-d) & ppm 7.71 (d, J = 8.48 Hz, 1 H) 7.17 (dd, J = 8.77, 2.19 Hz, 1 H) 7 , 07 - 7.11 (m, 1 H) 7.01 - 7.04 (m, 1 H) 6.95 - 7.00 (m, 1 H) 6.88 - 6.93 (m, 1 H ) 5.71 - 5.92 (my, 2 H) 4.00 - 4.11 (my, 3 HE) 3.84 (d 1 J = 15.20 Hz, 1 HE) 3.70 (d 1, J = 14.03 Hz, 1 HE) 3.30 (d, J = 14.32 Hz, 1 H) 3.17 (s, 3 H) 3.08 - 3.15 (my, 2 H) 3, 06 (s, 3 H 3.01 (s, 1 H) 2.94 (s, 3 H) 2.65 - 2.87 (m, 3 H) 2.39 - 2.65 (m, 3 H) 2.02 - 2.21 (my, 4 H) 1.51 - 1.97 (my, 11 H) 1.30 - 1.47 (m, 5 H) 1.05 (dy, J = 6.14 Hz, 3 H) .MS (ESI, + ve) m / z 666.2 [M - OMe] *. Example 100003 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R ) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7' - (2-pyridinyl) -3,4-dihydro-2H, 15'H-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide o QN om O OH = as / DANA AS AA Cc Steps Cl Cl, Elapa2 xo Í. ojo N If N If N If "o" o "os / a C | RA & N 2820" o Example 100003 Step 1: (18,3'R, 6'R, 7'R, 8'E, 11'S, 12 'R) -6-chloro-71'-hydroxy-11', 12'-dimethyl-7 '- (2-pyridinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1, 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7'- (2-pyridinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000533] [000533] A solution of 2-bromopyridine (105 µL, 1.1 mmol) in THF (4 mL) was cooled to - 78 “* C under a nitrogen atmosphere. A solution of n-butyllithium in hexanes (2.5 M, 422 µl, 1.1 mmol) was added dropwise and the reaction mixture was stirred for 30 min. A solution of (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H , 15'H-spiro [naphthalene- 1.22 '[20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19, 24-] pentacosa [8.16, 18.24] tetraene] -7 ', 15'-dione 13', 13'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7'- (2-pyridinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a light yellow solid (129 mg). The mixture was used in the next step without further purification. MS (ESI, + ve ion) m / z 676.0 (MHH) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000534] [000534] The mixture of (1S8,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7 '- (2-pyridinyl) -3,4-di-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7'- (2-pyridinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (129 mg, 0.19 mmol) was dissolved in THF (5 mL) and the solution was cooled with a water bath. Sodium hydride (60% dispersion in mineral oil, 201 mg, 5 mmol) was added in one portion. After 15 min, iodomethane (624 µl, 10 mmol) was added. An additional portion of each of NaH and Mel was added after 2 h. A saturated aqueous solution of NH.Cl was added and the reaction mixture was extracted with EtOAc. The solvent was removed under reduced pressure. The concentrate was purified by preparative reverse phase HPLC using a Phenomenex Gemini column, 10 µm, C18, 110 À, 100 x 50 mm, 0.1% TFA in CH; CN / H2O0, gradient 10% to 100% over 20 min, giving 21 mg of [(18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl -7 '- (2-pyridinyl) -3,4-dihydro-2H, 15'H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide, the second peak to elute, as a white solid. '! H NMR (400 MHz, CHLOROPHORMUM-d) 5 ppm 1.15 (m, 3 H) 1.24 - 1.34 (m, 2H) 1.48 (my, 3 H) 1.61 - 1, 80 (m, 2 H) 1.83 - 1.93 (m, 2 É) 1.95 - 2.07 (m, 3 H) 2.19 - 2.32 (m, 3 H) 2.62 - 2.82 (Mm, 5
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide oq oH ZA OMe e. RO Stage = OA Step - OE qx 8 = 0 ST qx 2820 77 qj 2820 “to oo Example 100348 Example 100004 Example 100349 Step 1: (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-1'-hydroxy-11 ', 12'-dimethyl-7' - (3-pyridazinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000535] [000535] To a solution of 2,2,6,6-tetramethylpiperidine (1.06 ml, 6.3 mmol) in THF (28 ml) which was cooled to 0 ºC was added a solution of n-butyl lithium ( 2.5 M in THF, 2.4 mL, 6.0 mmol) under a nitrogen atmosphere. The reaction was stirred at 0 ° C for 25 minutes, then cooled to -78 ° C. A solution of pyridazine (110 pL, 1.5 mmol) in THF (5 mL) was added dropwise, followed by a solution of
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide, the second peak to elute. MS (ESI, + ve ion) m / z 677.0 (M + H) *. Step 2: (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'- methoxy-11 ', 12'-dimethyl-7' - (3- pyridazinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000536] [000536] Sodium hydride (60% dispersion in mineral oil, 81 mg, 2.0 mmol) was added in one portion to a solution of (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7' - (3-pyridazinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (137 mg, 0.2 mmol) in tetrahydrofuran (6.7 mL). After 5 min, iodomethane (251 nuL, 4.1 mmol) was added and the reaction was stirred for 2 hours. MeOH (3 mL) was added and the reaction mixture was purified by preparative reverse phase HPLC using a Phenomenex Gemini column, 10 æm, C18, 110 Å, 100 x 50 mm, 0.1% TFA in CH; CN / H2O, gradient 10% to 100% over 20 min. The desired fractions were combined and the solvent was removed under reduced pressure to obtain 92 mg of (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy -11 ', 12'-dimethyl-7' - (3-pyridazinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide as a bronze-colored solid. 'H NMR (400 MHz, CHLOROPHORMUM-d) 5 ppm 1.03 (d, J = 6.06 Hz, 3 H) 1.35 (d, J = 6.65 Hz, 3 H) 1.72 - 1 , 87 (my, 2 H) 1.89 - 2.23 (m, 9 H) 2.73 - 2.84 (m, 3 H) 2.94 - 3.06 (my, 2 H) 3.11 (s, 3 H) 3.26 (d, J = 14.48 Hz, 1 H) 3.68 (dy, J = 7.04 Hz, 1 H) 3.75 (d, J = 14.48 Hz , 1 H) 4.04 - 4.14 (m, 2 H) 4.32 (d, J = 15.06 Hz, 1 H) 5.43 (s 1, 9 H) 5.91 (d, J = 16.24 Hz, 1 H) 6.85 - 6.92 (my, 2 H) 7.03 (s, 1 H) 7.09 (s, 1 H) 7.16 - 7.21 (my, 1 H) 7.18 (d, J = 8.61 Hz, 1 H) 7.70 (d, J = 8.41 Hz, 1 H) 8.18 (s 1, 2 H) 9.48 (s 1, 1 H). MS (ESI, + ve ion) m / z 691.0 (M + H) *. Example 100005 2 - ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-methoxy- 11', 12'-dimethyl-13 ', 13 '-dioxide-15'-ox0-3,4-dihydro-2H- spiro [naphthalene-11,22'-
[20] [20] oxa [13] tia [1,14 diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) -N - (2-methoxyethyl) -N- methylacetamide Ya and oH oH f) Ê CI, º 2 CI P -. o - o N -8 = o Stage1 N n-SsO Stage2 N nº So À no> HO> HO Ao “Ao * Xo
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate of 2-methyl-2-propanyl and ((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-71'-hydroxy-11 ', 12' -dimethyl-13 ', 13'-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1.14 diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[000537] [000537] 2-tert-Butoxy-2-oxoethylzinc chloride (0.5 M in diethyl ether, 48.6 ml, 24.28 mmol) was added to a stirred solution of (18.3'R, 6 ' R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene- 1.22 '-
[20] [20] oxa [13] tia [1,14] diazatetracycle [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13 ', 13'-dioxide (2.90 g, 4.86 mmol) in tetrahydrofuran (50 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH2 Cl (150 mL) and extracted with EtOAc (100 mL). The organic layer was separated, washed with 9: 1 of saturated aqueous NH.Cl: 30% aqueous NH.OH (200 mL), washed with brine (100 mL), dried over MgSOs, filtered and concentrated in vacuo, giving rise to a crude mixture of ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-13', 13 '-dioxide-l15'-ox0-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraen] -7'-yl) acetate 2-methyl-2-propanyl e ((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-71'- hydroxy-11 ', 12'- dimethyl-13 ', 13'-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate of 2-methyl-2-propanyl which was subjected to azeotropic treatment twice with toluene and used directly in the next step. MS (ESI, + ve) m / z 713.3 [M + H] *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- (2-hydroxyethyl) - 11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000538] [000538] Lithium borohydride (2.0 M solution in tetrahydrofuran, 10.41 mL, 20.82 mmol) was added to a stirred solution of the crude mixture of ((18.3'R, 6'R , 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-13', 13'-dioxide-15'-ox0-3,4-di- hydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate of 2-methyl-2-propanyl and ((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12' -dimethyl-13 ', 13'-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate of 2-methyl-2-propanyl in tetrahydrofuran (25 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. More lithium borohydride (2.0 M solution in tetrahydrofuran, 5.21 mL, 10.4 mmol) was added, followed by dropwise addition of methanol (1.69 mL, 41.6 mmol). The reaction mixture was stirred at room temperature for 24 h. More methanol (1.687 ml, 41.6 mmol) was added and the reaction mixture was stirred for an additional 2.5 h. The reaction mixture was slowly quenched with saturated aqueous NH.Cl (75 ml) and extracted twice with EtOAc (75 ml). The combined organic layers were separated, washed with brine (60 ml), dried over MgSOs, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, O to 10% MeOH in DCM) provided a mixture of (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-1 '- hydroxy-7' - (2-hydroxyethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- (2-hydroxyethyl) - 11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (2.58 g, 4.01 mmol, 96% yield) as a white solid. MS (ESI, + ve) m / z 643.2 [M + H] *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000539] [000539] Imidazole (1.274 gq, 18.72 mmol) and tert-butyldimethylsilyl chloride (1.41 9g, 9.36 mmol) were added to a stirred mixture of (18S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- (2-hydroxyethyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H -spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide and (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '- (2-hydroxyethyl) - 11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (3.01 g, 4.68 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 72 h. More tert-butyldimethylsilyl chloride (1.41 9, 9.36 mmol) and imidazole (1.274 gq, 18.72 mmol) were added and the reaction mixture was stirred at room temperature for an additional 4 h. More reagents were added multiple times with stirring at room temperature until the reaction stopped progressing on addition. The reaction mixture was quenched with saturated aqueous NH «Cl (125 ml) and extracted with DCM (75 ml). The organic layer was separated, dried over MgSOs, filtered and concentrated in vacuo. The resulting residue was again subjected to the original reaction conditions and stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH.Cl (125 ml) and extracted with DCM (75 ml). The organic layer was separated, dried over MgSOs, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, O to 50% EtOAc in heptane) provided
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (453 mg, 0.598 mmol, 13% yield), the second diastereomer to elute from the column, as a white solid. 'H NMR (400 MHz, CHLOROPHORM-d) 3 ppm 7.99 (1 H, s) 7.69 (1 H, d, J = 8.41 Hz) 7.18 (1 H, dd, J = 8 , 51, 2.25 Hz) 7.09 (1 H, d, J = 2.15 Hz 6.92 - 6.96 (3 H, m) 5.71 - 5.78 (1 H, m) 5 , 59 (1 H, d, J = 16.04 Hz) 4.55 (1 H, s 1) 3.96 - 4.19 (5 H, m) 3.67 - 3.82 (2 H, m ) 3.25 (1 H, d, J = 14.28 Hz) 3.02 (1 H, dd, J = 15.16, 10.27 Hz) 2.68 - 2.86 (2 H, m) 2.35 - 2.47 (1 H, m) 2.26 - 2.36 (1 H, m) 2.12 - 2.24 (3 H, m) 1.77 - 2.08 (6 H, m) 1.65 - 1.77 (1 H, m) 1.51 - 1.62 (1 H, m) 1.46 (3 H, d, J = 7.04 Hz) 1.36 - 1, 45 (1 H, m) 1.25 - 1.32 (1 H, m) 1.07 (3 H, qd, J = 6.06 Hz) 0.91 (9 H, s) 0.10 (6 H, d, J = 3.33 Hz) MS (ESI, + ve) m / z 757.2 [M + H] *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000540] [000540] Sodium hydride (60% dispersion in mineral oil, 119 mg, 2.97 mmol) was added to a stirred solution of (18.3'R, 6'R, 7'S, 8'E, 11'S, 12 ' R) -6-chloro-7 '- (2 - ((dimethyl (2-methyl-2-propanyl) silyl) oxy) ethyl) -7'-hydroxy-11', 12'-dimethyl-3,4-di -hydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (225 mg, 0.297 mmol) and iodomethane (0.185 mL, 2.97 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was quenched with saturated aqueous NH. Cl (50 mL) and extracted with EtOAc (70 mL). The organic layer was separated, washed with brine (50 ml), dried over MgSOs, filtered and concentrated in vacuo, yielding water (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6- chloro-7 '- (2 - ((dimethyl (2-methyl-2-propanyl) silyl) oxy) ethyl) - 7T'-methoxy-11', 12'-dimethyl-3,4-dihydro -2H, 15'H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-crude dioxide that was used directly in the next step. MS (ESI, + ve) m / z 793.3 [M + Na] *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000541] [000541] Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.356 mL, 0.356 mmol) was added to a stirred solution of (18S, 3'R, 6'R, 7'S, 8'E, 11'S, 12 'R) -6- chloro-7' - (2 - ((dimethyl (2-methyl-2-propanyl) silyl) oxy) ethyl) - 7'-methoxy-11 ', 12'-dimethyl-3,4- dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (229 mg, 0.297 mmol) in tetrahydrofuran (1.5 mL). The reaction mixture was stirred at room temperature for 3.5 h. More tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.356 ml, 0.356 mmol) was added and the reaction mixture was stirred for an additional 3 h. The reaction mixture was concentrated. Chromatographic purification of the residue (silica gel, O to 100% (EtOAc with 0.3% AcCOH) in heptane) provided (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7 '- (2-hydroxyethyl) -7'-methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (178 mg, 0.271 mmol, 91% yield) as a white solid. ! H NMR (400 MHz, CHLOROFORM-d) & ppm 8.10 (1 H, s 7.68 (1 H, d, J = 8.61 Hz) 7.18 (1 H, dd, J = 8, 51, 2.25 Hz) 7.09 (1 H, d, J = 2.15 Hz) 6.88 - 6.96 (3 H, m) 5.75 - 5.83 (1 H, m) 5 , 64 (1 H, d, J = 16.24 Hz) 4.29 -— 4.37 (1 H, m) 4.02 - 4.15 (2 H, m) 3.91 - 3.99 ( 1 H, m) 3.80 - 3.88 (2 H, m) 3.72 (1 H, d, J = 14.28 Hz) 3.25 (1 H, d, J = 14.28 Hz) 3.11 (3 H, s) 3.02 (1 H, dd, J = 14.96, 10.66 Hz) 2.69 - 2.85 (2 H, m) 2.59 (1 H, q , J = 9.06 Hz) 2.34 - 2.47 (2 H, m) 2.12 - 2.24 (2 H, m) 1.76 - 2.06 (8 H, m) 1.58 - 1.67 (1 H, m) 1.50 (3 H, d, J = 7.04 Hz) 1.38 (1 H, t, J = 12.91 Hz) 1.06 (3 H, d , J = 6.85 Hz) MS (ESI, + ve) m / z 657.2 [M + H] *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetaldehyde
[000542] [000542] Dess-Martin periodinane (67.4 mg, 0.159 mmol) was added to a stirred mixture of (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6- chloro-7 '- (2-hydroxyethyl) - 7'-methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (87 mg, 0.13 mmol) and sodium bicarbonate (111 mg, 1.32 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was quenched with NaHCO; saturated aqueous solution (25 ml) and extracted with EtoOAc (30 ml). The organic layer was separated, washed with 1 M aqueous Naz2S203 (20 ml), washed with brine (20 ml), dried over MgSOs, filtered and concentrated in vacuo, yielding ((18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxide-15'-oxo-3,4-dihydro -2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetaldehyde raw material that was used directly in the next step.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic
[000543] [000543] A solution of monobasic potassium phosphate (361 mg, 2.66 mmol) and sodium chlorite (240 mg, 2.66 mmol) in water (2 mL) was added to a stirred mixture of ((18.3 'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11', 12'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetaldehyde (174 mg, 0.266 mmol) and 2-methyl-2-butene (1.407 mL, 13.28 mmol) in tert-butanol (2 mL). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with EtoAc (50 ml), washed with 1 M aqueous HCl (40 ml), washed with Na; zS20; 3 1 M (40 ml), washed with brine (40 ml), dried over MgSOs, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, O to 100% (EtOAc with 0.3% AcCOH) in heptane) provided acid ((18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R ) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxide-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 ' -
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic (142 mg, 0.212 mmol, 80% yield) as a white solid. 'H NMR (400 MHz, CHLOROPHORM-d) 5 ppm 8.11 (1 H, s) 7.68 (1 H, d, J = 8.41 Hz) 7.17 (1 H, d, J = 8 , 41 Hz) 7.08 (1 H, s) 6.87 - 6.95 (3 H, m) 5.80 - 5.90 (1 H, m) 5.72 (1 H, d, J = 15.85 Hz 4.36 (1 H, q, J = 7.17 Hz) 4.07 (2 H, s) 3.99 (1 H, d, J = 15.65 Hz) 3.71 (1 H, d, J = 14.48 Hz) 3.16 - 3.27 (5 H, m) 3.01 (1 H, dd, J = 15.55, 10.86 Hz) 2.71 - 2, 84 (3 H, m) 2.66 (1 H, q, J = 9.00 Hz) 2.42 (1 H, quin, J = 9.15 Hz) 2.12 - 2.26 (2H, m ) 2.01 - 2.09 (1 H, m) 1.83 - 2.01 (5 H, m) 1.79 (1 H, qd, J = 7.24 Hz) 1.57 - 1.69 (1 H, m) 1.51 (3 H, d, J = 7.04 Hz) 1.35 (1 H, t, J = 13.11 Hz) 1.06 (3 H, d, J = 6 , 65 Hz) MS (ESI, + ve) m / z 671.2 [M + H] *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N- (2-methoxyethyl) -N- methylacetamide
[000544] [000544] Acid ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'- methoxy-11 ', 12'-dimethyl-13', 13 '-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraen] -7'-yl) acetic ( 28 mg, 0.042 mmol) was collected in THF (0.5 mL) and lithium hydroxide (2.0 M in water, 0.083 mL, 0.17 mmol) was added. The mixture was stirred at room temperature for 10 min before being concentrated in vacuo, yielding the lithium carboxylate of the starting material as an off-white solid that was used in the amide coupling. HATU (31.7 mg, 0.083 mmol) and N- (2-methoxyethyl) methylamine (0.022 mL, 0.21 mmol) were added to a stirred suspension of the lithium carboxylate previously prepared in N, N-dimethylformamide (0.50 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH.KCl (20 ml) and extracted with EtoOAc (30 ml). The organic layer was separated, washed with brine (15 ml), dried over MgSOs, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, O to 100% (EtOAc with 0.3% AcOH) in heptane) followed by chromatographic purification (silica gel, O to 100% EtOAc in heptane) provided 2 - ((18.3 'R, 6'R, 7'S, 8'E, 11'S, 12'R) -
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N- (2-methoxyethyl) -N-methylacetamide (23 mg, 0.031 mmol, 74% yield) as a white solid. ! H NMR (400 MHz, CHLOROPHORMUM-d) & ppm 8.27 (0.4 H, s) 8.10 (0.6 H, s) 7.69 (1 H, d, J = 8.61 Hz 7.17 (1 H, dd, J = 8.41, 2.15 Hz) 7.08 (1 H, d, J = 1.96 Hz) 6.90 - 7.06 (3 H, m) 5 , 84 - 5.90 (1 H, m) 5.72 - 5.83 (1 H, m) 4.28 (0.6 H, q, J = 7.04 Hz) 4.19 (0.4 H, q, JI = 7.04 Hz) 4.05 (1.2 H, s) 4.04 (0.8 H, s) 3.95 (0.4 H, d, J = 10.17 Hz ) 3.91 (0.6 H, d, J = 10.17 Hz) 3.52 - 3.77 (4 H, m) 3.22 - 3.34 (7 H, m) 2.97 - 3 , 19 (6 H, m) 2.57 - 2.82 (4 H, m) 2.38 - 2.54 (1 H, m) 1.99 - 2.23 (4 H, m) 1.72 - 1.99 (5 H, m) 1.57 - 1.68 (1 H, m) 1.46 - 1.51 (3 H, m) 1.27 - 1.37 (1 HE, m) 1 , 04 - 1.11 (3 H, m). MS (ESI, + ve) m / z 742.2 [M + H] *. Example 100006 (18.3'R, 6'R, 7'S, 8 ' E, 11'S, 12'R) -7 '- (2- (1-azetidinyl) -2-oxoethyl) -6-chloro-7'-methoxy-11', 12'-dimethyl-3,4-dihydro - 2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000545] [000545] Acid ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-1'- methoxy-11 ', 12'-dimethyl-13', 13 '-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic (28 mg, 0.042 mmol) was collected in THF (0.5 mL) and lithium hydroxide (2.0 M in water, 0.083 mL, 0.17 mmol) was added. The mixture was stirred at room temperature for 10 min before being concentrated in vacuo, yielding the lithium carboxylate of the starting material as an off-white solid that was used in the amide coupling. HATU (31.7 mg, 0.083 mmol) and azetidine (0.014 mL, 0.209 mmol) were added to a stirred suspension of the lithium carboxylate previously prepared in N, N-dimethylformamide (0.25 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH2 Cl (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, washed with brine (10 ml), dried over MgSOs, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, O to 100% (EtOAc with 0.3% ACOH) in heptane) followed by chromatographic purification (silica gel, O to 100% EtOAc in heptane) provided (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7 '- (2- (1- azetidinyl) -2-oxoethyl) -6-chloro-7'-methoxy-11', 12'-dimethyl - 3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (22 mg, 0.031 mmol, 74% yield) as a white solid. 'H NMR (400 MHz, CHLOROPHORM-d) 5 ppm 8.21 (1 H, s
