Progranulin regulator and method of use thereof

Abstract

Provided herein are compounds that modulate progranulin and methods of using the compounds in progranulin-related disorders, such as frontotemporal lobe dementia (FTLD).

Description

Technical field

[0001] Background technology Provided herein are compounds that modulate progranulin levels and can be useful as treatments for granulin (GRN) and / or progranulin (PGRN) related disorders. Mutations in the GRN gene cause frontotemporal lobar degeneration (FTLD) (e.g., Cruts et al., Granulin Mutations Associated with Frontotemporal Lobar Degeneration and Related Disorders: An Update, Hu Mutation,2008 and Baker et al., Nature , 2006). FTLD-associated mutations in GRN result in decreased progranulin protein expression, suggesting that progranulin haploinsufficiency is an important pathogenic factor in FTLD-GRN. Plasma and CSF progranulin levels are reduced by up to 70% in pathogenic GRN mutation carriers (Ghidoni, et al., Neurodegen Dis, 2012). More than 60 nonsense mutations in the GRN gene have been described. Plasma can be easily monitored for PGRN (see, eg, Meeter, Nature Neurology, volume 13, 2017). Therefore, granulin- and / or progranulin-related disorders can be modulated by compounds that increase progranulin secretion and / or activity.

[0002] All known FTLD-GRN-associated mutations cause progranulin haploinsufficiency, suggesting that restoration of adequate progranulin levels or progranulin protein function may be therapeutically beneficial for FTLD-GRN patients. There is. Several studies have shown that even small reductions in progranulin levels by genetic modifiers (e.g., TMEM106B, SLPI, Rs5848) significantly influence the age of onset of FTLD, increasing the risk of developing FTLD, and increasing the risk of developing FTLD. or worsen the course of autoimmune diseases such as osteoarthritis (e.g., Nicholson et al., J Neurochem, 2013, Cruchaga et al., Arch Neurol, 2012, and Wei et al, Plos One , 2014). Polymorphisms that affect progranulin levels have also been identified as genetic modifiers of several other neurodegenerative diseases, such as Alzheimer's disease and C9orf72-associated FTLD (e.g., Sheng et al., Gene, 2014 and van Blitterswijk et al., Mol Neurodegen, 2014). Accordingly, it is contemplated herein that therapies targeting progranulin will be effective across multiple neurodegenerative and autoimmune disorders.

[0003] Granulins are a family of secreted and glycosylated proteins. They are cleaved from a common precursor protein called progranulin (PGRN). Progranulin is a secreted glycoprotein expressed in neurons, glia, chondrocytes, epithelial cells, and leukocytes (Toh H et al.J Mol Neurosci 201 1 Nov;45(3):538-48 ). It is a precursor protein with an N-terminal signal peptide and seven granulin motifs. Each of these granulin motifs contains 12 cysteines, which are responsible for the 6 disulfide bridges of all granulins (Bateman A et al.Bioessays 2009:1245-54). Progranulin is encoded by the GRN gene. Mutations in the GRN gene are associated with up to 25% of frontotemporal lobar degenerations and are inherited in an autosomal dominant manner with high penetrance (e.g., Mackenzie, Acta Neuropathologica, 114(1):49-54 (2007)). Modulation of progranulin activity is therefore an attractive goal for treating disorders associated with GRN activity or GRN gene mutations.

[0004] The translocon complex is the main gate to the secretory pathway. It promotes the translocation of nascent proteins into the endoplasmic reticulum (ER) lumen or their incorporation in lipid membranes. Translocons are organized around a conserved core consisting of a trimeric protein complex, the Sec61 channel. It is associated with auxiliary components such as cytoplasmic chaperones such as signal recognition particles (SRPs), moving chain associated membranes (TRAMs), translocon associated proteins (TRAPs), and modifying enzymes such as oligosaccharyltransferases (OSTs). . The latter is involved in the proper glycosylation of proteins and binds to the ribosome-Sec61-TRAP complex in a near stoichiometric ratio. The importance of this complex is highlighted by mutations found in one of the TRAP components of the complex that lead to impaired glycosylation.

[0005] Lysosomes are organelles that contain over 60 different enzymes, such as lipases, proteases, and hydrolases, primarily involved in the breakdown of proteins, lipids, and carbohydrates. Mutations found in multiple lysosomal proteins are the underlying cause of several different diseases that fall into the class of neuronal ceroid lipofuscinosis (NCL), also known as Batten disease. In some cases, certain lysosomal proteins act as cofactors for lysosomal enzymes. Their distribution and / or expression level can modulate the activity of lysosomal enzymes and therefore have a regulatory downstream function in the overall function of the lysosome. [Summary of the invention]

[0006] Provided herein are compounds and methods for modulating progranulin, eg, increasing the level of progranulin or granulin in a subject. More specifically, modulators of progranulin, as well as progranulin-related disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal cognition. (FTD), frontotemporal dementia - granulin subtype (FTD-GRN), Lewy body dementia (LBD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), lysosomal storage disease, diseases associated with inclusion bodies and / or dysfunction of C9orf72, TDP-43, FUS, UBQLN2, VCP, CHMP28, and / or MAPT, acute Use of such modulators in treating neurological disorders, glioblastoma, or neuroblastoma is provided.

[0007] The present disclosure provides compounds of formula (I), [ka] In the formula, ring A is a 4- to 12-membered heterocycle containing a ring O or S atom, further containing 0 to 3 additional ring heteroatoms selected from O, N, and S, and R 1 is hydrogen, C 1-6 alkyl, halo, C 1-3 haloalkyl, O-C 1-3 haloalkyl, C 0-3 Alkylene-CN,C 0-3 Alkylene-NR N 2 ,C 0-6 Alkylene-OR N ,C 0-6 Alkylene-C(O)OR N ,C 0-6 Alkylene-C(O)N(R N ) 2 , or C 0-6 Alkylene-SO p R N and each R N is independently hydrogen or C 1-6 is alkyl, p is 0 to 2, and each R 2 are independently halo, each R 3 are independently hydrogen, halo, C 1-6 Alkyl, C 1-6 haloalkyl, C 0-6 Alkylene-OH,C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-O-C 1-6 Alkyl, C 0-6 Alkylene-NR a R b ,S-C 1-6 Alkyl, C 2-6 Alkenyl, C(O)-C 1-6 haloalkyl, SO 2 -C 1-6 Alkyl, S 2+ (O) - (NR a ) - C 1-6 Alkyl, OR 4 , a 5- to 8-membered heteroaryl containing 1 to 4 ring N atoms, or containing 1 to 4 heteroatoms selected from O, N, and S, in which at least one ring heteroatom is N is a 4- to 6-membered heterocycle, and the heteroaryl or heterocycle is optionally independently halo, C 1-6 Alkyl, OH, and C 1-6 substituted with one or two substituents selected from alkoxy or two geminal R 3 form an oxo group together with the atoms to which they are attached, and if ring A contains a ring N atom, then N is R a and ring A does not contain a ring N atom, at least one R 3 is C 0-6 Alkylene-NR a Rb and R a and R b are each independently hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 Alkylene-OH,C 1-6 Alkylene-O-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, C(O)-C 1-6 Haloalkyl, S(O) 2 -C 1-6 Alkyl, S(O) 2 -C 1-6 is haloalkyl, or R a and R b are 3- to 12-membered monocyclic or bicyclic rings which, together with the nitrogen to which they are attached, optionally further contain 1 to 3 additional ring heteroatoms selected from O, N, and S. Forming a heterocycle with the formula R 4 is C 2-6 alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-8 cycloalkyl, or C 0-6 Alkylene-C 6-10 aryl, each R d are independently H or D, and each R e are independently H, D, halo, OH, methyl, methoxy, or two geminal R e , together with the atoms to which they are attached, the oxo group or the spiro C 3-5 form cycloalkyl, m is 1-4, and n is 0-2.

[0008] Also provided is a compound of formula (Ia), [ka] where A is a 4- to 12-membered heterocycle containing a ring O or S atom, further containing 0 to 3 additional ring heteroatoms selected from O, N, and S; 1 is hydrogen, C 1-6 alkyl, halo, C 1-3 haloalkyl, O-C 1-3 haloalkyl, C 0-3 Alkylene-CN,C 0-3 Alkylene-NR N 2 ,C 0-6 Alkylene-OR N ,C 0-6 Alkylene-C(O)OR N ,C 0-6 Alkylene-C(O)N(R N ) 2 , or C 0-6 Alkylene-SO p R N and each R N is independently hydrogen or C 1-6 is alkyl, p is 0 to 2, and each R 2 are independently halo, each R 3 are independently hydrogen, halo, C 1-6 Alkyl, C 1-6 haloalkyl, C 0-6 Alkylene-OH,C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-O-C 1-6 Alkyl, C 0-6 Alkylene-NR a R b ,S-C 1-6 Alkyl, C 2-6 Alkenyl, C(O)-C 1-6 Haloalkyl or SO 2 -C 1-6 Alkyl or two geminal R 3 form an oxo group together with the atoms to which they are attached, and if ring A contains a ring N atom, then N is R a and ring A does not contain a ring N atom, at least one R 3 is C 0-6 Alkylene-NR a R b and R a and R b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OH,C 1-6 Alkylene-O-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, C(O)-C 1-6 Haloalkyl, S(O) 2 -C 1-6 Alkyl, S(O) 2 -C 1-6 is haloalkyl, or R a and R b are 5- to 12-membered monocyclic or bicyclic rings which, together with the nitrogen to which they are attached, optionally further contain 1 to 3 additional ring heteroatoms selected from O, N, and S. m is 1-3, and n is 0-2.

[0009] In some cases, ring A is [ka] where * indicates the point of attachment of ring A to the adjacent carbonyl moiety of formula I. In some cases, ring A is [ka] where * indicates the point of attachment of ring A to the adjacent carbonyl moiety of formula I. In some cases, ring A is [ka] It is.

[0010] Further provided are methods of modulating progranulin in a subject. In some embodiments, methods of treating progranulin-related disorders in a subject are provided.

[0011] Other aspects of the disclosure provide compounds disclosed herein for use in the preparation of medicaments for the modulation of progranulin, and compounds disclosed herein in methods of treating or preventing progranulin-related disorders in a subject. Including the use of the compounds disclosed in this book. [Form for carrying out the invention]

[0012] Compounds as progranulin modulators Provided herein are compounds that can modulate the production and / or secretion of progranulin. In some cases, the compound can increase the level of progranulin or granulin in a subject. Also provided are methods of modulating the translocon complex to increase lysosomal protein levels using the compounds disclosed herein.

[0013] The present disclosure provides compounds of formula (I), [ka] During the ceremony, Ring A is a 4- to 12-membered heterocycle containing a ring O or S atom and further containing 0 to 3 additional ring heteroatoms selected from O, N, and S; R 1 is hydrogen, C 1-6 alkyl, halo, C 1-3 haloalkyl, O-C 1-3 haloalkyl, C 0-3 Alkylene-CN,C 0-3 Alkylene-NR N 2 ,C 0-6 Alkylene-OR N ,C 0-6 Alkylene-C(O)OR N ,C 0-6 Alkylene-C(O)N(R N ) 2 , or C 0-6 Alkylene-SO p R N and each R N is independently hydrogen or C 1-6 is alkyl, p is 0 to 2, Each R 2 is independently a halo, Each R 3 are independently hydrogen, halo, C 1-6 Alkyl, C 1-6 haloalkyl, C 0-6 Alkylene-OH,C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-O-C 1-6 Alkyl, C 0-6 Alkylene-NR a R b ,S-C 1-6 Alkyl, C 2-6 Alkenyl, C(O)-C 1-6 haloalkyl, SO 2 -C 1-6 Alkyl, S 2+ (O) - (NR a ) - C 1-6 Alkyl, OR 4 , a 5- to 8-membered heteroaryl containing 1 to 4 ring N atoms, or containing 1 to 4 ring heteroatoms selected from O, N, and S, where at least one ring heteroatom is N , a 4- to 6-membered heterocycle, and the heteroaryl or heterocycle is optionally independently halo, C 1-6 Alkyl, OH, and C 1-6 substituted with one or two substituents selected from alkoxy, or two geminal R3 together with the atoms to which they are bonded form an oxo group, When ring A contains a ring N atom, N is R a and ring A does not contain a ring N atom, at least one R 3 is C 0-6 Alkylene-NR a R b and R a and R b are each independently hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 Alkylene-OH,C 1-6 Alkylene-O-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, C(O)-C 1-6 Haloalkyl, S(O) 2 -C 1-6 Alkyl, S(O) 2 -C 1-6 is haloalkyl, or R a and R b are 3- to 12-membered monocyclic or bicyclic rings which, together with the nitrogen to which they are attached, optionally further contain 1 to 3 additional ring heteroatoms selected from O, N, and S. forming the formula heterocycle, R 4 is C 2-6 alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-8 cycloalkyl, or C 0-6 Alkylene-C 6-10 is an aryl, Each R d are independently H or D, Each R e are independently H, D, halo, OH, methyl, or methoxy, or two geminal R e , together with the atoms to which they are attached, the oxo group or the spiro C 3-5 forming a cycloalkyl m is 1 to 4, n is 0 to 2.

[0014] Also provided is a compound of formula (Ia), [ka] During the ceremony, A is a 4- to 12-membered heterocycle containing a ring O or S atom and further containing 0 to 3 additional ring heteroatoms selected from O, N, and S; R 1 is hydrogen, C 1-6 alkyl, halo, C 1-3 Haloalkylene, O-C 1-3 Haloalkylene, C 0-3 Alkylene-CN,C 0-3 Alkylene-NR N 2 ,C 0-6 Alkylene-OR N ,C 0-6 Alkylene-C(O)OR N ,C 0-6 Alkylene-C(O)N(R N ) 2 , or C 0-6 Alkylene-SO p R N and each R N is independently hydrogen or C 1-6 is alkyl, p is 0 to 2, Each R 2 is independently a halo, Each R 3 are independently hydrogen, halo, C 1-6 Alkyl, C 1-6 haloalkyl, C 0-6 Alkylene-OH,C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-O-C 1-6 Alkyl, C 0-6 Alkylene-NR a R b ,S-C 1-6 Alkyl, C 2-6 Alkenyl, C(O)-C 1-6 Haloalkyl or SO 2 -C 1-6 is alkyl, or two geminal R 3 together with the atoms to which they are bonded form an oxo group, When ring A contains a ring N atom, N is R a and ring A does not contain a ring N atom, at least one R 3 is C 0-6 Alkylene-NR a R b and R a and R b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OH,C 1-6 Alkylene-O-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, C(O)-C 1-6 Haloalkyl, S(O) 2 -C 1-6 Alkyl, S(O) 2 -C 1-6 is haloalkyl, or R a and R b are 5- to 12-membered monocyclic or bicyclic rings which, together with the nitrogen to which they are attached, optionally further contain 1 to 3 additional ring heteroatoms selected from O, N, and S. forming the formula heterocycle, m is 1 to 3; n is 0 to 2.

[0015] In some cases, Ring A is a 4-6 membered heterocycle. In some cases, Ring A is a 6-8 membered heterocycle. In some cases, Ring A is a 4-membered heterocycle. In some cases, Ring A is a 5-membered heterocycle. In some cases, Ring A is a 6-membered heterocycle. In some cases, Ring A is a 7-membered heterocycle. In some cases, Ring A is an 8-membered heterocycle. In some cases, Ring A is a 9-membered heterocycle. In some cases, Ring A is a 10-membered heterocycle. In some cases, Ring A is an 11-membered heterocycle. In some cases, Ring A is a 12-membered heterocycle.

[0016] In some cases, ring A includes a ring O atom and 0-3 additional ring heteroatoms selected from O, N, and S. In some cases, Ring A includes a ring O atom and 0 additional ring heteroatoms. In some cases, Ring A includes a tetrahydropyranyl ring. In some cases, ring A includes a ring O atom and one additional ring heteroatom selected from O, N, and S. In some cases, ring A includes a ring O atom and a ring N atom. In some cases, ring A includes a ring O atom and two additional ring heteroatoms selected from O, N, and S. In some cases, ring A includes a ring O atom and three additional ring heteroatoms selected from O, N, and S.

[0017] In some cases, ring A includes a ring S atom and 0 to 3 additional ring heteroatoms. In some cases, ring A includes a ring S atom and zero additional ring heteroatoms selected from O, N, and S. In some cases, ring A includes a ring S atom and one additional ring heteroatom selected from O, N, and S. In some cases, ring A includes a ring S atom and two additional ring heteroatoms selected from O, N, and S. In some cases, ring A includes a ring S atom and three additional ring heteroatoms selected from O, N, and S.

[0018] In some cases, ring A contains a ring N atom, and N is R a has been replaced with When ring A contains a ring N atom, ring A contains C 0-6 Alkylene-NR a R b is R 3 can be replaced with If ring A does not contain a ring N atom, at least one R 3 is C 0-6 Alkylene-NR a R b It is.

[0019] In some cases, ring A is [ka] where * indicates the point of attachment of ring A to the adjacent carbonyl moiety of formula I. In some cases, ring A is [ka] where * indicates the point of attachment of ring A to the adjacent carbonyl moiety of formula I. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, ring A is [ka] It is. In some cases, NR in ring A a exists, then R a is H. All rings A described in this paragraph include m (i.e., 1 to 3) R 3 Can be substituted with a substituent.

[0020] In some cases, m is 1-3. In some cases m is 1 or 2. In some cases m is 1. In some cases m is 2. In some cases m is 3. In some cases m is 4.

[0021] In some cases, ring A is [ka] It is.

[0022] In some cases, each R 3 are independently hydrogen, halo, C 1-6 Alkyl, C 1-6 haloalkyl, C 0-6 Alkylene-OH,C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-O-C 1-6 Alkyl, C 0-6 Alkylene-NR a R b ,S-C 1-6 Alkyl, C 2-6 Alkenyl, C(O)-C 1-6 Haloalkyl or SO 2 -C 1-6 Alkyl or two geminal R 3 form an oxo group together with the atoms to which they are attached, and if ring A contains a ring N atom, then N is R a and ring A does not contain a ring N atom, at least one R 3 is C 0-6 Alkylene-NR a R b It is.

[0023] In some cases, two geminal R 3 together with the atoms to which they are attached form an oxo group. In some cases, R 3 is hydrogen, halo, C 1-6 Alkyl, C 1-6 haloalkyl, C 0-6 Alkylene-OH,C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 0-6 Alkylene-NR a R b ,S-C 1-6 Alkyl, C 2-6 Alkene, C(O)-C 1-6 haloalkyl, or SO 2 -C 1-6 It is an alkyl. In some cases, R 3 is hydrogen, halo, C 1-6 alkoxy or C 0-6 Alkylene-NR a R b It is. In some cases, R 3 halo, C 1-6 alkoxy or C 0-6 Alkylene-NR a R b It is. In some cases, R 3 is H. In some cases, R 3 is a halo. In some cases, R 3 is F. In some cases, R 3 is C 1-6 It is an alkyl. In some cases, R 3 is C 1-6 It is haloalkyl. In some cases, R 3 is C 0-6 It is alkylene-OH. In some cases, R 3 is C 1-6 It is alkoxy. In some cases, R 3 is methoxy or ethoxy. In some cases, R 3 is methoxy. In some cases, R 3 is ethoxy. In some cases, R 3 is C 1-6 It is haloalkoxy. In some cases, R 3 is C 1-6 Alkoxy-C 1-6 It is an alkyl. In some cases, R 3 is C 0-6 Alkylene-NR a R b It is. In some cases, R 3 is NH 2 Or NHMe. In some cases, R 3 is NH 2 It is. In some cases, R 3 is NHMe. In some cases, R 3 is S-C 1-6 It is an alkyl. In some cases, R 3 is C 2-6 It is an alkyl. In some cases, C(O)-C 1-6 haloalkyl. In some cases, R 3 is SO 2 -C 1-6 It is an alkyl.

[0024] In some cases, R 3 is halo or C 0-6 Alkylene-NR a R b It is. In some cases, R 3 is F or NH 2 It is. In some cases, R 3 is F or NHMe. In some cases, R 3 is C 1-6 Alkoxy or C 0-6 Alkylene-NR a R b It is. In some cases, R 3 is methoxy or NH 2 It is. In some cases, R 3 is methoxy or NHMe. In some cases, R 3 is ethoxy or NH 2 It is. In some cases, R 3 is ethoxy or NHMe. In some cases, R 3 is S 2+ (O) - (NR a ) - C 1-6 It is an alkyl. In some cases, R 3 teeth, [ka] It is. In some cases, R 3 is OR 4 It is. In some cases, R 3 teeth, [ka] It is. In some cases, R 3 teeth, [ka] It is.

[0025] In some cases, R a and R b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OH,C 1-6 Alkylene-O-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, C(O)-C 1-6 Haloalkyl, S(O) 2 -C 1-6 Alkyl, S(O) 2 -C 1-6 haloalkyl, or R a and R b are 5- to 12-membered monocyclic or bicyclic rings which, together with the nitrogen to which they are attached, optionally further contain 1 to 3 additional ring heteroatoms selected from O, N, and S. Forms the formula heterocycle. In some cases, R a and R b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OH,C 1-6 Alkoxy-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, C(O)-C 1-6 Haloalkyl, S(O) 2 -C 1-6 Alkyl, S(O) 2 -C 1-6 It is haloalkyl. In some cases, R a and R b are 5- to 12-membered monocyclic or bicyclic rings which, together with the nitrogen to which they are attached, optionally further contain 1 to 3 additional ring heteroatoms selected from O, N, and S. Forms the formula heterocycle. In some cases, R a and R b are each independently C 1-6 It is haloalkyl.

[0026] In some cases at least one R d is H. In some cases, each R d is H. In some cases at least one R d is D. In some cases, each R d is D. In some cases at least one R e is H. In some cases, each R e is H. In some cases at least one R e is D. In some cases, each R e is D. In some cases at least one R e is OH. In some cases, each R e is OH. In some cases at least one R e is a halo. In some cases at least one R e is F. In some cases, each R e is a halo. In some cases, each R e is F. In some cases, two geminal R e together with the atoms to which they are attached form an oxo group.

[0027] In some cases, R 4 is C 2-6 alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-8 cycloalkyl, or C 0-6 Alkylene-C 6-10 It is an aryl. In some cases, R 4 is C 2-6 Alkynyl, C 0-6 Alkylene-C 3-8 cycloalkyl, or C 0-6 Alkylene-C 6-10 It is an aryl. In some cases, R 4 is C 2-6 It is alkenyl. In some cases, R 4 is C 2-6 It is alkynyl. In some cases, R 4 is propargyl. In some cases, R 4 is C 0-6 Alkylene-C 3-8 It is cycloalkyl. In some cases, R 4 is C 0-6 It is alkylene-cyclopropyl. In some cases, R 4 is C 0-6 It is alkylene-cyclobutyl. In some cases, R 4 is C 0-6 Alkylene-C 6-10 It is an aryl. In some cases, R 4 is C 0-6 Alkylene-C 6 It is an aryl. In some cases, R 4 is phenyl. In some cases, R 4 is benzyl.

[0028] In some cases n is 1 or 2. In some cases n is 0. In some cases n is 1. In some cases n is 2.

[0029] In some cases, R 2 is F or Cl. In some cases, R 2 is F.

[0030] In some cases, R 1 is H. In some cases, R 1 is a halo. In some cases, R 1 is F.

[0031] Particular compounds contemplated include those listed in Table A, or a pharmaceutically acceptable salt thereof.

table 1

[0032] In some cases, the compounds include compounds 5605, 5602, 5599, 5575, 5564, 5550, 5472, 5545, 5543, 5461, 5267, 5448, 5475, 5087, 5077, 5051, 5045, 5042, 5021, and 5012, and their pharmaceutically acceptable salts. In some cases, the compound is selected from compounds 5599, 5564, 5472, 5077, and 5087, and pharmaceutically acceptable salts thereof. In some cases, the compound is Compound 5599 or a pharmaceutically acceptable salt thereof. In some cases, the compound is Compound 5564 or a pharmaceutically acceptable salt thereof. In some cases, the compound is Compound 5472 or a pharmaceutically acceptable salt thereof. In some cases, the compound is Compound 5077 or a pharmaceutically acceptable salt thereof. In some cases, the compound is Compound 5087 or a pharmaceutically acceptable salt thereof.

[0033] As used herein, the term "alkyl" refers to straight-chain and branched saturated hydrocarbon groups containing from 1 to 6 carbon atoms. C n The term means that the alkyl group has "n" carbon atoms. For example, C 6 Alkyl refers to an alkyl group having 6 carbon atoms. C 1 -C 6Alkyl includes all ranges (e.g., 1 to 6 carbon atoms) as well as all subgroups (e.g., 1 to 6, 2 to 6, 1 to 5, 3 to 6, 1, 2, 3, 4, 5 , and 6 carbon atoms). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), t-butyl (1,1-dimethylethyl), and 3- Examples include methylpentyl. Unless otherwise indicated, alkyl groups can be unsubstituted or substituted alkyl groups.

[0034] The term "alkylene" as used herein refers to a substituted alkyl group. For example, an alkylene group is -CH 2 CH 2 -or-CH 2 -Can be. C n The term means that the alkylene group has "n" carbon atoms. For example, C 1-6 Alkylene refers to an alkylene group having a number of carbon atoms including the full range and all subgroups as described above for the "alkyl" group. C 0 Alkylene indicates a direct bond. Unless otherwise indicated, alkylene groups can be unsubstituted or substituted alkylene groups. Particular substitutions on alkylene groups can be specified, eg, alkylene-halo, alkylene-CN, and the like.

[0035] The term "alkene" or "alkenyl" as used herein refers to an unsaturated aliphatic group similar in length and possible substitution to the alkyl groups described above, but containing at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (eg, ethenyl, propenyl, butenyl, pentenyl, hexenyl) and branched alkenyl groups. For example, a straight chain or branched alkenyl group can have six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 , C in the branched chain 3 -C 6 ). "C 2 -C 6 '' refers to all ranges (e.g., 2 to 6 carbon atoms), as well as all subgroups (e.g., 2 to 6, 2 to 5, 2 to 4, 3 to 6, 2, 3, 4, 5 , and 6 carbon atoms). Unless otherwise indicated, alkenyl groups can be unsubstituted or substituted alkenyl groups.

[0036] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen substituents. Haloalkyl is alternatively referred to as "alkylene-halo." For example, C 1 -C 6 Haloalkyl is C substituted with one or more halogen atoms, e.g. 1, 2, 3, 4, 5, or 6 halogen atoms. 1 -C 6 Refers to an alkyl group. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl groups. Similarly, haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms, such as 1, 2, 3, 4, 5, or 6 halogen atoms.

[0037] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0038] As used herein, the term "oxo" refers to a =O substituent; for example, carbon can be substituted with oxo to form a carbonyl (C=O) group.

[0039] As used herein, the term "carbocycle" or "carbocyclyl" refers to 3 to 11 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or 11 carbon atoms). refers to a cyclic hydrocarbon group containing carbon atoms). The term "n-membered carbocycle" means a carbocyclic group having "n" carbon atoms. For example, a 5-membered carbocycle refers to a carbocyclic group having 5 carbon atoms in the ring. 6-8 membered carbocycles include all ranges (e.g., 6-8 carbon atoms), as well as all subgroups (e.g., 6-7, 6-8, 7-8, 6, 7, and 8 carbon atoms). refers to a carbocyclic group having a number of carbon atoms including carbon atoms). Non-limiting examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise indicated, a carbocyclic group can be an unsubstituted carbocyclic group or a substituted carbocyclic group. The carbocyclic groups described herein can be isolated or fused to another carbocycle. In particular, the carbocycles described herein can have fused, bridged, or spiro structures.

[0040] As used herein, the term "heterocycle" refers to a carbocyclic ring, except that the ring contains 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. is defined in the same way. In particular, the term "heterocycle" refers to a ring containing a total of 4 to 12 atoms (e.g., 4 to 6, or 6 to 8), in which 1, 2, 3, or Four are independently heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and the remaining atoms in the ring are carbon atoms. The heterocycles disclosed herein can be in monocyclic, fused (e.g., bicyclic), bridged, or spiro forms, but still include the rings and heteroatoms as discussed herein. Shows 4 to 12 members. Non-limiting examples of heterocyclic groups include azetidine, piperidine, piperazine, pyrazolidine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, quinuclidine, and the like. A heterocyclic group can be a saturated or partially unsaturated ring system, optionally for example halo, C 1-6 Alkyl, C 1-6 Haloalkyl, OH, C 1-6 Alkylene-OH,C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, -NR a R b (For example, -NH 2 or -NHMe), C 1-6 Alkylene-NR a R b (For example, C 1-6 Alkylene-NH 2 or C 1-6 alkylene-NHMe), S-C 1-6 Alkyl, C 2-6 Alkene, C(O)-C 1-6 haloalkyl, or SO 2 -C 1-6 Substituted with 1 to 3 substituents such as alkyl. Other contemplated substituents on the heterocycle are discussed elsewhere in this disclosure.

[0041] As used herein, the term "substitution" when used to modify a chemical functional group refers to replacing at least one hydrogen radical on the functional group with a substituent group. Unless otherwise indicated for a particular moiety, substituents include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, oxy, alkoxy, heteroalkoxy, ester, thioester, May include, but are not limited to, carboxy, cyano, nitro, amino, amido, acetamido, and halo (eg, fluoro, chloro, bromo, or iodo). When a chemical functional group contains multiple substituents, the substituents can be attached to the same carbon atom or to two or more different carbon atoms.

[0042] Compounds of the present disclosure can exist in particular geometric or stereoisomeric forms having one or more asymmetric carbon atoms. This disclosure describes such forms as falling within the scope of the disclosed compounds, including cis and trans isomers, R isomers and S enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof. plan. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included herein.

[0043] As used herein, the term "pharmaceutically acceptable" refers to a reference substance, such as a compound of the present disclosure, or a formulation containing the compound or certain excipients, and the administration to a patient or subject. means safe and suitable for use. The term "pharmaceutically acceptable excipient" refers to a vehicle that does not interfere with the effectiveness of the biological activity of the active ingredient and is not toxic to the host to which it is administered.

[0044] Compounds disclosed herein can be pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" means salts that, within the scope of sound medical judgment, can be used in humans and lower animals without undue toxicity, irritation, allergic reactions, etc. Salts suitable for use in contact with tissues and corresponding to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or acetic, trifluoroacetic, oxalic, maleic, tartaric acids. , citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate. (camphorate), camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, Gluconate, glutamate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, apple acid salt, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate ), persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluene Includes sulfonates, undecanoates, valerates, etc. Salts of compounds containing carboxylic acids or other acidic functional groups may be prepared by reaction with a suitable base. Such salts include alkali metal, alkaline earth metal, aluminum salts, ammonium, N + (C 1-4 alkyl) 4 salts and salts of organic bases, such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, trimethylamine, Bases such as -(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabiethylamine, N,N'-bisdehydroabiethylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and lysine and arginine. including, but not limited to, amino acids. This invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water-soluble or oil-soluble or dispersible products can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include amine cations, such as halides, hydroxides, carboxylates, formed using non-toxic ammonium, quaternary ammonium, and counterions, where appropriate. , sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0045] Pharmaceutical formulation, administration, and route of administration A pharmaceutical formulation (alternatively referred to herein as a composition) comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. , further provided.

