TW202336016A - Progranulin modulators and methods of using the same - Google Patents

Abstract

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

Description

Progranulin modulators and methods of use

Provided herein are compounds that modulate progranulin levels, which may be useful as therapeutics for granulin (GRN) and/or progranulin (PGRN) related disorders. Mutations in the GRN gene cause frontotemporal lobar degeneration (FTLD) (see, e.g., Cruts et al., Granulin Mutations Associated with Frontotemporal Lobar Degeneration and Related Disorders: An Update Related Disorders: An Update, Hu Mutation, 2008; and Baker et al., Nature, 2006). FTLD-related mutations in GRN reduce progranulin protein expression, suggesting that haploinsufficiency of progranulin is a key causative factor in FTLD-GRN. Carriers of pathogenic GRN mutations have up to 70% lower plasma and CSF progranulin levels (Ghidoni et al., Neurodegen Dis, 2012). More than 60 nonsense mutations in the GRN gene have been described. PGRN in plasma can be easily monitored (see, e.g., Meeter, Nature Neurology, Vol. 13, 2017). Thus, granulin and/or progranulin-related disorders can be modulated by compounds that increase progranulin secretion and/or activity.

All known FTLD-GRN-associated mutations cause progranulin haploinsufficiency, suggesting that restoring appropriate progranulin levels or progranulin protein function would be beneficial in the treatment of FTLD-GRN patients. Some studies have shown that even a slight reduction in progranulin content caused by genetic modifiers (such as TMEM106B, SLPI, Rs5848) can have a significant impact on the age of onset of FTLD, increase the risk of developing FTLD, or cause bone abnormalities such as The progression of autoimmune diseases such as arthritis worsens (see, e.g., Nicholson et al., J Neurochem, 2013; Cruchaga et al., Arch Neurol, 2012; and Wei et al. People, PLoS One, 2014). Polymorphisms affecting progranulin content have also been identified as genetic modifiers in several other neurodegenerative diseases, such as Alzheimer's disease and C9orf72-related FTLD (see, e.g., Sheng et al. (Human, Gene, 2014 and van Blitterswijk et al., Mol Neurodegen, 2014). Therefore, as considered carefully here, progranulin-targeted therapeutics are effective in a variety of neurodegenerative and autoimmune conditions.

Granulins are a family of secreted and glycosylated proteins. It is cleaved from a common precursor protein called progranulin (PGRN). Pregranulin is a secreted glycoprotein and is expressed in neurons, glial cells, chondrocytes, epithelial cells and leukocytes (Toh H et al. J Mol Neurosci 2011 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 generate 6 disulfide bridges in each granulin (Bateman A et al., Bioessays )》2009:1245-54). Pregranulin is encoded by the GRN gene. Mutations in the GRN gene account for up to 25% of the causes of frontotemporal lobar degeneration and are inherited in an autosomal dominant fashion with high penetrance (see, e.g., Mackenzie, Acta Neuropathologica )》,114(1):49-54 (2007)). Modulation of progranulin activity is therefore an attractive target for the treatment of conditions associated with GRN activity or GRN gene mutations.

The translocon complex is the main gate leading to the secretory pathway. It facilitates the translocation of nascent proteins into the lumen of the endoplasmic reticulum (ER) or the integration of these proteins in lipid membranes. The translocon is organized around a conserved core composed of a trimeric protein complex (the Sec61 channel). It binds to: cytosolic chaperones such as signal recognition particles (SRP); accessory elements such as translocation strand-associated membrane (TRAM), translocon-associated protein (TRAP); and modifying enzymes such as oligosaccharyltransferases ( OST). Oligosaccharyltransferases are responsible for proper glycosylation of proteins and bind to the ribosome-Sec61-TRAP complex at a near-stoichiometric ratio. The importance of this complex was highlighted by the discovery of mutations that cause glycosylation disorders in one of the TRAP elements of the complex.

Lysosomes are cellular organelles containing over 60 different enzymes such as lipases, proteases and hydrolases that are primarily involved in the breakdown of proteins, lipids and carbohydrates. Mutations found in various lysosomal proteins are potential causes of a number of different diseases classified as neuronal ceroid lipofuscinosis (NCL), also known as Batten disease. In some cases, certain lysosomal proteins serve as cofactors for lysosomal enzymes. Its distribution and/or degree of expression can modulate the activity of lysosomal enzymes, and therefore has a downstream regulatory function on the overall function of lysosomes.