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 100007) and (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 ', 11', 12 '-trimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (Example 100016) o
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000546] [000546] Lanthanum (III) bis (lithium chloride) complex (0.5 M solution in THF, 0.616 mL, 0.308 mmol) was added to a stirred solution of (18.3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracycle [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13 ', 13'-dioxide (184 mg, 0.308 mmol) in tetrahydrofuran (3 mL) at 0 ° C. The mixture was stirred at 0 ° C for 45 min before methylmagnesium bromide (3.0 M solution in diethyl ether, 0.462 ml, 1.39 mmol) was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was quenched with saturated aqueous NH2 Cl (30 ml) and extracted with EtOAc (45 ml). The organic layer was separated, washed with brine (30 ml), dried over MgSOs, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, up to 75% O (EtOAc with 0.3% AcCOH) in heptane) provided (18.3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7'-hydroxy-7 ', 11', 12'-trimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (92 mg, 0.150 mmol, 49% yield), the second diastereomer to elute from the column, as a white solid. 'H NMR (400MHz, Dichloromethane-ds) 3 7.71 (d, J = 8.6 Hz, 1H), 7.18
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000547] [000547] (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-1'-hydroxy-7 ', 11', 12'-trimethyl-3,4 -di-hydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (33 mg, 0.054 mmol), 4- (2-bromoethyl) morpholine hydrobromide (296 mg, 1.08 mmol) and sodium hydride (60% dispersion in mineral oil, 86 mg, 2.2 mmol) were mixed in N, N-dimethylformamide (1.5 ml). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with saturated aqueous NH.Cl (20 ml) and extracted twice with EtOAc (30 ml). The combined organic layers were washed with brine (15 ml), dried over MgSO4s, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 50% to 100% EtOAc in DCM until the starting material eluted and then O to 10% (NH; 2 M in MeOH) in DCM) provided (1S, 3'R, 6 'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7', 11 ', 12'-trimethyl-7' - (2- (4-morpholinyl) ethoxy) -3,4- di -hydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (25 mg, 0.034 mmol, 64% yield) as an off-white solid. '! H NMR (400 MHz, CHLOROPHORMUM-d) 5 7.68 (1 H, qd, J = 8.41 Hz) 7.17 (1 H, dd, J = 8.41, 2.15 Hz) 7 .08 (1 H, d, J = 2.15 Hz) 6.89 - 6.96 (3 H, m) 5.82 (1 H, ddd, J = 15.85, 9.59, 2.74 Hz) 5.65 (1 H, d, J = 15.85 Hz) 4.29 (1 H, q, J = 7.11 Hz) 4.00 - 4.11 (2 H, m) 3.83 (1 H, d, J = 14.67 Hz) 3.68 - 3.77 (5 H, m) 3.33 - 3.46 (2 H, m) 3.26 (1 H, d, J = 14.28 Hz 3.00 (1 H, dd, J = 15.16, 10.66 Hz) 2.69 - 2.84 (2 H, m) 2.52 - 2.61 (6 H, m) 2.40 (1 H, quin, J = 8.95 Hz) 2.28 (1 H, q, J = 9.13 Hz) 1.74 - 2.21 (9 H, m) 1.52 - 1 , 64 (1 H, m) 1.48 (3 H, d, J = 7.04 Hz) 1.33 - 1.43 (4 H, m) 1.04 (3 H, d, J = 6, 85 Hz) .MS (ESI, + ve) m / z 726.3 [M + H] *. Example 100008 2 - (((18.3'R, 6'R, 7'S, 8'E, 11'S, 12 ' R) -6-chloro-7 '-methoxy-11', 12'-dimethyl-13 ', 13'-dioxide-l15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22 '-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N-methyl-N- (2-methyl-2-propanyl) acetamide x YZ XY = P DP HO FROG FROG cl cl
[000548] [000548] A drop of DMF was added to a stirred solution of oxalyl chloride (10 npL, 0.11 mmol) and acid ((18.3'R, 6'R, 7'S, 8'E, 11'S, 12 ' R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxide-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic (37 mg, 0.055 mmol) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 20 min before being concentrated in vacuo. The resulting yellow residue was taken up in dichloromethane (1 ml) and N-tert-butylmethylamine (0.066 ml, 0.55 mmol) was added. The reaction mixture was stirred at room temperature for 40 min. The reaction mixture was quenched with saturated aqueous NH «Cl (20 ml) and extracted with EtOAc (30 ml). The organic layer was separated, washed with brine (20 ml), dried over MgSOs, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, O to 50% (EtOAc with 0.3% AcOH) in heptane) provided 2 - ((1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12 ' R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22 '-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraen] -7'-yl) -N -methyl-N- (2-methyl-2-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N-methylacetamide> D + Cc! in AA o 3rd AA Re R -S = O TT, s. X -S = O
[000549] [000549] Acid ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-1'- methoxy-11 ', 12'-dimethyl-13', 13 '-dioxide-15'-ox0-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic (50 mg, 0.074 mmol) was collected in THF (2 mL) and lithium hydroxide (2.0
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraen] -7'-yl) -N -methylacetamide (44 mg, 0.064 mmol, 86% yield) as a white solid. ! H NMR (300 MHz, Dichloromethane-ds) 5 7.69 - 7.79 (m, 1 H) 7.19 (d ld, J = 8.84, 1.10 Hz, 1 H) 7.12 ( s, 1 H) 6.88 - 7.03 (m, 3 H) 6.74 - 6.86 (my, 1 H) 5.75 - 5.89 (my, 1 H) 5.62 - 5, 73 (my, 1 H) 4.21 - 4.36 (my, 1 H) 4.09 (s, 2 HE) 3.91 - 4.04 (m, 1 H) 3.72 (d 1, J = 15.05 Hz, 1 HE) 3.29 (d 1, J = 14.03 Hz, 1 H) 3.16 (s, 3 H) 2.92 - 3.09 (m, 2 H) 2, 73 - 2.90 (m,
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide to Q 2 OH ds OH e IS CI, RA e ÊP o - o - 5 N. S = o Stepi N. no Step 2 N & -o S no S in WD o o "o * Xy Example 100288 Example 100252
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate of methyl
[000550] [000550] A flame-dried round bottom flask was charged with tetrahydrofuran (6.28 mL) and lithium diisopropylamide (2.0 M solution in heptane / tetrahydrofuran / ethylbenzene, 7.54 mL, 15 , 1 mmol). The solution was cooled to -78 * C, then a solution of methyl acetate (1.197 ml, 15.07 mmol) in tetrahydrofuran (6.28 ml) was added dropwise and the reaction was stirred at -78 " ºC for 45 minutes. The flask was equipped with an addition funnel which was then charged with a solution of (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl -3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-11,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide (1.5 gq, 2.5 mmol) in tetrahydrofuran (12.56 ML). The reaction was stirred at -78 ° C for 30 minutes. The reaction was quenched with water and warmed to room temperature. The reaction was diluted with water and EtOAc and transferred to a separatory funnel. 1M HCl was added. The phases were mixed and the organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified via Flash chromatography on silica gel using a gradient of 20% to 70% EtOAc with 0.3% ACOH in heptane, giving rise to ((18.3'R, 6'R, 7'S8, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxide-l15'-oxo-3,4-dihydro-2H - spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate methyl (0.666 g, 0.992 mmol, 40% yield), the second diastereomer to elute, as a white solid. ! H NMR (300 MHz, DICLOROMETHANE-d :) à 8.06 - 8.25 (m, 1 H) 7.74 (d, J = 8.62 Hz, 1 H) 7.20 (d 1, J = 8.77 Hz, 1 H) 7.13 (s, 1 H) 6.96 (s, 2 H) 6.92 (s, 1 H) 5.64 - 5.81 (m, 2 H) 4 06 - 4.25
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000551] [000551] To a solution of ((15,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13 ', 13'-dioxide-15'-oxo- 3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate methyl (0.343 g, 0.511 mmol) in THF (10.22 mL) was added lithium hydroxide (2.0 M in water, 0.639 mL, 1.28 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and used without further purification. To a suspension of the lithium carboxylate previously generated in DMF (2.5 ml) was added HATU (0.069 g, 0.18 mmol) followed by pyrrolidine (0.050 ml, 0.60 mmol). The reaction was stirred at room temperature for minutes. The reaction was diluted with water and EtOAc and transferred to a separatory funnel. 1.0 M HCl was added and the phases were mixed. The organic layer was separated, then washed sequentially with 1.0M LiCl and brine, then dried over magnesium sulfate and concentrated under reduced pressure. Purification via Flash chromatography on silica gel using a gradient of 75% to 100% EtOAc with 0.3% AcOH in heptane gave (1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12 ' R) -6- chloro-7'-hydroxy-11 ', 12'-dimethyl-7' - (2-0ox0-2- (1-pyrrolidinyl) ethyl) -3,4-dihydro-2H, 15 ' H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.0608 gq, 0.086 mmol, 71% yield) as a white solid. MS (ESI, + ve) m / z 710.3 [M + H] *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000552] [000552] A solution of (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'- (2-0ox0-2- (1-pyrrolidinyl) ethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.0608 g, 0.086 mmol) in THF (0.856 mL) was cooled to 0 ° C prior to the addition of sodium hydride (0.017 g, 0.428 mmol). The reaction was stirred for 30 minutes, then iodomethane (0.053 ml, 0.856 mmol) was added and the reaction was warmed to room temperature and stirred for 1 hour. A larger portion of iodomethane (0.150 ml) was added and the reaction was allowed to stir at room temperature overnight. An additional portion of MeI (0.15 ml) was added and the reaction was continued at room temperature for 6 h. The reaction was quenched with water and diluted with water and EtOAc. The reaction was transferred to a separatory funnel and 1 M HCl was added. The phases were mixed and the organic layer was separated, washed with brine and dried over magnesium sulfate. The crude material was purified via Flash chromatography on silica gel using 100% EtOAc with 0.6% ACOH. The reaction was repeated a second time on the same scale and the material from both reactions was combined and further purified by preparative SFC supercritical fluid chromatography using the following conditions: Column Diol (21.2 x 250 mm, 5 µm); 20% MeOH with NH; 20 mM in CO ,, giving rise to (1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6- chloro-7'-methoxy-11 ', 12'-dimethyl- 7 '- (2-0x0-2- (1-pyrrolidinyl) ethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.018 g, 0.025 mmol, 15% yield) as a white solid. 'H NMR (300 MHz, DICLOROMETHANE-d;) 53 7.75 (d 1, J = 8.18 Hz, 1 H) 7.20 (d 1, J = 8.48 Hz, 1 H) 7.12 (s 1, 2 H) 7.00 - 7.06 (m, 1 H) 6.90 - 6.98 (m, 1 H) 5.75 - 5.99 (m, 2 H) 4.13 - 4.24 (my, 1 H) 4.10 (s, 2 HE) 3.86 - 3.96 (m, 1 H) 3.74 (d 1, J = 14.32 Hz, 1 H) 3, 57 - 3.68 (m, 2 H) 3.41 - 3.54 (m, 2 H) 3.34 (d 1, J = 14.62 Hz, 1 H) 3.07 - 3.25 (my , 4 E) 3.03 (d 1, J = 15.93 Hz, 1 H) 2.69 - 2.92 (m, 2 H) 2.46 - 2.67 (m, 2 H) 2.04 - 2.26 (my, 4 H) 1.74 - 2.03 (my, 9 H) 1.49 - 1.73 (my, 9 H) 1.46 (d 1, J = 6.72 Hz, 3 H) 1.29 - 1.41 (mM, 2 H) 1.03 - 1.14 (my, 3 H). MS (ESI, + ve) m / z 692.2 [M - OMe] *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide o aa oH a OMe Bd Stage to Beato Stage Bed Ss H * H * H o o
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000553] [000553] To a cooled (-78 ° C) solution of 4- (tert-butyldimethylsilyl) -1-butino (2.50 ml, 12.1 mmol) in tetrahydrofuran (30 ml) was added butyl lithium 2, 5 M in toluene (4.0 mL, 10 mmol) dropwise via syringe over a period of 15 min. After 1 h, a solution of (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-di-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide (1.008 g, 1.688 mmol) in THF (10 mL) was added dropwise and stirred for 1 h. The reaction was quenched with pH 7 buffer (10 mL) and warmed to room temperature. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine and dried over NaszSO0s. The solution was filtered, evaporated on silica gel and purified by Flash chromatography (Isco, 40 g) eluting with 0.3% ACOH in EtOAc: 0.3% ACOH in heptane (0: 1 to 1: 3), giving rise to (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-71 '- (4- ((dimethyl (2-methyl-2-propanyl) silyl) oxy) -l-butin-1-i11) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (468 mg, 36% yield) as a white solid. MS (ESI, + ve ion) m / z 763.4 (M + 1) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000554] [000554] To a cooled (0 ºC) solution of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (4- ((dimethyl ( 2-methyl-2-propanyl) silyl) oxy) -l-butin-11-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.510 g, 0.653 mmol) in tetrahydrofuran (10 mL) was added 60% sodium hydride in mineral oil (0.211 g, 5.28 mmol) in portions. After 15 min, iodomethane (0.160 ml, 2.58 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with pH 7 buffer and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x), then the combined organic layers were washed with brine, evaporated on silica gel and purified by Flash chromatography (Isco, 25 g) eluting with 0.3% AcCOH in EtOAc: AcCOH 0.3 % in heptane (0: 1 to 1: 3), giving rise to (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (4- ((dimethyl (2-methyl-2-propanyl) silyl) oxy) -l-butin-1-1-11) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15 'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (368 mg, 71% yield) as a white solid. MS (ESI, + ve ion) m / z 795.4 (M + 1) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000555] [000555] To a solution at room temperature of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (4- ((dimethyl (2-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.365 gq, 0.459 mmol) in tetrahydrofuran (5 mL) 1 M tetrabutylammonium fluoride in tetrahydrofuran (1.5 mL, 1.5 mmol) was added via syringe. The reaction was evaporated on silica gel and purified by Flash chromatography (Bait (HP 12 grams)) eluting with 0.3% ACOH in EtOAc: 0.3% AcOH in heptane (0: 1 to 1: 1), giving rise to (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (4-hydroxy-1-butin-1-i1) -7'-methoxy- 11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (279 mg, 89% yield) as a white solid. MS (ESI, + ve ion) m / z 681.3 (M + 1) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000556] [000556] To a cooled (0 ºC) solution of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (4-hydroxy-l- butin-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[20] [20] oxa [13] tia [1,14 diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide - OU (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7 '- (4- (4-morpholinyl) -l-butin-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide>> O o. o à oH oH o o o zo 0 + 0 -> EIB Stage Beka Beta Stage2 sn H = H = H o o + 2 o o Ae ”ú o o O + = o
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (4- ((dimethyl (2-methyl- 2-propanyl) silyl) oxy) -l-butin-11-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000557] [000557] To a cooled (-78 ° C) solution of 4- (tert-butyldimethylsilyloxy) -l-butino (0.600 mL, 2.91 mmol) in tetrahydrofuran (9 mL) was added 2.5 M butyl solution -lithium in toluene (1.00 mL, 2.50 mmol) dropwise over a period of 10 min. After 1 h, a solution of (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H , 7'H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide (0.249 g, 0.417 mmol) in THF (2 mL) was added dropwise via syringe. After 1 h, the reaction mixture was quenched with pH 7 buffer, partitioned between EtOAc and brine and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were evaporated on silica gel and purified by Flash chromatography (Isco, 12 g) eluting with 0.3% ACOH in EtOAc: 0.3% ACOH in heptane (0: 1 to 1: 3), giving rise to (1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-71'- (4- ((dimethyl (2-methyl-2-propanyl) silyl) oxy) -l-butin-l1-yl) - 7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-l1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (4- ((dimethyl (2-methyl- 2-propanyl) silyl) oxy) -l-butin-l1-yl1) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (254 mg, 78% yield) as a white solid. MS (ESI, + ve ion) m / z 784.5 (M + 1) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (4- ((dimethyl (2-methyl- 2-propanyl) silyl) oxy) -l-butin-11-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000558] [000558] To a cooled (0 ºC) solution of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (4 - ((dimethyl ( 2-methyl-2-propanyl) silyl) oxy) -l-butin-1-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.254 gq, 0.325 mmol) in tetrahydrofuran (5 mL) 60% NaH in mineral oil (0.105 g, 2.63 mmol) was added in portions. After 10 min, iodomethane (0.080 ml, 1.3 mmol) was added via syringe and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with pH 7 buffer and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x), then the combined organic layers were washed with brine, evaporated on silica gel and purified by Flash chromatography (Isco, 25 g) eluting with 0.3% AcOH in EtOAc: ACOH 0.3 % in heptane (0: 1 to 1: 3), giving rise to (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (4- ((dimethyl (2-methyl-2-propanyl) silyl) oxy) -l-butin-11-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15 'H-spiro [naphthalene- 1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (4 - ((dimethyl (2-methyl- 2-propanyl) silyl) oxy) -l-butin-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (173 mg, 67% yield) as a white solid. MS (ESI, + ve ion) m / z 796.3 (M + 1) *.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (4-hydroxy-l-butin-l1- il) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000559] [000559] To a solution at room temperature of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (4- ((dimethyl (2- methyl-2-propanyl) silyl) oxy) -l-butin-l1-11) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene - 1.22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (4 - ((dimethyl (2-methyl- 2-propanyl) silyl) oxy) -l-butin-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.173 gq, 0.217 mmol) in tetrahydrofuran (3 mL) was added 1 M solution of tetrabutylammonium fluoride in THF (0.700 mL, 0.700 mmol). The reaction was partitioned between EtOAc and brine and the organic layer was evaporated on silica gel and purified by Flash chromatography (Bait (12 grams)) eluting with 25% EtOH / EtOAc: heptane (0: 1 to 1: 0) giving gives rise to (1S8,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-71'- (4-hydroxy-l-butin-1-yl) -7'- methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '- (4-hydroxy-l-butin-l1- il) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (91 mg, 61% yield) as a white solid.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7 '- (4- (4-morpholinyl) -l-butin-1-i1) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide
[000560] [000560] To a cooled (0 ºC) solution of (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '- (4-hydroxy-l- butin-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide E
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (0.057 gq, 0.084 mmol) in dichloromethane (1.5 mL) was added triethylamine (0.060 mL, 0.43 mmol) followed by methanesulfonyl chloride (0.035 mL, 0.45 mmol) resulting in a mixture Yellow. After 15 min, morpholine (0.075 mL, 0.86 mmol) was added and the reaction was stirred for 1 h. To the reaction, morpholine (0.035 ml) was added and the reaction was stirred at room temperature overnight. The reaction mixture was partitioned between CHxCl; and brine and the aqueous layer was extracted with CH2Cl2, and brine (2x). The combined organic layers were dried over Naz2SO4s, filtered and concentrated under reduced pressure, yielding 110 mg of yellow tar. The material was purified following a 2-step SFC method: (Step 1: Cyan column, 20% isopropanol / NH; 20 mM 80 g / min Step 2: MSA column, 40% MeOH / NH; 20 mM), giving rise to to the first isomer to elute, (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7'- (4- (4-morpholinyl) -1-butin-1-i1) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- dimethyl-7 '- (4- (4-morpholinyl) -l-butin-1-1i1) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -7'-yl) -N, N-dimethylacetamide / CN, or oe RA, ci RA, -> o N. SPO S HO "o“ o Example 100013
[000561] [000561] N-butyl lithium solution (1.6 M in hexane, 0.83 mL, 1.3 mmol) was added to a solution of diisopropylamine (0.19 mL, 1.3 mmol) in THF (1.0 mL) at O ҼC.