[0046] The compounds described herein can be administered to a subject in a therapeutically effective amount alone or as part of a pharmaceutically acceptable composition or formulation. Additionally, the compound may be administered once, in multiple doses, or delivered substantially uniformly over a period of time. It is also noted that the dosage of the compound may vary over time.

[0047] The particular dosing regimen for a particular subject will depend in part on the compound, the amount of compound administered, the route of administration, and the cause and extent of any side effects. The amount of compound administered to a subject (eg, a mammal such as a human) according to the present disclosure must be sufficient to produce the desired response over a reasonable time frame. The amount administered typically depends on the route, timing, and frequency of administration. Accordingly, the clinician titrates the dosage and modifies the route of administration to obtain the optimal therapeutic effect. Conventional range searching techniques are known to those skilled in the art.

[0048] Merely by way of example, the method includes administering, for example, from about 0.1 mg / kg up to about 100 mg / kg or more of the compound, depending on the factors described above. In other embodiments, the dosage ranges from 1 mg / kg up to about 100 mg / kg, or 5 mg / kg up to about 100 mg / kg, or 10 mg / kg up to about 100 mg / kg. In some situations, long-term treatment may be required, with or without multiple administrations of lower doses of the compound. If desired, the dose of the compound is administered as two, three, four, five, six or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage form. The duration of treatment depends on the specific condition and type of pain and can last from one day to several months.

[0049] Suitable methods of administering physiologically acceptable compositions, such as pharmaceutical compositions, containing the compounds disclosed herein are well known in the art. Although more than one route can be used to administer a compound, a particular route may provide a more rapid and effective response than another route. Depending on the situation, pharmaceutical compositions containing the compounds are applied or instilled into body cavities, absorbed through the skin or mucous membranes, ingested, inhaled, and / or introduced into the circulating blood. For example, in certain circumstances, pharmaceutical compositions containing drugs may be administered orally, intravenously, intraperitoneally, intracerebral (intraparenchymal), intracerebroventricularly, intramuscularly, intraocularly, intraarterially, intraportally, intralesionally, By injection by intravenous, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, urethral, ​​intravaginal, or rectal means, by sustained release systems, or by implantation. Preferably delivered by a device. If desired, the compound is administered locally by intrathecal, intracerebral (intraparenchymal), intraventricular, or intraarterial or intravenous administration to the area of ​​interest. Alternatively, the compositions are administered topically by implantation of a membrane, sponge, or other suitable material into which the desired compound is absorbed or encapsulated. If an implantable device is used, the device is, in one aspect, implanted in any suitable tissue or organ, and delivery of the desired compound is via, for example, diffusion, slow-release bolus, or continuous administration.

[0050] To facilitate administration, the compounds, in various embodiments, are formulated into physiologically acceptable compositions that include a carrier (eg, a vehicle, adjuvant, or diluent). The particular carrier employed is limited only by physicochemical considerations such as solubility and lack of reactivity with the compound, and the route of administration. Physiologically acceptable carriers are well known in the art. Exemplary pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (see, e.g., U.S. Pat. No. 5,466,468). Please refer). Injectable formulations are described, for example, in Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia.Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed. , pages 622-630 (1986)). A pharmaceutical composition comprising a compound, in one aspect, is placed within a container along with packaging material that provides instructions regarding the use of such pharmaceutical composition. Generally, such instructions include reagent concentrations and, in certain embodiments, excipient components or diluents that may be necessary to reconstitute the pharmaceutical composition (e.g., water, saline, or PBS). ) Contains specific expressions that explain the relative amounts of

[0051] Compositions suitable for parenteral injection include sterile physiologically acceptable aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and for reconstitution into sterile injectable solutions or dispersions. May include sterile powder. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol), suitable mixtures thereof, vegetable oils (such as olive oil), and oleic acid. Injectable organic esters such as ethyl acid. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the necessary particle size in the case of dispersions, and by the use of surfactants.

[0052] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Microbial contamination can be prevented by adding various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents that delay absorption, such as aluminum monostearate and gelatin.

[0053] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is present in at least one customary inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler or bulking agent, such as starch, lactose, etc. , sucrose, mannitol, and silicic acid, (b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, such as glycerol, (d) disintegrants, such as , agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (a) dissolution retardants, such as paraffin, (f) absorption enhancers, such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin and bentonite; (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols; mixed with sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage form may also include a buffering agent. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0054] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. Solid dosage forms may also contain opacifying agents. Additionally, solid dosage forms can be embedded compositions such that they release the active compound(s) in a delayed manner into a certain part of the intestinal tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compound may also be in microencapsulated form, optionally containing one or more excipients.

[0055] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetic acid. Ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol , polyethylene glycol and fatty acid esters of sorbitan, or mixtures of these substances.

[0056] Besides such inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions can contain, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, or It may include mixtures of these substances and the like.

[0057] Compositions for rectal administration are preferably suppositories, which contain a compound of the present disclosure that is solid at normal room temperatures but becomes liquid at body temperature and therefore dissolves in the rectal or vaginal cavity. They may be prepared by mixing the active compound with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycols, or suppository waxes.

[0058] Compositions used in the methods of the invention may be formulated in micelles or liposomes. Such formulations include sterically stabilized micelles or liposomes and sterically stabilized mixed micelles or liposomes. Such formulations may facilitate intracellular delivery, as the lipid bilayers of liposomes and micelles are known to condense with the plasma membrane of cells and deliver entrapped contents to intracellular compartments. can.

[0059] Once formulated, solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are readily administered in a variety of dosage forms such as injection solutions, drug release capsules, and the like. For example, for parenteral administration in aqueous solutions, it is necessary to suitably buffer the solution and to make the liquid diluent initially isotonic with sufficient saline or glucose, if necessary. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration.

[0060] The frequency of administration depends on the pharmacokinetic parameters of the drug and the route of administration. The optimal pharmaceutical formulation will be determined by one of skill in the art depending on the route of administration and desired dosage. See, eg, Remington's Pharmaceutical Sciences, 18th Ed. (1990) Mack Publishing Co., Easton, PA, pages 1435-1712, which is incorporated herein by reference. Such formulations can affect the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered drug. Depending on the route of administration, the appropriate dose is calculated according to body weight, body surface area or organ size. Further refinement of the calculations necessary to determine appropriate therapeutic doses is warranted, particularly in light of the dosage information and assays disclosed herein, as well as pharmacokinetic data observed in animal or human clinical trials. , is routinely performed by those skilled in the art without undue experimentation.

[0061] The precise dose to be employed will depend on the host, whether veterinary or human medicine, the nature and severity of the condition, such as the disease or disorder being treated, the mode of administration, and the particular active substance used. Depends on that factor. The compounds may be administered by any conventional route, particularly enterally and, in one aspect, orally in the form of a tablet or capsule. The compound administered may be in free form or in the form of a pharmaceutically acceptable salt, as appropriate for pharmaceutical use, particularly for use in the prophylactic or therapeutic treatment of the disease of interest. These measures slow down the rate of progression of the disease state and help the body reverse the direction of the process in a natural way.

[0062] It will be appreciated that the pharmaceutical compositions and treatment methods of the present invention are useful in the fields of human and veterinary medicine. Accordingly, the subject being treated is, in one aspect, a mammal. In another aspect, the mammal is a human.

[0063] In jurisdictions that prohibit patenting methods performed on the human body, "administering" a composition to a human subject means administering the composition to a human subject by any means (e.g., oral, inhalation, topical application, injection, shall be limited to prescribing prepared substances that will be self-administered (e.g., by insertion). The broadest reasonable interpretation consistent with the laws or regulations defining patentable subject matter is intended. In jurisdictions that do not prohibit patenting methods performed on a human body, "administration" of a composition includes both methods performed on a human body and the aforementioned activities.

[0064] how to use The compounds disclosed herein (eg, the compounds of Formula I and the compounds shown in Table A) can increase the amount of progranulin or granulin in a subject. In some cases, the compound increases the amount of progranulin in the subject. In some cases, the compound increases the amount of granulin in the subject. In some cases, compounds affect cells to increase secretion of progranulin. Accordingly, the compounds disclosed herein (e.g., compounds of Formula I and the compounds shown in Table A) are useful for treating disorders associated with aberrant (e.g., reduced) progranulin secretion or activity. Can be useful.

[0065] In particular, a therapeutically effective amount of a compound disclosed herein is used to modulate progranulin (e.g., increase secretion of progranulin) for use as a therapeutic agent in a subject. A method is contemplated. As used herein, the term "therapeutically effective amount" ameliorates, attenuates, or eliminates one or more symptoms of a particular disease or condition (e.g., progranulin or granulin-related disorder). or, alternatively, an amount of a compound or combination of therapeutically active compounds (eg, a progranulin modulator or combination of modulators) that prevents or delays the onset of one or more symptoms of a particular disease or condition.

[0066] The therapeutically effective amount will depend on the intended application or the subject and disease state being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the method of administration, and the weight and age of the patient. may vary, which can be readily determined by one of ordinary skill in the art. The term also applies to doses that induce a specific response in target cells, such as increasing the secretion of progranulin. The specific dosage will depend, for example, on the particular compound selected, the species of interest and their age / pre-existing health conditions or risks to health conditions, the dosing regimen to be followed, the severity of the disease, and whether it is combined with other drugs. It will vary depending on whether it is administered, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0067] As used herein, the terms "patient" and "subject" are used interchangeably and refer to animals such as dogs, cats, cows, horses, and sheep (e.g., non-human animals) and humans. do. A particular patient or subject is a mammal (eg, a human). The terms patient and subject include men and women.

[0068] Contemplated disorders associated with aberrant progranulin activity include Alzheimer's disease (AD), Parkinson's disease (PD) and PD-related disorders, amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration ( FTLD), Lewy body dementia (LBD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), and other neurodegenerations. Includes diseases. Other disorders contemplated include lysosomal storage diseases (e.g., Paget's disease, Gaucher disease, Nieman's Pick disease, Tay-Sachs disease, Fabry disease, Pompe disease, and Naso-Hakula disease). Includes disorders of lysosomal dysfunction or dysfunction such as Hakula disease). Other diseases contemplated include diseases associated with inclusion bodies and / or dysfunction of C9orf72, TDP-43, FUS, UBQLN2, VCP, CHMP28, and / or MAPT. Other diseases include acute neurological disorders such as stroke, cerebral hemorrhage, traumatic brain injury, and other head trauma, and diseases of the brain such as glioblastoma and neuroblastoma.

[0069] In some cases, progranulin-related disorders include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and frontotemporal dementia. Disease-granulin subtype (FTD-GRN), Lewy body dementia (LBD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), lysosomal storage diseases, renal disorders, diseases associated with inclusion bodies and / or dysfunction of C9orf72, TDP-43, FUS, UBQLN2, VCP, CHMP28, and / or MAPT, acute neurological disorders, glioblastoma, Or neuroblastoma. In some cases, Parkinson's disease is Parkinson's disease with GBA mutations. In some cases, the lysosomal storage disease is Paget's disease, Gaucher disease, Niemann-Pick disease, Tay-Sachs disease, Fabry disease, Pompe disease, or Naso-Hakra disease. In some cases, the acute neurological disorder is a stroke, cerebral hemorrhage, traumatic brain injury, or head trauma. In some cases, the progranulin-related disorder is frontotemporal dementia (FTD). In some cases, the progranulin-related disorder is frontotemporal dementia-granulin subtype (FTD-GRN).

[0070] Compounds disclosed herein (eg, compounds of Formula I and compounds shown in Table A) can increase the levels of lysosomal proteins by modulating the translocon complex. Translocons are complexes of proteins involved in the translocation of proteins across the cell membrane, such as nascent polypeptides, from the cytoplasm into the internal (cisternal or luminal) space of the endoplasmic reticulum (ER), along with targeting signal sequences. It is a transporting complex. This translocation process requires the protein to pass through a hydrophobic lipid bilayer. The same complex is also used to incorporate nascent proteins into the membrane itself (membrane proteins). The translocon complex is a heterotrimeric protein complex called Sec61. It contains the subunits Sec61α, Sec61β, and Sec61γ. Sec61α is a large pore subunit. During protein translocation, the channel rearranges itself to move an alpha-helical "plug" out of the pathway, and the polypeptide chain is moved from the cytoplasmic funnel through the pore ring, the extracellular funnel, into the extracellular space. Proteins destined for secretion are elongated through the Sec61 channel and finally N-glycosylated on asparagine residues by the OST before their signal peptide is cleaved by a signal peptidase.

[0071] The level of one or more lysosomal proteins can be increased by contacting the translocon complex with an agent that modulates the translocon complex, thereby increasing the lysosomal protein level. Levels of lysosomal proteins can be increased intracellularly and / or secretion of lysosomal proteins can be increased such that extracellular levels are increased.

[0072] Increased lysosomal protein levels It has been discovered that by modulating the activity of the translocon complex, levels of lysosomal proteins can be increased. Without being bound to a particular theory, it is hypothesized that the amount of lysosomal proteins is increased by one of four mechanisms, or any combination of these four mechanisms. Increased trafficking of lysosomal proteins may result from increased translation of mRNA subpopulations, enhanced translocation to the endoplasmic reticulum, increased glycosylation of lysosomal proteins, which increases lysosomal protein stability, and / or the transmembrane protein mannose-6-phosphorus. It may be due to enhanced transport of lysosomal proteins through acid receptors (M6PR) and / or sortilin.

[0073] The compounds disclosed herein modulate the translocon complex and thereby increase the amount of lysosomal proteins by administering the compounds to a subject suffering from a disorder associated with low levels of lysosomal proteins. , can be used in methods for treating disorders associated with low levels of lysosomal proteins, and can treat disorders.

[0074] Lysosomal protein levels are at least 5%, at least 10%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 90%, at least 100%, at least 125% compared to control , can be increased by at least 150%, or at least 200%.

[0075] The amount of lysosomal proteins can be assessed using typical biological assays, including those described in the Examples section below. The level of lysosomal protein measured can be intracellular, extracellular (ie, secreted protein), or a combination of each. In some cases, the level of lysosomal proteins secreted from the cell has been increased (eg, extracellular protein levels have been increased). In some cases, intracellular lysosomal protein levels are increased.

[0076] Provided herein are methods of increasing the levels of lysosomal proteins in a subject by administering a compound disclosed herein. Lysosomal proteins include progranulin, prosaposin, β-glucocerebrosidase, galactosidase alpha, cathepsin B, cathepsin Z, neuraminidase 1, tripeptidyl peptidase, alpha-L-fucosidase 2, mannosidase alpha class 2B member 2, mannosidase beta, serine It can be carboxypeptidase 1, acid ceramidase, GM2 ganglioside activator, cathepsin D, cathepsin S, cathepsin K, cathepsin L, or hexosaminidase. Increasing the levels of lysosomal proteins can impact disorders associated with abnormal levels of lysosomal proteins. For example, the disease may be a lysosomal storage disorder, a neurodegenerative disease, an inflammatory disease, or a stroke, Down syndrome, congenital heart disease, diabetes, unclassifiable immunodeficiency (CVID), tubulointerstitial kidney disease (TKD). , polycystic liver disease, myocarditis, dermatitis hyperhomocysteinemia, endotoxic shock, lung injury, bone defects (eg, inflammatory alveolar bone defects), or osteolysis.

[0077] In various cases, the subject suffers from a lysosomal storage disorder. Lysosomal storage disorders include mucopolysaccharidosis, sphingolipidosis, glycogen storage disease type II, glycoprotein storage disease, Hurler disease, Scheie disease, Hunter disease, Sanfilippo disease A, Sanfilippo disease B, Sanfilippo disease C, and Sanfilippo disease. D, Morquio disease A, Morquio disease B, Maroteau-Lamy disease, Sly disease, mucopolysaccharidosis type IX, mucopolysaccharidosis plus syndrome, Fabry disease, Gaucher disease, Tay-Sachs disease, sialidosis, Niemann-Pick type A, Niemann ·Pick type B, galactosialidosis, Niemann-Pick type C, I cell disease, mucolipidosis type III, GM1 gangliosidosis, β-galactosidase deficiency, α-mannosidosis, GM2 gangliosidosis, β-mannosidosis dosis, Krabbe, fucosidosis, metachromatic leukodystrophy, aspartylglucosaminuria, multiple sulfatase deficiency, Schindler, Farber lipogranulomatosis, Pompe disease, Wolman disease, Danon disease, free sialic acid storage disease, ceroid lipofuscin syndrome, β-glucuronidase hypofunction, Sandhoff disease, or cholesterol ester storage disease.

[0078] In various cases, this disorder is a neurodegenerative disease. Neurodegenerative diseases include Parkinson's disease (e.g. Parkinson's disease with GBA mutations), frontotemporal dementia, Alzheimer's disease, Huntington's disease, traumatic brain injury, neuronal ceroid lipofuscinosis (NCL), multiple sclerosis , amyotrophic lateral sclerosis (ALS), argyrophilic granular dementia, Alexander disease, Alpers disease, cerebral palsy, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, boxer dementia (dementia pugilistica) , diffuse neurofibrillary tangle disease with calcification, HIV-associated dementia, dementia with Lewy bodies, Kennedy disease, neuroborreliosis, primary lateral sclerosis, Refsum disease, Gerstmann-Steussler-Scheinker disease , Hallerforden-Spatz disease, hereditary diffuse leukoencepholopathy with spheroids (HDLS), inclusion body myositis, multiple system atrophy, myotonic dystrophy, Nasu-Hakola disease, Schilder disease, hedgehog dizziness syndrome (WHS), Duchenne-Alain muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, HIV-associated neurocognitive disorder (HAND), tauopathy, chronic traumatic encephalopathy, or cerebellar downward nystagmus.

[0079] In various cases, the disorder is an inflammatory disease. The inflammatory disease can be Sjögren's disease, inflammatory arthritis, osteoarthritis, inflammatory bowel disease, or immune thrombocytopenia.

[0080] As used herein, the term "therapy" or "treating" refers to a method of reducing, delaying, or ameliorating a disease or disorder, either before or after it occurs. Treatment may be directed at one or more effects or symptoms of the disease and / or underlying pathology. Treatment is aimed at obtaining beneficial or desired results, including, but not limited to, therapeutic and / or prophylactic benefits. Therapeutic benefit means eradication or amelioration of the underlying disorder being treated. Also, therapeutic benefit is achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that improvement is observed in the patient, but the patient nevertheless They may still suffer from an underlying disorder. For prophylactic benefit, pharmaceutical compounds and / or compositions are administered to patients who are at risk of developing a particular disease or who report one or more of the physiological symptoms of the disease. It can be administered even if the disease has not been diagnosed. Treatment can be any reduction in the disease or symptoms of the disease, and can be, but is not limited to, their complete elimination. The degree of such reduction or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, as measured by any standard technique, as compared to an equivalent untreated control. 90%, 95%, or 100%.

[0081] As used herein, the term "therapeutic effect" refers to the therapeutic and / or prophylactic benefits described herein. A prophylactic effect may include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, delaying, halting, or reversing the progression of a disease or condition, or any of the above. including combinations of

[0082] Synthesis of compounds disclosed herein The compounds can be prepared using standard syntheses, either known to those skilled in the art or in light of the teachings herein, using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates. By employing the methods and procedures, they can be synthesized using typical synthetic chemistry techniques. In general, the synthesis of the disclosed compounds can be accomplished according to similar syntheses as detailed in Schemes A and B and the Examples below. [ka]

[0083] Compounds with structure e can be synthesized using the procedure shown in Scheme A. For example, reaction of an optionally substituted benzoic acid derivative having structure a with an optionally substituted 2-phenylethan-1-amine b results in the reaction of an optionally substituted benzoic acid derivative having structure a with an optionally substituted benzoic acid derivative having structure c. Generates N-phenylbenzamide compound. Cyclization under appropriate conditions yields an optionally substituted 1-phenyl-3,4-dihydroisoquinoline compound having structure d. Subsequent reduction followed by resolution or optional isolation of single stereoisomers by chromatographic means yields substituted tetrahydroquinoline compounds having structure e.

[0084] The coupling of compounds a and b can be catalyzed by appropriate reagents selected based on the precise nature of compounds a and b. For example, if compound a is an acid chloride compound (ie, Z is Cl), the coupling of compounds a and b can be catalyzed by, for example, triethylamine. Compounds a and b can be purchased commercially or prepared by various methods from commercially available starting materials.

[0085] Cyclization of compound c can be effected through the use of various reactions known in the art. For example, cyclization can include acid-catalyzed aromatic electrophilic substitution reactions, such as cyclization under Bischler-Napieralski reaction conditions. For example, c can be cyclized by treatment with triflic anhydride in the presence of eg chloropyridine in a solvent such as dichloromethane. Alternatively, compound c can be cyclized by treatment with polyphosphoric acid (PPA).

[0086] Compound d can be reduced to form compound e with or without asymmetric induction of the stereocenter. For example, compound d can be treated with a reducing agent such as sodium borohydride in a solvent such as methanol. Reduction of compound d can be followed by formation of the desired stereoisomer, for example crystallization in the presence of D-tartaric acid. Alternatively, compound d can be reduced via asymmetric hydrogenation to directly produce substituted tetrahydroquinoline compound e as the desired stereoisomer. For example, compound d is [{Ir(H)[(S,S)-(f)-binaphane]} 2 (μ-I) 3 ] + I - In the presence of an iridium catalyst such as H 2 It can be reduced using gas. [ka]

[0087] Compounds described herein, eg, compounds of formula I, can be synthesized from compounds of structure e using the procedure shown in Scheme B. For example, reaction of a compound having structure e with an alcohol or amine compound having structure f under coupling conditions i produces a substituted tetrahydroquinolinyl compound having structure g. Coupling can be facilitated by suitable reagents such as carbodiimide reagents. Subsequent optional derivatization provides compounds disclosed herein, eg, compounds of formula (I).

[0088] Suitable coupling conditions i for the reaction between compounds e and f are known to those skilled in the art. For example, the reaction may be performed under carbodiimide coupling conditions, e.g., EDC / HOBt, or other peptide coupling conditions, e.g., (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4, 5-b] Pyridinium 3-oxide hexafluorophosphate (HATU) and a base such as N,N-diisopropylethylamine (DIPEA) or trimethylamine (TEA), i.e. HATU / DIPEA or HATU / TEA, in an organic solvent, e.g. It can be carried out using dichloromethane (DCM) or dimethylformamide (DMF).

Example

[0089] General method LCMS: Instrument: Agilent 1260 Bin. Pump: G1312B, degasser, autosampler, ColCom, DAD: Agilent G1315D, 220~320nm, MSD: Agilent LC / MSD G6130B ESI, pos / neg100~1000, ELSD Alltech 3300 gas flow rate 1.5 ml / min, gas temperature: 40 °C, eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water).

[0090] Method A: Column: Waters XSelect(TM) C18, 30 x 2.1 mm, 3.5 μ, Temperature: 35°C, Flow rate: 1 mL / min, Gradient: t 0 =5%A,t 1.6分 =98%A,t 3分 =98%A, post time: 1.3 minutes.

[0091] Method C: Column: Waters XSelect(TM) C18, 50 x 2.1 mm, 3.5 μ, Temperature: 35°C, Flow rate: 0.8 mL / min, Gradient: t 0 =5%A,t 3.5分 =98%A,t 6分 =98%A, post time: 2 minutes.

[0092] Method AK: Column: Waters XSelect(TM) CSH C18, 50 x 2.1 mm, 3.5 μ, Temperature: 40°C, Flow rate: 0.8 mL / min, Gradient: t 0 =5%A,t 4.5分 =98%A,t 6分 =98%A, post time: 2 minutes.

[0093] Method BV: Column: Waters XSelect(TM) C18, 30 x 2.1 mm, 3.5 μ, Temperature: 25°C, Flow rate: 1 mL / min, Gradient: t 0 =5%A,t 1.6分 =98%A,t 4分 =98%A, post time: 1.3 minutes.

[0094] LCMS: Instrument: Agilent 1260 Bin. Pump: G1312B, Degasser, Autosampler, ColCom, DAD: Agilent G1315C, 220~320nm, MSD: Agilent LC / MSD G6130B ESI, pos / neg 100~1000, Eluent A: Acetonitrile, eluent B: 10mM ammonium bicarbonate in water (pH=9.5).

[0095] Method B: Column: Waters XSelect™ CSH C18, 30 x 2.1 mm, 3.5 μ, Temperature: 25°C, Flow rate: 1 mL / min, Gradient: t 0 =5%A,t 1.6分 =98%A,t 3分 =98%A, post time: 1.3 minutes.

[0096] Method D: Column: Waters XSelect(TM) CSH C18, 50 x 2.1 mm, 3.5μ, temperature: 25°C, flow rate: 0.8mL / min, gradient: t 0 =5%A,t 3.5分 =98%A,t 6分 =98%A, post time: 2 minutes.

[0097] Method AQ: Column: Waters XSelect(TM) CSH C18, 50 x 2.1 mm, 3.5 μ, Temperature: 25°C, Flow rate: 0.8 mL / min, Gradient: t 0 =5%A,t 4.5分 =98%A,t 6分 =98%A, post time: 2 minutes.

[0098] Method J: Column: Phenomenex GeminiNX C18, 50×2.0mm, 3μ, temperature: 25℃, flow rate: 0.8mL / min, gradient: t 0 =5%A,t 3.5分 =98%A,t 6分 =98%A, post time: 2 minutes.

[0099] LCMS: Instrument: Agilent 1290 series with UV detector (220nm, 270nm (bandwidth 100nm)), and HP6130MSD mass detector (API-ES positive and negative).

[0100] Method E: Column: Waters XBridge BEH XP (2.1 x 50 mm, 2.5 μm, 1034 bar), temperature: 35 °C, flow rate: 0.6 mL / min, t 0 =80%A,t 1.5分 =0%A,t 3分 =0%A, eluent A: 100% water, eluent B: 100% methanol / acetonitrile 1:1.

[0101] Method O: Column: Waters XBridge BEH XP (2.1 x 50 mm, 2.5 μm, 1034 bar), temperature: 35 °C, flow rate: 0.6 mL / min, t 0 =100%A,t 1.5分 =50%A,t 2分 =20%A, eluent A: 0.05% trifluoroacetic acid in water, eluent B: 100% acetonitrile.

[0102] Method K: Column: Waters XBridge BEH XP (2.1 x 50 mm, 2.5 μm, 1034 bar), temperature: 35 °C, flow rate: 0.6 mL / min, t 0 =80%A,t 1.5分 =0%A,t 4分 =0%A, eluent A: ammonium acetate (10mM), water / methanol / acetonitrile (90:6:4), eluent B: ammonium acetate (10mM), water / methanol / acetonitrile (10:54:36) .

[0103] LCMS: Instrument: Agilent Infinty II, Bin. Pump: G7120A, Multisampler, VTC, DAD: Agilent G7117B, 220 and 220~320nm, PDA: 210~320nm, MSD: Agilent G6135B ESI, pos / neg100~1000, ELSD G7102A :Evap 40℃, Neb 40℃, gas flow rate 1.6ml / min.

[0104] Method P: Column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5 μm, temperature: 40 °C, flow rate: 0.6 mL / min, gradient: t 0 =5%A,t 2分 =98%A,t 2.7分 =98%A, post time: 0.3 min, eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water.

[0105] Method Q: Column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5 μm, temperature: 25°C, flow rate: 0.6 mL / min, gradient: t 0 =5%A,t 2分 =98%A,t 2.7分 =98%A, post time: 0.3 min, eluent A: acetonitrile, eluent B: 10mM ammonium bicarbonate in water (pH=9.5).

[0106] Method AH: Column: XBridge Shield RP C18 (50×2.1mm 2.5μm), temperature: 25℃, flow rate: 0.6mL / min, gradient: t 0 =5%A,t 2分 =98%A,t 2.7分 =98%A, post time: 0.3 min, eluent A: 100mM ammonia in acetonitrile, eluent B: 100mM ammonia in water (pH=10).

[0107] Method BB: Column: Waters XBridge BEH Shield RP (50 × 2.1 mm, 2.5 μm), temperature: 40 °C, flow rate: 0.6 mL / min, t 0 =5%A,t 2.0分 =98%A,t 2.7分 =98%A, post time: 0.3 min, eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water.

[0108] Method CA: Column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5 μm, temperature: 40°C, flow rate: 0.8 mL / min, gradient: t 0 =5%A,t 0.5 =5%A,t 4.5分 =98%A,t 5分 =98%A, post time: 0.5 min, eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water.

[0109] Method CB: Column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5 μm, temperature: 25 °C, flow rate: 0.8 mL / min, gradient: t 0 =5%A,t 0.5分 =5%A,t 4.5分 =98%A,t 5分 =98%A, post time: 0.5 min, eluent A: acetonitrile, eluent B: 10mM ammonium bicarbonate in water (pH=9.5).

[0110] LCMS: Instrument: Waters Acquity UPLC H class (API-ES positive and negative) with PDA detector and SQD mass detector.

[0111] Method R: Column: Waters XBridge BEH C18 (2.1 x 50 mm, 2.5 μm), temperature: 30°C, flow rate: 0.6 mL / min, t 0 =80%A,t 1.5分 =5%A,t 2.5分= 5%A, post time: 0.5 min, eluent A: 10mM ammonium acetate in water with 5% acetonitrile, eluent B: acetonitrile.

[0112] Method BI: Column: Waters Acquity CSH C18, 100 x 2.1 mm, 1.7 μm, temperature: 40°C, flow rate: 0.45 mL / min, gradient: t 0 =5%A,t 5.0分 =98%A,t 6.0分=98%A, post time: 0.5 min, eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water.

[0113] LCMS: Instrument: Waters Iclass, Bin. Pump: UPIBSM, SM: UPISMFTN with SO, UPCMA, PDA: UPDATC, 210~320 nm, SQD: ACQ-SQD2 ESI, ELSD: Gas pressure 40 psi, Drift tube temperature: 50 °C .

[0114] Method AV: Column: Waters Acquity Shield RP18 (50 x 2.1 mm, 1.7 μm), temperature: 25°C, flow rate: 0.5 mL / min, t 0 =5%B,t 2.0分 =98%B,t 2.7分 =98%B, post time: 0.3 min, eluent A: 10mM ammonium bicarbonate in water (pH=9.5), eluent B: acetonitrile.

[0115] Chiral LC: Equipment: Agilent 1260 Quat. Pump: G1311C, degasser, autosampler, ColCom, DAD: Agilent G1315D (210nm, 220nm, 220~320nm).

[0116] Method H: Column: Chiralcel OD-H (250 x 4.6 mm, 5 μm), column temperature: 25 °C, flow rate: 1.0 mL / min, isocratic solvent gradient of 0.1% diethylamine in heptane / isopropanol 95 / 05.

