substituted quinolizine-derived compounds, pharmaceutical composition comprising them and use of sai

专利摘要:
SUBSTITUTED QUINOLIZINE DERIVATIVES, PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS THEM AND USE OF THE SAME. The present invention relates to Substituted Quinolizine Derivatives of formula (I): (I) and pharmaceutically acceptable salts or prodrugs, wherein X, Y, R 1, R 2, R 3, R 4, R 5 , R 9 and R 10 are as defined in the present invention. The present invention also relates to compositions comprising at least one substituted quinolizine derivative, and methods of using the Substituted Quinolizine Derivatives for the treatment or prevention of HIV infection in a subject.
公开号:BR112016006651B1
申请号:R112016006651-0
申请日:2014-09-26
公开日:2021-01-12
发明作者:Tao Yu；Yonglian Zhang；Sherman Tim Waddell；Andrew Stamford；John S. Wai；Paul J. Coleman；John M. Sanders；Ronald Ferguson
申请人:Merck Sharp & Dohme Corp.；
IPC主号:

专利说明:

FIELD OF THE INVENTION
The present invention relates to substituted quinolizine derivatives, compositions comprising at least one substituted quinolizine derivative, and methods of using the substituted quinolizine derivatives for the treatment or prevention of HIV infection in a subject. BACKGROUND OF THE INVENTION
[002] A retrovirus called human immunodeficiency virus (HIV), in particular strains known as HIV type 1 virus (HIV-1) and HIV type 2 virus (HIV-2), is the etiological agent of complex disease that includes the progressive destruction of the immune system (acquired immunodeficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. A common feature of retrovirus replication is the insertion by viral-encoded integrase of pro-viral DNA into the host cell genome, a necessary step in the replication of HIV in human lymphoid and monocytoid cells. It is believed that integration is mediated by integrase in three stages: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from 3 'ends of linear pro-viral DNA; covalent attachment of the 3 'OH terminals of the pro-viral DNA in a zigzag cut made at the host's target site. The fourth step in the process, synthesis of repair of the resulting gap, can be carried out by cellular enzymes. Nucleotide sequencing of HIV shows the presence of a pol gene in an open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for HIV replication.
[003] The following references may be of interest as a basis:
[004] International Publications no. WO 11/045330 and WO 11/121105 disclose macrocyclic compounds having HIV integrase inhibitory activity.
[005] Kinzel et al., Tet. Letters 2007, 48 (37): pp. 6552-6555 discloses the synthesis of tetrahydropyride pyrimidones as a framework for HIV integrase inhibitors 1.
[006] Ferrara et al., Tet. Letters 2007, 48 (37), pp. 8379-8382 discloses the synthesis of a hexahydropyrimido derivative [1,2-a] azepine-2-carboxamide useful as an inhibitor of HIV integrase.
[007] Muraglia et al., J. Med. Chem. 2008, 51: 861-874 discloses the design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV 1 integrase inhibitors.
[008] US2004 / 229909 discloses certain compounds that have integrase inhibitory activity.
[009] US 7232819 and US 2007/0083045 disclose certain 5,6-dihydroxy-pyrimidine-4-carboxamides as HIV integrase inhibitors.
[010] US7169780, US7217713 and US2007 / 0123524 disclose certain N-substituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides as inhibitors of HIV integrase.
[011] US7279487 discloses certain hydroxy-naphtridinone carboxamides that are useful as inhibitors of HIV integrase.
[012] US7135467 and US7037908 disclose certain carboxamide pyrimidines that are useful as inhibitors of HIV integrase.
[013] US7211572 discloses certain nitrogen condensed ring compounds that are inhibitors of HIV integrase.
[014] US7414045 discloses certain tetrahydro-4H-pyrido [1,2-a] pyrimidine carboxamides, hexahydropyrimido [1,2-a] azepine carboxamides, and related compounds that are useful as inhibitors of HIV integrase.
[015] US 8129385 discloses certain hexahydro-2H-pyrido [1 ', 2': 4,5] pyrazine [2,1-b] [1,3] oxazine-9-carboxamides, and related compounds are useful as inhibitors of HIV integrase.
[016] WO2006 / 103399 discloses certain tetrahydro-4H-pyrimido-oxazepine carboxamides, tetrahydropyrazinopyrimidine carboxamides, hexahydropyrimidodiazepine carboxamides, and related compounds that are useful as HIV integrase inhibitors.
[017] US2007 / 0142635 discloses processes for the preparation of hexahydropyrimido [1,2-a] azepine-2-carboxylates and related compounds.
[018] US 2007/0149556 discloses certain hydroxy-pyrimidinone derivatives having HIV integrase inhibitory activity.
[019] Various pyrimidinone compounds useful as HIV integrase inhibitors are also disclosed in the documents of US7115601, US7157447, US7173022, US7176196, US7192948, US7273859 and US7419969.
[020] US2007 / 0111984 discloses a series of bicyclic pyrimidine compounds useful as inhibitors of HIV integrase.
[021] US2006 / 0276466, US2007 / 0049606, US2007 / 0111985, US2007 / 0112190, US2007 / 0281917, US2008 / 0004265 each disclose a series of bicyclic pyrimidine compounds useful as HIV integrase inhibitors.
[022] For future reference, it will be necessary to include the published application for MRL-IFH-0009-PSP. SUMMARY OF THE INVENTION
[023] In one aspect, the present invention provides Compounds of Formula (I):
or a pharmaceutically acceptable salt thereof, where: X is selected from a 5- or 6-membered, single-bonded and -N (R6) C (O) - monocyclic heteroaryl; Y is a single bond or C1-C3 alkylene; R1 is selected from C6-C10 aryl, 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl, wherein said C6-C10 aryl group, said 5- or 6-membered monocyclic heteroaryl group and said group 9- or 10-membered bicyclic heteroaryl can optionally be substituted with up to three R8 groups; R2 is H, C1-C6 alkyl, -N (R11) 2, or -OR7 or R2 and R4, together with the carbon atoms to which they are attached, can join to form a monocyclic cycloalkyl group of 5 to 8 members, a 5-8 membered monocyclic heterocycloalkyl group, a 5-8 membered monocyclic heterocycloalkyl group or an 8-11 membered bicyclic heterocycloalkyl group, wherein said 5-8 membered monocyclic cycloalkyl group, said 5 to 8 membered monocyclic heterocycloalkyl group, said 5 to 8 membered monocyclic heterocycloalkenyl group and said 8 to 11 membered bicyclic heterocycloalkyl group can be optionally substituted with up to three R8 groups, which may be the same or different; R3 is H, C1-C6 alkyl, -N (R11) 2 or -OR7; R4 is selected from H, C1-C6 alkyl, - (C1-C6 alkylene) -O- (C1-C6 alkyl), -N (R11) 2 and -OR7, so that when R2 and / or R3 are -N (R11) 2, so R4 is different from H; R5 is selected from H, C1-C6 alkyl, - (C1-C6 alkylene) -O- (C1-C6 alkyl), -N (R11) 2 and -OR7, so that when R2 and / or R3 are -N (R11) 2, so R5 is different from H; each occurrence of R6 is independently H or C1-C6 alkyl; each occurrence of R7 is independently selected from H, C1-C6 alkyl, - (C1-C6 alkylene) -O- (C1-C6 alkyl) and C3-C7 cycloalkyl; each occurrence of R8 independently selected from C, 1-C6 alkyl, halo, -OR6, -SR6, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -O- (C1-C6 haloalkyl), -CN, -NO2, -N (R6) 2, -C (O) OR7, -C (O) N (R7) 2 and -NHC (O) R7; R9 is selected from H, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, - C1-C6 alkyl-NR6-C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl ; R10 is selected from H, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-NR6-C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 hydroxyalkyl ; each occurrence of R11 is independently selected from H, C1-C6 alkyl, -S (O) 2R12 and —C (O) R12; and each occurrence of R12 independently selected from C, 1- C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 4 to 7 membered monocyclic heterocycloalkyl, 8 to 11 membered bicyclic heterocycloalkyl, 5 or 6 membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl, wherein said C3-C7 cycloalkyl group, said C6-C10 aryl group, 4- to 7-membered monocyclic heterocycloalkyl, said 8 to 11-membered bicyclic heterocycloalkyl group, said monocyclic heteroaryl group of 5 or 6 members and said group of 9 or 10-membered bicyclic heteroaryl can optionally be substituted with up to three R8 groups.
[024] The compounds of formula (I) (also referred to herein as "substituted quinolizine derivatives") and the pharmaceutically acceptable salts or prodrugs thereof can be useful, for example, to inhibit replicon activity or viral replication by HIV, or to treat or prevent HIV infection in a subject. Without sticking to any specific theory, substituted quinolizine derivatives are believed to inhibit HIV viral replication by inhibiting HIV integrase.
[025] Therefore, the present invention provides methods for the treatment or prevention of HIV infection in a subject, comprising administering to the subject an effective amount of at least one substituted quinolizine derivative.
[026] The details of the invention are presented in the detailed description that accompanies below.
[027] Although any methods and materials similar to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other embodiments, aspects and features of the present invention are either further described or will be apparent from the following description, examples and appended claims. DETAILED DESCRIPTION OF THE INVENTION
[028] The present invention includes substituted quinolizine derivatives, compositions comprising at least one substituted quinolizine derivative, and methods of using the substituted quinolizine derivatives for the treatment or prevention of HIV infection in a subject. Definitions and abbreviations
[029] The terms used in the present invention have their normal meaning and the meaning of such terms is independent in each occurrence of the same. Notwithstanding and except where indicated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names and chemical structures can be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used alone or in combination with other terms, unless otherwise indicated. Thus, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl", "-O-alkyl", etc ...
[030] As used in the present invention, and throughout this disclosure, the following terms, unless otherwise indicated, are to be understood to have the following meanings:
[031] A "subject" is a human or non-human mammal. In one embodiment, a subject is a human being. In another mode, a subject is a primate. In another modality, a subject is a monkey. In another modality, a subject is a chimpanzee. In yet another modality, a subject is a rhesus monkey.
[032] The term "effective amount" as used in the present invention, refers to an amount of substituted quinolizine derivative and / or an additional therapeutic agent, or a composition thereof that is effective in inhibiting HIV replication and in producing the desired therapeutic, enhancing, inhibitory or preventive effect when administered to a subject suffering from HIV or AIDS infection. In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, where the amounts of all agents administered are effective together, but where the component component of the combination may not be present individually in an effective amount.
[033] The term "prevent", as used in the present invention in connection with a viral infection with HIV or AIDS, refers to reducing the likelihood or severity of HIV or AIDS infection.
[034] The term "alkyl", as used in the present invention, refers to an aliphatic hydrocarbon group with one of its hydrogen atoms replaced by a bond. An alkyl group can be linear or branched and contain between about 1 to about 20 carbon atoms. In one embodiment, an alkyl group that contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C1-C6alkyl) or from about 1 to about 4 carbon atoms (C1-C4 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl . An alkyl group can be unsubstituted or substituted by one or more substituents that can be the same or different, each substituent being selected independently from the group consisting of halogen, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O- alkyl, -O-aryl, alkylene-O- alkyl, alkylthio, -NH2, -NH (alkyl), -N (alkyl) 2, -NH (cycloalkyl), -OC (O) - alkyl, -OC (O) -aryl, -OC (O) -cycloalkyl, -C (O) OH and -C (O) O-alkyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.
[035] The term "alkenyl", as used in the present invention, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond. An alkenyl group can be linear or branched and contain between about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groups include ethylene, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. An alkenyl group can be unsubstituted or substituted by one or more substituents that can be the same or different, each substituent being selected independently from the group consisting of halogen, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O- alkyl, -O-aryl, -alkylene-S-alkyl, alkylthio, -NH2, -NH (alkyl), -N (alkyl) 2, -NH (cycloalkyl), -OC (O) -alkyl, -OC (O ) -aryl, OC (O) -cycloalkyl, -C (O) OH and -C (O) O-alkyl. The term "C2-C6alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.
[036] The term "alkynyl", as used in the present invention, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and having one of its hydrogen atoms replaced with a bond. An alkynyl group can be linear or branched and contain between about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. An alkynyl group can be unsubstituted or substituted by one or more substituents that can be the same or different, each substituent being selected independently from the group consisting of halogen, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O- alkyl, -O-aryl, -alkylene-S-alkyl, alkylthio, -NH2, -NH (alkyl), -N (alkyl) 2, -NH (cycloalkyl), -OC (O) -alkyl, -OC (O ) -aryl, OC (O) - cycloalkyl, -C (O) OH and -C (O) O-alkyl. The term "C2-C6alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms. Unless otherwise indicated, an alkynyl group is unsubstituted.
[037] The term "alkylene", as used in the present invention, refers to an alkyl group, as defined above, in which one of the hydrogen atoms in the alkyl group has been replaced by a bond. Non-limiting examples of alkylene groups include -CH2-, -CH2CH2-, -CH2CH2CH2-, - CH2CH2CH2CH2-, -CH (CH3) CH2CH2-, -CH (CH3) - and -CH2CH (CH3) CH2-. In one embodiment, an alkylene group that has from 1 to about 6 carbon atoms, in the other embodiment, an alkylene group that has from about 3 to about 5 carbon atoms. In another embodiment, it is a branched alkylene group. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is -CH2-. The term "C1-C6 alkylene" refers to an alkylene group having 1 to 6 carbon atoms. The term "C2-C4 alkylene" refers to an alkylene group having 2 to 4 carbon atoms.
[038] The term "alkenylene", as used in the present invention, refers to an alkenyl group, as defined above, in which one of the hydrogen atoms in the alkenyl group has been replaced with a bond. Non-limiting examples of alkenylene groups include -CH = CH-, -CH = CHCH2-, -CH2CH = CH-, - CH2CH = CHCH2-, -CH = CHCH2CH2-, -CH2CH2CH = CH- and -CH (CH3) CH = CH- In one embodiment, an alkenylene group has 2 and about 6 carbon atoms. In another embodiment, an alkenylene group has between about 3 to about 5 carbon atoms. In another embodiment, an alkenylene group is branched. In another embodiment, an alkenylene group is linear. The term "C2-C6 alkylene" refers to an alkenylene group having 2 to 6 carbon atoms. The term "C3-C5-alkenylene" refers to an alkenylene group having between 3 and 5 carbon atoms.
[039] The term "aryl", as used in the present invention, refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains about 6 to about 10 carbon atoms. An aryl group can be optionally substituted with one or more "ring system substituents" which can be the same or different, and are as defined herein below. In one embodiment, an aryl group can optionally be fused with a cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and naphthyl. In one embodiment, an aryl group is phenyl. Unless otherwise indicated, an aryl group is unsubstituted.
[040] The term "arylene", as used in the present invention, refers to a divalent group derived from an aryl group, as defined above, by removing a hydrogen atom from a carbon in the ring of an aryl group . An arylene group can be derived from a monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an arylene group comprises from about 6 to about 10 carbon atoms. In another embodiment, an arylene group is a naphthylene group. In another embodiment, an arylene group is a phenylene group. An arylene group can be optionally substituted with one or more "ring system substituents", which can be the same or different, and are as defined here below. An arylene group is divalent and any bond available in an arylene group can connect to either group that flanks the arylene group. For example, the group "A-arylene-B-" where the arylene group is:
is understood to comprise both:

[041] In one embodiment, an arylene group can optionally be fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of arylene groups include phenylene and naphthalene. In one embodiment, an arylene group is unsubstituted. In another modality, an arylene group is:

[042] Unless otherwise indicated, an arylene group is unsubstituted.
[043] The term "cycloalkyl," as used in the present invention, refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, cycloalkyl contains from about 3 to about 7 ring atoms. In another embodiment, cycloalkyl contains from about 5 to about 6 ring atoms. The term "cycloalkyl" also encompasses a cycloalkyl group, as defined above, which is fused to an aryl ring (for example, benzene) or heteroaryl ring. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples of multicyclic cycloalkyls include 1-decalynyl, norbornyl and adamantyl. A cycloalkyl group can be optionally substituted with one or more "ring system substituents" which can be the same or different, and are as defined in the present invention below. In one embodiment, a cycloalkyl group is unsubstituted. The term "3- to 7-membered cycloalkyl" refers to a cycloalkyl group having 3 to 7 ring carbon atoms. Unless otherwise indicated, a cycloalkyl group is unsubstituted. A ring carbon atom of a cycloalkyl group can be functionalized as a carbonyl group. An illustrative example of such a cycloalkyl group (also called a "cycloalkanoyl" group here) includes, but is not limited to, cyclobutanoyl:

[044] The term "halo," as used in the present invention, means -F, -Cl, -Br or -I.
[045] The term "haloalkyl," as used in the present invention, refers to an alkyl group as defined above, in which one or more of the hydrogen atoms in the alkyl group has been replaced with a halogen. In one embodiment, a haloalkyl group has 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with 1 to 3 F atoms. Non-limiting examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2Cl and -CCl3. The term "C1-C6 haloalkyl" refers to an alkyl halogroup having 1 to 6 carbon atoms.
[046] The term "hydroxyalkyl," as used in the present invention, refers to an alkyl group as defined above, in which one or more of the hydrogen atoms of the alkyl group have been replaced with an -OH group. In one embodiment, a hydroxyalkyl group has 1 to 6 carbon atoms. Non-limiting examples of hydroxyalkyl groups include -CH2OH, -CH2CH2OH, -CH2CH2CH2OH and -CH2CH (OH) CH3. The term "C1-C6 hydroxyalkyl" refers to a hydroxyalkyl group having 1 to 6 carbon atoms.
[047] The term "heteroaryl," as used in the present invention, refers to an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, where 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms In another embodiment, a heteroaryl group is bicyclic In another embodiment, a heteroaryl group is bicyclic and has 9 or 10 ring atoms. A heteroaryl group can be optionally substituted by one or more "ring system substituents" that can be the same or different, and are as defined in the present invention below: A heteroaryl group is joined via a ring carbon atom, and any nitrogen atom in a heteroaryl can be optionally oxidized to the corresponding N-oxide. heteroaryl ”also comprises a heteroaryl group, as defined above, which is fused to a benzene ring. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanil, pyrrolyl, 1,2-triazolyl, 1,2-triazole , pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, quinidine, benzidine , thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and all isomeric forms thereof. The term "heteroaryl" also refers to partially saturated heteroaryl fractions such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In one embodiment, a heteroaryl group is a 5-membered heteroaryl. In another embodiment, a heteroaryl group is a 6-membered monocyclic heteroaryl. In another embodiment, a heteroaryl group comprises a 5- to 6-membered monocyclic heteroaryl group fused to a benzene ring. Unless otherwise indicated, a heteroaryl group is unsubstituted.
[048] The term "heterocycloalkyl," as used in the present invention, refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 11 ring atoms, where 1 to 4 of the ring atoms are independently O, S, N or Si, and the rest of the ring atoms are carbon atoms. A heterocycloalkyl group can be joined via a ring carbon, ring silicon atom or ring nitrogen atom. In one embodiment, a heterocycloalkyl group is monocyclic and has about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group that is monocyclic has from about 5 to about 8 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has about 8 to about 11 ring atoms. In yet another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There is no adjacent oxygen and / or sulfur atom present in the ring system. Any -NH group on a heterocycloalkyl ring can exist protected such as, for example, as a -N (BOC), -N (Cbz), -N (Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention. The term "heterocycloalkyl" also encompasses a group of heterocycloalkyl, as defined above, which is fused to an aryl ring (e.g., benzene) or heteroaryl ring. A heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which can be the same or different, and are as defined in the present invention below. The nitrogen or sulfur atom of the heterocycloalkyl can optionally be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanil, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone and the like, and the like isomers thereof.
[049] A ring carbon atom of a heterocycloalkyl group can be functionalized as a carbonyl group. An illustrative example of such a heterocycloalkyl group is:

[050] In one embodiment, a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl. The term "4- to 7-membered monocyclic heterocycloalkyl" refers to a group of monocyclic heterocycloalkyl having 4 to 7 ring atoms. The term "5- to 8-membered monocyclic heterocycloalkyl" refers to a group of monocyclic heterocycloalkyl having 5 to 8 ring atoms. The term "8 to 11 membered bicyclic heterocycloalkyl" refers to a group of bicyclic heterocycloalkyl having 8 to 11 ring atoms. Unless otherwise indicated, a heterocycloalkyl group is unsubstituted.
[051] The term "heterocycloalkenyl" as used in the present invention, refers to a heterocycloalkyl group, as defined above, which is non-aromatic and contains at least one endocyclic double bond between two adjacent ring atoms. A heterocycloalkenyl group can be joined through a ring carbon, ring silicon atom or ring nitrogen atom. In one embodiment, a heterocycloalkenyl group is monocyclic and has about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkenyl group is monocyclic having from about 5 to about 8 ring atoms. In another embodiment, a heterocycloalkenyl group is bicyclic and has about 8 to about 11 ring atoms. In yet another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkenyl group is monocyclic. In another embodiment, a heterocycloalkenyl group is bicyclic. There is no adjacent oxygen and / or sulfur atom present in the ring system. Any -NH group on a heterocycloalkenyl ring can be substituted or protected such as, for example, as a -N (BOC), -N (Cbz), -N (Tos) group and the like; such protected heterocycloalkenyl groups are considered part of this invention. The term "heterocycloalkenyl" also encompasses a heterocycloalkenyl group, as defined above, which is fused to an aryl ring (e.g., benzene) or heteroaryl ring. A heterocycloalkenyl group can be optionally substituted by one or more "ring system substituents" which can be the same or different, and are as defined in the present invention below. The nitrogen or sulfur atom of the heterocycloalkenyl can optionally be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.
[052] A ring carbon atom of a heterocycloalkenyl group can be functionalized as a carbonyl group. An illustrative example of such a heterocycloalkenyl group is:

[053] In one embodiment, a heterocycloalkenyl group is a 5-membered monocyclic heterocycloalkenyl. In another embodiment, a heterocycloalkenyl group is a 6-membered monocyclic heterocycloalkenyl. The term "4- to 7-membered monocyclic heterocycloalkenyl" refers to a group of monocyclic heterocycloalkenyl having 4 to 7 ring atoms. The term "5- to 8-membered monocyclic heterocycloalkenyl" refers to a group of monocyclic heterocycloalkenyl having 5 to 8 ring atoms. The term "8 to 11-membered bicyclic heterocycloalkenyl" refers to a group of bicyclic heterocycloalkenyl having 8 to 11 ring atoms. Unless otherwise indicated, a heterocycloalkenyl group is unsubstituted.
[054] The term "ring system substituent," as used in the present invention, refers to a substituted group attached to an aromatic or non-aromatic ring system, for example, replacing an available hydrogen in the ring system. Substituents of the ring system may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, - arylene-alkyl, -alkylene-heteroaryl, - alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, - alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C ( O) -aryl, halo, -NO2, -CN, -SF5, -C (O) OH, -C (O) O-alkyl, -C (O) O-aryl, -C (O) O-alkylene- aryl, -S (O) -alkyl, -S (O) 2-alkyl, -S (O) -aryl, -S (O) 2-aryl, -S (O) -heteroaryl, -S (O) 2 -heteroaryl, -S- alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S (O) 2-alkylene-aryl, -S (O) 2- alkylene-heteroaryl, -Si (alkyl) 2, -Si (aryl) 2, - Si (heteroaryl) 2, -Si (alkyl) (aryl), -Si (alkyl) (cycloalkyl), - Si (alkyl) (heteroaryl ), cycloalkyl, heterocycloalkyl, -OC (O) -alkyl, -OC (O) - aryl, -OC (O) -cycloalkyl, -C (= N-CN) -NH2, -C (= N H) -NH2, -C (= NH) -NH (alkyl), - N (Y1) (Y2), -alkylene-N (Y1) (Y2), -C (O) N (Y1) (Y2) and -S (O) 2N (Y1) (Y2), where Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and - alkylene-aryl. “Ring system substitute” can also mean a single fraction that simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) in a ring system. Examples of such fractions are methylenedioxy, ethylenedioxy, -C (CH3) 2- and the like that form fractions such as, for example:

[055] The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the normal valence of the designated atom under the existing circumstances is not exceeded and that the replacement results in a stable compound . Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent.
[056] The term "in substantially purified form", as used in the present invention, refers to the physical state of a compound after the compound is isolated from a synthesis process (for example, from a reaction mixture ), a natural source, or a combination thereof. The term "in substantially purified form" also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein well known to those skilled in the art (for example, chromatography, recrystallization and similar), in sufficient purity to be characterized by standard analytical techniques described in the present invention or well known to those skilled in the art.
[057] It should also be noted that any carbon atom, as well as a hetero atom with valences not satisfied in the text, schemes, examples and tables in this invention, is considered to have enough hydrogen atom (s) to satisfy the valences.
[058] When a functional group in a so-called compound is "protected", this means that the group is in modified form to prevent undesirable side reactions at the protected site when the compound is subjected to a reaction. Suitable protection groups will be recognized by those skilled in the art, as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
[059] When any substituent or variable (for example, alkyl, R1, R7, etc.) occurs more than once in any constituent or in Formula (I), its definition in each occurrence is independent of its definition in any another occurrence, unless otherwise indicated.
[060] As used in the present invention, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results from combining the specified ingredients in the specified amounts.
[061] The prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to provide a substituted quinolizine derivative or a pharmaceutically acceptable salt of the compound. Transformation can occur by several mechanisms (for example, by metabolic or chemical processes), such as, for example, through hydrolysis in the blood. For example, if a substituted quinolizine derivative or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a functional group of carboxylic acid, a prodrug can comprise an ester formed by replacing the hydrogen atom of the acid group with such a group. such as (C 1 -C 8) alkyl, (C 2 -C 2) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having 5 to 10 carbon atoms, carbonyloxymethyl alkoxy having 3 to 6 carbon atoms, 1- (carbonyloxy alkoxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (carbonyloxy alkoxy) ethyl having 5 to 8 carbon atoms, N- (carbonyl alkoxy) aminomethyl having 3 to 9 carbon atoms, 1- (N- (carbonyl alkoxy) amino) ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N- (C1-C2) alkylamino (C2-C3) alkyl (such as β-dimethylaminoethyl), carbamoyl- (C1-C2) alkyl, N, N-di (C1 - C2) alkylacarbamoyl- (C1-C2) alkyl and piperidino-, pyrrolidine- or morpholino (C2-C3) alkyl and the like.
[062] Similarly, if a Substituted Quinolizine Derivative contains an alcohol functional group, a prodrug can be formed by replacing one or more hydrogen atoms in the alcohol groups with a group such as, for example, (C1 -C6) methyl alkanoyloxy, 1 - ((C1- C6) alkanoyloxy) ethyl, 1-methyl-1 - ((C1-C6) alkanoyloxy) ethyl, (C1-C6) methyl carbonyloxy alkoxy, N- (C1-C6) carbonylaminomethyl alkoxy, succinyl, (C1-C6) alkanoyl, α-amino (C1-C4) alkyl, α-amino (C1-C4) alkylene-aryl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from naturally occurring L-amino acids, or glycosyl (the radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate).
[063] If a Substituted Quinolizine Derivative incorporates a functional amine group, a prodrug can be formed by replacing a hydrogen atom in the amine group with a group such as, for example, R-carbonyl-, RO-carbonyl- , NRR'-carbonyl- where R and R 'are each independently (C1-C10) alkyl, (C3-C7) cycloalkyl, benzyl, natural α-aminoacyl, -C (OH) C (O) OY1 where Y1 is H, (C1-C6) alkyl or benzyl, -C (OY2) Y3 where Y2 is (C1-C4) alkyl and Y3 is (C1-C6) alkyl; carbonoxy (C1-C6) alkyl; amino (C1-C4) alkyl or mono-N- or di-N, N- (C1-C6) alkylaminoalkyl; -C (Y4) Y5 where Y4 is H or methyl and Y5 is mono-N- or di-N, N- (C1-C6) alkylamino morpholino; piperidin-1-yl or pyrrolidin-1-yl and the like.
[064] The pharmaceutically acceptable esters of the compounds of the present invention include the following groups: (1) esters of carboxylic acids obtained by esterification of the hydroxy group of a hydroxyl compound, wherein the non-carbonyl fraction of the carboxylic acid portion of the ester group is selected from straight or branched chain alkyl (for example, methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkyl alkoxy (for example, methyl methoxy), aralkyl ( for example, benzyl), aryloxyalkyl (for example, phenoxy methyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C1-4alkyl, -O- (C1-4alkyl) or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters, including those corresponding to both natural and unnatural amino acids (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters can be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24) acyl glycerol.
[065] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, and the invention is intended to encompass both solvated and unsolvated forms. "Solvate" means a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvate will be capable of isolation, for example, when molecules of one or more solvents are incorporated into the crystal network of the crystalline solid. "Solvate" encompasses both phase and solution solvates. Non-limiting examples of solvates include ethanolates, methanolates and the like. A "hydrate" is a solvate in which the solvent molecule is water.
[066] One or more compounds of the present invention can optionally be converted to a solvate. The preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93 (3), 601-611 (2004) describe the preparation of the antifungal fluconazole solvates in ethyl acetate, as well as from water. Similar preparations of solvates, hydrates, hemisolvates and the like are described by E. C. van Tonder et al, AAPS PharmSciTechoras. , 5 (1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical non-limiting process involves dissolving the compound of the present invention in desired amounts of the desired solvent (organic or water or mixtures thereof) at a temperature greater than room temperature, and cooling the solution at a rate sufficient to form crystals that are , then isolated by conventional methods. Analytical techniques such as, for example, IR spectroscopy, show the presence of solvent (or water) in the crystals as a solvate (or hydrate).
[067] Substituted quinolizine derivatives can form salts that are also within the scope of the present invention. Reference to a substituted quinolizine derivative herein is understood to include reference to its salts, unless otherwise indicated. The term "salt (s)", as used in the present invention, means salts of acids formed with inorganic acids and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. In addition, when a substituted quinolizine derivative contains a basic portion, such as, but not limited to, a pyridine or imidazole, and an acidic fraction, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts" ") can be formed and are included within the term" salt (s) "as used in the present invention. In one embodiment, the salt is a pharmaceutically acceptable salt (i.e., non-toxic, physiologically acceptable). In another embodiment, the salt is different from a pharmaceutically acceptable salt. The salts of the compounds of Formula (I) can be formed, for example, by reacting a substituted quinolizine derivative with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
[068] Illustrative acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, iodhydrates, lactates, maleates, methanesulfonates, naphthalenesulfonates, oxaphthalenesulfonates , phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. In addition, acids that are generally considered suitable for the formation of pharmaceutically useful salts of basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, D.C. on its website). These disclosures are hereby incorporated by reference.
[069] Illustrative basic salts include ammonium salts, alkali metal salts, such as sodium, lithium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butylamine, choline and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (eg, methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl and dibutyl sulfates), halides long-chain (eg, decyl, lauryl, chlorides and stearyl, bromides and iodides), arylalkyl halides (eg benzyl and phenethyl bromides), and others.
[070] All of these acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and basic salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention.
[071] Diastereoisomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical-chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereoisomeric mixture by reaction with an appropriate optically active compound (eg, chiral auxiliary such as a chiral alcohol or Mosher acid chloride), separating the diastereoisomers and converting (eg, hydrolyzing ) the individual diastereoisomers for the corresponding pure enantiomers. Pure stereochemicals can also be prepared using chiral starting materials or using salt-solving techniques. In addition, some of the substituted quinolizine derivatives can be atropisomers (for example, substituted biaryls) and are considered to be part of this invention. The enantiomers can also be directly separated using chiral chromatographic techniques.
[072] It is also possible that the substituted quinolizine derivatives can exist in different tautomeric forms and all of these forms are included within the scope of the invention. For example, all forms of keto-enol and imine-enamine of the compounds are included in the invention.
[073] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as their salts, solvates and esters of the pro- drugs), such as those that may exist due to asymmetric carbons in various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereoisomeric forms, are contemplated within the scope of this invention. If a substituted quinolizine derivative incorporates a double bond or a fused ring, both cis and trans isomers, as well as mixtures, are included within the scope of the invention.
[074] The individual stereoisomers of the compounds of the invention can, for example, be substantially free of other isomers, or they can be mixed, for example, as racemates or with all others, or other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC Recommendations of 1974. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended for also apply to the salt, solvate, ester and prodrug of the enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the compounds of the invention.
[075] In the compounds of Formula (I), atoms can have their natural isotopic abundance, or one or more of the atoms can be artificially enriched with a particular isotope having the same atomic number, but with a different atomic mass or mass number of the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variations of the compounds of Formula I. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Procium is the predominant hydrogen isotope found in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or it can provide a useful compound as a standard for the characterization of biological samples. Isotopically enriched compounds of formula (I) can be prepared, without undue experimentation, by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples presented here, using appropriate isotopically reagents and / or intermediates enriched. In one embodiment, a compound of Formula (I) has one or more of its hydrogen atoms replaced with deuterium.
[076] Substituted quinolizine derivatives are useful in human and veterinary medicine for the treatment or prevention of HIV infection in a subject. In one embodiment, the substituted quinolizine derivatives can be inhibitors of HIV viral replication. In a specific embodiment, the substituted quinolizine derivatives are HIV-1 inhibitors. As a consequence, substituted quinolizine derivatives are useful for the treatment of HIV and AIDS infections. According to the invention, substituted quinolizine derivatives can be administered to a subject in need of treatment or prevention of HIV infection.
[077] Therefore, in one embodiment, the invention provides methods for treating HIV infection in a subject comprising administering to the subject an effective amount of at least one substituted quinolizine derivative or pharmaceutically acceptable salt thereof. In a specific embodiment, the present invention provides methods for treating AIDS in a subject, comprising administering to the subject an effective amount of at least one substituted quinolizine derivative or pharmaceutically acceptable salt thereof.
[078] List of Abbreviations Anal. = analytical ACN = acetonitrile AcOH = acetic acid n-BuLi = n-butyl lithium BnBr = benzyl bromide br = broad calc. = calculated m-CPBA = 3-chloroperoxybenzoic acid d = doublet DBU = 1,8-diazabicycloundec-7-en DCM = dichloromethane DEA = diethylamine DIPEA or DIEA = N, N-diisopropylethylamine DMF = dimethylformamide DMSO = dimethyl sulfoxide ESI = ionization by electrospray Et2O = diethyl ether Et3N = triethylamine EtOAc = ethyl acetate EtOH = ethanol HCl = hydrochloric acid HPLC = high pressure liquid chromatography IPA = isopropyl alcohol IPAc = isopropyl acetate KF = Karl-Fischer titration (to determine the content KOt-Bu = potassium tert-butoxide LCMS = liquid chromatography-mass spectrometry LiHMDS = lithium hexamethyl silazane m = multiplet MeCN = acetonitrile MeOH = methyl alcohol MPa = millipascal MS = mass spectroscopy MTBE = methyl tert butyl ether NaHCO3 = sodium bicarbonate NBS = N-bromosuccinimide NHS = normal human serum NMP = N-methyl pyrrolidine NMR = nuclear magnetic resonance spectroscopy Piv = pivalate, 2,2-dimethyl propanoyl Pd / C = palladium on carbon rt = room temperature s = singlet SFC = supercritical fluid chromatography SiO2 = silica gel t = triplet TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMSN3 = trimethylsilyl azide p-TsOH = paratoluenesulfonic acid wt% = percentage in weight wt% = percentage The Compounds of Formula (I)
[079] Present invention provides Quinolizine Derivative
and pharmaceutically acceptable salts thereof, wherein X, Y, R1, R2, R3, R4, R5, R9 and R10 are defined above for the Compounds of Formula (I).
[080] In one mode, X is a simple link.
[081] In another mode, X is -NHC (O) -.
[082] In another embodiment, X is a 5- or 6-membered heteroaryl.
[083] In yet another modality, X is a 5-membered heteroaryl.
[084] In another embodiment, X is 1,3,4-thiadiazole.
[085] In one embodiment, Y is a simple link.
[086] In another embodiment, Y is C1-C3 alkylene.
[087] In another mode, Y is CH2.
[088] In one embodiment, X is -NHC (O) - and Y is CH2.
[089] In another embodiment, X is 5-membered heteroaryl and Y is CH2.
[090] In one embodiment, R1 is optionally substituted C6-C10 aryl or optionally substituted 9 or 10 membered bicyclic heteroaryl.
[091] In another embodiment, R1 is optionally substituted C6-C10 aryl.
[092] In another embodiment, R1 is optionally substituted phenyl.
[093] In one mode, R1 is selected from:

[094] In another embodiment, R1 is phenyl which is substituted with one or more halo groups.
[095] In another embodiment, R1 is phenyl which is substituted with 1-3 halo groups.
[096] In yet another embodiment, R1 is phenyl which is replaced with one or two F groups.
[097] In another embodiment, R1 is 4-fluorophenyl.
[098] In yet another embodiment, R1 is 2,4-difluorophenyl.
[099] In another embodiment, R1 is 3-chloro-2-fluorophenyl.
[0100] In one embodiment, the group R1-Y- is phenyl-CH2-, in which said phenyl group is replaced with 1-3 groups, independently selected from F and Cl.
[0101] In another embodiment, the group R1-Y- is phenyl-CH2-, in which said phenyl group is replaced with one or two F groups.
[0102] In one embodiment, R2 is H.
[0103] In another embodiment, R2 is -O- (C1-C6 alkylene) -O- (C1-C6 alkyl).
[0i04] In one mode, R3 is H.
[0i05] In another mode, R3 is -OH.
[0106] In one embodiment, R3 is -O- (C1 -C6 alkyl).
[0i07] In another modality, R3 is methoxy.
[0108] In one embodiment, R2 and R3 are each independently H, -OH or -O- (C1 -C6 alkyl).
[0109] In another embodiment, R2 is H and R3 is -OH or -O- (C1 -C6 alkyl).
[0110] In another modality, R2 is H and R3 is methoxy.
[0111] In one mode, R4 is H.
[0112] In another embodiment, R4 is C1 -C6 alkyl.
[0113] In another embodiment, R4 is - (C1-C6 alkylene) -O- (C1-C6 alkyl).
[0114] In yet another modality, R4 is methyl.
[0115] In another embodiment, R4 is -CH2CH2OCH3.
[0116] In one mode, R5 is H.
[0117] In another embodiment, R5 is C1 -C6 alkyl.
[0118] In another embodiment, R5 is - (C1-C6 alkylene) -O- (C1-C6 alkyl).
[0119] In another embodiment, R5 is methyl.
[0120] In yet another modality, R5 is -CH2CH2OCH3.
[0121] In one embodiment, R4 and R5 are each independently H, C1-C6 alkyl or - (C1-C6 alkylene) -O- (C1-C6 alkyl).
[0122] In another embodiment, R4 and R5 are each C1-C6 alkyl.
[0123] In yet another modality, R4 and R5 are each methyl.
[0124] In one embodiment, R2 and R4, together with the carbon atoms to which they are attached, come together to form a 5- to 8-membered monocyclic heterocycloalkyl group.
[0125] In one embodiment, R3 is -O- (C1-C6 alkyl) and R4 is - (C1-C6 alkylene) -O- (C1-C6 alkyl).
[0126] In one mode, R9 is H.
[0127] In another mode, R10 is H.
[0128] In another mode, R9 and R10 are each H.
[0129] In one embodiment, the compounds of formula (I) have the
or a pharmaceutically acceptable salt thereof, wherein: R2 and R4, together with the carbon atoms to which they are attached, join to form a 5- to 8-membered monocyclic heterocycloalkyl group; R5 is H or C1-C6 alkyl; and R8 represents 1 or 2 substituents of the phenyl group, each independently selected from halo.
[0130] In one embodiment, the compounds of formulas (I) and (Ia), R2 and R4, together with the carbon atoms to which they are attached, can join to form a group of monocyclic heterocycloalkyl of 5 to 8 members, a 5- to 8-membered monocyclic heterocycloalkyl group, or 8 to 11-membered bicyclic heterocycloalkyl group, wherein said 5 to 8-membered monocyclic heterocycloalkyl group, said to be 5 to 8-membered monocyclic heterocycloalkenyl group and said 8 to 11-membered bicyclic heterocycloalkyl group can be optionally substituted with up to three R8 groups, which can be the same or different;
[0131] In one embodiment, the compounds of formulas (I) and (Ia), R2 and R4, together with the carbon atoms to which they are attached, come together to form a group of 5 to 8 monocyclic heterocycloalkyl members, R3 is H and R5 is H.
[0132] In another embodiment, the compounds of formulas (I) and (Ia), R2 and R4, together with the carbon atoms to which they are attached, come together to form a group of monocyclic heterocycloalkyl of 5 to 8 members, R3 is H and R5 is methyl.
[0133] In another embodiment, the compounds of formulas (I) and (Ia), R2 and R4, together with the carbon atoms to which they are attached, come together to form a 6-membered monocyclic heterocycloalkyl group.
[0134] In yet another embodiment, the compounds of formulas (I) and (Ia), R2 and R4, together with the carbon atoms to which they are attached, join to form a 5-membered monocyclic heterocycloalkyl group .
[0135] In another embodiment, the compounds of formulas (I) and (Ia), R2 and R4, together with the carbon atoms to which they are attached, come together to form a 1,3-dioxane group or a 1,4-dioxane group.
[0136] In one embodiment, for the compounds of formulas (I) and (Ia), R2 and R4, together with the carbon atoms to which they are attached, come together to form a group selected from:

[0137] In another embodiment, for the compounds of formulas (I) and (Ia), R2 and R4, together with the carbon atoms to which they are attached, unite to form a group selected from:

[0138] In another embodiment, for the compounds of formulas (I) and (Ia), R2 and R4, together with the carbon atoms to which they are attached, join to form the following group:

[0139] In one embodiment, for the compounds of formulas (I) and (Ia), R3 is H; R5 is H or methyl; and R2 and R4, together with the carbon atoms to which they are attached, come together to form a group selected from:

[0140] In another embodiment, for the compounds of formulas (I) and (Ia), R3 is H; R5 is methyl; and R2 and R4, together with the carbon atoms to which they are attached, come together to form a group having the structure:

[0141] In one embodiment, the compounds of formula (I) have the formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein: R3 is H or -O-C1-C6 alkyl; R4 is H, C1-C6 alkyl or - (C1-C6alkylene) -O- (C1-C6 alkyl); R5 is H or C1-C6 alkyl; and R8 represents 1 or 2 substituents of the phenyl group, each independently selected from halo.
[0142] In one embodiment, for the compounds of formula (Ib), R3 is H.
[0143] In one embodiment, for the compounds of formula (Ib), R3 is -O- (C1-C6 alkyl).
[0144] In another embodiment, for the compounds of formula (Ib), R3 is methoxy.
[0145] In one embodiment, for the compounds of formula (Ib), R4 is H.
[0146] In another embodiment, for the compounds of formula (Ib), R4 is C1-C6 alkyl.
[0147] In another embodiment, for the compounds of formula (Ib), R4 is - (C1-C6 alkylene) -O- (C1-C6 alkyl).
[0148] In another embodiment, for the compounds of formula (Ib), R4 is methyl.
[0149] In another embodiment, for the compounds of formula (Ib), R4 is -CH2CH2OCH3.
[0150] In one embodiment, for the compounds of formula (Ib), R5 is H.
[0151] In another embodiment, for the compounds of formula (Ib), R5 is C1-C6 alkyl.
[0152] In another embodiment, for the compounds of formula (Ib), R5 is - (C1-C6 alkylene) -O- (C1-C6 alkyl).
[0153] In another embodiment, for the compounds of formula (Ib), R5 is methyl.
[0154] In one embodiment, for the compounds of formula (Ib), R4 and R5 are each independently H, C1-C6 alkyl or - (C1-C6 alkylene) -O- (C1- C6 alkyl).
[0155] In another embodiment, for the compounds of formula (Ib), R4 and R5 are each C1-C6 alkyl.
[0156] In yet another embodiment, for the compounds of formula (Ib), R4 and R5 are each methyl.
[0157] In one embodiment, for the compounds of formula (Ib), R3 is -O- (C1-C6 alkyl) and R4 is - (C1-C6 alkylene) -O- (C1-C6 alkyl).
[0158] In another embodiment, for the compounds of formula (Ib), R4 is - (C1-C6 alkylene) -O- (C1-C6 alkyl) and R5 is C1-C6 alkyl.
[0159] In another embodiment, for the compounds of formula (Ib), R4 is -CH2CH2OCH3 and R5 is methyl.
[0160] In one embodiment, for the compounds of formula (Ib), R8 represents a fluorine substituent and an ortho fluorine substituent.
[0161] In one embodiment, the variables X, Y, R1, R2, R3, R4, R5, R9 and R10 for the compounds of formula (I) are selected independently from each other.
[0162] In another embodiment, the compounds of formula (I) are in a substantially purified formula.
[0163] Other embodiments of the present invention include the following: (a) a pharmaceutical composition comprising an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (b) The pharmaceutical composition of (a), which further comprises a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infectious agents. (c) The pharmaceutical composition of (b), wherein the HIV antiviral agent is an antiviral selected from the group consisting of protease inhibitors, HIV integrase inhibitors, nucleoside reverse transcriptase inhibitors, CCR5 co-receptor antagonists and non-nucleoside reverse transcriptase inhibitors. (d) A pharmaceutical combination that is (i) a Compound of Formula (I) and (ii) a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents; wherein the compound of Formula (I) and the second therapeutic agent are each used in an amount that makes the combination effective to inhibit HIV replication, or to treat HIV infection and / or reduce the likelihood or severity of symptoms of HIV infection. (e) The combination of (d), wherein the HIV antiviral agent is an antiviral selected from the group consisting of protease inhibitors, HIV integrase inhibitors, nucleoside reverse transcriptase inhibitors, CCR5 co-receptor antagonists and non-nucleoside reverse transcriptase inhibitors. (f) A method of inhibiting HIV replication in a subject in need thereof which comprises administering to the subject an effective amount of a Compound of Formula (I). (g) A method of treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need of it which comprises administering to the subject an effective amount of a Formula (I) Compound. (h) The method of (g), wherein the compound of Formula (I) is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators and agents anti-infectives. (i) The method of (h), wherein the HIV antiviral agent is an antiviral selected from the group consisting of protease inhibitors, HIV integrase inhibitors, nucleoside reverse transcriptase inhibitors, CCR5 co-receptor antagonists and non-nucleoside reverse transcriptase inhibitors. (j) A method of inhibiting HIV replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c), or the combination of (d) or (e) . (k) A method of treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection in a subject in need of it which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).
[0164] The present invention also includes a compound of the present invention for use (i) in, (ii) in the form of a medicament for, or (iii) in the preparation of a medicament for: (a) medicine, (b) inhibiting HIV replication or (c) treating HIV infection and / or reducing the likelihood or severity of symptoms of HIV infection. In these uses, the compounds of the present invention can optionally be used in combination with one or more second therapeutic agents selected from HIV antiviral agents, and immunomodulatory anti-infective agents.
[0165] Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set out in (a) - (k) above and the uses defined in the previous paragraph, wherein the compound of the present invention used therein is a compound of one of the modalities, aspects, classes, subclasses or resources of the compounds described above. In all of these embodiments, the compound can optionally be used in the form of a pharmaceutically acceptable salt or hydrate, as appropriate. It is understood that references to compounds should include the compound in its current form, as well as in different forms, such as polymorphs, solvates and hydrates, as applicable.
[0166] It should also be understood that the modalities of the compositions and methods provided as (a) to (k) above, are understood to include all modalities of the compounds, including modalities as a result of combinations of modalities.
[0167] The compounds of formula (I) can be referred to here by their chemical structure and / or by their chemical name. In the example that both the structure and the name of a Compound of Formula (I) are provided and a discrepancy is found between the chemical structure and the corresponding chemical name, it is understood that the chemical structure will predominate.
[0168] Examples of the non-limiting compounds of Formula (I) include compounds 1-124, as set forth in the examples below, compounds 125-137 as set forth immediately below, and their pharmaceutically acceptable salts.
Methods for Preparation of Compounds of Formula (I)
[0169] The compounds of formula (I) can be prepared from known or easily prepared starting materials, following methods known to one skilled in the art of organic synthesis. Useful methods for the preparation of the compounds of formula (I) are shown in the Examples below and generalized in Schemes 1 and 2 below. Alternative synthetic pathways and analogous structures will be evident to those skilled in the technique of organic synthesis.
[0170] Scheme 1 describes a method for producing the compounds of formula (I), which corresponds to the tricyclic 4-pyridinone compounds of formula (I). Layout 1
Where M is a metal capable of participating in the SN2 'reaction (ie Sn, In and Mg).
[0171] A Pyridyl aldehyde compound of formula i can be reacted with a compound of formula ii to provide a compound of formula iii. The hydroxyl group of iii can then be protected and the olefin oxidized by hydroboration and the corresponding iv alcohol can then be cyclized to provide the bicyclic compounds of formula v. The hydroxyl group of v can then be deprotected and oxidized to provide the bicyclic ketones of formula vi, which can be converted to their amide derivatives of formula vii using a carbon monoxide and amine, then reacted with lithium chloride to convert the methoxy group of vii with the corresponding hydroxyl group and obtain the compounds of formula viii, which correspond to the compounds of formula (I) where X is -NHC (O) -. Alternatively, a compound of formula vi can be oxidized to obtain the carboxylic acids of formula ix, which can subsequently be cycled to provide the 1,3,4-thiadiazole derivatives of formula x, which correspond to the compounds of formula (I) , where X is a 5- or 6-membered heteroaryl. Layout 2

[0172] The hydroxyl group of an olefin of general formula iii can be protected and the olefin oxidized to provide the corresponding diols of formula xi, which can then be cyclized to provide the bicyclic compounds of formula xiii. A compound of formula xii can then be reacted with an alkyl halide and base to derivatize the free hydroxyl group of xii, followed by deprotection and oxidation of the other hydroxyl group to provide the bicyclic ketones of formula xiii. The compounds of formula xiii can be converted to their amide derivatives of formula xiv using a carbon monoxide and amine and then reacted with lithium chloride to convert the methoxy group of xiv with the corresponding hydroxyl group and obtain the compounds of formula xv, which correspond to the compounds of formula (I) where X is - NHC (O) -. The hydroxyl group of v can then be deprotected and oxidized to provide the bicyclic ketones of formula vii, which can be reacted with lithium chloride to convert the methoxy group of vii by a hydroxyl group and supply the compounds of formula viii, which correspond to compounds of formula (I) where X is -NHC (O) - and R3 is OR7. Alternatively, a compound of formula xii can be oxidized to obtain the carboxylic acids of formula xvi which can subsequently be cycled to provide the 1,3,4-thiadiazole derivatives of formula xvii, which correspond to the compounds of formula (I), where X is a 5- or 6-membered heteroaryl, and R3 is OR7.
[0173] In the methods for the preparation of the compounds of the present invention presented in the previous schemes, the functional groups in the various fractions and substituents (in addition to those already explicitly indicated in the previous schemes) can be sensitive or reactive in the reaction conditions used and / or in presence of used reagents. This sensitivity / reactivity can interfere with the progress of the desired reaction to reduce the yield of the desired product or, possibly, even prevent its formation. As a consequence, it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules in question. Protection can be achieved by means of conventional protection groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973 and in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999, and 2nd edition, 1991. Protection groups can be removed at a convenient subsequent stage using methods known in the art. Alternatively, the interfering group can be introduced into the molecule subsequent to the reaction step of interest.
[0174] One versed in the technique of organic synthesis will recognize that the synthesis of compounds with multiple reactive functional groups, such as OH and NH2, may require protection from certain functional groups (that is, derivatization for the purpose of chemical compatibility with a condition special reaction). Suitable protecting groups for the various functional groups of these compounds and methods for their installation and removal are well known in the art of organic chemistry. A summary of many of these methods can be found in Greene & Wuts, Protecting Groups in Organic Synthesis, John Wiley & Sons, 3rd edition (1999).
[0175] One skilled in the organic synthesis technique will also recognize that a pathway for the synthesis of the compounds of Formula (I) may be more desirable depending on the choice of attached substituents. Furthermore, one skilled in the pertinent technique will recognize that, in some cases, the order of reactions may be different from what is presented here, to avoid incompatibilities of functional groups and, therefore, adjust the synthesis path accordingly.
[0176] The compounds of formula vii, x, xv and xvii can be further elaborated using methods that will be well known to those skilled in the art of organic synthesis or, for example, the methods described in the Examples below, to produce the full scope of the Compounds of Formula (I).
[0177] The starting materials used and the intermediates prepared using the methods presented in Schemes 1 and 2 can be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation , crystallization, chromatography and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. EXAMPLES General Methods
[0178] The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limiting the scope or spirit of the invention. In these examples, all temperatures are degrees Celsius, unless otherwise indicated, and "room temperature" refers to a temperature in the range of about 20 ° C to about 25 ° C. The reactions sensitive to humidity or air were carried out under nitrogen, using solvents and anhydrous reagents. The progress of the reactions was determined either by analytical thin layer chromatography (TLC) performed with E. Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm or mass spectrum - liquid chromatography ( LC-MS). For HPLC / MS data, the two HPLC conditions used were as follows: 1) LC2 (Waters C18 XTerra ™ 3.5 μm 2 1x20 mm column with 10: 9098 gradient: 2 v / v CH3CN / H2O + v 0.05% TFA for 1.25 min then maintained at 98: 2 v / v CH3CN / H2O + v 0.05% TFA for 0.75 min; flow rate 1.5 mL / min , UV wavelength 254 nm); and 2) LC4 (Waters C18 XTerra 3.5 μm 2.1x20 mm column with 10: 90-98 gradient: 2 v / v CH3CN / H2O + v 0.05% TFA for 3.25 min then maintained at 98: 2 v / v CH3CN / H2O + v 0.05% TFA for 0.75 min; flow rate 1.5 mL / min, UV wavelength 254 nm).
[0179] Mass analysis was performed with electrospray ionization in positive ion detection mode. The 1H NMR spectra were recorded on Varian or Bruker instruments at 400-500 MHz. The solutions were concentrated on a rotary evaporator under reduced pressure or by lyophilization. Flash chromatography was performed on pre-packaged silica gel columns using a commercial MPLC system. The compounds described herein were synthesized as racemic mixtures, unless otherwise indicated, in experimental procedures. Example 1 Preparation of the Int-1 Intermediate Compound
Int-1
[0180] The Int-1 compound was prepared using the method described in US Patent Publication No. US2006 / 066414. Example 2 Preparation of Compound 1
Step A - Synthesis of Compound Int-2a
[0181] To a mixed solution of NaI (279 mg, 1.862 mmol), powdered indium (891 mg, 7.76 mmol) and prenyl bromide (278 mg, 1.862 mmol) in 3 mL of DMF, 4- (benzyloxy) -5-bromo-3-methoxy picolinaldehyde (500 mg, 1.552 mmol). The mixture was left stirring at room temperature for 1 hour. The reaction was diluted with 100 ml of EtOAc. The organic phase was washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to provide a residue, which was purified using a preparative TLC plate eluting with 20% EtOAc / hexane to provide the compound Int-2a as a colorless oil. LCMS analysis calculated for C19H22BrNO3: 391.08; found: 392.07 (M + 1) +. Step B- Synthesis of Compound Int-2b
[0182] To a solution of the compound Int-2a (380 mg, 0.969 mmol) in 0.1 mL of DMF, TBSCl (292 mg, 1.937 mmol) and imidazole (198 mg, 2.91 mmol) were added. The mixture was allowed to stir at 60 ° C overnight. It was diluted with 20 ml of EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4 and concentrated. The resulting residue was purified using a silica gel column (40 g) eluting with 15% EtOAc / hexane to provide compound Int-2b as a colorless oil. LCMS analysis calculated for C25H36BrNO3Si: 505.16; found: 506.14 (M + 1) +. Step C- Synthesis of Compound Int-2c
[0183] For an ice-cooled solution of 4- (benzyloxy) -5-bromo-2- (1 - ((tert-butyladimethyl silyl) oxy) -2,2-dimethylbut-3-en-1-yl) - 3-methoxy pyridine (200 mg, 0.395 mmol) in 4 ml of dry THF was added borane-tetrahydrofuran complex (1 M in THF) (0.592 ml, 0.592 mmol) under an atmosphere of nitrogen. The mixture was left stirring at room temperature for 1 h. After successive addition of water (2.0 ml), sodium hydroxide (aq) (1.974 ml, 3.95 mmol) and hydrogen peroxide in water (35% by weight) (448 mg, 3.95 mmol), the resulting mixture was stirred for an additional hour. The mixture was extracted with EtOAc (3x20 ml). The combined organic extracts were washed with 20 ml of brine and dried over anhydrous MgSO4. After concentration, the resulting residue was purified using silica gel column chromatography eluting with 30% EtOAc / hexane to provide the compound Int-2c. LCMS analysis calculated for C25H38BrNO4Si: 523.18; found: 524.10 (M + 1) +. Step D- Synthesis of Compound Int-2d
[0184] To a stirred solution of triphenylphosphine (255 mg, 0.972 mmol) in 4 ml of dichloromethane iodine (247 mg, 0.972 mmol) was added. The mixture was allowed to stir at room temperature for 5 min, followed by the addition of 4- (4- (benzyloxy) -5-bromo-3-methoxy pyridin-2-yl) -4 - ((tert-butyladimethyl silyl) oxy ) -3,3-dimethylbutan-1-ol (170 mg, 0.324 mmol) and imidazole (66.2 mg, 0.972 mmol). The reaction was left under stirring at room temperature for 2 h. Upon completion of the reaction, it was concentrated to remove most of the dichloromethane. To the resulting residue, 3 mL of 2: 1 ACN / H2O were added and the resulting solution was directly purified using a C18 reverse phase column (40 mg, 12 runs, 5% ACN / H2O-100% ACN / H2O with 0.1% TFA) to produce the compound Int-2d as a colorless oil. LCMS analysis calculated for C18H30BrNO3Si: 415.12; found: 416.10 (M + 1) +. Step E- Synthesis of Compound Int-2e
[0185] A mixture of 7-bromo-1 - ((tert-butyladimethyl silyl) oxy) -9-methoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizin-8 (2H) -one (50 mg, 0.120 mmol), 2,4-difluorobenzylamine (25.8 mg, 0.180 mmol), diethylpropylethylamine (38.8 mg, 0.300 mmol) and Pd (PPh3) 4 (13.87 mg, 0.012 mmol) in 1 ml of DMSO was degassed and heated to 90 ° C under a CO flask for 16 h. LC-mass showed partial completion of the reaction. The above reaction was directly injected onto C18 reverse phase column (40 mg, 12 runs, 5% ACN / H2O-100% ACN / H2O with 0.1% TFA) to produce the compound Int-2e as a white solid. LCMS analysis calculated for C26H36F2N2O4Si: 506.24; found: 507.30 (M + 1) +.
[0186] Step F- Synthesis of Compound Int-2f
[0187] The solution of 1 - ((tert-butyladimethyl silyl) oxy) -N- (2,4-difluorobenzyl) -9-methoxy-2,2-dimethyl-8-oxo-2,3,4,8- tetrahydro-1H-quinolizine-7-carboxamide (14.0 mg, 0.028 mmol) in 1 ml of THF was added to a solution of tetrabutylammonium fluoride (1 N in THF) (0.055 ml, 0.055 mmol). The mixture was left stirring at room temperature for 1.5 h. Upon completion of the reaction, the reaction mixture was directly purified using a preparative TLC plate eluting with EtOAc to produce the compound Int-2f as a white solid. LCMS analysis calculated for C20H22F2N2O4: 392.15; found: 393.08 (M + 1) +. Step G- Synthesis of Compound Int-2g
[0188] To the solution of N- (2,4-difluorobenzyl) -1-hydroxy-9-methoxy-2,2-dimethyl-8-oxo-2,3,4,8-tetrahydro-1H-quinolizine- 7-carboxamide (8.0 mg, 0.020 mmol) in 1 mL of dichloromethane was added Dess-Martin periodinane (17.29 mg, 0.041 mmol). The mixture was left stirring at room temperature for 30 min. The mixture was then directly purified using a preparative TLC plate eluting with EtOAc to produce the compound Int-2g as a white solid. LCMS analysis calculated for C20H20F2N2O4: 390.14; found: 391.07 (M + 1) +. Step H- Synthesis of Compound 1
[0189] A mixture of N- (2,4-difluorobenzyl) -9-methoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-tetrahydro-1H-quinolizine-7- carboxamide (5.0 mg, 0.013 mmol) and lithium chloride (5.43 mg, 0.128 mmol) in 1 ml of DMF was heated to 100 ° C for 4 hours. It was cooled to room temperature and directly purified using a reverse phase HPLC analysis (Gilson system with a Waters Sunfire C18 ODB column, 5 µM, 19 mm x 100 mm, Part No. 186002567, no. Series 20913930114, 10% to 75% MeCN / water + 0.10% TFA for 10 min, 25 mL / min, UV 254 nM). Fractions containing the product were lyophilized to produce compound 1 as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.41 (s, 1 H); 8.47 (s, 1 H); 7.40 (m, 1 H); 6.81-6.86 (m, 2 H); 4.67 (d, J = 4.8 Hz, 2 H); 4.27-4.29 (t, J = 4.8 Hz, 2 H); 2.20-2.22 (t, J = 4.8 Hz, 2 H); 1.40 (s, 6 H). LCMS analysis calculated for C19H18F2N3O5: 376.12; found: 377.12 (M + 1) +. Example 3 Preparation of Compound 2
Step A- Synthesis of Compound Int-3a
[0190] To a solution of the compound Int-2d (60 mg, 0.144 mmol) in THF (2.0 ml) was added tetrabutylammonium fluoride (1 M in THF) (0.288 ml, 0.288 mmol). The mixture was left stirring at room temperature for 1.5 h. The reaction mixture was directly purified using a preparative TLC plate eluting with 10% MeOH / dichloromethane to produce the crude compound Int-3a with some TBAF impurity. LCMS analysis calculated for C12H16BrNO3: 301.03; found: 301.98 (M + 1) +. Step B- Synthesis of Compound Int-3b
[0191] For the solution of 7-bromo-1-hydroxy-9-methoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizin-8 (2H) -one (43.0 mg, 0.142 mmol) in 2 ml of dichloromethane Dess-Martin periodinane (121 mg, 0.285 mmol) was added. The mixture was left stirring at room temperature for 30 min. The mixture was then directly purified using a preparative TLC plate eluting with EtOAc to produce compound Int-3b as a white solid. LCMS analysis calculated for C12H14BrNO3: 299.02; found: 300.00 (M + 1) +. Step C- Synthesis of Compound Int-3c
[0192] A mixture of 7-bromo-9-methoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizine-1,8 (2H) -dione (20 mg, 0.067 mmol), 4- fluorobenzylamine (12.5 mg, 0.101 mmol), diisopropylethylamine (34.4 mg, 0.267 mmol) and Pd (PPh3) 4 (7.70 mg, 6.66 μmol) in 2 mL of DMSO was degassed and heated to 90 ° C under a CO flask for 16 h. After cooling to room temperature, the reaction mixture was directly purified using a reverse phase C18 column (40 mg, 12 runs, 5% ACN / H2O-100% ACN / H2O with 0.1% TFA) to produce the compound Int-3c. LCMS analysis calculated for C20H21FN2O4: 372.15; found: 373.16 (M + 1) +. Step D- Synthesis of Compound 2
[0193] A mixture of N- (4-fluorobenzyl) -9-methoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-tetrahydro-1H-quinolizine-7-carboxamide ( 5.0 mg, 0.013 mmol) and lithium chloride (5.69 mg, 0.134 mmol) in 1 mL of DMF was heated to 100 ° C for 2 h. It was cooled to room temperature. The mixture was directly purified using a reverse phase HPLC analysis (Gilson system with a Waters Sunfire C18 ODB column, 5 µM, 19 mm x 100 mm, Part No. 186002567, Serial No. 20913930114, 10% to 75 % 0.1% TFA in MeCN / 0.1% TFA in water for 10 min, 25 ml / min, UV 254 nM). Fractions containing the product were lyophilized to produce compound 2 as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.41 (s, 1 H); 8.46 (s, 1 H); 7.35 (m, 2 H); 7.01 (m, 2 H); 5.3 (s, 2 H); 4.64 (d, J = 4.8 Hz, 2 H); 4.28 (t, J = 4.8 Hz, 2 H); 2.21 (t, J = 4.8 Hz, 2 H); 1.40 (s, 6 H). LCMS analysis calculated for C19H19FN2O4: 358.13; found: 359.12 (M + 1) +. Example 4 Preparation of Compound 3

[0194] Compound 3 was prepared from the compound Int-3b, using essentially the same method described in Step C and Step D in Example 3, replacing 4-fluorobenzylamine with pyrazolo [1,5-a] pyridin-2-yl - methanamine in Step C. 1H NMR (400 MHz, CDCl3): δ 10.60 (s, 1 H); 8.53 (d, J = 4.9 Hz, 1 H); 8.52 (s, 1 H); 7.48 (d, J = 7.2 Hz, 1 H); 7.15 (dd, J = 7.2, 5.2 Hz, 1 H); 6.78 (dd, J = 5.2, 5.1 Hz, 1 H); 6.54 (s, 1 H); 4.90 (d, J = 4.0 Hz, 1 H); 4.30 (t, J = 4.8 Hz, 2 H); 2.21 (t, J = 4.8 Hz, 2 H); 1.40 (s, 6 H). LCMS analysis calculated for C20H20N4O4: 380.15; found: 381.16 (M + 1) +. Example 5 Preparation of Compound 4
Step A- Synthesis of Compound Int-4a
[0195] For the solution of 1- (4- (benzyloxy) -5-bromo-3-methoxy pyridin-2-yl) -2,2-dimethylbut-3-en-1-ol (230 mg, 0.586 mmol) in 10 ml of dichloromethane a drop of water was added, followed by addition of Dess-Martin periodinane (497 mg, 1.173 mmol). The mixture was left stirring at room temperature for 2 h. It was diluted with 20 ml of dichloromethane. The organic phase was washed with 20 ml of Na2CO3 (aq), dried over Na2SO4 and then concentrated. The resulting residue was purified using a silica gel column (40 g) eluting with 20% EtOAc / hexane to produce the compound Int-4a as a colorless oil. LCMS analysis calculated for C19H20BrNO3: 389.06; found: 390.09 (M + 1) +. Step B- Synthesis of Compound Int-4b
[0196] For the solution of 1- (4- (benzyloxy) -5-bromo-3-methoxy pyridin-2-yl) -2,2-dimethylbut-3-en-1-one (190 mg, 0.477 mmol) in 4 ml of THF and 1 ml of water, the solution of osmium tetroxide in t-BuOH (2.5% by weight) (0.122 ml, 9.74 μmol) and 4-methylmorpholine N-oxide (171 mg, 1.461 mmol). The mixture was left stirring at room temperature overnight. It was diluted with 20 ml of EtOAc. The organic phase was washed with NaS2O3 (aq) and brine, dried over anhydrous Na2SO4 and then concentrated. The resulting residue was purified using a silica gel column eluting with EtOAc to produce the compound Int-4b as a light green oil. LCMS analysis calculated for C19H22BrNO5: 423.07; found: 423.97 (M + 1) +. Step C- Synthesis of Compound Int-4c
[0197] For the solution of 1- (4- (benzyloxy) -5-bromo-3-methoxy pyridin-2-yl) -3,4-dihydroxy-2,2-dimethylbutan-1-one (170 mg , 0.401 mmol) in 3 mL of pyridine, p-toluenesulfonyl chloride was added
[0198] (153 mg, 0.801 mmol). The reaction was left under stirring at room temperature for 6 h. It was diluted with 10 ml of MeOH. The resulting solution was then concentrated in vacuo. The resulting residue was diluted with 2 ml of DMSO and purified using a reverse phase C18 column (40 g, 12 runs, 5% ACN / H2O-100% ACN / H2O with 0.1% TFA ) to provide the crude product which was further purified using a preparative TLC plate eluting with 10% MeOH / dichloromethane to produce the compound Int-4c as a yellow oil. LCMS analysis calculated for C12H14BrNO4: 315.01; found: 316.05 (M + 1) +. Step D - Synthesis of Compound Int-4d
[0199] A mixture of 7-bromo-3-hydroxy-9-methoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizine-1,8 (2H) -dione (9 mg, 0.028 mmol ), 2,4-difluorobenzylamine (6.11 mg, 0.043 mmol), diisopropylethylamine (9.20 mg, 0.071 mmol) and Pd (PPh3) 4 (3.29 mg, 2.85 μmol) in 1 mL of DMSO was degassed by passing through a stream of CO gas for 5 min. It was then heated to 90 ° C under a CO flask for 16 h. After the reaction was cooled to room temperature, it was purified using a reverse phase C18 column (40 mg, 12 runs, 5% ACN / H2O-100% ACN / H2O with 0.1% TFA ) to produce the compound Int-4d. LCMS analysis calculated for C20H20F2N2O5: 406.13; found: 407.16 (M + 1) +. Step E- Synthesis of Compound 4
[0200] A mixture of N- (2,4-difluorobenzyl) -3-hydroxy-9-methoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-tetrahydro-1H- quinolizine-7-carboxamide (5.0 mg, 0.012 mmol) and lithium chloride (5.22 mg, 0.123 mmol) in 1 mL of DMF was heated to 100 ° C for 2 h. It was cooled to room temperature. The resulting solution was directly purified using a reverse phase HPLC (Gilson system with a Waters Sunfire C18 ODB column, 5 µM, 19 mm x 100 mm, Part No. 186002567, Serial No. 20913930114, 10% to 75% MeCN / water with 0.10% TFA for 10 min, 25 mL / min, UV 254nM). Fractions containing the product were lyophilized to produce compound 4 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1 H); 8.34 (s, 1 H); 7.35 (m, 1 H); 6.84 (m, 2 H); 4.65 (d, J = 3.0 Hz, 2 H); 4.46-4.48 (apparent d, J = 10.0 Hz, 1 H); 4,234.27 (dd, J = 11.6, 2.4 Hz, 1 H); 4.11 (brs apparent, 1 H); 1.48 (s, 1 H); 1.35 (s, 1 H). LCMS analysis calculated for C19H18F2N2O5: 392.12; found: 393.14 (M + 1) +. Example 6 Preparation of Compound Int-5e
Step A- Synthesis of Compound Int-5a
[0201] For the solution of 4- (benzyloxy) -5-bromo-2- (1 - ((tert-butyladimethyl silyl) oxy) -2,2-dimethylbut-3-en-1-yl) -3-methoxy pyridine (430 mg, 0.849 mmol) in 5 ml of (4: 1) THF / water, osmium tetroxide (2.5% by weight) in t-BuOH (0.213 ml, 0.017 mmol) and N-oxide of 4-methylmorpholine (298 mg, 2.55 mmol). The mixture was left stirring at room temperature overnight. Upon completion of the reaction, 20 mL of EtOAc was added. The organic phase was washed with aqueous Na2S2O3 solution and brine. It was dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified using a column of silica gel eluting with 50% EtOAc to produce the compound Int-5a as a light green oil. LCMS analysis calculated for C25H38BrNO5Si: 539.17; found: 540.22 (M + 1) +. Step B- Synthesis of Compound Int-5b
[0202] A mixture of 4- (4- (benzyloxy) -5-bromo-3-methoxy pyridin-2-yl) -4 - ((tert-butyladimethyl silyl) oxy) -3,3-dimethylbutane-1,2 -diol (650 mg, 1.202 mmol) and 4-methylbenzene-1-sulfonyl chloride (344 mg, 1.804 mmol) in 10 ml of pyridine was left under stirring at room temperature overnight. Upon completion of the reaction, it was concentrated in vacuo to remove most of the pyridine. The resulting residue was then added 2 ml of DMSO and the resulting solution was purified using a reversed phase C18 column (120 mg, 12 runs, 5% ACN / H2O-100% ACN / H2O with 0, 1% TFA) to produce the compound Int-5b as a white solid. C18H30BrNO4Si: 431.11; found: 432.15 (M + 1) +. Step C- Synthesis of Compound Int-5c
[0203] For the solution of 7-bromo-1 - ((tert-butyladimethyl silyl) oxy) -3-hydroxy-9-methoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizin-8 (2H) -one (160 mg, 0.370 mmol) in 4 mL of THF, iodomethane (158 mg, 1.11 mmol) was added, followed by NaH (60% by weight in mineral oil) (44.4 mg, 1 , 11 mmol). The mixture was left stirring at room temperature for 2 h. It was quenched by the addition of 1 mL of water. The resulting mixture was directly purified using a preparative TLC plate eluting with 50% EtOAc / hexane to produce the compound Int-5c as a yellow oil. LCMS analysis calculated for C19H32BrNO4Si: 445.13; found: 446.01 (M + 1) +. Step D- Synthesis of Compound Int-5d
[0204] For the solution of 7-bromo-1 - ((tert-butyladimethyl silyl) oxy) -3,9-dimethoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizin-8 (2H ) -one (105 mg, 0.235 mmol) in 2 mL of THF, tetrabutylammonium fluoride (1 M in THF) (0.470 mL, 0.470 mmol) was added. The mixture was left stirring at room temperature for 1.5 h. The reagent solution was directly purified using a preparative TLC plate eluting with 10% MeOH / dichloromethane to provide the crude compound Int-5d, which was immediately used in the next reaction. LCMS analysis calculated for C13H18BrNO4: 331.94; found: 333.02 (M + 1) +. Step E- Synthesis of Compound Int-5e
[0205] For the solution of 7-bromo-1-hydroxy-3,9-dimethoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizin-8 (2H) -one (78 mg, 0.235 mmol) in 2 ml of dichloromethane, Dess-Martin periodinane (199 mg, 0.470 mmol) was added. The mixture was left stirring at room temperature for 1 h. The reaction mixture was then directly purified using a preparative TLC plate eluting with EtOAc to produce compound Int-5e as a light yellow solid. LCMS analysis calculated for C13H16BrNO4: 329.03; found: 330.05 (M + 1) +. Example 7 Preparation of Compound 5