Provided herein are compounds and methods for modulating progranulin, eg, increasing progranulin or granulin levels in an individual. More specifically, modulators of progranulin and the use of such modulators in the treatment of progranulin-related disorders, such as Alzheimer's disease (AD), Parkinson's disease, are provided Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), frontotemporal dementia-granulin subtype (FTD-GRN), Lewy body Dementia (Lewy body dementia; LBD), prion disease, motor neurone disease (MND), Huntington's disease (HD), spinocerebellar disorder (SCA), spinal muscular atrophy ( SMA), lysosomal storage diseases, diseases associated with inclusion bodies and/or C9orf72, TDP-43, FUS, UBQLN2, VCP, CHMP28 and/or MAPT dysfunction, acute neurological disorders, glioblastoma, or Neuroblastoma.

The present invention provides compounds of formula (I): , wherein ring A is a 4- to 12-membered heterocyclic ring containing ring O or S atoms, and the heterocyclic ring further contains 0-3 additional ring heteroatoms selected from O, N and S; R ¹ is hydrogen, C _1-6 Alkyl group, halo group, C _1-3 haloalkyl group, OC _1-3 haloalkyl group, C _0-3 alkylene group-CN, C _0-3 alkylene group-NR ^N ₂ , C _0-6 alkylene group- 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 ; Each R ^N is independently hydrogen or C _1-6 alkyl, and p is 0-2; each R ² is independently halo; each R ³ is 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-OC _1-6 alkyl, C _{0- 6} Alkylene-NR ^a R ^b , SC _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 , 5- to 8-membered heteroaryl containing 1-4 ring N atoms, or 1-4 rings selected from O, N and S A 4- to 6-membered heterocyclic heteroatom, in which at least one ring heteroatom is N, and the heteroaryl group or heterocyclic ring is optionally selected from halo, C _1-6 alkyl, OH and C by 1 or 2 _{The 1-6} alkoxy group is substituted by a substituent, or the two simultaneous R ^3s together with the atom to which they are connected form a side oxy group, and when ring A contains ring N atoms, N is substituted by R ^a , and if ring A does not Contains ring N atoms, then at least one R ³ is C _0-6 alkylene-NR ^a R ^b ; 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-OC _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 connected form a 3 to 12-membered monocyclic or bicyclic heterocyclic ring, which depends on Cases further include 1-3 additional ring heteroatoms selected from O, N and S; R ⁴ is C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-C _3-8 ring Alkyl or C _0-6 alkylene-C _6-10 aryl; each R ^d is independently H or D; each R ^e is independently H, D, halo, OH, methyl, methoxy, Or the two synposition R ^e together with the atom to which they are connected form a side oxy group or a spiro C _3-5 cycloalkyl group; m is 1-4; and n is 0-2.

Compounds of formula (Ia) are also provided: , where A is a 4- to 12-membered heterocyclic ring containing ring O or S atoms, and the heterocyclic ring further contains 0-3 additional ring heteroatoms selected from O, N and S; R ¹ is hydrogen, C _1-6 alkane group, halo group, C _1-3 haloalkyl group, OC _1-3 haloalkyl group, C _0-3 alkylene group-CN, C _0-3 alkylene group-NR ^N ₂ , C _0-6 alkylene group-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 ; each R ^N is independently hydrogen or C _1-6 alkyl, and p is 0-2; each R ² is independently halo; each R ³ is 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 alkyl-OC _1-6 alkyl, C _0-6 Alkylene-NR ^a R ^b , SC _1-6 alkyl, C _2-6 alkenyl, C(O)-C _1-6 haloalkyl or SO ₂ -C _1-6 alkyl, or two simultaneous positions R ³ together with the atom to which it is attached forms a pendant oxygen group, and when ring A contains ring N atoms, N is substituted by R _a , and if ring A does not contain ring N atoms, at least one R ³ is a C _0-6 extension Alkyl-NR ^a R ^b ; R ^a and R ^b are each independently hydrogen, C _1-6 alkyl, C _1-6 alkyl-OH, C _1-6 alkyl-OC _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 5 to 12-membered monocyclic or bicyclic heterocyclic ring, which optionally further contains 1-3 additional ring heteroatoms selected from O, N and S; m is 1 -3; and n is 0-2.