[0117] Method I: Column: Chiralcel OD-H (250 x 4.6 mm, 5 μm), column temperature: 25 °C, flow rate: 1.0 mL / min, isocratic solvent gradient of 0.1% diethylamine in heptane / ethanol 80 / 20.

[0118] Method L: Column: Chiralcel OD-H (250 x 4.6 mm, 5 μm), column temperature: 25 °C, flow rate: 1.0 mL / min, isocratic solvent gradient of 0.1% diethylamine in heptane / isopropanol 90 / 10.

[0119] Method AB: Column: Chiralpak AD-H (250 x 4.6 mm, 5 μm, column temperature: 25 °C, flow rate: 0.8 mL / min, isocratic solvent gradient of 0.1% diethylamine in heptane / ethanol 30 / 70.

[0120] Method AC: Column: Chiralpak AD-H (250 × 4.6 mm, 5 μm, column temperature: 25 °C, flow rate: 1.0 mL / min, isocratic solvent gradient of 0.1% diethylamine in heptane / ethanol 70 / 30.

[0121] Method AG: Column: Chiralpak AD-H (250 x 4.6 mm, 5 μm, column temperature: 25 °C, flow rate: 1.0 mL / min, homogeneous solvent gradient of heptane / isopropanol 70 / 30.

[0122] SFC: Equipment: Waters Acquity UPC 2 :Waters ACQ-ccBSM Binary Pump, Waters ACQ-CCM Convergence Manager, Waters ACQ-SM Sample Manager-Fixed Loop, Waters ACQ-CM Column Manager-30S, Waters ACQ-PDA Photodiode Array Detector(210-400nm), Waters ACQ- ISM Make Up Pump, Waters Acquity QDa MS Detector (pos100-650).

[0123] Method F: Column: Phenomenex Cellulose-2 (100 x 4.6 mm, 5 μm), temperature: 35 °C, BPR: 170 bar, flow rate: 2.5 mL / min, gradient: t 0 =5%B,t 5分 =50%B,t 6分 =50%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0124] Method BL: Column: Phenomenex Cellulose-2 (100 × 4.6 mm, 5 μm), temperature: 35 °C, BPR: 170 bar, flow rate: 2.5 mL / min, gradient: t 0 =10%B,t 5分 =40%B,t 6分 =40%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in 2-propanol

[0125] Method G: Column: Phenomenex Amylose-1 (100 × 4.6 mm, 5 μm), temperature: 35 °C, BPR: 170 bar, flow rate: 2.5 mL / min, gradient: t 0 =5%B,t 2.5分 =50%B,t 10分 =50%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0126] Method W: Column: Phenomenex Amylose-1 (100 × 4.6 mm, 5 μm), temperature: 35 °C, BPR: 170 bar, flow rate: 2.5 mL / min, gradient: t 0 =5%B,t 5分 =50%B,t 6分 =50%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0127] Method 0 =5%B,t 5分 =30%B,t 6分 =30%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0128] Method N: Column: Diacel Chiralpak IG-3 (3.0×150mm, 3μm), temperature: 40℃, BPR: 126bar, flow rate 2.0mL / min, pump program: 30% B homogeneous solvent, eluent A: CO 2 , Eluent B: 0.2% ammonia in methanol

[0129] Method V: Column: Phenomenex Cellulose-1 (100 x 4.6 mm, 5 μm), temperature: 35 °C, BPR: 170 bar, flow rate: 2.5 mL / min, gradient: t 0 =5%B,t 5分 =50%B,t 6分 =50%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0130] Method AO: Column: Phenomenex Cellulose-1 (100 × 4.6 mm, 5 μm), temperature: 35 °C, BPR: 170 bar, flow rate: 2.5 mL / min, gradient: t 0 =2%B,t 5分 =10%B,t 6分 =10%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0131] Method BM: Column: Phenomenex Cellulose-1 (100 x 4.6 mm, 5 μm), Temperature: 35°C, BPR: 170 bar, Flow rate: 2.5 mL / min, Gradient: t 0 =10%B,t 5分 =40%B,t 6分 =40%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0132] Method AA: Column: Phenomenex Lux Cellulose4 (3.0×150mm, 3μm), Temperature: 40℃, BPR: 138bar, Flow rate: 2.5mL / min, Gradient: t 0 =2%B,t 4分 =27%B, post time: 1 min, eluent A: CO 2 , Eluent B: methanol

[0133] Method AD: Column: Diacel Chiralpak IC (4.6 × 100 mm, 5 μm), temperature: 35 °C, BPR: 170 bar, flow rate 2.5 mL / min, gradient: t 0 =5%B,t 5分 =50%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0134] Method AI: Column: Diacel Chiralpak IC (4.6 × 100 mm, 5 μm), temperature: 35 °C, BPR: 170 bar, flow rate: 2.5 mL / min, gradient: t 0 =5%B,t 5分 =50%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in 2-propanol

[0135] Method AR: Column: Waters Acquity UPC2 BEH (3.0×100mm, 1.7μm), Temperature: 35℃, BPR: 210bar, Flow rate: 1.0mL / min, Gradient: t0 =2%B,t 4分 =20%B,t 6分 =20%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0136] Method AS: Column: Waters Acquity UPC2 BEH (3.0×100mm, 1.7μm), Temperature: 35℃, BPR: 210bar, Flow rate: 1.0mL / min, Gradient: t 0 =2%B,t 4分 =50%B,t 6分 =50%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0137] Method AU: Column: Waters Acquity UPC2 Torus 2-PIC (100×3.0mm 1.7μm), temperature: 35℃, BPR: 170bar, flow rate 1.0mL / min, gradient: t 0 =2%B,t 4分 =50%B,t 6分 =50%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0138] Method AZ: Column: Phenomenex iAmylose-3 (100 x 4.6 mm, 5 μm), Temperature: 35°C, BPR: 170 bar, Flow rate: 2.5 mL / min, Gradient: t 0 =5%B,t 5分 =50%B,t 6分 =50%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0139] Method BZ: Column: Phenomenex iAmylose-3 (100 × 4.6 mm, 5 μm), temperature: 35 °C, BPR: 170 bar, flow rate: 2.5 mL / min, gradient: t 0 =5%B,t 5分 =50%B,t 6分 =50%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in ethanol

[0140] Method BE: Column: Phenomenex Cellulose-1 (100 × 4.6 mm, 5 μm), temperature: 35 °C, BPR: 120 bar, flow rate: 2.5 mL / min, gradient: t 0 =10%B,t 5分 =30%B,t 6分 =30%B, post time: 0.5 min, eluent A: CO 2 , Eluent B: 20mM ammonia in methanol

[0141] GCMS1: Instrument: GC: Agilent 6890 N and MS: 5973 MSD, EI-positive, detection temperature: 280℃, mass range: 50~550, column: RXi-5MS 20m, ID 180μm, df 0.18μm, average velocity: 50cm / s, injection volume: 1μl, injector temperature: 250℃, split ratio: 100 / 1, carrier gas: He,

[0142] Method A20: Initial temperature: 100°C, initial time: 1.5 min, solvent delay: 1.0 min, ramp rate 75°C / min, final temperature 250°C, final time 3.5 min.

[0143] Method SC_S20: Initial temperature: 60°C, initial time: 1.0 min, solvent delay: 1.3 min, ramp rate 50°C / min, final temperature 250°C, final time 3.5 min.

[0144] Preparative method: Basic reversed-phase MPLC: Instrument type: Revelleris(TM) prep MPLC, eluent A: 99% acetonitrile + 1% 10mM ammonium bicarbonate in water (pH=9.0), eluent B: 10mM ammonium bicarbonate in water. (pH=9.0). Unless otherwise specified, column: Waters XSelect CSH C18 (145×25 mm, 10 μ), flow rate: 40 mL / min, column temperature: room temperature was used. Other columns: Phenomenex Gemini C18 (185 x 25 mm, 10 μ), flow rate: 40 mL / min, column temperature: room temperature.

[0145] Acidic reverse phase MPLC: Instrument type: Revelleris(TM) prep MPLC, column: Phenomenex LUNA C18(3) (150 x 25 mm, 10μ), flow rate: 40 mL / min, column temperature: room temperature, eluent A: 0.1 in acetonitrile % (v / v) formic acid, eluent B: 0.1% (v / v) formic acid in water.

[0146] Preparative SFC: Equipment: Waters Prep 100 SFC UV / MS Direction System, Waters 2998 Photodiode Array (PDA) Detector, Waters Acquity QDa MS Detector, Waters 2767 Sample Manager. Eluent A: CO 2 , Eluent B: 20mM ammonia in methanol. Eluent C: 20mM ammonia in 2-propanol. Eluent D: 20mM ammonia in ethanol.

[0147] Method S: Column: Phenomenex Lux Cellulose-2 (250 × 21.2 mm, 5 μm), column temperature: 35 °C, flow rate: 70 mL / min, ABPR: 120 bar, linear gradient: t = 0 min 10% B, t = 6 min 50%B, detection: PDA (210~400nm) / TIC.

[0148] Method T: Column: Phenomenex Lux Amylose-1 (250 × 21 mm, 5 μm), column temperature: 35 °C, flow rate: 70 mL / min, ABPR: 120 bar, linear gradient: t = 0 min 5%B, t = 3 min 10 %B, t=8.5 min 10%B, detection: PDA (210~400nm) / TIC.

[0149] Method Y: Column: Phenomenex Lux Amylose-1 (250 × 21 mm, 5 μm), column temperature: 35 °C, flow rate: 70 mL / min, ABPR: 120 bar, linear gradient: t = 0 min 10%B, t = 6 min 40 %B, t=7.5 min 40%B, detection: PDA (210~400nm) / TIC.

[0150] Method Z: Column: Phenomenex Lux Amylose-1 (250 × 21 mm, 5 μm), column temperature: 35 °C, flow rate: 70 mL / min, ABPR: 120 bar, linear gradient: t = 0 min 10%B, t = 6 min 50 %B, t=7.5 min 50%B, detection: PDA (210~400nm) / TIC.

[0151] Method AW: Column: Phenomenex Lux Amylose-1 (250 × 21 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 mL / min, ABPR: 120 bar, Linear gradient: t = 0 min 5%B, t = 6 min 50 %B, t=7.5 min 50%B, detection: PDA (210~400nm) / TIC.

[0152] Method U: Column: Phenomenex Lux Cellulose-1 (250×21.2mm, 5μm), Column temperature: 35℃, Flow rate: 70mL / min, ABPR: 120bar, Linear gradient: t=0min 10%B, t=6.5min 30%B, t=8 min 30%B, detection: PDA (210~400nm) / TIC.

[0153] Method AE: Column: Diacel Chiralpak IC for SFC (250 × 20 mm, 5 μm), column temperature: 35 °C, flow rate: 70 ml / min, ABPR: 120 bar, linear gradient: t = 0 min 10%B, t = 6 min 40 %B, t=7.5 min 40%B, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0154] Method AL: Column: Phenomenex Lux Cellulose-2 (250 × 21.2 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 mL / min, ABPR: 120 bar, Linear gradient: t = 0 min 30% B, t = 6 min 50%B, t=7.5 min 50%B, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0155] Method AM: Column: Diacel Chiralpak IC for SFC (250 x 20 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 ml / min, ABPR: 120 bar, Linear gradient: t = 0 min 25% B, t = 6 min 50 %B, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0156] Method AN: Column: Diacel Chiralpak IC for SFC (250 × 20 mm, 5 μm), column temperature: 35 °C, flow rate: 70 ml / min, ABPR: 120 bar, linear gradient: t = 0 min 10%B, t = 6 min 50 %B, t=7.5 min 50%B, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0157] Method AP: Column: Diacel Chiralpak IC for SFC (250 x 20 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 ml / min, ABPR: 120 bar, Linear gradient: t = 0 min 10%C, t = 6 min 50 %C, t=7.5 min 50%C, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0158] Method AT: Column: Waters Torus 2-PIC 130A OBD (250×19mm, 5μm), Column temperature: 35℃, Flow rate: 70ml / min, ABPR: 120bar, Linear gradient: t=0 min 10%B, t=4 min 50%B, t=7 min 50%B, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0159] Method BA: Column: Diacel Chiralpak IC for SFC (250 × 20 mm, 5 μm), column temperature: 35 °C, flow rate: 70 ml / min, ABPR: 120 bar, linear gradient: t = 0 min 50%B, t = 6 min 50 %B, t=7.5 min 50%B, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0160] Method BD: Column: Phenomenex Lux Cellulose-1 (250 × 21.2 mm, 5 μm), column temperature: 35 °C, flow rate: 70 mL / min, ABPR: 120 bar, linear gradient: t = 0 min 10% B, t = 6.5 min 40%B, t=8 min 40%B, detection: PDA (210~400nm) / TIC.

[0161] Method BG: Column: Phenomenex Lux Cellulose-2 (250 × 21.2 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 mL / min, ABPR: 120 bar, Linear gradient: t = 0 min 20% B, t = 6 min 30%B, detection: PDA (210~400nm) / TIC.

[0162] Method BH: Column: Waters Torus 2-PIC 130A OBD (250×19mm, 5μm), Column temperature: 35℃, Flow rate: 70ml / min, ABPR: 120bar, Linear gradient: t=0 min 5%B, t=4 min 30%B, t=7 min 30%B, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0163] Method BK: Column: Phenomenex Lux Cellulose-2 (250×21.2mm, 5μm), Column temperature: 35℃, Flow rate: 70mL / min, ABPR: 120bar, Linear gradient: t=0 min 10%C, t=6 min 40%C, detection: PDA (210~400nm) / TIC.

[0164] Method BN: Column: Diacel Chiralpak IC for SFC (250 x 20 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 ml / min, ABPR: 120 bar, Linear gradient: t = 0 min 35%B, t = 6 min 50 %B, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0165] Method BO: Column: Phenomenex Lux Amylose-1 (250 x 21 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 mL / min, ABPR: 120 bar, Linear gradient: t = 0 min 50% B, t = 4 min 50 %B, detection: PDA (210~400nm) / TIC.

[0166] Method BP: Column: Diacel Chiralpak IC for SFC (250 x 20 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 ml / min, ABPR: 120 bar, Linear gradient: t = 0 min 20% B, t = 3.5 min 30 %B, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0167] Method BQ: Column: Phenomenex Lux iAmylose-3 (250 × 21 mm, 5 μm), column temperature: 35 °C, flow rate: 70 ml / min, ABPR: 120 bar, linear gradient: t = 0 min 10% B, t = 5 min 50 %B, t=7 min 50%B, detection: PDA (210-400 nm), fraction collection: PDA TIC.

[0168] Method BR: Column: Phenomenex Lux Cellulose-1 (250 x 21.2 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 mL / min, ABPR: 120 bar, Linear gradient: t = 0 min 10% B, t = 6.5 min 50%B, t=8 min 50%B, detection: PDA (210~400nm) / TIC.

[0169] Method BS: Column: Waters Viridis BEH Prep OBD (250 x 19 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 ml / min, ABPR: 120 bar, Linear gradient: t = 0 min 2% B, t = 5 min 50 %B, detection: PDA (210-400 nm), fraction collection based on PDA TIC.

[0170] Method BT: Column: Phenomenex Lux Cellulose-2 (250 x 21.2 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 mL / min, ABPR: 120 bar, Linear gradient: t = 0 min 5% B, t = 6 min 50%B, detection: PDA (210~400nm) / TIC.

[0171] Method BW: Column: Waters Viridis BEH Prep OBD (250 x 19 mm, 5 μm), Column temperature: 35 °C, Flow rate: 70 ml / min, ABPR: 120 bar, Homogenous solvent method: 10% B for 8 min, Detection: PDA (210 ~400nm), fraction collection based on PDA TIC.

[0172] Method BX: Column: Phenomenex Lux iAmylose-3 (250 × 21 mm, 5 μm), column temperature: 35 °C, flow rate: 70 ml / min, ABPR: 120 bar, linear gradient: t = 0 min 5%C, t = 5 min 50 %C, t=7 min 50%C, detection: PDA (210~400nm), fraction collection: PDA TIC.

[0173] Method BY: Column: Phenomenex Lux iAmylose-3 (250 × 21 mm, 5 μm), column temperature: 35 °C, flow rate: 70 ml / min, ABPR: 120 bar, linear gradient: t = 0 min 5%D, t = 5 min 50 %D, t=7 min 50%D, detection: PDA (210-400 nm), fraction collection: PDA TIC.

[0174] Preparative chiral HPLC: Equipment: Shimadzu LC8-A preparative pump, Shimadzu SCL-10Avp system controller, Shimadzu SPD-10Avp UV-VIS detector, fraction collector: Gilson 215 Liquid Handler.

[0175] Method AF: Column: Diacel Chiralpak AD-H, 20 x 250 mm, 5 μm, flow rate: 18 mL / min, homogeneous solvent heptane / isopropanol. Time: 60 minutes, eluent A: 70%, eluent B: 30%.

[0176] Method AJ: Column: Diacel Chiralpak AD-H, 20 x 250 mm, 5 μm, flow rate: 18 mL / min, 0.1% diethylamine in heptane / ethanol homogeneous solvent. Time: 60 minutes, eluent A: 30%, eluent B: 70%.

[0177] Method AY: Column: Diacel Chiralcel OD, 20 x 250 mm, 10 μm, flow rate: 18 mL / min, homogeneous solvent heptane / ethanol. Time: 60 minutes, eluent A: 90%, eluent B: 10%.

[0178] Preparative LCMS: Instrument: Agilent Technologies 1290 Preparative LC, MS Instrument type: Agilent Technologies G6130B Quadrupole, Detection: DAD (220~320nm), MSD (ESI pos / neg) Mass range: 100~800, MS and / or DAD Fraction collection based on.

[0179] Method M: Column: Xbridge Amide (150x19mm, 5μ), flow rate: 25mL / min, column temperature: room temperature, eluent A: 100% acetonitrile, eluent B: 10mM ammonium bicarbonate in water (pH=9.0).

[0180] Preparative LCMS: Agilent Technologies G6130B Quadrupole, HPLC Instrument type: Agilent Technologies 1200 Preparative LC, Detection: DAD (220~320nm), Detection: MSD (ESI pos / neg) Mass range: 100~1000, based on MS and DAD Collect fractions.

[0181] Method AX: Column: Xbridge Amide (150 x 19 mm, 5 μ), flow rate: 25 mL / min, column temperature: room temperature, eluent A: 100% acetonitrile, eluent B: 10 mM ammonium bicarbonate in water (pH = 9.0). Linear gradient: t=0 min 2%A, t=2.5 min 2%A, t=11 min 30%A, t=13 min 100%A, t=17 min 100%A.

[0182] Method BC: Column: Waters XSelect CSH (C18, 100 x 30 mm, 10 μ), flow rate: 25 ml / min, column temperature: room temperature, eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water, Linear gradient: t=0 min 2%A, t=2 min 2%A, t=8.5 min 30%A, t=10 min 100%A, t=13 min 100%A.

[0183] Method BU: Column: Waters XBridge Shield (C18, 150x19mm, 5μ), flow rate: 25ml / min, column temperature: room temperature, eluent A: 10mM ammonium bicarbonate in water pH=9.5, eluent B: 100% acetonitrile , Linear gradient: t=0 min 20%B, t=2.5 min 20%B, t=11 min 60%B, t=13 min 100%B, t=17 min 100%B.

[0184] Preparative LCMS: Agilent Technologies G6120AA Quadrupole, HPLC Instrument type: Agilent Technologies 1200 Preparative LC, Detection: DAD (220~320nm), Detection: MSD (ESI pos / neg) Mass range: 100~1000, based on MS and DAD Collect fractions.

[0185] Method BF: Column: Waters XSelect CSH (C18, 100 x 30 mm, 10 μm), flow rate: 55 ml / min, column temperature: room temperature, eluent A: 100% acetonitrile, eluent B: 0.1% formic acid in water, linear gradient: t=0 min 30%A, t=2 min 30%A, t=8.5 min 70%A, t=10 min 100%A, t=13 min 100%A.

[0186] Preparative LCMS: MS instrument type: ACQ-SQD2, HPLC instrument type: Waters Modular Preparative HPLC system. Detection: DAD (220~320nm), Detection: MSD (ESI pos / neg) Mass range: 100~800, Fraction collection based on MS and DAD.

[0187] Method BJ: Column: Waters Xselect (C18, 100x30mm, 10μm), flow rate: 55mL / min, column temperature: room temperature, eluent A: 10mM ammonium bicarbonate in water pH=9.5, eluent B: 100% acetonitrile, Linear gradient: t=0 min 5%B, t=2.5 min 5%B, t=4 min 20%B, t=13 min 60%B, t=14.5 100%B, t=17 min 100%B.

[0188] 1 H-NMR: 400MHz 1 H-NMR spectrum, CDCl 3 Or recorded on a Bruker Avance-400 ultrashield NMR spectrometer using DMSO-d6 as solvent and reported in ppm using TMS (0.00 ppm) as internal standard.

[0189] 300MHz 1 H-NMR spectra were recorded on a Varian VNMRS:7.05 Tesla magnet from Oxford Instruments. Chemical shifts are given in δ (ppm) and refer to residual protic solvent.

[0190] All CP analysis-SFC experiments were performed using SFC Method Station (Thar, Waters), column temperature: 40°C, mobile phase: CO containing 0.2% MA. 2 / methanol (or ethanol or isopropanol) (MA = 7M methanol ammonia), flow rate: 4.0 ml / min, back pressure: 120 bar, detection wavelength: 214 nm.

[0191] All CP analysis-chiral HPLC experiments were performed on Agilent-1200 (Agilent), column temperature: 40 °C, mobile phase: n-hexane (0.1% DEA) / ethanol (0.1% DEA). Flow rate: 1.0 ml / min, detection wavelength: 214 nm and 254 nm.

[0192] Preparative method: All CP preparative-SFC experiments were performed using SFC-80 (Thar, Waters), column temperature: 35°C, mobile phase: CO 2 / Methanol (or ethanol or isopropanol) containing 0.2% MA (MA=7M methanolic ammonia). Flow rate: 80 g / min, back pressure: 100 bar, detection wavelength: 214 nm.

[0193] All CP preparative chiral HPLC experiments were performed using Gilson-281 (Gilson), column temperature: 40 °C, mobile phase: n-hexane (0.1% DEA) / ethanol (0.1% DEA). Flow rate: 50 ml / min, detection wavelength: 214 nm.

[0194] LCMS experiment: All CP LCMS experiments were performed on an Agilent 1200 using a column temperature of 40 °C, with UV absorption monitored at 214 nm and scanning the mass range from 100 to 1000. Individual conditions differ slightly as explained in the following manner.

[0195] LCMS CP method A: Column: ZORBAX SB-C18 3.0 x 50 mm, 3.5 μm, Mobile phase: A: Water (0.1% TFA), B: ACN (0.1% TFA), Gradient: 5% B over 1.3 min at 95 Increases to %B and stops after 3 minutes. Flow rate: 1.8mL / min

[0196] LCMS CP Method B: Column: XBridge C18 50 x 4.6 mm, 3.5 μm, Mobile phase: A: Water (0.1% TFA), B: ACN (0.1% TFA), Gradient: 5% B to 95% over 1.2 min. Increases to B and stops in 3 minutes. Flow rate: 2.0mL / min

[0197] LCMS CP method C: Column: XBridge SB-C18 3.0 x 50 mm, 3.5 μm, mobile phase: A: Water (10 mM NH 4 HCO 3 ), B:ACN, gradient: 5% B increasing to 95% B over 1.2 min. Flow rate: 2.0mL / min,

[0198] LCMS CP method C1: Column: XBridge SB-C18 3.0 × 50 mm, 3.5 μm, mobile phase: A: Water (10 mM NH 4 HCO 3 ), B:ACN, gradient: 5% B increasing to 95% B over 1.4 min. Flow rate: 2.0mL / min,

[0199] LCMS CP method C2: Column: SunFire-C18 4.6 x 50 mm, 3.5 μm, mobile phase: A: Water (10 mM NH 4 HCO 3 ), B:ACN, gradient: 5% B increasing to 95% B over 1.4 min. Flow rate: 2.0mL / min,

[0200] LCMS CP Method D: Column: SunFire-C18 3.0 x 50 mm, 3.5 μm, Mobile phase: A: Water (0.01% TFA), B: ACN (0.01% TFA), Gradient: 5% B to 95% over 1.3 min. Increases to B and stops in 3 minutes. Flow rate: 2.0mL / min,

[0201] LCMS CP method E: Column: XBridge SB-C18 3.0 × 50 mm, 3.5 μm, mobile phase: A: water (0.1% TFA), B: ACN (0.1% TFA), gradient: 5% B over 1.8 min at 95 Increases to %B and stops after 3 minutes. Flow rate: 1.8mL / min,

[0202] LCMS CP Method F: Column: XBridge C18 4.6 x 50 mm, 3.5 μm, Mobile phase: A: Water (0.1% TFA), B: ACN (0.1% TFA), Gradient: 5% B to 95% B over 1.7 min. and stop after 3 minutes. Flow rate: 1.8mL / min

[0203] Experimental procedure Example 1 ((2R,5S)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5000) and ((2S,5R)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Synthesis of methanone (compound 5001) [ka]

[0204] tert-Butyl(((2S,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl) Carbamate and tert-butyl (((2R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl) Synthesis of methyl)carbamate.

[0205] Cis-5-(((tert-butoxycarbonyl)amino)methyl)tetrahydrofuran-2-carboxylic acid (97.4 mg, 0.397 mmol) and (S)-1-(4-fluorophenyl)-1,2,3,4 -Tetrahydroisoquinoline (98.6 mg, 0.434 mmol) as the first eluting isomer tert-butyl (((2S,5R)-5-(S)-1-(4-fluorophenyl)-1, 2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl)carbamate (51 mg, 28%) and tert-butyl (((2R,5S)-5-( (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl)carbamate, (S and R)-5-((S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one (see compound 5004), additional acid Workup (1M aqueous HCl / dichloromethane) and prepared according to preparative chiral SFC (Method S). The absolute configuration of the cis-tetrahydropyran-2-carboxamide center was arbitrarily assigned.

[0206] First eluting isomer: SFC: retention time = 2.89 minutes, (M+Na) + =472(Method F). ((2R,5S)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5000) synthesis.

[0207] tert-Butyl(((2S,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl) Starting from carbamate (51 mg, 0.112 mmol), ((2R5S)-5-(aminomethyl)tetrahydrofuran-2-yl)(S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2 (1H)-yl)methanone (compound 5000) was prepared by basic work-up (saturated NaHCO 3 Prepared according to the procedure described for compound 5008 after lyophilization from acetyl and water (1:1).

[0208] LCMS: 98%, retention time = 1.06 min, (M+H) + =355(Method P). ((2S,5R)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5001) synthesis.

[0209] tert-Butyl(((2R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl) Starting from carbamate (35 mg, 0.077 mmol), ((2S,5R)-5-(aminomethyl)tetrahydrofuran-2-yl)(S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline -2(1H)-yl)methanone (compound 5001) was purified by basic work-up (saturated NaHCO 3 Prepared according to the procedure described for compound 5008 after lyophilization from acetyl and water (1:1).

[0210] LCMS: 99%, retention time = 1.07 min, (M+H) + =355(Method P).

[0211] Example 2 ((2R,5R)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5002) synthesis [ka]

[0212] tert-Butyl(((2R,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl) Synthesis of carbamates.

[0213] (2R,5R)-5-(((tert-butoxycarbonyl)amino)methyl)tetrahydrofuran-2-carboxylic acid (Tetrahedron Lett.,2014,55,3569 and J.Org.Chem.,2010,65,6441) Synthesized according to the reported method, starting from 0.11 g, 0.44 mmol) and (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.11 g, 0.48 mmol), tert. -Butyl(((2R,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl)carbamate is described for (S and R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one (see Compound 5004).

[0214] LCMS: 84%, retention time=2.31 min, (M+H) + =455(Method K).

[0215] ((2R,5R)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5002) synthesis.

[0216] HCl (6M in 2-propanol, 0.25 mL, 1.5 mmol) was added to tert-butyl (((2R,5R)-5-((S)-1-(4-fluorophenyl) in 2-propanol (1 mL)). )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl)carbamate (53 mg, 0.12 mmol) at room temperature. After stirring the reaction mixture for 6 hours, additional HCl (6M in 2-propanol, 0.25 mL, 1.5 mmol) was added and stirring continued for 72 hours. K the reaction mixture 2 C.O. 3 Diluted with aqueous solution (2M, 10 mL) and extracted with dichloromethane (2 x 25 mL). The combined organic layer was diluted with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was analyzed by acid preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 2 min 10% A, t = 17 min 50% A, t = 18 min 100%, t=23 min 100% A, detection: 220 nm) (product was converted to basic (saturated NaHCO 3 The product was isolated by dichloromethane extraction from the aqueous (aqueous) fraction) and lyophilized from a mixture of acetonitrile and water (1:1). ((2R,5R)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5002).

[0217] LCMS: 99%, retention time = 1.05 min, (M+H) + =355(Method P).

[0218] Example 3 ((2S,5S)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5003) synthesis [ka]

[0219] tert-Butyl(((2S,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl) Synthesis of carbamates.

[0220] (2S,5S)-5-(((tert-butoxycarbonyl)amino)methyl)tetrahydrofuran-2-carboxylic acid (using (R,R)-salen Co(II) as catalystTetrahedron Lett.,2014,55 (S)-1-(4-fluorophenyl)-1,2, Starting from 3,4-tetrahydroisoquinoline (0.14 g, 0.59 mmol), tert-butyl (((2S,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl)carbamate, (S and R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4 Prepared according to the procedure described for -tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one (see compound 5004).

[0221] LCMS: 81%, retention time = 2.30 min, (M+H) + =455(Method K). ((2S,5S)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5003) synthesis.

[0222] tert-Butyl(((2S,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl) Starting from carbamate (66 mg, 0.15 mmol), ((2S,5S)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1H)-yl)methanone (compound 5003) was prepared following the procedure described for compound 5002 and analyzed by acidic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A , t = 2 min 10% A, t = 17 min 50%, t = 18 min 100% A, t = 23 min 100% A, detection: 220 nm). 3 The product was isolated by dichloromethane extraction from the aqueous (aqueous) fraction) and lyophilized from a mixture of acetonitrile and water (1:1).

[0223] LCMS: 98%, retention time = 1.04 min, (M+H) + =355(Method P).

[0224] Example 4 ((2S,4R)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) methanone (compound 5004), ((2S,4S)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline -2(1H)-yl)methanone (compound 5005), (((2R,4S)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5006), and ((2R,4R)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S) Synthesis of -1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5007) [ka]

[0225] (R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one and (S)-5 Synthesis of -((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one.