[0206] Compound 5 was prepared using essentially the same method described in Step D and Step E in Example 5, and replacing the Int-4c compound with the Int-5e compound in Step D. 1H NMR (400 MHz, CDCl3): 10.41 (s, 1 H), 8.42 (s, 1 H); 7.38 (m, 1 H); 6.83-6.85 (m, 2 H); 4.67 (m, 2 H); 4.38 (dd, J = 11.2, 1.6 Hz, 1 H); 4.35 (dd, J = 11.2, 2.8 Hz, 1 H); 3.57 (dd, J = 2.8, 1.6 Hz, 1 H); 3.46 (s, 3 H); 1.43 (s, 3 H); 1.35 (s, 3 H). LCMS analysis calculated for C20H20F2N2O5: 406.13; found: 407.12 (M + 1) +. Example 8 Preparation of Compound 6
Step A- Synthesis of Compound Int-6a
[0207] A mixture of 7-bromo-3,9-dimethoxy-2,2-dimethyl-3,4-dihydro-1H-quinolizine-1,8 (2H) -dione (120 mg, 0.363 mmol), methanol (58.2 mg, 1.817 mmol), diisopropylethylamine (235 mg, 1.817 mmol) and Pd (PPh3) 4 (84 mg, 0.073 mmol) in 3 mL of DMSO, was degassed by passing through a stream of CO for 5 min. The reaction mixture was then heated to 90 ° C under a CO flask for 16 h. After the reaction was cooled to room temperature, it was directly purified using a reverse phase C18 column (40 mg, 12 runs, 5% ACN / H2O-100% ACN / H2O with 0.1% TFA) to produce the compound Int-6a as a brown solid. LCMS analysis calculated for C15H19NO6: 309.12; found: 310.12 (M + 1) +. Step B- Synthesis of Compound Int-6b
[0208] For the solution of methyl 3,9-dimethoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-tetrahydro-1H-quinolizine-7-carboxylate (20.0 mg, 0.065 mmol) in 1 mL of MeOH, 2 N aqueous lithium hydroxide solution (0.323 mL, 0.647 mmol) was added. The mixture was left under stirring at room temperature for 2 h. It was concentrated to remove most of MeOH. To the resulting residue, 2 mL of DMSO were added, and the resulting solution was directly purified using Gilson (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA ) / H2O, 12 min) to produce the compound Int-6b as a white solid. LCMS analysis calculated for C14H17NO6: 295.11; found: 296.12 (M + 1) +. Step C- Synthesis of Compound Int-6c
[0209] For a stirred solution of 3,9-dimethoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-tetrahydro-1H-quinolizine-7-carboxylic acid (14.0 mg, 0.047 mmol) in 1 mL of DMF, 2- (2,4-difluorophenyl) acetohydrazide (10.59 mg, 0.057 mmol), diisopropylethylamine (24.51 mg, 0.190 mmol) and hexafluorophosphate (V) were added ((1H-benzo [d] [1,2,3] triazol-1-yl) oxy) tri (pyrrolidin-1-yl) phosphonium (29.6 mg, 0.057 mmol) sequentially. The mixture was left stirring at room temperature for 1 h. It was diluted with 1.0 ml of DMF and 0.3 ml of water. The clear solution was purified using a reversed phase Gilson HPLC (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA) / H2O, 12 min) to produce the Int-6c compound as a light yellow solid. LCMS analysis calculated for C22H23F2N3O6: 463.16; found: 464.25 (M + 1) +. Step D- Synthesis of Compound Int-6d
[0210] A mixture of N '- (2- (2,4-difluorophenyl) acetyl) -3,9-dimethoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-tetra- hydro-1H-quinolizine-7-carbohydrazide (12 mg, 0.026 mmol) and Lawesson's Reagent (11.52 mg, 0.028 mmol) in 0.5 mL of THF was heated to 60 ° C overnight. The solvent was removed in vacuo. The resulting residue was dissolved in 2 ml of DMSO. The resulting solution was purified using a reversed-phase Gilson HPLC (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA) / H2O, 12 min) to produce the Int-6d compound as a yellow solid. LCMS analysis calculated for C22H21F2N3O4S: 461.12; found: 462.20 (M + 1) +. Step E- Synthesis of Compound 6
[0211] A mixture of 7- (5- (2,4-difluorobenzyl) -1,3,4-thiadiazol-2-yl) -3,9-dimethoxy-2,2-dimethyl-3,4-di- hydro-1H-quinolizine-1,8 (2H) -dione (6.0 mg, 0.013 mmol) and lithium chloride (16.54 mg, 0.390 mmol) in 1 mL of DMF was heated at 100 ° C for 1 h . It was cooled to room temperature, and the mixture was diluted with 1.0 ml of DMF and 0.3 ml of water. The resulting solution was purified by a reversed-phase Gilson HPLC (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA) / H2O, 12 min) to produce the compound 6 as a light yellow solid. 1H NMR (399 MHz, CDCl3): 8.76 (s, 1 H); 7.35 (m, 1 H); 6.86-6.91 (m, 2 H); 4.49 (dd, J = 1.6, 11.2 Hz, 1 H); 4.45 (dd, J = 2.8, 11.2, Hz, 1 H); 3.63 (dd, J = 2.8, 1.6 Hz, 1 H); 3.50 (s, 3 H); 1.44 (s, 3 H); 1.39 (s, 3 H). LCMS analysis calculated for C21H19F2N3O4S: 447.11; found: 448.01 (M + 1) +. Example 9 Preparation of Compound Int-7b
Step A- Synthesis of Compound Int-7a
[0212] For the solution of 6 - ((tert-butyldiphenyl silyl) oxy) -3-methyl-hex-2-en-1-ol (3 g, 8.14 mmol) in 60 ml of dichloromethane, di - isopropylethylamine (3.54 ml, 20.35 mmol) followed by methanesulfonyl chloride (1.029 ml, 13.02 mmol). The reaction was left under stirring at room temperature for 2 h. It was diluted with 200 ml of dichloromethane and washed with 100 ml of 0.2 N HCl (aq.) Solution, then with 100 ml of brine. The organic phase was concentrated, and the resulting residue was purified using a silica gel column (80 g) eluting with 5% EtOAc / hexanes to provide compound Int-7a as a mixture (2.5: 1) of stereoisomers ( E) and (Z). 1H NMR (400 MHz, CDCl3): δ 7.71-7.74 (m, 4 H); 7.417.50 (m, 6 H); 5.42-5.56 (m, 1 H); 4.12 & 4.13 (d, J = 8.0 Hz, 2 H); 3.71 & 3.72 (t, J = 6.4 Hz, 2 H); 2.19 & 2.26 (dd, J = 8.0, 7.7 Hz, 2 H); 1.74 & 1.79 (s, 3 H), 1.66-1.76 (m, 2 H), 1.11 & 1.12 (s, 9 H). Step B- Synthesis of Compound Int-7b
[0213] For the solution of lithium diisopropylamide (7.17 ml, 14.34 mmol) in 20 ml of THF cooled to 0 ° C, tributyltin hydride (3.48 ml, 13.04 mmol) was added ). The reaction was left under stirring at 0 ° C for 15 min. It was cooled to -78 ° C, and a solution of the compound Int-7a (2523 mg, 6.52 mmol) in 10 ml of THF was added via syringe. The reaction was left under stirring at -78 ° C for 30 min. It was diluted with 150 ml of 20% EtOAc / hexanes, and 150 ml of water was washed. The organic phase was concentrated in vacuo. The resulting residue was purified using a silica gel column (80 g) eluting initially with hexanes to remove tributyltin hydride, and then with 3% EtOAc / hexanes to provide the compound Int-7b as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.69-7.73 (m, 4 H); 7.38-7.47 (m, 6 H); 5.28-5.37 (m, 1 H); 3.64-3.75 (m, 2 H); 2.01-2.13 (m, 2 H); 1.63-1.70 (m, 5 H); 1.46-1.59 (m, 8 H); 1.28-1.36 (m, 6 H), 1.08 (s, 9 H), 0.840.94 (m, 15 H). Example 10 Preparation of Compounds 7 and 8
Step A- Synthesis of Compound Int-8a
[0214] For the solution of 4- (benzyloxy) -5-bromo-3-methoxy picolinaldehyde (390 mg, 1.21 mmol) and tert-butyl (((4-methyl-6- (stannyl tributyl) hex-4- en-1-yl) oxy) diphenyl silane (932 mg, 1.45 mmol) in 11 mL of ACN with stirring at 0 ° C, Tin (II) Cl2 (344 mg, 1.50 mmol) was added. The reaction was then warmed to room temperature and stirred for 15 min. This was diluted with 100 ml of 30% EtOAc / hexanes, and 100 ml of (15% by weight) aqueous NH4F solution. The resulting mixture was left under stirring at room temperature for 15 min. The solid was filtered. The organic phase of the mother liquor was concentrated in vacuo and the resulting residue was purified using a silica gel column (80 g) eluting initially with dichloromethane to remove the tin reagent, and then with 3% EtOAc / dichloromethane to provide the Int-8a compound as a mixture of stereoisomers. LCMS analysis calculated for C37H44BrNO4Si: 675.22; found: 676.18 (M + 1) +. Step B- Synthesis of Compound Int-8b
[0215] To a solution of the compound Int-8a (1200 mg, 1.78 mmol) in 8 ml of acetic anhydride, triethylamine (2200 mg, 21.7 mmol) and DMAP (65.2 mg, 0.534 mmol) were added. The reaction was left under stirring at room temperature for 1 h. It was diluted with 50 ml of dichloromethane. The solution was cooled to 0 ° C and 10 ml of MeOH was added. It was stirred for 1 h at room temperature. The solvent was removed in vacuo. The resulting residue was purified using a silica gel column (120 g) eluting with 25% EtOAc / hexanes to provide compound Int-8b as a colorless film. LCMS analysis calculated for C39H46BrNO5Si: 717.23; found: 718.35 (M + 1) +. Step C- Synthesis of Compound Int-8c
[0216] To a solution of the Int-8b compound (410 mg, 0.572 mmol) in 3.6 mL of THF / t-BuOH / water (5: 5: 1), 4-methylmorpholine 4-oxide (67 mg , 0.572 mmol) followed by osmium (VIII) oxide (2.5 wt% in t-BuOH) (1.06 ml, 0.086 mmol). The reaction was left under stirring at room temperature for 16 h. To this was added 10 g of solid Na2S2O5. The mixture was left stirring at room temperature for 1 h. The content was diluted with 70 ml of 50% EtOAc / hexanes. The brown solid was filtered. The filtrate was washed with water and then concentrated. The resulting residue was purified using a silica gel column (40 g) eluting with 55% EtOAc / hexanes to provide compound Int-8c as a colorless oil. LCMS analysis calculated for C39H48BrNO7Si: 751.24; found: 752.29 (M + 1) +. Step D - Synthesis of Compound Int-8d
[0217] For a mixture of the compound Int-8c (300 mg, 0.400 mmol) and 4-methylbenzene-1-sulfonyl chloride (137 mg, 0.719 mmol), 3 ml of pyridine was added. The reagent solution was left under stirring at room temperature overnight. 10 ml of MeOH were added to this solution. It was left under stirring at room temperature for 1 h. It was diluted with 80 ml of EtOAc, and washed with 100 ml of 0.4 N HCl (aq.). The organic phase was concentrated. The resulting residue was purified using a silica gel column (40 g) eluting with 5% MeOH / dichloromethane to provide compound Int-8d as a colorless film. LCMS analysis calculated for C32H40BrNO6Si: 643.18; found: 644.05 (M + 1) +. Step E- Synthesis of Compound Int-8e
[0218] For a solution of the Int-8d compound (125 mg, 0.195 mmol) in 4 ml of dichloromethane, Dess-Martin periodinane (165 mg, 0.389 mmol) was added. The reaction was left under stirring at room temperature for 30 min. It was diluted with 15 ml of EtOAc. The solid was filtered. The liquid portion was washed with 15 ml of saturated Na2CO3 solution (aq.) And then 15 ml of brine. It was concentrated in vacuo and purified using a silica gel column (40 g) eluting with 4% MeOH / dichloromethane to provide the compound Int-8e as a white solid. LCMS analysis calculated for C32H38BrNO6Si: 641.16; found: 642.13 (M + 1) +. Step F- Synthesis of Compound Int-8f
[0219] A solution of the compound Int-8e (115 mg, 0.180 mmol) in 4 ml of 1.25 M HCl in MeOH (50 ml, 63.4 mmol) was left under stirring at room temperature for 16 h. The solvent was removed in vacuo. To the resulting residue, 5 ml of dichloromethane and 0.5 ml of diisopropylethylamine were added. The resulting solution was purified using a silica gel column (25 g) eluting with 6% MeOH / dichloromethane to provide the compound Int-8f as a white solid. LCMS analysis calculated for C16H20BrNO6: 401.05; found: 402.09 (M + 1) +. Step G- Synthesis of Compound Int-8g
[0220] To a solution of the Int-8f compound (66 mg, 0.164 mmol) in 2 mL of dichloromethane was added triethyl silane (382 mg, 3.28 mmol) followed by methanesulfonic acid (200 mg, 2.08 mmol). The reaction was left under stirring at room temperature for 10 h. This was diluted with 15 ml of dichloromethane. NaHCO3 solid (2 g) was added. The resulting mixture was left under stirring at room temperature until the color of the mixture became pale yellow. It was filtered. The filtrate was purified using a preparative TLC plate eluting with 5% MeOH / dichloromethane to provide the compound Int-8g as a colorless film. LCMS analysis calculated for C16H20BrNO5: 387.05; found: 388.06 (M + 1) +. Step H- Synthesis of Compound Int-8h
[0221] For a solution of the Int-8g compound (57 mg, 0.148 mmol) in 5 mL of MeOH, K2CO3 (82 mg, 0.59 mmol) was added. The reaction was then stirred at 60 ° C for 1 h. Most of the solvent was removed in vacuo. To the resulting residue, 50 ml of dichloromethane was added. The solvent was removed in vacuo. The resulting residue was purified using a silica gel column (25 g) eluting with 7% MeOH / dichloromethane to provide compound Int-8h as a white solid. LCMS analysis calculated for C14H18BrNO4: 343.04; found: 344.05 (M + 1) +. Step I- Synthesis of Compound Int-8i and Compound Int-8j
[0222] For a solution of the Int-8h compound (46 mg, 0.134 mmol) in 4 mL of dichloromethane, Dess-Martin Reagent (85 mg, 0.20 mmol) was added. The reaction was left under stirring at room temperature for 45 min. It was diluted with 15 ml of EtOAc. The solid was filtered. The liquid portion was concentrated. The resulting residue was purified by a reverse phase C18 column (120 g) eluting with 0.05% TFA in water / 0.05% TFA in ACN (from 0-90%) over a length column column 15 to provide the cis-fused isomer compound Int-8i and the trans-fused isomer compound Int-8j separately as white solids. LCMS analysis calculated for C14H16BrNO4: 341.03; found: 342.04 (M + 1) +. Step J - Synthesis of the Int-8k Compound
[0223] For a solution of the compound Int-8i (18 mg, 0.053 mmol) in 1 mL of DMSO, (2,4-difluorophenyl) methanamine (11.3 mg, 0.079 mmol), diisopropylethylamine (17, 0 mg, 0.132 mmol) and Pd (PPh3) 4 (12.2 mg, 10.5 μmol) sequentially. The reaction vessel was filled with CO gas. It was stirred under a CO flask at 90 ° C for 8 h. It was cooled to room temperature. The content was purified using a reverse phase C18 column (40 mg) eluting with 0.05% TFA in water / 0.05% TFA in ACN (from 5-100%) over a column length of 12 to provide a mixture of the crude compound Int-8k together with triphenylphosphine oxide. This material was further purified using a chiral preparative SFC (ChiralPak IA, 30 X 250 mm, 70 mL / min, 120 bar, 40% (2: 1 MeOH: ACN) / CO2, 35 ° C) to provide enantiomer A from Int-8k compound (early eluting component) and B-enantiomer of Int-8k compound (late eluting component). LCMS analysis calculated for C22H22F2N2O5: 432.15; found: 433.18 (M + 1) +. Step K- Synthesis of Compound 7 and Compound 8
[0224] To the solution of the early eluting Enantiomer A of the compound Int-8k (5 mg, 0.012 mmol) in 1 mL of DMF, lithium chloride (4.90 mg, 0.116 mmol) was added. The reaction was left under stirring at 100 ° C for 2 h. It was cooled to room temperature, and the contents were purified using Gilson's reverse phase HPLC eluting with 0.05% TFA in water / 0.05% TFA in ACN (from 10% to 90%) to provide compound 7 as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.44 (brs, 1 H); 8.46 (s, 1 H); 7.35-7.40 (m, 1 H); 6.80-6.86 (m, 2 H); 4.67 (m, 2 H); 4.50 (dd, J = 11.2, 1.6 Hz, 1 H); 4.24 (dd, J = 11.2, 2.4 Hz, 1 H); 4.00 (dd, J = 9.2, 1.6 Hz, 1 H); 3.82 (dd, J = 2.4, 1.6 Hz, 1 H), 3.51-3.56 (m, 1 H); 2.69 (dd, J = 9.2, 1.2 Hz, 1 H); 1.56-1.58 (m, 2 H); 1.43-1.50 (m, 1 H); 1.30 (s, 3H). LCMS analysis calculated for C21H20F2N2O5: 418.13; found: 419.18 (M + 1) +.
[0225] For the solution of the late eluting Enantiomer B of the compound Int-8k (5 mg, 0.012 mmol) in 1 mL of DMF, lithium chloride (4.90 mg, 0.116 mmol) was added. The reaction was left under stirring at 100 ° C for 2 h. It was cooled to room temperature, and the contents were purified using Gilson's reverse phase HPLC eluting with 0.05% TFA in water / 0.05% TFA in ACN (from 10% to 90%) to provide compound 8 as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.46 (brs, 1 H); 8.48 (s, 1 H); 7.35-7.40 (m, 1 H); 6.80-6.86 (m, 2 H); 4.67 (m, 2 H); 4.50 (dd, J = 11.2, 1.6 Hz, 1 H); 4.25 (dd, J = 11.2, 2.4 Hz, 1 H); 3.99 (dd, J = 9.2, 1.6 Hz, 1 H); 3.82 (dd, J = 2.4, 1.6 Hz, 1 H), 3.51-3.56 (m, 1 H); 2.69 (dd, J = 9.2, 1.2 Hz, 1 H); 1.56-1.58 (m, 2 H); 1.42-1.50 (m, 1 H); 1.29 (s, 3 H). LCMS analysis calculated for C21H20F2N2O5: 418.13; found: 419.18 (M + 1) +. Example 11
Step A- Synthesis of Compound Int-15a
[0226] For the solution of the enantiomer A of the compound Int-8k (61 mg, 0.141 mmol) in 1 ml of toluene, di-tert-butyl dicarbonate (123 mg, 0.564 mmol) was added followed by DMAP (51.7 mg , 0.423 mmol). The reaction was left under stirring at 110 ° C for 1 h. The solvent was removed in vacuo. The resulting residue was dissolved in 2 ml of MeOH. To the resulting solution, potassium carbonate (78 mg, 0.564 mmol) was added. The reaction was left under stirring at room temperature for 2.5 h. To the resulting mixture, 1.4 ml of LiOH 0.5 N aqueous solution was added. The reaction was left under stirring at room temperature for 1 h. The solvent was removed in vacuo. The resulting residue was purified using a reversed phase Gilson (5100% 0.05% TFA in ACN / 0.05% TFA in water) to provide the compound Int-15a as a white solid. C15H17NO6: 307.11; found: 308.02 (M + 1) +. Step B - Synthesis of Compound Int-15b
[0227] For a solution of the compound Int-15a (12 mg, 0.039 mmol) in 0.5 ml of DMF, (2,4,6-trifluorophenyl) methanamine (9.44 mg, 0.059 mmol), 4- methylmorpholine (15.80 mg, 0.156 mmol), and HATU (22.27 mg, 0.059 mmol) sequentially. The reaction was left under stirring at room temperature for 16 h. The reagent solution was purified using Gilson's reverse phase HPLC (0-100% 0.05% TFA in ACN / 0.05% TFA in water) to provide compound Int-15b as a light yellow film. C22H21F3N2O5: 450.14; found: 451.01 (M + 1) +. Step C- Synthesis of Compound 14
[0228] Using the method described in Step K in Example 10, compound 14 was prepared from compound Int-15b. 1H NMR (500 MHz, CDCl3): δ 10.40 (brs, 1 H); 8.48 (s, 1 H); 6.69 (t, J = 8.2 Hz, 2 H); 4.65-4.74 (m, 2 H); 4.46-4.55 (m, 1 H); 4.20-4.28 (m, 1 H); 3.99 (dd, J = 11.5, 2.0 Hz, 1 H); 3.82 (m, 1 H); 3.48-3.57 (m, 1 H); 2.64-2.78 (m, 1 H); 1.53-1.61 (m, 2 H); 1.42-1.52 (m, 1 H); 1.29 (s, 3 H). LCMS analysis calculated for C21H19F3N2O5: 436.12; found: 437.01 (M + 1) +. Example 12 Preparation of Compound 15-18

[0229] Starting from the compound Int 15a, following essentially the same method described in Step B and Step C of Example 11, just replacing (2,4,6-trifluorophenyl) methanamine with the appropriate amine in Step B, compounds 15 - 18 were prepared.
[0230] Compound 15: 1H NMR (500 MHz, CDCl3): δ 10.50 (brs, 1 H); 8.50 (s, 1 H); 7.27-7.35 (m, 2 H); 7.06 (t, J = 7.9 Hz, 1 H); 4.70-4.78 (m, 2 H); 4.52 (dd, J = 13.7, 1.4 Hz, 1 H); 4.27 (dd, J = 13.8, 2.4 Hz, 1 H); 3.99 (dd, J = 11.5, 2.4 Hz, 1 H); 3.82 (m, 1 H); 3.51-3.56 (m, 1 H); 2.65-2.78 (m, 1 H); 1.53-1.61 (m, 2 H); 1.42-1.52 (m, 1 H); 1.30 (s, 3 H). LCMS analysis calculated for C21H20ClFN2O5: 434.10; found: 434.97 (M + 1) +.
[0231] Compound 16: 1H NMR (500 MHz, CDCl3): δ 10.53 (brs, 1 H); 8.51 (s, 1 H); 7.40 (d, J = 7.0 Hz, 1 H); 7.19-7.27 (m, 1 H); 7.11 (t, J = 8.6 Hz, 1 H); 4.57-4.66 (m, 2 H); 4.48-4.55 (m, 1 H); 4.28 (dd, J = 13.6, 1.6 Hz, 1 H); 4.00 (dd, J = 11.5, 2.0 Hz, 1 H); 3.83 (m, 1 H); 3.50-3.58 (m, 1 H); 2.66-2.79 (m, 1 H); 1.531.61 (m, 2 H); 1.22-1.52 (m, 1 H); 1.30 (s, 3 H). LCMS analysis calculated for C21H20ClFN2O5: 434.10; found: 434.97 (M + 1) +.
[0232] Compound 17: 1H NMR (400 MHz, CDCl3): 10.46 (broad, 1 H); 8.45 (s, 1 H); 7.10-7.14 (m, 1 H); 6.91-6.96 (m, 1 H); 4.65-4.70 (m, 2 H); 4.51 (dd, J = 10.8 Hz, 1 H); 4.24 (dd, J = 1.6, 11.2 Hz, 1 H); 3.99 (dd, J = 8.8 Hz, 1 H); 3.83 (m, 1 H); 3.52-3.56 (m, 1 H); 2.68-2.73 (m, 1 H); 1.55-1.60 (m, 2 H); 1.43-1.50 (m, 1 H); 1.30 (s, 3 H). LCMS analysis calculated for C21H19F3N2O5: 436.12; found: 437.17 (M + 1) +.
[0233] Compound 18: 1H NMR (400 MHz, CDCl3): 10.47 (broad, 1 H); 8.48 (s, 1 H); 7.33-7.36 (m, 2 H); 7.01-7.05 (m, 2 H); 4.60-4.68 (m, 2 H); 4.51 (dd, J = 10.8 Hz, 1 H); 4.26 (dd, J = 1.6, 11.2 Hz, 1 H); 3.98 (dd, J = 1.2, 8.8 Hz, 1 H); 3.83 (m, 1 H); 3.51-3.57 (m, 1 H); 2.68-2.73 (m, 1 H); 1.56-1.61 (m, 2 H); 1.44-1.50 (m, 1 H); 1.30 (s, 3 H). LCMS analysis calculated for C21H21FN2O5: 400.14; found: 401.18 (M + 1) +. Example 13 Preparation of Compounds 19-30
[0234] Starting from the B 8 enantiomer of the Int 8k compound, using essentially the same method described in Steps A to C in Example 11 and only replaced with the appropriate amines in Step B, the following compounds were prepared:


[0235] The Int-8j trans-fused compound (prepared in Step I of Example 10) was converted to compound 9 using the method described in Step J and Step K of Example 10. 1H NMR (400 MHz, CDCl3): δ 10.36 (brs, 1 H); 8.49 (s, 1 H); 7.35-7.41 (m, 1 H); 6.82-6.88 (m, 2 H); 4.68 (d, J = 5.9 Hz, 2 H); 4,124.24 (m, 3 H); 3.92 (dd, J = 11.3, 5.4 Hz, 1 H); 3.52-3.59 (m, 1 H); 2.25-2.31 (m, 1 H); 1.96-2.03 (m, 1 H); 1.68-1.79 (m, 2 H); 1.37 (s, 3 H). LCMS analysis calculated for C21H20F2N2O5: 418.13; found: 419.18 (M + 1) +. Example 15 Preparation of Compound 33 and Compound 34

[0236] Using the methods described above for the production of compounds 7 and 8, and starting from the compound Int-8j, compounds 33 and 34 were prepared by chiral separation (column IC, 20x250mm, 50% MeOH (0.2% NH4OH) / CO2, 50 ml / min, 100 bar) of the intermediate before the last step in the synthesis of compound 9. The early-eluting compound was deprotected using the conditions described in Step K of Example 10 to provide compound 33, the compound of Late elution was unprotected to provide compound 34.
[0237] Compound 33: 1H NMR (400 MHz, CDCl3): δ 10.36 (brs, 1 H); 8.49 (s, 1 H); 7.35-7.41 (m, 1 H); 6.82-6.88 (m, 2 H); 4.68 (d, J = 5.9 Hz, 2 H); 4,124.24 (m, 3 H); 3.92 (dd, J = 11.3, 5.4 Hz, 1 H); 3.52-3.59 (m, 1 H); 2.25-2.31 (m, 1 H); 1.96-2.03 (m, 1 H); 1.68-1.79 (m, 2 H); 1.37 (s, 3 H). LCMS analysis calculated for C21H20F2N2O5: 418.13; found: 419.18 (M + 1) +.
[0238] Compound 34: 1H NMR (400 MHz, CDCl3): δ 10.36 (brs, 1 H); 8.49 (s, 1 H); 7.35-7.41 (m, 1 H); 6.82-6.88 (m, 2 H); 4.68 (d, J = 5.9 Hz, 2 H); 4,124.24 (m, 3 H); 3.92 (dd, J = 11.3, 5.4 Hz, 1 H); 3.52-3.59 (m, 1 H); 2.25-2.31 (m, 1 H); 1.96-2.03 (m, 1 H); 1.68-1.79 (m, 2 H); 1.37 (s, 3 H). LCMS analysis calculated for C21H20F2N2O5: 418.13; found: 419.18 (M + 1) +. Example 16 Preparation of Compound 35 and Compound 36

[0239] Starting from compound Int 8j, compound 35 and 36 were prepared essentially by the same method described in step J and K of Example 10, just replacing 2,4-difluorobenzylamine with 2-fluoro-3-chlorobenzylamine. The early eluting compound in the chiral separation process (IC column, 20x250mm, 40% MeOH (0.2% NH4OH) / CO2, 55 ml / min, 100bar) from step J was deprotected to provide compound 35, the late eluting compound was deprotected to provide compound 36.
[0240] Compound 35: 1H NMR (500 MHz, CDCl3): δ 10.36 (brs, 1 H), 8.49 (s, 1 H), 7.34-7.27 (m, 2H), 7 , 05 (t, J = 7.8 Hz, 1 H), 4.73 (m, 2 H), 4.20-4.28 (m, 1 H), 4.09-4.19 (m, 2 H), 3.88-3.96 (m, 1 H), 3.48-3.59 (m, 1 H), 2.21-2.32 (m, 1 H), 1.96- 2.06 (m, 1 H), 1.68-1.78 (m, 2 H), 1.36 (s, 3 H). LCMS analysis calculated for C21H20ClFN2O5: 434.10; found: 435.04 (M + 1) +.
[0241] Compound 36: 1H NMR (500 MHz, CDCl3): δ 10.36 (brs, 1 H), 8.49 (s, 1 H), 7.35-7.27 (m, 2H), 7 , 05 (t, J = 7.8 Hz, 1 H), 4.73 (m, 2 H), 4.20-4.28 (m, 1H), 4.09-4.19 (m, 2 H), 3.88-3.98 (m, 1 H), 3.51-3.57 (m, 1 H), 2.21-2.32 (m, 1 H), 1.96-2 , 06 (m, 1 H), 1.68-1.78 (m, 2 H), 1.36 (s, 3 H). LCMS analysis calculated for C21H20ClFN2O5: 434.10; found: 435.06 (M + 1) +. Example 17 Preparation of Compound Int-9b
Step A- Synthesis of Compound Int-9a
[0242] For the solution of 5 - ((tert-butyladimethyl silyl) oxy) pent-2-en-1-ol (2070 mg, 9.57 mmol) in 25 ml of dichloromethane, diisopropylethylamine (1545 mg , 11.96 mmol). The reaction solution was cooled to 0 ° C, and methanesulfonyl chloride (1205 mg, 10.52 mmol) was then added. The reaction was left under stirring at room temperature overnight. It was diluted with 60 ml of dichloromethane, and washed with 50 ml of 0.5 N HCl (aq.), And then 60 ml of saturated NaHCO3 solution (aq.). The organic phase was concentrated. The resulting residue was purified using a silica gel column (40 g) eluting with 10% EtOAc / hexanes to provide compound Int-9a as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.62-5.84 (m, 2 H), 4.06 (d, J = 7.0 Hz, 2 H), 3.68 (t, J = 6 , 5 Hz, 2 H), 2.31 (apparent q, J = 6.6 Hz, 2 H), 0.92 (s, 9 H), 0.08 (s, 6 H). Step B- Synthesis of Compound Int-9b
[0243] For the solution of lithium diisopropylamide (3.85 ml, 7.69 mmol) in 10 ml THF cooled to 0 ° C, tributyltin hydride (1.953 ml, 7.31 mmol) was added. The reaction was left under stirring at 0 ° C for 15 min. The resulting solution of tributyltin was then cooled to -78 ° C, and a solution of the compound Int-9a (903 mg, 3.85 mmol) in 10 ml of THF was then added. The reaction was left under stirring at -78 ° C for 30 min. It was diluted with 80 ml of 20% EtOAc / hexanes, and 100 ml of water was washed. The organic phase was concentrated in vacuo. The resulting residue was purified using a silica gel column (80 g) eluting with hexanes to provide compound Int-9b as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.62 (dt, J = 15.3, 8.4 Hz, 1 H), 5.62 (dt, J = 15.1, 7.0 Hz, 1 H ), 3.87 (t, J = 7.3 Hz, 2 H), 2.22 (apparent q, J = 7.3 Hz, 2 H), 1.72 (d, J = 8.5 Hz, 2 H), 1.42-1.58 (m, 6 H), 1.28-1.36 (m, 6 H), 0.79-1.06 (m, 24 H), 0.08 ( s, 6 H). Example 18 Preparation of Compound Int-10f
Step A- Synthesis of Compound Int-10a
[0244] To a solution of the compound Int-1 (500 mg, 1.552 mmol) and compound Int-9b (912 mg, 1.862 mmol) in 15 mL of ACN with stirring at 0 ° C, Tin (II) Cl2 ( 441 mg, 2.328 mmol). The reaction was stirred for 30 min. The contents were diluted with 100 ml of 30% EtOAc / hexanes, and washed with 100 ml of 15% by weight NH4F in water. The organic phase was separated and filtered. The mother liquor was concentrated in vacuo and the resulting residue was purified using a silica gel column (80 g) eluting initially with dichloromethane to remove the tin reagent, and then with 5% EtOAc / dichloromethane to provide the compound Int- 10a as a mixture of stereoisomers. LCMS analysis calculated for C25H36BrNO4Si: 523.16; found: 524.07 (M + 1) +. Step B- Synthesis of Compound Int-10b
[0245] For a solution of the Int-10a compound (610 mg, 1.167 mmol) in 8 mL of dichloromethane, acetic anhydride (2000 mg, 19.59 mmol), triethylamine (800 mg, 7.91 mmol), and DMAP (143 mg, 1.167 mmol) sequentially. The reaction was left under stirring at room temperature for 1 h. It was diluted with 20 ml of dichloromethane, and then 3 ml of MeOH was added. It was left under stirring at room temperature for 2 h to abruptly cool the excess acetic anhydride. The solvent was removed in vacuo and the resulting residue was purified using a silica gel column (120 g) eluting with 15% EtOAc / hexanes to provide the compound Int-10b as a colorless film. LCMS analysis calculated for C27H38BrNO5Si: 565.17; found: 566.11 (M + 1) +. Step C- Synthesis of Compound Int-10c
[0246] To a solution of the compound Int-10b (293 mg, 0.519 mmol) in 4.5 mL of THF / t-BuOH / water (5: 5: 1), 4-methylmorpholine 4-oxide (66, 9 mg, 0.571 mmol) followed by 4-methylmorpholine N-oxide (66.9 mg, 0.571 mmol). The reaction was left under stirring at room temperature for 16 h. For this reaction, 5 g of solid Na2S2O5 were added. The mixture was left stirring at room temperature for 1 h. The content was diluted with 70 ml of 50% EtOAc / hexanes. The brown solid was filtered. The filtrate was washed with water and then concentrated. The resulting residue was purified using a silica gel column (40 g) eluting with 5% MeOH / dichloromethane to provide the compound Int-10c as a colorless oil. LCMS analysis calculated for C27H40BrNO7Si: 599.17; found: 600.12 (M + 1) +. Step D- Synthesis of Compound Int-10d
[0247] For a solution of the compound Int-10c (272 mg, 0.454 mmol) in 3 ml of pyridine, 4-methylbenzene-1-sulfonyl chloride (130 mg, 0.682 mmol) was added. The reaction was left under stirring at room temperature for 36 h. For the reaction, 1 mL of MeOH was added. It was left under stirring at room temperature for 1 h. The contents were diluted with 30 ml of dichloromethane, and washed with 20 ml and 0.5 N HCl (aq.) Solution. The organic phase was concentrated. The resulting residue was purified using a silica gel column (80 g) eluting with EtOAc to provide the compound Int-10d as a colorless film. LCMS analysis calculated for C20H32BrNO6Si: 491.12; found: 492.02 (M + 1) +. Step E- Synthesis of Compound Int-10e
[0248] For a solution of the compound Int-10d (80 mg, 0.163 mmol) in 2 mL of MeOH, 1.25 N HCl in MeOH (0.5 mL, 0.625 mmol) was added. The reaction was left under stirring at room temperature for 2 h. The solvent was removed in vacuo. The resulting residue was purified using a silica gel column (40 g) eluting with 20% MeOH / dichloromethane to provide the compound Int-10e as a colorless film. LCMS analysis calculated for C14H18BrNO6: 377.03; found: 378.00 (M + 1) +. Step F- Synthesis of Compound Int-10f
[0249] For a solution of the compound Int-10e (18.64 mg, 0.090 mmol) in 1 mL of ACN, methanesulfonic anhydride (14.82 mg, 0.085 mmol) was added. The reaction was left under stirring at room temperature for 30 min. This solution was then added via syringe to a vial containing 7-bromo-3-hydroxy-2- (2-hydroxy ethyl) -9-methoxy-8-oxo- 2,3,4,8-tetra- hydro-1H-quinolizin-1-yl (20 mg, 0.053 mmol). The reaction was left under stirring at 50 ° C overnight. The solvent was removed in vacuo. The resulting residue was purified using reverse phase Gilson's Column eluting with 0.05% TFA in ACN / 0.05% TFA in water (0 to 90%) to provide the compound Int-10f as a colorless film. LCMS analysis calculated for C14H16BrNO5: 359.02; found: 359.96 (M + 1) +. Example 19 Preparation of Compound 10
[250] Compound 10 was prepared following essentially the same reaction sequence from Step H to Step K in Example 10, and replacing the Int-8g compound with the Int-10f compound. 1H NMR (400 MHz, CDCI3): δ 10.27 (b, 1 H), 8.46 (s, 1 H), 7.35-7.40 (m, 1 H), 6.81-6, 86 (m, 2 H), 4.67 (m, 2 H), 4.59 (m, 1 H), 4.24 (dd, J = 2.4, 11.2 Hz, 1 H), 3 , 98 (dd, J = 1.6, 9.2 Hz, 1 H), 3.76 (m, 1 H), 3.54 (m, 1 H), 3.42 (m, 1 H), 2.77 (m, 1 H), 2.48 (m, 1 H). LCMS analysis calculated for C19H16F2N2O5: 390.10; found: 391.12 (M + 1) +. Example 20 Preparation of Compound Int-11

[0251] Compound Int-11 was prepared as a mixture of approximately 1: 1 isomers (E) and (Z) using the method described in Baldwin et al, Chem. Commun. 22: 2786 (2003). Example 21 Preparation of Compound Int-12

[0252] Compound Int-12 was prepared as a mixture of approximately 1: 1 isomers (E) and (Z) following essentially the same method described in Example 17, and replacing 5 - ((tert-butyladimethyl silyl) oxy) pent-2-en-1-ol with the compound Int-11 in Step A. 1H NMR (400 MHz, CDCl3): δ 5.60 & 5.40 (dt, J = 9.0, 1.1 Hz, 1 H), 4.16 & 4.03 (s, 2 H), 1.70-1.84 (m, 2 H), 1.61 & 1.59 (s, 3 H), 1.42- 1.58 (m, 6 H), 1.28-1.36 (m, 6 H), 0.79-1.02 (m, 24 H), 0.11 & 0.08 (s, 6 H ). Example 22 Preparation of Compound Int-13

[0253] Compound Int-13 was prepared using the method described in Steps A to D of Example 18, and replacing compound Int-9b with compound Int-12 in Step A. Analysis by LCMS calculated for C20H32BrNO6Si: 491 , 12; found: 492.04 (M + 1) +. Example 23 Preparation of Compounds 11 and 12
Step A- Synthesis of Compound Int-14a
[0254] To the solution of paraformaldehyde (93 mg, 3.09 mmol) in 4 mL of AcOH, sulfuric acid (120 mg, 1.224 mmol) was added. The reaction was left under stirring at room temperature for 20 min before compound Int-13 (160 mg, 0.309 mmol) was added. The reaction was left under stirring at room temperature for 1 h and then at 70 ° C for 1 h. It was cooled to room temperature. To the content, 1 g of solid NaHCO3 was added little by little. The mixture was diluted with 20 ml of EtOAc and then filtered. The filtrate was concentrated in vacuo and purified using a reverse phase column (120 g) eluting with 0.05% TFA in water and 0.05% TFA in ACN (from 0% to 90% over a column length of 10) to provide the compound Int-14a. LCMS analysis calculated for C15H18BrNO6: 389.03; found: 390.02 (M + 1) +. Step B- Synthesis of Compound Int-14b
[0255] To a solution of the compound Int-14a, TFA salt (150 mg, 0.299 mmol) in 5 mL of MeOH, potassium carbonate (165 mg, 1.195 mmol) was added. The reaction was left under stirring at room temperature for 2 h. The solvent was removed in vacuo. The resulting residue was purified using a silica gel column (40 g) eluting with 8% MeOH / dichloromethane to provide compound Int-14b as a colorless film. LCMS analysis calculated for C13H16BrNO5: 347.02; found: 348.11 (M + 1) +. Step C- Synthesis of Compound Int-14c and Compound Int-14d
[0256] For a solution of the compound Int-14b (88 mg, 0.254 mmol) in 5 ml of dichloromethane, Dess-Martin periodinane (162 mg, 0.381 mmol) was added. The reaction was left under stirring at room temperature for 45 min. It was diluted with 60 ml of EtOAc. The solid was filtered. The liquid portion was concentrated. The resulting residue was purified by a silica gel column (40 g) eluting with EtOAc to provide cis-molten compound Int-14c and trans-molten compound Int-14d individually as a white solid. LCMS analysis calculated for C13H14BrNO5: 345.00; found: 346.02 (M + 1) +. Step D - Synthesis of Compound Int-14e
[0257] For a solution of the compound Int-14d (42 mg, 0.122 mmol) in 2 mL of DMSO, (2,4-difluorophenyl) methanamine (34.9 mg, 0.244 mmol), diisopropylethylamine (39, 4 mg, 0.305 mmol) and Pd (PPh3) 4 (35.3 mg, 0.031 mmol) sequentially. The reaction vessel was filled with CO gas by bubbling CO into the solution through a needle for 20 min. It was stirred under a CO flask at 90 ° C for 6 h. It was cooled to room temperature. The content was purified using reverse phase Gilson eluting with 0.05% TFA in water / 0.05% TFA in ACN (from 10-90%) to provide the crude compound Int-14e. This material was further purified using a chiral preparative SFC (Chiral AD column 30X250 mm, 40% 2: 1 MeOH: ACN / CO2, 70 mL / min, 100 bar, 4 mg / mL in MeOH / dichloromethane, 35 ° C, 254 nM) to provide enantiomer A of compound Int-14e (early eluting component) and enantiomer B of compound Int-14e (late eluting component). LCMS analysis calculated for C21H20F2N2O6: 434.13; found: 435.04 (M + 1) +. Step E- Synthesis of Compound 11 and 12
[0258] For the solution of the enantiomer A of the compound Int-14e (4.0 mg, 9.21 μmol) in 4 ml of DMF, lithium chloride (7.81 mg, 0.184 mmol) was added. The mixture was left under stirring at 100 ° C for 1 h. It was cooled to room temperature. The mixture was separated by reversed phase Gilson (10% ACN (0.05% TFA) / H2O- 90% ACN (0.05% TFA) / H2O, 12 min) to produce compound 11 as a white solid. 1H NMR (400 MHz, CDCI3): δ 10.25 (b, 1 H), 8.51 (s, 1 H), 7.35-7.40 (m, 1 H), 6.81-6, 87 (m, 2 H), 5.19 (d, J = 5.2 Hz, 1 H), 4.80 (d, J = 5.2 Hz, 1 H), 4.67 (d, J = 4.8 Hz, 2 H), 4.28-4.34 (4 H), 3.87 (d, J = 9.2 Hz, 1 H), 1.6 (brs, 1 H), 1, 57 (s, 3 H). LCMS analysis calculated for C20H18F2N2O6: 420.11; found: 421.04 (M + 1) +.
[0259] For the solution of the enantiomer B of the compound Int-14e (4.0 mg, 9.21 μmol) in 4 ml of DMF, lithium chloride (7.81 mg, 0.184 mmol) was added. The mixture was left under stirring at 100 ° C for 1 h. It was cooled to room temperature. The mixture was separated by reversed phase Gilson (10% ACN (0.05% TFA) / H2O- 90% ACN (0.05% TFA) / H2O, 12 min) to produce compound 12 as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.29 (b, 1 H); 8.53 (s, 1 H), 7.35-7.40 (m, 1 H), 6.81-6.87 (m, 2 H), 5.19 (d, J = 5.2 Hz , 1 H), 4.80 (d, J = 5.2 Hz, 1 H), 4.67 (d, J = 4.8 Hz, 2 H), 4.27-4.34 (4 H) , 3.87 (d, J = 9.2 Hz, 1 H), 1.6 (brs, 1 H); 1.61 (s, 3 H). LCMS analysis calculated for C20H18F2N2O6: 420.11; found: 421.04 (M + 1) +. Example 24 Preparation of Compound 13