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene] -7 ', 15'-diona 13 ', 13'-dioxide (0.040 g, 0.067 mmol) in THF (1.3 mL) was added and maintained at 0 ° C for 17 min. The reaction was quenched with saturated ammonium chloride solution and acidified with 1 N HCl to pH 2-3 and extracted with EtOAc. The organic phase was washed with brine and dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure, giving rise to the crude product which was purified by preparative SFC chromatography (CC4 column 250 mm x 21 mm, Phenomenex; 33 g / minute MeOH (2 M ammonia as a modifier) + 27 g / minute CO, in SFC Thar 200; discharge pressure = 100 bar; temperature = 40 ºC; wavelength = 246 nm; injection of 2.0 mL of sample 30 mg / mL 1: 1 DCM: MeOH (2.0 mL), giving rise to 2 - ((18,3'R, 6'R, 7'R, 11'S, 12'R) -6- chlorine -7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxide-15'-oxo-3,4-dihydro-2h-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -7'-yl) -N, N-dimethylacetamide (17 mg, 37% yield) as the first diastereomer to elute. 1H NMR (400MHz, DICLOROMETHANE-d2) 53 7.71 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 2.2, 8.5 Hz, 1H), 7.09 ( d, J = 2.2 Hz, 1H), 7.04 - 6.98 (m, 2H), 6.97 - 6.91 (m, 1H), 5.23 (s l1, 1H), 4, 17 - 4.06 (m, 3H), 3.68 (d, J = 14.3 Hz, 1H), 3.58 (dy, J = 15.3 Hz,
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide o 4, OH A QE slap NS Ftapa NES S Ho S HO S Ho ooo Example 100016 Example 100014 Step 1: (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-CHLORINE-7'- HYDROXY-7 ' , 11 ', 12'-TRIMETHYL-3,4-DI-HYDRO-2H, 15'H- SPIRUS [NAFTALENE-1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13 ', 13'-DIOXIDE
[000562] [000562] (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-Chlorine-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H , 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- diona 13 ', 13'-dioxide (200 mag, 0.335 mmol) was dissolved in THF (3.00 mL) and cooled to 0 ° C. Lanthanum (III) bis (lithium chloride) complex solution (0.6 M in THF, 0.63 mL,
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' .13'-dioxide (124 mg, 60% yield) as the second diastereomer to elute. MS (ESI, + ve ion) m / z 613.1 (M + 1) *.
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3.6> -. 0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13 ', 13'-DIOXIDE.
[000563] [000563] (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chlorine-71'-hydroxy-7 ', 11', 12'-trimethyl-3,4 -di-hydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (29 mg, 95% yield). ! H NMR (400MHz, DMSO-ds) 5 11.89 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.27 (dd, J = 2.1, 8, 5 Hz, 1H), 7.17 (dy, J = 2.0 Hz, 1H), 7.03 (dd, Jel, 5, 8.1 Hz, 1H), 6.89 (dy, J = 8, 2 Hz, 1H), 6.79 (s, 1H), 5.72 (dd, J = 3.2, 9.3 Hz, 1H), 5.65 - 5.55 (my, 1H), 4, 16 - 4.08 (m, 1H), 4.07 - 3.94 (m, 2H), 3.69 (d, J = 14.7 Hz, 1H), 3.59 (d, J = 14, 3 Hz, 1H), 3.24 (dy, J = 14.3 Hz, 1H), 3.08 (dd, J = 9.6, 14.7 Hz, 1H), 2.94
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-22 ', 1' '- naphthalen] -15'-one 13 ', 13'-dioxide OR (2R, 3'R, 6'R, 11'S, 12'R, 22'S) -6' '- chlorine- 11', 12'-dimethyl-3 '' , 4 '' - dihydro-2''H, 15'H-diespiro [1,4-dioxane-2,7'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-22 ', 1' '- naphthalen] -15'-one 13 ', 13'-dioxide oH pH CI CI. CC! o o Stage the N. and the Step N 2 $ = o Pp N. $ = o v o à o ACE o “o“ o "o
[20] [20] OXA [13] TIA [1, 14] DIAZATETRACYCLE [14.7.2. -3,6-.0-19,24-] PENTACOSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13 '-DIOXIDE
[000564] [000564] A solution of methyltriphenylphosphonium bromide (1.80 g, 5.0 mmol) in THF (15 mL) was cooled to O “ºC. N-butyllithium solution (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added dropwise and the solution was stirred at O “C for 10 minutes. The solution was added dropwise to a solution of (18,3'R, 6'R, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H , 7'H, 15'H-spiro [naphthalene-l1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [16,18,24] triene] -7 ', 15'-diona 13' , 13'-dioxide (0.30 g, 0.50 mmol) in THF (6.0 mL), cooled in an ice bath, until the yellow color persists. The solution was stirred at 0 ° C for 12 min. The reaction mixture was added to stirred ice water (20 ml) and acidified with 1 N HCl to pH 2-4. The organic phase was separated and the aqueous was extracted with EtoOAc (50 ml). The organic phase was washed with brine and dried over magnesium sulfate. The filtrate was concentrated, yielding crude product. The compound was purified by chromatography (silica, up to 50% EtOAc (HOAC 0.3%: hexanes), giving rise to (1S8,3'R, 6'R, 8'E, 11'S, 12'R) - 6- chloro-11 ', 12'-dimethyl-7'-methylidene-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (290 mg, 97% yield). MS (ESI, + ve ion) m / z 595.2 (M + H) *.
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.03 -6,019,24] PENTA- COSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE
[000565] [000565] The AD-Mix-alpha mixture (640 mg, 0.43 mmol) was dissolved in a mixture of tert-butanol (10.0 mL) and water (10.0 mL) and cooled to 0 ºC. (18,3'R, 6'R, 8'E, 11'S, 12'R) - 6-Chlorine-11 ', 12'-dimethyl-7'-methylidene-3,4-dihydro-2H, 15 'H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (255 mg, 0.428 mmol) was added and the reaction mixture was slowly warmed to room temperature overnight. An additional 5.0 mL of t-BuoH was added to homogenize the mixture. The reaction was stirred overnight. Another 320 mg of AD-Mix-alpha mixture was added and the reaction was stirred for another three days. The reaction was quenched by adding 575 mg of sodium sulfite at 0 ºC and stirring for 45 minutes. The mixture was then extracted with EtoAc (2 x 25 ml). The combined organic layers were washed with brine (1 x 20 ml) and dried over sodium sulfate. The crude product was then purified by chromatography (silica, O to 100% EtOAc (+ 0.3% HOAc): heptanes), yielding (1S8,3'R, 6'R, 8'E, 11'S, 12 'R) -6-chloro-7'-hydroxy-7'- (hydroxymethyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 ' -
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (31 mg, 12% yield). MS (ESI, + ve ion) m / z 629.2 (M + H) *.
[20] [20] OXA [13] TIA [1.14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24-] PENTACOSA [16,18,24] TRIEN] -15'-ONA 13 ', 13'-DIOXIDE
[000566] [000566] (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-Chlorine-7'-hydroxy-7'- (hydroxymethyl) -11 ', 12'-dimethyl-3 , 4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]] Jpentacosa [8,16,18,24] tetraen] -15 '-one 13 ', 13'-dioxide (30.0 mg, 0.048 mmol) was dissolved in THF (1.0 mL) and cooled to 0 ° C. Sodium hydride (60% dispersion, 19.0 mg, 0.48 mmol) was added and the resulting slurry was stirred for ten minutes, then 2-bromoethyl trifluoromethanesulfonate (Ark Pharm Inc.) (61 mg, 0.24 mmol ) was added and the reaction was allowed to warm slowly to room temperature over 45 minutes. The reaction was then quenched with slow addition of water (5 ml) and the mixture was extracted (2 x 25 ml) with ethyl acetate. The combined organic layers were washed with brine (1 x 15 ml) and then dried over magnesium sulfate. The residue was then purified by chromatography (silica, O to 50% EtOAc (+ 0.3% HOAC): hexanes), yielding (18.3'R, 6'R, 11'S, 12'R) -7 '- (((2-bromoethoxy) methyl) -6-chloro-7'-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 ' -
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 '-dioxide (25 mg, 71% yield). MS (ESI, + ve ion) m / z 739.1 (M + H) *.
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24-] PENTACOSA [16,18,24] TRIENO-22 ', 1' '- NAFTALEN ] -15 '-ONA 13', 13'-DIOXIDE OR (2R, 3'R, 6'R, 11'S, 12'R, 22'S) -6 '' -CHLORINE- 11 ', 12' -DIMETHYL-3 ' ', 4' '- DI-HYDRO-2' 'H, 15'H-DIESPIRO [1,4- DIOXAN-2,7'-
[20] [20] OXA [13] TIA [1.14] DIAZATETRACYCLE [14.7.2.0-3,6> -. 0-19,24- PENTACOSA [16,18,24] TRIENO-22 ', 1' '- NAFTALEN] -15'-ONA 13 ', 13' -DIOXIDE
[000567] [000567] (18,3'R, 6'R, 11'S, 12'R) -7 '- ((2-Bromoethoxy) methyl) - 6-chloro-7'-hydroxy-11', 12'-dimethyl- 3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] trien] -15'-one 13 ', 13 Dioxide (25.0 mg, 0.034 mmol) was then dissolved in DMF (0.5 mL) and sodium hydride (60% dispersion, 19 mg, 0.48 mmol) was added. This mixture was then heated to 85 ҼC for 10 minutes. The reaction mixture was then cooled to room temperature and quenched with the dropwise addition of water (5 ml). This mixture was extracted with ethyl acetate (2 x 20 ml). The combined organic layers were washed with 1 N LiCl solution (1 x 15 ml) and brine (1 x 10 ml) and dried over magnesium sulfate. The crude product was purified by chromatography (silica, O to 50% EtOAc (+ 0.3% HOAC): hexanes), giving (28.3'R, 6'R, 11'S, 12'R, 22'S) -6 '' "-chloro-11 ', 12'-dimethyl- 3' ', 4' '- dihydro-2''H, 15'H-dispyro [1,4-dioxane-2,7'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-22 ', 1' '- naphthalen] -15'-one 13 ', 13'-dioxide or (2R, 3'R, 6'R, 11'S, 12'R, 22'S) -6' '- chlorine-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene-22 ', 1' '- naphthalen] -15'-one 13 ', 13'-dioxide (14 mg, 45% yield). 'H NMR (400MHz, Me0OH) at 7.73 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 2.2, 8.4 Hz, 1H), 7.13 - 7 , 08 (m, 2H), 7.02 (d, J = 1.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 4.08 (s, 2H), 4 , 06 - 4.01 (m, 1H), 3.76 (d, J = 11.9 Hz, 2H), 3.73 - 3.59 (m, 4H), 3.58 - 3.49 (m , 1H), 3.46 - 3.38 (m, 1H), 3.23 - 3.15 (my, 1H), 3.10 (dd, J = 9.1, 15.4 Hz, 1H), 2.86 - 2.68 (m, 2H), 2.62 - 2.50 (m, 1H), 2.11 - 2.03 (my, 1H), 1.96 - 1.84 (m, 3H ), 1.76 - 1.51 (m, 7H) 1.49 - 1.40 (m, 1H), 1.36 (d, J = 7.0 Hz, 3H), 1.34 - 1.27 (m, 2H), 1.23 - 1.19 (m, 2H), 1.01 (d, J = 6.8 Hz, 3H). MS (ESI, + ve ion) m / z 657.2 (M + H) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7 '- (4- (4-morpholinyl) -l-butin-1-11) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide oo E, and [=] 4X and REA of TT Re> ão ”Re SO + H s HS o by Example 100017 by
[000568] [000568] To a cooled (-78 ° C) solution of 4- (but-3-in-1-yl) morpholine (0.163 g, 1.171 mmol) in tetrahydrofuran (3 mL) was added 2.5 M solution of butyl lithium in toluene (0.400 mL, 1.00 mmol) dropwise via syringe. After 45 min, a solution of (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H , 7'H, 15'H-spiro [naphthalene-l1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide (0.100 g, 0.167 mmol) in THF (1 ml) was added dropwise. After 1 h, the reaction was quenched with saturated NH2 Cl (3 mL) and the mixture was warmed to room temperature. The mixture was extracted with dichloromethane (3x) and the combined organic layers were washed with brine and dried over NaszSOs. The solution was filtered and the filtrate was concentrated under reduced pressure, giving an orange oil. The crude material was purified by preparative SFC (Waters Thar 200; Column Cyan (21.1x250 mm, 5 µm) with 18% methanol (NH; 20 mM), 82% carbon dioxide; flow rate = 95 mL / min, column temperature = 40 ºC, pressure = 100 bar, detection at 220 nm), giving rise to the first diastereomer to elute, (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R ) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7' - (4- (4-morpholinyl) -1-butin-1-yl1) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7 '- (4- (4-morpholinyl) -l-butin-1-1i1) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (32 mg, 26%) as a white solid. 'H NMR (400 MHz, CD2Cl2) d 7.72 (d, J = 8.41 Hz, 1 H), 7.13 -— 7.24 (m, 2 H), 7.09 (d, J = 1.96 Hz, 1 H), 6.83 - 6.96 (m, 2 H), 6.25 - 6.41 (my, 1 H), 5.75 (d, J = 15.26 Hz, 1 H), 4.38 (d, J = 15.06 Hz, 1 H), 4.29 (q, J = 7.37 Hz, 1 H), 3.97 - 4.13 (my, 2 H ), 3.69 (d, J = 14.08 Hz, 1 H), 3.58 (t, J = 4.69 Hz, 4 H), 3.26 (d, J = 14.28 Hz, 1 H), 3.00 (dd, J = 15.26, 10.37 Hz, 1 H), 2.47 - 2.87 (m, 7 H), 2.29 - 2.46 (my, 5 H ), 1.80 - 2.21 (my, 9 H), 1.61 - 1.72 (my, 1 H), 1.44 (dy, J = 7.24 Hz, 3 HH), 1.33 - 1.41 (mM, 1 H), 1.03 (d, J = 6.85 Hz, 3 H). MS (ESI, + ve ion) m / z 736.2 (M + 1) *. Example 100018 (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7' - (3- ( 4-morpholinyl) -1-propin-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7 '- (3- (4-morpholinyl) -l-propin-11-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide o. O.
[000569] [000569] To a cooled (-78 "C) solution of 4- (prop-2-in-1-yl) morpholine (0.170 mL, 1.35 mmol, Ark Pharm, Inc,) in tetrahydrofuran (3 mL ) butyl lithium solution (2.5 M in toluene, 0.500 mL, 1.25 mmol) was added dropwise via syringe. After 45 min, a solution of (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H , 7'H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide (0.100 g, 0.167 mmol) in THF (1 ml) was added dropwise. After 1 h, the reaction was quenched with saturated NH2 Cl (3 mL) and the mixture was warmed to room temperature. The mixture was extracted with DCM (3x) and the combined organic layers were washed with brine and dried over NasSOs. The solution was filtered and the filtrate was concentrated under reduced pressure, giving a yellow oil. The crude material was purified using preparative SFC (Premier (2 x 25 cm); 50% methanol / COs, 100 bar; 50 mL / min, 254 nm), giving rise to the first isomer to elute, (18.3'R , 6'R, 7'S, 8'E, 11'S, 12'R) - 6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7' - (3- (4-morpholinyl) -1-1- propin -1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide (40 mg, 33% yield) as a solid. 'H NMR (400 MHz, CD2Cl2) 3 7.71 (d, J = 8.41 Hz, 1 H), 7.12 - 7.23 (Mm, 2 H), 7.09 (d, J = 2 , 15 Hz, 1 H), 6.84 - 6.97 (m, 2 H), 6.22 - 6.40 (m, 1 H), 5.78 (d, J = 14.87 Hz, 1 Hd), 4.25 (dy, J = 14.67 Hz, 2 H), 4.07 (s, 2 H), 3.70 (d, J = 14.28 Hz, 1 H), 3.59 - 3.66 (my, 4 H), 3.56 (s, 2 H), 3.25 (dy, J = 14.08 Hz, 1 E), 3.02 (dd, J = 15.16, 10.47 Hz, 1 HH), 2.67 - 2.89 (m, 2 É), 2.51 - 2.65 (my, 5 HE), 2.33 - 2.49 (my, 1 H) , 2.02 - 2.16 (Mm, 4 H), 1.76 - 2.01 (my, 7 HH), 1.62 - 1.73 (m, 1 HH), 1.43 (d, J = 7.04 Hz, 3 H), 1.34 - 1.41 (my, 1 H), 1.04 (d, J = 6.46 Hz, 3 H). MS (ESI, + ve ion) m / z 722.2 (M + 1) *.
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7'- ((2S) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7 '- ((2S) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7 '- ((2R) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide 2 and AR
[000570] [000570] To a solution of diisopropylamine (1.183 mL, 8.44 mmol) in tetrahydrofuran (4.22 mL) to O “C was added butyl lithium (2.5 M in hexanes, 3.38 mL) , 8.44 mmol) for 3 minutes. The solution was then cooled to -78 "ºC. 4-Methyl-morpholin-3-one (0.887 ml, 8.44 mmol) was added dropwise and the solution was allowed to stir for 1 hour. (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-Chlorine-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15' H-spiro [naphthalene-l1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide (0.252 g, 0.422 mmol) in a 0.5 mL solution of THF was added dropwise. After completion, saturated aqueous ammonium chloride solution was added. 1 N HCl was added until the pH reached 2-3 and the solution was extracted with EtOAc. The organic extract was washed with saturated NaCl, dried over Na7SO4: filtered and concentrated in vacuo. The crude product was adsorbed on a silica gel buffer and chromatographed through a Biotage SNAP Ultra silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc: EtOH (3: 1) in hexane with 0.5% AcOH. The material was further purified by preparative SFC using an achiral Me-sulfone column (21x150 mm, 5 µm), 60% methanol with NH; 20 mM, flow rate 60 mL / min, column temperature 40 ºC, pressure 100 bar, detection at 220 nm. The third isomer to elute was isolated, giving rise to (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7 '- ((2R) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7'- ((2S) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7 '- (((2S) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' , 13'-dioxide OR (18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-7 '- ((2R) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one. 1H NMR (400 MHz, DMSO-ds) at 0.92 (d, J = 6.06 Hz, 3 H) 1.02 (s 1, 2 H) 1.36 (t, J = 12.72 Hz, 1 H) 1.61 (s 1, 3 H) 1.87 (s 1, 3 H) 1.92 - 2.13 (m, 3 H) 2.25 (d, J = 7.63 Hz, 1 H) 2.62 - 2.79 (m, 2 H) 2.84 (s, 3 H) 2.86 - 3.06 (my, 3 H) 3.29 (s 1, 1 H) 3.55 (d, J = 13.50 Hz, 1 H) 3.71 (s 1, 1 H) 3.79 -— 4.01 (m, 4 H) 4.10 (dy, J = 13.30 Hz, 1 H) 4.26 (s 1, 1 H) 5.33 (s 1, 1 H) 5.71 (dy, J = 15.45 Hz, 1 HE) 6.17 (s 1, 1 H) 6 , 67 -— 6.84 (my, 1 H) 6.98 - 7.41 (m, 4 H) 7.65 (d, J = 8.61 Hz, 1 H). MS (ESI, + ve ion) m / z 712.2 (M + 1) *. Example 100020 1 - ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13 '-dioxide-15'-ox0-3,4-dihydro-2H- spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N, N- dimethylmethanesulfonamide OR 1- ((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-13 ', 13'-dioxide-l15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N, N-dimethylmethanesulfonamide
[000571] [000571] To a solution of N, N-dimethylmethanesulfonamide (206 mg, 1.68 mmol) in 2-methyltetrahydrofuran (4 mL) at 0 ° C was added n-butyllithium (1.6 M in hexanes, 0 , 67 mL, 1.7 mmol) and the reaction was stirred at O “ºC for 5 min. (18,3'R, 6'R, 8'E, 11'S, 12'R) -6-Chlorine-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15' H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'- dione 13 ', 13'-dioxide (100 mg, 0.167 mmol) in 2-methyltetrahydrofuran (1 ml) was added at low temperature and, after 15 min, the system was quenched with saturated aqueous NH «Cl (50 ml) , brine (50 ml) and EtOAc (100 ml). The organic layer was separated, dried (Na2zSOs), filtered and concentrated on silica. Purification by chromatography on silica gel (0 to 100% EtOAc (0.3% ACOH) in heptane gave 1 - ((1S8,3'R, 6'R, 7'R, 8'E, 11'S, 12 'R) - 6-chloro-7'-hydroxy-11', 12'-dimethyl-13 ', 13'-dioxide-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1, 22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N, N- dimethylmethanesulfonamide and 1- ((18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl- 13 ', 13'-dioxide-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0-3,6-.0-19,24-]
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N, N- dimethylmethanesulfonamide OR 1- ((18,3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- dimethyl-13 ', 13'-dioxide-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) - N, N-dimethylmethanesulfonamide (10 mg, 0.014 mmol, 8% yield), was isolated. ! H NMR (400 MHz, CHLOROPHORMUM-d) 3 7.69 (d, J = 8.41 Hz, 1H), 7.17 (dd, J = 2.25, 8.51 Hz, 1H), 7, 09 (d, J = 2.15 Hz, 1H), 6.94 (s, 2H), 6.87 (s, 1H), 5.68-5.80 (m, 2H), 4.00-4 , 22 (m, 4H), 3.67-3.83 (m, 2H), 3.57 (d 1, J = 14.48 Hz, 1H), 3.20-3.32 (m, 2H) , 3.05-3.16 (m, 1H) 2.96 (s, 6H), 2.89-2.93 (m, 1H), 2.69-2.83 (m, 2H), 2, 38-2.50 (m, 1H), 2.03-2.17 (m, 3H), 1.85-2.02 (m, 3H), 1.727 1.84 (m, 2H), 1.58 -1.70 (m, 2H), 1.46 (d, J = 7.24 Hz, 3H) 1.32-1.41 (my, 1H), 1.06 (dy, J = 6.06 Hz , 3H). An interchangeable proton was not observed. MS (ESI, + ve ion) m / z 720.2 (M + H) *.