[0226] N,N-diisopropylethylamine (3.83mL, 22.0mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU , 3.54 g, 9.3 mmol) in dichloromethane (40 mL) with 4-oxotetrahydrofuran-2-carboxylic acid (1.1 g, 8.46 mmol) and (S)-1-(4-fluorophenyl)-1,2,3 ,4-tetrahydroisoquinoline (1.92g, 8.46mmol). After stirring at room temperature for 20 h, the reaction mixture was dissolved in saturated NaHCO 3 Wash with aqueous solution (3 x 50 mL) and 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-30% ethyl acetate in heptane) to give (R)-5-((S)-1-(4-fluorophenyl) as the first eluting isomer. )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one, and (S)-5-((S)-1-(4 -fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one was obtained. The absolute configuration of the tetrahydropyran-2-carboxamide center was determined by X-ray crystallography.

[0227] First eluting isomer: LCMS: 95%, retention time = 2.04 min, (M+H) + =340(Method K).

[0228] Second eluting isomer: LCMS 95%, retention time = 2.03 min, (M+H) + =340(Method K).

[0229] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S)-4-hydroxy-4-(nitromethyl)tetrahydrofuran-2-yl)methanone Synthesis.

[0230] (S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one in methanol (3 mL) A mixture of (0.22 g, 0.65 mmol), nitromethane (300 mg, 4.91 mmol), and triethylamine (2.6 mL, 19 mmol) was heated to reflux for 5 minutes and then stirred at room temperature for 4 days. The reaction mixture was evaporated to dryness under reduced pressure (at 60 °C) and the residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to give ((S)-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S)-4-hydroxy-4-(nitromethyl)tetrahydrofuran-2-yl)methanone was obtained and used as received.

[0231] LCMS: 44:54 mixture of isomers, (M+H) with retention time = 2.00 min and 2.04 min. + =401(Method K).

[0232] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R)-4-hydroxy-4-(nitromethyl)tetrahydrofuran-2-yl)methanone Synthesis.

[0233] (R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one (0.20 g, 0.59 mmol ) starting from ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R)-4-hydroxy-4-(nitromethyl)tetrahydrofuran- 2-yl)methanone, ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S)-4-hydroxy-4-(nitromethyl)tetrahydrofuran -2-yl)methanone was prepared according to the procedure described (see above) and used as is in the next step.

[0234] LCMS: 48:51 mixture of isomers, (M+H) with retention time = 2.02 min and 2.05 min. + =401(Method K).

[0235] ((2S,4S)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) methanone (compound 5005) and ((2S,4R)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline Synthesis of -2(1H)-yl)methanone (compound 5004).

[0236] NaBH 4 (0.13 g, 3.5 mmol) of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S)-4- Hydroxy-4-(nitromethyl)tetrahydrofuran-2-yl)methanone (70 mg, 0.17 mmol) and NiCl 2 ·6H 2 Added portionwise to a solution of O (21 mg, 0.087 mmol) at room temperature, resulting in an initial intense exotherm. After stirring at room temperature for 20 h, saturated NaHCO 3 Aqueous solution (25 mL) was added and stirring continued for 30 minutes. Ethyl acetate (50 mL) was added and the mixture was mixed thoroughly. Brine (20 mL) was added and the mixture was mixed thoroughly. The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic phase was (Na 2 S.O. 4 ) and concentrated under reduced pressure. The residue was purified by preparative chiral SFC (Method Z) and the product-containing fractions were lyophilized from a mixture of acetone and water (1:1, 4 mL) to give ((2S, 4S)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5005), and as the second eluting isomer ((2S,4R)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3, 4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5004) was obtained. The absolute configuration of the tetrahydropyran-2-carboxamide was determined by X-ray crystallography, and the tetrahydropyran-4-hydroxy-aminomethyl center was assigned arbitrarily.

[0237] Compound 5005: LCMS: 98%, retention time = 2.54 min, (M+H) + =371(Method AK). SFC: 100%, retention time = 4.16 minutes, (M+H) + =371(Method W).

[0238] Compound 5004: LCMS: 95%, retention time = 2.50 min, (M+H) + =371(Method AK). SFC: d.e.=96.5%, retention time=4.90 minutes, (M+H) + =371(Method W). ((2R,4R)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) methanone (compound 5007) and ((2R,4S)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline Synthesis of -2(1H)-yl)methanone (compound 5006).

[0239] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R)-4-hydroxy-4-(nitromethyl)tetrahydrofuran-2-yl)methanone( ((2R,4R)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4- ((2R,4S)-4-(aminomethyl)-4-hydroxytetrahydrofuran -2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5006), ((2S,4S and 2S,4R) Described for -4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone Prepared according to the procedure (see above) and purified by chiral SFC (Method AN). Absolute configuration was determined by X-ray crystallography.

[0240] Compound 5007: LCMS: 97%, retention time = 2.49 min, (M+H) + =371(Method AK). SFC: 100%, retention time = 3.72 minutes, (M+H) + =371(Method AD).

[0241] Compound 5006: LCMS: 99%, retention time = 2.53 min, (M+H) + =371(Method AK). SFC: d.e.=97.5%, retention time=4.16 minutes, (M+H) + =371(Method AD).

[0242] Example 5 ((2S,4S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5008) and ((2S,4R)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Synthesis of methanone (compound 5009) [ka]

[0243] Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(methoxymethylene)tetrahydrofuran-2-yl)methanone.

[0244] Dimethyl (1-diazo-2-oxopropyl)phosphonate (0.5 g, 2.6 mmol) and K 2 C.O. 3 (512 mg, 3.7 mmol) in methanol (8 mL) was dissolved in (S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydro Added to a solution of furan-3(2H)-one (see compound 5004, 300 mg, 0.88 mmol). The reaction mixture was allowed to warm to room temperature. After 2.5 hours, the mixture was diluted with water (15 mL) and ethyl acetate (50 mL) and the aqueous phase was saturated with NaCl. The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic phase was 2 S.O. 4 dried over and evaporated under reduced pressure to give ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(methoxymethylene )tetrahydrofuran-2-yl)methanone was obtained.

[0245] LCMS: Retention time = 2.20 min, (M+H) + =368(Method K).

[0246] Synthesis of (5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde.

[0247] Aqueous HCl (2.0 M, 2.5 mL, 5.0 mmol) was dissolved in ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(( Added to a solution of S)-4-(methoxymethylene)tetrahydrofuran-2-yl)methanone (325 mg, 0.884 mmol). After 20 minutes, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was 2 S.O. 4 and evaporated to dryness under reduced pressure to give (5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl). Tetrahydrofuran-3-carbaldehyde was obtained and used directly in the next step.

[0248] LCMS: Retention time = 2.00 min, (M+H) + =354(Method K).

[0249] ((2S)-4-((benzylamino)methyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone Synthesis.

[0250] Benzylamine (1.0 g, 9.3 mmol) followed by titanium(IV) isopropoxide (1.0 mL, 3.5 mmol) was dissolved in crude (5S)-5-((S)-1-(4) in dichloromethane (3 mL). -fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde (0.884 mmol). The reaction mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was taken up in methanol (30 mL) and NaBH 4 (981 mg, 25.9 mmol) was added portionwise. After stirring the mixture for 1 h, aqueous NaOH (0.1 M, 25 mL) was added and the mixture was extracted with methyl tert-butyl ether (3 x 50 mL). The combined organic layers were evaporated under reduced pressure (at 60 °C) and the residue was coevaporated from ethanol (2 x 20 mL) to yield ((2S)-4-((benzylamino)methyl)tetrahydrofuran-2-yl. )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained and used directly in the next step.

[0251] LCMS: Retention time = 2.14 min, (M+H) + =445(Method K).

[0252] Synthesis of ((2S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

[0253] Palladium (10% on activated charcoal, 200 mg, 0.188 mmol) was dissolved in ((2S)-4-((benzylamino)methyl)tetrahydrofuran-2-yl)((S)-1-(4- fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (380 mg, 0.855 mmol). The mixture was stirred under an atmosphere of hydrogen for 24 hours, then flushed with nitrogen, filtered through Celite, and washed with methanol (2 x 40 mL). The combined filtrates were evaporated under reduced pressure (at 65°C). The residue was purified by flash column chromatography (silica, 0-25% methanol in dichloromethane) to give ((2S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4 -fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0254] LCMS: 100%, retention time = 1.78 min, (M+H) + =355(Method K).

[0255] tert-Butyl(((3R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)methyl) Carbamate and tert-butyl (((3S,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl) Synthesis of methyl)carbamate.

[0256] Di-tert-butyl dicarbonate (93 mg, 0.426 mmol) was dissolved in ((2S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl) in dichloromethane (3 mL). )-3,4-dihydroisoquinolin-2(1H)-yl)methanone (134 mg, 0.378 mmol). After 5.5 h, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by flash column chromatography (silica, 10-50% ethyl acetate in heptane) and preparative chiral SFC (Method AP). tert-butyl(((3R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran as the first eluting isomer) -3-yl)methyl)carbamate, and tert-butyl (((3S,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)methyl)carbamate was obtained. The absolute configuration of the tetrahydrofuran-aminomethyl center was arbitrarily assigned.

[0257] First eluting isomer: LCMS: 97%, retention time = 2.13 min, (M+Na) + =477(Method A). SFC:d.e.=100%, retention time=3.66 minutes, (M+Na) + =477(Method AI).

[0258] Second eluting isomer: LCMS: 97%, retention time = 2.12 min, (M+H) + =455(Method A). SFC: d.e.=97%, retention time=3.98 minutes, (M+H) + =455(Method AI).

[0259] ((2S,4S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5008).

[0260] Trifluoroacetic acid (0.1 mL) was dissolved in tert-butyl (((3R,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4) in dichloromethane (2.0 mL). -tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)methyl)carbamate (22.3 mg, 0.049 mmol). After stirring at room temperature for 4.5 hours, the reaction mixture was evaporated under reduced pressure, desalted (SCX-2 (1 g) ion exchange chromatography) and lyophilized from a mixture of acetonitrile and water (1:1). ((2R,4R)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone. The absolute configuration of the tetrahydrofuran-aminomethyl center was arbitrarily assigned.

[0261] LCMS: 99%, retention time = 2.54 min, (M+H) + =355(Method AK).

[0262] ((2S,4R)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5009).

[0263] tert-Butyl(((3R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)methyl) Starting from carbamate (18.6 mg, 0.041 mmol), ((2S,4R)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone (compound 5009) was prepared as described for compound 5008, desalted (SCX-2 (1 g) ion exchange chromatography), purified with acetate and water (1 :1) was freeze-dried from the mixture. The absolute configuration of the tetrahydrofuran-aminomethyl center was arbitrarily assigned.

[0264] LCMS: 99%, retention time = 2.54 min, (M+H) + =355(Method AK).

[0265] Example 6 ((2S,4R)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5010) and ((2S,4S)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5011) synthesis [ka]

[0266] Synthesis of ((2S)-4-(benzylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

[0267] (S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one (see compound 5004, Starting from ((2S)-4-(benzylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H)-yl)methanone (368 mg) was converted into ((2S)-4-((benzylamino)methyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Prepared as described for isoquinolin-2(1H)-yl)methanone (see compound 5008). I used it as is.

[0268] LCMS: 63%, retention time=2.22 min, (M+H) + =431(Method K).

[0269] Synthesis of ((2S)-4-(benzylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

[0270] ((2S)-4-(benzylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (368 mg, 0.855 mmol) starting from ((2S)-4-(benzylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- methanone, ((2S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Prepared as described for methanone (see compound 5008) and used without purification.

[0271] LCMS: 81%, retention time = 1.79 min, (M+H) + =341(Method K).

[0272] tert-Butyl ((3R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate and tert Synthesis of -butyl ((3S,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate.

[0273] Di-tert-butyl dicarbonate (131 mg, 0.600 mmol) was dissolved in ((2S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl) in dichloromethane (5 mL). )-3,4-dihydroisoquinolin-2(1H)-yl)methanone (178 mg, 0.523 mmol). After 5.5 hours, the reaction mixture was dissolved in dichloromethane (10 mL) and saturated NaHCO 3 Diluted with aqueous solution (2 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 10-50% ethyl acetate in heptane) and preparative chiral SFC (Method S) to yield tert-butyl ((3S,5S) as the first eluting isomer. -5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate, and tert- as the second eluting isomer. Butyl ((3R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate was obtained. The absolute configuration of the tetrahydrofuran-amine center was arbitrarily assigned.

[0274] First eluting isomer: LCMS: 98%, retention time = 2.17 min, (M+Na) + =463(Method A). SFC:d.e.=100%, retention time=2.64 minutes, (M+Na) + =463(Method F).

[0275] Second eluting isomer: LCMS: 98%, retention time = 2.12 min, (M+H) +=441(Method A). SFC: d.e.=98%, retention time=3.14 minutes, (M+H) + =441(Method F).

[0276] ((2S,4R)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5010) Synthesis.

[0277] tert-Butyl ((3R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate (6.4 mg, 0.0145 mmol), ((2S,4R)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl) methanone (compound 5010) was prepared as described for compound 5008 and desalted (SCX-2 (1 g) ion exchange chromatography) in a mixture of acetonitrile and water (1:1). Freeze-dried from. The absolute configuration of the tetrahydrofuran-amine center was arbitrarily assigned.

[0278] LCMS: 98%, retention time=2.50 min, (M+H) + =341(Method AK).

[0279] ((2S,4S)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5011) Synthesis.

[0280] tert-Butyl ((3S,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate (55.7 mg, 0.126 mmol), ((2S,4S)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl) methanone (compound 5011) was prepared as described for compound 5008 and desalted (SCX-2 (1 g) ion exchange chromatography) in a mixture of acetonitrile and water (1:1). Freeze-dried from. The absolute configuration of the tetrahydrofuran-amine center was arbitrarily assigned.

[0281] LCMS: 100%, retention time = 2.54 min, (M+H) + =341(Method AK).

[0282] Example 7 ((2R,4R)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5012) and ((2R,4S)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5013) synthesis [ka]

[0283] Synthesis of ((2R)-4-(benzylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

[0284] (R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one (see compound 5005, Starting from ((2R)-4-(benzylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H)-yl)methanone, ((2S)-4-((benzylamino)methyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2 (1H)-yl)methanone (see compound 5008) was prepared as described and used directly in the next step.

[0285] LCMS: 64%, retention time = 2.24 min, (M+H) + =431(Method K).

[0286] Synthesis of ((2R)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

[0287] ((2R)-4-(benzylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (368 mg, 0.855 starting from ((2R)-4-(benzylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- methanone, ((2S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Prepared as described for methanone (see compound 5008) and used as is in the next step.

[0288] LCMS: 83%, retention time = 1.80 min, (M+H) + =341(Method K).

[0289] tert-Butyl ((3S,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate and tert Synthesis of -butyl ((3R,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate.

[0290] Di-tert-butyl dicarbonate (194 mg, 0.889 mmol) was dissolved in ((2R)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl) in dichloromethane (5 mL). )-3,4-dihydroisoquinolin-2(1H)-yl)methanone (270 mg, 0.793 mmol). After 5.5 hours, the reaction mixture was dissolved in dichloromethane (10 mL) and saturated NaHCO 3 Diluted with aqueous solution (2 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 10-50% ethyl acetate in heptane) and preparative chiral SFC (Method AN) to obtain tert-butyl ((3S,5R) as the first eluting isomer. -5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate, and tert- as the second eluting isomer. Butyl ((3R,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate was obtained. The absolute configuration of the tetrahydrofuran-amine center was arbitrarily assigned.

[0291] First eluting isomer: LCMS: 91%, retention time = 2.17 min, (M+Na) + =463(Method A). SFC: d.e.=100%, retention time=2.66 minutes, (M+a) + =463(Method AD).

[0292] Second eluting isomer: LCMS: 98%, retention time = 2.12 min, (M+H) + =441(Method A). SFC: d.e.=96.5%, retention time=3.30 minutes, (M+H) + =441(Method AD).

[0293] ((2R,4R)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5012) Synthesis.

[0294] tert-Butyl ((3R,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate (15.0 starting from ((2R,4R)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl) methanone (compound 5012) was prepared as described for compound 5008 and desalted (SCX-2 (1 g) ion exchange chromatography) in a mixture of acetonitrile and water (1:1). Freeze-dried from. The absolute configuration of the tetrahydrofuran-amine center was arbitrarily assigned.

[0295] LCMS: 97%, retention time = 2.50 min, (M+H) + =341(Method AK).

[0296] ((2R,4S)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5013) Synthesis.

[0297] tert-Butyl ((3S,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamate (91.0 mg, 0.207 mmol), ((2R,4S)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl) methanone (compound 5013) was prepared as described for compound 5008 and desalted (SCX-2 (1 g) ion exchange chromatography) in a mixture of acetonitrile and water (1:1). Freeze-dried from. The absolute configuration of the tetrahydrofuran-amine center was arbitrarily assigned.

[0298] LCMS: 100%, retention time = 2.55 min, (M+H) + =341(Method AK).

[0299] Example 8 ((2R)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5014) synthesis of. [ka]

[0300] Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(methoxymethylene)tetrahydrofuran-2-yl)methanone.

[0301] Dimethyl (1-diazo-2-oxopropyl)phosphonate (270 mg, 1.41 mmol) and (R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- Starting from 2-carbonyl)dihydrofuran-3(2H)-one (see compound 5005, 40 mg, 0.12 mmol), ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline- 2(1H)-yl)((R)-4-(methoxymethylene)tetrahydrofuran-2-yl)methanone, ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H)-yl)((S)-4-(methoxymethylene)tetrahydrofuran-2-yl)methanone (see compound 5008).

[0302] LCMS: E / Z mixture, retention time = 2.20 and 2.22 min, (M+H) + =368(Method K).

[0303] Synthesis of (5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde.

[0304] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(methoxymethylene)tetrahydrofuran-2-yl)methanone (40 mg, 0.11 starting from (5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde, (5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde (see compound 5008) is described. It was prepared as follows. It was used as is in the next step.

[0305] LCMS: Retention time = 2.02 min, (M+H) + =354(Method K).

[0306] ((2R)-4-((benzylamino)methyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone formation synthesis of things.

[0307] Starting from crude (5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde (0.11 mmol) , ((2R)-4-((benzylamino)methyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone The product was converted to ((2S)-4-((benzylamino)methyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- yl)methanone (see compound 5008). It was used as is in the next step.

[0308] LCMS: Retention time = 2.17 min, (M+H) + =445(Method K).

[0309] Synthesis of ((2R)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

[0310] ((2R)-4-((benzylamino)methyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone( ((2R)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H)-yl)methanone (compound 5014) was converted into ((2S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline- 2(1H)-yl)methanone (see Compound 5008) and purified as its Boc-protected derivative (di-tert-butyl dicarbonate (18.3 mg, 0.084 mmol) in dichloromethane (3 mL). ), N,N-diisopropylethylamine (0.080 mL, 0.458 mmol) for 1 day, flash chromatography (silica, 10-70% ethyl acetate in heptane)), deprotection (trifluoroacetic acid (0.5 mL), dichloromethane (2 mL) for 1.5 h, SCX-2 (1 g)), then lyophilized from acetonitrile and water (1:1).

[0311] LCMS: 95%, retention time = 1.02 min, (M+H) + =355(Method P).

[0312] Example 9 ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone( Synthesis of compound 5015). [ka]

[0313] tert-Butyl((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl ) Synthesis of carbamates.

[0314] (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}oxane-2-carboxylic acid (1.00g, 4.08mmol) and (S)-1-(4-fluorophenyl)-1,2, Starting from 3,4-tetrahydroisoquinoline (0.927 g, 4.08 mmol), tert-butyl ((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3, 4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate, tert-butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1, 2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate (see Compound 5042) and flash chromatography (silica, 0~ (50% ethyl acetate).

[0315] LCMS: 99%, retention time = 2.14 min, (M+H) + =455(Method A).

[0316] ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone( Synthesis of compound 5015).

[0317] HCl (5-6M in 2-propanol, 15 mL, 75 mmol) was added to tert-butyl ((3R,6S)-6-((S)-1-(4-fluorophenyl)) in 2-propanol (30 mL). -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate (1.71 g, 3.76 mmol) and stirred overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with water (40 mL) and aqueous HCl (1M, 4.0 mL (pH<3)) and the mixture was extracted with ethyl acetate (20 mL). K saturates the aqueous phase 2 C.O. 3 It was basified by the addition of aqueous solution (20 mL) and extracted with ethyl acetate (50 mL). The latter organic layer is Na 2 S.O. 4((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl) after drying on top and evaporation under reduced pressure and lyophilization from a mixture of acetonitrile and water (1:1, 30 mL). ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5015) was obtained.

[0318] LCMS: 99%, retention time=1.03 min, (M+H) + =355(Method P).

[0319] Example 10 Synthesis of compound 5016 and compound 5017 [ka] Step 1: To a solution of 5-(tert-butoxycarbonylamino)-tetrahydro-2H-pyran-2-carboxylic acid (200 mg, 0.8 mmol) in DMF (4 mL) was added )-1,2,3,4-tetrahydroisoquinoline (185 mg, 0.8 mmol), HATU (372 mg, 1.0 mmol), and Et 3 N (0.2 mL, 1.6 mmol) was added at 0°C. The resulting reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate (20 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (3 x 30 mL) and the combined organic phases were washed with brine (30 mL) and Na 2 S.O. 4 Dry on top, filter and concentrate. The residue was purified by column chromatography to give tert-butyl 6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-tetrahydro-2H- Pyran-3-yl carbamate was obtained.

[0320] LCMS:(M+H) + =455, retention time = 1.933 min, LCMS CP method A

[0321] Step 2: tert-Butyl 6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-tetrahydro-2H-pyran- in dioxane (2 mL) To a solution of 3-yl carbamate (300 mg, 0.7 mmol) was added HCl in dioxane (4N, 2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residue was purified by Prep-HPLC to give (5-amino-tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone was obtained.

[0322] LCMS:(M+H) + =355, retention time = 1.381 min, LCMS CP Method E

[0323] Diastereomers were analyzed using CO using an EnantioPak® AD column (20 x 250 mm, 10 μm). 2 Separation by chiral SFC eluting with / MeOH containing 0.2% MA gave compound 5016 (retention time = 3.332 min) and compound 5017 (retention time = 1.193 min). The stereochemical configuration of (S) at position 1 of tetrahydroisoquinoline is based on enantiomerically pure starting material, and the configuration at the tetrahydropyran chiral center is compared to related analogs of known configuration. and are arbitrarily assigned based on the chromatographic elution order.

[0324] Compound 5016:LCMS:(M+H) + =355, purity = 100% (214nm), retention time = 1.490 min, LCMS CP method F

[0325] Chiral SFC: CO using CHIRALPAK® IG column (4.6 x 100 mm, 5 μm) 2 / 0.2% MA in MeOH (65%:35%), retention time = 3.086 min, 100%ee.

[0326] Compound 5017:LCMS:(M+H) + =355, purity = 97.36% (214nm), retention time = 1.489 min, LCMS CP method F

[0327] Example 11 Synthesis of compound 5018 and compound 5019 [ka] Step 1: A solution of 1-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline (300 mg, 1.2 mmol) in DMF (5 mL) was added tert-Butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (223 mg, 0.99 mmol), HATU (480 mg, 1.26 mmol), and TEA (0.3 mL, 2 mmol) were added at 0°C. The resulting reaction mixture was stirred at room temperature for 2 h, diluted with EA (10 mL) and diluted with saturated NH 4 Washed with Cl (2 x 10 mL) followed by brine (2 x 10 mL). organic phase with Na 2 S.O. 4 Dry on top and concentrate in vacuo. The residue was purified by Prep-HPLC to give tert-butyl((3S,6R)-6-(1-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tetrahydro-2H-pyran-3-yl)carbamate was obtained.

[0328] LCMS:(M+H) + =473.1, purity=100%(214nm), retention time=1.68 min, method C1

[0329] Step 2: Add tert-butyl ((3S,6R)-6-(1-(2,4-difluorophenyl)-1,2 ,3,4-tetrahydroisoinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate (320 mg, 0.68 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give a residue, which was purified by Prep-HPLC to give ((2R,5S)-5-aminotetrahydro-2H-pyran-2-yl)((R)-1-(2,4 -difluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0330] LCMS:(M+H) + =373.1, purity = 100% (214nm), retention time = 1.42 minutes. Method C1

[0331] The diastereomers were separated by chiral SFC using a Daicel® IG column (20 x 250 mm, 10 μm) and eluting with CO2 / MeOH (0.2% methanolic ammonia) = 45 / 55 to give compound 5018 and compound 5019. I got it. The configuration of the stereocenters in the pyran ring is based on commercially available starting materials, and the tetrahydrosioquinoline stereochemistry is arbitrarily assigned based on the chromatographic elution order of the related analogs.

[0332] Compound 5018:LCMS:(M+H) + =373.0, purity = 100% (214nm), retention time = 1.49 min, method C1.

[0333] Chiral SFC: CO using a Daicel® IG column (20 x 250 mm, 10 um) 2 / 0.2% MeOH containing ammonia = 60:40, retention time = 2.698 minutes), 98.7%ee.

[0334] Compound 5019:LCMS:(M+H) + =373.0, purity=100%(214nm), retention time=1.43 min, method C1

[0335] Chiral SFC: CO using a Daicel® IG column (20 x 250 mm, 10 μm) 2 / 0.2% MeOH containing methanol and ammonia = 60:40, retention time = 1.503 min), 100% ee.

[0336] Example 12 Synthesis of compound 5020, compound 5021, compound 5022, and compound 5023 [ka] Step 1: 4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.1]heptane-1-carboxylic acid (150 mg, 0.58 mmol) and TEA (0.16 mL, 0.17 mmol) in DMF (2 mL) HATU (266 mg, 0.7 mmol) was added to the solution of ) at room temperature. After stirring at room temperature for 30 min, (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (145 mg, 0.64 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. . The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified by Prep-HPLC to give tert-butyl (1-((S)-1-(4-fluorophenyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)-2-oxabicyclo[2.2.1]heptan-4-yl)carbamate was obtained.

[0337] LCMS:(M+1) +=467.0, retention time = 1.78 min, LCMS CP method C2

[0338] Step 2: tert-Butyl(1-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2-oxabicyclo[ To a solution of 2.2.1]heptan-4-yl) carbamate (62 mg, 0.13 mmol) was added TFA (0.5 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours, then concentrated and the residue was dissolved in water. The mixture was basified with 1N NaOH and extracted with DCM (3 x 20 mL). The combined organic layer was diluted with anhydrous Na 2 S.O. 4 dried, filtered, and concentrated to give a residue, which was purified by Prep-HPLC to give (4-amino-2-oxabicyclo[2.2.1]heptan-1-yl)((S)-1 -(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0339] LCMS:(M+H) + =367.0, retention time = 1.47 min, LCMS CP method C2

[0340] The diastereomers (26 mg) were separated by chiral SFC using a Daicel® IG column (20 x 250 mm, 10 μm) eluting with CO2 / MEOH (0.2% methanol ammonia) = 50 / 50 to give compound 5020. , Compound 5021, Compound 5022, and Compound 5023 were obtained. The stereochemical configuration of (S) at the 1-position of the tetrahydroisoquinoline is assigned based on the starting material, and the stereochemical configuration at the bicyclic center is arbitrary.

[0341] Compound 5020:LCMS:(M+H) + =367.0, retention time = 1.79 min, LCMS CP method C

[0342] Chiral SFC: CO using CHIRALPAK® IG column (4.6 x 100 mm, 5 μm) 2 / IPA containing 1% ammonia (60%:40%), retention time = 1.462 minutes, 99.59%ee.

[0343] Compound 5021:LCMS:(M+H) + =367.2, retention time = 1.53 min, LCMS CP method A1

[0344] Chiral SFC: CO using CHIRALPAK® IG column (4.6 x 100 mm, 5 μm) 2 / IPA containing 1% ammonia (60%:40%), retention time = 3.957 minutes, 80.32%ee.

[0345] Compound 5022:LCMS:(M+H) + =367.0, retention time = 1.76 min, LCMS CP method C

[0346] Chiral SFC: CO using CHIRALPAK® IG column (4.6 x 100 mm, 5 μm) 2 / IPA containing 1% ammonia (60%:40%), retention time = 1.843 min), 95.5%ee.

[0347] Compound 5023:LCMS:(M+H) + =367.0, retention time = 1.78 min, LCMS CP method C

[0348] Chiral SFC: CO using CHIRALPAK® IG column (4.6 x 100 mm, 5 μm) 2 / IPA containing 1% ammonia (60%:40%), retention time = 2.947 minutes), 96.64%ee.

[0349] Example 13 ((2S,4S)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5024) synthesis [ka]

[0350] ((2S,4S)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5024).

[0351] Acetaldehyde (10 wt% solution in ethanol, 73.0 μL, 0.130 mmol) was added to ((2S,4S)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5005, 32 mg, 0.086 mmol). The mixture was stirred for 1 hour, then sodium borohydride (4.90 mg, 0.130 mmol) was added. After stirring overnight, water was added and the mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was purified by preparative SFC (method AT) and flash column chromatography (silica, 0-10% (3.5M ammonia in methanol) in dichloromethane) to give ((2S ,4S)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Methanone (compound 5024) was obtained. The absolute configuration of tetrahydropyran-2-carboxamide was determined by X-rays, and the stereochemistry of the tetrahydropyran-4-hydroxy-aminomethyl center was arbitrarily assigned.

[0352] LCMS: 96%, retention time = 2.56 min, (M+H) + =399(Method AK). SFC: retention time = 2.78 minutes,

[0353] Example 14 Compound 5027 and synthesis of compound 5027 [ka] A solution of 4-aminotetrahydro-2H-pyran-2-carboxylic hydrochloride (362 mg, 2 mmol) in DCM (50 mL) was added with SOCl 2 (1 mL, excess) was added under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 h, then concentrated to give a white solid, (S)-1-(4-fluorophenyl)-1,2,3,4- in DCM (10 mL). Added to another solution of tetrahydroisoquinoline (454 mg, 2 mmol) and TEA (404 mg, 4 mmol). The resulting mixture was stirred for 3 hours, then quenched with water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and the combined organic phases were washed with brine (20 mL) and anhydrous Na 2 S.O. 4 Dry on top, filter and concentrate to give a residue. This was purified by Prep-HPLC and (4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- Il) methanone was obtained.

[0354] LCMS:(M+H) + =355.1, purity = 100% (214nm), retention time = 1.38 min, LCMS CP method C

[0355] Diastereomers were separated using an EnantioPak® OX-H column (20 x 250 mm, 10 μm) with CO 2 Separation by chiral SFC eluting with / MeOH (0.2% methanol ammonia) = 65 / 35 gave compound 5028 (retention time = 2.32 minutes) and compound 5027 (retention time = 3.07 minutes). The stereochemical configuration of the tetrahydroisoquinoline was based on enantiomerically pure starting materials, and the tetrahydropyran stereochemistry was determined by X-ray crystallography of related analogs.

[0356] Compound 5028:LCMS:((M+H) + =355.1, purity = 100% (214nm), retention time = 1.38 min, LCMS CP method C

[0357] Chiral SFC: CO using a CHIRALPAK® IG column (4.6 x 100 mm, 5 μm) 2 / 0.2% MeOH containing ammonia = 65:35, retention time = 1.73 min), 100% ee.