[0260] The cis-fused compound Int-14c prepared in Step C of Example 23 was converted to compound 13 using the method described in Step D and Step E of Example 23. 1H NMR (400 MHz, CDCl3) δ 10.38 (b, 1 H); 8.47 (s, 1 H); 7.35-7.42 (m, 1 H); 6.81-6.88 (m, 2 H), 5.07 (d, J = 6.3 Hz, 1 H), 4.82 (d, J = 6.3 Hz, 1 H), 4, 78 (d, J = 11.5 Hz, 1 H), 4.62-4.73 (m, 2 H), 4.51 (d, J = 13.8 Hz, 1 H), 4.31 ( d, J = 13.9 Hz, 1 H), 4.16 (s, 1 H), 3.45 (d, J = 11.4 Hz, 1 H), 1.21 (s, 3 H). LCMS analysis calculated for C20H18F2N2O6: 420.11; found: 421.06 (M + 1) +. Example 25 Preparation of Compound 37 and 38
Step A- Synthesis of Compound Int-16a
[0261] For the solution of but-3-in-1-ol (10 g, 143 mmol) in 110 ml of dichloromethane tert-butylchlorodiphenyl silane (37.3 g, 136 mmol) was added followed by 1H-imidazole (14 , 6 g, 214 mmol) and N, N-dimethylpyridin-4-amine (17.4 g, 143 mmol). The reaction was left under stirring at 20 ° C for 2 hours. The progress of the reaction was monitored by TLC. It was diluted with 150 ml of water, extracted with 50% EtOAc / hexanes (2 x 150 ml). The organic phase was concentrated in vacuo and the resulting residue was purified using silica gel column chromatography (PET: EtOAc = 200: 1) to provide the compound Int-16a as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 6.4 Hz, 4 H), 7.34-7.48 (m, 6 H), 3.79 (t, J = 7 , 0 Hz, 2 H), 2.45 (dt, J = 7.0, 2.4 Hz, 2 H), 1.95 (brs, 1H), 1.06 (s, 9 H). Step B- Synthesis of Compound Int-16b
[0262] To a stirred solution of Int-16a compound (13.4 g, 43.4 mmol) in 200 ml of THF at -78 ° C was added butyl lithium (18.24 ml, 45.6 mmol). It was left under stirring at this temperature for 20 min. To this was added the solution of methyl carbonochlorhydrate (5.336 g, 56.5 mmol) in 20 mL of THF via canula, and the reaction was stirred for 2 hours during heating to 0 ° C. The reaction was quenched by the addition of saturated NH4Cl solution (100 ml) and extracted with EtOAc (2 x 200 ml). The organic layer was dried over anhydrous Na2SO4. The solvent was filtered and the filtrate was concentrated to provide the compound Int-16b as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 6.4 Hz, 4 H), 7.33-7.50 (m, 6 H), 3.81 (t, J = 6 , 8 Hz, 2 H), 3.76 (s, 3 H), 2.58 (t, J = 6.8 Hz, 2 H), 1.05 (s, 9 H). Step C- Synthesis of Compound Int-16c
[0263] To a stirred solution of copper (I) iodide (13.8 g, 72.6 mmol) in THF (10 mL) at 0 ° C methyl lithium (29.7 ml, 47.5 mmol) was added and stirred for 15 min at 0 ° C. The resulting solution was cooled to -78 ° C and a solution of the Int-16b compound (17.4 mg, 47.5 mmol) in THF (5 mL) was added via cannula and stirred for 2 hours at that temperature. The reaction mixture was then quenched by the addition of saturated NH4Cl (10 ml) followed by water (200 ml). The mixture was extracted with EtOAc (3 x 20 ml), the combined organic layer was dried over anhydrous Na2SO4, then filtered. The filtrate was concentrated to provide the compound Int-16c as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 6.4 Hz, 4 H), 7.35-7.42 (m, 6 H), 5.72 (s, 1 H) , 3.83 (t, J = 6.4 Hz, 2 H), 3.62-3.70 (m, 3 H), 2.91 (t, J = 6.4 Hz, 2 H), 1 , 92 (s, 3 H), 1.03 (s, 9 H). Step D - Synthesis of Compound Int-16d
[0264] To a solution of the compound Int-16c (19 g, 49.7 mmol) in dichloromethane (200 ml) cooled to -78 ° C, isopropyl aluminum dihydride (109 ml, 109 mmol) was added. The reaction was left under stirring at -78 ° C for 1 h. and heated to 0 ° C. At this point, it was quenched by the addition of 500 mL of saturated Rochelle salt solution. The mixture was left under stirring at 0 ° C for 1 hour and the organic phase was isolated. The organic layer was washed with 50 ml of brine and dried over Na2SO4, then it was filtered and the filtrate was concentrated. The resulting residue was purified using silica gel column chromatography (PET: EtOAc = 10: 1) to provide the compound Int-16d as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 6.4 Hz, 4 H), 7.36-7.44 (m, 6 H), 5.64 (t, J = 6 , 8 Hz, 1 H), 4.04 (d, J = 6.8 Hz, 2 H), 3.67 (t, J = 6.4 Hz, 2 H), 2.36 (t, J = 6.4 Hz, 2 H), 1.69 (s, 3 H), 1.04 (s, 9 H Step E- Synthesis of Compound Int-16e
[0265] To a solution of the compound Int-16d (7 g, 19.74 mmol) and lithium chloride (1.7 g, 39.5 mmol) in dichloromethane (70 mL) was added N-ethyl-N-isopropylpropan -2-amine (6.4 g, 49.4 mmol) followed by methanesulfonyl chloride (3619 mg, 31.6 mmol). The reaction mixture was left under stirring at 20 ° C for 2 hours. Then, it was diluted with 200 ml of dichloromethane and washed with 200 ml of 0.2 N HCl (aq.) Solution and 100 ml of brine. The organic phase was concentrated to provide the compound Int-16e as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 6.4 Hz, 4 H), 7,367.46 (m, 6 H), 5.50 (t, J = 7.6 Hz, 1 H), 3.96-4.14 (m, 2 H), 3.64-3.80 (m, 2 H), 2.35 (t, J = 6.8 Hz, 2 H), 1 , 63-1.77 (m, 3 H), 1.04 (s, 9 H). Step F- Synthesis of Compound Int-16f
[0266] For the solution of lithium diethylamide (19.17 ml, 38.3 mmol) in THF (70 ml) cooled to 0 ° C, tributyltin (10 g, 34.9 mmol) was added. The reaction was left under stirring at 0 ° C for 30 minutes. It was cooled to -78 ° C, and a solution of the compound Int-16e (6.5 g, 17.43 mmol) in 30 ml of THF was added via syringe. The reaction was left under stirring at -78 ° C for 30 minutes. It was diluted with 100 ml of 20% EtOAc / hexanes and washed with 100 ml of water. The organic phase was isolated and the aqueous phase was extracted with 100 ml of 20% EtOAc / hexanes. The combined organics were washed with water, brine and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (PET: EtOAc = 100: 1) to provide compound Int-16f as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.63-7.75 (m, 4 H), 7.32-7.45 (m, 6 H), 5.30 (t, J = 8.8 Hz , 1 H), 3.66 (t, J = 7.6 Hz, 2 H), 2.18-2.33 (m, 2 H), 1.54-1.63 (m, 5 H), 1.39-1.50 (m, 6 H), 1.21-1.33 (m, 6 H), 1.03-1.08 (m, 9 H), 0.74-0.92 ( m, 15 H). MS (M + H) +: 628. Step G- Synthesis of Compound Int-16g
[0267] For a solution of Int-16f compound (7.6 g, 12.11 mmol) and Int-1 compound (3.3 g, 10.09 mmol) in acetonitrile (100 mL) with stirring at 0 ° C Tin (II) chloride (5.8 g, 30.3 mmol) was added. The reaction was then heated to 20 ° C and stirred for 15 minutes. This color gradually disappeared in 5 minutes. The progress of the reaction was monitored by TLC. The reaction was found to be complete when almost all the color disappeared. This was diluted with 100 ml of 30% EtOAc / hexane, and 100 ml of 15% aqueous NH4F solution (weight). The resulting mixture was left under stirring at 20 ° C for 20 min. The solid was filtered. The organic phase of the mother liquor was concentrated in vacuo and the resulting residue was purified using silica gel column chromatography (PET: EtOAc = 10: 1) to produce the compound Int-16g as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.35 (brs, 1 H), 7.66 (brs, 4 H), 7.48 (d, J = 5.4 Hz, 2 H), 7.36 (brs, 9 H), 5.61 - 5.81 (m, 1 H), 5.15 ~ 5.27 (m, 1 H), 4.90-5.14 (m, 2 H), 4 , 77 (d, J = 18.0 Hz, 2 H), 3.84 (brs, 3 H), 3.59-3.78 (m, 3 H), 1.87 (d, J = 5, 4 Hz, 1 H), 1.68-1.80 (m, 1 H), 1.03 (brs, 9 H), 0.88-0.96 (m, 3 H). MS (M + H) +: 662. Step H- Synthesis of Compound Int-16h
[0268] For a solution of the compound Int-16g (11 g, 16.65 mmol), N, N-dimethylpyridin-4-amine (407 mg, 3.33 mmol) and N-ethyl-N-isopropylpropan-2- amine (10 g, 83 mmol) in dichloromethane (100 mL) chlorine (methoxy) methane (6.7 g, 83 mmol) was added. The reaction mixture was left under stirring at 30 ° C for 16 hours, LCMS showed that the starting material was completely consumed. The solvent was removed in vacuo. The resulting residue was purified using silica gel column chromatography (PET: EtOAc = 10: 1) to provide the compound Int-16h as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.43 (s, 1 H), 7.64 (d, J = 6.8 Hz, 4 H), 7.47 (d, J = 5.8 Hz, 2 H), 7.30-7.43 (m, 9 H), 5.75-5.85 (m, 1 H), 5.18-5.25 (m, 1 H), 5.11 ( d, J = 11.6 Hz, 1 H), 4.98 (d, J = 11.0 Hz, 1 H), 4.84-4.90 (m, 1 H), 4.71 - 4, 79 (m, 1 H), 4.54-4.60 (m, 1 H), 4.37-4.44 (m, 1 H), 3.85 (s, 3 H), 3.62- 3.72 (m, 2 H), 3.12-3.31 (m, 3 H), 1.94-2.03 (m, 1 H), 1.59-1.68 (m, 1 H ), 1.02 (s, 9 H), 0.82-0.96 (m, 3 H). MS (M + H) +: 706. Step I - Synthesis of Compound Int-16i
[0269] For a solution of the Int-16h compound (10 g, 14.19 mmol) in 100 mL of THF / water (3: 2), 4-methylmorpholine 4-oxide (3.3 g, 28.4 mmol) followed by osmium (VIII) oxide (541 mg, 2.128 mmol). The reaction was left under stirring at 35 ° C for 48 hours. To this mixture 10 g of solid Na2S2O5 were added. The mixture was left under stirring at 35 ° C for 1 hour. The mixture was diluted with 100 ml of 50% EtOAc / hexanes. The brown solid was filtered and the filtrate was washed with water, brine and dried over anhydrous Na2SO4. The solid was filtered and the filtrate was concentrated. The resulting residue was purified using silica gel column chromatography (PET: EtOAc = 1: 1) to provide the compound Int-16i as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.27-8.48 (m, 1 H), 7.62-7.74 (m, 4 H), 7.27-7.46 (m, 11 H ), 5.18-5.26 (m, 1 H), 5.10-5.16 (m, 1 H), 5.07 (d, J = 3.6 Hz, 1 H), 4.49 (t, J = 7.0 Hz, 1 H), 4.34 (d, J = 6.8 Hz, 1 H), 3.77-3.89 (m, 5 H), 3.45-3 , 76 (m, 3 H), 3.08-3.26 (m, 3 H), 2.40-2.58 (m, 1 H), 1.67-2.07 (m, 1 H) , 1.40-1.58 (m, 1 H), 1.01-1.10 (m, 9 H), 0.78 (s, 3 H). MS (M + H) +: 740.
[0270] Stage J - Synthesis of Compound Int-16j
[0271] The solution of 4-methylbenzene-1-sulfonyl chloride (2.8 g, 14.62 mmol) in Pyridine (10 mL) was added to a solution of the compound Int-16i (6 g, 8.12 mmol ) in Pyridine (50 ml). The reaction mixture was left under stirring at 35 ° C for 16 hours. LCMS showed that the starting material was completely consumed. The reaction was concentrated in vacuo and the resulting residue was purified using silica gel column chromatography (PET: EtOAc = 1: 1 then dichloromethane: MeOH = 100: 1) to provide compound Int-16i as a white solid . 1H NMR (400 MHz, CDCl3): δ 7.52-7.82 (m, 5 H), 7.34-7.51 (m, 6 H), 4.62-4.96 (m, 3 H ), 4.33-4.57 (m, 2 H), 3.91 - 4.00 (m, 3 H), 3.64-3.90 (m, 3 H), 3.24-3, 41 (m, 3 H), 1.21-1.31 (m, 2 H), 0.60-1.17 (m, 12 H). MS (M + H) +: 632. Step K- Synthesis of the Int-16k Compound
[0272] For a solution of the compound Int-16j (246 mg, 0.390 mmol) in 5 mL of DMF, allyl iodide (262 mg, 1.560 mmol) was added, followed by sodium hydride (31.2 mg, 0.780 mmol) ). The reaction was left under stirring at room temperature for 40 min. It was cooled to 0 ° C, and quenched by the addition of 1 ml of water. The mixture was diluted with 70% EtOAc / hexanes (80 ml) and washed with 80 ml of water. The organic phase was concentrated. The resulting residue was purified using a silica gel column eluting with 3% MeOH / dichloromethane to provide the compound Int-16k as a colorless film. LCMS analysis calculated for C34H44BrNO6Si: 670.7; found: 671.9 (M + 1) +. Step L- Synthesis of Compound Int-16l
[0273] For a solution of the Int-16k compound (248 mg, 0.370 mmol) in 4 mL of THF, 1 M TBAF in THF (387 mg, 1.479 mmol) was added. The reaction was left under stirring at room temperature for 1 h. The solvent was removed in vacuo. The resulting residue was purified using a silica gel column (40 g) eluting with 8% MeOH / dichloromethane to provide the compound Int-16l as a colorless film. LCMS analysis calculated for C18H26BrNO6: 433.1; found: 433.8 (M + 1) +. Stage M- Synthesis of the Int-16m Compound
[0274] For a solution of the Int-16l compound (152 mg, 0.352 mmol) in 4 ml of dichloromethane, Dess-Martin periodinate (373 mg, 0.879 mmol) was added. The reaction was left under stirring at room temperature for 1 h. To this was added 2 drops of water, and the resulting mixture was diluted with 20 ml of EtOAc. The solid was filtered. The mother liquor was concentrated in vacuo. The resulting residue was purified using a silica gel column eluting with 6% MeOH / dichloromethane to provide the compound Int-16m as a colorless film. LCMS analysis calculated for C18H24BrNO6: 429.1; found: 429.9 (M + 1) +. Step N- Synthesis of Compound Int-16n
[0275] For a mixture of bromine (methyl) triphenyl phosphorane (7472 mg, 20.92 mmol) (pre-dried under vacuum at 120 ° C in a flask overnight) in 60 ml of THF cooled to 0 ° C ° C, lithium bis (trimethyl silyl) amide (13.94 ml, 20.92 mmol) was added. It was left under stirring at 0 ° C for 0.5 h. A solution of the Int-16m compound (3000 mg, 6.97 mmol) in 20 ml of THF was then added. The reaction was warmed to room temperature and stirred for 1 h. This was diluted with 200 ml of 70% EtOAc / hexanes. The solid was filtered. The filtrate was concentrated in vacuo. The resulting residue was purified using a silica gel column (220 g) eluting with 70% EtOAc / hexanes to provide the compound Int-16n as a colorless film. LCMS analysis calculated for C19H26BrNO5: 427.1; found: 428.0 (M + 1) +. Stage O - Synthesis of the Int-16o Compound
[0276] For the solution of the Int-16n compound (28 mg, 0.065 mmol) in 5 ml of dichloromethane, Zhang's olefin metathesis catalyst (1B) (8 mg, 10.89 μmol) was added. The reaction was left under stirring at room temperature for 2 h. It was concentrated in vacuo. The resulting residue was purified using a silica gel column (25 g) eluting with 5% MeOH / dichloromethane to provide the compound Int-16o as a colorless film. LCMS analysis calculated for C17H22BrNO5: 401.1; found: 401.8 (M + 1) +. Step P- Synthesis of the Int-16p Compound
[0277] To a solution of the Int-16o compound (24 mg, 0.060 mmol) in MeOH (1 mL), aqueous 12 N HCl (200 μl, 2.435 mmol) was added. The reaction was left under stirring at 60 ° C for 1h. The reaction mixture was concentrated in vacuo. The resulting residue was neutralized by the addition of Et3N. It was purified using ISCO, HP Gold normal phase silica gel (12g), eluting with dichloromethane / MeOH (100% DCM for 5 min; gradient to 10% MeOH in dichloromethane over 12 min, isocratic over 5 min) to provide the compound Int-16p as a white solid. LCMS analysis calculated for C15H18BrNO4: 355.04; found: 355.84 (M + 1) +. Stage Q- Synthesis of the Int-16q Compound and Int-16r Compound
[0278] For a solution of the Int-16p compound (190 mg, 0.533 mmol) in 8 mL of dry dichloromethane, Dess-Martin periodinate (339 mg, 0.800 mmol) was added. The reaction was left under stirring at room temperature for 1 h. Two drops of water were added to the resulting solution. A white solid was formed. The mixture was diluted with 20 ml of dichloromethane and filtered. The filtrate was washed with 10 ml of saturated aqueous Na2CO3 solution. The organic phase was isolated. The aqueous phase was extracted with 20 ml of 10% MeOH / dichloromethane solution. The organic phases were concentrated. The resulting residue was purified using a silica gel column (80 g) eluting with EtOAc to provide the cis-fused compound Int-16q and the transfused compound Int-16r separately as white solids. LCMS analysis calculated for C15H16BrNO4: 353.03; found: 353.82 (M + 1) +. Step R- Synthesis of Compound Int-16s
[0279] A mixture of Int-16q compound (25.6 mg, 0.072 mmol), N-ethyl-N -isopropylpropan-2-amine (38.6 μl, 0.217 mmol), (3-chloro-2-fluorophenyl ) methanamine (14.99 mg, 0.094 mmol) and (oxybis (2,1-phenylene)) bis (diphenylphosphine) (11.68 mg, 0.022 mmol) in DMSO (1.8 mL) was degassed for 5 min before add palladium diacetoxy (4.87 mg, 0.022 mmol). The resulting mixture was washed with a stream of CO under a CO flask for 30 minutes. The mixture was heated to 90 ° C under a CO flask for 1 h. Upon completion of the reaction, the reaction was diluted with DMSO and filtered. The crude product was purified using preparative HPLC (reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile / water / 0.05% TFA (20% to 90% organic product in 10 min, then to 100% in 2 min, 20 mL / min). The related fractions were pooled and evaporated under reduced pressure to produce the compound Int-16s as its racemic mixture. This material was resolved by chiral preparative SFC (ChiralPak OJ, 20 X 250 mm, 50 ml / min, 100bar, 25% MeOH (0.2% NH4OH) / CO2, 35 ° C) to provide the A enantiomer of compound Int-16s (the first eluting compound)) and the B enantiomer of the Int-16s compound (the second eluting compound). LCMS analysis calculated for C23H22ClFN2O5 racemate: 460.12; found: 461.01 (M + 1) +. Step S- Synthesis of the Int-16t Compound
[0280] Two enantiomers of compound Int-16s were converted to enantiomers of compound Int-16t separately following the same method described in Step K of Example 10. LCMS analysis calculated for C22H20ClFN2O5: 446.10; found: A-446.97 enantiomer (M + 1) +; enantiomer B-446.99 (M + 1) +. Step T- Synthesis of Compound 37 and Compound 38
[0281] For the solution of the enantiomer B of the compound Int-16t (6 mg, 10.70 μmol) in 2 ml of MeOH, Pd-C (0.569 mg, 5.35 μmol) was added. The mixture was allowed to stir at room temperature under an H2 flask for 1 h. Upon completion, the catalyst was filtered. The filtrate was concentrated in vacuo. The resulting residue was purified using preparative HPLC (reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile / water / 0.1% TFA (20% to 90% organic product in 10 min, then to 100% in 2 min, 20 mL / min). The related fractions were pooled and evaporated under reduced pressure to produce compound 38. Under essentially the same conditions, B enantiomer of compound Int-16t was converted to compound 37. Compound 37 and compound 38 showed identical NMR and LCMS spectra . 1H NMR (500 MHz, CDCl3): δ 10.48 (brs, 1 H); 8.48 (s, 1 H); 7.29-7.33 (m, 2 H); 7.05 (t, J = 7.7 Hz, 1 H); 4.74 (m, 2 H); 4.42-4.45 (m, 1 H); 4.23-4.31 (m, 1 H); 3.94-3.98 (m, 1 H); 3.85 (m, 1 H); 3.67-3.69 (m, 1 H); 2.33-2.46 (m, 1 H); 1.77-1.80 (m, 1 H); 1.62-1.75 (m, 4 H); 1.30 (s, 3 H). LCMS analysis calculated for C22H22ClFN2O5: 448.12; found: 448.97 (M + 1) +. Example 26

[0282] Starting from compound Int-16q, compounds 39-42 were prepared essentially by the same method described in Step R to Step T of Example 25, only replacing 2,4-difluorobenzylamine with appropriate benzylamines in Step R. Compounds 39 and 41 were prepared from the early eluting enantiomer in the chiral separation process from the corresponding intermediate in step R. Compounds 40 and 42 were prepared from the late elution enantiomer in the chiral separation process from the corresponding intermediate in step R.
Example 27 Preparation of Compound 43-46

[0283] Starting from compound Int-16r, compounds 43-46 were prepared essentially by the same method described in Step R to Step T of Example 25, using appropriate benzylamines in Step R. Compounds 43 and 45 were prepared from the enantiomer of early elution in the chiral separation process from the corresponding intermediate in step R. Compounds 44 and 46 were prepared from the late elution enantiomer in the chiral separation process from the corresponding intermediate in step R.
[0284] Compound 43: 1H NMR (500 MHz, CDCl3): δ 10.44 (s, 2 H); 8.51 (s, 1 H); 7.38 (q, J = 7.7 Hz, 2 H); 7.29 (s, 1 H); 6.81-6.86 (m, 2 H); 4.68 (m, 2 H); 4.05-4.20 (m, 3 H); 3.88-3.92 (m, 2 H); 2.26-2.29 (m, 1 H); 1.92-2.01 (m, 1 H); 1.85-1.91 (m, 1 H); 1.72-1.83 (m, 3 H); 1.32 (s, 3H). LCMS analysis calculated for C22H22F2N2O5: 432.15; found: 433.06 (M + 1) +.


[0285] Starting from compound Int 16q, compound 47 and compound 48 were prepared essentially by the same method described from step R to step S of Example 25. Compound 47 was prepared from the early eluting enantiomer in the separation process chiral from the corresponding intermediate in Step R. Compound 48 was prepared from the late eluting enantiomer in the process of chiral separation from the corresponding intermediate in Step R. Similarly, compound 49 and compound 50 were prepared starting from compound Int 16r .
[0286] Compound 47: 1H NMR (500 MHz, CDCl3) δ 10.42 (brs, 1 H); 8.53 (s, 1H); 7.30-7.39 (m, 1 H); 6.75-6.90 (m, 2 H); 5.81 - 5.96 (m, 1 H); 5.62-5.77 (m, 1 H); 4.63-4.73 (m, 2 H); 4.12-4.53 (m, 4 H); 3.90-4.12 (m, 1 H); 2.90 (dd, J = 14.2, 6.6 Hz, 1 H); 2.38 (dd, J = 14.4, 6.7 Hz, 1 H); 1.39 (s, 3 H). LCMS analysis calculated for C22H20F2N2O5: 430.13; found: 431.00 (M + 1) +.
[0287] Compound 48: 1H NMR (500 MHz, CDCl3) δ 10.42 (brs, 1 H); 8.53 (s, 1H); 7.30-7.39 (m, 1 H); 6.75-6.90 (m, 2 H); 5.81 - 5.96 (m, 1 H); 5.62-5.77 (m, 1 H); 4.63-4.73 (m, 2 H); 4.12-4.53 (m, 4 H); 3.90-4.12 (m, 1 H); 2.90 (dd, J = 14.2, 6.6 Hz, 1 H); 2.38 (dd, J = 14.4, 6.7 Hz, 1 H); 1.39 (s, 3 H). LCMS analysis calculated for C22H20F2N2O5: 430.13; found: 431.00 (M + 1) +.
[0288] Compound 49: 1H NMR (500 MHz, CDCl3): δ 10.36 (brs, 1 H); 8.52 (s, 1 H); 7.32-7.45 (m, 1 H); 6.81-6.85 (m, 2 H); 5.94 (m, 2 H); 4.60-4.72 (m, 2 H); 4.35-4.50 (m, 1 H); 4.06-4.32 (m, 4 H); 3.02-3.15 (m, 1 H); 2.35-2.50 (m, 1 H); 1.33 (s, 3 H). LCMS analysis calculated for C22H20F2N2O5: 430.13; found: 430.98 (M + 1) +.
[0289] Compound 50: 1H NMR (500 MHz, CDCl3): δ 10.36 (brs, 1 H); 8.52 (s, 1 H); 7.32-7.45 (m, 1 H); 6.81-6.85 (m, 2 H); 5.94 (m, 2 H); 4.60-4.72 (m, 2 H); 4.35-4.50 (m, 1 H); 4.06-4.32 (m, 4 H); 3.02-3.15 (m, 1 H); 2.35-2.50 (m, 1 H); 1.33 (s, 3 H). LCMS analysis calculated for C22H20F2N2O5: 430.13; found: 430.98 (M + 1) +. Example 29 Preparation of Compound 51-52
Step A - Synthesis of Compound Int-17a
[0290] For the solution of butane-1,3-diol (3.8 g, 42.2 mmol) in 30 ml of DMF, 1H-imidazole (5.74 g, 84 mmol) was added. The solution was cooled to 0 ° C and tert-butylchlorodimethyl silane (6.67 g, 44.3 mmol) was added. The reaction was left under stirring at room temperature overnight. The solution was poured into 200 ml of water. The resulting mixture was extracted with 40% EtOAc / hexanes (120 ml x 2). The combined organic phase was washed with 100 ml of 0.2 N aqueous HCl solution, and then 100 ml of brine. The solvent was removed in vacuo to provide the compound Int-17a as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.00-4.08 (m, 1 H), 3.80-3.94 (m, 2 H), 1.55-1.72 (m, 2 H ), 1.21 (d, J = 6.2 Hz, 3 H), 0.92 (s, 9H), 0.10 (s, 6 H). Step B - Synthesis of Compound Int-17b
[0291] To a solution of the compound Int-17a (1500 mg, 7.34 mmol) in 23 mL of THF, triphenylphosphine (4812 mg, 18.35 mmol) and 1-phenyl-1H-tetrazole-5-thiol were added (1962 mg, 11.01 mmol). The solution was cooled to 0 ° C, and diisopropyl diazene-1,2-dicarboxylate (3.61 ml, 18.35 mmol) was then added dropwise. The reaction was then warmed to room temperature and stirred for 20 h. The mixture was diluted with 100 ml of 20% EtOAc / hexanes. It was then filtered. The filtrate was concentrated. The resulting residue was purified using a silica gel column (120 g) eluting with 10% EtOAc / hexanes to provide compound Int-17b as a colorless oil. LCMS analysis calculated for C17H28N4OSSi: 364.2; found: 365.1 (M + 1) +. Step C- Synthesis of Compound Int-17c
[0292] To a solution of the Int-17b compound (1.840 g, 5.05 mmol) in 20 mL of EtOH cooled to 0 ° C, a solution of NH4 molybdate tetrahydrate premix (2.495 g) was added , 2.019 mmol) in 10 mL of 30% H2O2 in water. The resulting mixture was warmed to room temperature and stirred for 3 h. To it was added 100 ml of saturated aq. NaHCO3 solution. It was extracted by 50% EtOAc / hexanes (60 ml x 2). The organic phase was concentrated. The resulting residue was purified using a silica gel column eluting with 20% EtOAc / hexanes to provide compound Int-17c as a colorless oil. LCMS analysis calculated for C17H28N4OSSi: 396.2; found: 397.2 (M + 1) +. Step D - Synthesis of Compound Int-17d
[0293] To a solution of the compound Int-17c (98 mg, 0.248 mmol) in 4 ml of THF cooled to -78 ° C, sodium bis (trimethyl silyl) amide (1 M in THF) (0.497 ml, 0.497) was added mmol). The yellowish solution was left under stirring at -78 ° C for 30 min. A solution of the compound Int-1 (80 mg, 0.248 mmol) in 1 ml of THF was then added. The reaction was left under stirring at -78 ° C for 1 h. It was heated to 0 ° C allowing the ice bath to expire. During that time, the color of the reaction changed from blue / green to yellowish. It was quenched by 10 ml of saturated aqueous NH4Cl solution. The resulting mixture was extracted with 20 ml of 50% EtOAc / hexanes. The organic phase was concentrated in vacuo. The resulting residue was purified using a silica gel column (40 g) eluting with 12% EtOAc / hexanes to provide the compound Int-17d as a colorless film. LCMS analysis calculated for C24H34BrNO3Si: 491.2; found: 492.0 (M + 1) +. Stage E- Synthesis of Compound Int-17e
[0294] For a solution of the compound Int-17d (40 mg, 0.081 mmol) in 1 ml of t-BuOH / water / pyridine (5: 5: 1), methanesulfonamide (15.45 mg, 0.162 mmol) was added, potassium ferricyanide (80 mg, 0.244 mmol), and potassium carbonate (67.3 mg, 0.487 mmol), followed by osmium oxide (VIII) (0.050 ml, 4.06 μmol). The reaction was left under stirring at room temperature for 1 day. LCMS indicates that it was less than half completed. To this was added the 1 M sodium hydroxide solution (0.162 ml, 0.162 mmol). The reaction was stirred for another day. It was diluted with 1 ml of THF, and quenched by the addition of 700 mg of sodium bisulfite. The mixture was diluted with 20 ml of EtOAc, and washed with water (20 ml). The organic phase was concentrated in vacuo and the resulting residue was purified using a TCL-plate prepared on silica gel (1000 mm) eluting with 50% EtOAc / hexanes to provide the compound Int-17e as a white film. LCMS analysis calculated for C24H36BrNO5Si: 527.2; found: 528.0 (M + 1) +. Step F- Synthesis of Compound Int-17f
[0295] 2-Iodoxy benzoic acid (42.5 mg, 0.152 mmol) was stirred in 1 ml of DMSO for 5 min until dissolved. The resulting solution was added to a vial containing the compound Int-17e (40 mg, 0.076 mmol). The reaction was left under stirring at room temperature for 4 h. This was diluted with 20 ml of 50% EtOAc / hexanes, and washed with water. The organic phase was concentrated in vacuo and purified using a TCL-plate prepared on silica gel (1000 mm) eluting with 30% EtOAc / hexanes to provide the compound Int-17f as a colorless film. LCMS analysis calculated for C24H34BrNO5Si: 525.1; found: 526.0 (M + 1) +. Step G - Synthesis of Compound Int-17g
[0296] For a solution of the Int-17f compound (28 mg, 0.053 mmol) in 1 mL of DMF, iodomethane (30.3 mg, 0.214 mmol) was added. This was cooled to 0 ° C and sodium hydride (6.41 mg, 0.160 mmol) was then added. The reaction was left under stirring at 0 ° C for 15 min. It was then quenched by the addition of 10 mL of water. This was extracted with 20 ml of 40% EtOAc / hexanes. The organic phase was concentrated. The resulting residue was purified using a TCL-plate prepared on silica gel (1000 mm) eluting with 10% EtOAc / hexanes to provide the compound Int-17g as a colorless film. LCMS analysis calculated for C25H36BrNO5Si: 539.2; found: 540.1 (M + 1) +. Stage H- Synthesis of Compound Int-17h
[0297] For a solution of the Int-17g compound (20 mg, 0.037 mmol) in 1 ml of MeOH, 0.5 ml of 1.25 M HCl in MeOH was added. The reaction was left under stirring at room temperature for 15 min. The solvent was removed in vacuo. The resulting residue was diluted with 2 ml of dichloromethane. To this was added 0.2 ml of NEt3. The resulting solution was purified using a silica gel column (25 g), eluting with 80% EtOAc / hexanes to provide the compound Int-17h as a colorless film. LCMS analysis calculated for C19H22BrNO5: 425.1; found: 425.9 (M + 1) +. Step I - Synthesis of Compound Int-17i
[0298] For a solution of the compound Int-17h (10 mg, 0.024 mmol) in 0.5 ml of pyridine, 4-methylbenzene-1-sulfonyl chloride (17.97 mg, 0.094 mmol) was added. The reaction was left under stirring at room temperature overnight. At this time, 0.5 mL of MeOH was added. It was left under stirring at room temperature for 1 h. The reaction was diluted with 2 ml of toluene and then concentrated in vacuo. The resulting residue was purified using a TCL-plate prepared on silica gel eluting with EtOAc to provide the compound Int-17i as a colorless film. LCMS analysis calculated for C12H14BrNO4: 317.0; found: 318.1 (M + 1) +. Stage J- Synthesis of Compound Int-17j
[0299] A mixture of the compound Int-17i (18 mg, 0.057 mmol), N-ethyl-N-isopropylpropan-2-amine (30.4 μl, 0.171 mmol)), (2,4-difluorophenyl) methanamine (10 , 19 μl, 0.085 mmol) and (oxybis (2,1-phenylene)) bis (diphenylphosphine) (6.13 mg, 0.011 mmol) in DMSO (569 μl) diacetoxide palladium (2.56 mg, 0.011 mmol) was added . A CO flask was connected to a reaction vessel and CO gas was bubbled through a long needle into the mixture at room temperature for 20 min. The mixture was then heated in a CO flask at 80 ° C for 2 h. Upon completion of the reaction, the reaction was diluted with 1.5 ml of DMSO and was then filtered. The filtrate was purified using preparative HPLC (reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile / water / 0.1% TFA (10% to 90% organic product in 10 min, then to 100% in 2 min, 20 ml / min). The related fractions were pooled and evaporated under reduced pressure to produce the compound Int-17j as a racemate. This material was further resolved by a chiral preparative SFC (ChiralPak AD, 30 X 250 mm, 70 mL / min, 100 bar, 40% MeOH (0.2% NH4OH) / CO2, 35 ° C) to provide the A enantiomer of the Int-17j compound (first to elute) and the B-enantiomer of the Int-17j compound (second to elute) as the pure enantiomers. LCMS analysis calculated for C20H20F2N2O5: 406.13; found: 407.05 (M + 1) +. Step K- Synthesis of Compound 51 and Compound 52
[0300] Using the method described in Step K in Example 10, compound 51 was prepared from the A-enantiomer of compound Int-17j. Similarly, compound 52 was prepared from the B-enantiomer of compound Int-17j.
[0301] Compound 51: 1H NMR (500 MHz, CDCl3): δ 10.32 (brs, 1 H); 8.46 (s, 1 H); 7.35-7.42 (m, 1 H); 6.78-6.88 (m, 2 H); 4.56-4.71 (m, 3 H); 4,014.15 (m, 1 H); 3.30 (s, 3 H); 2.26-2.47 (m, 2 H); 1.51 (s, 3 H). LCMS analysis calculated for C19H18F2N2O5: 392.12; found: 392.94 (M + 1) +.
[0302] Compound 52: 1H NMR (500 MHz, CDCl3): δ 10.32 (brs, 1 H); 8.46 (s, 1 H); 7.35-7.42 (m, 1 H); 6.78-6.88 (m, 2 H); 4.56-4.71 (m, 3 H); 4,014.15 (m, 1 H); 3.30 (s, 3 H); 2.26-2.47 (m, 2 H); 1.51 (s, 3 H). LCMS analysis calculated for C19H18F2N2O5: 392.12; found: 392.94 (M + 1) +. Example 30 Preparation of Compound 53