[000572] [000572] Table 2 lists compounds prepared by the General Methods outlined in this specification. TABLE 2: Examples Prepared by the General Methods The resulting homogeneous was heated to reflux for 18 h. The reaction mixture was cooled to O * C in an ice water bath and quenched with sodium sulfate decahydrate. The resulting mixture was filtered through Celite, rinsing with THF. Concentration of the filtrate gave N-methyl-2-morpholinoethanamine which was used without further purification. (38) -1-Cyclobutyl-3-methyl-hex-5-ene-2-sulfonamide usa 8 ((((Do -> ye,: OA - SP É Stage 1 .ots - Stage2 PMB Stage 3 Rs Stage 4 “ x It is due to PB HoN Step 1. (R) -4-methylbenzenesulfonate of pent-4-en-2-yl
[000575] [000575] To a solution of vinylmagnesium bromide (226 9, 1722 mmol, 1.0 M in THF) was added CuI (29.5 g, 155 mmol, 0.09 equiv) in THF (200 mL) at 40 ° C . The reaction mixture was stirred for 30 min followed by the addition of a cooled solution of (R) -2-methyloxyrane (100 gq, 1722 mmol in THF (500 mL) dropwise at the same temperature. The resulting reaction mixture was stirred at - 40 º * C for 1 h After completion of the reaction (monitored by TLC) triethylamine (261 g, 2583 mmol) was added at -40 "ºC. After 30 min, cooled solution of pr toluenesulfonyl chloride (427 g, 2238 mmol) in THF (1000 mL) was added slowly to the reaction mixture at the same temperature and stirred for 16 h at room temperature After completion of the reaction (monitored by TLC), the reaction mixture was quenched with 1.5 N HCl solution to pH 3.0 The resulting reaction mixture was filtered through a pad of Celite, layers were separated and the aqueous layer was re-extracted with ethyl acetate (2 x 2000 mL). The combined organic layers were washed with water (800 mL), brine (500 mL), dried over Na7szSOs and concentrated under reduced pressure. crude product was purified by Flash column chromatography (silica gel, 230-400 mesh) using 1% to 2% ethyl acetate in petroleum ether, yielding pent-4-en (R) -4-methylbenzenesulfonate -2-yl (207 g, 50% yield) as a colorless liquid. 'H NMR (300 MHz, Chloroform-d) 53 7.83 - 7.75 (m, 2H), 7.37 - 7.31 (m, 2H), 5.69 -— 5.52 (my, 1H ), 5.09 - 5.04 (m, 1H), 5.01 (t, J = 1.3 Hz, 1H), 4.65 (h, J = 6.3 Hz, 18), 2.45 (s, 3H), 2.37 - 2.22 (my, 2H), 1.26 (dy, J = 6.3 Hz, 3H).
[000576] [000576] To a stirred solution of N, N-bis (4-methoxybenzyl) methanesulfonamide (207 g, 617 mmol) in THF (2000 mL) was added n-BuLi (321 mL, 802 mmol, 2.5 M in hexane ) at -78 ºC. The resulting reaction mixture was stirred for 1 h at the same temperature, followed by dropwise addition of (R) -4-methylbenzenesulfonate of pent-4-en-2-yl (206 g, 858 mmol) in THF (400 ml) to -78 "C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 2000 mL). The combined organic layers were washed with water (1000 ml), brine (600 ml), dried over Na7sSOs, filtered and concentrated under reduced pressure. The crude product was purified by Flash column chromatography (silica gel, 230-400 mesh) using 2% to 4% ethyl acetate in petroleum ether, giving (S) -N, N-bis (4- methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide (105 gq, 42% yield) as a colorless liquid. 1 H NMR (400 MHz, Chloroform-d) 5 7.25 - 7.20 (m, 4H), 6.92 - 6.85 (m, 4H) 5.70 (ddt, J = 17.2, 10 , 2, 7.1 Hz, 1H), 5.12 - 4.98 (m, 2H), 4.32 - 4.19 (m, 4H), 3.83 (s, 6H), 2.90 - 2.80 (m, 1H), 2.66 - 2.55 (my, 1H), 2.27 - 2.17 (my, 1H), 2.17 - 2.02 (m, 2H) 1.11 (dy, J = 6.7, 3H).
[000577] [000577] To a stirred solution of (S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide (40 g, 99 mmol) in THF (400 mL) was added n -butyl lithium (86.73 mL, 139 mmol, 1.6 M in hexane) at -78 "* C. The reaction mixture was allowed to stir for 20 min at the same temperature. (Bromomethyl) cyclobutane (59.1 g, 396 mmol) was added dropwise at the same temperature and stirred for 30 min. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 400 mL). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over NazSOs, filtered and concentrated under reduced pressure. The crude product was purified by Flash column chromatography (silica gel, 230-400 mesh) using 2% up to
[000578] [000578] To a stirred solution of (3S) -1-cyclobutyl-N, N-bis (4-methoxybenzyl) -3-methyl-hex-5-ene-2-sulfonamide (33 g, 70.0 mmol), anisole (33 mL) and TFA (33 mL) at 0 ° C. The resulting reaction mixture was heated to 40 ° C for 16 h. After the reaction was completed (monitored by TLC), volatiles were removed in vacuo and the crude product was purified by Flash column chromatography (silica gel, 230-400 mesh) using 15% to 20% ethyl acetate in ether of petroleum as eluent, giving rise to (3S) -1-cyclobutyl-3-methyl-hex-5-ene-2-sulfonamide which was further purified by HPLC [Sunfire C18 column (250 mm x 19 mm) 5 um, formic acid 0.1% in water and acetonitrile, 90 mg / injection, ELSD detector, processing time 35 min.], Giving rise to (38) -1-cyclobutyl-3-methyl-hex-5-ene-2-sulfonamide ( 10.3 g, 64% yield) as a colorless liquid. MS (ESI, -ve ion) m / z 230 (M-H). 'H NMR (400 MHz, DMSO-ds) 3 6.78 (d, J = 9.1 Hz, 2H), 5.73 (tdd, I = 12.4, 10.1, 6.5 Hz, 1H ), 5.05 (tt, J = 17.7, 4.5 Hz, 2H), 2.70 -— 2.54 (m, 2H), 2.30 (p, J = 7.1 Hz, 1H ), 2.00 (da, I
[000579] [000579] To a cooled paste (0 ºC) of 60% sodium hydride in mineral oil (0.600 g, 15.00 mmol) in THF (40 mL) was added a solution of 1-Boc-3-oxopiperazine (2, 0 g, 9.99 mmol; Combi-Blocks, San Diego, CA) in N, N-dimethylformamide (10 mL). After the addition was complete, the reaction was allowed to warm to room temperature for 30 min. The mixture was cooled to 0 ºC and treated with 1-bromo-2-butino (1.2 ml, 13.71 mmol). The reaction was allowed to warm to r.t. for 30 min. The reaction was quenched with saturated NH.Cl solution, partitioned between EtOAc / brine and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over NazSOs, filtered and the filtrate was concentrated under reduced pressure, yielding tert-butyl 4- (but-2-in-1-yl) -3-oxopiperazine-1-carboxylate as a light brown liquid.
[000580] [000580] To a solution at room temperature of tert-butyl 4- (but-2-in-1-yl) -3-oxopiperazine-1-carboxylate (2.52 g, 9.99 mmol) in DCM (40 ml), trifluoroacetic acid (10 ml, 135 mmol) was added via syringe. After 1 h, the
[000582] [000582] To a suspension at room temperature of 1-boc-3-oxopiperazine (2.0 g, 9.99 mmol; Combi-Blocks, San Diego, CA), tetrabutylammonium bromide (0.620 g, 1.923 mmol) and hydroxide potassium (1.42 g, 25.3 mmol) in THF (25 mL) 4- (2-bromoethyl) morpholine hydrobromide (2.78 g, 10.11 mmol; Combi-Blocks, San Diego, CA ) as a solid. After stirring at room temperature overnight, the mixture was filtered and the filtrate was evaporated on silica gel and purified by Flash chromatography (Bait, (80 grams)) eluting with NH; 2 M in MeOH: CH.Cl7 (0: 1 - 1: 9), yielding tert-butyl 4- (2-morpholinoethyl) -3-oxopiperazine-1-carboxylate (1.923 g, 61% yield) in form of a solid. MS (ESI, + ve ion) m / z 314.3 (M + 1) *.
[000583] [000583] To a solution at room temperature of tert-butyl 4- (2-morpholinoethyl) -3-oxopiperazine-1-carboxylate (1.84 g, 5.87 mmol) in DCM (15 mL) was added trifluoroacetic acid (5 mL). After 3 h, the solvent was removed under reduced pressure and the residue was dissolved in DCM and loaded in a Si-propylsulfonic acid buffer (Silicycle) and the buffer was washed with 1: 1 MeOH / DCM until NH; 2 M in MeOH / DCM. Fractions containing the desired product were concentrated under reduced pressure, giving 1- (2-morpholinoethyl) piperazin-2-one (1.52 g) as a yellow oil. MS (ESI, + ve ion) m / z 214.1 (M + 1) *. (28,38) - 3-Methyl-11-phenyl-hex-5-ene-2-sulfonamide E (2R, 3S) - 3-methyl-1-phenyl-hex-5-ene-2-sulfonamide
[000584] [000584] To a solution of vinylmagnesium bromide (226 g, 1722 mmol, 1.0 M in THF) was added CuI (29.5 g, 155 mmol) in THF (200 mL) at - 40 ° C. The reaction mixture was stirred for 30 min followed by the dropwise addition of a cooled solution of (R) -2-methyloxyrane (100 g, 1722 mmol) in THF (500 mL) at the same temperature. The resulting reaction mixture was stirred at 40 ° C for 1 h. After the reaction was completed (monitored by TLC), triethylamine (261 g, 2583 mmol) was added at -40 “C. After 30 min, cooled solution of p-toluenesulfonyl chloride (427 g, 2238 mmol) in THF (1000 mL) was added slowly to the reaction mixture at the same temperature and stirred for 16 h at room temperature. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with 1.5 N HCl solution until pH 3.0. The resulting reaction mixture was filtered through a pad of Celite, layers were separated and the aqueous layer was re-extracted with ethyl acetate (2 x 2000 ml). The combined organic layers were washed with water (800 ml), brine (500 ml), dried over Na; zSOs and concentrated under reduced pressure. The crude product was purified by column chromatography
[000585] [000585] To a stirred solution of N, N-bis (4-methoxybenzyl) methanesulfonamide (207 g, 617 mmol, 1.0 equiv) in THF (2000 mL) was added n-BuLi (321 mL, 802 mmol, 2 , 5 M in hexane) at -78 ° C. The resulting reaction mixture was stirred for 1 h at the same temperature followed by dropwise addition of (R) -4-methylbenzenesulfonate of pent-4-en-2-yl (206 g, 858 mmol) in THF (400 ml) at -78 ºC. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 2000 mL). The combined organic layers were washed with water (1000 ml), brine (600 ml), dried over Na> zSO:., Filtered and concentrated under reduced pressure. The crude product was purified by Flash column chromatography (silica gel, 230-400 mesh) using 2% to 4% ethyl acetate in petroleum ether, giving (S) -N, N-bis (4- methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide (105 g, 42.2%
[000586] [000586] To a stirred solution of (S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide (65 gq, 161 mmol) in THF (650 mL) was added n -butyl lithium (140.9 mL, 226 mmol, 1.6 M in hexane) at -78 ° C. The reaction mixture was stirred for 20 min at the same temperature. (Bromomethyl) benzene (110 g, 644 mmol) was added dropwise at the same temperature and stirred for 30 min at -—78 “ºC. The resulting reaction mixture was warmed to room temperature and stirred for 1 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with water (300 ml), brine (100 ml), dried over NaszSOs, filtered and concentrated under reduced pressure. The crude product was purified by Flash column chromatography (silica gel, 230-400 mesh) using 2% to 4% ethyl acetate in petroleum ether as the eluent, yielding (2S, 3S) -N, N- bis (4-methoxybenzyl) -3-methyl-1-phenyl-hex-5-ene-2-sulfonamide E (2R, 3S) -N, N-bis (4-
[000587] [000587] To a stirred solution of (28,3S) -N, N-bis (4-methoxybenzyl) -3-methyl-1-phenyl-hex-5-ene-2-sulfonamide E (2R, 3S) -N , N-bis (4-methoxybenzyl) -3-methyl-1-phenyl-hex-5-eno- 2-sulfonamide (60 g, 122 mmol) in anisole (99 g, 915 mmol) was added TFA (148 g, 1298 mmol) to O “C. The resulting reaction mixture was heated to 40 ° C for 16 h. After the reaction was completed (monitored by TLC), volatiles were removed under reduced pressure and the crude product was purified by Flash column chromatography (silica gel, 230-400 mesh) using 15% to 20% ethyl acetate in ether of petroleum as eluent, giving rise to (28S, 3S) -3-methyl-1-phenyl-hex-5-ene-2-sulfonamide E (2R, 3S) -3-methyl-1-phenyl-hex-5- eno-2-sulfonamide (21.5 9g, 70% yield) as a liquid. MS (ESI, -ve ion) m / z 254.2 (M-1) -. 1 H NMR (400 MHz, DMSO-ds) 5 7.37 - 7.15 (my, 5H), 6.94 - 6.86 (m, 2H), 5.62 - 5.54 (m, 1H) , 4.96 —- 4.70 (m, 2H), 3.32 - 3.20 (m, 2H), 2.92 - 2.80 (m, 1H), 2.49 - 2.28 (m , 1H), 2.10 - 1.78 (m, 2H), 1.08 - 0.90 (m, 3H).
[000588] [000588] A solution of meso-2,3-dimethyl succinic acid (50.0 g, 342 mmol) in THF (700 mL) was cooled to 0 ° C. Lithium and aluminum hydride (2.0 M solution in tetrahydrofuran, 428.0 mL, 855.0 mmol) was then cannulated into the addition funnel and then added to the chilled mixture stirred dropwise over 15 min. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 12 h under an atmosphere of nitrogen. The reaction mixture was quenched with MeOH (350 ml) dropwise at 0 ° C and then 20% aqueous KOH solution (150 ml) was added slowly. The reaction mixture was stirred at 0 ° C for 20 min, EtOAc (1000 mL) was added and the organic phase was dried over MgSOs, filtered and concentrated under reduced pressure, giving rise to meso-2,3-dimethylbutane-1,4- diol (40.0 g, 100% yield) which was used as such in the next step. MS (ESI, + ve ion) m / z 119.2 (MH + H) *. Step 2: rac- (2R, 3S) -4 - ((tert-butyldimethylsilyl) oxy) - 2,3-dimethylbutan-l1-ol
[000589] [000589] To a suspension of sodium hydride (60% dispersion in mineral oil, 20.31 g, 508.0 mmol) in THF (1200 mL) at O
[000590] [000590] To a solution of rac- (2R, 3S8) -4- ((tert-butyldimethylsilyl) oxy) -2,3-dimethylbutan-l-ol (70.0 g, 301.0 mmol) and (diacetoxy- iodine) benzene (107.0 g, 301.0 mmol) in DCM (250 mL) 2,2,6,6-tetramethyl-1-piperidinyloxy (2.35 g, 15.06 mmol) was added in one portion to the room temperature. The reaction mixture was stirred for 12 h at room temperature. The reaction mixture was poured into DCM (500 ml) and washed with saturated aqueous sodium bicarbonate solution (250 ml) and brine (250 ml). The organic layer was dried over MgSOs: and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel
[000591] [000591] A solution of methyltriphenylphosphonium bromide (185.0 g, 521.0 mmol) in THF (1500 mL) was treated with n-butyl lithium (2.5 M solution in hexane, 174.0 mL, 18, 8 mmol) at O ºC. After 10 min, the resulting yellow mixture was allowed to stir at room temperature for 20 min. A solution of rac- (2R, 38S) -4- ((tert-butyldimethylsilyl) oxy) -2,3-dimethylbutanal (40.0 g, 174.0 mmol) in THF (50 mL) was added to the reaction mixture at -78 "C. After 10 min, the reaction mixture was allowed to stir at O “* C for 2 h and then quenched with saturated aqueous NH «Cl solution (500 ml) and water (200 ml). Diethyl ether (500 ml) was added and layers were separated. The aqueous layer was extracted with ether (3 x 500 ml). The combined organic layer was dried over MgSOs and concentrated under reduced pressure to obtain the crude material. The crude compound was dissolved in DCM (300 ml) and treated with 1.0 N HCl in diethyl ether (250 ml). The reaction mixture was stirred at room temperature for min. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography using silica gel (60-120 mesh), eluting with
[000592] [000592] To a solution of rac- (2S, 3S) -2,3-dimethylpent-4-en- 1-0l (5.0 g, 43.8 mmol) and triethylamine (13.43 mL, 96.0 mmol) in DCM (200 mL) methanesulfonyl chloride (5.12 mL, 65.7 mmol, 1.5 equiv) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. Then the reaction was quenched with saturated NH.Cl solution (100 mL) and extracted with EtOAc (3 x 200 mL) and the combined organic extracts were washed with brine, dried over MgSOs, filtered and concentrated under reduced pressure, giving rise to rac- (28.3S) - 2,3-dimethylpent-4-en-1-yl methanesulfonate which was used without further purification. MS (ESI, + ve) m / z 193.2 (M + H) *.
[000593] [000593] A solution of 2-mercapto-pyrimidine (27.5 9, 245.0 mmol) and potassium carbonate (36.3 g, 263.0 mmol) in DMF (1000 mL) was stirred at room temperature for 10 min. A solution of 2,3-dimethylpent-4-en-1-yl rac- (2S, 3S) -methanesulfonate (337 g, 175.0 mmol) in THF (1000 mL) was added at room temperature. The resulting mixture was heated to 50 ° C for 4 h and stirred at room temperature for 12 h. The crude mixture was quenched with cold water (500 ml) and extracted with EtOAc (3 x 500 ml). The combined organic layer was concentrated under reduced pressure. The crude material was purified by column chromatography (EtOAcC / hexanes, 0% to 15%, silica gel), giving rise to rac-2 - (((28.3S) -2, 3-dimethylpent-4-en-l -yl) thio) pyrimidine (19.0 g, 91.0 mmol, 52% yield). 'H NMR (300 MHz, Chloroform-d) at 8.50 (d, J = 4.7 Hz, 2H), 6.94 (t, J = 4.8 Hz, 1H), 5.76 (ddd, J = 16.8, 10.6, 8.2 Hz, 1H), 5.19 - 4.97 (m, 2H), 3.25 (dd, J = 13.2, 5.9 Hz, 1H) , 2.99 (dd, J = 13.1, 7.9 Hz, 1H), 2.50 - 2.32 (my, 1H), 1.93 - 1.74 (m, 1H), 1.07 (dy, J = 6.8 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H). MS (ESI, + ve) m / z 209.0 (M + H) *.