[0358] Compound 5027:LCMS:((M+H) + =355.1, purity = 100% (214nm), retention time = 1.38 min, LCMS CP method C

[0359] Chiral SFC: CO using a CHIRALPAK® IG column (4.6 x 100 mm, 5 μm) 2 / 0.2% MeOH containing ammonia = 65:35, retention time = 1.67 min), 100% ee.

[0360] Example 15 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5029) [ka]

[0361] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl ) Synthesis of carbamates.

[0362] (2S,5S)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (241 mg, 0.983 mmol) and (S)-1-(4-fluorophenyl)-1,2 Starting from ,3,4-tetrahydroisoquinoline (213 mg, 0.937 mmol), tert-butyl ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3, 4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate, tert-butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1, Prepared as described for 2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate (Compound 5042). white form.

[0363] LCMS: 97%, retention time = 2.15 min, (M+Na) + =477(Method A).

[0364] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(2-methoxyethyl)carbamate synthesis.

[0365] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl ) carbamate (76.6 mg, 0.169 mmol), tert-butyl ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline) -2-carbonyl)tetrahydro-2H-pyran-3-yl)(2-methoxyethyl)carbamate, tert-butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)- Prepared as described for 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)(2-methoxyethyl)carbamate (see compound 5030) and subjected to acid preparative MPLC (linear gradient: t=0 min 10%A, t=1 min 10%A, t=2 min 40%A, t=17 min 80%A, t=18 min 100%, t=23 min 100% A, Detection: 220 nm).

[0366] LCMS: 100%, retention time = 2.27 min, (M+H) + =513(Method A).

[0367] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5029).

[0368] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(2-methoxyethyl)carbamate (44.8 mg, 0.087 mmol), ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(( 2S,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H-pyran-2-yl)methanone (Compound 5029) was converted to ((S)-1-(4 -fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H-pyran-2-yl)methanone (compound 5030).

[0369] LCMS: 99%, retention time = 1.09 min, (M+H) + =413(Method P).

[0370] Example 16 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5030) [ka]

[0371] tert-Butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(2-methoxyethyl)carbamate synthesis.

[0372] Under a nitrogen atmosphere, sodium hydride (60% dispersion in oil, 11.4 mg, 0.286 mmol) was dissolved in tert-butyl ((3S,6R)-6 in N,N-dimethylformamide (anhydrous, 1.5 mL). -((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate (see compound 5042, 100 mg, 0.220 mmol) solution. After 15 minutes, 2-bromoethyl methyl ether (38 μL, 0.396 mmol) was added and stirring continued overnight. The reaction mixture was diluted with ethyl acetate (25 mL), washed with brine (4 x 10 mL), and washed with Na 2 S.O. 4 dried over and evaporated under reduced pressure to give tert-butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -carbonyl)tetrahydro-2H-pyran-3-yl)(2-methoxyethyl)carbamate was obtained and used directly in the next step.

[0373] LCMS: 79%, retention time = 2.27 min, (M+H) + =513(Method A).

[0374] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5030).

[0375] Trifluoroacetic acid (0.307 mL, 3.98 mmol) was dissolved in tert-butyl ((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3) in dichloromethane (2.7 mL). ,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)(2-methoxyethyl)carbamate (102 mg (79 wt%)), 0.157 mmol). After 1 h, the reaction mixture was diluted with dichloromethane (15 mL) and saturated with NaHCO 3 Washed with aqueous solution (10 mL). The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was dissolved in dimethyl sulfoxide (2 mL) and subjected to acidic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 16.6 min 45% A, t = 17.6 min 100% , t=22.6 min 100% A, detection: 220 nm). Pool product-containing fractions and brine, saturated NaHCO 3 Aqueous solution and saturated Na 2 C.O. 3 Diluted with a mixture of aqueous solutions (1:1:1, 15 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic phase was 2 S.O. 4 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline) after drying on top and evaporation under reduced pressure and lyophilization from a mixture of acetonitrile and water (3:2, 2 mL). -2(1H)-yl)((2R,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H-pyran-2-yl)methanone (Compound 5030) was obtained.

[0376] LCMS: 99%, retention time = 1.07 min, (M+H) + =413(Method P). SFC: retention time = 3.84 minutes.

[0377] Example 17 ((2S,4R)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5031) synthesis [ka]

[0378] ((2S,4R)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5031).

[0379] Acetaldehyde (10 wt% solution in ethanol, 120 μL, 0.207 mmol) was added to ((2S,4R)-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)((S) in ethanol (1.5 mL)). -1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5004, 51 mg, 0.138 mmol). The mixture was stirred for 1 hour, then sodium borohydride (7.81 mg, 0.207 mmol) was added. After stirring overnight, water (a few drops) and methanol (2 mL) were added and the mixture was filtered through a 0.45 μm nylon filter. The filtrate was evaporated under reduced pressure and the residue was subjected to flash column chromatography (silica, 0-10% (7M ammonia in methanol) in dichloromethane) and acidic preparative MPLC (linear gradient: t = 0 min 10% A, t = 1 min 5% A, t = 16 min 50% A, t = 17 min 100%, t = 22 min 100% A, detection: 220 nm) and purified by a mixture of acetonitrile and water (1:1, ((2S,4R)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3, 4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5031) was obtained. The absolute configuration of tetrahydropyran-2-carboxamide was determined by X-rays, and the stereochemistry of the tetrahydropyran-4-hydroxy-aminomethyl center was arbitrarily assigned.

[0380] LCMS: 98%, retention time = 1.03 min, (M+H) + =399(Method P).

[0381] Example 18 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5R)-5-((2-hydroxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5032). [ka]

[0382] tert-Butyl((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)carbamate synthesis.

[0383] tert-Butyl((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl ) carbamate (see compound 5015, 100 mg, 0.220 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (53 μL, 0.352 mmol), starting with tert-butyl ((3R,6S)-6- ((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)(2-((tetrahydro-2H-pyran- tert-butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro-2H-pyran-3-yl)(2-methoxyethyl)carbamate (see compound 5030) was prepared as described and analyzed by basic preparative MPLC (linear gradient: t=0 min 10% A , t = 1 min 10% A, t = 2 min 40% A, t = 17 min 80% A, t = 18 min 100% A, t = 23 min 100% A, detection: 220 nm).

[0384] LCMS: 98%, retention time = 2.26 minutes, (M-THP+H) + =499(Method A).

[0385] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5R)-5-((2-hydroxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5032).

[0386] tert-Butyl((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(((S)-1-(4-fluorophenyl)-3,4- dihydroisoquinolin-2(1H)-yl)((2S,5R)-5-((2-hydroxyethyl)amino)tetrahydro-2H-pyran-2-yl)methanone (compound 5032), ((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H-pyran-2-yl ) Prepared as described for methanone (Compound 5030). Two additional portions of trifluoroacetic acid were added after 2 and 4 hours, respectively.

[0387] LCMS: 99%, retention time=1.03 min, (M+H) + =399(Method P). SFC: retention time = 5.19 minutes, (M+H) + =399(Method F).

[0388] Example 19 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5S)-5-((2-hydroxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5033). [ka]

[0389] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(2-methoxyethyl)carbamate synthesis.

[0390] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl ) carbamate (see compound 5029, 75.7 mg, 0.167 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (30.2 μl, 0.200 mmol), starting with tert-butyl ((3S,6S)- 6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)(2-((tetrahydro-2H- tert-butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- Prepared as described for 2-carbonyl)tetrahydro-2H-pyran-3-yl)(2-methoxyethyl)carbamate (see compound 5030) and subjected to acidic preparative MPLC (linear gradient: t=0 min 10% A, t = 1 min 10% A, t = 2 min 40% A, t = 17 min 80% A, t = 18 min 100%, t = 23 min 100% A, detection: 220 nm).

[0391] LCMS: 100%, retention time = 2.34 min, (M+Na) + =605(Method A).

[0392] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5S)-5-((2-hydroxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5033).

[0393] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)carbamate (21.1 mg, 0.036 mmol), ((S)-1-(4-fluorophenyl)-3, -dihydroisoquinolin-2(1H)-yl)((2S,5S)-5-((2-hydroxyethyl)amino)tetrahydro-2H-pyran-2-yl)methanone (compound 5033), ((2R, About 5S)-5-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5042) Prepared as described.

[0394] LCMS: 99%, retention time = 2.57 min, (M+H) + =399(Method AK).

[0395] Example 20 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-((2-hydroxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5034). [ka]

[0396] tert-Butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)carbamate synthesis.

[0397] tert-Butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl ) carbamate (see compound 5042, 100 mg, 0.220 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (60 μL, 0.396 mmol), starting with tert-butyl ((3S,6R)-6- ((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)(2-((tetrahydro-2H-pyran- tert-butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Prepared as described for carbonyl)tetrahydro-2H-pyran-3-yl)(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)carbamate (see compound 5030) to give a basic Preparative MPLC (linear gradient: t=0 min 10%A, t=1 min 10%A, t=2 min 40%A, t=17 min 80%A, t=18 min 100%A, t=23 100% A, detection: 220 nm).

[0398] LCMS: 99%, retention time = 2.27 minutes, (M-THP+H) + =499(Method A).

[0399] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-((2-hydroxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5034).

[0400] tert-Butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)carbamate (68 mg, 0.117 mmol), starting with dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-((2-hydroxyethyl)amino)tetrahydro-2H-pyran-2-yl)methanone (compound 5034), ((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H-pyran-2-yl ) Prepared as described for methanone (Compound 5030).

[0401] LCMS: 99%, retention time = 1.03 min, (M+H) + =399(Method P). SFC: Retention time = 4.34 minutes, (M+H) + =399(Method AD).

[0402] Example 21 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5R)-5-((2-methoxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5035) [ka]

[0403] tert-Butyl((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(2-methoxyethyl)carbamate synthesis.

[0404] tert-Butyl((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl ) carbamate (see compound 5015, 100 mg, 0.209 mmol), tert-butyl ((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)(2-methoxyethyl)carbamate was converted to tert-butyl((3S,6R)-6-((S)-1-(4- Prepared as described for fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)(2-methoxyethyl)carbamate (Compound 5030) and as such Used for next step.

[0405] LCMS: 70%, retention time = 2.21 min, (M-tBu) + =455(Method A).

[0406] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5R)-5-((2-methoxyethyl)amino)tetrahydro-2H- Synthesis of pyran-2-yl)methanone (compound 5035).

[0407] tert-Butyl((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl )(2-methoxyethyl)carbamate (99 mg (70 wt%)), 0.135 mmol), ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- yl)((2S,5R)-5-((2-methoxyethyl)amino)tetrahydro-2H-pyran-2-yl)methanone (Compound 5035), ((S)-1-(4-fluorophenyl) -3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H-pyran-2-yl)methanone (compound 5030) It was prepared as follows.

[0408] LCMS: 99%, retention time = 1.07 min, (M+H) + =413(Method P). SFC: retention time = 4.33 minutes, (M+H) + =413(Method F).

[0409] Example 22 ((2R,4S)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5036) synthesis [ka]

[0410] Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-methylenetetrahydrofuran-2-yl)methanone.

[0411] Under a nitrogen atmosphere at 0 °C, a solution of potassium tert-butoxide (1M solution in tetrahydrofuran, 2.53 mL, 2.53 mmol) was added to a solution of methyltriphenylphosphonium bromide (1054 mg, 2.95 mmol) in tetrahydrofuran (anhydrous, 15.0 mL). Added dropwise to the suspension. After 30 minutes, (R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran in tetrahydrofuran (anhydrous, 7.5 mL). A solution of -3(2H)-one (see compound 5004, 715 mg, 2.107 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was filtered through Celite and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica, 0-30% ethyl acetate in heptane) to give ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H) -yl)((R)-4-methylenetetrahydrofuran-2-yl)methanone was obtained.

[0412] LCMS: 99%, retention time = 2.14 min, (M+H) + =338(Method B).

[0413] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3R,6R)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3S,6R)-1,5-dioxaspiro[2.4]heptan-6-yl) Synthesis of methanone.

[0414] m-Chloroperbenzoic acid (70%, 513 mg, 2.081 mmol) was dissolved in ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)-) in dichloromethane (6.0 mL). yl)((R)-4-methylenetetrahydrofuran-2-yl)methanone (585 mg, 1.734 mmol). After stirring the reaction overnight, the mixture was purified by flash column chromatography (silica, 0-60% ethyl acetate in heptane) to give ((S)-1-(4- (( S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3S,6R)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone was obtained. Ta.

[0415] First eluting isomer: LCMS: 95%, retention time = 2.00 min, (M+H) + =354(Method A).

[0416] Second eluting isomer: LCMS: 96%, retention time = 1.97 min, (M+H) + =354(Method A).

[0417] ((2R,4S)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5036).

[0418] Ethylamine (2.0M in tetrahydrofuran, 1.026mL, 2.052mmol) was dissolved in ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H) in tetrahydrofuran (anhydrous, 1.0mL)). -yl)((3S,6R)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone (58 mg, 0.164 mmol). The reaction vial was sealed and heated at 40°C for 6 days. The reaction mixture was concentrated to dryness under reduced pressure and the residue was subjected to acidic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 16.6 min 40% A, t = 17.6 min 100%, t=23.8 min 100% A, detection: 220 nm). Pool the product-containing fractions and add saturated NaHCO 3 It was basified with aqueous solution (2.5 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organics were washed with brine (15 mL) and 2 S.O. 4 ((2R,4S)-4-((ethylamino)methyl)-4-hydroxy Tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5036) was obtained.

[0419] LCMS: 99%, retention time = 1.05 min, (M+H) + =399(Method P).

[0420] Example 23 ((2R,4R)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5037) synthesis [ka]

[0421] ((2R,4R)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5037).

[0422] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3R,6R)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone (See compound 5036, 53 mg, 0.150 mmol) starting from ((2R,4R)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-( 4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5037) was converted into ((2R,4S)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2 -yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5036).

[0423] LCMS: 97%, retention time = 1.03 min, (M+H) + =399(Method P).

[0424] Example 24 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4R)-4-hydroxy-4-(((2-hydroxyethyl)amino )Methyl)tetrahydrofuran-2-yl)methanone (compound 5038) synthesis [ka]

[0425] Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-methylenetetrahydrofuran-2-yl)methanone.

[0426] (R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one (see compound 5004, Starting from ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-methylenetetrahydrofuran-2- methanone (compound 5036).

[0427] LCMS: 99%, retention time = 2.17 min, (M+H) + =338(Method B).

[0428] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3S,6S)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3R,6S)-1,5-dioxaspiro[2.4]heptan-6-yl) Synthesis of methanone.

[0429] From ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-methylenetetrahydrofuran-2-yl)methanone (145 mg, 0.430 mmol) Starting with ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3S,6S)-1,5- dioxaspiro[2.4]heptan-6-yl)methanone, and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(( 3R,6S)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone, ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Prepared as described for ((3R,6R)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone (see compound 5036). The configuration of the spiro-epoxide was assigned arbitrarily.

[0430] First eluting isomer: LCMS: 98%, retention time = 1.99 min, (M+H) + =354(Method A).

[0431] Second eluting isomer: LCMS: 99%, retention time = 1.97 min, (M+H) + =354(Method A).

[0432] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4R)-4-hydroxy-4-(((2-hydroxyethyl)amino ) Synthesis of methyl)tetrahydrofuran-2-yl)methanone (compound 5038).

[0433] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3R,6S)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone (30 mg, 0.085 mmol) ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4R)-4-hydroxy- 4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone (Compound 5038) was converted into ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H)-yl)((2R,4R)-4-hydroxy-4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone (Compound 5040). The configuration of the tetrahydrofuran-hydroxy moiety was arbitrarily assigned.

[0434] LCMS: 97%, retention time = 1.02 min, (M+H) + =415(Method P).

[0435] Example 25 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4S)-4-hydroxy-4-(((2-hydroxyethyl)amino )Methyl)tetrahydrofuran-2-yl)methanone (compound 5039) [ka]

[0436] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4S)-4-hydroxy-4-(((2-hydroxyethyl)amino ) Synthesis of methyl)tetrahydrofuran-2-yl)methanone (compound 5039).

[0437] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3S,6S)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone (See Compound 5038, 71 mg, 0.201 mmol) ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4S) -4-hydroxy-4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone (compound 5039) was obtained after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL). ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4R)-4-hydroxy-4-(((2-hydroxyethyl)amino ) methyl)tetrahydrofuran-2-yl)methanone (Compound 5040). The configuration of the tetrahydrofuran-hydroxy moiety was arbitrarily assigned.

[0438] LCMS: 99%, retention time = 1.00 min, (M+H) + =415(Method P).

[0439] Example 26 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4R)-4-hydroxy-4-(((2-hydroxyethyl)amino )Methyl)tetrahydrofuran-2-yl)methanone (compound 5040) synthesis [ka]

[0440] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4R)-4-hydroxy-4-(((2-hydroxyethyl)amino ) Synthesis of methyl)tetrahydrofuran-2-yl)methanone (compound 5040).

[0441] Ethanolamine (0.055 mL, 0.906 mmol) was dissolved in ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3R, 6R)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone (see compound 5036, 64 mg, 0.181 mmol) was added to a solution. The reaction vial was sealed and heated at 35° C. overnight. The reaction mixture was concentrated to dryness under reduced pressure and the residue was subjected to acidic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 16.6 min 40% A, t = 17.6 min 100%, t=23.8 min 100% A, detection: 220 nm). Pool the product-containing fractions and add saturated NaHCO 3 It was basified with aqueous solution (2.5 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organics were washed with brine (15 mL) and 2 S.O. 4 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline) after drying on top and evaporation under reduced pressure and lyophilization from a mixture of acetonitrile and water (1:1, 4 mL). -2(1H)-yl)((2R,4R)-4-hydroxy-4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone (Compound 5040) was obtained.

[0442] LCMS: 99%, retention time = 1.01 min, (M+H) + =415(Method P).

[0443] Example 27 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S)-4-hydroxy-4-(((2-hydroxyethyl)amino )Methyl)tetrahydrofuran-2-yl)methanone (compound 5041) synthesis [ka]

[0444] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S)-4-hydroxy-4-(((2-hydroxyethyl)amino ) Synthesis of methyl)tetrahydrofuran-2-yl)methanone (compound 5041).

[0445] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3S,6R)-1,5-dioxaspiro[2.4]heptan-6-yl)methanone (See Compound 5036, 55 mg, 0.156 mmol) (S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S)- 4-Hydroxy-4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone (Compound 5041) was converted into ((S)-1-(4-fluorophenyl)-3,4-dihydro isoquinolin-2(1H)-yl)((2R,4R)-4-hydroxy-4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone (Compound 5040) It was prepared as follows.

[0446] LCMS: 99%, retention time = 1.02 min, (M+H) + =415(Method P).

[0447] Example 28 ((2R,5S)-5-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone( Synthesis of compound 5042). [ka]

[0448] tert-Butyl((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl ) Synthesis of carbamates.

[0449] Under nitrogen atmosphere, (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (281 mg, 1.237 mmol) and N,N-diisopropylethylamine (0.514 mL, 2.95 mmol) were (2R,5S)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (289 mg, 1.178 mmol) in N,N-dimethylformamide (anhydrous, 5.5 mL), N- (3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (248 mg, 1.296 mmol) and 1-hydroxy-7-azabenzotriazole (32.1 mg, 0.236 mmol) were added to a suspension of Stirred overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with brine (15 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic phases were washed with brine (3 x 15 mL) and Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-45% ethyl acetate in heptane) to give tert-butyl ((3S,6R)-6-((S)-1-(4-fluorophenyl) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate was obtained.

[0450] LCMS: 99%, retention time = 2.16 min, (M+H) + =455(Method A).

[0451] ((2R,5S)-5-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone( Synthesis of compound 5042).

[0452] HCl (5-6M in 2-propanol, 4.5 mL, 112 mmol) was added to tert-butyl ((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3, Added to 4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate (694 mg, 1.526 mmol). After 2 hours, the reaction mixture was diluted with dichloromethane (25 mL) and saturated Na 2 C.O. 3 Washed with aqueous solution (10 mL). The aqueous layer was extracted with dichloromethane (3 x 15 mL) and the combined organic phases were 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was dissolved in methanol, transferred to an SCX-2 column (5 g), and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (1M). The basic fractions were concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:2, 30 mL) to yield ((2R,5S)-5-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4 -fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5042) was obtained.

[0453] LCMS: 99%, retention time=1.03 min, (M+H) + =355(Method P). SFC: Retention time = 5.32 minutes, (M+H) + =355(Method W).

[0454] Example 29 ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5043). [ka]

[0455] Synthesis of tert-butyl ((3S,6S)-4-(benzyloxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)carbamate.

[0456] Aqueous NaOH (50%, 20 mL) was added to tert-butyl ((3S,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxytetrahydro-2H-pyrane in dichloromethane (20 mL). -3-yl)carbamate (0.70 g, 1.936 mmol), tetrabutylammonium hydrogen sulfate (1.972 g, 5.81 mmol), and benzyl bromide (0.576 mL, 4.84 mmol). The mixture was stirred for 5 hours, diluted with ice-cold water (50 mL), and extracted with dichloromethane (3 x 30 mL). The combined phase is Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-35% ethyl acetate in heptane) to give tert-butyl ((3S,6S)-4-(benzyloxy)-6-(((tert-butyl Dimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)carbamate was obtained.

[0457] LCMS: 85%, retention time = 2.69 minutes, (M-Boc+H) + =352(Method B).

[0458] Synthesis of tert-butyl ((3S,6S)-4-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate.

[0459] Under an argon atmosphere at 0 °C, tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 4.14 mL, 4.14 mmol) was dissolved in tert-butyl ((3S,6S)-4-( Added dropwise to a solution of benzyloxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)carbamate (0.623 g, 1.379 mmol). The reaction mixture was allowed to reach room temperature and stirred for 4 hours. Saturate the reaction mixture with NH 4 Quenched with aqueous Cl (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (20 mL) and washed with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-80% ethyl acetate in heptane) to give tert-butyl((3S,6S)-4-(benzyloxy)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3-yl)carbamate was obtained.

[0460] LCMS: 95%, retention time = 1.91 min, (M+Na) + =360(Method A)

[0461] Synthesis of (2S,5S)-4-(benzoyloxy)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid.

[0462] Sodium periodate (875 mg, 4.09 mmol) and ruthenium(III) chloride hydrate (30.7 mg, 0.136 mmol) were dissolved in tert-butyl chloride in a mixture of dichloromethane (6 mL), acetonitrile (6 mL), and water (9 mL). Added to a solution of ((3S,6S)-4-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (460 mg, 1.363 mmol). After stirring overnight, the mixture was cooled in an ice / water bath and saturated Na 2 S 2 O 3 Diluted with aqueous solution. After warming to room temperature, the pH was adjusted to approximately 6-7 by adding aqueous HCl (1M) and the mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with brine (10 mL) and washed with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was analyzed by acid preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 16 min 60% A, t = 17 min 100%, t = 22 min 100% A, Detection: 220 nm) to give (2S,5S)-4-(benzoyloxy)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid.

[0463] LCMS: 68%, retention time = 1.88 min, (M+H) + =364(Method A).

[0464] (2S,5S)-5-((tert-butoxycarbonyl)amino)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro Synthesis of -2H-pyran-4-ylbenzoate.

[0465] Under an argon atmosphere, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (23.91 mg, 0.125 mmol) and 1-hydroxy-7-azabenzotriazole (3.23 mg, 0.024 mmol) were added, followed by ( S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (27 mg, 0.119 mmol) and N,N-diisopropylethylamine (0.052 mL, 0.297 mmol) in (2S,5S)-4-(benzoyloxy)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (43.4 mg, 0.119 mmol) in Mido (anhydrous, 1 mL) added to the solution. After stirring for 3 days, the mixture was diluted with ethyl acetate (10 mL) and saturated NaHCO 3 Washed with aqueous solution (5 mL). The aqueous phase was extracted with ethyl acetate (3 x 10 mL) and the combined organics were washed with brine (15 mL) and Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to give (2S,5S)-5-((tert-butoxycarbonyl)amino)-2-((S)- 1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-ylbenzoate was obtained.

[0466] LCMS: 95%, retention time = 2.25 min, (M+H) + =575(Method A).

[0467] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran -3-yl)carbamate synthesis.

[0468] Aqueous NaOH (1M, 0.139mL, 0.139mmol) was dissolved in (2S,5S)-5-((tert-butoxycarbonyl)amino)-2-(( S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-ylbenzoate (40 mg, 0.070 mmol). After 4 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and extracted with dichloromethane (2 x 10 mL). The organic layers were combined and passed through a phase separator. The filtrate was evaporated under reduced pressure. The residue was analyzed by acid preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 16 min 60% A, t = 17 min 100%, t = 22 min 100% A, Detection: 220 / 254 nm) and purified by tert-butyl ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate was obtained.

[0469] LCMS: 100%, retention time = 2.07 min, (M+H) + =471(Method A).

[0470] ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5043).

[0471] HCl (5-6M in 2-propanol, 83 μL, 0.46 mmol) was dissolved in tert-butyl ((3S,4R,6S)-6-((S)-1-(4 -fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate (20 mg, 0.043 mmol) and stirred overnight. did. Three portions of HCl (5-6M in 2-propanol, 83 μL, 0.46 mmol) were added after stirring for 1, 2, and 3 days, respectively. After stirring for an additional 3 days, the reaction mixture was dissolved in dichloromethane (10 mL) and saturated K 2 C.O. 3 Diluted with aqueous solution (5 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3 x 10 mL). The combined phase is Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was dissolved in methanol (1 mL), transferred to an SCX-2 column (1 g), and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (7M). The basic fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((2S,4R,5S)-5-amino-4-hydroxytetrahydro -2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5043) was obtained.

[0472] LCMS: 100%, retention time = 1.01 min, (M+H) + =371(Method P).

[0473] Example 30 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-1,4-oxazepan-7-yl)methanone (compound 5044) and ( Synthesis of (S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-1,4-oxazepan-7-yl)methanone (Compound 5045). [ka]

[0474] tert-Butyl (S)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxazepane-4-carboxylate and Synthesis of (R)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxazepane-4-carboxylate.

[0475] N,N-diisopropylethylamine (80 μl, 0.459 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (153 mg, 0.404 mmol) was added to a solution of 4-(tert-butoxycarbonyl)-1,4-oxazepane-7-carboxylic acid (90 mg, 0.367 mmol) in dichloromethane (5 mL). After 10 minutes, (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (92 mg, 0.404 mmol) was added and stirring was continued for 2 hours. The reaction mixture was then mixed with aqueous HCl (1 M, 5 mL), saturated NaHCO 3 Wash with aqueous solution (5 mL) and brine (5 mL), and 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by preparative LCMS (Method BF) and preparative chiral SFC (Method Y) to yield tert-butyl (S)-7-((S)-1-(4) as the first eluting SFC isomer. -fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxazepane-4-carboxylate, and tert-butyl(R)-7- as the second eluting SFC isomer. ((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxazepane-4-carboxylate was obtained. The configuration of the oxazepane stereocenter was arbitrarily assigned.

[0476] First elution SFC isomer: LCMS: 97%, retention time = 2.18 min, (M-tBu+H) + =399(Method A). SFC: Retention time = 2.60 minutes, (M-tBu+H) + =399(Method W).

[0477] Second elution SFC isomer: LCMS: 99%, retention time = 2.17 min, (M-tBu+H) + =399(Method A). SFC: Retention time = 3.14 minutes, (M-tBu+H) + =399(Method W).

[0478] Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-1,4-oxazepan-7-yl)methanone (compound 5044) .

[0479] Trifluoroacetic acid (0.5 mL, 6.53 mmol) was dissolved in tert-butyl (S)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydro) in dichloromethane (5 mL). was added to a solution of isoquinoline-2-carbonyl)-1,4-oxazepane-4-carboxylate (10 mg, 0.022 mmol). After 4 hours, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL), transferred to an SCX-2 column (1 g), and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (3M). The basic fraction was concentrated to dryness under reduced pressure and after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL) ((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)((S)-1,4-oxazepan-7-yl)methanone (Compound 5044) was obtained. The configuration of the oxazepane stereocenter was arbitrarily assigned.

[0480] LCMS: 100%, retention time = 1.05 min, (M+H) + =355(Method P). SFC: Retention time = 4.16 minutes, (M+H) + =355(Method W).

[0481] Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-1,4-oxazepan-7-yl)methanone (compound 5045) .

[0482] tert-Butyl(R)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxazepane-4-carboxylate( ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-1,4-oxazepan-7 -yl)methanone (compound 5045), ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-1,4-oxazepan-7 -yl)methanone (Compound 5044). The configuration of the oxazepane stereocenter was arbitrarily assigned.

[0483] LCMS: 100%, retention time = 1.04 min, (M+H) + =355(Method P). SFC: retention time = 4.63 minutes, (M+H) + =355(Method W).

[0484] Example 31 ((2S,5S)-5-(aminomethyl)-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H)-yl)methanone (compound 5046) and ((2R,5R)-5-(aminomethyl)-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5047) [ka]

[0485] Synthesis of ethyl trans-1,5-dioxaspiro[2.5]octane-6-carboxylate.

[0486] Under nitrogen atmosphere, sodium hydride (60% dispersion in oil, 32.5 mg, 0.813 mmol) was added to a solution of trimethylsulfoxonium iodide (179 mg, 0.813 mmol) in dimethyl sulfoxide (2.0 mL). . After 0.5 h, a solution of ethyl 5-oxotetrahydro-2H-pyran-2-carboxylate (100 mg, 0.581 mmol) in 1,2-dimethoxyethane (1.0 mL) was added. After stirring for an additional 2 hours, the reaction mixture was diluted with saturated NH 4 Poured into a mixture of aqueous Cl and ice (20 mL) and the resulting mixture was extracted with diethyl ether (2 x 15 mL) and ethyl acetate (15 mL). The combined organic phases were washed with water and the Na 2 S.O. 4 Dry on top and concentrate under reduced pressure. The residue was purified by flash column chromatography (silica, 10-50% ethyl acetate in heptane) to yield ethyl trans-1,5-dioxaspiro[2.5]octane-6-carboxylate.

[0487] GCMS: 99%, retention time = 3.06 min, (M-CO 2 Et) + =113 (method A20).

[0488] Synthesis of ethyl trans-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2-carboxylate.

[0489] A mixture of sodium azide (52.4 mg, 0.806 mmol) in acetic acid (0.15 mL) and water (0.26 mL) was added to ethyl trans-1,5-dioxaspiro[2.5]octane-6-carboxylate (30 mg, 0.161 mmol). added to. After 3 hours, the reaction mixture was diluted with dichloromethane (10 mL) and saturated K 2 C.O. 3 Diluted with a mixture of aqueous solution (1 mL) and water (1 mL). The layers were separated using a phase separator and the organic filtrate was concentrated. The residue was purified by flash column chromatography (silica, 10-70% ethyl acetate in heptane) to yield ethyl trans-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2-carboxylate. .