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

Methods of modulating progranulin in an individual are also provided. In some embodiments, methods of treating progranulin-related disorders in an individual are provided.

Other aspects of the invention include compounds as disclosed herein for the preparation of medicaments for modulating granulin precursors, and the use of compounds as disclosed herein for treating or preventing granulin in a subject Methods for Precursor-Related Disorders.

Compounds that act as modulators of granulin precursors

Provided herein are compounds that modulate the production and/or secretion of granulin precursors. In some cases, the compounds may increase the levels of granulin precursors or granulin in an individual. Methods of modulating the translocon complex to increase lysosomal protein content using compounds as disclosed herein are also provided.

The present invention provides compounds of formula (I): , wherein ring A is a 4- to 12-membered heterocyclic ring containing ring O or S atoms, and the heterocyclic ring further contains 0-3 additional ring heteroatoms selected from O, N and S; R ¹ is hydrogen, C _1-6 Alkyl group, halo group, C _1-3 haloalkyl group, OC _1-3 haloalkyl group, C _0-3 alkylene group-CN, C _0-3 alkylene group-NR ^N ₂ , C _0-6 alkylene group- 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 ; Each R ^N is independently hydrogen or C _1-6 alkyl, and p is 0-2; Each R ² is independently halo; Each R ³ is 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-OC _1-6 alkyl, C _{0- 6} Alkylene-NR ^a R ^b , SC _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 , 5- to 8-membered heteroaryl containing 1-4 ring N atoms, or 1-4 rings selected from O, N and S A 4- to 6-membered heterocyclic heteroatom, in which at least one ring heteroatom is N, and the heteroaryl group or heterocyclic ring is optionally selected from halo, C _1-6 alkyl, OH and C by 1 or 2 _{The 1-6} alkoxy group is substituted by a substituent, or the two simultaneous R ^3s together with the atom to which they are connected form a side oxy group, and when ring A contains ring N atoms, N is substituted by R ^a , and if ring A does not Contains ring N atoms, then at least one R ³ is C _0-6 alkylene-NR ^a R ^b ; 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-OC _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 connected form a 3 to 12-membered monocyclic or bicyclic heterocyclic ring, which depends on Cases further include 1-3 additional ring heteroatoms selected from O, N and S; R ⁴ is C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-C _3-8 ring Alkyl or C _0-6 alkylene-C _6-10 aryl; each R ^d is independently H or D; each R ^e is independently H, D, halo, OH, methyl or methoxy, Or the two synposition R ^e together with the atom to which they are connected form a side oxy group or a spiro C _3-5 cycloalkyl group; m is 1-4; and n is 0-2.

Compounds of formula (Ia) are also provided: , where A is a 4- to 12-membered heterocyclic ring containing ring O or S atoms, and the heterocyclic ring further contains 0-3 additional ring heteroatoms selected from O, N and S; R ¹ is hydrogen, C _1-6 alkane group, halo group, C _1-3 haloalkylene group, OC _1-3 haloalkylene group, C _0-3 alkylene group-CN, C _0-3 alkylene group-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 ; Each R ^N is independently hydrogen or C _1-6 alkyl, and p is 0-2; Each R ² is independently a halo group; Each R ³ is 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 alkyl-OC _1-6 alkyl group, C _0-6 alkylene-NR ^a R ^b , SC _1-6 alkyl, C _2-6 alkenyl, C(O)-C _1-6 haloalkyl or SO ₂ -C _1-6 alkyl , or two synposition R ³ together with the atom to which they are connected form a pendant oxygen group, and when ring A contains a ring N atom, N is substituted by R _a , and if ring A does not contain a ring N atom, at least one R ³ is C _0-6 alkylene-NR ^a R ^b ; R ^a and R ^b are each independently hydrogen, C _1-6 alkyl, C _1-6 alkyl-OH, C _1-6 alkyl- OC _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 5 to 12-membered monocyclic or bicyclic heterocycle, which optionally further contains 1-3 additional rings selected from O, N and S heteroatoms; m is 1-3; and n is 0-2.