[0303] Starting from compound Int-17f, compound 53 was prepared as its racemic mixture following essentially the same procedure as in Step H to Step K of Example 29. 1H NMR (500 MHz, DMSO): δ 10.29 (brs, 1 H); 8.42 (s, 1 H); 7.37-7.42 (m, 1 H); 7.21-7.25 (m, 1 H); 7.05 (m, 1 H); 6.02 (s, 1 H); 4.50-4.58 (m, 2 H); 4.27-4.45 (m, 2 H); 2.11 - 2.30 (m, 2 H); 1.36 (s, 3 H). LCMS analysis calculated for C18H16F2N2O5: 378.10; found: 378.94 (M + 1) +. Example 31 Preparation of Compound 54-57
Step A - Synthesis of Compound Int-18a
[0304] For a mixture of NaH (60% by weight in mineral oil) (8.5 g, 212 mmol) in 800 mL of THF cooled to 0 ° C, methyl 2- (dimethoxy phosphoryl) acetate (33 , 7 g, 185 mmol) drop by drop (be careful!). It was left under stirring at 0 ° C for 10 min. The solution of 1-methoxy propan-2-one (12.5 g, 143 mmol) in 100 ml of THF was then added. The reaction was left under stirring at 18 ° C for 16 hours. The mixture was quenched by the addition of 200 ml of saturated NH4Cl (aq.). It was diluted with 800 ml of water and 600 ml of 50% EtOAc / hexanes. The organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (SiO2, EtOAc: PET = 1: 50) to provide compound Int-18a as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.92 (s, 1 H), 3.89 (s, 2 H), 3.69 (s, 3 H), 3.34 (s, 3 H), 2.08 (s, 3 H). Step B - Synthesis of Compound Int-18b
[0305] To a solution of the compound Int-18a (15 g, 104 mmol) in 600 ml of dichloromethane cooled to -78 ° C, DIBAL-H (228 ml, 228 mmol) was added. The reaction was left under stirring at -78 ° C for 1 hour and heated to 0 ° C. At this point, it was quenched by the addition of 600 mL of Rochelle salt (sat.) Solution. The mixture was left stirring at 20 ° C for 2 hours. The organic phase was isolated. It was washed with 200 ml of brine. The organic phase was then concentrated in vacuo at 30 ° C and the resulting residue was purified using a chromatographic column (SiO2, PET to EtOAc: PET = 1: 2) to provide the compound Int-18b as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.62 (s, 1 H), 4.17 (t, J = 6.0 Hz, 2 H), 3.79 (s, 2 H), 3.29 (s, 3 H), 1.66 (s, 3 H). Step C- Synthesis of Compound Int-18c
[0306] For a solution of the compound Int-18b (7.5 g, 65 mmol) in dichloromethane (100 mL), diisopropylethylamine (34 mL, 194 mmol) was added followed by methanesulfomyl chloride (7.5 mL, 97 mmol). The reaction was left under stirring at 17 ° C for 2 hours. It was diluted with 200 ml of dichloromethane and washed with 200 ml of water. The organic phase was concentrated in vacuo at 30 oC, and the resulting residue was purified quickly by a silica gel column (SiO2, PET: EtOAc = 30: 1) to provide the compound Int-18c as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 5.69 (t, J = 8.0 Hz, 1 H), 4.11 ~ 4.14 (m, 2 H), 3.83 (s, 2 H) , 3.31 (s, 3 H), 1.73 (s, 3 H). Step D - Synthesis of Compound Int-18d
[0307] For the lithium diisopropylamide solution (31.2 mL, 2 M in THF, 63 mmol) in 100 mL THF cooled to 0 ° C, tributyltin (15.1 g, 52 mmol) was added). The reaction was left under stirring at 0 ° C for 15 min. It was cooled to -78 ° C, and a solution of the compound Int-18c (7 g, 52 mmol) in 5 ml of THF was added via syringe. The reaction was left under stirring at -78 ° C for 30 min. It was diluted with 400 ml of 50% EtOAc: PET, and washed with 500 ml of water. The organic phase was concentrated in vacuo. The resulting residue was purified using a silica gel column eluting initially with PET to remove Bu3SnH, and then EtOAc: PET = 1: 50 to produce the compound Int-18d as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.60 ~ 5.72 (m, 1 H), 4.11 ~ 4.15 (m, 2 H), 3.31 (s, 3 H), 1.62 ~ 1.82 (m, 5 H), 1.43 ~ 1.53 (m, 6 H), 1.24 ~ 1.34 (m, 6 H), 0.76 ~ 0.96 (m, 15 H). Stage E- Synthesis of Compound Int-18e
[0308] For a solution of the Int-1 compound (4.1 g, 12.7 mmol) and the Int-18d compound (6 g, 15.27 mmol) in acetonitrile (100 mL) with stirring at 0 ° C, Tin (II) chloride (3.62 g, 19.1 mmol) was added. The reaction was then heated to 16 ° C and stirred for 2 hours. The progress of the reaction was monitored by TLC and LCMS. The mixture was diluted with 50 ml EtOAc, and 100 ml of 15% aqueous NH4F (weight) solution. The resulting mixture was left under stirring at 16 ° C for 15 min. The solid was filtered. The organic phase of the mother liquor was extracted with EtOAc (50 mL x 3) and the organic phase was dried over anhydrous Na2SO4, concentrated in vacuo and the resulting residue was purified using a chromatographic column (SiO2, PET: EtOAc = 3: 1) to supply the Int-18e compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1 H), 7.47 (d, J = 6.0 Hz, 2 H), 7.35-7.39 (m, 3 H) , 6.04-6.12 (m, 1 H), 4.88-5.22 (m, 4 H), 3.87-3.98 (m, 1 H), 3.86 (s, 3 H), 3.48-3.55 (m, 2 H), 3.37 (s, 3 H), 3.24-3.27 (m, 1 H), 0.93 (s, 3 H) . MS (M + H) +: 422. Step F- Synthesis of Compound Int-18f
[0309] Under a nitrogen atmosphere, MOMCl (4.3 mL, 56.8 mmol) was added to a solution of the compound Int-18e (4.8 g, 11.4 mmol), diisopropylethylamine (20 mL, 114 mmol) and DMAP (0.72 g, 5.76 mmol) in anhydrous dichloromethane (80 mL) at 0 oC. The reaction mixture was left under stirring at 35 oC for 16 hours and washed with saturated aqueous NaHCO3 solution, extracted with dichloromethane (40 mL x 3). The organic phase was dried over anhydrous Na2SO4, concentrated in vacuo and purified using a chromatographic column (SiO2, dichloromethane: EtOAc = 1: 1) to provide the compound Int-18f as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1 H), 7.47 (d, J = 6.0 Hz, 2 H), 7.35-7.39 (m, 3 H) , 6.08-6.14 (m, 1 H), 5.16-5.29 (m, 4 H), 4.87-5.11 (m, 2 H), 4.46-4.65 (m, 2 H), 3.88 (s, 3 H), 3.58-3.60 (m, 1 H), 3.35 (s, 3 H), 3.20 (s, 3 H) , 1.12 (s, 3 H). MS (M + H) +: 466. Step G- Synthesis of Compound Int-18g
[0310] For a solution of the compound Int-18f (4.8 g, 10.3 mmol)) in 110 mL of THF / t-BuOH / water (5: 5: 1), NMO (2.4 g , 20.6 mmol), followed by osmium tetroxide (262 mg, 1 mmol) in H2O. The reaction was left under stirring at 16 ° C for 16 hours. To this was added an aqueous solution of Na2SO3. The mixture was left stirring at 16 ° C for 1 hour and extracted with EtOAc (50 ml x 3), the organic phase was dried over anhydrous Na2SO4 and concentrated, the resulting residue was purified using chromatographic column (SiO2, dichloromethane: MeOH = 20: 1) to produce the Int-18g compound with yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 1 H), 7.47 (d, J = 6.0 Hz, 2 H), 7.35-7.39 (m, 3 H) , 5.17-5.35 (m, 4 H), 4.44-4.60 (m, 2 H), 3.91 (s, 3 H), 3.63-3.66 (m, 4 H), 3.19-3.34 (m, 8 H), 1.04 (s, 3 H). MS (M + H) +: 500. Stage H- Synthesis of Compound Int-18h
[0311] For a mixture of the compound Int-18g (4.0 g, 8.00 mmol) in pyridine (30 ml) p-TsCl (2.0 g, 10.4 mmol) was added. The reagent solution was left under stirring at 30 ° C for 16 hours. The reaction was concentrated. The resulting residue was purified using column chromatography (SiO2, DCM: EtOAc = 1: 1) to provide the compound Int-18h as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 1 H), 4.38 ~ 5.00 (m, 4 H), 3.75 ~ 4.25 (m, 4 H), 3, 18 ~ 3.47 (m, 8 H), 2.96 ~ 3.03 (m, 1 H), 0.85 ~ 0.88 (m, 3 H). MS (M + H) +: 392. Step I - Synthesis of Compound Int-18i
[0312] To a solution of the Int-18h compound (2.0 g, 5.1 mmol) in DMF (20 mL) was added NaH (60% by weight in mineral oil) (0.6 g, 15.3 mmol ). The reaction mixture was left under stirring at 15 ° C for 10 min, iodomethane (3.2 ml, 51 mmol) was then added, and the reaction mixture was left under stirring at 15 ° C for 1 hour. It was quenched with water, extracted with dichloromethane (20 ml x 5), the organic phase was concentrated. The resulting residue was purified using column chromatography (SiO2, DCM: MeOH = 30: 1) to produce the compound Int-18i as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1 H), 4.61-5.04 (m, 4 H), 3.94-3.98 (m, 4 H), 3, 20-3.45 (m, 12 H), 0.83-0.87 (m, 3 H). MS (M + H) +: 406. Step J- Synthesis of Compound Int-18j
[0313] To a stirred solution of the compound Int-18i (1.0 g, 2.46 mmol) in MeOH (20 mL) p-TsOH (1.883 g, 9.85 mmol) was added. The reaction mixture was left under stirring at 35 ° C for 48 hours. The solvent was removed in vacuo. The resulting residue was washed with saturated aqueous NaHCO3 solution, extracted with dichloromethane (30 ml x 5), the organic phase was concentrated in vacuo and purified using a chromatographic column (SiO2, dichloromethane: MeOH = 30: 1) to provide the compound Int -18j as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1 H), 4.70-5.08 (m, 2 H), 3.79-4.79 (m, 4 H), 3, 30-3.51 (m, 10 H), 1.19-1.26 (m, 3 H). MS (M + H) +: 362. Step K- Synthesis of Compound Int-18k
[0314] To a stirred solution of the compound Int-18j (500 mg, 1.38 mmol) in 1,2-dichloroethane (15 mL) Dess-Martin periodinane (585 mg, 1.38 mmol) was added. The reaction mixture was left under stirring at 15 ° C for 2 hours. The solvent was concentrated in vacuo and the resulting residue was purified using column chromatography (SiO2, dichloromethane: MeOH = 10: 1) to provide the compound Int-18k as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1 H), 3.26-4.35 (m, 14 H), 1.17 (m, 3 H). MS (M + H) +: 360. Step L - Synthesis of Compound Int-18l and Compound Int-18m
[0315] For a mixture of the compound Int-18k (60 mg, 0.167 mmol), disopropylethylamine (0.116 mL, 0.666 mmol) and (2,4-difluorophenyl) methanamine (47.7 mg, 0.333 mmol) in DMSO (5 mL ) Pd (Ph3P) 4 (96 mg, 0.083 mmol) was added under N2. The mixture was left with stirring at 80 ° C for 4 hours under a CO flask. The reaction mixture was diluted with EtOAc, and washed with diluted HCl. The organic phase was dried over anhydrous Na2SO4. It was then concentrated in vacuo and purified via TLC-prep (SiO2, EtOAc: PET = 1: 1) to produce compound Int-18l and compound Int-18m with yellow oil.
[0316] Compound Int-18l: 1H NMR (400 MHz, CDCl3): δ 10.39 (s, 1 H), 8.37 (s, 1 H), 7.26-7.32 (m, 1 H ), 6.70-6.78 (m, 2 H), 4.56 (d, J = 5.6 Hz, 2 H), 4.22 ~ 4.34 (m, 2 H), 3.93 (s, 3H), 3.75 (s, 1 H), 3.67 (d, J = 8.8 Hz, 1 H), 3.54 (d, J = 8.8 Hz, 1 H), 3.36 (s, 3 H), 3.30 (s, 3 H), 1.21 (m, 3 H). MS (M + H) +: 451.
[0317] Compound Int-18m: 1H NMR (400 MHz, CDCl3): δ 10.39 (s, 1 H), 8.39 (s, 1 H), 7.26-7.32 (m, 1 H ), 6.75-6.81 (m, 2 H), 4.62 (d, J = 5.6 Hz, 2 H), 4.46-4.49 (m, 1 H), 4.10 -4.19 (m, 1 H), 4.00 (s, 3 H), 3.84 (d, J = 3.2 Hz, 1 H), 3.71 (d, J = 8.8 Hz , 1 H), 3.38-3.42 (m, 4 H), 3.25 (s, 3 H), 1.17 (m, 3 H). MS (M + H) +: 451.
[0318] Compound Int-18l was further purified using a chiral preparative SFC (Column: Chiralpak AS-H 250x4.6mm ID, 5μm, Mobile phase: isopropanol (0.05% DEA) in CO2 of 5% to 40% flow rate: 2.5mL / min Wavelength: 220 nm) to provide an early eluting component that corresponds to the A-enantiomer of the Int-18l compound (MS (M + H) +: 451), and a late eluting component corresponding to the enantiomer B of the compound Int-18l (MS (M + H) +: 451).
[0319] Int-18m compound was further purified using a chiral preparative SFC (Column: Chiralpak AS-H 250x4.6mm ID, 5um Mobile phase: isopropanol (0.05% DEA) in CO2 from 5% to 40% Flow rate : 2.5mL / min Wavelength: 220 nm) to provide an early eluting component that corresponds to the A-enantiomer of the Int-18m compound (MS (M + H) +: 451), and a corresponding late eluting component to the B enantiomer of the Int-18m compound (MS (M + H) +: 451). Step M- Synthesis of Compound 54-57
[0320] Following essentially the same method described in Step K of Example 10, starting from enantiomer A of compound Int-18l, compound 54 was prepared. Similarly, compound 55 was prepared from the B-enantiomer of compound Int-18l.
[0321] Compound 54: 1H NMR (400 MHz, CDCl3): δ 10.40 (s, 1 H), 8.43 (s, 1 H), 7.32-7.36 (m, 1 H), 6.77-6.83 (m, 2 H), 4.63-4.66 (m, 2 H), 4.41 (d, J = 4.0 Hz, 1 H), 4.28-4 , 32 (m, 1 H), 3.83 (s, 1 H), 3.67-3.74 (m, 2 H), 3.44 (s, 3 H), 3.37 (s, 3 H), 1.35 (m, 3 H). MS (M + H) +: 437.
[0322] Compound 55: 1H NMR (400 MHz, CDCl3): δ 10.40 (s, 1 H), 8.43 (s, 1 H), 7.32-7.36 (m, 1 H), 6.77-6.83 (m, 2 H), 4.63-4.66 (m, 2 H), 4.41 (d, J = 4.0 Hz, 1 H), 4.28-4 , 32 (m, 1 H), 3.82 (s, 1 H), 3.67-3.74 (m, 2 H), 3.44 (s, 3 H), 3.37 (s, 3 H), 1.35 (m, 3 H). MS (M + H) +: 437.
[0323] Following essentially the same method as described in Step K of Example 10, starting from enantiomer A of compound Int-18m, compound 56 was prepared. Similarly, compound 57 was prepared from the B-enantiomer of compound Int-18m.
[0324] Compound 56: 1H NMR (400 MHz, CDCl3): δ 10.45 (s, 1 H), 8.43 (s, 1 H), 7.32-7.36 (m, 1 H), 6.77-6.83 (m, 2 H), 4.58-4.66 (m, 3 H), 4.26-4.29 (m, 1 H), 3.81 (d, J = 2.4 Hz, 1 H), 3.65 (d, J = 9.6 Hz, 1 H), 3.43-3.47 (m, 4 H), 3.24 (s, 3 H), 1.27 (m, 3 H). MS (M + H) +: 437.
[0325] Compound 57: 1H NMR (400 MHz, CDCl3): δ 10.45 (s, 1 H), 8.43 (s, 1 H), 7.32 ~ 7.36 (m, 1 H), 6.77 ~ 6.83 (m, 2 H), 4.58 ~ 4.66 (m, 3 H), 4.26 ~ 4.29 (m, 1 H), 3.81 (d, J = 2.4 Hz, 1 H), 3.65 (d, J = 9.6 Hz, 1 H), 3.43 ~ 3.47 (m, 4 H), 3.25 (s, 3 H), 1.27 (m, 3 H). MS (M + H) +: 437. Example 32 Preparation of Compounds 58-61
Step A- Synthesis of Compound Int-19a
[0326] To a stirred solution of the Int-16j compound (6.65 g, 10.54 mmol) in THF (60 mL) 1 M solution of tetrabutylammonium fluoride in THF (10.54 mL, 10.54 mmol). The reaction mixture was left under stirring at 10 ° C for 18 hours and the solvent was then removed in vacuo. The resulting residue was purified using silica gel column chromatography (dichloromethane: MeOH = 20: 1) to provide the compound Int-19a as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.70 (s, 1 H), 4.80-4.98 (m, 1 H), 4.65-4.72 (m, 1 H), 4, 34-4.58 (m, 2 H), 4.09-4.33 (m, 2 H), 3.96 (d, J = 7.2 Hz, 3 H), 3.70-3.90 (m, 2 H), 3.34-3.50 (m, 3 H), 1.64 (brs, 1 H), 1.45 (m, 1 H), 0.80 (d, J = 13 , 8 Hz, 3 H). MS (M + H) +: 392. Step B- Synthesis of Compound Int-19b
[0327] For a stirred mixture of compound Int-19a (3.5 g, 8.92 mmol) in THF (50 mL) cooled to 0 ° C, NaH (60% by weight in mineral oil) (2.141 g) was added , 53.5 mmol). The reaction mixture was left under stirring at 10 ° C for 20 minutes, and iodomethane (19 g, 134 mmol) was added. The reaction mixture was left under stirring at 10 ° C for 16 hours. It was quenched by water (2 ml) and the solvent was removed in vacuo. The resulting residue was purified using silica gel column chromatography (dichloromethane: MeOH = 25: 1) to provide the compound Int-19b as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.60-7.69 (m, 1 H), 4.89-5.05 (m, 1 H), 4,364.76 (m, 3 H), 4, 07-4.23 (m, 1 H), 3.93-4.05 (m, 3 H), 3.69-3.85 (m, 1 H), 3.55 (t, J = 7, 0 Hz, 1 H), 3.22-3.48 (m, 10 H), 1.66-1.73 (m, 1 H), 1.42-1.52 (m, 1 H), 0.711 , 03 (m, 3 H). MS (M + H) +: 420. Step C- Synthesis of Compound Int-19c
[0328] To a stirred solution of the compound Int-19b (3.4 g, 8.09 mmol) in MeOH (30 mL) TsOH (4616 mg, 24.27 mmol) was added. The reaction mixture was left under stirring at 35 ° C for 20 hours. The solvent was removed in vacuo. The resulting residue was purified using silica gel column chromatography (dichloromethane: MeOH = 10: 1) to provide the compound Int-19c as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.59 (s, 1 H), 4.94 (brs, 1 H), 4.10-4.17 (m, 2 H), 4.01 (s, 3 H), 3.78-3.88 (m, 1 H), 3.47-3.55 (m, 2 H), 3.42 (s, 3 H), 3.31 (s, 3 H ), 1.24-1.27 (m, 2 H), 1.17 (s, 3 H). MS (M + H) +: 376. Step D- Synthesis of Compound Int-19d
[0329] To a stirred solution of the Int-19c compound (2.5 g, 6.64 mmol) in 1,2-dichloroethane (30 mL) Dess-Martin periodinane (3.4 g, 7.97 mmol) was added ). The reaction mixture was left under stirring at 15 ° C for 1 hour. The solvent was removed in vacuo, the resulting residue was purified using silica gel column chromatography (dichloromethane: MeOH = 10: 1) to provide the compound Int-19d as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 1 H), 4.08-4.43 (m, 3 H), 4.00 (s, 3 H), 3.77-3, 85 (m, 1 H), 3.53 (t, J = 5.6 Hz, 1 H), 3.42 (d, J = 8.8 Hz, 3 H), 3.19-3.32 ( m, 3 H), 2.10 ~ 2.24 (m, 1 H), 1.94-2.03 (m, 1 H), 1.28 (d, J = 7.8 Hz, 3 H) . MS (M + H) +: 374. Step E- Synthesis of Compound Int-19e and 19f
[0330] To a solution of the compound Int-19d (300 mg, 0.802 mmol) in DMSO (5 mL) was added (2,4-difluorophenyl) methanamine (215 mg, 1,499 mmol), N-ethyl-N-isopropylpropan- 2-amine (259 mg, 2.004 mmol) and Pd (Ph3P) 4 (232 mg, 0.200 mmol). The reaction was stirred under a 96 ° C CO flask for 2 hours. It was cooled to 25 ° C. The reaction mixture was filtered and the filtrate was concentrated, the resulting residue was purified using prepared TLC (dichloromethane: EtOAc = 1: 1) to provide a crude mixture of all four stereoisomers of compound Int-19e and 19f as a colorless oil. This was further purified using SFC (M7 "Column: Chiralpak AD-H 250x4.6mm ID, 5 um Mobile phase: ethanol (0.05% DEA) in CO2 from 5% to 40% Flow rate: 2.35mL / min Wavelength: 220 nm ") to provide each individual stereoisomer: enantiomer A of the compound Int-19e (the first eluting compound), enantiomer B of the compound Int-19e (the second eluting compound), enantiomer A of the compound Int- 19f (the third eluting compound), and the B enantiomer of the Int-19f compound (the fourth eluting compound). MS (M + H) +: 465.
[0331] A-enantiomer of compound Int-19e: 1H NMR (400 MHz, CDCl3): δ 10.48 (brs, 1H), 8.40 (s, 1H), 7.32-7.42 (m, 1H ), 6.74-6.87 (m, 2H), 4.574.70 (m, 2H), 4.44 (dd, J = 1.60, 13.60 Hz, 1H), 4.22 (dd, J = 4.40, 13.60 Hz, 1H), 4.00 (s, 3H), 3.79 (d, J = 1.20 Hz, 1H), 3.46-3.51 (m, 1H ), 3.35-3.44 (m, 4H), 3.20 (s, 3H), 1.94-2.02 (m, 1H), 1.78 (m, 1H), 1.30 ( s, 3H).
[0332] B-enantiomer of compound Int-19e: 1H NMR (400 MHz, CDCl3): δ 10.49 (brs, 1 H), 8.40 (s, 1 H), 7.31-7.41 (m , 1 H), 6.80 (d, J = 8.40 Hz, 2 H), 4.63 (dd, J = 6.40, 8.80 Hz, 2 H), 4.44 (d, J = 13.60 Hz, 1 H), 4.23 (dd, J = 4.00, 13.60 Hz, 1 H), 3.99 (s, 3 H), 3.78 (brs, 1 H) , 3.46-3.50 (m, 1 H), 3.36-3.44 (m, 4 H), 3.20 (s, 3 H), 1.92-2.04 (m, 1 H), 1.78 (m, 1 H), 1.30 (s, 3 H).
[0333] A-enantiomer of compound Int-19f: 1H NMR (400 MHz, CDCl3): δ 10.35-10.56 (m, 1 H), 8.40 (s, 1 H), 7.30-7 , 42 (m, 1 H), 6.73-6.88 (m, 2 H), 4.63 (d, J = 5.60 Hz, 2 H), 4.24-4.35 (m, 2 H), 4.00 (s, 3 H), 3.85 (brs, 1 H), 3.493.59 (m, 2 H), 3.39 (s, 3 H), 3.30 (s, 3 H), 2.14-2.23 (m, 1 H), 1.95-2.03 (m, 1 H), 1.27 (s, 3 H).
[0334] B-enantiomer of the Int-19f compound: 1H NMR (400 MHz, CDCl3): δ 10.35-10.56 (m, 1 H), 8.40 (s, 1 H), 7.30-7 , 42 (m, 1 H), 6.73-6.88 (m, 2 H), 4.63 (d, J = 5.60 Hz, 2 H), 4.24-4.35 (m, 2 H), 4.00 (s, 3 H), 3.85 (brs, 1 H), 3.493.59 (m, 2 H), 3.39 (s, 3 H), 3.30 (s, 3 H), 2.14-2.23 (m, 1 H), 1.95-2.03 (m, 1 H), 1.27 (s, 3 H). Step F- Synthesis of Compound 58-61
[0335] Following essentially the same method as described in Step K of Example 10, compound 58 was prepared starting from enantiomer A of compound Int-19e. Similarly, compound 59 was prepared from the B-enantiomer of compound Int-19e.
[0336] Compound 58: 1H NMR (400 MHz, CDCl3): δ 10.44 (brs, 1 H), 8.41 (s, 1 H), 7.32-7.39 (m, 1 H), 6.76-6.85 (m, 2 H), 4.65 (d, J = 3.60 Hz, 2 H), 4.52 (d, J = 13.60 Hz, 1 H), 4, 28 (dd, J = 3.60, 13.60 Hz, 1 H), 3.82 (d, J = 1.60 Hz, 1 H), 3.52-3.59 (m, 1 H), 3.41 (s, 4 H), 3.22 (s, 3 H), 1.98-2.06 (m, 1 H), 1.73-1.80 (m, 1 H), 1, 38 (s, 3 H). MS (M + H) +: 451.
[0337] Compound 59: 1H NMR (400 MHz, CDCl3) δ 10.44 (brs, 1 H), 8.41 (s, 1 H), 7.31-7.40 (m, 1 H), 6 , 75-6.87 (m, 2 H), 4.65 (brs, 2 H), 4.52 (d, J = 13.60 Hz, 1 H), 4.24-4.31 (m, 1 H), 3.82 (brs, 1 H), 3.56 (t, J = 7.20 Hz, 1 H), 3.42 (s, 4 H), 3.22 (s, 3 H) , 2.02 (m, 1 H), 1.76 (d, J = 15.20 Hz, 1 H), 1.38 (s, 3 H). MS (M + H) +: 451.
[0338] Following essentially the same method as described in Step K of Example 10, compound 60 was prepared starting from enantiomer A of compound Int-19f. Similarly, compound 61 was prepared from the B-enantiomer of compound Int-19e.
[0339] Compound 60: 1H NMR (400 MHz, CDCl3) δ 10.43 (br. S., 1 H), 8.42 (s, 1 H), 7.31-7.40 (m, 1 H ), 6.74-6.89 (m, 2 H), 4.65 (t, J = 5.60 Hz, 2 H), 4,284.39 (m, 2 H), 3.91 (br. S ., 1 H), 3.52-3.63 (m, 2 H), 3.40 (s, 3 H), 3.31 (s, 3 H), 2.20 (dd, J = 5, 60, 7.60 Hz, 1 H), 2.09-2.16 (m, 1 H), 1.33 (s, 3 H). MS (M + H) +: 451.
[0340] Compound 61: 1H NMR (400 MHz, CDCl3) δ 10.45 (brs, 1 H), 8.44 (s, 1 H), 7.30-7.40 (m, 1 H), 6 , 72-6.89 (m, 2 H), 4.64 (t, J = 5.60 Hz, 2 H), 4.28-4.40 (m, 2 H), 3.91 (brs, 1 H), 3.58 (m, 2 H), 3.40 (s, 3 H), 3.31 (s, 3 H), 2.08-2.26 (m, 2 H), 1, 33 (s, 3 H). MS (M + H) +: 451. Example 33 Preparation of Compound 62-73

[0341] Compounds 62-71 were prepared essentially by the same method described in Example 32, just replacing (2,4-difluorophenyl) methanamine in Step E with appropriate benzylamines.
[0342] Compound 62: 1H NMR (400 MHz, CDCl3) δ 10.45 (brs, 1 H), 8.38 (s, 1H), 7.27-7.31 (m, 2 H), 7, 02 (t, J = 7.83 Hz, 1 H), 4.72 (brs, 2 H), 4.52 (d, J = 12.72 Hz, 1 H), 4.26 (dd, J = 4.01, 13.99 Hz, 1 H), 3.82 (brs, 1 H), 3.55 (dd, J = 2.93, 9.00 Hz, 1 H), 3.42 (s, 4 H), 3.23 (s, 3 H), 1.99-2.05 (m, 1 H), 1.75-1.79 (m, 1 H), 1.38 (s, 3 H ). MS (M + H) +: 467.
[0343] Compound 63: 1H NMR (400 MHz, CDCl3) δ 10.45 (brs, 1 H), 8.38 (s, 1 H), 7.26-7.32 (m, 2 H), 7 , 02 (t, J = 7.83 Hz, 1 H), 4.68-4.75 (m, 2 H), 4.52 (d, J = 13.11 Hz, 1 H), 4.26 (dd, J = 4.11, 13.89 Hz, 1 H), 3.82 (d, J = 1.76 Hz, 1 H), 3.53-3.59 (m, 1 H), 3 , 38-3.47 (m, 4 H), 3.22 (s, 3 H), 2.00-2.06 (m, 1 H), 1.78 (brs, 1 H), 1.38 (s, 3 H). MS (M + H) +: 467.
[0344] Compound 64: 1H NMR (400 MHz, CDCl3) δ 10.44 (brs, 1 H), 8.40 (s, 1 H), 7.28 (brs, 2 H), 7.02 (t , J = 7.73 Hz, 1 H), 4.71 (brs, 2 H), 4.33 (brs, 2 H), 3.91 (brs, 1 H), 3.53-3.62 ( m, 2 H), 3.40 (s, 3 H), 3.32 (s, 3 H), 2.18-2.23 (m, 1 H), 2.11 - 2.17 (m, 1 H), 1.34 (s, 3 H). MS (M + H) +: 467.
[0345] Compound 65: 1H NMR (400 MHz, CDCl3) δ 10.44 (brs, 1 H), 8.40 (s, 1 H), 7.28 (brs, 2 H), 7.02 (t , J = 7.63 Hz, 1 H), 4.71 (brs, 2 H), 4.32 (brs, 2 H), 3.91 (brs, 1 H), 3.53-3.62 ( m, 2 H), 3.40 (s, 3 H), 3.32 (s, 3 H), 2.18-2.24 (m, 1 H), 2.14 (t, J = 4, 99 Hz, 1 H), 1.34 (s, 3 H). MS (M + H) +: 467.
[0346] Compound 66: 1H NMR (400 MHz, CDCl3) δ 10.41 (brs, 1 H), 8.40 (s, 1 H), 7.36-7.40 (m, 1 H), 7 , 17 ~ 7.25 (m, 1 H), 6.98-7.12 (m, 2 H), 4.70 (d, J = 4.50 Hz, 2 H), 4.51 (d, J = 13.89 Hz, 1 H), 4.26 (dd, J = 3.72, 13.89 Hz, 1 H), 3.81 (brs, 1 H), 3.38-3.60 ( m, 5 H), 3.22 (s, 3 H), 2.00-2.05 (m, 1 H), 1.74-1.78 (m, 1 H), 1.37 (s, 3 H). MS (M + H) +: 433.
[0347] Compound 67: 1H NMR (400 MHz, CDCl3) δ 10.41 (brs, 1 H), 8.40 (s, 1 H), 7.38 (t, J = 6.85 Hz, 1 H ), 7.17-7.25 (m, 1 H), 6.95-7.14 (m, 2 H), 4.70 (d, J = 3.91 Hz, 2 H), 4.50 (d, J = 13.69 Hz, 1 H), 4.26 (dd, J = 3.72, 13.89 Hz, 1 H), 3.81 (brs, 1H), 3.52-3, 58 (m, 1 H), 3.41 (s, 4 H), 3.22 (s, 3 H), 1.99-2.05 (m, 1 H), 1.73-1.79 ( m, 1 H), 1.37 (s, 3 H). MS (M + H) +: 433.
[0348] Compound 68: 1H NMR (400 MHz, CDCl3) δ 10.39 (brs, 1 H), 8.41 (s, 1 H), 7.38 (t, J = 7.14 Hz, 1 H ), 7.17-7.25 (m, 1 H), 6.98-7.12 (m, 2 H), 4.70 (brs, 2 H), 4.25-4.39 (m, 2 H), 3.89 (brs, 1 H), 3.50-3.64 (m, 2 H), 3.39 (s, 3 H), 3.32 (s, 3 H), 2, 19 (dd, J = 5.58, 7.73 Hz, 1 H), 2.09-2.16 (m, 1 H), 1.33 (s, 3 H). MS (M + H) +: 433.
[0349] Compound 69: 1H NMR (400 MHz, CDCl3) δ 10.41 (brs, 1 H), 8.44 (brs, 1 H), 7.37 (t, J = 6.75 Hz, 1 H ), 7.17-7.25 (m, 1 H), 6.97-7.14 (m, 2 H), 4.70 (brs, 2 H), 4.24-4.41 (m, 2 H), 3.88 (brs, 1 H), 3.50 ~ 3.64 (m, 2 H), 3.39 (s, 3 H), 3.31 (s, 3 H), 2, 08-2.25 (m, 2 H), 1.33 (s, 3 H). MS (M + H) +: 433.
[0350] Compound 70: 1H NMR (400 MHz, CDCl3) δ 10.32 (brs, 1 H), 8.37 (s, 1H), 7.16-7.25 (m, 1 H), 6, 87 (t, J = 7.63 Hz, 2 H), 4.65-4.81 (m, 2 H), 4.49 (d, J = 13.50 Hz, 1 H), 4.23 ( dd, J = 3.91, 13.89 Hz, 1 H), 3.81 (brs, 1 H), 3.51-3.59 (m, 1 H), 3.36-3.47 (m , 4 H), 3.21 (s, 3 H), 1.97-2.06 (m, 1 H), 1.73-1.78 (m, 1 H), 1.36 (s, 3 H). MS (M + H) +: 451.
[0351] Compound 71: 1H NMR (400 MHz, CDCl3) δ 10.31 (brs, 1 H), 8.36 (s, 1 H), 7.14-7.23 (m, 1 H), 6 , 86 (t, J = 7.53 Hz, 2 H), 4.64-4.79 (m, 2 H), 4.47 (d, J = 13.50 Hz, 1 H), 4.22 (dd, J = 3.72, 13.69 Hz, 1 H), 3.79 (brs, 1 H), 3.49-3.56 (m, 1 H), 3.39 (s, 4 H ), 3.20 (s, 3 H), 1.97-2.04 (m, 1 H), 1.75 (d, J = 4.30 Hz, 1 H), 1.34 (s, 3 H). MS (M + H) +: 451.
[0352] Compound 72: 1H NMR (400 MHz, CDCl3) δ 10.33 (brs, 1 H), 8.36-8.44 (m, 1 H), 7.16-7.25 (m, 1 H), 6.88 (t, J = 7.53 Hz, 2 H), 4.73 (dq, J = 5.38, 14.51 Hz, 2 H), 4.26-4.36 (m , 2 H), 3.89 (brs, 1 H), 3.51-3.62 (m, 2 H), 3.39 (s, 3 H), 3.31 (s, 3 H), 2 , 10-2.21 (m, 2 H), 1.32 (s, 3 H). MS (M + H) +: 451.
[0353] Compound 73: 1H NMR (400 MHz, CDCl3) δ 10.32 (brs, 1 H), 8.40 (s, 1 H), 7.14-7.25 (m, 1 H), 6 , 87 (t, J = 7.63 Hz, 2 H), 4.66-4.80 (m, 2 H), 4.31 (brs, 2 H), 3.89 (brs, 1 H), 3.51-3.63 (m, 2 H), 3.38 (s, 3 H), 3.31 (s, 3 H), 2.10-2.22 (m, 2 H), 1, 32 (s, 3 H). MS (M + H) +: 451. Example 34 Preparation of Compound 74-93