[0490] LCMS: 99%, retention time = 1.76 min (Method B).

[0491] Synthesis of trans-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2-carboxylic acid.

[0492] Aqueous NaOH (2M, 0.079mL, 0.157mmol) was added to a solution of ethyltrans-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2-carboxylate (30mg, 0.131mmol) in methanol (0.3mL). added to. After 1 hour, the mixture was diluted with dichloromethane and acidified with aqueous HCl (1M) to pH ~1-2. The layers were separated using a phase separator and the aqueous layer was treated with brine (4 mL) and stirred with a mixture of dichloromethane and methanol (4:1, 4 mL). Separate the layers using a phase separator and combine the organic filtrate with the organic filtrate of the first extraction and evaporate under reduced pressure to obtain trans-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran- 2-carboxylic acid was obtained.

[0493] (trans-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Synthesis of methanone

[0494] 1-Hydroxy-7-azabenzotriazole (2.57 mg, 0.019 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (21.73 mg, 0.113 mmol) in acetonitrile (0.5 mL). (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (21.46 mg, 0.094 mmol) and trans-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2- Added to a solution of carboxylic acid (19 mg, 0.094 mmol). After stirring overnight, the mixture was diluted with water and acetonitrile (1:1, 1 mL) and subjected to acidic preparative MPLC (linear gradient: t = 0 min 20% A, t = 3 min 20% A, t = 18 min). 60% A, t=19 min 100%, t=24 min 100% A, detection: 210 nm). Product-containing fractions were pooled and volatiles were removed under reduced pressure. Saturate the aqueous residue with NaHCO 3 Diluted with aqueous solution (5 mL) and dichloromethane (5 mL) and stirred for 2 hours. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by preparative chiral SFC to yield ((2S,5S)-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2-yl)((S) -1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone, and as the second eluting SFC isomer ((2R,5R)-5-(azidomethyl)-5- Hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained. The configuration of the pyran stereocenter is arbitrarily assigned.

[0495] First eluting isomer: LCMS: 99%, retention time = 2.07 min, (M+H) + =411(Method C). SFC: retention time = 3.73 minutes, (M+H) + =411(Method W).

[0496] Second eluting isomer: LCMS: 99%, retention time = 2.07 min, (M+H) + =411(Method C). SFC: Retention time = 4.94 minutes, (M+H) + =411(Method W).

[0497] ((2S,5S)-5-(aminomethyl)-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( Synthesis of 1H)-yl)methanone (compound 5046).

[0498] Palladium on carbon (10 wt%, water content 50%, spatula end) was converted into ((2S,5S)-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-( Added to a solution of 4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (12.2 mg, 0.030 mmol). The mixture was hydrogenated at room temperature and ambient pressure for 4 hours, diluted with methanol, filtered through a nylon, 0.45 μm filter, and the filtrate was evaporated under reduced pressure. The residue was analyzed by acidic preparative MPLC (linear gradient: t = 0 min 5% A, t = 2 min 10% A, t = 17 min 50% A, t = 18 min 100%, t = 23 min 100% A, Detection: 210 nm). Pool the product-containing fractions and add saturated NaHCO 3 Diluted with aqueous solution (4 mL) and extracted with dichloromethane. The organic layer was passed through a phase separator, evaporated under reduced pressure and after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL), ((2S,5S)-5-(aminomethyl)-5-hydroxy Tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5046) was obtained. The configuration of the pyran stereocenter is arbitrarily assigned.

[0499] LCMS: 99%, retention time = 2.57 min, (M+H) + =385(Method AK).

[0500] ((2R,5R)-5-(aminomethyl)-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( Synthesis of 1H)-yl)methanone (compound 5047).

[0501] Palladium on carbon (10 wt%, water content 50%, spatula end) was converted into ((2R,5R)-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-( Added to a solution of 4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (12.2 mg, 0.030 mmol). The mixture was hydrogenated at room temperature and ambient pressure for 4 hours, diluted with methanol, filtered through a nylon, 0.45 μm filter, and the filtrate was evaporated under reduced pressure. The residue was analyzed by acidic preparative MPLC (linear gradient: t = 0 min 5% A, t = 2 min 10% A, t = 17 min 50% A, t = 18 min 100%, t = 23 min 100% A, Detection: 210 nm). Pool the product-containing fractions and add saturated NaHCO 3Diluted with aqueous solution (4 mL) and extracted with dichloromethane. The organic layer was passed through a phase separator, evaporated under reduced pressure and after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL), ((2S,5S)-5-(aminomethyl)-5-hydroxy Tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5047) was obtained. The configuration of the pyran stereocenter is arbitrarily assigned.

[0502] LCMS: 99%, retention time = 1.03 min, (M+H) + =385(Method P).

[0503] Example 32 (trans-5-amino-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5048) synthesis of. [ka]

[0504] Synthesis of ethyl 5-methylene-1,3-dioxane-2-carboxylate.

[0505] In 15 min, a suspension of ethyl 2,2-ditoxyacetate (6.58 mL, 36.8 mmol) and 2-methylenepropane-1,3-diol (3 mL, 36.8 mmol) in chloroform (10 mL) was dissolved in chloroform (20 mL). ) in boron trifluoride etherate (approximately 48%BF 3 , 9.33 mL, 73.6 mmol) dropwise. After stirring at reflux for 1.5 h, the reaction mixture was cooled to room temperature and treated with water, saturated Na 2 C.O. 3 Continuously wash with aqueous solution and water, Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to yield ethyl 5-methylene-1,3-dioxane-2-carboxylate.

[0506] GCMS: 96%, retention time = 2.67 min, (M-CO 2 Et) + =99 (method A20).

[0507] Synthesis of ethyl 5-oxo-1,3-dioxane-2-carboxylate.

[0508] Sodium periodate (10.39 g, 48.6 mmol) was dissolved in ethyl 5-methylene-1,3-dioxane-2-carboxylate (2.09 g) in a mixture of acetonitrile (20 mL), dichloromethane (20 mL), and water (20 mL). , 12.14 mmol) and ruthenium(III) chloride hydrate (0.109 g, 0.486 mmol). The reaction became exothermic and the mixture was cooled to ambient temperature with ice / water. After 1 hour, the reaction mixture was diluted with ethyl acetate, mixed well, and filtered. The residue was washed with ethyl acetate and the combined organic filtrates were washed with brine. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to yield ethyl 5-oxo-1,3-dioxane-2-carboxylate.

[0509] GCMS: Retention time = 2.54 min, (M-CO 2 Et) + =101 (method A20).

[0510] Synthesis of ethyl cis-5-(dibenzylamino)-1,3-dioxane-2-carboxylate and ethyl(trans)-5-(dibenzylamino)-1,3-dioxane-2-carboxylate.

[0511] Dibenzylamine (0.222 mL, 1.148 mmol) was added to a solution of ethyl 5-oxo-1,3-dioxane-2-carboxylate (200 mg, 1.148 mmol) in dichloromethane (3 mL). After 15 minutes, sodium triacetoxyborohydride (292 mg, 1.378 mmol) was added and the mixture was stirred overnight. Additional sodium triacetoxyborohydride (243 mg, 1.148 mmol) and acetic acid (2 drops) were added and the reaction mixture was warmed to 40°C. After 2 hours, the reaction mixture was allowed to cool to room temperature and diluted with water and dichloromethane. Separate the layers and saturated the aqueous phase with NaHCO 3 Diluted with aqueous solution and extracted twice with dichloromethane. The combined organic phase was 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was analyzed by acid preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 2 min 20% A, t = 17 min 60% A, t = 18 min 100%, t=23 min 100% A, detection: 220 / 270 nm). The product fractions were combined and lyophilized to yield ethyl cis-5-(dibenzylamino)-1,3-dioxane-2-carboxylate as the first eluting isomer after lyophilization of the product-containing fractions. , and ethyl trans-5-(dibenzylamino)-1,3-dioxane-2-carboxylate as the second eluting isomer.

[0512] Cis isomer: LCMS: Retention time = 1.76 min, (M+H) + =356(Method A).

[0513] Trans isomer: LCMS: Retention time = 2.15 min, (M+H) + =356(Method A).

[0514] Synthesis of lithium trans-5-(dibenzylamino)-1,3-dioxane-2-carboxylate.

[0515] Lithium hydroxide monohydrate (5.67 mg, 0.135 mmol) was dissolved in ethyl trans-5-(dibenzylamino)-1,3-dioxane-2-carboxylate in a mixture of water (2 mL) and tetrahydrofuran (2 mL). (32 mg, 0.090 mmol). After 1 hour, the reaction mixture was concentrated to dryness under reduced pressure to yield lithium trans-5-(dibenzylamino)-1,3-dioxane-2-carboxylate, which was used as received.

[0516] LCMS: Retention time = 1.73 min, (M-Li) - =326(Method B).

[0517] (trans-5-(dibenzylamino)-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone synthesis of.

[0518] (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (20.46 mg, 0.090 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (20.70 mg, 0.108 mmol) and 1-hydroxy-7-azabenzotriazole (1.225 mg, 9.00 μmol) in N,N-dimethylformamide (anhydrous, 3 mL) with lithium trans-5-(dibenzylamino)-1 ,3-dioxane-2-carboxylate (0.090 mmol). After stirring the reaction mixture overnight, aqueous HCl (1 M, a few drops) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (8.63 mg, 0.045 mmol) were added and stirring was continued for 1 h. continued. The mixture was diluted with water and extracted three times with dichloromethane. The combined organic phase was 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by basic preparative MPLC (linear gradient: t = 0 min 10% A, t = 1 min 10% A, t = 2 min 40% A, t = 17 min 80% A, t = 18 min 100% A, t=23 min 100% A, detection: 210 / 220 / 270 nm), and after concentration and lyophilization of the product-containing fractions, (trans-5-(dibenzylamino)-1,3-dioxane) -2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0519] LCMS: 100%, retention time = 2.48 min, (M+H) + =537(Method B).

[0520] (trans-5-amino-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5048) synthesis of.

[0521] (trans-5-(dibenzylamino)-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( A solution of 1H)-yl)methanone (27 mg, 0.050 mmol) was hydrogenated in the presence of palladium (10 wt% on carbon, 50% water content, 8 mg, 3.76 μmol) at 50° C. and atmospheric hydrogen pressure. After 5 hours, the reaction mixture was filtered and the filtrate was subjected to basic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 2 min 20% A, t = 17 min 60 %A, t=18 min 100% A, t=23 min 100% A, detection: 210 / 220 / 270 nm) and after concentration and lyophilization of the product-containing fractions (trans-5-amino- 1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5048) was obtained.

[0522] LCMS: 100%, retention time = 1.03 min, (M+H) + =357(Method P).

[0523] Example 33 (cis-5-amino-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5049) and (cis-5-(ethylamino)-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone Synthesis of (compound 5050) [ka]

[0524] Synthesis of lithium cis-5-(dibenzylamino)-1,3-dioxane-2-carboxylate.

[0525] Lithium hydroxide monohydrate (13.22 mg, 0.315 mmol) was dissolved in ethyl cis-5-(dibenzylamino)-1,3-dioxane-2-carboxylate ( 56 mg, 0.158 mmol). After 1 h, the reaction mixture was diluted with aqueous HCl (1 M, 0.150 mL, 0.150 mmol) and concentrated to dryness under reduced pressure to obtain lithium cis-5-(dibenzylamino)-1,3-dioxane-2. -carboxylate was obtained and used as received.

[0526] LCMS: Retention time = 1.73 min, (M-Li) - =326(Method B).

[0527] (cis-5-(dibenzylamino)-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone synthesis of.

[0528] (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (36.1 mg, 0.159 mmol) and lithium cis-5-(dibenzylamino)-1,3-dioxane-2- Starting from carboxylate (0.159 mmol), (cis-5-(dibenzylamino)-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4- dihydroisoquinolin-2(1H)-yl)methanone, (trans-5-(dibenzylamino)-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3, Prepared as described for 4-dihydroisoquinolin-2(1H)-yl)methanone (see compound 5048).

[0529] LCMS: 100%, retention time = 2.48 min, (M+H) + =537(Method B).

[0530] (cis-5-amino-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5049) and (cis-5-(ethylamino)-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone Synthesis of (compound 5050).

[0531] (cis-5-(dibenzylamino)-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( A solution of 1H)-yl)methanone (24 mg, 0.045 mmol) was hydrogenated in the presence of palladium (10 wt% on carbon, 50% water content, 8 mg, 3.76 μmol) at 45° C. and atmospheric hydrogen pressure. After 5 hours, the reaction mixture was filtered and the filtrate was subjected to basic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 2 min 20% A, t = 17 min 60 %A, t=18 min 100% A, t=23 min 100% A, detection: 210 / 220 / 270 nm) and after concentration and lyophilization of the product-containing fractions (cis-5-amino- 1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5049) and (cis-5-( Ethylamino)-1,3-dioxan-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5050) was obtained. .

[0532] Compound 5049: LCMS: 100%, retention time = 1.03 min, (M+H) + =357(Method P).

[0533] Compound 5050: LCMS: 97%, retention time = 1.06 min, (M+H) + =385(Method P).

[0534] Example 34 ((2R,4S,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5051). [ka]

[0535] ((2R,4S,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5051).

[0536] tert-Butyl((2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H -pyran-4-yl) carbamate (see compound 5052, 53 mg, 0.113 mmol) starting with ((2R,4S,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl) ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5051) can be obtained without the need for additional purification. -(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-((2-methoxyethyl)amino)tetrahydro-2H-pyran-2-yl) Prepared as described for methanone (Compound 5030).

[0537] LCMS: 98%, retention time = 1.03 min, (M+H) + =371(Method P). SFC: retention time = 4.64 minutes, (M+H) + =371(Method F).

[0538] Example 35 ((2R,4S,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5052) synthesis [ka]

[0539] tert-Butyl((3R,4S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl)carbamate, tert-butyl((3S,4R,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate, tert-butyl((2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H-pyran-4-yl)carbamate, and tert-butyl((2R,4R,5R)-2-((S)-1-( Synthesis of 4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H-pyran-4-yl)carbamate.

[0540] ((R)-3,6-dihydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2.45 Starting from tert-butyl ((3S,4R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4- Prepared as described for tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate (see compound 5053). Purification of the crude product by flash column chromatography (silica, 0-70% ethyl acetate in heptane) and further purification of the mixed fractions by silica and chiral preparative SFC (Method S) after crystallization from 2-propanol. tert-butyl ((3R,4S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl) carbamate and tert-butyl (( 3S,4R,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3- yl) carbamate and tert-butyl ((2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4) as the third eluting isomer on silica. tert as the fourth eluting isomer on silica after further purification by chiral preparative SFC (Method AI). -Butyl((2R,4R,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H- pyran-4-yl) carbamate was obtained.

[0541] First eluting isomer on silica: LCMS: 100%, retention time = 2.07 min, (M+H) + =471(Method A). SFC: retention time = 3.59 minutes, (M+H) + =471(Method F).

[0542] Second elution isomer on silica: LCMS: 95%, retention time = 2.06 min, (M+H) + =471(Method A). SFC: retention time = 3.06 minutes, (M+H) + =471(Method F).

[0543] 3rd elution isomer on silica: LCMS: 100%, retention time = 2.06 min, (M+H) + =471(Method A). SFC: retention time = 3.32 minutes, (M+H) + =471(Method F).

[0544] 4th eluting isomer on silica: LCMS: 93%, retention time = 2.05 min, (M-Boc+H) + =371(Method A). SFC: Retention time = 3.07 minutes, (M-Boc+H) + =371(Method F).

[0545] ((2R,4S,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5052).

[0546] tert-Butyl((3R,4S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl)carbamate (30 mg, 0.064 mmol), starting with ((2R,4S,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5052) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- Prepared as described for pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043).

[0547] LCMS: 99%, retention time = 1.00 min, (M+H) + =371(Method P). SFC: Retention time = 4.47 minutes, (M+H) + =371(Method F).

[0548] Example 36 ((2S,4S,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5053) synthesis [ka]

[0549] ((R)-3,6-dihydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone and ( Synthesis of (S)-3,6-dihydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

[0550] 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (32.6 g, 86 mmol) and N,N-diisopropylethylamine (20.45 mL) , 117 mmol) was added to a solution of 3,6-dihydro-2H-pyran-2-carboxylic acid (10 g, 78 mmol) in dichloromethane (150 mL). After 10 minutes, (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (19.51 g, 86 mmol) was added and stirring continued for 1 hour. The reaction mixture was diluted with dichloromethane (120 mL) and saturated NaHCO 3 Wash with aqueous solution (2 x 50 mL) and HCl aqueous solution (1M, 2 x 50 mL), 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to give ((R)-3,6-dihydro-2H-pyran-2-yl as the first eluting isomer). )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone, and as the second eluting isomer ((S)-3,6-dihydro- 2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0551] First eluting isomer: LCMS: 87%, retention time = 2.12 min, (M+H) + =338(Method A). SFC: 100%, retention time = 3.18 minutes, (M+H) + =338(Method F).

[0552] Second eluting isomer: LCMS: 95%, retention time = 2.12 min, (M+H) + =338(Method A). SFC: 100%, retention time = 2.72 minutes, (M+H) + =338(Method F).

[0553] tert-Butyl((3S,4R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl)carbamate, tert-butyl((3R,4S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate, tert-butyl((2S,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H-pyran-4-yl)carbamate, and tert-butyl((2S,4R,5R)-2-((S)-1-( Synthesis of 4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H-pyran-4-yl)carbamate.

[0554] Sodium dichloroisocyanurate (1.29 g, 5.84 mmol) was added to a stirred mixture of tert-butyl carbamate (684 mg, 5.84 mmol) in 1-propanol (26 mL) and aqueous LiOH (0.5 M, 11.3 mL, 5.65 mmol). . After 15 minutes, a fine suspension was formed of hydroquinidine 1,4-phthalazinediyl diether ((DHQD) in freshly prepared 1-propanol (13 mL). 2PHAL, 76 mg, 0.097 mmol) and ((S)-3,6-dihydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( A solution of 1H)-yl)methanone (657 mg, 1.95 mmol) was added slowly. The reaction mixture was stirred for an additional 2 minutes before a solution of potassium osmate(VI) dihydrate (28.7 mg, 0.078 mmol) in water (8.6 mL) was added dropwise. After 3.5 hours, saturated aqueous sodium metabisulfite solution was added (10 mL) and the mixture was stirred for an additional 15 minutes. The mixture was filtered through a glass filter (por-4) and washed with 1-propanol. The filtrate volatiles were removed under reduced pressure and the aqueous residue was extracted with dichloromethane (2 x 20 mL). The combined organic phases were washed with brine and 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-100% ethyl acetate in heptane) and further purified by flash column chromatography (silica, 0-10% 2-propanol in heptane) followed by a second chromatography on silica. tert-butyl((3S,4R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)- as the eluting isomer of 1 4-Hydroxytetrahydro-2H-pyran-3-yl)carbamate was obtained. The second eluting fraction on silica was further purified by chiral preparative SFC (Method BH) and the first eluting isomer on SFC was tert-butyl ((3R,4S,6S)-6-(( S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate and the second The eluting isomer is tert-butyl((2S,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- hydroxytetrahydro-2H-pyran-4-yl) carbamate and tert-butyl ((2S,4R,5R)-2-((S)-1-(4-fluorophenyl) as the third eluting isomer in SFC. )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H-pyran-4-yl)carbamate was obtained.

[0555] 1st elution isomer on silica: LCMS: 85%, retention time = 2.07 min, (M+H) + =471(Method A). SFC: Retention time = 2.31 minutes, (M+H) + =471(method AU).

[0556] Second eluting fraction on silica, first eluting isomer on SFC: SFC: retention time = 1.97 min, (M+H) + =471(method AU).

[0557] Second eluting fraction on silica, second eluting isomer on SFC: SFC: retention time = 2.10 min, (M-Boc+H) + =371(Method AU).

[0558] Second eluting fraction on silica, third eluting isomer on SFC: SFC: retention time = 2.31 min, (M+H) + =471(method AU).

[0559] ((2S,4S,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5053).

[0560] tert-Butyl((3R,4S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl)carbamate (16 mg, 0.034 mmol), starting with ((2S,4S,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5053) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- Prepared as described for pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043).

[0561] LCMS: 99%, retention time = 1.01 min, (M+H) + =371(Method P). SFC: Retention time = 3.94 minutes, (M+H) + =371(Method W).

[0562] Example 37 ((2S,4R,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5054) synthesis [ka]

[0563] ((2S,4R,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5054).

[0564] tert-Butyl((2S,4R,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H -pyran-4-yl) carbamate (see compound 5053, 33 mg, 0.070 mmol) starting with ((2S,4R,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl) ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5054) was converted into ((2S,4R,5S)-5-amino-4- As described for hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043) Prepared.

[0565] LCMS: 99%, retention time = 1.02 min, (M+H) + =371(Method P). SFC: Retention time = 4.48 minutes, (M+H) + =371(Method AD).

[0566] Example 38 ((2R,4S,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5055) synthesis [ka]

[0567] (3R,4S,6R)-4-((tert-butoxycarbonyl)amino)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl ) Synthesis of tetrahydro-2H-pyran-3-yl 4-nitrobenzoate.

[0568] tert-Butyl((2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H -pyran-4-yl)carbamate (see compound 5052, 50 mg, 0.106 mmol), (3R,4S,6R)-4-((tert-butoxycarbonyl)amino)-6-((S) -1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl 4-nitrobenzoate, and after 2 days triphenylphosphine and azodicarboxylic acid. With the re-addition of diisopropyl, (2S,4S,5S)-5-((tert-butoxycarbonyl)amino)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl 4-nitrobenzoate (see compound 5056) was prepared as described and used directly in the next step.

[0569] LCMS: 93%, retention time = 2.30 min, (M+Na) + =642(Method A).

[0570] tert-Butyl((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H Synthesis of -pyran-4-yl)carbamate.

[0571] (3R,4S,6R)-4-((tert-butoxycarbonyl)amino)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl ) Tetrahydro-2H-pyran-3-yl 4-nitrobenzoate (67 mg crude, 0.106 mmol) starting from tert-butyl ((2R,4S,5R)-2-((S)-1-(4- tert-butyl ((3S,4S,6S)-6- ((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate (see compound 5056) Prepared as described for.

[0572] LCMS: 100%, retention time = 2.05 min, (M+H) + =471(Method A).

[0573] ((2R,4S,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5055).

[0574] tert-Butyl((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H -pyran-4-yl)carbamate (11 mg, 0.023 mmol), ((2R,4S,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5055) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- Prepared as described for pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043).

[0575] LCMS: 99%, retention time=1.03 min, (M+H) + =371(Method P). SFC: Retention time = 3.68 minutes, (M+H) + =371(Method AD).

[0576] Example 39 ((2S,4S,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5056) synthesis [ka]

[0577] (2S,4S,5S)-5-((tert-butoxycarbonyl)amino)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl ) Synthesis of tetrahydro-2H-pyran-4-yl 4-nitrobenzoate.

[0578] Diisopropylazodicarboxylate (0.025 mL, 0.128 mmol) was dissolved in tert-butyl ((3S,4R,6S)-6-((S)-1) in anhydrous tetrahydrofuran (0.4 mL) under an argon atmosphere at 0 °C. -(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate (see compound 5053, 40 mg, 0.085 mmol), Added to a solution of triphenylphosphine (33.4 mg, 0.128 mmol) and 4-nitrobenzoic acid (21.3 mg, 0.128 mmol). The reaction mixture was warmed to room temperature and stirred for 1 day. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The aqueous phase was extracted with ethyl acetate (2 x 5 mL) and the combined phases were 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-35% ethyl acetate in heptane) to give (2S,4S,5S)-5-((tert-butoxycarbonyl)amino)-2-((S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl 4-nitrobenzoate was obtained and used as received.

[0579] LCMS: 98%, retention time = 2.27 min, (M+H) + =620(Method A).

[0580] tert-Butyl((3S,4S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H Synthesis of -pyran-3-yl)carbamate.

[0581] A solution of lithium hydroxide monohydrate (2.98 mg, 0.071 mmol) in water (0.5 mL) was added to the (2S,4S,5S)-5-((tert-butoxycarbonyl)amino )-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl 4-nitrobenzoate (40 mg, 0.065 mmol) solution. After stirring for 1 h, the mixture was dissolved in dichloromethane (10 mL) and saturated NaHCO 3 Diluted with aqueous solution (10 mL). The aqueous layer was extracted with dichloromethane (2 x 10 mL) and the combined phases were 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-70% ethyl acetate in heptane) to give tert-butyl ((3S,4S,6S)-6-((S)-1-(4-fluoro Phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate was obtained.

[0582] LCMS: 100%, retention time = 2.03 min, (M+H) + =471(Method A).

[0583] ((2S,4S,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5056).

[0584] tert-Butyl((3S,4S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl)carbamate (15 mg, 0.032 mmol), starting with ((2S,4S,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5056) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- Prepared as described for pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043).

[0585] LCMS: 98%, retention time = 1.01 min, (M+H) + =371(Method P). SFC: Retention time = 4.55 minutes, (M+H) + =371(Method F).

[0586] Example 40 ((2R,4R,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5057) synthesis [ka]

[0587] tert-Butyl((3R,4R,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H Synthesis of -pyran-3-yl)carbamate.

[0588] tert-Butyl((3R,4S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl) carbamate (see compound 5052, 40 mg, 0.085 mmol) starting with tert-butyl ((3R,4R,6R)-6-((S)-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate, (2S,4S,5S)-5-((tert-butoxycarbonyl) )-amino)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl 4-nitrobenzoate (compound 5056) and tert-butyl ((3S,4S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 -Hydroxytetrahydro-2H-pyran-3-yl)carbamate (see compound 5056). LCMS: 100%, retention time = 2.03 min, (M+H) + =471(Method A).

[0589] ((2R,4R,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5057).

[0590] tert-Butyl((3R,4R,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl)carbamate (29 mg, 0.062 mmol), starting with ((2R,4R,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5057) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- Prepared as described for pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043).

[0591] LCMS: 99%, retention time = 2.51 min, (M+H) + =371(Method AK). SFC: retention time = 5.31 minutes, (M+H) + =371(Method F).

[0592] Example 41 ((2S,4S,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5058) synthesis [ka]

[0593] ((2S,4S,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5058).

[0594] tert-Butyl((2S,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H -pyran-4-yl) carbamate (see compound 5053, 35 mg, 0.074 mmol) starting with ((2S,4S,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl) ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5058) was converted into ((2S,4R,5S)-5-amino-4- As described for hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043) Prepared. LCMS: 99%, retention time = 1.01 min, (M+H) + =371(Method P). SFC: Retention time = 4.00 minutes, (M+H) + =371(Method AD).

[0595] Example 42 ((2S,4S,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5059). [ka]

[0596] tert-Butyl((3S,4S,6S)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H Synthesis of -pyran-3-yl)carbamate.

[0597] tert-Butyl((3S,4R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl) carbamate (see compound 5053, 76 mg, 0.162 mmol) starting from tert-butyl ((3S,4S,6S)-4-fluoro-6-((S)-1-( tert-butyl((2R,4S,5R)-5-fluoro- 2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamate (see compound 5069, 80°C It was prepared as described in ).

[0598] LCMS: 100%, retention time = 2.15 min, (M+H) + =473(Method A).

[0599] ((2S,4S,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5059).

[0600] tert-Butyl((3S,4S,6S)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H -pyran-3-yl)carbamate (34 mg, 0.072 mmol), starting with ((2S,4S,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5059) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5043) and preparatively Purified by chiral SFC (Method AN).

[0601] LCMS: 100%, retention time = 1.05 min, (M+H) + =373(Method P). SFC: retention time = 3.56 minutes, (M+H) + =373(Method AD).

[0602] Example 43 ((2S,5S)-5-amino-4,4-difluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5060). [ka]

[0603] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-oxotetrahydro-2H-pyran -3-yl)carbamate synthesis.

[0604] At 0 °C, 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (Des-Martin periodinane, 49.6 mg, 0.117 mmol) of tert-butyl ((3S,4R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2) in dichloromethane (1 mL). -carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate (see compound 5053, 50 mg, 0.106 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. Saturated Na 2 S 2 O 3 Aqueous and saturated NaHCO 3The reaction mixture was quenched with a mixture of aqueous solutions (1:1, 2 mL) and stirred for 1 h. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0-35% ethyl acetate in heptane) to give tert-butyl ((3S,6S)-6-((S)-1-(4-fluorophenyl) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-oxotetrahydro-2H-pyran-3-yl)carbamate was obtained.

[0605] LCMS: 82%, retention time = 2.15 min, (M+Na) + =491 and 18% as hydrate: retention time = 2.03 min, (M+Na) + =509(Method A).

[0606] tert-Butyl((3S,6S)-4,4-difluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H Synthesis of -pyran-3-yl)carbamate.

[0607] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- A solution of [bis(2- methoxyethyl)amino]sulfur trifluoride (2.6M in toluene, 0.072 mL, 0.188 mmol). After addition, tert-butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) in dichloromethane (0.5 ml) A solution of )-4-oxotetrahydro-2H-pyran-3-yl)carbamate (42 mg, 0.090 mmol) was added followed by ethanol (0.523 μl, 8.96 μmol). The reaction mixture was warmed to room temperature and stirred for 3 days. The reaction mixture was diluted with dichloromethane (1 mL), cooled in an ice bath, and diluted with saturated NaHCO 3 Quenched with aqueous solution (2 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0-30% ethyl acetate in heptane) to give tert-butyl ((3S,6S)-4,4-difluoro-6-((S)-1- (4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate was obtained.

[0608] LCMS: 100%, retention time = 2.20 minutes, (M+Na) + =513(Method A).

[0609] ((2S,5S)-5-amino-4,4-difluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5060).

[0610] tert-Butyl((3S,6S)-4,4-difluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H -pyran-3-yl)carbamate (23 mg, 0.047 mmol) ((2S,5S)-5-amino-4,4-difluorotetrahydro-2H-pyran-2-yl)((S)-1 -(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5060) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H-pyran -2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043).

[0611] LCMS: 99%, retention time = 1.09 min, (M+H) + =391(Method P). SFC: retention time = 4.64 minutes, (M+H) + =371(Method F).

[0612] Example 44 ((2R,4R,5R)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5061) synthesis [ka]

[0613] tert-Butyl((3R,4R,6R)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H Synthesis of -pyran-3-yl)carbamate.

[0614] tert-Butyl((3R,4S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl) carbamate (see compound 5052, 100 mg, 0.213 mmol) starting from tert-butyl ((3R,4R,6R)-4-fluoro-6-((S)-1-( tert-butyl((2R,4S,5R)-5-fluoro- Description of 2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamate (see compound 5069) It was prepared as follows.

[0615] LCMS: 99%, retention time = 2.16 min, (M+H) + =473(Method A).

[0616] ((2R,4R,5R)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5061).