In some cases, Ring A is a 4- to 6-membered heterocycle. In some cases, Ring A is a 6- to 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 heterocyclic ring. In some cases, Ring A is a 10-membered heterocyclic ring. In some cases, Ring A is an 11-membered heterocycle. In some cases, Ring A is a 12-membered heterocycle.

In some cases, Ring A includes ring O atoms and 0-3 additional ring heteroatoms selected from O, N, and S. In some cases, Ring A contains ring O atoms and 0 additional ring heteroatoms. In some cases, Ring A contains a tetrahydropyranyl ring. In some cases, Ring A includes ring O atoms and 1 additional ring heteroatom selected from O, N, and S. In some cases, Ring A contains ring O atoms and ring N atoms. In some cases, Ring A includes a ring O atom and 2 additional ring heteroatoms selected from O, N, and S. In some cases, Ring A includes a ring O atom and 3 additional ring heteroatoms selected from O, N, and S.

In some cases, Ring A contains ring S atoms and 0-3 additional ring heteroatoms. In some cases, Ring A includes ring S atoms and 0 additional ring heteroatoms selected from O, N, and S. In some cases, Ring A includes a ring S atom and 1 additional ring heteroatom selected from O, N, and S. In some cases, Ring A includes a ring S atom and 2 additional ring heteroatoms selected from O, N, and S. In some cases, Ring A includes a ring S atom and 3 additional ring heteroatoms selected from O, N, and S.

In some cases, Ring A contains ring N atoms, and N is substituted with _Ra . In the case where ^Ring A contains ring N atoms, Ring A may be substituted with R ³ , which is C _0-6 alkylene-NR ^a R ^b . In the case where Ring A contains no ring N atoms, at least one R ³ is C _0-6 alkylene-NR ^a R ^b .

In some cases, ring A is , where * indicates the point of attachment of ring A to the adjacent carbonyl moiety of formula I. In some cases, ring A is , where * indicates the point of attachment of ring A to the adjacent carbonyl moiety of formula I. In some cases, ring A is . In some cases, ring A is or . In some cases, ring A is . In some cases, ring A is or . In some cases, ring A is . In some cases, ring A is . In some cases, ring A is . In some cases, ring A is . In some cases, ring A is . In some cases, ring A is . In some cases, ring A is . In some cases, ring A is . In some cases, ring A is . In some cases, ring A is . In some cases, ring A is . In some cases where NR ^a is present in ring A, R ^a is H. All Ring A mentioned in this paragraph may be substituted with m (i.e. 1 to 3) ^R3 substituents as discussed herein.

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.

In some cases, ring A is .

In some cases, each R ³ is 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-OC _1-6 alkyl, C _0-6 alkylene-NR ^a R ^b , SC _1-6 alkyl, C _2-6 alkenyl, C ( O)-C _1-6 haloalkyl or SO ₂ -C _1-6 alkyl, or two syn-position R ³ together with the atom to which they are connected form a side oxy group, and when ring A contains ring N atoms, N is R ^a is substituted, and if ring A contains no ring N atoms, then at least one R ³ is C _0-6 alkylene-NR ^a R ^b .

In some cases, the two synpositional ^R3 's together with the atom to which they are attached form a pendant oxy 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 haloalkyl Oxygen, C _1-6 alkoxy-C _1-6 alkyl, C _0-6 alkylene-NR ^a R ^b , SC _1-6 alkyl, C _2-6 olefin, C(O)-C _1-6 haloalkyl or SO ₂ -C _1-6 alkyl. In some cases, R ³ is hydrogen, halo, C _1-6 alkoxy, or C _0-6 alkylene-NR ^a R ^b . In some cases, R ³ is halo, C _1-6 alkoxy, or C _0-6 alkylene-NR ^a R ^b . In some cases, ^R3 is H. In some cases, ^R3 is halo. In some cases, ^R3 is F. In some cases, R ³ is C _1-6 alkyl. In some cases, R ³ is C _1-6 haloalkyl. In some cases, R ³ is C _0-6 alkylene-OH. In some cases, R ³ is C _1-6 alkoxy. In some cases, ^R3 is methoxy or ethoxy. In some cases, ^R3 is methoxy. In some cases, ^R3 is ethoxy. In some cases, R ³ is C _1-6 haloalkoxy. In some cases, R ³ is C _1-6 alkoxy-C _1-6 alkyl. In some cases, R ³ is C _0-6 alkylene-NR ^a R ^b . In some cases, ^R is _NH or NHMe. In some cases, ^R3 is _NH2 . In some cases, ^R3 is NHMe. In some cases, R ³ is SC _1-6 alkyl. In some cases, ^R3 is a _C2-6 olefin. In some cases, C(O)-C _1-6 haloalkyl. In some cases, R ³ is SO ₂ -C _1-6 alkyl.