[0354] Compounds 74-93 were prepared essentially by the same method described in Example 32, just replacing the compound Int-16j in Step A with the compound Int-20a, and replacing the appropriate benzylamine in Step E.
[0355] Compound 74: 1H NMR (400 MHz, CDCl3) δ 10.38 (br. S, 1 H), 8.39 (s, 1 H), 7.29-7.38 (m, 1 H) , 6.72-6.85 (m, 2 H), 4.55-4.71 (m, 2 H), 4.23-4.41 (m, 2 H), 3.64 (s., 1 H), 3.26-3.48 (m, 8 H), 1.86-1.92 (m, 2 H), 1.59-1.68 (m, 1 H), 1.47- 1.57 (m, 1 H), 1.27 (s, 3 H). MS (M + H) +: 465.
[0356] Compound 75: 1H NMR (400 MHz, CDCl3) δ 10.42 (br. S, 1 H), 8.44 (s, 1 H), 7.31-7.38 (m, 1 H) , 6.75-6.86 (m, 2 H), 4.56-4.70 (m, 2 H), 4.26-4.46 (m, 2 H), 3.65 (s., 1 H), 3.33-3.47 (m, 8 H), 1.85-1.95 (m, 2 H), 1.60-1.71 (m, 1 H), 1.48- 1.58 (m, 1 H), 1.29 (s, 3 H). MS (M + H) +: 465.
[0357] Compound 76: 1H NMR (400 MHz, CDCl3) δ 10.38 (br. S., 1 H), 8.38 (s, 1 H), 7.29-7.39 (m, 1 H ), 6.73-6.84 (m, 2 H), 4.56-4.69 (m, 2 H), 4.24-4.44 (m, 2 H), 3.65 (s, 1 H), 3.32-3.43 (m, 4 H), 3.18-3.30 (m, 4 H), 1.69-1.80 (m, 1 H), 1.53- 1.66 (m, 3 H), 1.33 (s, 3 H). MS (M + H) +: 465.
[0358] Compound 77: 1H NMR (400 MHz, CDCl3) δ 10.42 (br. S, 1 H), 8.42 (s, 1 H), 7.31-7.40 (m, 1 H) , 6.74-6.86 (m, 2 H), 4.56-4.71 (m, 2 H), 4.25-4.47 (m, 2 H), 3.66 (s, 1 H), 3.35-3.44 (m, 4 H), 3.21-3.31 (m, 4 H), 1.72-1.83 (m, 1 H), 1.54-1 , 69 (m, 3 H), 1.35 (s, 3 H). MS (M + H) +: 465.
[0359] Compound 78: 1H NMR (400 MHz, CDCl3) δ 10.48 (br. S, 1 H), 8.47 (s, 1 H), 7.24-7.31 (m, 2 H) , 7.02 (t, J = 7.6 Hz, 1 H), 4.64-4.78 (m, 2 H), 4,264.45 (m, 2 H), 3.65 (s, 1 H ), 3.32-3.47 (m, 8 H), 1.87-1.94 (m, 2 H), 1.60-1.70 (m, 1 H), 1.47-1, 58 (m, 1 H), 1.29 (s, 3 H). MS (M + H) +: 481.
[0360] Compound 79: 1H NMR (400 MHz, CDCl3) δ 10.48 (br. S, 1 H), 8.46 (s, 1 H), 7.23-7.32 (m, 2 H) , 7.02 (t, J = 7.6 Hz, 1 H), 4.64-4.77 (m, 2 H), 4,264.45 (m, 2 H), 3.65 (s, 1 H ), 3.30-3.49 (m, 8 H), 1.84-1.96 (m, 2 H), 1.60-1.71 (m, 1 H), 1.48-1, 59 (m, 1 H), 1.28 (s, 3 H). MS (M + H) +: 481.
[0361] Compound 80: 1H NMR (400 MHz, CDCl3) δ 10.47 (br. S, 1 H), 8.44 (s, 1 H), 7.24-7.31 (m, 2 H) , 7.02 (t, J = 7.6 Hz, 1 H), 4.65-4.77 (m, 2 H), 4,294.44 (m, 2 H), 3.66 (s, 1 H ), 3.35-3.43 (m, 4 H), 3.22-3.31 (m, 4 H), 1.72-1.82 (m, 1 H), 1.54-1, 67 (m, 3 H), 1.35 (s, 3 H). MS (M + H) +: 481.
[0362] Compound 81: 1H NMR (400 MHz, CDCl3) δ 10.48 (br. S, 1 H), 8.44 (s, 1 H), 7.23-7.31 (m, 2 H) , 7.02 (t, J = 7.6 Hz, 1 H), 4.65-4.77 (m, 2 H), 4,294.45 (m, 2 H), 3.66 (s, 1 H ), 3.34-3.45 (m, 4 H), 3.21-3.31 (m, 4 H), 1.72-1.82 (m, 1 H), 1.54-1, 68 (m, 3 H), 1.35 (s, 3 H). MS (M + H) +: 481.
[0363] Compound 82: 1H NMR (400 MHz, CDCl3) δ 10.31 (br. S, 1 H), 8.40 (s, 1 H), 7.14-7.23 (m, 1 H) , 6.86 (t, J = 7.6 Hz, 2 H), 4.64-4.77 (m, 2 H), 4.244.40 (m, 2 H), 3.63 (s, 1 H ), 3.28-3.46 (m, 8 H), 1.81-1.93 (m, 2 H), 1.58-1.67 (m, 1 H), 1.46-1, 55 (m, 1 H), 1.26 (s, 3 H). MS (M + H) +: 465.
[0364] Compound 83: 1H NMR (400 MHz, CDCl3) δ 10.32 (br. S, 1 H), 8.41 (s, 1 H), 7.16-7.23 (m, 1 H) , 6.86 (t, J = 7.6 Hz, 2 H), 4.63-4.77 (m, 2 H), 4.344.41 (m, 1 H), 4.24-4.31 ( m, 1 H), 3.63 (s, 1 H), 3.31-3.44 (m, 8 H), 1.84-1.92 (m, 2 H), 1.58-1, 67 (m, 1 H), 1.46-1.56 (m, 1 H), 1.26 (s, 3 H). MS (M + H) +: 465.
[0365] Compound 84: 1H NMR (400 MHz, CDCl3) δ 10.32 (br. S, 1 H), 8.40 (s, 1 H), 7.17-7.24 (m, 1 H) , 6.87 (t, J = 7.6 Hz, 2 H), 4.65-4.79 (m, 2 H), 4.364.42 (m, 1 H), 4.25-4.33 ( m, 1 H), 3.65 (s, 1 H), 3.33-3.43 (m, 4 H), 3.19-3.30 (m, 4 H), 1.71-1, 81 (m, 1 H), 1.53-1.67 (m, 3 H), 1.34 (s, 3 H). MS (M + H) +: 465.
[0366] Compound 85: 1H NMR (400 MHz, CDCl3) δ 10.35 (br. S, 1 H), 8.42 (s, 1 H), 7.16-7.25 (m, 1 H) , 6.87 (t, J = 7.6 Hz, 2 H), 4.65-4.79 (m, 2 H), 4.364.43 (m, 1 H), 4.25-4.34 ( m, 1 H), 3.65 (s, 1 H), 3.34-3.43 (m, 4 H), 3.20-3.30 (m, 4 H), 1.70-1, 81 (m, 1 H), 1.54-1.66 (m, 3 H), 1.34 (s, 3 H). MS (M + H) +: 465.
[0367] Compound 86: 1H NMR (400 MHz, CDCl3) (400 MHz, CDCl3) δ 10.38 (s, 1 H), 8.43 (s, 1 H), 7.37 (t, J = 7 , 2 Hz, 1 H), 7.18-7.24 (m, 1 H), 6.99-7.12 (m, 2 H), 4.64-4.76 (m, 2 H), 4.36-4.44 (m, 1 H), 4.24-4.31 (m, 1 H), 3.63 (s, 1 H), 3.30-3.47 (m, 8 H ), 1.87-1.93 (m, 2 H), 1.60-1.68 (m, 1 H), 1.47-1.57 (m, 1 H), 1.28 (s, 3 H). MS (M + H) +: 447.
[0368] Compound 87: 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1 H), 8.45 (s, 1 H), 7.37 (t, J = 7.2 Hz, 1 H ), 7.19-7.24 (m, 1 H), 7.00-7.11 (m, 2 H), 4.64-4.76 (m, 2 H), 4.36-4, 44 (m, 1 H), 4.24-4.31 (m, 1 H), 3.63 (s, 1 H), 3.32-3.47 (m, 8 H), 1.85- 1.95 (m, 2 H), 1.60-1.70 (m, 1 H), 1.47-1.57 (m, 1 H), 1.27 (s, 3 H). MS (M + H) +: 447.
[0369] Compound 88: 1H NMR (400 MHz, CDCl3) δ 10.37 (s., 1 H), 8.40 (s, 1 H), 7.36 (t, J = 7.2 Hz, 1 H), 7.16-7.23 (m, 1 H), 6.98-7.10 (m, 2 H), 4.63-4.74 (m, 2 H), 4.26-4 , 42 (m, 2 H), 3.64 (s, 1 H), 3.33-3.43 (m, 4 H), 3.19-3.30 (m, 4 H), 1.72 -1.79 (m, 1 H), 1.54-1.66 (m, 3 H), 1.33 (s, 3 H). MS (M + H) +: 447.
[0370] Compound 89: 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1 H), 8.40 (s, 1 H), 7.36 (t, J = 7.2 Hz, 1 H ), 7.16-7.23 (m, 1 H), 6.98-7.09 (m, 2 H), 4.63-4.74 (m, 2 H), 4.26-4, 40 (m, 2 H), 3.63 (s, 1 H), 3.32-3.42 (m, 4 H), 3.20-3.29 (m, 4 H), 1.72- 1.78 (m, 1 H), 1.54-1.64 (m, 3 H), 1.33 (s, 3 H). MS (M + H) +: 447.
[0371] Compound 90: 1H NMR (400 MHz, CDCl3) δ 10.29 (br. S, 1 H), 8.37 (s, 1 H), 6.63 (t, J = 8.0 Hz, 2 H), 4.56-4.72 (m, 2 H), 4.23-4.39 (m, 2 H), 3.63 (s, 1 H), 3.27-3.46 ( m, 8 H), 1.83-1.93 (m, 2 H), 1.57-1.67 (m, 1 H), 1.44-1.55 (m, 1 H), 1, 26 (s, 3 H). MS (M + H) +: 483.
[0372] Compound 91: 1H NMR (400 MHz, CDCl3) δ 10.29 (br. S, 1 H), 8.37 (s, 1 H), 6.63 (t, J = 8.0 Hz, 2 H), 4.57-4.72 (m, 2 H), 4.24-4.38 (m, 2 H), 3.63 (s, 1 H), 3.25-3.47 ( m, 8 H), 1.84-1.93 (m, 2 H), 1.58-1.67 (m, 1 H), 1.45-1.55 (m, 1 H), 1, 26 (s, 3 H). MS (M + H) +: 483.
[0373] Compound 92: 1H NMR (400 MHz, CDCl3) δ 10.27 (br. S, 1 H), 8.33 (s, 1 H), 6.59 (t, J = 8.0 Hz, 2 H), 4.54-4.67 (m, 2 H), 4.30-4.36 (m, 1 H), 4.184.25 (m, 1 H), 3.59 (s, 1 H ), 3.28-3.36 (m, 4 H), 3.15-3.23 (m, 4 H), 1.66-1.74 (m, 1 H), 1.49-1, 59 (m, 3 H), 1.28 (s, 3 H). MS (M + H) +: 483.
[0374] Compound 93: 1H NMR (400 MHz, CDCl3) δ 10.20 (br. S, 1 H), 8.34 (s, 1 H), 6.64 (t, J = 8.0 Hz, 2 H), 4.59-4.73 (m, 2 H), 4.23-4.46 (m, 2 H), 3.64 (s, 1 H), 3.33-3.41 ( m, 4 H), 3.19-3.28 (m, 4 H), 1.66-1.74 (m, 1 H), 1.49-1.59 (m, 3 H), 1, 32 (s, 3 H). MS (M + H) +: 483. Example 35 Preparation of Compound Int-20d
Step A- Synthesis of Compound Int-20a
[0375] To a mixture of sodium hydride (60% by weight in mineral oil) (2.56 g, 64.00 mmol) in 90 ml of THF at 0 ° C, methyl 2-oxocyclohexanecarboxylate (5 .00 g, 32.00 mmol) in 50 mL of THF dropwise. The resulting mixture was left under stirring at 0 ° C for 30 min. Diethyl phosphorokinidate (4.91 ml, 32.3 mmol) was then added to the above mixture. The reaction was left under stirring at 0 ° C for an additional 1 h. It was cooled abruptly with 200 ml of saturated aqueous NH4CI solution. The aqueous phase was extracted with 2x150 ml of EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated to provide the virtually pure phosphone ester derivative of the compound Int-20a as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.17-4.23 (m, 4 H); 3.72 (s, 3 H); 2.45-2.48 (m, 2 H); 2.35-2.37 (m, 2 H); 1.70-1.74 (m, 2 H); 1.62-1.64 (m, 2 H); 1.35-1.37 (m, 6 H). Step B - Synthesis of Compound Int-20b
[0376] In a 500 ml round bottom flask, methyl lithium (40.6 ml, 65.0 mmol) was added dropwise to a suspension of copper (I) iodide (4.95 g, 26.0 mmol) in 180 ml of ether at 0 ° C. The resulting solution was immediately cooled to -40 ° C, and a solution of the compound Int-20a (7.6 g, 26.0 mmol) in 10 ml Et2O was added. The reaction was slowly warmed up to room temperature overnight. Saturated NH4Cl (20 mL) was added slowly to abruptly cool the reaction. Filtration followed by concentration of the filtrate provided a residue that was purified using silica gel chromatographic column eluting with 10% EtOAc / hexanes to provide the compound Int-20b as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.73 (s, 3 H); 2.25-2.28 (m, 2 H); 2.11 - 2.14 (m, 2 H); 2.00 (s, 3 H); 1.61 - 1.62 (m, 4 H). Step C- Synthesis of Compound Int-20c
[0377] 1M Diisobutyl aluminum hydride in dichloromethane (20.75 ml, 20.75 mmol) was added to a solution of the Int-20b compound (1.6 g, 10.38 mmol) in 100 ml CH2Cl2 cooled to -78 ° C. The reaction was left under stirring at this temperature for 1.5 h. 10 ml of MeOH was added and followed by 10 ml of saturated Na2CO3 solution. The mixture was left stirring at room temperature for 1 h. To the above mixture, Na2SO4 was added. It was filtered through celite and the cake was washed with 50 ml of CH2Cl2. The combined organic phase was concentrated to provide the virtually pure Int-20c compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.13 (s, 2 H); 2.11 - 2.13 (m, 2 H); 1.98-2.00 (m, 2 H); 1.72 (s, 3 H); 1.62-1.67 (m, 4 H). Step D - Synthesis of Compound Int-20d
[0378] To a solution of the compound Int-20c in 50 ml Et2O tribromophosphine (0.452 ml, 4.75 mmol) was added at 0 ° C. The reaction was then slowly warmed up to room temperature overnight. It was quenched with 100 ml of saturated aqueous NaHCO3 solution at 0 ° C. The aqueous phase was extracted with 2x100 ml Et2O. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to produce the compound Int-20d as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.05 (s, 2 H); 2.14-2.15 (m, 2 H); 2.01-2.03 (m, 2 H); 1.74 (s, 3 H); 1.60-1.67 (m, 4 H). Example 36 Preparation of Compound 94 and 95
Step A- Synthesis of Compound Int-21a
[0379] The mixture of sodium iodide (1.331 g, 8.88 mmol) and the Int-20d compound (1.550 g, 8.19 mmol) in 15 mL of DMF was added powdered indium (3.92 g, 34 , 1 mmol). It was left under stirring at room temperature for 10 min. Compound Int-1 (2.2 g, 6.83 mmol) was then added to the above mixture. The reaction was left under stirring at room temperature for 1 hour, and then at 50 ° C for 30 min. It was diluted with 100 ml of EtOAc and filtered. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to provide a residue that was purified using silica gel chromatographic column eluting with 20% EtOAc / hexane to provide the compound Int-21a as a colorless oil. LCMS analysis calculated for C22H26BrNO3: 431.11; found: 432.00 (M + 1) +. Step B- Synthesis of Compound Int-21b
[0380] To a solution of the compound Int-21a (2.10 g, 4.86 mmol) in acetic anhydride (10 ml, 106 mmol) was added triethylamine (2.45 g, 24.29 mmol) and 4-dimethylaminopyridine (0.30 g, 2.429 mmol). The reaction was left under stirring at room temperature for 1 h. The solvent was removed in vacuo. The resulting residue was purified using silica gel column chromatography eluting with 20% EtOAc / hexanes to produce compound Int-21b as a colorless foam. LCMS analysis calculated for C24H28BrNO4: 473.12; found: 474.03 (M + 1) +. Step C- Synthesis of Compound Int-21c
[0381] A solution of the compound Int-21b (2.10 g, 4.43 mmol) in 35 mL of THF / 9 mL of H2O was added osmium tetroxide in t-BuOH (4.50 mL, 0.443 mmol) and 4-methylmorpholine 4-oxide (1.56 g, 13.28 mmol). The mixture was left stirring at room temperature overnight. It was diluted with 100 ml of EtOAc and then 3 g of solid sodium metathiosulfite was added. The mixture was then stirred for 30 min. It was filtered and the filtrate was concentrated. The resulting residue was purified using silica gel column chromatography eluting with 60% EtOAc / hexanes to produce the compound Int-21c as a white solid. LCMS analysis calculated for C24H30BrNO6: 507.13; found: 508.02 (M + 1) +. Step D- Synthesis of Compound Int-21d
[0382] To a stirred solution of the compound Int-21c (1.9 g, 3.74 mmol) in 12 ml pyridine 4-methylbenzene-1-sulfonyl chloride (1.07 g, 5.61 mmol) was added. The reaction was left under stirring at room temperature overnight, followed by heating at 60 ° C for 2 h. To the reaction, 5 ml of MeOH were then added and the reaction was concentrated to remove most of the pyridine. The resulting residue was purified using silica gel column chromatography eluting with 10% MeOH / DCM to produce compound Int-21d as a white solid. LCMS analysis calculated for C17H22BrNO5: 399.07; found: 400.03 (M + 1) +. Step E- Synthesis of Compound Int-21e
[0383] To a solution of the compound Int-21d (0.22 g, 0.550 mmol) in 6 mL of MeOH, potassium carbonate (380 mg, 2.75 mmol) was added. The reaction was left under stirring at 60 ° C for 30 min. Most of the solvent was removed in vacuo. To the resulting residue, 10 mL of 10% mL MeOH / dichloromethane was added. The resulting mixture was filtered. The mother liquor was concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel eluting with 10% MeOH / dichloromethane to produce the compound Int-21e as a white solid. LCMS analysis calculated for C15H20BrNO4: 357.06; found: 357.98 (M + 1) +. Step F- Synthesis of Compound Int-21f
[0384] To a stirred solution of the compound Int-21e (0.70 g, 1.95 mmol) in 20 ml of dichloromethane Dess-Martin periodinate (1.32 g, 3.13 mmol) was added. The mixture was left stirring at room temperature for 2 h. 1 ml of H2O was added and the precipitate was filtered. The filtrate was concentrated in vacuo and to the resulting residue was added 2 ml of DMSO. The mixture was purified using C18 reverse phase column (150 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA to produce the compound Int-21f as a white solid. LCMS analysis calculated for C15H18BrNO4: 355.04; found: 356.02 (M + 1) +. Stage G - Synthesis of Int-21g and Int-21h Compounds
[0385] For a mixture of the compound Int-21f (0.50 g, 1.404 mmol), N-ethyl-N-isopropylpropan-2-amine (0.54 g, 4.21 mmol), (2,4-difluorophenyl ) methanamine (0.30 g, 2.105 mmol) and (oxybis (2,1-phenylene)) bis (diphenylphosphine) (0.15 mg, 0.281 mmol) in 12 mL of DMSO, diacetoxide palladium (63.0 mg, 0.281 mmol). The above mixture was then washed with CO for 20 min with a CO flask at room temperature, then heated to 80 ° C under a CO flask for 2 h. The reaction was cooled and directly purified using a reversed phase C18 column (150 g) eluting with 5% ACN / H2O-100% ACN / H2O with 0.1% TFA to produce the desired product as its racemic mixture. The enantiomers were then separated by a chiral AD column (30x250 mm) eluting with 50% MeOH / CO2 at 70 ml / min to produce the compound Int-21g and the compound Int-21h as white solids. LCMS analysis calculated for C23H24F2N2O5: 446.17; found: 446.99 (M + 1) +. Step H- Synthesis of Compounds 94 and 95
[0386] To a stirred solution of the compound Int-21g (0.13 g, 0.291 mmol) in 3 mL of DMF, lithium chloride (0.25 g, 5.82 mmol) was added. The mixture was left with stirring at 100 ° C for 30 min. It was cooled and 0.2 ml of H2O was added. The mixture was purified directly by a reversed phase C18 column (40 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA. The fraction was collected and dried by a lyophilizer to produce compound 94 (0.11g, 0.250 mmol) as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.46 (s, 1 H); 8.40 (s, 1 H); 7.33-7.37 (m, 1 H); 6.81-6.86 (m, 2 H); 4.63 (d, 2 H); 4.21 - 4.33 (2 H); 1.52-2.01 (8 H); 1.39 (s, 3 H). LCMS analysis calculated for C22H22F2N2O5: 432.15; found: 433.06 (M + 1) +.
[0387] Compound 95 was prepared using the method described in Step H of Example 36, and replacing the compound Int-21g with the compound Int-21h. 1H NMR (400 MHz, CDCl3): δ 10.47 (s, 1 H); 8.43 (s, 1 H); 7.35-7.38 (m, 1 H); 6.81-6.86 (m, 2 H); 4.65 (d, 2 H); 4.21 - 4.33 (2 H); 1.52-2.03 (8 H); 1.39 (s, 3 H). LCMS analysis calculated for C22H22F2N2O5: 432.15; found: 433.06 (M + 1) +. Example 37 Preparation of Compound 96, and 97

[0388] Compound 96 was prepared using the method described in Step G to Step H of Example 36, and replacing the compound (2,4-difluorophenyl) methanamine with (3-chloro-4-fluorophenyl) methanamine in Step G The stereoisomeric mixture was separated by a chiral OD column instead of a chiral AD column in Step G. 1H NMR (400 MHz, CDCl3): δ 10.52 (s, 1 H); 8.42 (s, 1 H); 7.38 (d, J = 5.2 Hz, 1 H); 7.22 (d, J = 1.6 Hz, 1 H); 7.10 (dd, J = 6.8, 1.6 Hz, 1 H); 4.55-4.62 (m, 2 H); 4.18-4.32 (2 H); 2.02-2.03 (m, 2 H); 1.51-1.84 (6 H); 1.40 (s, 3 H). LCMS analysis calculated for C22H22ClFN2O5: 448.87; found: 449.05 (M + 1) +.
[0389] Compound 97 was prepared following essentially the same method as described for compound 96. 1H NMR (400 MHz, CDCl3): δ 10.52 (s, 1 H); 8.44 (s, 1 H); 7.39 (d, J = 5.2 Hz, 1 H); 7.22 (d, J = 1.6 Hz, 1 H); 7.10 (dd, J = 6.8, 1.6 Hz, 1 H); 4.54-4.60 (m, 2 H); 4.18-4.32 (2 H); 2.02-2.03 (m, 2 H); 1.51-1.84 (6 H); 1.40 (s, 3 H). LCMS analysis calculated for C22H22ClFN2O5: 448.87; found: 449.05 (M + 1) +. Example 38 Preparation of Compound Int-22

[0390] Compound Int-22 was prepared using the method described in Step A to Step D of Example 35, and replacing methyl 2-oxocyclohexanecarboxylate with methyl 2-oxocycloheptanecarboxylate in Step A. 1H NMR ( 400 MHz, CDCl3): δ 4.10 (s, 2 H); 2.28-2.29 (m, 2 H); 2.19-2.21 (m, 2 H); 1.82 (s, 3 H); 1.72-1.77 (m, 2 H); 1.54-1.58 (m, 2 H); 1.46-1.50 (m, 2 H). Example 39 Preparation of Compound Int-23

[0391] Compound Int-23 was prepared using the method described in Step A to Step F of Example 36, and replacing the Int-20d compound with the Int-22 compound in Step A. Analysis by LCMS calculated for C16H2BrNO4: 369.06; found: 370.95 (M + 1) +. Example 40 Preparation of Compound 98-101
Step A - Synthesis of Int-24a, Int-24b, Int-24c and Int-24d Compounds
[0392] For a mixture of the compound Int-23 (0.12 g, 0.32 mmol), N-ethyl-N-isopropylpropan-2-amine (0.13 g, 0.97 mmol), (2.4- difluorophenyl) methanamine (0.07 g, 0.48 mmol) and (oxybis (2,1-phenylene)) bis (diphenylphosphine) (0.03 mg, 0.05 mmol) in 3 mL of DMSO, palladium diacetoxy ( 11.0 mg, 0.049 mmol). The resulting mixture was then washed with CO for 20 min with a CO flask at room temperature, then heated to 80 ° C under a CO flask for 2 h. The reaction was cooled and directly purified using the reverse phase C18 Column (40 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA to produce the stereoisomeric mixture (104 mg, 0.226 mmol) as a yellow solid. The stereoisomeric mixture was then separated by a chiral IC column (30x250 mm) eluting with 30% MeOH / CO2 at 70 mL / min to produce the compound Int-24a, the compound Int-24b, the compound Int-24c, the compound Int -24d individually as a white solid. LCMS analysis calculated for C24H26F2N2O5: 460.18; found: 461.15 (M + 1) +. Step B- Synthesis of Compound 98-101
[0393] To a stirred solution of the compound Int-24a (15.0 mg, 0.032 mmol) in 3 mL of DMF, lithium chloride (0.27 g, 6.52 mmol) was added. The mixture was left with stirring at 100 ° C for 30 min. It was cooled and 0.2 ml of H2O was added. The mixture was purified directly by the reverse phase C18 column (40 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA. The fraction was collected and dried by a lyophilizer to produce compound 98 as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.49 (s, 1 H); 8.69 (s, 1 H); 7.35-7.38 (m, 1 H); 6.83-6.87 (m, 2 H); 4.54-4.59 (m, 2 H); 3.86 (d, J = 9.6 Hz, 1 H); 3.77 (d, J = 9.6 Hz, 1 H); 2.34-2.37 (m, 2 H); 2,132.19 (m, 2 H); 1.53-1.90 (6 H); 1.46 (s, 3 H). LCMS analysis calculated for C23H24F2N2O5: 446.44; found: 446.99 (M + 1) +.
[0394] Compound 99 was prepared using the method described in Step B of Example 40, and replacing compound Int-24a with compound Int-24b. LCMS analysis calculated for C23H24F2N2O5: 446.44; found: 446.99 (M + 1) +. 1H NMR (400 MHz, CDCl3): δ 10.39 (s, 1 H); 8.79 (s, 1 H); 7.39-7.42 (m, 1 H); 6.81-6.86 (m, 2 H); 4.54-4.62 (m, 2 H); 3.88 (d, J = 9.2 Hz, 1 H); 3.87 (d, J = 9.2 Hz, 1 H); 2.34-2.39 (m, 2 H); 2.15-2.19 (m, 2 H); 1.53-1.90 (6 H); 1.45 (s, 3 H).
[0395] Compound 100 was prepared using the method described in Step B of Example 40, and replacing compound Int-24a with compound Int-24c. 1H NMR (400 MHz, CDCl3): δ 10.51 (s, 1 H); 8.32 (s, 1 H); 7.33-7.37 (m, 1 H); 6.81-6.84 (m, 2 H); 4.63-4.65 (m, 2 H); 4.48 (d, J = 9.6 Hz, 1 H); 4.16 (d, J = 9.6 Hz, 1 H); 2.24-2.27 (m, 1 H); 2.03-2.11 (m, 2 H); 1.49-1.82 (7 H); 1.44 (s, 3 H). LCMS analysis calculated for C23H24F2N2O5: 446.44; found: 446.99 (M + 1) +.
[0396] Compound 101 was prepared using the method described in Step B of Example 40, and replacing compound Int-24a with compound Int-24d. 1H NMR (400 MHz, CDCl3): δ 10.45 (s, 1 H); 8.32 (s, 1 H); 7.30-7.33 (m, 1 H); 6.82-6.84 (m, 2 H); 4.61 - 4.63 (m, 2 H); 4.48 (d, J = 9.6 Hz, 1 H); 4.16 (d, J = 9.6 Hz, 1 H); 2.24-2.27 (m, 1 H); 2.03-2.11 (m, 2 H); 1.49-1.82 (7 H); 1.44 (s, 3 H). LCMS analysis calculated for C23H24F2N2O5: 446.44; found: 446.99 (M + 1) +. Example 41 Preparation of Compound 102, 103

[0397] Compound 102 was prepared using the method described in Step A to Step B of Example 40, and replacing the compound (2,4-difluorophenyl) methanamine with the compound (3-chloro-2-fluorophenyl) methanamine in Step A. 1H NMR (400 MHz, CDCl3): δ 10.55 (s, 1 H); 8.38 (s, 1 H); 7.32 (m, 1 H); 7.22 (m, 1 H); 7.05 (m, 1H); 4.65 (m, 2 H); 4.51 (d, J = 9.2 Hz, 1 H); 4.37 (d, J = 9.2 Hz, 1 H); 3.05 (m, 1 H); 1.28-2.18 (9 H); 1.43 (s, 3 H). LCMS analysis calculated for C23H24ClFN2O5: 462.14; found: 462.79 (M + 1) +.
[0398] Compound 103 was prepared using the method described in Step A to Step B of Example 40, and replacing (2,4-difluorophenyl) methanamine with (3-chloro-2-fluorophenyl) methanamine in Step A. 1H NMR (400 MHz, CD3OD): δ 8.45 (s, 1 H); 7.38 (m, 1 H); 7.34 (m, 1 H); 7.12 (m, 1H); 4.68 (m, 2 H); 4.51 (d, J = 9.2 Hz, 1 H); 4.18 (d, J = 9.2 Hz, 1 H); 1.59-2.20 (10 H); 1.40 (s, 3 H). LCMS analysis calculated for C23H24ClFN2O5: 462.14; found: 462.79 (M + 1) +. Example 42 Preparation of Compound Int-25

[0399] Compound Int-25 was prepared using the method described in Step A to Step D of Example 35, and replacing methyl 2-oxocyclohexanecarboxylate with methyl 2-oxocyclopentanecarboxylate in Step A. 1H NMR (400 MHz, CDCl3): δ 4.12 (s, 2 H); 2.48-2.51 (m, 2 H); 2.35-2.38 (m, 2 H); 1.83-1.88 (m, 2 H); 1.73 (s, 3 H). Example 43

[0400] To the mixture of sodium iodide (0.907 g, 6.05 mmol) and the Int-25 compound (1.06 g, 6.05 mmol) in 10 mL of DMF was added indium (2.67 g, 23 , 28 mmol). It was left under stirring at room temperature for 10 min. Compound Int-1 (1.5 g, 4.66 mmol) was then added to the above mixture. The reaction was left under stirring at room temperature for 1 hour, and then at 50 ° C for 30 min. It was diluted with 100 ml EtOAc and filtered. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to provide a residue which was purified using a silica gel chromatographic column eluting with 20% EtOAc / hexane to provide the compound Int-26a as a colorless oil. LCMS analysis calculated for C21H24BrNO3: 417.09; found: 417.93 (M + 1) +. Step B- Synthesis of Compound Int-26b
[0401] To the solution of the compound Int-26a (1.30 g, 3.11 mmol) in 6 ml of DMF was added tert-butylchlorodimethyl silane (0.94 g, 6.22 mmol) and imidazole (0.64 g , 9.32 mmol). The mixture was allowed to stir at 60 ° C overnight. 50 ml of EtOAc was added. The organic phase was washed with H2O and brine, dried over Na2SO4 and concentrated. The resulting residue was purified using silica gel column chromatography eluting with 5% EtOAc / hexane to provide compound Int-26b as a colorless oil. LCMS analysis calculated for C27H38BrNO3Si: 531.18; found: 532.03 (M + 1) +. Step C- Synthesis of Compound Int-26c
[0402] To a solution of the compound Int-26b (1.40 g, 2.63 mmol) in 21 ml of THF and 5 ml of water was added osmium tetroxide (1.67 ml, 0.263 mmol) and 4-methylmorpholine 4-oxide (0.92 g, 7.89 mmol). The mixture was left stirring at room temperature overnight. 20 ml EtOAc was added. To the organic phase, 2 g of solid sodium metathiosulfite was added and stirred for 30 min. It was filtered and the filtrate was concentrated. The resulting residue was purified using column chromatography on silica gel eluting with 30% EtOAc / hexane to produce the compound Int-26c as a light green oil. LCMS analysis calculated for C27H40BrNO5: 565.19; found: 566.04 (M + 1) +. Step D - Synthesis of Compound Int-26d
[0403] To a stirred solution of the compound Int-26c (0.50 g, 0.88 mmol) in 4 ml of pyridine 4-methylbenzene-1-sulfonyl chloride (022 g, 1.15 mmol) was added. The reaction was left under stirring at room temperature overnight, followed by heating at 60 ° C for 2 h. To the reaction, 5 ml of MeOH were then added and the reaction was concentrated to remove most of the pyridine. The resulting residue was purified using silica gel column chromatography eluting with 5% MeOH / dichloromethane to produce the compound Int-26d as a white solid. LCMS analysis calculated for C20H32BrNO4: 457.13; found: 457.98 (M + 1) +. Step E- Synthesis of Compound Int-26e
[0404] A solution of the compound Int-26d (0.12 g, 0.26 mmol) in 2 mL of THF at room temperature was added to the solution of 1 N tetrabutylammonium fluoride in THF (0.52 mL, 0.524 mmol) . The mixture was left stirring at room temperature for 3 h. The mixture was then directly purified using silica gel column chromatography eluting with 10% MeOH / dichloromethane to produce the compound Int-26e as a white solid. LCMS analysis calculated for C14H18BrNO4: 343.03; found: 344.01 (M + 1) +. Step F- Synthesis of Compound Int-26f
[0405] To a stirred solution of the Int-26e compound (86 mg, 0.25 mmol) in 3 ml of dichloromethane Dess-Martin periodinate (0.15 g, 0.38 mmol) was added. The mixture was left stirring at room temperature for 1 h. 1 ml of H2O was added and the precipitate was filtered. The filtrate was concentrated in vacuo and to the resulting residue was added 2 ml of DMSO. The mixture was purified using C18 reverse phase column (40 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA to produce the compound Int-26f as a white solid. LCMS analysis calculated for C14H16BrNO4: 341.03; found: 341.97 (M + 1) +. Step G- Synthesis of Compound Int-26g
[0406] A mixture of the compound Int-26f (12 mg, 0.035 mmol), N-ethyl-N-isopropylpropan-2-amine (14 mg, 0.105 mmol), (2,4-difluorophenyl) methanamine (7.5 mg , 0.053 mmol) and (oxybis (2,1-phenylene)) bis (diphenylphosphine) (4.7 mg, 0.008 mmol) in 2 mL of DMSO, palladium diacetoxy (2.0 mg, 0.008 mmol) was added. The above mixture was then washed with CO for 20 min with a CO flask at room temperature, then heated to 80 ° C with a CO flask for 2 h. The reaction was cooled and directly purified using reverse phase C18 column (25 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA to produce the stereoisomeric mixture of the compound Int-26g as a yellow solid. LCMS analysis calculated for C22H22F2N2O5: 432.15; found: 433.10 (M + 1) +. Step H- Synthesis of Compound 104
[0407] To a stirred solution of the compound Int-26g (8.0 mg, 0.019 mmol) in 1 mL of DMF, lithium chloride (16 mg, 0.37 mmol) was added. The mixture was left with stirring at 100 ° C for 30 min. It was cooled and 0.2 ml of H2O was added. The mixture was purified directly by the reverse phase C18 column (40 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA. The fraction was collected and dried by a lyophilizer to produce compound 104 as a white solid. 1H NMR (400 MHz, CD3OD): δ 10.52 (m, 1 H); 8.45 (s, 1 H); 7.39-7.44 (m, 1 H); 6.91-6.98 (m, 2 H); 4.59-4.77 (m, 2 H); 4.36 (d, J = 10.8, 1 H); 4.20 (d, J = 10.8, 1 H); 3.30 (s, 3 H); 2.26-2.31 (m, 1 H); 1.83-2.04 (m, 4 H); 1.64-1.69 (m, 1 H); 1.34 (s, 3 H). LCMS analysis calculated for C21H20F2N2O5: 418.13; found: 418.98 (M + 1) +. Example 44 Preparation of Compound 105
Step A - Synthesis of Compound Int-27a
[0408] To a solution of the compound Int-26d (145 mg, 0.316 mmol) in 2 mL of THF at room temperature was added iodomethane (135 mg, 0.949 mmol) and followed by the addition of sodium hydride (22.77 mg, 0.949 mmol)). The mixture was left stirring at room temperature for 5 h. The reaction was then quenched by 1 mL of H2O. The mixture was then directly purified using column chromatography on silica gel eluting with 30% EtOAc / hexane to produce compound Int-27a as a light yellow solid. LCMS analysis calculated for C21H34BrNO4Si: 471.14; found: 472.28 (M + 1) +. Step B- Synthesis of Compound Int-27b
[0409] To a solution of the compound Int-27a (90 mg, 0.19 mmol) in 2 mL of THF at room temperature, a solution of 1 N tetrabutylammonium fluoride in THF (0.40 mL, 0.40 mmol) was added ). The mixture was left stirring at room temperature for 3 h. The mixture was then directly purified using silica gel column chromatography eluting with 10% MeOH / dichloromethane to produce the compound Int-27b as a white solid. LCMS analysis calculated for C15H20BrNO4: 357.06; found: 358.01 (M + 1) +. Step C- Synthesis of Compound Int-27c
[0410] For a stirred solution of the compound Int-27b (60 mg, 0.17 mmol) in 2 ml of dichloromethane Dess-Martin periodinate (71 mg, 0.17 mmol) was added. The mixture was left stirring at room temperature for 1 h. 1 ml of H2O was added and the precipitate was filtered. The filtrate was concentrated in vacuo and to the resulting residue was added 2 ml of DMSO. The mixture was purified using C18 reverse phase column (40 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA to produce the compound Int-27c as a white solid. LCMS analysis calculated for C15H18BrNO4: 355.04; found: 356.04 (M + 1) +. Step D- Synthesis of Compound Int-27d
[0411] For a mixture of the compound Int-27c (20 mg, 0.056 mmol), N-ethyl-N-isopropylpropan-2-amine (21 mg, 0.168 mmol), (2,4-difluorophenyl) methanamine (12 mg, 0.084 mmol) and (oxybis (2,1-phenylene)) bis (diphenylphosphine) (7.6 mg, 0.014 mmol) in 2 mL of DMSO, palladium diacetoxy (3.0 mg, 0.014 mmol) was added. The above mixture was then washed with CO for 20 min with a CO flask at room temperature, then heated to 80 ° C under a CO flask for 2 h. The reaction was cooled and directly purified using reverse phase C18 column (25 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA to produce the stereoisomeric mixture of the compound Int-27d as a yellow solid. LCMS analysis calculated for C23H24F2N2O5: 446.17; found: 447.18 (M + 1) +. Step E- Synthesis of Compound 105
[0412] For a stirred solution of the compound Int-27d (12.0 mg, 0.027 mmol) in 1 ml of DMF, lithium chloride (23 mg, 0.54 mmol) was added. The mixture was left with stirring at 100 ° C for 30 min. It was cooled and 0.2 ml of H2O was added. The mixture was purified directly by the reverse phase C18 column (40 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA. The fraction was collected and dried by a lyophilizer to produce compound 105 as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.54 (s, 1 H); 7.43 - 7.45 (m, 1 H); 6.90-6.97 (m, 2 H); 4.61 - 4.64 (2 H); 4.34-4.36 (2 H); 3.31 (s, 3 H); 2.26-2.32 (m, 1 H); 2.13-2.19 (m, 1 H); 1.97-2.00 (m, 1 H); 1,841.91 (m, 2 H); 1.73-1.79 (m, 1 H); 1.34 (s, 3 H). LCMS analysis calculated for C22H22F2N2O5: 432.15; found: 433.17 (M + 1) +. Example 45 Preparation of Compound 106 and 107

[0413] Compound 106 was prepared following essentially the same method described in Example 44 for compound 105, and replacing (2,4-difluorophenyl) methanamine with (4-fluorophenyl) methanamine in Step D. 1H NMR (400 MHz, CD3OD) : δ 8.56 (s, 1 H); 7.36-7.39 (m, 2 H); 7.05-7.08 (m, 2 H); 4.60-4.65 (2 H); 4.31 - 4.37 (2 H); 3.31 (s, 3 H); 2.26-2.32 (m, 1 H); 2.14-2.20 (m, 1 H); 1.97-2.01 (m, 1 H); 1.84-1.91 (m, 2 H); 1.73-1.79 (m, 1 H); 1.34 (s, 3 H). LCMS analysis calculated for C22H23FN2O5: 414.16; found: 415.16 (M + 1) +.
[0414] Compound 107 was prepared following essentially the same method described in Example 44 for compound 105, and replacing (2,4-difluorophenyl) methanamine with (2,3,4-trifluorophenyl) methanamine in Step D. 1H NMR ( 400 MHz, CD3OD): δ 8.53 (s, 1 H); 7.04-7.21 (m, 2 H); 4.60-4.67 (2 H); 4.33-4.36 (2 H); 3.31 (s, 3 H); 2.26-2.31 (m, 1 H); 2.14-2.20 (m, 1 H); 1.97-2.01 (m, 1 H); 1.84-1.90 (m, 2 H); 1.73-1.79 (m, 1 H); 1.34 (s, 3 H). LCMS analysis calculated for C22H21F3N2O5: 450.14; found: 450.97 (M + 1) +. Example 46 Preparation of Compound Int-28b
Step A - Synthesis of Compound Int-28a
[0415] Diisobutyl aluminum hydride (35.50 ml, 35.50 mmol) was added to the 2,6,6-trimethylcyclohex-1-enocarbaldehyde solution (4.50 g, 29.60 mmol) in 200 ml of CH2Cl2 cooled to -40 ° C. The resulting mixture was left under stirring at this temperature for 1.5 h. 10 ml of MeOH was added and followed by 200 ml of saturated Rochelle solution. The mixture was left stirring at room temperature for 1 h. The organic phase was separated and the aqueous phase was extracted with 2 x 50 ml of EtOAc. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to provide the compound Int-28a as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.15 (s, 2 H); 1.99 (t, J = 4.8 Hz, 2 H); 1.77 (s, 3 H); 1.59-1.64 (m, 2 H); 1.45-1.48 (m, 2 H); 1.06 (s, 6 H). Step B- Synthesis of Compound Int-28b
[0416] For a solution of the compound Int-28a (3.70 g, 23.99 mmol) in 200 mL of Et2O, tribromophosphine (1.14 mL, 11.99 mmol) was added at 0 ° C. The reaction was then slowly warmed up to room temperature overnight. It was quenched with 200 ml of saturated aqueous NaHCO3 solution at 0 ° C. The aqueous phase was extracted with 2x200 ml Et2O. The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated to produce compound Int-28b as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.11 (s, 2 H); 2.05 (t, J = 4.8 Hz, 2 H); 1.77 (s, 3 H); 1.57-1.64 (m, 2 H); 1.45-1.49 (m, 2 H); 1.13 (s, 6 H). Example 47 Preparation of Compound 108 and 109