[0617] tert-Butyl((3R,4R,6R)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H -pyran-3-yl)carbamate (86 mg, 0.182 mmol), ((2R,4R,5R)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5061) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- Pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043) and flash chromatographed. Purified by chromatography (silica, 0-2% (7M ammonia in methanol) in dichloromethane).

[0618] LCMS: 99%, retention time = 1.04 min, (M+H) + =373(Method P). SFC: Retention time = 3.37 minutes, (M+H) + =373(Method AD).

[0619] Example 45 ((2R,4S,5S)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5062). [ka]

[0620] tert-Butyl((2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro-2H Synthesis of -pyran-4-yl)carbamate.

[0621] Tetrabutylammonium hydrogen sulfate (15 mg, 0.043 mmol), followed by aqueous NaOH (50 wt%, 119 μL, 2.23 mmol) and methyl iodide (14.9 μL, 0.238 mmol) in toluene (1.2 mL) were added to tert-butyl (( 2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H-pyran-4- yl)carbamate (see compound 5052, 70 mg, 0.149 mmol). After stirring for 3 hours, additional amounts of aqueous NaOH (50 wt%, 119 μL, 2.23 mmol) and methyl iodide (14.9 μL, 0.238 mmol) were added and stirring continued overnight. The reaction mixture was diluted with water (4 mL) and dichloromethane (4 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to give tert-butyl ((2R,4S,5S)-2-((S)-1-(4-fluoro Phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro-2H-pyran-4-yl)carbamate was obtained.

[0622] LCMS: 99%, retention time = 2.18 min, (M+H) + =485(Method A).

[0623] ((2R,4S,5S)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5062).

[0624] tert-Butyl((2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro-2H -pyran-4-yl)carbamate (69 mg, 0.142 mmol), ((2R,4S,5S)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5062) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- Prepared as described for pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043).

[0625] LCMS: 99%, retention time = 1.06 min, (M+H) + =385(Method P). SFC: Retention time = 3.97 minutes, (M+H) + =385(Method AD).

[0626] Example 46 ((2R,4S,5S)-4-amino-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5063). [ka]

[0627] tert-Butyl((2R,4S,5S)-5-ethoxy-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H Synthesis of -pyran-4-yl)carbamate.

[0628] tert-Butyl((2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H -pyran-4-yl) carbamate (see compound 5052, 70 mg, 0.149 mmol) and ethyl iodide (19.0 μL, 0.238 mmol), tert-butyl ((2R,4S,5S)-5-ethoxy -2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamate 2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro-2H-pyran-4- yl)carbamate (see compound 5062).

[0629] LCMS: 99%, retention time = 2.24 min, (M+H) + =485(Method A).

[0630] ((2R,4S,5S)-4-amino-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5063).

[0631] tert-Butyl((2R,4S,5S)-5-ethoxy-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H -pyran-4-yl)carbamate (69 mg, 0.142 mmol), starting from ((2R,4S,5S)-4-amino-5-ethoxytetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5063) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- Prepared as described for pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043).

[0632] LCMS: 99%, retention time = 1.10 min, (M+H) + =399(Method P). SFC: Retention time = 3.91 minutes, (M+H) + =399(Method F).

[0633] Example 47 ((2R,4S,5R)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5064) synthesis [ka]

[0634] tert-Butyl((3R,4S,6R)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H Synthesis of -pyran-3-yl)carbamate.

[0635] tert-Butyl((3R,4R,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl)carbamate (see compound 5057, 114 mg, 0.242 mmol) starting from tert-butyl ((3R,4S,6R)-4-fluoro-6-((S)-1-( tert-butyl((2R,4S,5R)-5-fluoro- Description of 2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamate (see compound 5069) It was prepared as follows.

[0636] LCMS: 95%, retention time=2.19 min, (M+H) + =473(Method A).

[0637] ((2R,4S,5R)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5064).

[0638] tert-Butyl((3R,4S,6R)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H -pyran-3-yl)carbamate (50 mg, 0.106 mmol), methanol, and dichloroethane (to dissolve the starting material), ((2R,4S,5R)-5-amino-4-fluorotetrahydro-2H -pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5064), ((2S,4R,5S) -5-Amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043 ) and purified by flash chromatography (silica, 0-2% (7M ammonia in methanol) in dichloromethane).

[0639] LCMS: 98%, retention time = 1.04 min, (M+H) + =373(Method P). SFC: retention time = 3.43 minutes, (M+H) + =373(Method AD).

[0640] Example 48 ((2R,4R,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5065) synthesis [ka]

[0641] ((2R,4R,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5065).

[0642] tert-Butyl((3S,4R,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H -pyran-3-yl)carbamate (compound 5052, 50 mg, 0.106 mmol), starting from ((2R,4R,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)(( S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5065) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro -2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043) .

[0643] LCMS: 99%, retention time = 1.00 min, (M+H) + =371(Method P). SFC: Retention time = 4.70 minutes, (M+H) + =371(Method F).

[0644] Example 49 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4R)-4-((2-hydroxyethyl)amino)tetrahydrofuran-2- yl) methanone (compound 5066) and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4S)-4-((2-hydroxy Synthesis of ethyl)amino)tetrahydrofuran-2-yl)methanone (compound 5067). [ka]

[0645] ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4R)-4-((2-hydroxyethyl)amino)tetrahydrofuran-2- yl) methanone (compound 5066) and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4S)-4-((2-hydroxy Synthesis of ethyl)amino)tetrahydrofuran-2-yl)methanone (compound 5067).

[0646] Under a nitrogen atmosphere, ethanolamine (0.029 mL, 0.486 mmol) was dissolved in (S)-5-((S)-1-(4-fluorophenyl)-1,2,3 in ethanol (anhydrous, 3.0 mL). ,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one (see compound 5004, 150 mg, 0.442 mmol). After 3.5 hours, NaBH 4 (21.74 mg, 0.575 mmol) was added and stirring continued for an additional 1.5 h. The reaction mixture was diluted with water (1 mL), ethyl acetate (15 mL), and brine water (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic phase was 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 1-7% (7M ammonia in methanol) in dichloromethane). The product (109 mg) was mixed with that of a similar reaction (64 mg) and purified by preparative chiral SFC (Method BN) and purified after lyophilization from a mixture of water and acetonitrile (1:3, 3 mL). As the eluting isomer of 1 ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4R)-4-((2-hydroxyethyl) (amino)tetrahydrofuran-2-yl)methanone (compound 5066) and ((S)-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,4S)-4-((2-hydroxyethyl)amino)tetrahydrofuran-2-yl)methanone (Compound 5067) was obtained.

[0647] First eluting isomer: LCMS: 96%, retention time = 1.00 min, (M+H) + =385(Method P). SFC: retention time = 3.73 minutes, (M+H) + =385(Method AD).

[0648] Second eluting isomer: LCMS: 97%, retention time = 1.01 min, (M+H) + =385(Method P). SFC: Retention time = 4.31 minutes, (M+H) + =385(Method AD).

[0649] Example 50 ((2S,4R,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5068) synthesis [ka]

[0650] ((2S,4R,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5068).

[0651] ((1R,4R,6S)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( Starting from 1H)-yl)methanone (see compound 5072, 75 mg, 0.212 mmol), ((2S,4R,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)(( S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5068) was purified by preparative chiral SFC ((2S, 4R,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Prepared as described for methanone (see compound 5070).

[0652] LCMS: 98%, retention time = 1.03 min, (M+H) + =371(Method P). SFC: Retention time = 3.65 minutes, (M+H) + =371(Method W).

[0653] Example 51 ((2R,4S,5R)-4-amino-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5069) synthesis [ka]

[0654] tert-Butyl((2R,4S,5R)-5-fluoro-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H -pyran-4-yl)carbamate synthesis.

[0655] Triethylamine trifluoride (0.076 mL, 0.468 mmol) and perfluoro-1-butanesulfonyl fluoride (0.084 mL, 0.468 mmol) were dissolved in tert-hydrogen trifluoride (0.076 mL, 0.468 mmol) in anhydrous acetonitrile (1.5 mL) under an argon atmosphere in a microwave vial. Butyl((2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H-pyran -4-yl)carbamate (see compound 5052, 100 mg, 0.213 mmol) and triethylamine (0.196 mL, 1.407 mmol). The vial was sealed, transferred to a preheated oil bath at 60° C., and stirred for 3.5 hours. After cooling the mixture to room temperature, saturated NaHCO 3 Poured into a mixture of aqueous solution and ice (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL) and the combined phases were 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-35% ethyl acetate in heptane) to give tert-butyl ((2R,4S,5R)-5-fluoro-2-((S)-1- (4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamate was obtained.

[0656] LCMS: 99%, retention time = 2.18 min, (M+H) + =473(Method A).

[0657] ((2R,4S,5R)-4-amino-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5069).

[0658] tert-Butyl((2R,4S,5R)-5-fluoro-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H -pyran-4-yl)carbamate (36 mg, 0.076 mmol), ((2R,4S,5R)-4-amino-5-fluorotetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5069) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- Prepared as described for pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043).

[0659] LCMS: 99%, retention time = 1.07 min, (M+H) + =373(Method P). SFC: Retention time = 3.15 minutes, (M+H) + =373(Method AD).

[0660] Example 52 ((2R,4S,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5070) synthesis [ka]

[0661] ((1R,4R,6S)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H)-yl)methanone and ((1S,4R,6R)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3, Synthesis of 4-dihydroisoquinolin-2(1H)-yl)methanone.

[0662] m-Chloroperbenzoic acid (70%, 4.09 g, 16.60 mmol) was dissolved in ((R)-3,6-dihydro-2H-pyran-2-yl)((S)-1- (4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (see compound 5053, 2.8 g, 8.30 mmol) and NaHCO 3 (2.091g, 24.90mmol) in portions. The mixture was stirred for 3 days, then diluted with dichloromethane (300 mL) and saturated with NaHCO 3 Washed with aqueous solution. The aqueous phase was extracted with dichloromethane and the combined organic layers were extracted with saturated NaHCO 3 Wash with aqueous solution and brine, Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-100% ethyl acetate in heptane) to give ((1R,4R,6S)-3,7-dioxabicyclo[4.1 .0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone, and as the second eluting isomer ((1S ,4R,6R)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- Il) methanone was obtained.

[0663] First eluting isomer: LCMS: 88%, retention time = 2.01 min, (M+H) + =354(Method A).

[0664] Second eluting isomer: LCMS: 95%, retention time = 1.96 min, (M+H) + =354(Method A).

[0665] ((2R,4S,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5070).

[0666] Ammonia (32% in water, 517 μL, 8.55 mmol) was added to ((1R,4R,6S)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (302 mg, 0.855 mmol) and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was analyzed by acid preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 10% A, t = 16 min 50% A, t = 17 min 100%, t = 22 min 100% A, (Detection: 220 nm) and purified by preparative chiral SFC (method AN) and after lyophilization from a mixture of acetonitrile and water (1:1) ((2R,4S,5S)-5-amino-4-hydroxytetrahydro- 2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5070) was obtained.

[0667] LCMS: 99%, retention time = 1.00 min, (M+H) + =371(Method P). SFC: Retention time = 3.23 minutes, (M+H) + =371(Method AD).

[0668] Example 53 ((2R,4S)-4-amino-4-(hydroxymethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Synthesis of methanone (compound 5071). [ka]

[0669] Synthesis of (3S,5R)-3-amino-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbonitrile.

[0670] Titanium(IV) isopropoxide (0.109 mL, 0.368 mmol) was dissolved in (R)-5-((S)-1- in a mixture of methanol (super dry, 2 mL) and ammonia in methanol (7M, 2 mL) Added to a solution of (4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2H)-one (see compound 50004, 104 mg, 0.306 mmol). After stirring for 4 hours, trimethylsilyl cyanide (0.041 mL, 0.306 mmol) was added and stirring continued for 16 hours. Saturate the mixture with NaHCO 3 Diluted with aqueous solution (0.5 mL) and extracted with dichloromethane (20 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0-100% ethyl acetate in heptane) to give (3S,5R)-3-amino-5-((S)-1 as the first eluting isomer. -(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbonitrile, and (3R,5R)-3-amino-5- as the second eluting isomer. ((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbonitrile was obtained. The configuration of the tetrahydrofuran-amine stereocenter was arbitrarily assigned.

[0671] First eluting isomer: LCMS: 98%, retention time = 1.87 min, (M+H) + =366 (Method A), SFC: 99%, retention time = 3.49 minutes, (M+H) + =366(Method W).

[0672] Second eluting isomer: LCMS: 87%, retention time = 1.86 min, (M+H) + =366(Method A). SFC:99%, retention time=4.06 minutes, (M+H) + =366(Method W).

[0673] Synthesis of (3R,5R)-3-amino-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carboxylic acid

[0674] Sodium hydroxide (85 mg, 2.14 mmol) was dissolved in (3S,5R)-3-amino-5-((S)-1-(4-fluorophenyl)) in a mixture of methanol and water (1:1, 2 mL). -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbonitrile (78mg, 0.213mmol) was added to a solution and the mixture was stirred at 65°C for 4 hours. The volatiles were removed under reduced pressure and aqueous HCl (1M) was added until pH ~5. The mixture was extracted with ethyl acetate (4 mL) and Na 2 S.O. 4Dry above and evaporate under reduced pressure to give (3R,5R)-3-amino-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -carbonyl)tetrahydrofuran-3-carboxylic acid was obtained. The configuration of the tetrahydrofuran-amine stereocenter was arbitrarily assigned.

[0675] LCMS: 89%, retention time=1.72 min, (M+H) + =385(Method A).

[0676] ((2R,4S)-4-amino-4-(hydroxymethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) Synthesis of methanone (compound 5071)

[0677] At 0 °C, the borane-tetrahydrofuran complex (1M in tetrahydrofuran, 0.293 mL, 0.293 mmol) was dissolved in (3R,5R)-3-amino-5-((S)-1-( Added to a solution of (4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carboxylic acid (45 mg, 0.117 mmol). After 4 hours, aqueous NaOH (3M, 1 mL) was added and stirring was continued for 16 hours. The reaction mixture was 2 C.O. 3 and the product was extracted with ethyl acetate (10 mL). organic layer with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was analyzed by acid preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 16 min 40% A, t = 17 min 100%, t = 22 min 100% A, Detection: 220 / 216 nm). The residue was dissolved in methanol (2 mL), transferred to an SCX-2 column (1 g), and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (3M). The basic fraction was concentrated to dryness under reduced pressure and the residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((2R,4S)-4-amino-4-(hydroxy Methyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5071) was obtained. The configuration of the tetrahydrofuran-amine stereocenter was arbitrarily assigned.

[0678] LCMS: 95%, retention time = 1.01 min, (M+H) + =371(Method P). SFC:97%, retention time=3.45 minutes, (M+H) + =371(Method W).

[0679] Example 54 ((2S,4R,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5072) synthesis [ka]

[0680] ((1S,4S,6R)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H)-yl)methanone and ((1R,4S,6S)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3, Synthesis of 4-dihydroisoquinolin-2(1H)-yl)methanone.

[0681] ((S)-3,6-dihydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (2.71 g, 8.03 mmol) as the first eluting isomer on silica ((1S,4S,6R)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone, and as the second eluting isomer on silica ((1R,4S,6S)-3,7 -dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone, ((1R, 4R,6S)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) methanone and ((1S,4R,6R)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline -2(1H)-yl)methanone was prepared as described for.

[0682] First eluting isomer: LCMS: 84%, retention time = 2.00 min, (M+H) + =354(Method A).

[0683] Second eluting isomer: LCMS: 96%, retention time = 1.97 min, (M+H) + =354(Method A).

[0684] ((2S,4R,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5072).

[0685] ((1S,4S,6R)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H)-yl)methanone (200 mg, 0.447 mmol) was dissolved in ammonia (7M in methanol, 10 mL, 70 mmol). The reaction vial was sealed, heated to 60° C., and stirred for 3 days. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica, 0.5-8% (7M ammonia in methanol) in dichloromethane) and a portion of the product (45 mg out of 145 mg) was dissolved in methanol and applied to an SCX-2 column. (6g) and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (1M). The basic fractions were concentrated to dryness under reduced pressure. The product (35 mg) was mixed with a similarly prepared batch (53 mg) and purified by preparative chiral SFC (method AN) and after lyophilization from a mixture of acetonitrile and water (1:3, 3 mL). ((2S,4R,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5072) was obtained.

[0686] LCMS: 98%, retention time = 1.01 min, (M+H) + =371(Method P). SFC: Retention time = 3.35 minutes, (M+H) + =371(Method AD).

[0687] Example 55 ((2R,4R,5R)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5073) synthesis [ka]

[0688] tert-Butyl((2R,4R,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro-2H Synthesis of -pyran-4-yl)carbamate.

[0689] tert-Butyl((2R,4R,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H -pyran-4-yl) carbamate (see compound 5052, 35 mg, 0.074 mmol) starting with tert-butyl ((2R,4R,5R)-2-((S)-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro-2H-pyran-4-yl)carbamate, tert-butyl((2R,4S,5S)-2-(( Description of S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro-2H-pyran-4-yl)carbamate (see compound 5062) It was prepared as follows.

[0690] LCMS: 95%, retention time = 2.15 min, (M+Na) + =507(Method A).

[0691] ((2R,4R,5R)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5073).

[0692] tert-Butyl((2R,4R,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro-2H -pyran-4-yl)carbamate (34 mg, 0.070 mmol), starting with ((2R,4R,5R)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5073) was converted into ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H- Prepared as described for pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043).

[0693] LCMS: 99%, retention time = 1.05 min, (M+H) + =385(Method P).

[0694] Example 56 ((2R,4R,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5074) synthesis [ka]

[0695] ((2R,4R,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5074).

[0696] tert-Butyl((2R,4R,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H -pyran-4-yl) carbamate (see compound 5052, 22 mg, 0.047 mmol) starting with ((2R,4R,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl) ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5074) was converted into ((2S,4R,5S)-5-amino-4- As described for hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5043) Prepared.

[0697] LCMS: 99%, retention time = 1.00 min, (M+H) + =371(Method P).

[0698] Example 57 ((2R,4R)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone( Compound 5028) and ((2R,4S)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- Synthesis of yl)methanone (compound 5080) [ka]

[0699] Synthesis of (S)-1-(1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxyethan-1-one.

[0700] N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.320 g, 12.10 mmol) and 1-hydroxy-7-azabenzotriazole (0.150 g, 1.100 mmol) were dissolved in ( S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (2.5 g, 11.00 mmol) and glycolic acid (0.725 mL, 12.10 mmol). After 2 hours, the mixture was diluted with water and the layers were separated on a phase separation filter. The organic layer was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 10-60% ethyl acetate in heptane) to give (S)-1-(1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H)-yl)-2-hydroxyethan-1-one was obtained.

[0701] LCMS: 99%, retention time = 1.90 min, (M+H) + =286(Method A).

[0702] Synthesis of (S)-2-(1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetaldehyde.

[0703] A solution of dimethyl sulfoxide (0.850 mL, 11.97 mmol) in dichloromethane (15.0 mL) was added to a solution of oxalyl chloride (0.685 mL, 7.98 mmol) in dichloromethane (anhydrous, 7.5 mL) under a nitrogen atmosphere at -78 °C. Added dropwise. After 20 minutes, (S)-1-(1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxyethane-1-one in dichloromethane (7.5 mL). A solution of (1.138 g, 3.99 mmol) was added dropwise and after a further 30 minutes triethylamine (2.77 mL, 19.94 mmol) was added. After 30 minutes, the reaction mixture was warmed to room temperature and stirred for 1 hour. reaction mixture. Partitioned between water (50 mL) and dichloromethane (50 mL) and the aqueous phase extracted with dichloromethane (15 mL). The combined organic phases were washed with brine (30 mL) and washed with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. A portion of the residue was purified by basic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 2 min 20% A, t = 17 min 50% A, t = (S)-2-(1-(4-fluorophenyl)-3, 4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetaldehyde was obtained.

[0704] LCMS: 97%, retention time = 1.93 min, (M+H 2 O(hydrated ketone)+H) + =302(Method B).

[0705] (R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H-pyran-4-one Synthesis.

[0706] Copper(II) triflate (38.3 mg, 0.106 mmol) was dissolved in (S)-2-((2-(hydroxydiphenylmethyl)pyrrolidine) in cyclopentyl methyl ether (8.0 mL) under a nitrogen atmosphere in a microwave vial. -1-yl)methyl)-6-(trifluoromethyl)phenol (45.3 mg, 0.106 mmol) and triethylamine (0.015 mL, 0.106 mmol) were added to a stirred solution. The reaction vial was sealed with a septum and stirred for 1 hour. (S)-2-(1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetaldehyde (200 mg, 0.706 mmol) and powdered 4Å molecular sieve (400 mg) was added and the reaction mixture was cooled to -18°C and stirred for 30 minutes. Then (E)-((4-methoxybut-1,3-dien-2-yl)oxy)trimethylsilane (0.241 mL, 1.235 mmol) was added dropwise. After the mixture was slowly warmed to room temperature, stirring was continued for 45 minutes. After 2.25 hours, the reaction mixture was cooled in an ice / water bath and quenched by dropwise addition of trifluoroacetic acid (0.135 mL, 1.765 mmol). After 5 minutes, the reaction vial was stored in the freezer overnight. After warming to room temperature, the mixture was diluted with ethyl acetate (10 mL) and filtered through a small pad of Celite. The residue was rinsed with ethyl acetate (2 x 5 mL) and the combined filtrates were diluted with saturated Na 2 C.O. 3 Washed with aqueous solution (12.5 mL). The aqueous phase was extracted with ethyl acetate (12.5 mL). The combined organics were washed with brine (12.5 mL) and 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to obtain a small amount of (S)-2-((S)-1-(4-fluorophenyl)-1,2 (R)-2-((S)-1-(4-fluorophenyl)-1 containing ,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H-pyran-4-one ,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H-pyran-4-one was obtained.

[0707] LCMS: 95%, retention time = 1.99 min, (M+H) + =352(Method A).

[0708] Synthesis of (R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-4H-pyran-4-one.

[0709] Palladium on carbon (10 wt%, water content 50%, 72.7 mg, 0.068 mmol) was dissolved in (R)-2-((S)-1-(4- fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H-pyran-4-one (240 mg, 0.683 mmol). The mixture was hydrogenated at room temperature and ambient pressure for 1 hour. The reaction mixture was filtered through a nylon, 0.45 μm filter and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) and preparative chiral SFC (Method AM) to give (R)-2-((S)-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)tetrahydro-4H-pyran-4-one was obtained.

[0710] LCMS: 99%, retention time = 2.01 min, (M+H) + =354(Method A). SFC: Retention time = 3.79 minutes, (M+H) + =354(method AD

[0711] ((2R,4R)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone( Compound 5028) and ((2R,4S)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- Synthesis of yl)methanone (compound 5080).

[0712] Ammonium acetate (262 mg, 3.40 mmol) was dissolved in (R)-2-((S)-1-(4-fluorophenyl)-1,2,3 in 2,2,2-trifluoroethanol (4.0 mL)). ,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-4H-pyran-4-one (120 mg, 0.340 mmol). After stirring overnight, sodium cyanoborohydride (64.0 mg, 1.019 mmol) was added and after 2 hours an additional amount of sodium cyanoborohydride (64.0 mg, 1.019 mmol) was added. After a further 2 hours ammonium acetate (262 mg, 3.40 mmol) was added and after a further 1 hour sodium cyanoborohydride (64.0 mg, 1.019 mmol) was added. After continuing stirring for 1 hour, the reaction mixture was subjected to acidic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 2 min 10% A, t = 17 min 50% A). , t=18 min 100%, t=23 min 100% A, detection: 220 nm) and purified by preparative chiral SFC (method AL), as the first eluting SFC isomer ((2R,4R)-4- aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5028), and the second elution As the SFC isomer ((2R,4S)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- yl)methanone (compound 5080) was obtained after lyophilization, both from a mixture of acetyl and water (3:2, 2.5 mL).

[0713] Compound 5028: LCMS: 99%, retention time = 1.06 min, (M+H) + =355(Method P). SFC: Retention time = 4.24 minutes, (M+H) + =355(Method F).

[0714] Compound 5080: LCMS: 99%, retention time = 1.04 min, (M+H) + =355(Method P). SFC: Retention time = 4.58 minutes, (M+H) + =355(Method F).

[0715] Example 58 ((2S,4S)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone( Compound 5027) and ((2S,4R)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- Synthesis of yl)methanone (compound 5081) [ka]

[0716] (S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H-pyran-4-one Synthesis.

[0717] (R)-2-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)phenol (74.4 mg, 0.175 mmol) and (S)-2-(1-( Starting from 4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetaldehyde (330 mg, 1.165 mmol), (R)-2-((S)-1-( (S)-2-((S)- as a mixture with 4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H-pyran-4-one 1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H-pyran-4-one (207 mg) was converted into (R)-2-( Describes (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H-pyran-4-one (see compound 5028) It was prepared as follows.

[0718] LCMS: 98%, retention time = 1.98 min, (M+H) + =352(Method A).

[0719] Synthesis of (S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-4H-pyran-4-one.

[0720] (R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H-pyran-4-one and (S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H-pyran- as a mixture of Starting from 4-one (205 mg, 0.583 mmol), (S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro -4H-pyran-4-one, (R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-4H-pyran Prepared as described for -4-one (see compound 5028).

[0721] LCMS: 99%, retention time=2.00 min, (M+H) + =354(Method A). SFC: Retention time = 3.48 minutes, (M+H) + =354(Method AD).

[0722] ((2S,4S)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone( Compound 5027) and ((2S,4R)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- Synthesis of yl)methanone (compound 5081).

[0723] (S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-4H-pyran-4-one (80 mg, 0.226 mmol) Starting from ((2S,4S)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -dihydroisoquinolin-2(1H)-yl)methanone (compound 5027), and as the second eluting SFC isomer ((2S,4R)-4-aminotetrahydro-2H-pyran-2-yl)((S) -1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5081) )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5028).

[0724] Compound 5027: LCMS: 99%, retention time = 1.06 min, (M+H) + =355(Method P). SFC: Retention time = 3.84 minutes, (M+H) + =355(Method AD).

[0725] Compound 5081: LCMS: 99%, retention time = 1.04 min, (M+H) + =355(Method P). SFC: Retention time = 4.11 minutes, (M+H) + =355(Method F).

[0726] Example 59 Synthesis of compound 5090 and compound 5091 [ka] Step 1: To a solution of (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (470 mg, 1.6 mmol) in DMF (5 mL), add 4-(tert-butoxycarbonyl) -1,4-oxazepane-2-carboxylic acid (200 mg, 0.81 mmol), HATU (456 mg, 1.2 mmol), and TEA (0.3 mL, 2 mmol) were added at 0°C. The resulting reaction mixture was stirred at room temperature for 2 h, diluted with EA (10 mL) and diluted with saturated NH 4 Washed with Cl (2 x 10 mL) followed by brine (2 x 10 mL). organic phase with Na 2 S.O. 4 Dry on top, filter and concentrate in vacuo. The residue was purified by Prep-HPLC to give tert-butyl 2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4- Oxazepane-4-carboxylate was obtained.

[0727] LCMS:(M+H) + =455.1, purity = 100% (214nm), retention time = 1.77 min, method C1.

[0728] Step 2: Add tert-butyl 2-((S)-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)-1,4-oxazepane-4-carboxylate (320 mg, 0.70 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give a residue, which was purified by Prep-HPLC to give ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1, 4-Oxazepan-2-yl)methanone was obtained.

[0729] LCMS:(M+H) + =355.1, purity = 100% (214nm), retention time = 1.47 min, method C1.

[0730] The diastereomers were separated by chiral SFC using a Daicel® OZ column (20 x 250 mm, 10 μm) and eluting with CO2 / IPA (0.2% methanol ammonia) = 50 / 50 to give compound 5091 and compound 5090. I got it. The stereochemical configuration of (S) at position 1 of the tetrahydroisoquinoline is based on enantiomerically pure starting materials, and the stereochemical configuration of the chiral center in the 7-membered ring is assigned arbitrarily.

[0731] Compound 5090:LCMS:(M+H) + =355.0, purity = 100% (214nm), retention time = 1.74 min, method C1. Chiral SFC: CO using a Daicel® OZ column (4.6 x 100 mm, 3 um) 2 / MeOH containing 0.2% MA=60 / 40, retention time=2.009 min, 100%ee.

[0732] Compound 5091:LCMS:(M+H) + =355.0, purity = 100% (214nm), retention time = 1.73 min, method C1. Chiral SFC: CO using a Daicel® OZ column (4.6 x 100 mm, 3 um) 2 / MeOH containing 0.2% MA=60 / 40, retention time=1.935 min, 100%ee.

[0733] Example 60 ((2R,4R,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5075) [ka]

[0734] ((2R,4S,5S)-5-azido-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone synthesis.

[0735] Ammonium chloride (0.605 g, 11.32 mmol) and sodium azide (1.472 g, 22.64 mmol) were dissolved in ((1R,4R,6S)-3,7-di oxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (see compound 5070, 0.80 g , 2.264 mmol). The reaction mixture was warmed to 60°C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (2x). Wash the combined organics with brine and remove Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-100% ethyl acetate in heptane) to give ((2R,4S,5S)-5-azido-4-hydroxytetrahydro-2H-pyran-2-yl )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0736] LCMS: 92%, retention time = 2.04 min, (M+H) + =397(Method A).

[0737] ((2R,4R,5S)-5-azido-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone synthesis.

[0738] Under an argon atmosphere, triethylamine (0.174 mL, 1.249 mmol), triethylamine hydrogen trifluoride (0.068 mL, 0.416 mmol), and perfluoro-1-butanesulfonyl fluoride (0.075 mL, 0.416 mmol) were dissolved in acetonitrile (anhydrous, 2 mL). ) in ((2R,4S,5S)-5-azido-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline- Added to a solution of 2(1H)-yl)methanone (75 mg, 0.189 mmol). The reaction mixture was warmed to 60°C and stirred for 2 hours. The mixture was then cooled to room temperature and stirred overnight. Additional triethylamine (0.087 mL, 0.624 mmol), hydrogen trifluoride triethylamine (0.034 mL, 0.208 mmol), and perfluoro-1-butanesulfonyl fluoride (0.037 mL, 0.208 mmol) were added. The reaction mixture was warmed to 60°C and stirred for 2 hours. Cool the reaction mixture on ice with saturated NaHCO 3 It was poured into aqueous solution and the mixture was extracted with ethyl acetate (2x). The combined organic layer was diluted with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-100% ethyl acetate in heptane) to give ((2R,4R,5S)-5-azido-4-fluorotetrahydro-2H-pyran-2-yl )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (purity 50%, 50 mg) was obtained.

[0739] LCMS: 91%, retention time = 2.19 min, (M+H) + =399(Method A). SFC:50%, retention time=2.10 minutes, (M+H) + =399(Method AD).

[0740] ((2R,4R,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5075).