In some cases, R ³ is halo or C _0-6 alkylene-NR ^a R ^b . In some cases, ^R3 is F or _NH2 . In some cases, ^R3 is F or NHMe. In some cases, R ³ is C _1-6 alkoxy or C _0-6 alkylene-NR ^a R ^b . In some cases, ^R3 is methoxy or _NH2 . In some cases, ^R3 is methoxy or NHMe. In some cases, ^R3 is ethoxy or _NH2 . In some cases, ^R3 is ethoxy or NHMe. In some cases, R ³ is S ²⁺ (O) ^- (NR ^a ) ^- C _1-6 alkyl. In some cases, R ³ is . In some cases, R ³ is OR ⁴ . In some cases, R ³ is . In some cases, R ³ is .

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-OC _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 5 to 12 membered monocyclic or bicyclic heterocycle, which optionally further contains 1 to 3 additional ring heteroatoms selected from O, N and S. 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 haloalkyl. In some cases, R ^a and R ^b together with the nitrogen to which they are attached form a 5- to 12-membered monocyclic or bicyclic heterocycle, which optionally further contains 1-3 additional ring heteroatoms selected from O, N, and S. In some cases, R ^a and R ^b are each independently C _1-6 haloalkyl.

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 ^Re is H. In some cases, at least one ^Re is D. In some cases, each ^Re is D. In some cases, at least one ^Re is OH. In some cases, each ^Re is OH. In some cases, at least one ^Re is halo. In some cases, at least one ^Re is F. In some cases, each ^Re is halo. In some cases, each ^Re is F. In some cases, the two co-positions ^Re together with the atom to which they are attached form a pendant oxy group.

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 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 aryl. In some cases, R ⁴ is C _2-6 alkenyl. In some cases, R ⁴ is C _2-6 alkynyl. In some cases, R ⁴ is propargyl. In some cases, R ⁴ is C _0-6 alkylene-C _3-8 cycloalkyl. In some cases, R ⁴ is C _0-6 alkylene-cyclopropyl. In some cases, R ⁴ is C _0-6 alkylene-cyclobutyl. In some cases, R ⁴ is C _0-6 alkylene-C _6-10 aryl. In some cases, R ⁴ is C _0-6 alkylene-C ₆ aryl. In some cases, ^R4 is phenyl. In some cases, R ⁴ is benzyl.

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.

In some cases, ^R2 is F or Cl. In some cases, ^R2 is F.

In some cases, ^R1 is H. In some cases, ^R1 is halo. In some cases, ^R1 is F.