[0417] Compound 108 was prepared following essentially the same method described in Example 36 for compound 94, and replacing compound Int-20d with compound Int-28b in Step A. 1H NMR (400 MHz, CDCl3): δ 10 , 51 (s, 1 H); 8.52 (s, 1 H); 7.36-7.41 (m, 1 H); 6.81-6.87 (m, 2 H); 4,644.73 (m, 2 H); 4.37 (d, J = 10.4, 1 H); 4.23 (d, J = 10.4, 1 H); 2.32-2.34 (m, 1 H); 1.57-1.72 (m, 3 H); 1.37 (s, 3 H); 1.29-1.34 (m, 2 H); 1.24 (s, 3 H); 0.73 (s, 3 H). LCMS analysis calculated for C24H26F2N2O5: 460.18; found: 461.18 (M + 1) +.
[0418] Compound 109 was prepared following essentially the same method described in Example 36 for compound 95, and replacing compound Int-20d with compound Int-28b in Step A. 1H NMR (400 MHz, CDCl3): δ 10 , 46 (s, 1 H); 8.49 (s, 1 H); 7.37-7.40 (m, 1 H); 6.84-6.89 (m, 2 H); 4,664.69 (m, 2 H); 4.34 (d, J = 10.4, 1 H); 4.22 (d, J = 10.4, 1 H); 2.33-2.35 (m, 1 H); 1.61 - 1.72 (m, 3 H); 1.37 (s, 3 H); 1.29-1.34 (m, 2 H); 1.14 (s, 3 H); 0.73 (s, 3 H). LCMS analysis calculated for C24H26F2N2O5: 460.18; found: 461.18 (M + 1) +. Example 48 Preparation of Compound 110 and 111
Step A - Synthesis of Compound Int-29a
[0419] To a stirred solution of the compound Int-21f (70 mg, 0.197 mmol) in 2 ml of CH2Cl2 was added chlorine (methoxy) methane (15.82 mg, 0.197 mmol), N-ethyl-N-isopropylpropan-2 -amine (25.4 mg, 0.197 mmol) and N, N-dimethylpyridin-4-amine (24.01 mg, 0.197 mmol). The mixture was left with stirring at 60 ° C for 4 hours. The reaction was concentrated in vacuo and the resulting residue was added 2 ml of DMSO. It was purified using Gilson eluting with 10% ACN (0.1% TFA) / H2O to 90% ACN (0.1% TFA) / H2O for 12 min to produce the compound Int-29a as a yellow solid clear .. LCMS analysis calculated for C17H22BrNO5: 399.07; found: 400.07 (M + 1) +. Stage B - Synthesis of Compounds Int-29b and Int-29c
[0420] For a mixture of the compound Int-29a (50 mg, 0.125 mmol)), N-ethyl-N-isopropylpropan-2-amine (48.4 mg, 0.375 mmol)), (2,4-difluorophenyl) methanamine (26.8 mg, 0.187 mmol) and (oxybis (2,1-phenylene)) bis (diphenylphosphine) (10.09 mg, 0.019 mmol) in 2 mL of DMSO was added palladium diacetoxide (4.21 mg, 0.019 mmol ). The above mixture was washed through CO for 20 min with a CO flask at room temperature, then heated to 80 ° C under a CO flask for 2 h. The reaction was cooled and directly purified using the reverse phase C18 Column (40 g) eluting with 5% ACN / H2O to 100% ACN / H2O with 0.1% TFA to produce the stereoisomeric mixture of the desired product which it was then separated by a chiral AD column (30x250 mm) eluting with 45% MeOH / CO2 at 70 ml / min to produce compound Int-29b and compound Int-29c individually as a white solid. LCMS analysis calculated for C25H228F2N2O6: 490.19; found: 491.15 (M + 1) +. Step C- Synthesis of Compound 110 and 111
[0421] Compound 110 was prepared following essentially the same method described in Example 36 for compound 94, and replacing compound Int-21g with compound Int-29b in Step H. 1H NMR (400 MHz, CDCl3): δ 10 , 48 (s, 1 H); 8.47 (s, 1 H); 7.36-7.40 (m, 1 H); 6.81-6.87 (m, 2 H); 4.98 (d, J = 6.4 Hz, 1 H); 4.64-4.67 (m, 2 H); 4.58 (d, J = 6.4 Hz, 1 H); 4.54 (1 H); 4.35 (d, J = 11.2, 1 H); 3.20 (s, 3 H); 1.66-1.96 (6 H); 1.49-1.51 (2 H); 1.42 (s, 3 H). LCMS analysis calculated for C24H26F2N2O5: 476.18; found: 477.16 (M + 1) +.
[0422] Compound 111 was prepared following essentially the same method described in Example 36 for compound 95, and replacing compound Int-21h with compound Int-29c in Step H. 1H NMR (400 MHz, CDCl3): δ 10 , 46 (s, 1 H); 8.45 (s, 1 H); 7.36-7.40 (m, 1 H); 6.80-6.86 (m, 2 H); 4.97 (d, J = 6.4 Hz, 1 H); 4.64-4.67 (m, 2 H); 4.57 (d, J = 6.4 Hz, 1 H); 4.53 (1 H); 4.35 (d, J = 11.2, 1 H); 3.20 (s, 3 H); 1.66-1.95 (6 H); 1.48-1.49 (2 H); 1.41 (s, 3 H). LCMS analysis calculated for C24H26F2N2O5: 476.18; found: 477.16 (M + 1) +. Example 49 Preparation of Compound 112 and 113
Step A - Synthesis of Compound Int-30a
[0423] For a solution of the compound Int-21e (0.25 g, 0.698 mmol) in 7 ml of CH2Cl2, N-ethyl-N-isopropylpropan-2-amine (0.45 g, 3.49 mmol) was added, N, N-dimethylpyridin-4-amine (17.05 mg, 0.140 mmol) and chlorine (methoxy) methane (281 mg, 3.49 mmol). The mixture was left with stirring at 50 ° C for 1 h. It was cooled and concentrated. The resulting residue was dissolved in 5 ml of DMSO and purified using Gilson (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA) / H2O, 12 min) to produce the Int-30a compound as a light yellow solid. LCMS analysis calculated for C17H24BrNO5: 401.08; found: 402.07 (M + 1) +. Step B- Synthesis of Compound Int-30b
[0424] To a solution of the compound Int-30a (85 mg, 0.211 mmol) in 2 ml of DMF iodomethane (90 mg, 0.634 mmol) was added followed by sodium hydride (15.21 mg, 0.634 mmol). The mixture was left stirring at 0 ° C for 30 min. It was quenched with 0.5 ml of saturated aqueous NH4Cl solution. The mixture was diluted with 3 ml of DMF and purified using Gilson (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA) / H2O, 12 min) to provide the Int-30b compound as a light yellow solid. LCMS analysis calculated for C18H26BrNO5: 415.10; found: 415.98 (M + 1) +. Step C- Synthesis of Compound Int-30c
[0425] To a stirred solution of the Int-30b compound (50 mg, 0.120 mmol) in 2 mL of MeOH, hydrogen chloride (1201 μl, 1.201 mmol) was added. The mixture was left stirring at 50 ° C for 30 min. She was concentrated. For the crude product, 2 ml of CH2Cl2 was added, followed by Dess-Martin periodinane (102 mg, 0.240 mmol). The reaction was left under stirring at room temperature for 30 min. It was concentrated in vacuo and the resulting residue was dissolved in 3 ml of DMSO. The mixture was purified using Gilson (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA) / H2O, 12 min) to provide the compound Int-30c as a solid White. LCMS analysis calculated for C16H20BrNO4: 369.06; found: 370.05 (M + 1) +. Step D- Synthesis of Compound Int-30d and Int-30e
[0426] Compound Int-30d and compound Int-30e were prepared following essentially the same method as that of compound Int-29b and compound Int-29c described in Example 48, and replacing compound Int-29a with compound Int -30c in Step B. LCMS analysis calculated for C24H26F2N2O5: 460.18; found: 461.08 (M + 1) +. Step F- Synthesis of Compound 112 and 113
[0427] Compound 112 was prepared following essentially the same method as described in Example 36 for compound 94, and replacing compound Int-21g with compound Int-30d in Step H. 1H NMR (400 MHz, CDCl3): δ 10 , 56 (s, 1 H); 8.52 (s, 1 H); 7.36-7.40 (m, 1 H); 6.82-6.87 (m, 2 H); 4.64 - 4.67 (m, 2 H); 4.40 (1 H); 4.25 (d, J = 10.8, 1 H); 3.26 (s, 3 H); 1.47-1.97 (8 H); 1.37 (s, 3 H). LCMS analysis calculated for C24H26F2N2O5: 446.16; found: 447.07 (M + 1) +.
[0428] Compound 113 was prepared following essentially the same method as described in Example 36 for compound 95, and replacing compound Int-21h with compound Int-30e in Step H. 1H NMR (400 MHz, CDCl3): δ 10 , 56 (s, 1 H); 8.47 (s, 1 H); 7.32-7.40 (m, 1 H); 6.81-6.86 (m, 2 H); 4,674.69 (m, 2 H); 4.37 (1 H); 4.22 (d, J = 10.8, 1 H); 3.27 (s, 3 H); 1.47-1.97 (8 H); 1.37 (s, 3 H). LCMS analysis calculated for C24H26F2N2O5: 446.16; found: 447.07 (M + 1) +. Example 50 Preparation of Compound 114-117

[0429] Compound 114 was prepared following essentially the same method described in Example 49 for compound 112, and replacing iodomethane with 1-bromo-2-methoxy ethane in Step B. 1H NMR (400 MHz, CDCl3): δ 10.42 (s, 1 H); 8.37 (s, 1 H); 7.36-7.40 (m, 1 H); 6.82-6.87 (m, 2 H); 4.67 (d ,, J = 4.8.2 H); 4.35 (1 H); 4.22 (d, J = 11.2, 1 H); 3.63-3.65 (m, 2 H); 3.49-3.53 (m, 2 H); 3.42 (s, 3 H); 3.28 (s, 3 H); 1.43-1.97 (8 H); 1.39 (s, 3 H). LCMS analysis calculated for C25H28F2N2O6: 490.19; found: 491.06 (M + 1) +.
[0430] Compound 115 was prepared following essentially the same method described in Example 49 for compound 113, and replacing iodomethane with 1-bromo-2-methoxy ethane in Step B. 1H NMR (400 MHz, CDCl3): δ 10, 42 (s, 1 H); 8.39 (s, 1 H); 7.34-7.40 (m, 1 H); 6.79-6.86 (m, 2 H); 4.67 (d ,, J = 4.4.2 H); 4.40 (1 H); 4.23 (d, J = 10.8, 1 H); 3.62-3.66 (m, 2 H); 3.49-3.53 (m, 2 H); 3.42 (s, 3 H); 3.27 (s, 3 H); 1.43-1.97 (8 H); 1.39 (s, 3 H). LCMS analysis calculated for C25H28F2N2O6: 490.19; found: 491.06 (M + 1) +.
[0431] Compound 116 was prepared following essentially the same method described in Example 49 for compound 112, and replacing iodomethane with 1-bromo-3-methoxy propane in Step B. 1H NMR (400 MHz, CDCl3): δ 10, 46 (s, 1 H); 8.44 (s, 1 H); 7.36-7.39 (m, 1 H); 6.81-6.86 (m, 2 H); 4.67 (d ,, J = 4.4, 2 H); 4.38 (1 H); 4.22 (d, J = 10.8, 1 H); 3.58-3.62 (m, 2 H); 3.29-3.41 (4 H); 3.25 (6 H); 1.43-1.97 (8 H); 1.38 (s, 3 H). LCMS analysis calculated for C25H28F2N2O6: 504.21; found: 505.11 (M + 1) +.
[0432] Compound 117 was prepared following essentially the same method described in Example 49 for compound 113, and replacing iodomethane with 1-bromo-3-methoxy propane in Step B. 1H NMR (400 MHz, CDCl3): δ 10, 46 (s, 1 H); 8.44 (s, 1 H); 7.36-7.41 (m, 1 H); 6.81-6.86 (m, 2 H); 4.67 (d ,, J = 4.4, 2 H); 4.38 (1 H); 4.22 (d, J = 10.8, 1 H); 3.58-3.62 (m, 2 H); 3.29-3.41 (4 H); 3.25 (6 H); 1.43-1.97 (8 H); 1.38 (s, 3 H). LCMS analysis calculated for C25H28F2N2O6: 504.21; found: 505.11 (M + 1) +. Example 51 Preparation of Compound Int-31

[0433] Compound Int-31 was prepared using the method described in Step A to Step E of Example 36, and replacing the Int-20d compound with the Int-22 compound in Step A. Analysis by LCMS calculated for C16H22BrNO4: 371.06; found: 372.95 (M + 1) +. Example 52 Preparation of Compound 118 and Compound 119

[0434] Compound 118 was prepared following essentially the same method as described in Example 49 for compound 112, and replacing compound Int-21e with compound Int-31 in Step A. 1H NMR (400 MHz, CDCl3): δ 10 , 60 (s, 1 H); 8.54 (s, 1 H); 7.36-7.40 (m, 1 H); 6.82-6.87 (m, 2 H); 4.65-4.73 (m, 2 H); 4.52 (d, J = 11.2, 1 H); 4.30 (d, J = 10.8, 1 H); 3.17 (s, 3 H); 1.48-2.02 (10 H); 1.43 (s, 3 H). LCMS analysis calculated for C24H26F2N2O5: 460.18; found: 461.16 (M + 1) +.
[0435] Compound 119 was prepared following essentially the same method described in Example 49 for compound 113, and replacing compound Int-21e with compound Int-31 in Step A. 1H NMR (400 MHz, CDCl3): δ 10 , 60 (s, 1 H); 8.55 (s, 1 H); 7.36-7.40 (m, 1 H); 6.82-6.87 (m, 2 H); 4.64-4.73 (m, 2 H); 4.52 (d, J = 11.2, 1 H); 4.30 (d, J = 10.8, 1 H); 3.16 (s, 3 H); 1.48-2.02 (10 H); 1.43 (s, 3 H). LCMS analysis calculated for C24H26F2N2O5: 460.18; found: 461.16 (M + 1) +. Example 53 Preparation of Compound Int-32h
Step A - Synthesis of Compound Int-32a
[0436] To a stirred solution of tri-O-acetyl-D-glucal (10.0 g, 36.7 mmol) in 100 mL of CH2Cl2 was added triethyl silane (5.13 g, 44.1 mmol) and trifluoride boron etarate (5.21 g, 36.7 mmol) at 0 ° C. The mixture was left stirring at this temperature for 2 h. It was quenched by the addition of 100 ml of 0.2 N aqueous HCl solution and 200 ml of CH2Cl2. The organic phase was separated and dried over anhydrous Na2SO4. It was concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel eluting with 40% EtOAc / hexane to provide the compound Int-32a as a colorless oil. LCMS analysis calculated for C10H14O5: 214.08; found: 237.07 (M + Na) +. Step B - Synthesis of Compound Int-32b
[0437] To a solution of the compound Int-32a (6.8 g, 31.7 mmol) in 100 mL of MeOH, sodium methanolate (0.686 g, 3.17 mmol) was added. The reaction was left under stirring at room temperature overnight. She was concentrated. The resulting residue was purified using silica gel column chromatography eluting with 80% EtOAc / hexane to provide the compound Int-32b as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.81 - 5.89 (2 H); 4.16-4.24 (3 H); 3.89 (dd, J = 3.2, 5.6 Hz, 1 H); 3.83 (dd, J = 3.2, 5.6 Hz, 1 H); 3.34-3.38 (m, 1 H), 2.67 (2 H). Step C- Synthesis of Compound Int-32c
[0438] A solution of the compound Int-32b (3.5 g, 26.9 mmol) in 120 mL of MeOH was added 10 wt% palladium on carbon (2.86 g, 2.69 mmol). The mixture was stirred under a H2 balloon overnight. It was filtered through celite. The filtrate was concentrated to provide the compound Int-32c as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.93 (dd, J = 0.8, 9.6 Hz, 1 H); 3.84 (dd, J = 2.4, 9.2 Hz, 1 H); 3.78 (dd, J = 4.0, 5.6 Hz, 1 H); 3.54-3.59 (m, 1 H); 3.36-3.43 (m, 1 H); 3.13-3.16 (m, 1 H); 2.84 (broad, 1 H); 2.12-2.15 (m, 1 H); 1,671.74 (m, 2 H); 1.41 - 1.49 (m, 1 H). Step D - Synthesis of Compound Int-32d
[0439] A solution of the compound Int-32c (3.0 g, 22.70 mmol) in 40 mL of DMF was added imidazole (4.64 g, 68.10 mmol) and tert-butyl dimethyl chlorosilane (4.45 g, 29.50 mmol). The mixture was left stirring at room temperature for 3 h. 200 mL of H2O was added. The aqueous phase was extracted with 2x200 ml of EtOAc. The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified using column chromatography on silica gel eluting with 15% EtOAc / hexane to provide the compound Int-32d as a colorless oil. LCMS analysis calculated for C12H26O3Si: 246.17; found: 247.17 (M + H) +. Step E- Synthesis of Compound Int-32e
[0440] To a solution of the Int-32d compound (5.0 g, 20.29 mmol) in 150 mL of CH2Cl2 and 30 mL of DMSO was added triethylamine (6.16 g, 60.9 mmol)) and PySO3 (6.46 g, 40.6 mmol) at 0 ° C. After 10 min, the ice bath was removed and the mixture was left to stir at room temperature for 2 h. To the resulting mixture, 100 ml of H2O and 100 ml of CH2Cl2 were added. The organic phase was separated and the aqueous phase was extracted with 2x50 ml of CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified using column chromatography on silica gel eluting with 10% EtOAc / hexane to provide the compound Int-32e as a colorless oil. LCMS analysis calculated for C12H26O3Si: 244.40; found: 245.33 (M + H) +. Step F- Synthesis of Compound Int-32f
[0441] To the solution of 2- (trimethyl silyl) ethyl acetate (4.98 g, 31.1 mmol) in 150 mL of THF at -78 ° C was added the 2 N diisopropylamide lithium solution in THF (17.10 ml, 34.2 mmol) drop by drop. The reaction mixture was stirred for 15 minutes, then compound Int-32e (3.8 g, 15.55 mmol) was added. The reaction mixture was allowed to warm to 40 ° C for 3 h, and was quenched by the addition of 100 ml of saturated aqueous NH4 Cl solution. The mixture was extracted with 2x150 ml of ethyl acetate and the combined organic extracts were washed with 150 ml of brine. After drying over MgSO4 and filtration, the solvent was removed under reduced pressure. The resulting residue was purified using column chromatography on silica gel eluting with 15% EtOAc / hexane to produce the compound Int-32f as a colorless oil. LCMS analysis calculated for C16H30O4Si: 314.19; found: 315.12 (M + H) +. Step G- Synthesis of Compound Int-32g
[0442] To the solution of the Int-32f compound (4.0 g, 12.72 mmol) in 120 ml of CH2Cl2 cooled to -78 ° C, 1 N diisobutyl aluminum hydride in toluene (28.0 ml) was added , 28.0 mmol). The reaction was left under stirring at -78 ° C for 1 h and then heated to 0 ° C. At this point, it was quenched by the addition of 100 mL of saturated Rochelle salt solution. The mixture was left stirring at room temperature for 1 h. The organic phase was separated. It was washed with 50 ml of brine and concentrated to provide the compound Int-32g as a colorless oil. LCMS analysis calculated for C14H28O3Si: 272.18; found: 255.05 (M-H2O) +. Stage H- Synthesis of Compound Int-32h
[0443] To a solution of the Int-32g compound (1.0 g, 3.67 mmol) in 36 mL of THF, triethylamine (1.11 g, 11.01 mmol) was added, followed by methanesulfonyl chloride (0, 84 g, 7.34 mmol) at 0 ° C. The reaction was left under stirring at 0 ° C for 1 h. It was diluted with 100 ml of EtOAc and washed with 100 ml of 0.2 N aqueous HCl solution 3 times, then with 100 ml of brine. The organic phase was concentrated in vacuo. The resulting crude mesylate was dissolved in 10 ml of THF and used in the next reaction without further purification.
[0444] In a separate reaction vessel, the 2 N diisobutyl amide solution in THF solution (3.77 ml, 7.53 mmol) was cooled to 0 ° C. To this was added tributyltin (1.993 g, 6.85 mmol). The reaction was left under stirring at 0 ° C for 15 min. It was cooled to -78 ° C, and the mesylate solution mentioned above was added via syringe. The reaction was left under stirring at -78 ° C for 30 min. It was diluted with 150 ml of 20% EtOAc / hexanes, and 150 ml of water was washed. The organic phase was concentrated in vacuo. The resulting residue was purified using silica gel column chromatography eluting initially with hexanes to remove Bu3SnH, and then with 10% EtOAc / hexanes to provide the compound Int-32h as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.40-5.43 (m, 1 H); 4.52-4.54 (m, 1 H); 3.91-3.98 (2 H); 3.76-3.90 (m, 2 H); 3.62-3.68 (m, 2 H); 2.31-2.37 (m, 2 H); 2.11 - 2.18 (m, 2 H); 1.58-1.70 (m, 6 H); 1.44 (m, 6 H); 1.301.37 (m, 6 H); 0.86-1.00 (19 H); 0.09-0.11 (6 H). Example 54 Preparation of Compound 120
Step A - Synthesis of Compound Int-33a
[0445] To a solution of the Int-1 compound (810 mg, 2.51 mmol)) and the Int-32h compound (1.50 g, 2.75 mmol) in 25 ml of ACN at 0 ° C, chloride was added stannous (763 mg, 4.02 mmol). The reaction was then warmed to room temperature and stirred for 30 min. 20 ml of saturated aqueous NH4Cl solution was added. The resulting mixture was left under stirring at room temperature for 5 min. This was diluted with 100 ml of 30% EtOAc / hexanes, and washed with 100 ml of water. The organic phase was separated and filtered. The mother liquor was concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel eluting with 10% EtOAc / hexane to produce the compound Int-33a as a colorless oil. LCMS analysis calculated for C28H40BrNO5Si: 577.19; found: 578.12 (M + H) +. Step B- Synthesis of Compound Int-33b
[0446] To a solution of the compound Int-33a (755 mg, 1.305 mmol) in acetic anhydride (6 ml, 63.5 mmol) was added triethylamine (660 mg, 6.52 mmol) and N, N-dimethylpyridin-4 -amine (80 mg, 0.652 mmol). The reaction was left under stirring at room temperature for 1 h. The solvent was removed in vacuo. The resulting residue was purified using silica gel column chromatography eluting with 20% EtOAc / hexanes to provide compound Int-33b as a colorless film. LCMS analysis calculated for C30H42BrNO6Si: 619.20; found: 620.16 (M + H) +. Step C- Synthesis of Compound Int-33c
[0447] For a stirred solution of the Int-33b compound (800 mg, 1.289 mmol) in 12 mL of THF, 1 N tetrabutylammonium fluoride in THF (2578 μl, 2.58 mmol) was added. The mixture was left stirring at room temperature for 3 h. It was concentrated to remove most of the THF. The resulting residue was purified using column chromatography on silica gel eluting with 50% EtOAc / hexane to produce the compound Int-33c as a colorless foam. LCMS analysis calculated for C30H42BrNO6: 505.11; found: 505.96 (M + H) +. Step D- Synthesis of Compound Int-33d
[0448] To the solution of the Int-33c compound (70 mg, 0.138 mmol) in 10 mL of THF at 0 ° C, triethylamine (42.0 mg, 0.415 mmol) and methanesulfonyl chloride (31.7 mg, 0.276) were added mmol). The mixture was left stirring at this temperature for 15 min. It was diluted with 20 ml of EtOAc. The organic phase was washed with 20 ml of 0.5 N HCl, dried over Na2SO4. After filtration, it was concentrated. The resulting residue was dissolved in 2 ml of DMF and then sodium iodide (207 mg, 1.382 mmol) was added. The reaction was left under stirring at 70 ° C for 30 min. After cooling to room temperature, it was then purified using Gilson (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA) / H2O, 12 min) to produce the desired iodine intermediate. This intermediate was then dissolved in 2 ml of DMF, followed by the addition of cesium carbonate (225 mg, 0.691 mmol). The reaction mixture was left under stirring at 70 ° C for 30 min. It was cooled to room temperature and purified using Gilson (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA) / H2O, 12 min) to produce the compound Int- 33d as a white solid. LCMS analysis calculated for C17H20NO5: 397.05; found: 398.02 (M + H) +. Step D - Synthesis of Compound Int-33e
[0449] To a stirred mixture of the compound Int-33d (40 mg, 0.101 mmol) in 2 mL of MeOH, potassium carbonate (45 mg, 0.303 mmol) was added. The mixture was left stirring at room temperature for 1 h. It was concentrated in vacuo and the resulting residue was dissolved in 3 ml of DMSO. This was purified using Gilson (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA) / H2O, 12 min) to provide the desired alcohol intermediate, which was then dissolved in 3 ml of CH2Cl2. Dess-Martin periodinane (79 mg, 0.187 mmol) was then added. The reaction was left under stirring at room temperature for 30 min. 1 drop of water was added and the resulting reaction mixture was filtered. The filtrate was concentrated in vacuo and the resulting residue was dissolved in 3 ml of DMSO. It was purified using Gilson (10% ACN (0.1% TFA) / H2O- 90% ACN (0.1% TFA) / H2O, 12 min) to produce the compound Int-33e as a white solid . LCMS analysis calculated for C15H16BrNO4: 353.03; found: 353.97 (M + H) +. Step E- Synthesis of Compound Int-33f
[0450] For a mixture of the compound Int-33e (20 mg, 0.056 mmol), N-ethyl-N-isopropylpropan-2-amine (21.89 mg, 0.169 mmol), (2,4-difluorophenyl) methanamine (12 , 12 mg, 0.085 mmol) and (oxybis (2,1-phenylene)) bis (diphenylphosphine) (6.08 mg, 0.011 mmol) in 1 mL of DMSO, palladium diacetoxide (2.54 mg, 0.011 mmol) was added. The above mixture was then washed with CO for 20 min with a CO flask at room temperature, then heated to 80 ° C under a CO flask for 2 h. The reaction was cooled to room temperature and directly purified using Gilson (10% ACN (0.1% TFA) / H2O - 90% ACN (0.1% TFA) / H2O, 12 min) to produce the product of carbonylation, which was then dissolved in 2 ml of MeOH. To this was added 10 mg 10% Pd on carbon. The reaction was left under stirring at room temperature under an H2 flask for 3 h. It was filtered. The filtrate was concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel eluting with 20% EtOAc / CH2Cl2 to provide the compound Int-33f as a white solid. LCMS analysis calculated for C23H24F2N2O5: 446.17; found: 447.12 (M + H) +. Step F- Synthesis of Compound 120
[0451] Compound 120 was prepared following essentially the same method as that of compound 94 described in Example 36, and replacing compound Int-21g with compound Int-33f in Step H. 1H NMR (400 MHz, CDCl3): δ 10.36 (s, 1 H); 8.47 (s, 1 H); 7.36-7.40 (m, 1 H); 6.81-6.87 (m, 2 H); 4.68 (d, J = 8.4 Hz, 2 H); 4.20 (m, 2 H); 4.13 (dd, J = 4.8, 9.2 Hz, 1 H); 3.99 (dd, J = 4.8, 9.2 Hz, 1 H); 3.56 (m, 1 H); 2.45-2.48 (m, 1 H); 2.27 (m, 1 H); 1.85 (m, 1 H); 1.65 (m, 1 H); 1.54 (m, 1 H); 0.91 (t, J = 5.6, 3 H). LCMS analysis calculated for C22H22F2N2O5: 432.15; found: 433.07 (M + 1) +. Example 55 Preparation of Compound 121 and Compound 122
Step A - Synthesis of Compound Int-34a
[0452] To a solution of the compound Int-8a (4.85 g, 7.19 mmol) in CH2Cl2 (71.9 ml) Hunig's Base (6.28 ml, 35.9 mmol) was added followed by methyl chloromethyl ether (2.457 ml, 32.3 mmol) and DMAP (0.044 g, 0.359 mmol). The reaction was left under stirring at room temperature for 72 h. In conclusion, the volatiles were removed under vacuum. The resulting residue was purified using ISCO, HP Gold silica gel normal phase (120g), eluting with hexanes / EtOAc (100% hexanes for 5 min; gradient to 30% EtOAc in hexanes over 30 min, isocratic for 5 min ) to produce the compound Int-34a as a colorless oil. LCMS analysis calculated for C39H48BrNO5Si: 717.25; found: 717.81 (M + 1) +. Step B- Synthesis of Compound Int-34b
[0453] To a solution of the compound Int-34a (4.35 g, 6.05 mmol) in THF (30.3 ml) TBAF (1M in THF) (18.16 ml, 18.16 mmol) was added. The reaction was left under stirring at room temperature for 2 h. In conclusion, the volatiles were removed under vacuum. The resulting residue was purified using ISCO, HP Gold silica gel normal phase (80g), eluting with hexanes / EtOAc (100% hexanes for 5 min; gradient to 100% EtOAc in hexanes over 25 min, isocratic for 10 min ) to produce the compound Int-34b as a colorless oil. LCMS analysis calculated for C23H30BrNO5: 479.13; found: 480.01 (M + 1) +. Step C- Synthesis of Compound Int-34c
[0454] For a solution of the compound Int-34b (3 g, 6.24 mmol) in THF (62.4 ml), Hunig's base (3.27 ml, 18.73 mmol) was added. It was cooled to 0 ° C, and methanesulfonyl chloride (0.888 ml, 11.24 mmol) was then added. The reaction was left under stirring at 0 ° C for 30 min. It was diluted with 60 ml of hexanes and then filtered. The filtrate was concentrated in vacuo. The resulting residue was mixed with sodium azide (4.06 g, 62.4 mmol) and then DMF (62.4 ml) was added. The resulting mixture was heated to 60 ° C for 1 h. The reaction was allowed to cool to room temperature. It was diluted with 500 ml of 50% EtOAc / hexanes and washed with 300 ml of water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using a silica gel column (120 g) eluting with 0-35% EtOAc / hexanes in 35 min to provide the compound Int-34c. LCMS analysis calculated for C23H29BrN4O4: 504.14; found: 505.08 (M + 1) +. Step D- Synthesis of Compound Int-34d
[0455] To a solution of the Int-34c compound (2.4 g, 4.75 mmol) in 47.3 mL of THF / t-BuOH / water (5: 5: 1), 4-N-oxide was added -methylmorpholine (0.612 g, 5.22 mmol) followed by 4% by weight osmium tetroxide in water (8.93 ml, 0.712 mmol). The reaction was left under stirring at room temperature for 24 h. To this was added 30 g of solid Na2S2O5. The mixture was left stirring at room temperature for 1 h. The contents were diluted with 300 ml of 50% EtOAc / hexanes. The brown solid was filtered. The filtrate was washed with water and concentrated. The resulting residue was purified using a silica gel column (120 g) eluting with 0-100% EtOAc / hexanes for 30 min, 100% for 5 min to provide the compound Int-34d as a colorless oil. LCMS analysis calculated for C23H31BrN4O6: 538.14; found: 539.09 (M + 1) +. Step E- Synthesis of Compound Int-34e
[0456] For a mixture of the compound Int-34d (2.2 g, 4.08 mmol) and 4-methylbenzene-1-sulfonyl chloride (1.555 g, 8.16 mmol), pyridine (20.39 ml ). The reagent solution was left under stirring at room temperature for 7 h. To this was added 20 mL of MeOH. It was left under stirring at room temperature for 20 min. The volatile was removed in vacuo. The resulting residue was diluted with 200 ml of CH2Cl2, and washed with 100 ml of 0.5 N HCl (aq.) Twice. The organic layer was dried over anhydrous Na2SO4 and then concentrated. The resulting residue was purified using ISCO, HP Gold silica gel normal phase (120g), eluting with hexanes / EtOAc (100% hexanes for 5 min; gradient to 100% EtOAc in hexanes over 25 min, isocratic for 5 min ) to provide the compound Int-34e. LCMS analysis calculated for C16H23BrN4O5: 430.09; found: 431.00 (M + 1) +. Step F- Synthesis of Compound Int-34f
[0457] For the solution of the Int-34e compound (1.55 g, 3.59 mmol) in CH2Cl2 (71.9 ml) at room temperature under N2, Dess-Martin Periodinane (3.05 g, 7 , 19 mmol) little by little. The reaction was left under stirring at room temperature for 1 h. To the reaction mixture, 1 ml of water was added and stirred for a while. Then the reaction was diluted with 50 ml of EtOAc. The solid was filtered. The filtrate was concentrated in vacuo. The resulting residue was purified using ISCO, HP Gold silica gel normal phase (120g), eluting with hexanes / EtOAc (100% hexanes over 5 min; gradient to 100% EtOAc over 15 min, isocratic over 10 min) to provide the compound Int-34f. LCMS analysis calculated for C16H21BrN4O5: 428.07; found: 429.00 (M + 1) +. Step G- Synthesis of Compound Int-34g
[0458] For a solution of the compound Int-34f (1.4 g, 3.26 mmol) and Et3N (2.273 ml, 16.31 mmol) in THF (26.1 ml) and Water (6.52 ml) was Ph3P (1.711 g, 6.52 mmol) is added. The reaction was left under stirring at room temperature overnight. The volatile was removed under vacuum. The resulting residue was purified using ISCO, HP Gold C18 reverse phase (100g), eluting with acetonitrile (with 0.1% TFA) / water (0% water for 2 min; gradient to 100% ACN in water over 30 min, isocratic for 5 min). The related fractions were pooled and evaporated under reduced pressure to produce the compound Int-34g. LCMS analysis calculated for C16H23BrN2O5: 402.08; found: 402.98 (M + 1) +. Stage H- Synthesis of Compound Int-34h
[0459] To a mixture of the compound Int-34g salt of TFA form (1.641 g, 3.29 mmol) in CH2Cl2 (49.8 ml) and MeOH (9.96 ml) was added sodium cyanoborohydride (0.413 g, 6.57 mmol). The mixture was left stirring at room temperature for 2 h. The mixture was quenched by the dropwise addition of 1 ml of HOAc, and then concentrated in vacuo. The resulting residue was purified using ISCO, HP Gold C18 reverse phase (275 g), eluting with acetonitrile (with 0.1% TFA) / water (0% water for 4 min; gradient to 40% ACN in water over 30 min, isocratic for 5 min). The related fractions were pooled and evaporated under reduced pressure to provide the compound Int-34h as a colorless oil. LCMS analysis calculated for C16H23BrN2O4: 386.08; found: 387.00 (M + 1) +. Step I - Synthesis of Compound Int-34i
[0460] To a mixture of the compound Int-34h TFA-shaped salt (600 mg, 1.197 mmol) in 12 mL of CH2Cl2 was added triethylamine (1001 μl, 7.18 mmol) followed by benzyl chloroformate (342 μl, 2.394 mmol) drop by drop. The mixture was left stirring at room temperature for 2 h. The mixture was diluted with water and extracted with ethyl acetate twice. The combined organic fractions were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified using ISCO, HP Gold silica gel normal phase (40 g), eluting with hexanes / EtOAc (100% hexanes for 5 min; gradient to 100% EtOAc over 20 min, isocratic for 10 min) to provide the Int-34i compound. LCMS analysis calculated for C24H29BrN2O6: 520.12; found: 521.03 (M + 1) +. Stage J- Synthesis of Compound Int-34j
[0461] For a solution of the Int-34i compound (527 mg, 1.011 mmol) in 10 ml of MeOH, 2 ml of 12 N aqueous HCl were added. The reaction was left under stirring at 60 ° C for 5 h. The volatile was removed under vacuum. The resulting residue was dissolved in EtOAc and neutralized by the addition of Et3N dropwise. The resulting mixture was washed with water followed by brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using ISCO, HP Gold silica gel normal phase (80 g), eluting with CH2Cl2 / MeOH (100% CH2Cl2 for 5 min; gradient to 10% MeOH in CH2Cl2 over 24 min, isocratic over 5 min ) to provide the compound Int-34j. LCMS analysis calculated for C22H25BrN2O5: 476.09; found: 477.05 (M + 1) +. Step K- Synthesis of the Int-34k Compound
[0462] For the solution of the compound Int-34j (482 mg, 1.010 mmol) in 20 mL of CH2Cl2 at room temperature under N2, Dess-Martin periodinane (557 mg, 1.313 mmol) was added. The reaction was left under stirring at room temperature for 2 h. The reaction was diluted with EtOAc and washed with saturated aqueous Na2CO3 solution. The organic suspension was concentrated in vacuo. To the resulting residue, 10 ml of CH2Cl2 was added. The solid was collected by filtration to provide the compound Int-34k. The filtrate was purified using ISCO, HP Gold normal phase silica gel (80 g) column and eluting with hexanes / EtOAc (100% hexanes over 5 min; gradient to 100% EtOAc over 35 min, isocratic over 6 min) to provide additional Int-34k compound as a white solid. LCMS analysis calculated for C22H23BrN2O5: 474.08; found: 475.03 (M + 1) +. Step L- Synthesis of Compound Int-34l
[0463] For a mixture of the compound Int-34k (93.7 mg, 0.197 mmol), N-ethyl-N -isopropylpropan-2-amine (105 μl, 0.591 mmol), (2,4-difluorophenyl) methanamine ( 42.3 μl, 0.355 mmol) and (oxybis (2,1-phenylene)) bis (diphenylphosphine) (42.5 mg, 0.079 mmol) in 5 mL of DMSO, palladium diacetoxide (17.70 mg, 0.079 mmol) was added . The mixture was rinsed with a CO balloon for 30 minutes. Then the mixture was heated at 90 ° C for 1 h under a CO flask. The reaction mixture was purified using preparative HPLC (reverse phase, YMC-Pack ODS C-18 100x20 mm) eluting with acetonitrile / water / 0.05% TFA (20% to 90% organic product in 10 min, then to 100% in 2 min, 20 mL / min). The related fractions were pooled and evaporated under reduced pressure to produce the compound Int-34l as its racemic mixture. This material was resolved by a chiral preparative SFC (ChiralPak AS, 30 X 250 mm, 70 mL / min, 100 bar, 50% MeOH (0.2% NH4OH) / CO2, 35 ° C) to provide enantiomer A from compound Int-34l (first to elute) and enantiomer B of compound Int-34l (second to elute). LCMS analysis calculated for C30H29F2N3O6: 565.20; found: 566.16 (M + 1) +. Stage M- Synthesis of the Int-34m Compound
[0464] For the solution of the enantiomer A of the compound Int-34l (8.8 mg, 0.016 mmol) in MeOH (2 ml), 10% by weight Pd-C (2.484 mg, 2.334 μmol) was added. The mixture was stirred under a H2 balloon for 1 h. Upon completion, the catalyst was filtered. The filtrate was concentrated in vacuo to produce Int-34m A-enantiomer as an opaque yellow solid. LCMS analysis calculated for C22H23F2N3O4: 431.17; found: 432.11 (M + 1) +. Step N- Synthesis of Compound 121 and 122
[0465] A mixture of the enantiomer A of the compound Int-34m (7.5 mg, 0.017 mmol) and lithium chloride (7.37 mg, 0.174 mmol) in DMF (435 μl) was heated at 100 ° C for 2 h . Upon completion of the reaction, it was cooled and diluted with 1 mL of DMSO. The crude product was purified using preparative HPLC (reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile / water / 0.1% TFA (0% to 70% organic product in 10 min, then 100% in 2 min, 20 mL / min). The related fractions were pooled and evaporated under reduced pressure to produce compound 121 as an opaque yellow solid. 1H NMR (500 MHz, CD3OD): δ 10.3 (brs, 1 H); 8.50 (s, 1 H); 7.417.45 (m, 1 H); 6.93-6.99 (m, 2 H); 4.93-5.02 (m, 1 H); 4.51-4.67 (m, 3 H); 4,024.07 (m, 1 H); 3.36-3.45 (m, 1 H); 3.13-3.24 (m, 1 H); 2.60-2.75 (m, 1 H); 1,831.93 (m, 1 H); 1.52-1.68 (m, 2 H); 1.48 (s, 3 H). LCMS analysis calculated for C21H21F2N3O4: 417.15; found: 418.11 (M + 1) +.
[0466] Compound 122 was prepared from the B-enantiomer of compound Int-34l, using essentially the same method described in Step M and Step N of Example 55 to produce compound 121. 1H NMR (500 MHz,
1.48 (s, 3 H). LCMS analysis calculated for C21H21F2N3O4: 417.15; found: 418.11 (M + 1) +. Example 56
[0467] For a mixture of the compound Int-34h (724 mg, 1.870 mmol) in 15 mL of CH2Cl2 and 3 mL of MeOH, formaldehyde (696 μl, 9.35 mmol) was added followed by sodium cyanoborohydride (235 mg, 3 , 74 mmol). The mixture was left stirring at room temperature for 1 h. Upon completion of the reaction, acetic acid (642 μl, 11.22 mmol) was added to the mixture slowly to abruptly cool the reaction. The mixture was concentrated in vacuo. The resulting residue was purified using ISCO, HP Gold C18 reverse phase (150 g), eluting with acetonitrile (0.05% TFA) / water (0.05% TFA) (0% water for 4 min; gradient to 60% ACN in water for 10 min, isocratic for 5 min). The related fractions were pooled and evaporated under reduced pressure to provide the compound Int-35a as a colorless oil. LCMS analysis calculated for C17H25BrN2O4: 400.10; found: 401.01 (M + 1) +. Step B- Synthesis of Compound Int-35b
[0468] To a solution of the compound Int-35a salt in the form of TFA (680 mg, 1.320 mmol) in MeOH (10 ml), HCl (concentrate) (2 ml, 24.35 mmol) was added. The reaction was left under stirring at 60 ° C for 5 h. The volatile was removed under vacuum. The resulting residue was redissolved in CH2Cl2 and neutralized by the addition of Et3N dropwise. The resulting residue was purified using ISCO, HP Gold C18 reverse phase (150 g), eluting with acetonitrile (0.05% TFA) / water (0.05% TFA) (0% water for 4 min; gradient to 50% ACN in water for 10 min, isocratic for 5 min). The related fractions were pooled and evaporated under reduced pressure to provide the compound Int-35b as a colorless oil. LCMS analysis calculated for C21H21F2N3O4: 356.07; found: 357.01 (M + 1) +. Step C- Synthesis of Compound Int-35c
[0469] To the solution of the compound Int-35b salt of the form of TFA (520 mg, 1.103 mmol) in 22 mL of CH2Cl2 mixed at room temperature under N2, Dess-Martin Periodinane (608 mg, 1.434 mmol) was added. The reaction was left under stirring at room temperature for 2 h. To the mixture, 1 drop of water was added and stirred for 5 min. The solid was filtered. The filtrate was concentrated in vacuo. The resulting residue was purified using ISCO, HP Gold silica gel normal phase (80 g), eluting with CH2Cl2 / MeOH (gradient of 5% to 10% MeOH in CH2Cl2 over 25 min, isocratic over 5 min) to provide the Int-35c compound as a white solid. LCMS analysis calculated for C15H19BrN2O3: 354.06; found: 355.01 (M + 1) +. Step D- Synthesis of Compound Int- 35d
[0470] For a mixture of the compound Int-35c (20 mg, 0.056 mmol), N-ethyl-N-isopropylpropan-2-amine (30.1 μl, 0.169 mmol), (2,4-difluorophenyl) methanamine ( 8.06 μl, 0.068 mmol) and (oxybis (2,1-phenylene)) bis (diphenylphosphine) (18.19 mg, 0.034 mmol) in DMSO (1408 μl) diacetoxide palladium (7.58 mg, 0.034 mmol) was added ). The above reaction was washed with a CO flask through a long needle into the solution for 30 minutes. Then the mixture was heated to 90 ° C under a CO flask for 1 h. The reaction was diluted with 2 ml of DMSO and filtered through a filter disc. The filtrate was purified using preparative HPLC (reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile (0.05% TFA) / water (0.05% TFA) (0% to 70% organic product in 10 min, then to 100% in 2 min, 20 mL / min). The related fractions were pooled and evaporated under reduced pressure to produce the Int-35d compound as its racemic mixture. This material was resolved by a chiral preparative SFC (ChiralPak OJ, 20 X 250 mm, 50 mL / min, 100 bar, 40% MeOH (0.2% NH4OH) / CO2, 35 ° C) to provide enantiomer A from compound Int-35d (first to elute) and B enantiomer of compound Int-35d (second to elute). LCMS analysis calculated for C21H21F2N3O4: 445.18; found: 446.14 (M + 1) +. Step D - Synthesis of Compound 123 and 124
[0471] A mixture of the A-enantiomer of compound Int-35d (3.9 mg, 8.76 μmol) and lithium chloride (7.42 mg, 0.175 mmol) in DMF (292 μl) was heated to 100 ° C for 2 h. Upon completion of the reaction, it was cooled and diluted with 1 mL of DMSO. The crude product was purified using preparative HPLC (reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile (0.05% TFA) / water (0.05% TFA) (0% to 70% product organic in 10 min, then to 100% in 2 min, 20 mL / min). The related fractions were pooled and evaporated under reduced pressure to produce compound 123 as an opaque yellow solid. 1H NMR (500 MHz, CD3OD): δ 8.63 (s, 1 H); 7.43 (m, 1 H); 6,926.99 (m, 2 H); 4.81 - 5.16 (m, 2 H); 4.57-4.69 (m, 2 H); 3.93-4.04 (m, 1 H); 3,473.57 (m, 1 H); 3.15-3.26 (m, 1 H); 3.07 (s, 3 H); 2.64-2.75 (m, 1 H); 1.80-1.92 (m, 1 H); 1.60-1.73 (m, 2 H); 1.52 (s, 3 H). LCMS analysis calculated for C21H21F2N3O4: 431.17; found: 432.12 (M + 1) +.
[0472] A mixture of the B-enantiomer of the Int-35d compound and lithium chloride (7.42 mg, 0.175 mmol) in DMF (88 μl) was heated at 100 ° C for 2 h. Upon completion of the reaction, it was cooled and diluted with 1 mL of DMSO. The crude product was purified using preparative HPLC (reverse phase, YMC-Pack ODS C-18 100x20mm) eluting with acetonitrile (0.05% TFA) / water (0.05% TFA) (0% to 70% product organic in 10 min, then to 100% in 2 min, 20 mL / min). The related fractions were pooled and evaporated under reduced pressure to produce compound 124 as an opaque yellow solid. 1H NMR (500 MHz, CD3OD): δ 8.63 (s, 1 H); 7.43 (m, 1 H); 6.92-6.99 (m, 2 H); 4.81 - 5.16 (m, 2 H); 4.57-4.69 (m, 2 H); 3.93-4.04 (m, 1 H); 3.47-3.57 (m, 1 H); 3.15-3.26 (m, 1 H); 3.07 (s, 3 H); 2.64-2.75 (m, 1 H); 1.80-1.92 (m, 1 H); 1.60-1.73 (m, 2 H); 1.52 (s, 3 H). LCMS analysis calculated for C21H21F2N3O4: 431.17; found: 432.12 (M + 1) +. Example 57 HIV Replication Inhibition Assay
[0473] This assay is a kinetic assay that employs a reporter cell line (MT4-gag-GFP) to quantify the number of new infected cells in each replication cycle.
[0474] MT4-GFP cells (250,000 cells / ml) were mass-infected with HIV-1 (strain NL4-3) at low multiplicity of infection (MOI) in RPMI + 10% FBS for 24 hours. The cells were then washed once in RPMI + 10% FBS medium and resuspended in RPMI + 0% or 10% or 100% normal human serum (NHS). The test compounds were serially diluted in DMSO in ECHO. The infected MT4-GFP cells were added to a black plate coated with 384-well poly-D-lysine with a transparent bottom on which the diluted test compounds were placed. The cells were seeded at 8,000 cells per well and the final concentration of DMSO was 0.4%. Infected cells (green GFP cells) were quantified at 24 and 48 hours after incubation using Acumen eX3. The viral reproduction ratio (R0) was determined using the number of infected cells in 48 hours, divided by the number of infected cells in 24 hours. The percentage inhibition of viral growth was calculated by [1- (R-Rfármacotriplo) / (RDMSO- Rfármacotriplo)] * 100 .. The IP potency of the Compound or IC50 was determined by a 4-parameter dose response curve analysis .
[0475] The illustrative compounds of the present invention were tested using this assay protocol and the results are shown in the Table below.