[0741] ((2R,4R,5S)-5-azido-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 in methanol (super dry, 5 mL) A solution of ,4-dihydroisoquinolin-2(1H)-yl)methanone (purity 50%, 50 mg, 0.063 mmol) was heated with palladium (10 wt% on carbon, water content 50%, 26.7 mg, 0.013 mmol) and atmospheric hydrogen pressure. hydrogenated in the presence of After 3 days, the reaction mixture was filtered and evaporated under reduced pressure. The residue was purified by basic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 2 min 20% A, t = 17 min 60% A, t = 18 min 100% A, t=23 min 100% A, detection: 220 nm) and purified by ((2R,4R,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5075) was obtained.

[0742] LCMS: 97%, retention time = 1.22 min, (M+H) + =373(Method P). SFC: 92%, retention time = 3.20 minutes, (M+H) + =373(Method W).

[0743] Example 61 ((2S,4R,5R)-5-amino-4-methyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl) methanone (compound 5084) and ((2S,4S,5R)-5-amino-4-methyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)- 3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5076) [ka]

[0744] tert-Butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-oxotetrahydro-2H-pyran -3-yl)carbamate synthesis.

[0745] At 0 °C, Dess-Martin periodinane (191 mg, 0.450 mmol) was dissolved in tert-butyl ((3S,4R,6S)-6-((S)-1-(4) in dichloromethane (anhydrous, 4.0 mL). -fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate (see compound 5053, 200 mg, 0.409 mmol). did. The reaction mixture was stirred at room temperature overnight. The mixture was then saturated with NaHCO 3 Aqueous solution and saturated Na 2 S 2 O 3 Diluted with a mixture of aqueous solutions (1 / 1 (v / v), 5 mL) and stirred vigorously for 15 minutes. The mixture was dissolved in dichloromethane (10 mL) and saturated NaHCO 3 Aqueous solution and saturated Na 2 S 2 O 3 It was further diluted with a mixture of aqueous solutions (1 / 1 (v / v), 5 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (5 mL). The combined organic matter is Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 1-35% ethyl acetate in heptane) to give tert-butyl ((3S,6S)-6-((S)-1-(4-fluorophenyl) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-oxotetrahydro-2H-pyran-3-yl)carbamate was obtained.

[0746] LCMS: 83%, retention time = 2.16 min, (M+Na) + =491 and 16% hydration product retention time = 2.03 min, (M+Na) + =509(Method A).

[0747] tert-Butyl((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methylenetetrahydro-2H-pyran -3-yl)carbamate synthesis.

[0748] At 0 °C, potassium tert-butoxide (1.0 M solution in tert-butanol, 0.423 mL, 0.423 mmol) was dissolved in a suspension of methyltriphenylphosphonium bromide (176 mg, 0.493 mmol) in tetrahydrofuran (anhydrous, 2.4 mL). added to. After 30 minutes, tert-butyl((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-) in tetrahydrofuran (anhydrous, 1.2 mL) A solution of 2-carbonyl)-4-oxotetrahydro-2H-pyran-3-yl)carbamate (165 mg, 0.352 mmol) was added dropwise and the mixture was stirred for 75 minutes. The reaction mixture was then filtered through Celite and washed with tetrahydrofuran. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by flash column chromatography (silica, 10-45% ethyl acetate in heptane) to give tert-butyl ((3R,6S)-6-(( S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methylenetetrahydro-2H-pyran-3-yl)carbamate was obtained.

[0749] LCMS: 93%, retention time=2.20 min, (M+H) + =467(Method A).

[0750] tert-Butyltert-butyl((3R,4R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methyl Tetrahydro-2H-pyran-3-yl)carbamate and tert-butyl((3R,4S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline) Synthesis of -2-carbonyl)-4-methyltetrahydro-2H-pyran-3-yl)carbamate.

[0751] ((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methylenetetrahydro in ethanol (2.0 mL) A solution of -2H-pyran-3-yl)carbamate (133 mg, 0.285 mmol) was hydrogenated in the presence of palladium (10 wt% on carbon, 50% water content, 60.7 mg, 0.029 mmol) and atmospheric hydrogen pressure. After 3.5 hours, the reaction mixture was filtered through Celite and the filter cake was washed with methanol. The filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 10-35% ethyl acetate in heptane) to give tert-butyl ((3R,4R,6S)-6-((S) -1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methyltetrahydro-2H-pyran-3-yl)carbamate, and tert as the second eluting isomer -Butyl((3R,4S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methyltetrahydro-2H- pyran-3-yl) carbamate was obtained.

[0752] First eluting isomer: LCMS: 99%, retention time = 2.26 min, (M+H) + =469(Method A).

[0753] Second eluting isomer: LCMS: 97%, retention time = 2.20 min, (M+H) + =469(Method A).

[0754] ((2S,4R,5R)-5-amino-4-methyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5084).

[0755] HCl (5-6M in 2-propanol, 83 μL, 0.46 mmol) was dissolved in tert-butyl ((3R,4R,6S)-6-((S)-1-(4 -fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methyltetrahydro-2H-pyran-3-yl)carbamate (9.0 mg, 0.019 mmol) and stirred for 24 hours. did. The reaction mixture was diluted with dichloromethane (2 mL) and saturated Na 2 C.O. 3 Diluted with aqueous solution (1 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2 x 2 mL). The combined organic matter is Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was dissolved in methanol (1 mL), transferred to an SCX-2 column (1 g), and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (1M). The basic fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((2S,4R,5R)-5-amino-4-methyltetrahydro- 2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5084) was obtained.

[0756] LCMS: 99%, retention time = 1.06 min, (M+H) + =369(Method P). SFC: retention time = 3.76 minutes, (M+H) + =369(Method W).

[0757] ((2S,4S,5R)-5-amino-4-methyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5076).

[0758] At 0 °C, HCl (5-6M in 2-propanol, 0.854 mL, 4.70 mmol) was added to tert-butyl ((3R,4S,6S)-6-((S)-1-(4-fluorophenyl) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methyltetrahydro-2H-pyran-3-yl)carbamate (44.0 mg, 0.094 mmol). After 5 minutes, the reaction mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with dichloromethane (7 mL) and saturated Na 2 C.O. 3 Diluted with aqueous solution (4 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2 x 3 mL). The combined organic matter is Na 2 S.O. 4Dry on top and evaporate under reduced pressure. The residue was dissolved in methanol (1 mL), transferred to an SCX-2 column (6 g), and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (1M). The basic fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((2S,4S,5R)-5-amino-4-methyltetrahydro- 2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5076) was obtained.

[0759] LCMS: 99%, retention time=1.06 min, (M+H) + =369(Method P). SFC: Retention time = 3.79 minutes, (M+H) + =369(Method W).

[0760] Example 62 ((2R,4S,5R)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5077) [ka]

[0761] ((2R,4S,5R)-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone synthesis.

[0762] Ammonium chloride (0.103 g, 6.04 mmol) and sodium azide (0.786 g, 12.1 mmol) were dissolved in ((1S,4R,6R)-3,7-di Oxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (see compound 5070, 0.427g , 1.208 mmol). The reaction mixture was warmed to 60°C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (2x). Wash the combined organics with brine and remove Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-100% ethyl acetate in heptane) to give ((2R,4S,5R)-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0763] LCMS: 100%, retention time = 2.04 min, (M+H) + =397(Method A).

[0764] ((2R,4S,5R)-4-azido-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone synthesis.

[0765] Under an argon atmosphere, sodium hydride (60% dispersion in oil, 17.7 mg, 0.443 mmol) was dissolved in ((2R,4S, 5R)-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone( 70 mg, 0.177 mmol). The reaction mixture was warmed to room temperature and stirred for 18 hours. KHSO reaction mixture 4 Diluted with aqueous solution (0.1M) and extracted with ethyl acetate (2x). The combined organic layer was diluted with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-100% ethyl acetate in heptane) to give ((2R,4S,5R)-4-azido-5-methoxytetrahydro-2H-pyran-2-yl )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0766] LCMS: 99%, retention time = 2.18 min, (M+H) + =411(Method A).

[0767] ((2R,4S,5R)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5077).

[0768] ((2R,4S,5R)-4-azido-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 in methanol (super dry, 5 mL) A solution of ,4-dihydroisoquinolin-2(1H)-yl)methanone (51.7 mg, 0.126 mmol) in the presence of palladium (10 wt% on carbon, 50% water content, 26.8 mg, 0.013 mmol) and atmospheric hydrogen pressure. Hydrogenated with After 3 days, the reaction mixture was filtered and evaporated under reduced pressure. The residue was purified by basic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 2 min 20% A, t = 17 min 60% A, t = 18 min 100% A, t=23 min 100% A, detection: 220 nm) and purified by ((2R,4S,5R)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5077) was obtained.

[0769] LCMS: 99%, retention time = 1.25 min, (M+H) + =385(Method P).

[0770] Example 63 ((2R,4S,5R)-4-amino-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5078) [ka]

[0771] ((2R,4S,5R)-4-azido-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone synthesis.

[0772] Under an argon atmosphere, sodium hydride (60% dispersion in oil, 12.6 mg, 0.315 mmol) followed by iodoethane (20 μL, 0.252 mmol) was dissolved in ((2R,4S,5R )-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5077, 50 mg, 0.126 mmol). The reaction mixture was warmed to room temperature and stirred for 18 hours. Another portion of sodium hydride (60% dispersion in oil, 12.6 mg, 0.315 mmol) and iodoethane (20 μL, 0.252 mmol) were then added and stirring continued for a further 2 hours. KHSO reaction mixture 4 Diluted with aqueous solution (0.1M) and extracted with ethyl acetate (2x). The combined organic layer was diluted with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-100% ethyl acetate in heptane) to give ((2R,4S,5R)-4-azido-5-ethoxytetrahydro-2H-pyran-2-yl )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0773] LCMS: 98%, retention time = 2.25 min, (M+H) + =425(Method A).

[0774] ((2R,4S,5R)-4-amino-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5078).

[0775] ((2R,4S,5R)-4-azido-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 in methanol (super dry, 5 mL) ,4-dihydroisoquinolin-2(1H)-yl)methanone (53 mg, 0.126 mmol) in the presence of palladium (10 wt% on carbon, 50% water content, 26.8 mg, 0.013 mmol) and atmospheric hydrogen pressure. Hydrogenated. After 3 days, the reaction mixture was filtered and evaporated under reduced pressure. The residue was purified by basic preparative MPLC (linear gradient: t = 0 min 5% A, t = 1 min 5% A, t = 2 min 20% A, t = 17 min 60% A, t = 18 min 100% A, t=23 min 100% A, detection: 220 nm) and purified by ((2R,4S,5R)-4-amino-5-ethoxytetrahydro-2H-pyran-2-yl)((S)- 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5078) was obtained.

[0776] LCMS: 99%, retention time = 1.21 min, (M+H) + =399(Method P).

[0777] Example 64 (3aS,6R,7aS)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro-2H-pyrano[4,3-d ]Oxazol-2-one (Compound 5079) [ka]

[0778] Sodium hydride (60 wt% dispersion in mineral oil, 25.5 mg, 0.638 mmol) was dissolved in tert-butyl ((2R,4S,5S)-2-((S)-1-( In a solution of 4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H-pyran-4-yl)carbamate (see compound 5052, 300 mg, 0.638 mmol) was added and the mixture was stirred at 40° C. overnight. The mixture was dissolved in dichloromethane (25 mL) and saturated NH 4 Diluted with aqueous Cl solution (20 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2 x 25 mL). The combined organic matter is Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 40-100% ethyl acetate in heptane) to give (3aS,6R,7aS)-6-((S)-1-(4-fluorophenyl)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro-2H-pyrano[4,3-d]oxazol-2-one was obtained.

[0779] LCMS: 100%, retention time = 1.51 min, (M+H) + =397(Method P).

[0780] Example 65 ((2R,4S,5R)-5-amino-4-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5082) [ka]

[0781] tert-Butyl((3R,4S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methoxytetrahydro-2H Synthesis of -pyran-3-yl)carbamate.

[0782] Tetrabutylammonium hydrogen sulfate (7.3 mg, 0.022 mmol), followed by aqueous NaOH (50 wt%, 11.7 μL, 0.223 mmol), and methyl iodide (21 μL, 0.335 mmol) were dissolved in tert-butyl ( (3R,4S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3 -yl)carbamate (see compound 5052, 35 mg, 0.074 mmol). After stirring for 3 days, additional amounts of aqueous NaOH (50 wt%, 11.7 μL, 0.223 mmol) and methyl iodide (21 μL, 0.335 mmol) were added and stirring continued for 7 days. The reaction mixture was dissolved in dichloromethane (5 mL) and saturated NaHCO 3 Diluted with aqueous solution (5 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to give tert-butyl ((3R,4S,6R)-6-((S)-1-(4-fluoro Phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methoxytetrahydro-2H-pyran-3-yl)carbamate was obtained.

[0783] LCMS: 99%, retention time = 2.24 min, (M+H) + =485(Method A).

[0784] ((2R,4S,5R)-5-amino-4-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5082).

[0785] HCl (5-6M in 2-propanol, 0.2 mL, 1.1 mmol) was dissolved in tert-butyl ((3R,4S,6R)-6-((S)-1-( Added to a solution of 4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methoxytetrahydro-2H-pyran-3-yl)carbamate (34 mg, 0.070 mmol). After 3 days, additional HCl (5-6M in 2-propanol, 0.2 mL, 1.1 mmol) was added and stirring was continued for another day. The reaction mixture was diluted with dichloromethane (10 mL) and saturated NaHCO 3 Neutralized with aqueous solution. Separate the layers and wash the organic phase with brine and Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was dissolved in methanol (1 mL), transferred to an SCX-2 column (1 g), and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (1.5M). The basic fractions were concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:3, 3 mL) to yield ((2R,4S,5R)-5-amino-4-methoxytetrahydro-2H-pyran-2-yl)((S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5082) was obtained.

[0786] LCMS: 99%, retention time = 1.05 min, (M+H) + =385(Method P).

[0787] Example 66 ((2S,4S,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5083) [ka]

[0788] ((2S,4S,5R)-4-azido-5-((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Synthesis of isoquinolin-2(1H)-yl)methanone.

[0789] Under nitrogen atmosphere, ((1S,4S,6R)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4- dihydroisoquinolin-2(1H)-yl)methanone (see compound 5072, 305 mg, 0.863 mmol) in (R,R)-N,N'-bis(3,5- di-tert-butylsalicylidene)-1,2-cyclohexanediaminochrome(III) chloride (10.91 mg, 0.017 mmol) was added to a dark red suspension. The resulting dark orange suspension was incubated for 15 min. Stir and then add trimethylsilyl azide (0.127 mL, 0.906 mmol). The reaction mixture was stirred overnight then add another portion of trimethylsilyl azide (0.089 mL, 0.636 mmol). Stirring was continued for 5 days. The reaction mixture was concentrated under reduced pressure at room temperature. The residue was purified by flash column chromatography (silica, 6-16% ethyl acetate in heptane) to give ((2S,4S,5R)-4- Azido-5-((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone Obtained.

[0790] LCMS: 62%, retention time=2.34 min, (M+H) + =469 and 38% product-TMS, retention time = 2.00 min, (M+H) + =397(Method A).

[0791] ((2S,4S,5R)-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone synthesis.

[0792] Potassium carbonate (80 mg, 0.578 mmol) was dissolved in ((2S,4S,5R)-4-azido-5-((trimethylsilyl)oxy)tetrahydro-2H- in a mixture of methanol (3.0 mL) and water (0.375 mL)). pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (91.5 mg, 0.193 mmol). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane (30 mL) and washed with brine (10 mL). The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were 2 S.O. 4Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 15-50% ethyl acetate in heptane) to give ((2S,4S,5R)-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0793] LCMS: 100%, retention time = 2.03 min, (M+H) + =397(Method A).

[0794] ((2S,4S,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5083).

[0795] ((2S,4S,5R)-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- A solution of dihydroisoquinolin-2(1H)-yl)methanone (27.0 mg, 0.067 mmol) was hydrogenated in the presence of palladium (10 wt% on carbon, 50% water content, 14.35 mg, 6.74 μmol) and atmospheric hydrogen pressure. did. After 2 hours, the reaction mixture was filtered through Celite and the filter cake was washed with tetrahydrofuran. The filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (1 mL), transferred to an SCX-2 column (1 g), and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (7M). The basic fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((2S,4S,5R)-4-amino-5-hydroxytetrahydro- 2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5083) was obtained.

[0796] LCMS: 98%, retention time = 1.01 min, (M+H) + =371(Method P). SFC: 100%, retention time = 3.77 minutes, (M+H) + =371(Method AD).

[0797] Example 67 ((2S,4S,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5085) [ka]

[0798] ((2R,4S,5R)-5-(dimethylamino)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline- Synthesis of 2(1H)-yl)methanone (compound 5085).

[0799] Formaldehyde (37 wt% solution in water stabilized with 10-15% methanol, 8.5 μL, 0.113 mmol), followed by sodium triacetoxyborohydride (34.3 mg, 0.162 mmol) in dichloromethane (1 mL) ((2R ,4S,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl ) was added to a solution of methanone (compound 5052, 60 mg, 0.162 mmol). After 30 minutes, another portion of formaldehyde (37 wt% solution in water stabilized with 10-15% methanol, 0.037 mL, 0.486 mmol) and sodium triacetoxyborohydride (103 mg, 0.486 mmol) were added. After 15 min, the reaction mixture was dissolved in dichloromethane (5 mL) and saturated NaHCO 3 Partitioned between aqueous solution (5 mL). The organic layer was separated, washed with brine (5 mL), and washed with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was dissolved in methanol (2 mL), transferred to an SCX-2 column, and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (1.5M). The basic fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:2, 3 mL) to yield ((2R,4S,5R)-5-(dimethylamino)-4- Hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5085) was obtained.

[0800] LCMS: 99%, retention time = 1.01 min, (M+H) + =399(Method P).

[0801] Example 68 ((2S,4R,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5086) [ka]

[0802] ((2S,4R,5R)-4-fluoro-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone synthesis.

[0803] In a microwave vial, triethylhydrogen trifluoride (363 μL, 2.228 mmol) was dissolved in ((1R,4S,6S)-3,7-dioxabicyclo[4.1.0]heptan-4-yl)((S) -1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (see compound 5072, 175 mg, 0.495 mmol). The vial was capped and placed in a preheated sand bath at 120°C. After 2.5 hours, the reaction mixture was diluted with ice-cold water (approximately 1 mL) and dichloromethane (2 mL), followed by saturated NaHCO 3 Aqueous solution (4 mL) was added slowly. The mixture was further treated with dichloromethane (10 mL) and saturated NaHCO 3 Diluted with aqueous solution (2 mL) and separated the layers. The aqueous layer was extracted with ethyl acetate (10 mL), and the combined organic layers were 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 15-55% ethyl acetate in heptane) and preparative chiral SFC (Method Y) to give ((2S,4R,5R)-4-fluoro-5-hydroxy Tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0804] LCMS: 99%, retention time = 2.01 min, (M+H) + =374(Method A).

[0805] (3R,4R,6S)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3 Synthesis of -yltrifluoromethanesulfonate.

[0806] Triflic acid anhydride (36.7 μL, 0.221 mmol) was dissolved in ((2S,4R,5R)-4-fluoro-5-hydroxytetrahydro-2H-pyran in dichloromethane (anhydrous, 750 μL) under an argon atmosphere at 0 °C. -2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (55.0 mg, 0.147 mmol) and pyridine (35.7 μL, 0.442 mmol) was added dropwise to the solution. After 45 min, the reaction mixture was diluted with dichloromethane (6 mL), aqueous citric acid (0.5 M, 2 mL), saturated NaHCO 3 Washed with aqueous solution (2 mL) and brine (2 mL). organic layer with Na 2 S.O. 4 Dry over and evaporate under reduced pressure to give (3R,4R,6S)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline. -2-carbonyl)tetrahydro-2H-pyran-3-yl trifluoromethanesulfonate (76 mg) was obtained as an orange solid and used as is.

[0807] LCMS: 99%, retention time = 2.28 min, (M+H) + =506(Method A).

[0808] ((2S,4R,5S)-5-azido-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone synthesis.

[0809] Under an argon atmosphere, tetrabutylammonium azide (46.1 mg, 0.162 mmol) was dissolved in (3R,4R,6S)-4-fluoro-6-((S)- Add to a solution of 1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl trifluoromethanesulfonate (74.5 mg, 0.147 mmol) and Stirred overnight. The reaction mixture was diluted with ethyl acetate (10 mL) and saturated NaHCO 3 Washed with a mixture of aqueous solution and brine (1:1, 4 mL), then brine (3 x 2 mL). organic layer with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 1-30% ethyl acetate in heptane) to give ((2S,4R,5S)-5-azido-4-fluorotetrahydro-2H-pyran-2-yl )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0810] LCMS: 100%, retention time = 2.16 min, (M+H) + =399(Method A).

[0811] ((2S,4R,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5086).

[0812] ((2S,4R,5S)-5-azido-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- in tetrahydrofuran (1 mL) A solution of dihydroisoquinolin-2(1H)-yl)methanone (46 mg, 0.115 mmol) was hydrogenated in the presence of palladium (10 wt% on carbon, 50% water content, 24.5 mg, 0.011 mmol) and atmospheric hydrogen pressure. . After 1 hour, the reaction mixture was filtered through Celite and the filter cake was washed with tetrahydrofuran. The filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (1 mL), transferred to an SCX-2 column (1 g), and eluted with methanol until neutral. The column was then eluted with ammonia in methanol (1M). The basic fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water to give ((2S,4R,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5086) was obtained.

[0813] LCMS: 99%, retention time = 1.04 min, (M+H) + =373(Method P). SFC: retention time = 3.38 minutes, (M+H) + =373(Method AD).

[0814] Example 69 ((2R,4S,5S)-4-amino-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5087) [ka]

[0815] ((2R,4S,5S)-4-azido-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone synthesis.

[0816] Under an argon atmosphere, triethylamine (0.116 mL, 0.832 mmol), triethylamine hydrogen trifluoride (0.045 mL, 0.277 mmol), and perfluoro-1-butanesulfonyl fluoride (0.050 mL, 0.277 mmol) were dissolved in acetonitrile (anhydrous, 2 mL). ) in ((2R,4S,5R)-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline- Added to a solution of 2(1H)-yl)methanone (see compound 5077, 50 mg, 0.126 mmol). The reaction mixture was warmed to 50°C and stirred for 18 hours. The mixture was then cooled to room temperature and additional triethylamine (0.058 mL, 0.416 mmol), triethylhydrogen trifluoride (0.023 mL, 0.139 mmol), and perfluoro-1-butanesulfonyl fluoride (0.025 mL, 0.139 mmol) were added. Added. The reaction mixture was warmed to 50°C and stirred for 2 hours. Cool the reaction mixture on ice with saturated NaHCO 3 It was poured into aqueous solution and the mixture was extracted with ethyl acetate (2x). The combined organic layer was diluted with Na 2 S.O. 4 Dry on top and evaporate under reduced pressure. The residue was purified by flash column chromatography (silica, 0-100% ethyl acetate in heptane) to give ((2R,4S,5S)-4-azido-5-fluorotetrahydro-2H-pyran-2-yl )((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone was obtained.

[0817] LCMS: 99%, retention time=2.20 min, (M+H) + =399(Method A).

[0818] ((2R,4S,5S)-4-amino-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5087).

[0819] ((2R,4S,5S)-4-azido-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 in methanol (super dry, 4 mL) A solution of ,4-dihydroisoquinolin-2(1H)-yl)methanone (38.7 mg, 0.063 mmol) in the presence of palladium (10 wt% on carbon, 50% water content, 25.1 mg, 0.012 mmol) and atmospheric hydrogen pressure. Hydrogenated with After stirring overnight, the reaction mixture was filtered and evaporated under reduced pressure. The residue was purified by preparative LCMS (Method BU)

[0820] ((2R,4S,5S)-4-amino-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5087) was obtained.

[0821] LCMS: 99%, retention time = 1.57 min, (M+H) + =373(Method Q).

[0822] Example 70 ((2R,4S,5R)-5-amino-4-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5088) [ka]

[0823] tert-Butyl((3R,4S,6R)-4-ethoxy-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H Synthesis of -pyran-3-yl)carbamate.

[0824] Tetrabutylammonium hydrogen sulfate (10.5 mg, 0.031 mmol), followed by aqueous NaOH (50 wt%, 5.6 μL, 0.106 mmol), and ethyl iodide (31 μL, 0.383 mmol) were dissolved in tert-butyl sulfate in toluene (4 mL). ((3R,4S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran- 3-yl)carbamate (50 mg, 0.106 mmol). After stirring for 3 days, additional amounts of NaOH aqueous solution (50 wt%, 5.6 μL, 0.106 mmol) and ethyl iodide (31 μL, 0.383 mmol) were added, and after another 5 days, NaOH aqueous solution (50 wt%, 22.4 μL, 0.425 mmol) and ethyl iodide (92 μL, 1.15 mmol) were added. Stirring was continued for an additional 5 days, after which time the reaction mixture was diluted with water (10 mL) and dichloromethane (15 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0-50% ethyl acetate in heptane) to give tert-butyl ((3R,4S,6R)-4-ethoxy-6-((S)-1- (4-fluorophenyl)-1,2,3...

Claims

1. A compound having the structure of formula (I), or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, Ring A is a 4-12 membered heterocycle containing a ring O or S atom and further containing 0-3 additional ring heteroatoms selected from O, N, and S; R １ is hydrogen, C １－６ Alkyl, halo, C １－３ Haloalkyl, O-C １－３ Haloalkyl, C ０－３ Alkylene-CN,C ０－３ Alkylene -NR Ｎ ２ , C ０－６ Alkylene-OR Ｎ , C ０－６ Alkylene -C(O)OR Ｎ , C ０－６ Alkylene -C(O)N(R Ｎ ) ２ , or C ０－６ Alkylene-SO ｐ R Ｎ and each R Ｎ are independently hydrogen or C １－６ alkyl, p is 0 to 2, Each R ２ But independently, it is a halo, Each R ３ are independently hydrogen, halo, C １－６ Alkyl, C １－６ Haloalkyl, C ０－６ Alkylene-OH,C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkylene -O-C １－６ Alkyl, C ０－６ Alkylene -NR ａ R ｂ , S.C. １－６ Alkyl, C ２－６ Alkenyl, C(O)-C １－６ Haloalkyl, SO ２ -C １－６ Alkyl, S ２＋ (O) － (NR ａ ) － C １－６ Alkyl, OR ４ , a 5-8 membered heteroaryl containing 1-4 ring N atoms, or a 4-6 membered heterocycle containing 1-4 ring heteroatoms selected from O, N, and S, with at least one ring heteroatom being N, wherein the heteroaryl or heterocycle is optionally independently selected from halo, C １－６ Alkyl, OH, and C １－６ substituted with one or two substituents selected from alkoxy; Two Germinal R ３ form an oxo group together with the atom to which they are attached, When ring A contains a ring N atom, said N is R ａ and when ring A does not contain a ring N atom, at least one R ３ But, C ０－６ Alkylene -NR ａ R ｂ and R ａ and R ｂ each independently represents hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkylene-OH,C １－６ Alkylene -O-C １－６ Alkyl, C(O)-C １－６ Alkyl, C(O)-C １－６ Haloalkyl, S(O) ２ -C １－６ Alkyl, S(O) ２ -C １－６ haloalkyl, or R ａ and R ｂ together with the nitrogen to which they are attached form a 3-12 membered mono- or bicyclic heterocycle optionally further containing 1-3 additional ring heteroatoms selected from O, N, and S; R ４ But, C ２－６ Alkenyl, C ２－６ Alkynyl, C ０－６ Alkylene-C ３－８ Cycloalkyl, or C ０－６ Alkylene-C ６－１０ is aryl, Each R ｄ is independently H or D; Each R ｅ is independently H, D, halo, OH, methyl, or methoxy; Two Germinal R ｅ together with the atoms to which they are attached, an oxo group or a spiro C ３－５ Forming a cycloalkyl, m is 1 to 4; A compound, or a pharma- ceutically acceptable salt thereof, wherein n is 0 to 2.

2. The compound or salt according to claim 1, wherein ring A is a 4- to 6-membered heterocycle.

3. The compound or salt according to claim 1, wherein ring A is a 6- to 8-membered heterocycle.

4. The compound or salt according to claim 1, wherein ring A is a 10- to 12-membered heterocycle.

5. Ring A is 【Chemistry 2】 5. The compound or salt of any one of claims 1 to 4, wherein * indicates the point of attachment of ring A to the adjacent carbonyl moiety of formula I.

6. The compound or salt according to any one of claims 1 to 5, wherein m is 1.

7. The compound or salt according to any one of claims 1 to 5, wherein m is 2 or 3.

8. The compound or salt according to any one of claims 1 to 7, wherein at least one R 3 is C 1-6 alkyl.

9. The compound or salt according to claim 8, wherein at least one R 3 is methyl.

10. At least one R ３ but, (i) Hydrogen (ii) C ０－６ Alkylene -NR ａ R ｂ ; (iii) halo; (iv) C 1-6 alkoxy; (v) S 2+ (O) — (NR a ) — C 1-6 alkyl; (vi) OR 4 ; or (vii) C 2-6 alkenyl, C 0-6 alkylene-C 3-8 cycloalkyl, or C 0-6 alkylene-C 6-10 aryl. The compound or salt according to any one of claims 1 to 7,

11. At least one R ３ but, ((i)NH) ２ ; (ii) NHMe; (iii) F; (iv) methoxy; (vi) ethoxy; (vii) 【Chemistry 7】 or (viii) 【Chemistry 8】 11. The compound or salt of claim 10,

12. 12. The compound or salt according to any one of claims 1 to 11, wherein n is 0 or 2.

13. 12. The compound or salt according to any one of claims 1 to 11, wherein n is 1.

14. R ２ The compound or salt according to any one of claims 1 to 11 and 13, wherein is F or Cl.

15. R １ The compound or salt of any one of claims 1 to 14, wherein is halo.

16. R １ The compound or salt of claim 15, wherein is F.

17. R １ The compound or salt according to any one of claims 1 to 14, wherein is hydrogen.

18. Each R ｄ The compound or salt according to any one of claims 1 to 17, wherein is H.

19. Each R ｅ The compound or salt according to any one of claims 1 to 18, wherein is H.

20. At least one R ｅ The compound or salt of any one of claims 1 to 18, wherein R e is D, halo, OH, or two geminal R e together with the atom to which they are attached form an oxo group.

21. A compound having the structure shown in Table A, or a pharma- ceutically acceptable salt thereof:

22. A pharmaceutical composition for treating a progranulin-related disorder, comprising a compound or salt according to any one of claims 1 to 21.

23. The pharmaceutical composition of claim 22, wherein the progranulin-related disorder is Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), frontotemporal dementia-granulin subtype (FTD-GRN), Lewy body dementia (LBD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), lysosomal storage disease, nephropathy, a disease associated with inclusions and / or dysfunction of C9orf72, TDP-43, FUS, UBQLN2, VCP, CHMP28, and / or MAPT, acute neurological disorder, glioblastoma, or neuroblastoma.

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