[000594] [000594] To a solution of rac-2 - (((2S8S, 3S) -2,3-dimethylpent-4-en-l1-yl) thio) pyrimidine (25.0 g, 120.0 mmol) in acetonitrile ( 500 mL) and water (50 mL), dehydrated sodium tungstate (7.92 g, 24.0 mmol) was added followed by hydrogen peroxide (61.3 mL, 600.0 mmol) at O “* C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated sodium thiosulfate (750 ml). The reaction mixture was extracted with ethyl acetate (3 x 1000 mL) and the combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure, giving rise to rac-2 - (((28.38) -2 , 3-dimethylpent-4-en-1-yl) sulfonyl) pyrimidine (25.0 g, 104.0 mmol, 86% yield). 'H NMR (400 MHz, Chloroform-d) 5 8.98 (d, J = 4.8 Hz, 2H), 7.59 (t, J = 4.9 Hz, 1H), 5.78 -
[000595] [000595] To a solution of rac-2 - (((2S, 3S) -2,3-dimethylpent-4-en-11-yl) sulfonyl) pyrimidine (25.0 g, 104.0 mmol) in methanol ( 500 mL) sodium methoxide (22.48 g, 104.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was diluted with water (500 ml) and washed with ethyl acetate (3 x 250 ml). Sodium acetate (10.24 g, 125 mmol) and hydroxylamino-o-sulfonic acid (14.12 g, 125 mmol) were added to the aqueous layer. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with MTBE (3 x 500 ml) and the combined organic layer was washed with saturated sodium carbonate (2 x 300 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure, giving rise to (28.38) -2, 3-dimethylpent-4-ene-1-sulfonamide (14.0 g, 79.0 mmol, 76% yield). 1 H NMR (400 MHz, Chloroform-d) 5 5.71 (ddd, IJ = 17.8, 10.5, 7.2 Hz, 1H), 5.19 - 4.92 (m, 4H), 3 , 19 (dd, J = 14.6, 3.7 Hz, 1H), 2.89 (dd, J = 14.6, 8.3 Hz, 1H), 2.36 (q, J = 6.2 Hz, 1H), 2.19 (th, J = 7.5, 4.0, 3.3 Hz, 1H), 1.11 (dd, J = 6.6, 2.9 Hz, 3H), 1 , 03 (dd, J = 6.7, 2.9 Hz, 3H). MS (ESI, + ve) m / z 178.2 (M + H) *. (S) -Hexa-hydropyrazine [2,1-c] [1,4] oxazin-4 (3H) -one
[000596] [000596] To a solution of (S) -1-boc-2- (hydroxymethyl) piperazine (5.0 q, 23.12 mmol) in 1,2-dichloroethane (100 ml) was added benzaldehyde (7.04 ml , 69.4 mmol). The resulting mixture was then stirred at room temperature for 30 min and then sodium triacetoxyborohydride (6.85 ml, 46.2 mmol) was added. The resulting mixture was then stirred at room temperature overnight. Then, the mixture was quenched with saturated NaHCO; 3 (20 ml) and was stirred at room temperature for min. The organic layer was collected and the aqueous layer was extracted with EtoOAc (1 x 30 ml). The combined organic extracts were then dried over MgSOs: and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) provided tert-butyl (S) -4-benzyl-2- (hydroxymethyl) piperazine-1-carboxylate (5.86 g, 19.13 mmol, 83% yield) as an oil. MS (ESI, + ve ion) m / z 307.3 (M + H) *.
[000597] [000597] To a solution of tert-butyl (S) -4-benzyl-2- (hydroxymethyl) piperazine-1-carboxylate (5.86 g, 19.13 mmol) in DCM (30 mL) was added trifluoroacetic acid (11.37 mL, 153 mmol). After the addition, the mixture was then stirred at room temperature for 2.5 h. Then, more trifluoroacetic acid (7 ml) was added and the mixture was stirred at room temperature for an additional 1 h. Then, the mixture was concentrated in vacuo and H2O (10 ml) was added. The mixture was then adjusted to pH = 14 with NaOH (1 N). The mixture was then extracted with EtOAc (3 x 30 ml). The combined organic extracts were dried over MgS0O.s, concentrated and dried in vacuo at 40 ° C overnight, providing (S) - (4-benzylpiperazin-2-yl) methanol as an oil which was used without further purification. 'H NMR (400 MHz, CHLOROPHORM-d) 5 7.26 - 7.38 (5H, m) 3.62 - 3.81 (2H, m) 3.54 (2H, d, J = 4.11 Hz ) 3.25 - 3.35 (2H, m) 3.02 - 3.14 (1H, m) 2.77 - 2.90 (2H, m) 2.41 (1H, td, Je11.88, 2 , 45 Hz) 2.18 - 2.30 (1H, m). MS (ESI, + ve ion) m / z 207.1 (M + H) *.
[000598] [000598] To a solution of (S) - (4-benzylpiperazin-2-yl) methanol (1.4 g, 6.79 mmol) and triethylamine (2.83 mL, 20.36 mmol) in DCM (5 mL ) at O ºC under No. chloroacetyl chloride (0.540 mL, 6.79 mmol) was added dropwise. After the addition, the mixture was then stirred at 0 ° C for 48 min. Then, MeOH (10 ml) was added and the mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) provided (S) - 1- (4-benzyl-2- (hydroxymethyl) piperazin-11-yl) -2-chloroethanone (530 mg, 1,874 mmol, 27.6% yield) as an oil. MS (ESI, + ve ion) m / z 283.1 (M + H) *.
[000599] [000599] To a solution of (S) -1- (A4-benzyl-2- (hydroxymethyl) piperazin-1-1yl) -2-chloroethanone (530 mg, 1.874 mmol) in THF (40 mL) at 0 ° C under No. Potassium tert-butoxide (421 mg, 3.75 mmol) was added. After the addition, the mixture was stirred at 0 ° C for 2 h. LCMS did not show any starting material. Then, MeOH (10 ml) was added and the mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) provided (S) -8-benzyl-hexahydropyrazine [2,1-c] [1,4] oxazin-4 (3H) -one (262 mg, 1.064 mmol, 56.8% yield) as an oil. MS (ESI, + ve ion) m / z 247.1 (M + H) *.
[000600] [000600] A solution of (S) -8-benzyl-hexahydropyrazine [2,1-c] [1,4] oxazin-4 (3H) -one (262 mg, 1.064 mmol) and acetic acid (0.123 mL , 2.127 mmol) in methanol (2.5 mL) in a pressure flask was added to a solution of palladium (5% activated carbon, 34 mg, 0.319 mmol) in EtOAc (0.3 mL). Then, the mixture was degassed with hydrogen times and then loaded with hydrogen at 40 psi. The mixture was then stirred for 3.5 h. LCMS showed some starting material. Then, palladium (5% activated wood carbon, 34 mg, 0.319 mmol) and acetic acid (0.123 mL, 2.127 mmol) were added. Then, the mixture was degassed 5 times with hydrogen and then charged with hydrogen at 40 psi. The resulting mixture was stirred at room temperature overnight at 40 psi. Then, the mixture was filtered through Celite and Celite was washed with MeoOH / EtOAc 1: 1
[000601] [000601] To a solution of (S) - (4-benzylpiperazin-2-yl) methanol (1.4 g, 6.79 mmol) and triethylamine (2.83 mL, 20.36 mmol) in DCM (10 mL ) at 0 ºC was added 2-chloropropionyl chloride (0.862 mL, 6.79 mmol). After the addition, the mixture was stirred at 0 ° C for 2 h. LCMS did not show any starting material. Then, MeOH (10 ml) was added and the mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) provided (S) -1- ((S) -4-benzyl-2- (hydroxymethyl) piperazin-11-yl) -2-chloropropan- l-one (176 mg,
[000602] [000602] To a solution of (R) -1- ((S) -4-benzyl-2- (hydroxymethyl) piperazin-l1-yl) -2-chloropropan-l-one (142 mg, 0.478 mmol) in THF (50 mL) under nitrogen at 0 ºC, potassium tert-butoxide (59.1 mg, 0.526 mmol) was added. The resulting mixture was then stirred at 0 ° C for 1 h and at room temperature for 10 d. Then, MeOH (10 ml) was added and the mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) provided (3S, 9aS) -8-benzyl-3-methylhexhydropyrazine [2,1-c] [1,4] oxazin- 4 (3H) -one (33 mg, 0.127 mmol, 26.5% yield) as an oil. ! H NMR (400 MHz, DICLOROMETHANE-dz) at 7.11 -— 7.28 (6H, m), 4.31 - 4.42
[000603] [000603] To a solution of (3S, 9aS) -8-benzyl-3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one (33 ma, 0.127 mmol ) in methanol (0.5 ml), acetic acid (0.015 ml, 0.254 mmol) and palladium (10% dry basis on activated carbon, wet, Degussa type, 6.74 mg, 0.063 mmol) were added. The resulting mixture was then purged with hydrogen, then loaded with hydrogen at 40 psi. The resulting mixture was then stirred at room temperature overnight. Then, the mixture was filtered through Celite and Celite was washed with EtOAc (2x 3mL). The combined filtrates were concentrated in vacuo and chromatographic purification of the residue (silica gel, 0% to 50% MeOH / DCM) provided (3S, 9aS) -3-methyl-hexahydropyrazine [2,1-c] [1, 4] oxazin-4 (3H) -one (20 mg, 0.118 mmol, 93% yield) as an oil. 'H NMR (400 MHz, DICLOROMETHANE-d;) 53 4.43 - 4.58 (1H, m), 4.09 - 4.19 (1H, m), 3.86 (1H, dd, J = 12 , 52, 4.50 Hz), 3.66 - 3.75 (1H, m), 3.53 (1H, td, J = 7.53, 3.72 Hz), 2.97 - 3.12 ( 2H, m), 2.65 - 2.87 (3H, m), 1.41 (3H, d, J = 6.85 Hz). MS (ESI, + ve ion) m / z 171.1 (M + H) *.
[000604] [000604] To a solution of (S) -1- ((S) -4-benzyl-2- (hydroxymethyl) piperazin-l1-yl) -2-chloropropan-l-one (176 mg,
[000605] [000605] To a solution of (3R, 9aS) -8-benzyl-3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one (154 mg, 0.592 mmol ) in methanol (2 mL) a solution of palladium (10% dry basis on activated carbon, wet, Degussa type, 18.89 mg, 0.177 mmol) in EtOAc (0.2 mL) was added. The resulting mixture was then purged with hydrogen five times and charged with hydrogen at 40 psi. The resulting mixture was then stirred for 10 d. Then, the mixture was filtered through Celite and Celite was washed with EtOAc (2 x 5 ml). The combined filtrates were concentrated. Chromatographic purification of the residue (silica gel, 0% to 20% MeOH / DCM) afforded (3R, 9aS) - 3-methyl-hydroxopyrazine [2,1-c] [1,4] oxazin-4 ( 3H) -one (93 mg, 0.546 mmol, 92% yield) as an oil. ! 'H NMR (400 MHz, DICLOROMETHANE-d2) 5 ppm 4.27 - 4.45 (1H, m), 4.05 (1H, q, J = 6.85 Hz), 3.74 (1H, dd , J = 12.23, 4.60 Hz), 3.54 - 3.63 (1H, m), 3.24 - 3.36 (1H, m), 2.84 -
[000608] [000608] To a solution of tert-butyl (R) -2- (aminomethyl) piperidine-1-carboxylate (475 mg, 2.216 mmol) in DCM (5.0 mL) at 0 ºC was added iPraNet (0.424 mL, 2.438 mmol) followed by benzyl chloroformate (0.693 mL, 2.438 mmol). The resulting mixture was then stirred at 0 ° C for 2 h and at room temperature for 14 h. So, NaHCO3; saturated (30 ml) was added to the mixture and the mixture was stirred at room temperature for 3 min. The organic layer was collected and the aqueous layer was extracted with EtOAc (1 x 20 ml). The combined organic extracts were dried over Na> zSO. and concentrated in vacuo. Chromatographic purification of the residue (silica gel,% to 100% EtOAc / heptane) provided tert-butyl (R) -2- ((((benzyloxy) carbonyl) amino) methyl) piperidine-1-carboxylate (772 mg, 2.216 mmol, 100% yield) as an oil. MS (ESI, + ve ion) m / z 371.1 (M + Na) *. Step 2: Benzyl (R) - (piperidin-2-ylmethyl) carbamate
[000609] [000609] To a solution of tert-butyl (R) -2- ((((benzyloxy) carbonyl) amino) methyl) piperidine-1-carboxylate (772 mg, 2.216 mmol) in DCM (5 mL) trifluoroacetic (1.646 mL, 22.16 mmol). The resulting mixture was then stirred at room temperature for 2 h. Then, iPr); Net (3.85 ml, 22.16 mmol) was added dropwise to the mixture at 0 ° C and the mixture was stirred at room temperature for 5 min. Then, the mixture was concentrated in vacuo and chromatographic purification of the residue (silica gel, 0% to 100% EtOH: EtOAC (3: 1) / heptane) provided benzyl (R) - (piperidin-2-ylmethyl) carbamate ( 495 mg, 90% yield) as an oil. MS (ESI, + ve ion) m / z 249.2 (M + H) *.
[000610] [000610] To a solution of benzyl (R) - (piperidin-2-ylmethyl) carbamate (150 mg, 0.604 mmol) in 1,2-dichloroethane (1 mL) and DCM (1 mL) at O ºC under nitrogen was iPr.Net (0.168 ml, 0.966 mmol) is added followed by chloroacetyl chloride (0.063 ml, 0.785 mmol). After the addition, the mixture was then stirred at O “ºC for 1 h. Then, the mixture was quenched with NaHCO; saturated (2.5 mL) and extracted with EtoOAc (2 x 3 mL). The combined organic extracts were then dried over Na; xSOs and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) provided benzyl (R) - ((1- (2-chloroacetyl) piperidin-2-yl) methyl) carbamate (126 mg, 0.388 mmol, 64.2% yield) as a solid. MS (ESI, + ve ion) m / z 325.1 (M + H) *.
[000611] [000611] To a solution of benzyl (R) - ((1- (2-chloroacetyl) piperidin-2-yl) methyl) carbamate (126 mg, 0.388 mmol) in tetrahydrofuran (5 mL) sodium (60% dispersion in mineral oil, 31 mg, 0.776 mmol) in portions. After the addition, the mixture was then stirred at room temperature for 5 h. Then, the mixture was carefully quenched with water (5 ml). The mixture was then extracted with EtOAc (2 x 10 ml). The combined organic extracts were then dried on Nas; SO. and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) provided (R) -4-oxo-hexahydro-1H-pyrido [1,2-a] pyrazine-2 (6H) -carboxylate benzyl (112 mg, 0.388 mmol, 100% yield) as an oil. MS (ESI, + ve ion) m / z 289.1 (M + H) *.
[000612] [000612] To a solution of benzyl (R) -4-oxo-hexahydro-11H-pyrido [1,2-a] pyrazine-2 (6H) -carboxylate (112 mg, 0.388 mmol) in ethanol (3 ml) was added ammonium formate (122 mg, 1.942 mmol) and 10% palladium on carbon (124 mg, 0.117 mmol). The resulting mixture was then stirred at 70 ° C for 1 h. The mixture was filtered through Celite and the filter cake was washed with a mixture of EtOAc and MeOH (1: 1, 3 x 2 ml). The combined filtrates were concentrated and chromatographic purification of the residue (silica gel, 0% to 15% 2M ammonia in MeOH / DCM) provided (R) -hexa-hydro-1H-pyrido [1,2-
[000613] [000613] To a stirred solution of tert-butyl hexahydro-11H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (0.680 g, 2.82 mmol) in DCM (10 mL) diisopropylethylamine (1.078 mL, 6.20 mmol) was added at room temperature under argon followed by 2,5-dioxopyrrolidin-11-yl acetate (0.885 g, 5.64 mmol) in a solid portion . The resulting mixture was stirred at room temperature for 24 h. The crude mixture was directly loaded onto a silica gel pre-column (25 g), previously covered with a layer of sodium bicarbonate, and subjected to Flash column chromatography on a 24 g ISCO Gold column eluting with 0% to 3 % MeOH / DCM, yielding tert-butyl 8-acetyl-hexahydro-1H-pyrazine [1,2-alpyrazine-2 (6H) -carboxylate as an oil. This was carried on to the next step without further purification. MS (ESI, + ve ion) m / z 306.4 (M + Na) *.
[000614] [000614] To a solution of tert-butyl 8-acetyl-hexahydro-11H-pyrazine [1,2-a] pyrazine-2 (6H) -carboxylate in DCM (10 mL), 2.2, 2-trifluoroacetic (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature overnight and the volatiles were removed, yielding 1- (hexahydro-1H-pyrazino [1,2-a] pyrazin-2 (2,2H-trifluoroacetate) (6H ) -yl) ethanone as a solid that was used without further purification. 2- (Methylsulfonyl) octahydro-1H-pyrazine [1,2-a] lpyrazine Bee NT - soe Xl - rar Step 1: 8- (methylsulfonyl) hexahydro-1H-pyrazine [1,2- a] lpyrazine -2 (6H) tert-butyl carboxylate
[000615] [000615] To an ice-cold stirred mixture of tert-butyl hexahydro-1H-pyrazine [1,2-a] 2-(6H) -carboxylate (1,000 g, 4.14 mmol) and diisopropylethylamine (1.442 ml, 8.29 mmol) in DCM (14 ml) methanesulfonyl chloride (0.385 ml, 4.97 mmol) was added dropwise via syringe. The resulting mixture was stirred at 0 ° C for 10 min and stirred at room temperature for 19 h. The volatiles were removed and the residue was loaded onto a silica gel pre-column (25 g) and subjected to Combi-Flash column chromatography on a 24 g ISCO Gold column eluting with% to 100% MeOH / DCM, giving 8- (methylsulfonyl) hexahydro-1H-pyrazine [1,2-a] pyrazine-2 (6H) - tert-butyl carboxylate (1.30 g, 4.07 mmol, 98% yield) in the form of an oil. MS (ESI, + ve ion) m / z 320.1 (M + 1) *.
[000616] [000616] To a stirred solution of tert- 8- (methylsulfonyl) hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate
[000617] [000617] To a stirred mixture of tert-butyl hexahydro-11H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (0.46 g, 1.906 mmol) and 3- (phenylsulfonyl) acid propionic (0.490 g, 2.287 mmol) in DCM (6.5 mL) was added at room temperature iPrxNet (0.829 mL, 4.77 mmol) via a syringe followed by HATU (1.450 g, 3.81 mmol) in one portion at form of a solid. The resulting mixture was stirred at room temperature for 75 min. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to Combi-Flash column chromatography on a 24 g ISCO Gold column eluting with 0% to 15% MeOH / DCM, giving rise to 1.28 g of 8- (3- (phenylsulfonyl) propanoyl) hexahydro-
[000618] [000618] A mixture of tert-butyl 8- (3- (phenylsulfonyl) propanoyl) hexahydro-1H-pyrazino [1,2- to] lpyrazin-2 (6H) -carboxylate (1.28 g, 2, 93 mmol) and 2,2,2-trifluoroacetic acid (4.0 mL, 2.93 mmol) in DCM (15 mL) was stirred at room temperature for 50 min. The volatiles were removed and the residue was subjected to high vacuum overnight, giving rise to 1.5 gq of 1- (dihydro-1H-pyrazino [1,2-a] pyrazin-2 (6H, 7H, 8H , 9H, 9aH) -11) -3- (phenylsulfonyl) propan-1-one as an oil that was used without further purification. MS (ESI, + ve ion) m / z 338.1 (M + 1) *. 2-Isopropyloctahydro-1H-pyrazine [1,2-a] pyrazine MV es Mo es OS BN NH - Bon Bon à NY Step 2 HAN Y Step 1: 8-isopropyl-hexahydro-1H-pyrazine [1, 2- a] tert-butyl lpyrazine-2 (6H) -carboxylate
[000619] [000619] A mixture of tert-butyl hexahydro-1H-pyrazine [1,2- a] lpyrazine-2 (6H) -carboxylate (0.53 g, 2.196 mmol) and acetone (0.806 mL, 10.98 mmol) in DCM (5.0 mL) was stirred at rt for 10 min before sodium triacetoxyhydroborate (2.327 g, 10.98 mmol) was added at room temperature in one portion as a solid. The resulting mixture was stirred at room temperature for 24 h. The reaction was quenched with MeOH (5 mL) and the resulting paste was directly loaded onto a silica gel pre-column (25 g) and subjected to Combi- Flash column chromatography on a 12 gq ISCO Gold column eluting with 0% up to 20% MeOH / DCM, yielding tert-butyl 8-isopropyl-hexahydro-11H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (0.65 g, 2.293 mmol, 104% yield) in the form of an oil. MS (ESI, + ve ion) m / z 284.3 (M + 1) *.