Treatment or prevention of HIV infection
[0476] Substituted quinolizine derivatives are useful in inhibiting HIV, in inhibiting HIV integrase, in treating HIV infection and / or reducing the likelihood or severity of HIV infection symptoms and in inhibiting HIV viral replication and / or the viral production of HIV in a cell-based system. For example, substituted quinolizine derivatives are useful in treating HIV infection after suspected previous exposure to HIV by means such as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to the subject's blood during surgery or other medical procedures.
[0477] As a consequence, in one embodiment, the invention provides methods for the treatment of HIV infection in a subject, methods comprising administering to the subject an effective amount of at least one substituted quinolizine derivative or a salt or pro- pharmaceutically acceptable drug thereof. In a specific embodiment, the amount administered is effective for treating or preventing HIV infection in the subject. In another specific embodiment, the amount administered is effective to inhibit HIV viral replication and / or viral production in the subject. In one embodiment, HIV infection progressed to AIDS.
[0478] Substituted quinolizine derivatives are also useful in the preparation and execution of screening tests for antiviral compounds. For example, substituted quinolizine derivatives are useful for identifying mutations that harbor resistant HIV cell lines, which are excellent screening tools for more powerful antiviral compounds. In addition, substituted quinolizine derivatives are useful for establishing or determining the binding site of other antivirals for HIV integrase.
[0479] The compositions and combinations of the present invention can be useful for the treatment of a subject suffering from infection related to any HIV genotype. Combination Therapy
[0480] In another embodiment, the present methods for the treatment or prevention of HIV infection may further comprise the administration of one or more additional therapeutic agents, which are not Substituted Quinolizine Derivatives.
[0481] In one embodiment, the additional therapeutic agent is an antiviral agent.
[0482] In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent.
[0483] As a consequence, in one embodiment, the present invention provides methods for treating a viral infection in a subject, the method comprising administering to the subject: (i) at least one substituted quinolizine derivative (which may include two or more different Substituted Quinolizine Derivatives), or a pharmaceutically acceptable salt or prodrug thereof, and (ii) at least one additional therapeutic agent that is different from a substituted quinolizine derivative, in which the administered amounts are together , effective to treat or prevent a viral infection.
[0484] When administering a combination therapy of the invention to a subject, the combination therapeutic agents, or a pharmaceutical composition or compositions comprising therapeutic agents can be administered in any order, such as, for example, sequentially, simultaneously, in simultaneously and the like. The amounts of the various actives in such a combination therapy can be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for the purpose of non-limiting illustration, a substituted Quinolizine Derivative and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single unit dosage (for example, a capsule, a tablet and the like).
[0485] In one embodiment, at least one substituted quinolizine derivative is administered during a time when the additional therapeutic agent (s) exerts its therapeutic or prophylactic effect, or vice versa.
[0486] In another embodiment, at least one substituted quinolizine derivative and the additional therapeutic agent (s) are administered in doses normally and employed when such agents are used alone to treat a viral infection.
[0487] In another embodiment, at least one substituted quinolizine derivative and the additional therapeutic agent (s) are administered in lower doses than the doses normally employed when such agents are used as monotherapy in the treatment of a viral infection.
[0488] In yet another embodiment, at least one substituted quinolizine derivative and the additional therapeutic agent (s) act synergistically and are administered in lower doses than the doses normally employed when such agents are used alone in the treatment of an infection viral.
[0489] In one embodiment, at least one substituted quinolizine derivative and the additional therapeutic agent (s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration. In another embodiment, this composition is suitable for subcutaneous administration. In yet another embodiment, this composition is suitable for parenteral administration.
[0490] Viral infections and virus-related disorders that can be treated or prevented using the combination therapy methods of the present invention include, but are not limited to, those listed above.
[0491] In one embodiment, the viral infection is an HIV infection.
[0492] In another modality, the viral infection is AIDS.
[0493] The at least one substituted quinolizine derivative and the additional therapeutic agent (s) can act additively or synergistically. A synergistic combination may allow the use of lower doses of one or more agents and / or less frequent administration of one or more agents of a combination therapy. Administration with a lower or less frequent dosage of one or more agents can decrease the toxicity of the therapy without reducing the effectiveness of the therapy.
[0494] In one embodiment, administration of at least one substituted quinolizine derivative and the additional therapeutic agent (s) can inhibit the resistance of a viral infection to these agents.
[0495] As noted above, the present invention is also directed to the use of a compound of Formula I with one or more anti-HIV agents. An "anti-HIV agent" is any agent that is directly or indirectly effective in inhibiting HIV reverse transcriptase or another enzyme required for HIV replication or infection, the treatment or prophylaxis of HIV infection, and / or the treatment, prophylaxis or delay in the onset or progression of AIDS. An anti-HIV agent is understood to be effective in treating, preventing or delaying the onset or progression of HIV or AIDS infection and / or diseases or conditions resulting or associated therewith. For example, the compounds of this invention can be effectively administered, either in pre-exposure and / or post-exposure periods, in combination with effective amounts of one or more anti-HIV agents selected from HIV agents Antivirals, immunomodulators, anti- infections, or vaccines useful for the treatment of HIV infection or AIDS. HIV antivirals suitable for use in combination with the compounds of the present invention include, for example, those listed in Table A, as follows:

EI = entry inhibitor; FI = fusion inhibitor; PI = protease inhibitor; nRTI = nucleoside reverse transcriptase inhibitor; II = integrase inhibitor; nnRTI = non-nucleoside reverse transcriptase inhibitor. Some of the drugs listed in the table are used in the form of salt; for example, abacavir sulfate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate.
[0496] In one embodiment, one or more anti-HIV drugs are selected from lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.
[0497] In another embodiment, the compound of formula (I) is used in combination with lamivudine.
[0498] In yet another embodiment, the compound of formula (I) is used in combination with atazanavir.
[0499] In another embodiment, the compound of formula (I) is used in combination with darunavir.
[0500] In another embodiment, the compound of formula (I) is used in combination with rilpivirine.
[0501] In one embodiment, the compound of formula (I) is used in combination with lamivudine and abacavir.
[0502] In another embodiment, the compound of formula (I) is used in combination with darunavir.
[0503] In another embodiment, the compound of formula (I) is used in combination with emtricitabine and tenofovir.
[0504] In yet another embodiment, the compound of formula (I) is used in combination with atazanavir.
[0505] In another embodiment, the compound of formula (I) is used in combination with ritonavir and lopinavir.
[0506] In another embodiment, the compound of formula (I) is used in combination with lamivudine.
[0507] In one embodiment, the compound of formula (I) is used in combination with abacavir and lamivudine.
[0508] In another embodiment, the compound of formula (I) is used in combination with lopinavir and ritonavir.
[0509] In one embodiment, the present invention provides pharmaceutical compositions comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof; (ii) a pharmaceutically acceptable carrier; and (iii) one or more additional anti-HIV agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a pharmaceutically acceptable salt or prodrug thereof, wherein the present amounts of components (i) and (iii) are, together, effective for the treatment or prophylaxis of HIV infection or for the treatment, prophylaxis, or delay of the onset or progression of AIDS in the subject in need of it.
[0510] In another embodiment, the present invention provides a method for the treatment or prophylaxis of HIV infection or for the treatment, prophylaxis, or delay of the onset or progression of AIDS in a subject in need thereof, which comprises administration to the subject of (i) a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof and (ii) one or more anti-HIV agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a salt or pro - pharmaceutically acceptable drug thereof, in which the administered amounts of components (i) and (ii) are, together, effective for the treatment or prophylaxis of HIV infection or for the treatment, prophylaxis, or delay of the onset or progression of AIDS in the subject in need of it.
[0511] It is understood that the scope of combinations of the compounds of the present invention with anti-HIV agents is not limited to the HIV antiviral agents listed in Table A, but in principle includes any combination with any pharmaceutical composition useful for treatment or prophylaxis AIDS. HIV antiviral agents and other agents will typically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in Physicians' Desk Reference, Thomson PDR, Thomson PDR, 57th edition (2003), the 58th edition (2004), the 59th edition (2005), and the like. The dosage ranges for a compound of the invention in these combinations are the same as those set out above.
[0512] The dose and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of HIV infection can be determined by the attending physician, taking into account the approved doses and the dosage regimen in the package insert. the packaging; the subject's age, sex and general health; and the type and severity of the viral infection or related disease or disorder. When administered in combination, the substituted quinolizine derivative (s) and the other agent (s) can be administered simultaneously (i.e., in the same composition or in separate compositions one after the other) or sequentially. This is particularly useful when the components of the combination are given in different dosage schedules, for example, one component is administered once a day and another component is administered every six hours, or when the pharmaceutical compositions are different, for example , one is a pill and the other is a capsule. A kit that comprises separate dosage forms, as a consequence, is advantageous. Compositions and Administration
[0513] When administered to a subject, Substituted Quinolizine Derivatives can be administered as a component of a composition comprising a pharmaceutically acceptable carrier or vehicle. The present invention provides pharmaceutical compositions that comprise an effective amount of at least one substituted quinolizine derivative and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials, suitably selected with respect to the intended form of administration, that is, oral tablets, capsules (solid, semi-solid or filler). liquid), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with any pharmaceutically acceptable non-toxic oral inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, sulfate calcium, talc, mannitol, ethyl alcohol (liquid forms) and the like. Solid form preparations include powders, tablets, dispersible granules, capsules, wafers and suppositories. Powders and tablets can be comprised of about 0.5 to about 95 percent inventive composition. Tablets, powders, wafers and capsules can be used as solid dosage forms suitable for oral administration.
[0514] In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. Among the lubricants, boric acid, sodium benzoate, sodium acetate, sodium chloride and the like can be mentioned for use in these dosage forms. Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives can also be included where appropriate.
[0515] Preparations in liquid form include solutions, suspensions and emulsions and may include solutions of propylene glycol - water or water for parenteral injection.
[0516] Preparations in liquid form may also include solutions for intranasal administration.
[0517] Also included are preparations in solid form that are intended to be converted, shortly before use, into preparations in liquid form for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
[0518] For the preparation of suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed in it homogeneously, for example, by stirring. The melted homogeneous mixture is then poured into convenient sized molds, left to cool and thereby solidify.
[0519] Furthermore, the compositions of the present invention can be formulated in a sustained release form to provide a controlled release rate of any one or more of the active components or ingredients to optimize therapeutic effects, i.e., antiviral activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying rates of disintegration or polymeric controlled release matrices impregnated with the active components and shaped into tablets or capsules containing such impregnated or encapsulated porous polymeric matrices.
[0520] In one embodiment, the one or more Substituted Quinolizine Derivatives are administered orally.
[0521] In another embodiment, the one or more Substituted Quinolizine Derivatives are administered intravenously.
[0522] In one embodiment, a pharmaceutical preparation comprising at least one substituted quinolizine derivative is in unit dosage form. In such a way, the preparation is subdivided into unit doses which contain effective amounts of the active components.
[0523] The compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the compositions of the present invention can contain, in one embodiment, between about 0.1% to about 99% of ( s) substituted quinolizine derivative, by weight or volume. In various embodiments, the present compositions may, in one embodiment, contain from about 1% to about 70% or from about 5% to about 60% of the substituted quinolizine derivative, by weight or volume.
[0524] The compounds of Formula I can be administered orally in a dosage range between 0.001 and 1000 mg / kg of mammalian body weight (for example, human) per day in a single dose or in divided doses. A dosage range is 0.01 to 500 mg / kg of body weight per day orally in a single dose or in divided doses. Another dosage range is 0.1 to 100 mg / kg of body weight per day orally in single or divided doses. For oral administration, the compositions can be supplied in the form of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the active ingredient for symptomatic adjustment of the dosage to the subject to be treated. The specific dose level and dosing frequency for any particular subject can be varied and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and duration of action of that compound, age, body weight, general health , sex, diet, mode and time of administration, rate of excretion, combination of drugs, the severity of the particular condition and the host undergoing therapy.
[0525] For convenience, the total daily dosage can be divided and administered in portions during the day if desired. In one embodiment, the daily dose is administered in one portion. In another embodiment, the total daily dosage is administered in two divided doses over a 24-hour period. In another embodiment, the total daily dosage is administered in three divided doses over a 24-hour period. In yet another embodiment, the total daily dosage is administered in four divided doses over a 24-hour period.
[0526] Unit dosages of Substituted Quinolizine Derivatives can be administered at different frequencies. In one embodiment, a unit dosage of a substituted quinolizine derivative can be administered once daily. In another embodiment, a unit dosage of a substituted quinolizine derivative can be administered twice a week. In another embodiment, a unit dosage of a substituted quinolizine derivative can be administered once a week. In yet another embodiment, a unit dosage of a substituted quinolizine derivative can be administered once every two weeks. In another embodiment, a unit dosage of a substituted quinolizine derivative can be administered once a month. In yet another embodiment, a unit dosage of a substituted quinolizine derivative can be administered once every two months. In another embodiment, a unit dosage of a substituted quinolizine derivative can be administered once every 3 months. In another embodiment, a unit dosage of a substituted quinolizine derivative can be administered once every 6 months. In another embodiment, a unit dosage of a substituted quinolizine derivative can be administered once a year.
[0527] The quantity and frequency of administration of Substituted Quinolizine Derivatives will be regulated according to the judgment of the attending physician considering factors such as age, condition and size of the subject, as well as the severity of the symptoms to be treated. The compositions of the invention may further comprise one or more additional therapeutic agents, selected from those listed above in this document. Kits
[0528] In one aspect, the present invention provides a kit that comprises a therapeutically effective amount of at least one substituted quinolizine derivative, or a pharmaceutically acceptable salt of the same or prodrug of said compound and a pharmaceutically carrier, vehicle or diluent acceptable.
[0529] In another aspect, the present invention provides a kit comprising an amount of at least one substituted quinolizine derivative, or a pharmaceutically acceptable salt or prodrug of said compound and an amount of at least one therapeutic agent supplement listed above, in which the amounts of the two or more active ingredients result in a desired therapeutic effect. In one embodiment, one or more Substituted Quinolizine Derivatives and one or more additional therapeutic agents are provided in the same container. In one embodiment, the one or more Substituted Quinolizine Derivatives and the one or more additional therapeutic agents are provided in separate containers.
[0530] The present invention should not be limited by the specific modalities described in the examples that are intended as illustrations of some aspects of the invention and any modalities that are functionally equivalent are part of the scope of the present invention. In fact, various modifications of the invention in addition to those presented and described here will be evident to those skilled in the art and are intended to be part of the scope of the appended claims.
[0531] Numerous references have been cited here, the full descriptions of which are incorporated by reference.

权利要求:
Claims (35)
[0001]
1. Compound, characterized by the fact that it presents the formula:
[0002]
2. Compound according to claim 1, characterized by the fact that X is -NHC (O) -.
[0003]
3. Compound according to claim 1, characterized by the fact that X is 5-membered monocyclic heteroaryl.
[0004]
Compound according to any one of claims 1 to 3, characterized in that Y is CH2.
[0005]
Compound according to any one of claims 1 to 4, characterized in that R1 is optionally substituted phenyl or optionally substituted 9-membered bicyclic heteroaryl.
[0006]
A compound according to claim 5, characterized by the fact that R1 is phenyl, which is replaced by 1 to 3 halo groups, which can be the same or different.
[0007]
Compound according to claim 5, characterized by the fact that R1 is 2,4-difluorophenyl or 3-chloro-2-fluorophenyl.
[0008]
A compound according to any one of claims 1 to 7, characterized in that R2 and R3 are each independently selected from H, -OH and -O- (C 1 -C 6 alkyl).
[0009]
Compound according to any one of claims 1 to 8, characterized in that R2 is H and R3 is -OH or -O- (C1-C6 alkyl).
[0010]
Compound according to any one of claims 1 to 9, characterized in that R4 is selected from C1-C6 alkyl and - (C-C6 alkylene) -O- (C1-C6 alkyl).
[0011]
11. Compound according to claim 9, characterized by the fact that R4 is selected from methyl and -CH2CH2OCH3.
[0012]
A compound according to any one of claims i to 7, characterized by the fact that R2 and R4, together with the carbon atoms to which they are attached, join to form a 5- to 7-membered monocyclic heterocycloalkyl group.
[0013]
A compound according to any one of claims i to i2, characterized in that R5 is methyl.
[0014]
14. Compound according to claim 5, characterized by the fact that R3 is H; R5 is methyl; and R2 and R4, together with the carbon atoms to which they are attached, come together to form a group selected from:
[0015]
A compound according to any one of claims ia 7 or i2 to i4, characterized by the fact that R2 and R4, together with the carbon atoms to which they are attached, come together to form:
[0016]
16. Compound, characterized by the fact that it is selected from the group consisting of:
[0017]
Pharmaceutical composition, characterized in that it comprises a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 16, and a pharmaceutically acceptable carrier.
[0018]
18. Use of a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 16 and, optionally, of one to three additional therapeutic agents, characterized in that it is for the preparation of a separate composition or compositions for the treatment or prophylaxis of HIV infection or for the treatment, prophylaxis, or delay of the onset or progression of AIDS, wherein the additional therapeutic agent is selected from lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.
[0019]
19. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, characterized in that it is for use in the preparation of a medicament to inhibit HIV integrase, for the treatment or prophylaxis of HIV infection, or for treatment, prophylaxis, or delaying the onset or progression of AIDS in a subject in need of it.
[0020]
20. Pharmaceutical composition according to claim 17, characterized by the fact that it further comprises from one to three additional therapeutic agents, selected from lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.
[0021]
21. Compound, characterized by the fact that it presents the formula:
[0022]
22. Compound, characterized by the fact that it presents the formula:
[0023]
23. Compound, characterized by the fact that it presents the formula:
[0024]
24. Compound, characterized by the fact that it presents the formula:
[0025]
25. Compound, characterized by the fact that it presents the formula:
[0026]
26. Compound, characterized by the fact that it presents the formula:
[0027]
27. Compound, characterized by the fact that it presents the formula:
[0028]
28. Compound, characterized by the fact that it presents the formula:
[0029]
29. Compound, characterized by the fact that it presents the formula:
[0030]
30. Compound, characterized by the fact that it presents the formula: or a pharmaceutically acceptable salt thereof.
[0031]
31. Compound, characterized by the fact that it presents the formula:
[0032]
32. Compound, characterized by the fact that it presents the formula:
[0033]
33. Compound, characterized by the fact that it presents the formula:
[0034]
34. Compound, characterized by the fact that it presents the formula:
[0035]
35. Compound, characterized by the fact that it presents the formula: or a pharmaceutically acceptable salt thereof.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR112016006651B1|2021-01-12|substituted quinolizine-derived compounds, pharmaceutical composition comprising them and use of said compounds

---

EP3008044B1|2018-11-21|Fused tricyclic heterocyclic compounds as hiv integrase inhibitors

---

EP3389380B1|2021-07-21|Spirocyclic quinolizine derivatives useful as hiv integrase inhibitors

---

EP3303341B1|2020-11-18|Fused tricyclic heterocyclic compounds useful for treating hiv infection

---

EP2997033B1|2017-11-15|Fused tricyclic heterocyclic compounds as hiv integrase inhibitors

---

AU2016381072B2|2020-11-26|Fused Tricyclic Heterocyclic compounds as HIV integrase inhibitors

---

EP3229805A1|2017-10-18|Spirocyclic heterocycle compounds useful as hiv integrase inhibitors

---

EP3285582A1|2018-02-28|Phosphate-substituted quinolizine derivatives useful as hiv integrase inhibitors

---

WO2017087256A1|2017-05-26|Spirocyclic pyridotriazine derivatives useful as hiv integrase inhibitors

---

BR112019010924B1|2020-11-24|HETEROCYCLIC TETRACYCLIC COMPOUNDS USEFUL AS HIV INTEGRASE INHIBITORS, PHARMACEUTICALLY ACCEPTABLE SALES OF THE SAME, PHARMACEUTICAL COMPOSURES AND USES OF THOSE COMPOUNDS

---

AU2017367714A1|2019-05-16|Tricyclic heterocycle compounds useful as HIV integrase inhibitors

---

NZ717864B2|2022-01-06|Substituted quinolizine derivatives useful as hiv integrase inhibitors

同族专利:

---

公开号 | 公开日

---

MD4794B1|2022-02-28|

---

ZA201601708B|2017-06-28|

---

HK1221648A1|2017-06-09|

---

JP6081662B2|2017-02-15|

---

US20160228419A1|2016-08-11|

---

EP3049081B1|2019-11-27|

---

PE20160501A1|2016-05-14|

---

MA38922A3|2018-11-30|

---

EA201690669A1|2016-12-30|

---

GT201600056A|2017-12-28|

---

JP2016531863A|2016-10-13|

---

MD20160044A2|2016-07-31|

---

EA201690669A8|2018-07-31|

---

CA2924829C|2019-10-29|

---

CN105744936A|2016-07-06|

---

CL2016000698A1|2016-09-23|

---

AP2016009157A0|2016-04-30|

---

BR112016006651A2|2017-08-01|

---

ES2768658T3|2020-06-23|

---

NI201600040A|2016-06-21|

---

EP3049081A1|2016-08-03|

---

CN105744936B|2019-07-30|

---

PH12016500553A1|2016-05-23|

---

TN2016000090A1|2017-07-05|

---

US9861620B2|2018-01-09|

---

ECSP16016726A|2017-08-31|

---

US20180028509A1|2018-02-01|

---

WO2015048363A1|2015-04-02|

---

AU2014324829B2|2017-09-07|

---

JP2017105793A|2017-06-15|

---

MA38922A2|2018-10-31|

---

UA117499C2|2018-08-10|

---

KR20170133521A|2017-12-05|

---

KR102102516B1|2020-04-20|

---

US10201533B2|2019-02-12|

---

SV2016005171A|2016-11-21|

---

SG11201602217XA|2016-04-28|

---

EA030695B1|2018-09-28|

---

AU2014324829A1|2016-03-24|

---

KR20160061404A|2016-05-31|

---

DOP2016000069A|2016-07-15|

---

MX2016003860A|2016-08-01|

---

NZ717864A|2021-09-24|

---

CR20160140A|2016-06-17|

---

KR101809392B1|2017-12-14|

---

EP3049081A4|2017-02-22|

---

CA2924829A1|2015-04-02|

---

IL244438D0|2016-04-21|

---

BR112016006651A8|2018-01-30|

---

PH12016500553B1|2016-05-23|

---

MX367057B|2019-08-02|

---

SA516370826B1|2020-10-27|

---

BR112016006651B8|2021-03-02|

---

IL244438A|2020-07-30|

---

JP6550083B2|2019-07-24|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

EP1115724A1|1998-09-21|2001-07-18|Shire Biochem Inc.|Quinolizinones as integrin inhibitors|

---

GB0110832D0|2001-05-03|2001-06-27|Virogen Ltd|Antiviral compounds|

---

KR100977701B1|2001-08-10|2010-08-24|시오노기세이야쿠가부시키가이샤|Antiviral agent|

---

DK1441734T3|2001-10-26|2007-06-11|Angeletti P Ist Richerche Bio|Dihydroxypyrimidine carboxamide inhibitors and HIV integrase|

---

SI1441735T1|2001-10-26|2006-06-30|Angeletti P Ist Richerche Bio|N-substituted hydroxypyrimidinone carboxamide inhibitors of hiv integrase|

---

EP1467970B1|2002-01-17|2007-08-22|Merck & Co., Inc.|Hydroxynaphthyridinone carboxamides useful as hiv integrase inhibitors|

---

AU2003267098B2|2002-09-11|2008-11-20|Merck & Co., Inc.|Dihydroxypyridopyrazine-1,6-dione compounds useful as HIV integrase inhibitors|

---

KR20050087865A|2002-12-27|2005-08-31|이스티투토 디 리세르쉐 디 비올로지아 몰레콜라레 피. 안젤레티에스.피.에이.|Tetrahydro-4h-pyrido[1,2-a]pyrimidines and related compounds useful as hiv integrase inhibitors|

---

US7135467B2|2003-01-13|2006-11-14|Bristol-Myers Squibb Company|HIV integrase inhibitors|

---

US7037908B2|2003-04-24|2006-05-02|Bristol-Myers Squibb Company|HIV integrase inhibitors|

---

TW200510425A|2003-08-13|2005-03-16|Japan Tobacco Inc|Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor|

---

JP2006232849A|2003-08-13|2006-09-07|Japan Tobacco Inc|Nitrogenous fused-ring compound and use thereof as hiv integrase inhibitor|

---

AR046938A1|2003-12-12|2006-01-04|Merck & Co Inc|PROCEDURE TO PREPARE HEXAHYDROPIRIMID [1,2-A] AZEPIN-2-CARBOXYLATES AND SIMILAR COMPUTERS|

---

TW200526635A|2003-12-22|2005-08-16|Shionogi & Co|Hydroxypyrimidinone derivative having HIV integrase inhibitory activity|

---

AU2005222391B2|2004-03-09|2010-11-11|Merck Sharp & Dohme Corp.|HIV integrase inhibitors|

---

WO2005087766A1|2004-03-09|2005-09-22|Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa|Hiv integrase inhibitors|

---

US7273859B2|2004-05-12|2007-09-25|Bristol-Myers Squibb Company|HIV integrase inhibitors: cyclic pyrimidinone compounds|

---

US7115601B2|2004-05-18|2006-10-03|Bristol-Myers Squibb Company|HIV integrase inhibitors|

---

US7192948B2|2004-05-28|2007-03-20|Bristol-Myers Squibb Company|Bicyclic heterocycles as HIV integrase inhibitors|

---

US7176196B2|2004-05-28|2007-02-13|Bristol-Myers Squibb Company|Bicyclic heterocycles as HIV integrase inhibitors|

---

US7173022B2|2004-05-28|2007-02-06|Bristol-Myers Squibb Company|Bicyclic heterocycles as HIV integrase inhibitors|

---

US7157447B2|2004-05-28|2007-01-02|Bristol-Myers Squibb Company|Bicyclic heterocycles as HIV integrase inhibitors|

---

WO2006033422A1|2004-09-21|2006-03-30|Japan Tobacco Inc.|Quinolizinone compound and use thereof as hiv integrase inhibitor|

---

US7745459B2|2004-09-21|2010-06-29|Japan Tobacco Inc.|Quinolizinone compound and use thereof as HIV integrase inhibitor|

---

US20060066414A1|2004-09-28|2006-03-30|Rockwell Scientific Licensing, Llc|Method and apparatus for changing the polarization of a signal|

---

EP1973906A1|2004-12-23|2008-10-01|Virochem Pharma Inc.|Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase|

---

JP5317257B2|2005-02-21|2013-10-16|塩野義製薬株式会社|Bicyclic carbamoylpyridone derivatives having HIV integrase inhibitory activity|

---

US7981879B2|2005-03-31|2011-07-19|Instituto di Ricerchi di Biologia Molecolare P. Angeletti S.p.A.|HIV integrase inhibitors|

---

UA96568C2|2005-04-28|2011-11-25|Глаксосмиткляйн Ллк|Polycyclic carbamoyl pyridone derivative as hiv-integrase inhibitor|

---

SI2465580T1|2005-04-28|2014-04-30|Viiv Healthcare Company|Polycyclic carbamoylpyridone derivatives having hiv integrase inhibitory activity|

---

JP2006342115A|2005-06-10|2006-12-21|Shionogi & Co Ltd|Polycyclic compound having hiv integrase inhibition activity|

---

US7494984B2|2005-08-31|2009-02-24|Bristol-Myers Squibb Company|Substituted imidazo[1,2-a]pyrimidines as HIV viral DNA integrase inhibitors|

---

US7897592B2|2005-11-15|2011-03-01|Bristol-Myers Squibb Company|HIV integrase inhibitors|

---

US7902182B2|2005-11-16|2011-03-08|Bristol-Myers Squibb Company|HIV integrase inhibitors|

---

US8039458B2|2005-11-17|2011-10-18|Bristol-Myers Squibb Company|HIV integrase inhibitors|

---

US7897593B2|2006-05-30|2011-03-01|Bristol-Myers Squibb Company|HIV integrase inhibitors|

---

US7893055B2|2006-06-28|2011-02-22|Bristol-Myers Squibb Company|HIV integrase inhibitors|

---

EP2470014A4|2009-08-26|2013-01-16|Merck Sharp & Dohme|Hiv integrase inhibitors|

---

US8497270B2|2009-10-13|2013-07-30|Elanco Animal Health Ireland Limited|Macrocyclic integrase inhibitors|

---

JP2013518107A|2010-01-27|2013-05-20|ヴィーブヘルスケアカンパニー|Antiviral therapy|

---

WO2011121105A1|2010-04-02|2011-10-06|Tibotec Pharmaceuticals|Macrocyclic integrase inhibitors|

---

ES2768658T3|2013-09-27|2020-06-23|Merck Sharp & Dohme|Substituted quinolizine derivatives useful as HIV integrase inhibitors|TWI642669B|2012-12-21|2018-12-01|美商基利科學股份有限公司|Polycyclic-carbamoylpyridone compounds and their pharmaceutical use|

---

PT3252058T|2013-07-12|2021-03-09|Gilead Sciences Inc|Polycyclic-carbamoylpyridone compounds and their use for the treatment of hiv infections|

---

NO2865735T3|2013-07-12|2018-07-21|

---

ES2768658T3|2013-09-27|2020-06-23|Merck Sharp & Dohme|Substituted quinolizine derivatives useful as HIV integrase inhibitors|

---

WO2015089847A1|2013-12-20|2015-06-25|Merck Sharp & Dohme Corp.|Spirocyclic heterocycle compounds useful as hiv integrase inhibitors|

---

TWI677489B|2014-06-20|2019-11-21|美商基利科學股份有限公司|Synthesis of polycyclic-carbamoylpyridone compounds|

---

TW201613936A|2014-06-20|2016-04-16|Gilead Sciences Inc|Crystalline forms of-8-hydroxy-7,9-dioxo-n--2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide|

---

NO2717902T3|2014-06-20|2018-06-23|

---

EP3757105A3|2014-08-22|2021-01-06|Shionogi & Co., Ltd|Polycyclic pyridone derivative having integrase inhibitory activity|

---

TWI695003B|2014-12-23|2020-06-01|美商基利科學股份有限公司|Polycyclic-carbamoylpyridone compounds and their pharmaceutical use|

---

WO2016154527A1|2015-03-26|2016-09-29|Merck Sharp & Dohme Corp.|Phosphate-substituted quinolizine derivatives useful as hiv integrase inhibitors|

---

EP3277691B1|2015-04-02|2019-01-30|Gilead Sciences, Inc.|Polycyclic-carbamoylpyridone compounds and their pharmaceutical use|

---

WO2016187788A1|2015-05-25|2016-12-01|Merck Sharp & Dohme Corp.|Fused tricyclic heterocyclic compounds useful for treating hiv infection|

---

WO2017106071A1|2015-12-15|2017-06-22|Merck Sharp & Dohme Corp.|Spirocyclic quinolizine derivatives useful as hiv integrase inhibitors|

---

EP3515438B1|2016-09-21|2022-03-02|Merck Sharp & Dohme Corp.|Drug delivery system for the delivery of integrase inhibitors|

---

CN110214142A|2016-12-02|2019-09-06|默沙东公司|It can be used as four ring heterocyclic compounds of hiv integrase inhibitor|

---

EP3573984A4|2017-01-26|2020-07-29|Merck Sharp & Dohme Corp.|Substituted quinolizine derivatives useful as hiv integrase inhibitors|

---

JP2019016012A|2017-07-03|2019-01-31|東芝テック株式会社|Printer and program|

---

BR112020024077A2|2018-05-31|2021-02-09|Shionogi & Co., Ltd.|polycyclic carbamoylpyridone derivative|

---

CA3128961A1|2019-03-22|2020-10-01|Hang CHU|Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use|

---

WO2021019071A1|2019-07-31|2021-02-04|Advanced Biodesign|Aminothiolester compounds and uses thereof|

法律状态:
2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

---

2019-12-17| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

---

2020-01-28| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2020-06-23| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

---

2020-11-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2021-01-12| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 26/09/2014, OBSERVADAS AS CONDICOES LEGAIS. |

---

2021-03-02| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: REF. RPI 2610 DE 12/01/2021 QUANTO A QUALIFICACAO. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201361883463P| true| 2013-09-27|2013-09-27|

---

US61/883,463|2013-09-27|

---

PCT/US2014/057572|WO2015048363A1|2013-09-27|2014-09-26|Substituted quinolizine derivatives useful as hiv integrase inhibitors|

---