[000620] [000620] A mixture of tert-butyl 8-isopropyl-hexahydro-11H-pyrazine [1,2-a] pyrazine-2 (6H) -carboxylate (0.65 g, 2.293 mmol) and 2.2 acid , 2-trifluoroacetic (4.0 ml, 2.293 mmol) in DCM (15 ml) was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was subjected to high vacuum overnight, yielding 1.74 g of 2-isopropyloctahydro-1H-pyrazine [1,2-a] lpyrazine as an oil which was used without further purification. MS (ESI, + ve ion) m / z 184.2 (M + 1) *. (1R, 4R) -2-Isopropyl-2,5-diazabicyclo [2.2.1] heptane 2H SH SH so So - A Ses Espaa Ad H H H
[000621] [000621] The title compound was synthesized from tert-butyl (1R, 4R) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (AstaTech, Inc.), similarly using the Synthesis protocol of 2-isopropyloctahydro-1H-pyrazine [1,2-a] pyrazine. MS (ESI, + ve ion) m / z 141.2 (M + 1) *. (18.48) -2-Isopropyl-2,5-diazabicyclo [2.2.1] heptane
[000622] [000622] The title compound was synthesized from tert-butyl (18.48) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (AstaTech, Inc.), similarly using the synthesis protocol of 2-isopropyloctahydro-1H-pyrazine [1,2-a] pyrazine. MS (ESI, + ve ion) m / z 141.2 (M + 1) *. Cis-l1- (2-methoxyethyl) -2,6-dimethylpiperazine OMe OMe
[000623] [000623] The title compound was synthesized from tert-butyl cis-3,5-dimethylpiperazine-1-carboxylate (AK Scientific), similarly using the 2-isopropyloctahydro-1H-pyrazine synthesis protocol [1 , 2-a] lpirazine. MS (ESI, + ve ion) m / z 173.2 (M + 1) *. Cis-1-isopropyl-2,6-dimethylpiperazine and cis-2,6-dimethylpiperazine
[000624] [000624] The title compounds were synthesized, and used as a mixture, from tert-butyl cis-3,5-dimethylpiperazine-1-carboxylate (AK Scientific), similarly using the 2-isopropylocta-synthesis protocol. hydro-1H-pyrazine [1,2-a] pyrazine. MS (ESI, + ve ion) m / z 157.1 and 115.3 (M + 1) *.
[000625] [000625] The title compound was synthesized from tert-butyl (S) -3-methylpiperazine-1-carboxylate, similarly using the 2-isopropyloctahydro-1H-pyrazine synthesis protocol [1,2-a ] lpirazine. MS (ESI, + ve ion) m / z 143.2 (M + 1) *. 1- (1,4-Dioxepan-6-yl) piperazine o. from TN
[000626] [000626] The title compound was synthesized from 1,4-dioxepan-6-one (Enamine), similarly using the 2-isopropyloctahydro-1H-pyrazine [1,2-a] pyrazine synthesis protocol. MS (ESI, + ve ion) m / z 187.2 (M + 1) *. (28.68) -1-Isopropyl-2,6-dimethylpiperazine mm AN tm, AN tm AN to SD ss VV Step 1 Step 2 N Ip: N Ip: N Boc Boc H
[000627] [000627] The title compound was synthesized from tert-butyl (38,58) -3,5-dimethylpiperazine-1-carboxylate (Anichem), similarly using the 2-isopropyloctahydro-1H- synthesis protocol pyrazine [1,2-a] pyrazine. MS (ESI, + ve ion) m / z 157.2 (M + 1) *. 4- (2-Methoxyethyl) piperazin-2-one in vacuo and the residue was dried, yielding impure 4- (piperazin-1-yl) tetrahydro-2H-pyran-2-one. This was used without further purification. MS (ESI, + ve ion) m / z 185.1 (M + 1) *. 8, 8-Difluoro-octa-hydro-1H-pyrido [1,2-a] pyrazine E 8-fluoro-octa-hydro-1H-pyrido [1,2-a] pyrazine o N No No if N ST ad to O
[000631] [000631] To a stirred solution of 2-benzyl-hexahydro-1H-pyrido [1,2-a] pyrazin-8 (2H) -one (200 mg, 0.819 mmol AstaTech) in DCM (5.0 mL) cooled in a brine-ice bath, bis (2-methoxyethyl) amino sulfur trifluoride solution (50% in THF, 0.989 ml, 2.456 mmol) was added dropwise via syringe. The resulting mixture was stirred for 2 h at -5 ºC and 3 h at room temperature. The crude mixture was directly loaded onto a silica gel pre-column (25 g) and subjected to Flash column chromatography on a 12 g ISCO Gold column eluting with 0% to 10% MeOH / DCM, yielding 170 mg a mixture of 2-benzyl-8,8-difluoro-octahydro-1H-pyrido [1,2-a] lpyrazine, 2-benzyl-8-fluoro-2,3,4,6,7,9a- hexahydro-1H-pyrido [1,2-a] pyrazine and 2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido [1,2-
[000632] [000632] A mixture of 2-benzyl-8,8-difluoro-octahydro-1H-pyrido [1,2-a] pyrazine, 2-benzyl-8-fluoro-2,3,4,6,7, 9a-hexahydro-1H-pyrido [1,2-a] pyrazine and 2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido [1,2- a] pyrazine (250 mg, 0.939 mmol) and palladium (5% dry basis on activated carbon, wet, Degussa type, spatula tip) in EtOH (25 mL) and concentrated hydrochloric acid (5 mL) was hydrogenated with hydrogen gas at 40-45 psi over a 22 h period. The reaction was quenched with water (5 ml) and the mixture was filtered through a layer of Celite covered with sand. The filtrate was concentrated in vacuo, yielding 8,8-difluoro-octahydro-1H-pyrido [1,2-a] pyrazine E 8-fluoro-octahydro-11H-pyrido [1,2-a] pyrazine in the form of a colorless film that was used without further purification. MS (ESI, + ve ion) m / z 177.2 and 159.2 (M + 1) *. 1- (5- (Piperazin-1-yl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethanone in O ”HO A, TIO, A make LU Neo fo) (Nec f (Neoc 3% oo NONH Step 1: tert-butyl 4- (3-acetyl-4-hydroxyphenyl) piperazine-1-carboxylate
[000633] [000633] To an ice-cold stirred mixture of 5'-bromo-2'-hydroxyacetophenone (2,000 g, 9.30 mmol, Oakwood), 1-boc-piperazine (2.77 g, 14.88 mmol) tris ( dibenzylidenoacetone) dipaladium (0) (0.426 g, 0.465 mmol and 2- (dicyclohexylphosphino) -2 '- (N, N-dimethylamino) biphenyl (0.183 g, 0.465 mmol) in THF (20 mL) was added dropwise lithium bis (trimethylsilyl) amide (1.0 M in THF, 32.6 mL, 32.6 mmol). The resulting mixture was stirred at room temperature for 10 min before being placed in an oil bath that was at room temperature The oil bath was then heated to 70 ° C and the reaction mixture was stirred at this temperature for 1.5 h The mixture was cooled in an ice bath before being carefully quenched with cold saturated aqueous ammonium chloride solution The resulting mixture was poured into a mixture of solutions of 1N aqueous HCl and saturated aqueous ammonium chloride and extracted with 10% MeOH / DCM (2 X). The combined organic layers were washed with with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in DCM and loaded onto a silica gel pre-column and subjected to Flash column chromatography on a 40 g ISCO Gold column eluting with 0% to 4% MeOH / DCM, giving rise to 1.84 g Tert-butyl 4- (3-acetyl-4-hydroxyphenyl) piperazine-1-carboxylate which was used directly in the next step. MS (ESI, + ve ion) m / z 321.2 (M + 1) *.
[000634] [000634] To a stirred solution of impure tert-butyl 4- (3-acetyl-4-hydroxyphenyl) piperazine-1-carboxylate (1.30 g, 4.06 mmol) and triethylamine (2.258 mL, 16.23 mmol ) in DCM (15 mL) N-phenyl-bis-trifluoromethanesulfonimide (2.90 g, 8.12 mmol) was added in one portion as a solid. The resulting mixture was stirred at room temperature for 2.5 d. The crude mixture was directly loaded onto a silica gel pre-column (25 gq) and subjected to Flash column chromatography on a 40 g ISCO Gold column eluting with 10% to 40% EtOAc / Hexanes, giving rise to 4- (Tert-butyl 3-acetyl-4- ((((trifluoromethyl) sulfonyl) oxy) phenyl) piperazine-1-carboxylate (1.4 g, 3.09 mmol, 76% yield). MS (ESI, + ve ion) m / z 475.1 (M + 1) *.
[000635] [000635] A 25 mL single-necked round-bottom flask previously loaded with tert-butyl 4- (3-acetyl-4- (((trifluoromethyl) sulfonyl) oxy) phenyl) piperazine-1-carboxylate (1, 17 g, 2.59 mmol), bis (pinacolate) diboro (1.642 g, 6.46 mmol), (1,1'-bis (diphenylphosphino) ferrocene) dichloropalladium (IIL) (0.189 gq, 0.259 mmol) and acetate potassium (0.888 g, 9.05 mmol) was subjected to 3 evacuation cycles and refilled with nitrogen before 1,4-dioxane (12 mL) was added. The resulting mixture under argon was placed in an oil bath and heated to 50 ºC and stirred under argon at this temperature for a period of 20 h. The temperature was decreased to 45 ° C and the mixture was stirred overnight at this temperature. The crude reaction mixture was processed through a plug of silica gel. The filtrate was concentrated in vacuo and the residue was dissolved in DCM and loaded onto a silica gel pre-column (25 g) and subjected to Flash column chromatography on a 24 g ISCO Gold column eluting with 0% to 40% EtOAc / hexanes, giving rise to tert-butyl 4- (3-acetyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (380 mg, 0.883 mmol, 34.1% yield) as a solid. MS (ESI, + ve ion) m / z 431.3 (M + 1) *.
[000636] [000636] 4- (3-Acetyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) tert-butyl piperazine-1-carboxylate in DCM was treated with TFA to remove the Boc group. 1- (5- (piperazin-l-yl) -2- (4,4,5,5-tetramethyl-l1,3,2-dioxaborolan-2-yl) phenyl) ethanone was isolated after concentration and used without further purification . MS (ESI, + ve ion) m / z 331.2 (M + 1) *. (28) -N, N-BIS (A-METOXYBENZYL) -2-METYLPENT-4-ENO-1-SULPHONAMIDE AND (2R) -N, N-BIS (4A-METOXYBENZYL) -2-METHYL- -1-SULPHONAMIDE 4 a == e —— = Er pOr * PO ”>
[000637] [000637] The title compound was prepared from Intermediate EEl2 and pent-4-en-2-yl 4-methylbenzenesulfonate following a similar procedure described below. (2R, 3R) -N, N-BIS (A-METOXYBenzyl) - 3-METHYL-HEX-5-ENO-2-SULPHONAMIDE E (2S, 3R) -N, N-BIS (4-METOXYBenzyl) -3- METHYL-HEX-5-ENO-2-SULPHONAMIDE “Fl EX mos na. »OE" LO MeO 'O. Meo O. OMe OMe
[000638] [000638] N, N-bis (4-methoxybenzyl) ethanesulfonamide (Intermediate EEl3; 1030 mg, 2.95 mmol) was subjected to azeotropic treatment in toluene under vacuum for 2 h. Under argon, THF was added and the solution was cooled to - 78 ° C. N-butyl lithium solution (2.5 M in hexane, 1.533 mL, 3.83 mmol) was then added and the mixture was stirred at - 78 ° C. ºC for 60 min. (S) -4-methylbenzenesulfonate of pent-4-en-2-yl (prepared according to the procedure of Sigman, MS et al., J. Am. Chem. Soc., 2012, 134 (28), 11408- 11411; 1417 mg, 5.90 mmol) was added as a solution in 3 ml. THF was then added. After 5 min, the mixture was allowed to warm to room temperature and stirred overnight under argon. The mixture was quenched with NH2 Cl satd and extracted with EtOAc, dried over MgSO. and concentrated. The crude material was injected into a SiO gel cartridge, purified by chromatography through a 40 g ISCO column, eluting with 5% to 10% to 20% to 40% EtOAc in hexane, giving with brine (2X600 mL ) and 330 g of Al20; (neutral) have been added. The resulting suspension was stirred for 5 min at 22 "* C, filtered and washed with MTBE (400 ml). The filtrate was concentrated, giving the product as a viscous red oil (125 g, 94%). STEP 2: (S) -6-CHLORINE-1,2,3,4-TETRA-HYDRONAPHTHALENE-1- CARBALDEHYDE AND (R) -6-CHLORINE-1,2,3,4-TETRA-HYDRONAPHTHALENE-1-
[000640] [000640] A 3 L 3-neck BFR was loaded with racemic 6-chloro-3,4-dihydro-2H-spiro [naphthalene-1,2'-oxirane] (160 g, 822 mmol) and THF ( 1760 ml). After the batch was cooled to -8 “C with a dry ice / IPA bath, boron trifluoride diethyl etherate (5.07 mL, 41.1 mmol) was added over 3 min. An exotherm increased the batch temperature to 10 ºC instantly. The batch was stirred at -5 to 0 ºC for 5 min and LC / MS analysis of a sample (quenched in cold NaHCO solution;) showed complete conversion. The reaction was quenched by the addition of NaHCO; sat. (300 ml) at -5 ° C followed by MTBE (400 ml) and the mixture was transferred to a separating funnel and rinsed with MTBE (240 ml). After partition, the aqueous layer was discarded along with some white solid (probably boric acid or borax). The organic layer was washed with brine (350 ml) and concentrated under reduced pressure, yielding a red oil. The raw material was used directly in Step 4.
[000644] [000644] The enantiomeric purity of the title compound could be improved by the following procedure: (R) -4- (6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl bromobenzoate) methyl (190 g) was added in toluene (950 mL) and heated to 50 ° C to complete the dissolution. The homogeneous solution was cooled to room temperature and seeded with racemic compound. The solution was cooled to -25 ºC and aged overnight. The mother liquor was then decanted and concentrated, yielding 160 g (6-chloro-l-formyl-1,2,3,4-tetrahydronaphthalen-l1-yl) methyl (R) -4-bromobenzoate enantiomerically enriched (94% ee determined by chiral HPLC). Chiral HPLC conditions: Column: ChiralCelº OD-H (250 mm x 4.6 mm); Mobile Phase: n-Hexane: IPA: 90:10. Processing Time: 20 min. Flow rate: 1 mL / min. Sample preparation: ethanol. Retention time (main peak): 8.488 min (96.97%); Retention time (minority peak): 9,592 min (3.03%). STEP 6: (R) - (6-CHLORINE-1- (DIMETOXIMETHIL) -1,2,3,4-TETRA- HYDRONAFTALEN-1-1L) METHANOL can be prepared from (6-chloro-1,2, 3,4-tetrahydronaphthalene-1,1-diyl) dimethanol (Step 4) as follows:
[000650] [000650] A 250 mL 3-neck BFR was charged with copper (II) chloride (0.095 g, 0.02 eq), 2,6-bis ((R) - 5-dibutyl-4-phenyl- 4,5-dihydro-oxazol-2-yl) pyridine (0.42 g, 0.02 eq) and THF (28.5 g, 4 V). After inerting with No, the batch was stirred at 20 ° C for 0.5 h. To the homogeneous green solution was added (6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-di-yl) dimethanol (8.0 9g, 1.00 eq) followed by THF (14.2 g, 2 V) and 4-methylmorpholine (3.75 g, 1.05 eq). The reaction mixture was cooled to -20 ºC and a solution of l-naphthyl chloride (7.06 g, 1.05 eq) in THF (21.3 9, 3 V) was added to the batch over 0.5 h keeping the temperature below -15 “ºC. After aging at -20 ºC for 20 h, an aliquot of the reaction paste was sampled and evaluated by HPLC. The paste was directly filtered through a glass frit funnel keeping the temperature at -20 ºC. The filter cake was washed with two portions of cold THF (<-10 ºC) (2 x 14.2 9, 2 V) rinsed through the reactor. The filter cake (4-methylmorpholine HCl) was transferred to a labeled container. The mother liquor and washes were concentrated to a minimum volume and exchange of the distillation solvent for toluene charge until the batch volume was 6 Ve the toluene / THF ratio was> 98: 2 (v / v) measured by QORMN. To the batch at 20 ºC heptane (11 g, 2 V) was added and the paste was heated to 85 ºC (dissolution observed). The solution was cooled to 75 ºC and loaded with seed (0.27 g, 0.02 eq). The paste was cooled to 20 ºC over 3 h and aged for> 1 h. The batch was filtered through a glass frit filter and the cake was washed with toluene / heptane (3: 1 v / v) (11 g, 2 V), then toluene / heptane (1: 1 v / v) ( 11 g, 2 V). The cake was dried under N2 for 12 h at room temperature and the cake was evaluated for dryness by ORMN (<1% w of toluene and heptane). The product was obtained as an off-white solid (8.75 g, 63% after adjustment by weight).
[000651] [000651] A 60 L jacketed reactor ventilated with a bleach scrubber was loaded with (6) chloro-l1- (hydroxymethyl) -1,2,3,4-tetrahydronaftalen-1 (S) -l-naphthoate - il) methyl (2.693 kg, 88.6% w, 6.3 mol) followed by DCM (17.9 kg, 5 vol) and EtNiPr, (2.84 kg, 3.5 eq). After inerting with Na, the batch was stirred and cooled to 0 ºC. To the reactor alcohol paste mixture, a freshly prepared solution of sulfur trioxide pyridine (2.10 kg, 2.5 eq of sulfur trioxide pyridine in 7.43 kg, 3 vol. Of DMSO) was added over 30 min keeping the batch temperature below 15 ºC. After the addition, an HPLC assay showed> 99% conversion. The batch was extinguished by adding HO (14 L, 5 vol) over -20 min. keeping the batch temperature below 15 ºC and then toluene (16.8 L, 6 vol) was added. After partition, the organic layer was treated with H2O (14 L, 5 vol) and toluene (16.8 L, 6 vol). The top organic layer was washed with 2 N HCl twice (14 L each, 5 vol) and brine (14 L, 5 vol). The organic layer was drained into a clean container, evaluated by HPLC and then transferred back to the clean 60 L reactor through an internal filter. The batch was concentrated to a minimum volume and the solvent was changed to MeOH until the batch volume was 28 L (10 vol) and the MeOH / toluene ratio was 3: 1 (v / v) measured by QORMN. The batch was then transferred to a 30 L jacketed reactor through an internal filter. After adjusting the batch temperature to 30 ºC, the batch was seeded with the aldehyde (51 g, 0.02 eq) as a paste in MeOH (400 mL) After the paste had aged for 30 min at 30 ºC, the solvent of the batch was exchanged for distillation with MeOH until the batch volume was 11 L (4 vol) and the MeOH / toluene ratio was> 99: 1 (v / v). The batch was then cooled to 5 “ºC and a mixture of MeO0H / H2O (3.70 kg MeOH + 1.34 kg HO) was added over 1.5 h to adjust the total solvent volume to approximately 5 , 5 vol and MeOH / H; 70 final for 90/10 (v / v). The batch was heated to 65 “C over min and cooled to 20 ºC over 2 h and aged for - 2 h. The batch was filtered through an Aurora filter equipped with a € 25 um filter cloth. The cake was washed with MeOOH / H2O (10: 1) (1x2 vol), then MeOH / H2; O (2: 1) (1x2 vol). The cake was dried under N7 at room temperature for 24 h until dry, giving the product as an off-white solid (1.99 kg, 72% after% w adjustment).
[000652] [000652] A 250 mL 3-neck BFR was loaded with (6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methyl (R) -1-naphthoate (10 gq, 94.4% w, 95.3% LCAP,> 99% ee), methanol (100 ml), trimethyl orthoformate (7 ml) and TsOoH + HO (0.24 g). The BFR was rendered inert with Nr and stirring was started. The batch was heated to 60 ºC and aged for 2 h. An HPLC assay showed 298% conversion.
[000653] [000653] The batch was concentrated under vacuum (-150-190 torr, external temp + -40 ºC) to the minimum volume using a rotoevaporator.
[000654] [000654] The batch was cooled to <20 ºC and K3PO4 * H2O (4.5 g) and HO (7 ml) were added. The batch was transferred to a separating funnel and the bottom water layer was drained, resulting in the crude solution of the aldehyde product. The combined raw organic stream was concentrated to a minimum volume using a rotary evaporator. The batch in a 500 mL BFR was loaded with AcOH (-50 mL, -50 mL) and distilled using a rotary evaporator under reduced pressure (30 mbar, external temp -40 ºC). The THF level was measured by QORMN and
[000676] [000676] To a solution of (S) -6'-chloro-5 - ((((1R, 2R) -2- ((S) - 1-hydroxyaloyl) cyclobutyl) methyl) -3 ', 4.4', Methyl 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (from Step 21; 4.59 9g, 9, 52 mmol) in a mixture of THF (18 mL), MeOH (6.00 mL) and H2O (6.00 mL) LiOH-H2O (0.799 g, 19.05 mmol) was added and the reaction was stirred at 50 ° C for 4 h. The reaction mixture was concentrated to - 15 ml, cooled to 0 ºC and acidified with 2 N HCl to pH = 3. The resulting viscous oil was diluted with 20 ml of HO and 50 ml of EtOAc and a clear two-layer mixture was obtained . More EtOAc (about 200 ml) was added and the organic layer was separated, washed with brine, dried over MgSOs, filtered and concentrated under reduced pressure. The crude material was loaded onto a column (220 g) and purified with EtOAc in hexane using the following gradient: 0-2.5 min 0% EtOAc, 2.5-6 min 0-20% EtOAc, 6-35 min 20-60% EtOAc, 35-40 min 70% EtOAc, giving (S) -6'-chloro-5 - (((1R, 2R) -2 - ((S) -1- hydroxy) acid ) cyclobutyl) methyl) -3 ', 4.4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic (4.22 gq, 9.02 mmol, 95% yield) as a white solid. Intermediate AAl2A ACID (S) -6'-CHLORINE-5 - ((((1R, 2R) -2- ((S, E) -1-HYDROXY-HEX-2-EN- 1-IL) CYCLEBUTYL) METHIL) - 3 ', 4,4', 5-TETRA-HYDRO-2H, 2'H- SPIRAL [BENZO [B] [1,4] OXAZEPINO-3,1'-NAFTALENE] -7-CARBOXYLIC The mixture was stirred at room temperature until all the solid has dissolved, then cooled to 0 ºC. Under an argon atmosphere, 54 mL of solution A were added slowly, via syringe, over 1.6 h. After stirring for 5 min at 0 ° C, the mixture was quenched with sat. NHCl (70 mL), diluted with H2O (30 mL) and extracted with EtOAc (3 x 270 mL), washed with brine, dried over Na7sSOs: anhydrous and concentrated. The residue was loaded onto a 330 g ISCO Gold column and eluted with 0% to 5% ELOAC / hexane, giving the title compound, 3.8 g, as a white solid. m / z (ESI, ion + ve) 524.1 (M + H) *. STEP 1B: (S) -6'-CHLORINE-5 - ((((1R, 2R) -2 - ((S, E) -1-HYDROXY-HEX- 2-EN-1-IL) CYCLEBUTYL) METHYL) - 3 ', 4,4', 5-TETRA-HYDRO-2H, 2'H- SPIRAL [BENZO [B] [1,4] OXAZEPINE-3,1'-NAFTALENE] - 7-TERC-BUTYL CARBOXYLATE AND ( S) -6 '-CHLORINE-5- ((((1R, 2R) -2- ((R, E) -1- HYDROXY-HEX-2-EN-1-1IL) CYCLEBUTYL) METHIL) -3', 4 , 4 ', 5-TETRA-HYDRO-2H, 2'H-SPIRAL [BENZO [B] [1,4] OXAZEPINE-3,1'-NAFTALENE] - 7-TERC-BUTYL CARBOXYLATE oH oH f ROO c 2 Qdo QE oo
[000678] [000678] The title compound was synthesized from (S) -6 '-chloro-5- ((((1R, 2R) -2-formylcyclobutyl) methyl) - 3', 4.4 ', 5-tetra- hydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-tert-butyl carboxylate (3.19 g, Intermediate AAll1A, Step 20B) following procedure described for Intermediate AALI2A, Step 1A. The crude material was absorbed in a SiO> buffer; and purified on a 330 g ISCO Gold column eluting with O to 15% EtOAc in heptanes over 45 min, yielding (S) -6'-chloro-5- (((1R, 2R) -2- ((S, E) -1-hydroxy-hex-2-en-1-yl) cyclobutyl) methyl) -3 ', 4.4', 5-tetrahydro-2H, 2'H-spiro [benzo [ b] tert-butyl [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (2.36 g). Additional elution provided (S) - 6'-chloro-5- ((((1R, 2R) -2- ((R, E) -1-hydroxy-hex-2-en-1-yl) cyclobutyl) methyl) - 3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-tert-butyl carboxylate (0 , 45 g). STEP 2: (S) -6'-CHLORINE-5 - ((((1R, 2R) -2 - (((S, E) -1-HYDROXY- HEX-2-EN-1-IL) CYCLEBUTYL) METHYL) -3 ', 4,4', 5-TETRA-HYDRO- 2H, 2'H-SPIRAL [BENZO [B] [1,4] OXAZEPINO-3,1'-NAFTALENE] -7- CARBOXYLIC
[000679] [000679] A mixture of (S) -6'-chloro-5- ((((1R, 2R) -2- ((S, E) - 1-hydroxy-hex-2-en-1-1yl) cyclobutyl)) methyl) -3 ', 4.4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepino-3, 1'-naphthalene] - 7T-methyl carboxylate ( Intermediate AAlIl2A, Step A; 4.6 g, 8.78 mmol) and LiOH-H7O (3.68 9 g, 88 mmol) in MeOH (98 mL) and THF (98 mL) (with a few drops of H7O) was stirred at 50 ° C overnight. The solvent was removed and the residue was acidified with 1 N HCl to pH 2-3. The mixture was extracted with EtOAc (80 ml x 3) and the combined organic layer was washed with brine (10 ml), dried over anhydrous MgSOs and concentrated under reduced pressure, giving (S) - 6'-chloro-5 acid - ((((1R, 2R) -2- ((S, E) -1-hydroxy-hex-2-en-1-yl) cyclobutyl) methyl) -3 ', 4.4', 5-tetrahydro -2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic (4.25 gq, 8.34 mmol, 95% yield).
[000685] [000685] A mixture of (S) -6'-chloro-5 - ((((1R, 2R) -2 - ((S) -1- hydroxybut-3-en-1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3, l'-naphthalene] - Methyl T-carboxylate (from Intermediate AALI3A, Step 1A; 1.88 g, 3.79 mmol) and solution of LiOH (1 M) (34.1 mL, 34.1 mmol) in MeOH (34 mL) and THF (50 mL) was stirred at 65 “C for 50 min. After cooling to room temperature, the mixture was acidified with 1 N HCl to pH 2 to 3, extracted with EtOAc (350 mL), dried over Na7; anhydrous SOs and concentrated, yielding 1.82 g of the title compound in in the form of a white solid. m / z (ESI, ion + ve) 482.0 (M + H) *.
[000686] [000686] Alternatively, the title compound can be synthesized as follows:
[000687] [000687] To a solution of (S) -6'-chloro-5 - ((((1R, 2R) -2 - ((S) - l-hydroxybut-3-en-l1-yl) cyclobutyl) methyl) - 3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] - tert-butyl T-carboxylate (Intermediate AALl3A, Step 1B; 250 mg, 0.465 mmol) in DCM (3.717 mL) at room temperature, TFA (0.929 mL) was added and the reaction mixture was stirred for 4 h. The crude reaction mixture was then concentrated, the residue was taken up in EtOAc, washed once with NaHCO; sat., dried over MgSOs, filtered and concentrated to give a white foam. The crude material was used as such, without further purification. Intermediate EE1l1 azeotropic treatment with toluene and dried under vacuum for 1 h. THF (890 mL) was added and the mixture was cooled to -78 ° C. Butyl lithium (2.5 M in hexane, 63.9 ml, 159.9 mmol) was then added and the reaction mixture was stirred at -78 ° C for 1 h. This anionic solution was added slowly to a solution of MeI (16.8 mL, 266.5 mmol) in THF (300 mL), cooled to -78 ºC. The resulting reaction mixture was stirred for an additional 15 min at —-78 ° C. After the reaction was completed (monitored by TLC), the mixture was quenched with sat. NHKCl and extracted with EtOAc. The organic layer was dried over Na7; SOs. and concentrated under reduced pressure to obtain crude material which was purified by column chromatography on SiO7 gel eluting with 5-10% EtOAc in hexane, giving the title compound as a racemic mixture (22.0 g) of semi-solid nature. Separation of enantiomers by SFC (Column: Chiralpakº AD-H, 50 X 250 mm, 5 µm; Mobile Phase A: CO ;; Mobile Phase B: Ethanol; Isocratic: 40% B with CO recycling on; Flow Rate : 200 g / min; Load: 2.0 mL of sample prepared as above (-100 mg); Detection: UV € & 230 nm; Cycle Time: 5 min; Total Elution Time: 10 min; Instrument: Thar 350 (Lakers)) provided (S) -N, N-bis (4-methoxybenzyl) pent-4-ene-2-sulfonamide as the first isomer to elute (retention time: 2.22 min) and (R) -N , N-bis (4-methoxybenzyl) pent-4-eno- 2-sulfonamide as the second isomer to elute (retention time: 2.57 min).
[000696] [000696] To a solution of (R) -N, N-bis (4-methoxybenzyl) pent-4-ene-2-sulfonamide (Intermediate EEl7, Step 1, second
[000698] [000698] N, N-bis (4-methoxybenzyl) but-3-ene-1-sulfonamide (Intermediate EEl6; 40.0 g, 106.6 mmol) was subjected to azeotropic treatment in toluene under vacuum for 2 h.
[000715] [000715] To a BFR of 3-necked 1000 mL was added (2R, 3S) -3-methyl-hex-5-ene-2-sulfinate (from Intermediate EE22, Step 5; 46 g, 225 mmol) , 500 mL of H20O and KOAc (44.1 g, 449 mmol) at rt The flask was placed in an oil bath at 45 ºC and hydroxylamino-O-sulfonic acid (21.09 g, 187 mmol) was added in portions over 90 min. The internal temperature of the reaction was monitored and the reaction was removed from the oil bath (if necessary) to control the exotherm (Tmax = 55 ºC). The reaction was monitored by LC / MS every 10 min and was completed after the addition of 0.83 eq. hydroxylamino-O-sulfonic acid. The mixture was then cooled to r.t. and was extracted with 1000 ml of EtOAc. The organic phase was extracted three times with 500 ml of 1N HCl, twice with 300 ml of sat. Sodium bicarbonate, once with 200 ml of brine, dried over NasSOs, filtered and concentrated by rotary evaporation, giving rise to (2R, 3S) - 3-methyl-hex-5-ene-2-sulfonamide (32 g, 181 mmol) as a white solid. INTERMEDIATE 1 was loaded onto a 220 ISCO Gold column and purified eluting with% to 20% EtOAc (containing 0.3% ACOH) / heptanes, yielding (S) -6'-chloro-5 - ((( 1R, 2R) -2- ((S) -1-hydroxyaloyl) cyclobutyl) methyl) -N - (((2R, 3S) -3-methyl-hex-5-en-2-yl) sulfonyl) -3 ' , 4,4 ', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxamide (7.89 gq, 12, 58 mmol, 76% yield). STEP 2: (18,3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-CHLORINE-7'-HYDROXY- 11 ', 12' -DIMETHYL-3,4-DI- HYDRO-2H, 15'H-SPIRAL [NAFTALENO- 1,22'-
[20] [20] OXA [13] TIA [1,14] DIAZATETRACYCLE [14.7.2.03 -6.019 24] PENTAC OSA [8,16,18,24] TETRAEN] -15 '-ONA 13', 13'-DIOXIDE
[000717] [000717] A 20 L reactor jacketed in argon was loaded with 14 L of 1,2-DCE. (S) -6'-chloro-5 - ((((1R, 2R) -2- ((S) -1-hydroxyaloyl) cyclobutyl) methyl) -N - ((((2R, 3S) -3-methyl-hex -5-en-2-yl) sulfonyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H- spiro [benzo [b] [1,4] oxazepine-3,1'- naphthalene] -7-carboxamide (18.75 g, 29.9 mmol) was added as a solution in 400 ml of 1,2-DCE followed by a 400 ml rinse. The reactor was sealed and purged with argon. Hoveyda-Grubbs II (1.873 g, 2.99 mmol) was added as a solution in 150 ml of 1,2-DCE followed by a 50 ml rinse. The reactor was heated to 60 ºC over 1 h with an argon sweep in the top space and kept at temperature for 9 h. The reaction was quenched by the addition of 2- (2- (vinyloxy) ethoxy) ethanol (1.501 g, 11.36 mmol), cooled to room temperature and concentrated to - 200 mL volume by rotary evaporation. The reaction was transferred to a 1 L BFR and diluted to 500 ml of volume with 1,2-DCE. The reaction was treated with 52 g of Si-Thiol Silicycle (SiliCycle Inc., Quebec City, Quebec CANADA Cat * t R51030B) with stirring for 9 h at 40 “ºC, filtered and rinsed with 2 x 65 ml of DCM. The solution was passed through a Whatman GF / F filtration cup (GE Healthcare Bio-Sciences Pittsburgh, PA, USA), yielding a clear yellow solution. The reaction was concentrated, giving a crude product mass of 27.4 g. The residue was slurried in 250 ml of IPAc and evaporated to dryness three times. The reaction was suspended in 270 ml of IPAc, heated to dissolve, allowed to cool to room temperature and stirred for
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0 6,019-2)] pentac osa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide which is 91.7% by weight. 'H NMR (500 MHz, CD2Cl2) 5 8.06 (s, 1 H), 7.71 (d, J = 8.56 Hz, 1 H), 7.17 (dd, J = 8.44, 2 , 32 Hz, 1 HH), 7.09 (d, J = 2.20 Hz, 1 H), 6.91 (s, 3 H), 5.81 (ddd, J = 14.92, 7.82 4.16 Hz, 1 H), 5.71 (dd, J = 15.41, 8.31 Hz, 1 HH), 4.16 - 4.26 (m, 2 H), 3.83 (d, J = 14.43 Hz, 1 H), 3.69 (d, J = 14.43 Hz, 1 H), 3.25 (d, J = 14.43 Hz, 1 H), 3.04 (dd , J = 15.28, 9.66 Hz, 1 H), 2.68 - 2.84 (my, 2 H), 2.41 (apparent qd, J = 9.80, 3.70 Hz, 1 H ), 2.25 - 2.34 (my, 1 H), 1.93 - 2.00 (my, 5 H), 1.74 - 2.11 (my, 9 H), 1.62 - 1, 73 (my, 1 H), 1.43 (d, J = 7.09 Hz, 3 H) 1.35 - 1.42 (my, 1 H) 1.03 (d, J = 6.60 Hz, 3 H). MS (ESI, + ve ion) m / z 599.2 (M + H) *.
[20] [20] oxa [13] aunt [1, 14] diazatetracycle [14.7.2.0 6,019-24)] pentac osa [16,18,24] triene] -7 ', 15'-dione 13', 13'-dioxide as a solid (0.85 g, 70% yield). MS (ESI, + ve ion) m / z 599.2 (M + H) *.
[000721] [000721] The inhibition of Mcl-1 / Bim interaction was measured using a time-resolved fluorescence resonance energy transfer assay (TR-FRET). Recombinant human Mcl-1 (Mcl-1 with 6xHis C-terminal tail containing residues 171-327) was generated at Amgen Inc (Thousand Oaks, CA). A biotinylated peptide derived from human Bim (residues 51-76) was purchased from CPC Scientific (San Jose, CA). The TR-FRET assay was conducted on a white 384-well OptiPlate! "" "(PerkinElmer, Waltham, MA) in a total volume of 40 ul. The reaction mixture contained 0.1 nM Mcl-1 (171-327),
[000722] [000722] The human multiple myeloma cell line, OPM-2, was cultured in complete growth medium containing RPMI 1640 and 10% fetal bovine serum (FBS). The cells were seeded in 384-well plates at a density of 3000 cells / well in complete growth medium containing 10% FBS and incubated for 16 h with test compounds diluted in series in an incubator at 37 ºC with 5% CO. Cell viability was tested using the CellTiter-Gloº assay (Promega, Madison, WI) according to the manufacturer's recommendations. Luminescence was determined using an EnVisionº Multilabel plate reader 25 min after adding detection reagent. ICso values were then calculated with Xlfit using a 4-parameter logistic adjustment model in GraphPad Prism (GraphPad Software, San Diego, CA) or in Genedata Screenerº (Genedata, Basel, Switzerland).
[000723] [000723] The results for compounds tested in these biological assays are shown below in Table 4 and Table 5. TABLE 4 Number of Mcl-1 HTRF ICso OPM-2 FBS 10% Example (uM) ICso IP (UM) 0.0007109 0, 0000294 EN 0.000116 Ds 0.0000729 0.000058 | so aee | 00 | aee | 00 and | oem | om and eee | or so | eos | the so | ones | one so eee | as so een | asso
[000724] [000724] Figures 1-7 illustrate the PD results of the cited Examples. Reference Compound 1, an internal Amgen MCl-11 inhibitor compound prepared by one of the general schemes outlined in US Patent No. 9,562,061 incorporated herein by reference, is (18,3'R, 6'R, 7'S, 8'E, 12'R) -6-chloro-12'-ethyl-7'-methoxy-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-
[20] [20] oxa [13] tia [1, 14] diazatetracyclo [14.7.2.0-3,6-.0-19,24 + pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide. OMe
[000725] [000725] Female athymic nude mice (Charles River Laboratories, Inc., Hollister CA) were inoculated subcutaneously with 5 x 10 th Luc OPM-2 cells. When did the tumors reach 300-500 mm in size, the mice were randomly assigned to treatment groups and collected 6 hours after a single dose of compound at various concentrations. Tumor lysates were analyzed for active Bak using a sandwich ELISA format (Active Bak MSD cat HN45ZA-1 plate; Bak detection antibody
[000726] [000726] Examples 8-13 illustrate Xenograft data for various compounds of the present invention. Female athymic nude mice (Charles River Laboratories, Inc., Hollister CA) were inoculated subcutaneously with 5 x 10 th Luc OPM-2 cells. When the average tumor volumes reached approximately 155-183 mm º, the animals were randomly distributed (n = 10 / group) and dosed once a day by oral gavage (10-12 days) with test compounds at various concentrations, at unless otherwise noted. Tumor volume and body weights were recorded twice a week using electronic calipers and an analytical balance. Statistical analysis was performed using ANOVA with Repeated Measurements (RMANOVA) followed by Dunnett's post-hoc analysis.
[000727] [000727] The foregoing description is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, compositions and methods. Variations and modifications, which are obvious to the person skilled in the art, are intended to be within the scope and nature of the invention, as defined in the accompanying Claims. From the above description, the person skilled in the art can easily determine the essential characteristics of this invention and, without abandoning its spirit and scope, can make several changes and modifications of the invention to adapt it to various uses and conditions.
All patents and other publications listed here are hereby incorporated by reference in their entirety.
6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members or a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, where heteroaryl, spiroheterocycloalkyl or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also in that the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO> z;
Rº is selected from H, -Ciçcalquil-halo, -C1i salquila, -Cr-salquenila, - (CH2CH2O) nRº, -C (= O) Ri, -C (= 0) ORº or —C (= O) NRºRbP;
each of Rº%, RCº, Ri, R, Rº, Rº and Rº is independently selected from H, halo, -Ci-shaloalkyl, -Ci-salquila, -O-Ci-salquila, -Corçalquenila, -Ci-salquil- O-C1- salkyl, —- (CH2CH20O) nRº, -SO2Rº , -C (= O) Rº, -C (= O) ORº, - OC (= O) Ri, -C (= O) NRºRº, um 6 to 12 membered aryl or heteroaryl, 5 to 12 membered spirocycloalkyl or spiroheterocycloalkyl, 3 to 12 membered cycloalkenyl, 3 to 12 membered monocyclic or bicyclic cycloalkyl or 3 to 12 monocyclic or bicyclic heterocycloalkyl group members, in which the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, in which the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a group C = O and also where the spiroheterocycloalkyl and heterocycloalkyl groups can include an S = O or SO>;
alternatively, R º and Ré, together with the atoms to which they are attached, can form a ring with 5 to 12 members, optionally containing a heteroatom selected from an N, O or S atom, in addition to the present S and N atoms in the ring, where the ring can optionally contain at least one double bond; and the ring can be substituted with 0, 1, 2 or 3 substituents Rº *;
where R º is selected from H, halo, -OH, Ci shaloalquila, Ci-salquila, O-Ci-salquila, Co-salquila, -C1i- salquil-O-Ci-salquila, - (CH2CH20) nRº, - -SO2Rº, -C (= O) Rê, - C (= 0) ORi, -OC (= O) Rº or -C (= O) NRºRP;
each of R%, RA, Rº5, RA and Rºº is independently selected from H, OH, halo or -Ci-salquila;
R'º and R% º are absent when b is a double chemical bond;
alternatively, R 'and Rº, together with the atoms to which they are attached, can form a ring with 3 to 12 members, where the ring can optionally contain at least one double bond;
Rº is independently selected from H, OH, - (= O), -Ci- «haloalkyl, -Ci-salkyl, -Ci-alkylene, - (CH2CH20) nRº, -C (= O) Ri, -C (= 0O ) ORi, -C (= O) NRIRr, -Cisalkyl-O-Ci-salkyl, cyano, an aryl or heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with
3 to 12 members, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C group = O and also where the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO> ;;
Rº ”* is independently selected from H, -OH, halo, cyano, -Ci-sehaloalkyl, -Ci-salkyl, -Co-Cealkenyl, -Co-Csalquinyl, - (CHoCH2O) nRº, -P (= 0) ORSORP, -CSRº, -CS (= O) Rº, -SRi, -SORº, -OSO2Rº, -SO2Ri, - (CH2CH20) nCH3, - (= O), -C (= 0), - C (= O) Rº, -C (= O) ORº, —C (= O) NRºR>, —-CH2-NRºR>, -NRºRP, -C1- salkyl-O-Ci-salkyl, -OCi-salkyl, -O-Ci-calkyl- O-C1- salkyl, phenyl, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the groups cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl may contain a double bond and may contain a group C = O and also in which the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO> z;
where R ** º is not H when W is absent;
where the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the Rº * substituent may be unsubstituted or substituted with 1, 2, 3 or 4 R! º substituents independently selected from OH, halo, -NRºRi, -Cicgalkyl, -Ci-Cralkenyl, -Ci-Kealquinyl, -OC1- salkyl, -Ci-salkyl-OH, -Ci-salkyl-O-Ci-csalkyl, C1- 6ehaloalkyl, -O-haloCi-salkyl, -SO2Rº, -CN, -C (= O) NRºRI, - C (= O) Re, -OC (= O) Rº, -C (= 0) OR “, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, in which the heteroaryl groups , spiroheterocycloalkyl and heterocycloalkyl have O, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, in which the cycloalkyl, spiroc groups icloalkyl, spiroheterocycloalkyl and heterocycloalkyl may include a C = O group and also in which spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO>;
alternatively, R 'and Rº, together with the atoms to which they are attached, can form a ring with 3 to 12 members, where the ring can optionally contain at least one double bond;
alternatively, Rº and R% 4, together with Q, W and the C to which W and Q are attached, can form a monocyclic or bicyclic ring with 3 to 12 members, optionally containing a heteroatom in addition to Q which is selected from
N, O or S, where the ring can contain a double bond, where the ring can optionally include a C = O group and also where the ring can be optionally substituted with 1, 2 or 3 R !! substituents;
R! ' is independently selected from H, -OH, halo, -Ci-salkyl, -OCi-salkyl, -Ci-salkyl-OH, -Ci-salkyl- O-Ci-salkyl, -Ci-haloalkyl, -O-haloCi-salkyl , -SOXRº, - CN, -NRºR4i, -C (= O) NRºRi, y -C (= O) Rº, -OC (= O) Rº, -C (= O) ORº, an aryl or heteroaryl with 6 up to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, in which groups heteroaryl, spiroheterocycloalkyl and heterocycloalkyl have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a double bond and in which cycloalkyl groups, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl may include a C = O group and also in which the spiroheterocycloalkyl and heterocyclo groups cloalkyl may include an S = O or SO> z;
where Ci-salquila, Coçalquenila, Cro-salquinila and -OCi-salquila of any of the substituents R !, R º, Rº, R $, Rº, Rº, R ', Rê, Rº, R! º, RU , R $, RA, R $, RA, R $, Rº, RIA and R “P are not substituted or are substituted with 1, 2 or 3 substituents R ' independently selected from OH, - OCi-salkyl, -Ci-salkyl-O-Ci-salkyl, halo, -O-haloC1-
salquila, CN, —-NRºRP, - (NRºRPRº) n, -OSO2R , —-SO2Rº, - (CH2CH20) nCH3, - (= O), -C (= O), -C (= O) Rº, - OC (= O) Rº, -C (= 0O) OR ”, -C (= O) NRIRP, —-O-SiRºRPRºe, -SiRºRPRºe, -O- (heterocycloalkyl with 3 to 10 members), an aryl or heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also in whereas the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO>;
in which the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any of the substituents Rº, Ré, Ró, Rº, R ', Rºà, Rº, R%, RV, RU, RV, RW and RW may not be substituted or substituted with 1, 2, 3 or 4 R! substituents independently selected from OH, halo, —-NRºR9, -Ci-salkyl, r-OCi-csalkyl, -Ci-salkyl-OH, -C1-calkyl-O-Ci-salkyl, Ci-haloalkyl, -O-haloCi-salkyl , - SO2Rº, -CN, -C (= O) NRºRi, -C (= O) Rº, -OC (= O) Ri, -C (= 0) ORº, an aryl or heteroaryl with 6 to 12 members, one spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, cycloalkenyl with 3 to 12 members, monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with
3 to 12 members, in which the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of R! º have 1, 2, 3 or 4 heteroatoms independently selected from O, N or Ss, in which the cycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of R! 3 or the heterocycloalkyl group of R ! they may include a C = O group and also in which the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO>;
where each Rº, RP, Rº and Rº is independently hydrogen, OH, -Ci-salquila, -Co-salkenyl, -Co-salquinyl, -Ci-salquyl-NRIRII, -NRIRII, -SO2RM, —- (CH2CH2O) nCH3 , - (= O), - C (= 0O) R'é, OC (= O) R! º, —-C (= O) OR! É, —C (= O) NRXRIA, -C1- ehaloalkyl, -O-haloCi-salkyl, -Ci-salkyl-O-Ci-salkyl, benzyl, phenyl, -Ci-salkyl-C (= 0) OH, -Ci-salkyl-C (= 0) -O-C1- salkyl , -Ci-salkyl-cycloalkyl, -Ci-salkyl-heterocycloalkyl, -Ci-salkyl-aryl with 6 to 12 members, -Ci-salkyl-heteroaryl with 6 to 12 members, one aryl or heteroaryl with 6 to 12 members, one spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members or cycloalkenyl with 3 to 12 members, monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, in which the heteroaryl group, spiro- heterocycloalkyl, heterocycloalkyl or the -C1i calkylheterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, Rº, RP, Rº and Rº heterocycloalkyl group or the heterocycloalkyl group or the -Ci-salquyl- group
or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt of its stereoisomer,
characterized by the fact that:
Zé CouN;
Qéocous;
W is CRWR "E or C = 0O;
RW and RW are independently selected from H, Ci-3alkyl, halo, -OH or -O-Ci-zalkyl;
b, represented by the symbol = "===== -, is a single or double chemical bond that can be cis or trans;
R! is independently selected from H, halo, C1-alkyl-halo, Ci xalkyl, - (CH2CH2O) nRêi, -SO2Rº, -C (= O) Ri, - C (= 0) ORº or -C (= O) NRºR> ;
Rº is selected from H, halo, -Ci- «haloalkyl, -C1-calkyl, -O-Ci-salkyl, -Cao-salkenyl, -Ci-salkyl-O-C1- salkyl, - (CH2CH2O) nRº, -SO2Rºi, -C (= O) Ri, -C (= 0) ORº, -OC (= 0) R or -C (= O) NRºR ',
Rº is independently selected from H, -Ci salquil-halo, -Ci-salquila, -Corçsalquenila, - (CHOCHO) nRi, - C (= O0) Ri, -C (= 0) ORº or -C (= O) NRºR > b;
each of Rº, Rº, Rº, R 'and Rº is independently selected from H, halo, -Ci «haloalkyl, -Ci-çalquila, -O-C1i- calquila, -Co-salquenila, -Ci-salquil-O- Ci-salquila, - (CH2CH20) nRº, -SO2R , -C (= O) Rº, —-C (= 0) ORº, OC (= O) Rº, - C (= O) NR&RP, an aryl or heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, in that the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO>;
alternatively, R º and Ré, together with the atoms to which they are attached, can form a ring with 5 to 12 members, optionally containing a heteroatom selected from an N, O or S atom, in addition to the present S and N atoms in the ring, where the ring can optionally contain at least one double bond; and the ring can be substituted with 0, 1, 2 or 3 substituents Rº *;
R * Is independently selected from H, halo, - OH, Ci-shaloalkyl, Ci-salquila, O-Ci-salquila, Co-salquenyl, -Ci-salquil-O-Ci-salquila, - (CHXCH2O) nRi, - SOXRi, -C (= O) Ra, - C (= 0) OR, -OC (= O) Rº, -C (= O) NRºRº;
each of Rº, Rºº, R & º, RA and Rºº is independently selected from H, OH, halo or -Ci-salquila;
R'º and R% º are absent when b is a double chemical bond;
Rº is independently selected from H, -C1i and & haloalkyl, -Cisalkyl, -Crçalquenila, -Corçalquinila, - (CH2CH20) nRº, -C (= O) Rº, -C (= 0) ORº, -C (= O) NRºRb, -Ci-salquil-o- Ci-salquila, an aryl or heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl groups , spiroheterocycloalkyl and heterocycloalkyl may include a C = O group and also in which spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO>;
Rº ”is independently selected from H, C1 ehaloalkyl, Ci-alkyl, -Corçalquenila, -Coçalquinila, - (CH2CH20) nRº, -SO2Rº, -C (= O) Ri, -C (= 0) ORº, -C (= O) NRºRP, -NRºRP, -N = N = N, -Cigalkyl-O-Ciçalquila, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, one cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, in which the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also where the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO>;
where the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the Rº * substituent may be unsubstituted or substituted with 1, 2, 3 or 4 R! º substituents independently selected from OH, halo, -NRºRi, -Cicgalquila, -Cr-Cralkenyl, -Co-Ceralquinyl, -OC1i- csalkyl, -Ci-salquyl-OH, -Ci-salquyl-O-Ci-salquila, C1- shaloalquila, -O-haloCi-salquila, -SO2Rº, -CN, -C (= O) NRºRI, - C (= O) Rº, -OC (= O) Ra, -C (= 0) ORº, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members , a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, in which the heteroaryl groups, spiroheterocycloalkyl and heterocycloalkyl have O, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, in which the cycloalkyl, spi rocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl may include a C = O group and also in which spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO>;
alternatively, Rº and R *% º, together with Q, W and the C to which W and Q are attached, can form a monocyclic or bicyclic ring with 3 to 12 members, optionally containing a heteroatom in addition to Q that is selected N, O or S, where the ring can contain a double bond, where the ring can optionally include a C = O group and also where the ring can be optionally substituted with 1, 2 or 3 R !! substituents;
R !! is independently selected from OH, halo, - NRºRi, -Cigalquila, -OCi-salquila, -Ci-salquil-OH, -Ci-salquil- O-Ci-salquila, Ci-khaloalkyl, -O-haloCi-salquila, -SOZRº , - CN, -C (= O) NRºRi, -C (= O) Rº, -OC (= O) Rº, -C (= 0) ORº, an aryl or heteroaryl with 6 to 12 members, a spirocycloalkyl or spiro -heterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocyclic group with 3 to 12 members, in which the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also where the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO>;
where the -Ci-salquila of any of the substituents R !, R , Rà, Ri, Rº, Rº, R /, Rº, Rº, RU, RU, RO, Rº% º, R%, RA, R8 and R % º are not substituted or are substituted with 1, 2 or 3 substituents R ! independently selected from OH, -OCi-salquila, -Ci- salquyl-O-Ci-salquila, halo, -O-haloCi-salquila, -CN, -NRºRº, - (NRºRPRº) n, -SO2Rº, - (CH2CH20) nCH3a , (= O), -C (= O), -C (= O) Rº, - OC (= O) Ra, —C (= 0) ORº, —C (= O) NRºR>, -O-SiRARPRº , -o- (heterocycloalkyl with 3 to 12 members), phenyl, an aryl or heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also in which the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO>;
where the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any of the substituents Rº, Ré, Ró, Rº, R ', Rº, Rº, R! |, RU and R! 2 may not be substituted or be substituted with 1, 2, 3 or 4 R! substituents independently selected from OH, halo, -Ci-salquila, - OCi-calkyl, -Ci-salkyl-OH, -Ci-salkyl-O-Ci-salkyl, C1- ehaloalkyl, -O-haloCi-salkyl, -SO2Rº, - -NR-Rº, -CN, - C (= O) NRºRi, -C (= O) Rº, -OC (= O0) Ri, -C (= 0) ORº, -B (OH) », an aryl or heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C = O group and also in which the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO>;
where each Ri, RP, Rº and Rº is independently H, OH, -Ci-salquila, -Ci-salquénila, -Co-salquinila, -Ci-salquil- NRURI, NRÚRII, -SOXRV, —- (CH2CH2O0) nCH3a, (= O), -C (= O) RV, - OC (= O) R !, -C (= O) ORM, -C (= O) NRKRX, Cirehaloalkyl, -O-
haloCi-salquila, -Ci-salquil-O-Ci-salquila, -Ci-salquil-OH, benzyl, phenyl, a -Ci-salkyl-heterocycloalkyl with 3 to 12 members, an aryl or heteroaryl with 6 to 12 members, one spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, cycloalkenyl with 3 to 12 members, monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl group with 3 to 12 members, in which the heteroaryl groups, spiro- heterocycloalkyl and heterocycloalkyl and the heterocycloalkyl group of the -Ci-salkylheterocycloalkyl group have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, in which cycloalkyl, spirocycloalkyl spiroheterocycloalkyl, heterocycloalkyl and heterocycloalkyl groups -Ci-salkylheterocycloalkyl may include a C = O group and also in which the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO> z;
the alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl and the heterocycloalkyl groups of the -Ci-salkylheterocycloalkyl groups of Ri, Rº, Rº and Rº may not be substituted or replaced with 1, 2, 3 or 4 R! º substituents independently selected from H, OH, - N = N = N, halo, -Ci-salkyl, -OCi-salkyl, Ci-haloalkyl, -O- haloCi-salkyl, phenyl, tolyl, -C (O ) C1-salkyl, -C (O0) OCH; 3, SO2-phenyl or -SO2-N (CH3) 2; and n is independently, in each case, an integer of 1, 2, 3 or 4.

权利要求:
Claims (1)
[1]
A compound according to any one of claims 5, 6 and 7, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Z is N.
A compound according to any one of claims 5, 6, 7, 8 and 9, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Q is O.
A compound according to any one of claims 5, 6, 7, 8, 9 and 10, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that W is CRWAR "AND,
A compound according to any one of claims 5, 6, 7, 8, 9, 10 and 11, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that R º and RP are both H.
A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11 and 12, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that would you like! it's halo.
A compound according to claim 13 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that R 'is Cl.
A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11, 12 and 13, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by fact that Rº is H.
A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is H or -Ci-.alkyl.
A compound according to claim 16, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is -CH;
A compound according to claim 16, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is H.
A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is selected from H, -Cisalkyl, -Cigalkyl-halo, -Cicalkyl- O-Ci-salkyl or - (CH2CH20) nRêi, in which -Ciçalquila is not substituted or is substituted with -OH, (= O), phenyl, -O- SiRºRPRºe, -NRºRP, a cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocycloalkyl with 3 to 12 members having 1, 2, 3 or 4 hetero atoms independently selected from O, N or S.
A compound according to claim 19, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that D is H.
21. The compound according to claim 19, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is -Cri salquila.
22. A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19 and 21, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is -CH; 3.
A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19, or its stereoisomer, its pharmaceutically salt acceptable or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is -CH2CH2OCH3.
24. A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and 23, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is H or -Ci-salquila.
25. A compound according to claim 24, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is -CH;
26. A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25, or O its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that R is H or -C1- alkyl.
27. A compound according to claim 26, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is H.
28. A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 , 25, 26 and 27, OR Its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that each of Rº, Rº, R% º, RA and Rºº is independently selected from H , OH, halo or -C1-salkyl.
29. A compound according to claim 28 or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that each of RA, R5A, R &%, RA and R $ is H ,
A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 and 29, or Its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is independently selected from H, -Ci-salquila, -Co-salquenila or -Ci-salquil- O-Ci-salquila or -Ci-shaloalkyl.
31. A compound according to claim 30, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is H.
32. A compound according to claim 30, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is -CH;
33. A compound according to claim 30, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is -CHsCH; 3.
34. A compound according to any one of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 , 25, 26, 27, 28, 29, 30, 31, 32 and 33, or Its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized by the fact that Rº is selected from H, Ci «Haloalkyl, Ci-salquila, -Co-salkenyl, —- (CH2CH20) nRºà, -SO2Rº, -C (= O) Ri, -C (= 0) ORº , -C (= O) NRºRP, -NRºRP, -N = N = N, -Ci-alkalkyl-O-Ci-csalkyl, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 up to 12 members, a monocyclic or bicyclic cycloalkyl with 3 to 12 members or a monocyclic or bicyclic heterocyclical group with 3 to 12 members, where the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, where the cycle groups alkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl may include a C = O group and also in which the spiroheterocycloalkyl and heterocycloalkyl groups may include an S = O or SO;
35. A compound according to claim 34, or its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutically acceptable salt of its stereoisomer, characterized in that the monocyclic heterocycloalkyl group with 3 to 12 members Rº * º may not be substituted or substituted with 1, 2, 3 or 4 R! º substituents independently selected from OH, halo, -NRºRi, -Cicgalquila, -Ci-Cralquenila, -Ci-Ceralquinila, -OC1-salquila, -Ci-salquil-OH , -Ci-salkyl-O-Ci-csalkyl, C1-6ehaloalkyl, -O-haloCi-salkyl, -SO2Rº, -CN, -C (= O) NRºRI, - C (= O) Re, -OC (= O ) Rº, -C (= 0) OR “, an aryl with 6 to 12 members, a heteroaryl with 6 to 12 members, a spirocycloalkyl or spiroheterocycloalkyl with 5 to 12 members, a cycloalkenyl with 3 to 12 members, a cycloalkyl monocyclic or bicyclic with 3 to 12 members or a monocyclic or bicyclic heterocyclic group with 3 to 12 members, in which the heteroaryl, spiroheterocycloalkyl or heteroc groups icloalkyl have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, in
48. Method, according to claim 47, characterized by the fact that cancer is a hematological malignancy.
49. Method according to claim 47, characterized by the fact that the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, cancer non-small cell lung, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia and acute myelogenous leukemia.
50. Method according to claim 49, characterized by the fact that cancer is multiple myeloma.
51. The method of claim 47, characterized in that it also comprises administering to the needy patient a therapeutically effective amount of an additional pharmaceutically active compound.
52. The method of claim 51, characterized in that the additional pharmaceutically active compound is carfilzomib.
53. The method of claim 51, characterized in that the additional pharmaceutically active compound is venetoclax.
54. The method of claim 51, characterized in that the additional pharmaceutically active compound is cytarabine.
55. Use of a compound as defined in any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
40, 41, 42, 43, 44 and 45, characterized by the fact that it is for the treatment of cancer in a subject.
56. A compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 and 45 , characterized by the fact that it is for the preparation of a drug for the treatment of cancer.
57. Compound according to claim 56, characterized by the fact that cancer is a hematological malignancy.
58. Compound according to claim 56, characterized by the fact that cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, cancer non-small cell lung, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia and acute myelogenous leukemia.
59. Compound according to claim 58 characterized by the fact that cancer is multiple myeloma.
60. Compound according to claim 58 characterized by the fact that cancer is acute myelogenous leukemia.
61. Compound according to claim 58 characterized by the fact that cancer is non-Hodgkin's lymphoma.

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法律状态:
2021-04-13| B15V| Prolongation of time limit allowed|Free format text: TENDO EM VISTA A PORTARIA INPI PR NO 120 DE 16/03/2020, PORTARIA INPI PR NO 161 DE 13/04/2020; PORTARIA INPI PR NO 166 DE 27/04/2020 E PORTARIA INPI PR NO 179 DE 11/05/2020, QUANTO A SUSPENSAO DOS PRAZOS VENCIDOS ENTRE 16/03/2020 A 31/05/2020, E PORTARIA INPI NO 334 DE 24/09/2020, QUANTO AOS PRAZOS VENCIDOS ENTRE 16/09/2020 A 25/09/2020, DEVOLVE-SE O PRAZO NESSE PEDIDO COM RELACAO A SOLICITACAO DO PEDIDO DE EXAME. |

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2021-09-21| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2022-02-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

优先权:

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