Specific compounds contemplated include those listed in Table A, or pharmaceutically acceptable salts thereof: Table A structure Compound number 5000 5001 5002 5003 5004 5005 5006 5007 5008 5009 5010 5011 5012 5013 5014 5015 5016 5017 5018 5019 5020 5021 5022 5023 5024 5027 5028 5029 5030 5031 5032 5033 5034 5035 5036 5037 5038 5039 5040 5041 5042 5043 5044 5045 5046 5047 5048 5049 5050 5051 5052 5053 5054 5055 5056 5057 5058 5059 5060 5061 5062 5063 5064 5065 5066 5067 5068 5069 5070 5071 5072 5073 5074 5075 5076 5077 5078 5079 5080 5081 5082 5083 5084 5085 5086 5087 5088 5089 5090 5091 5092 5200 5201 5202 5203 5204 5205 5206 5207 5210 5211 5212 5213 5214 5215 5216 5217 5218 5219 5220 5221 5222 5223 5224 5225 5226 5227 5228 5229 5230 5231 5232 5233 5234 5235 5236 5237 5238 5239 5240 5241 5242 5243 5244 5245 5246 5247 5248 5249 5250 5251 5252 5253 5254 5255 5256 5257 5258 5259 5260 5261 5262 5263 5264 5265 5266 5267 5400 5401 5402 5403 5404 5405 5406 5407 5408 5409 5410 5411 5412 5413 5414 5415 5416 5417 5418 5419 5420 5421 5422 5423 5424 5425 5426 5427 5428 5429 5430 5431 5432 5433 5434 5435 5436 5437 5438 5439 5440 5441 5442 5443 5444 5445 5446 5447 5448 5449 5450 5451 5452 5453 5454 5455 5456 5457 5458 5459 5460 5461 5462 5463 5464 5465 5466 5467 5468 5469 5470 5471 5472 5473 5474 5475 5476 5500 5501 5502 5503 5504 5505 5506 5507 5508 5509 5510 5511 5512 5513 5514 5516 5517 5518 5519 5520 5521 5523 5524 5525 5526 5527 5528 5529 5530 5531 5532 5533 5534 5535 5536 5537 5538 5539 5540 5541 5542 5543 5544 5545 5546 5547 5548 5549 5550 5551 5552 5553 5554 5555 5556 5557 5558 5559 5560 5561 5562 5563 5564 5565 5566 5567 5568 5569 5570 5571 5572 5573 5574 5575 5576 5577 5578 5579 5580 5581 5582 5583 5584 5585 5586 5587 5588 5589 5592 5593 5594 5595 5596 5597 5598 5599 5600 5601 5602 5603 5604 5605 5606 5607 5608 5700 5701 5702 5703 5704 5705 5706 5707 5708 5710 5711 5712 5713 5714 5715 5716 5717 5718 5719 5720 5721 5722 5723 5724 5725 5726 5727 5728 5729 5730 5731 5732 5733 5735 5737 5738 5739 5740 5741 5742 5743 5744 5745 5746 5747 5748 5749 5750 5751 5752 5753 5754 5755 5756 5757 5758 5759 5760 5761 5762 5763 5764 5765 5766 5767 5768 5769 5770 5771 5772 5773 5774 5775 5776 5777 5778 5779 5780 5781 5782 5783 5784 5785 5786 5787 5788 5789 5790 5791 5792 5793 5800 5801 5802 5803 5804 5805 5806 5807 5808 5809 5810 5812 5814 5815 5816 5817 5818 5819

In some cases, the compound is selected from the group consisting of compounds 5605, 5602, 5599, 5575, 5564, 5550, 5472, 5545, 5543, 5461, 5267, 5448, 5475, 5087, 5077, 5051, 5045, 5042, 5021, and 5012, and Its pharmaceutically acceptable salt. 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.

As used herein, the term "alkyl" refers to straight and branched chain saturated hydrocarbon groups containing one to six carbon atoms. The term C _n 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 ₆ alkyl refers to a group having carbon atoms covering the entire range (e.g., 1 to 6 carbon atoms) and all subgroups (e.g., 1-6, 2-6, 1-5, 3-6, 1 , 2, 3, 4, 5 and 6 carbon atoms) alkyl groups with a number of carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl (2-methylpropyl), tertiary butyl (1,1-dimethyl ethyl) and 3-methylpentyl. Unless otherwise indicated, an alkyl group may be unsubstituted alkyl or substituted alkyl.

The term "alkylene" as used herein refers to an alkyl group having a substituent. For example, the alkylene group may be -CH ₂ CH ₂ - or -CH ₂ -. The term _Cn 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 that encompasses the entire range and all subgroups, as previously described as "alkyl." C ₀ alkylene indicates a direct bond. Unless otherwise indicated, an alkylene group may be unsubstituted alkylene or substituted alkylene. Specific substitutions on the alkylene group may be designated, such as alkylene-halo, alkylene-CN or the like.

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, vinyl, propenyl, butenyl, pentenyl, hexenyl) and branched-chain alkenyl groups. For example, a straight or branched chain alkenyl group may have six or less than six carbon atoms in its backbone (eg, C ₂ -C ₆ for a straight chain, C ₃ -C ₆ for a branched chain). The term "C ₂ -C ₆ " includes terms that encompass the entire range (e.g., 2 to 6 carbon atoms) as well as all subgroups (e.g., 2-6, 2-5, 2-4, 3-6, 2 , 3, 4, 5 and 6 carbon atoms) chains with the number of carbon atoms. Unless otherwise indicated, an alkenyl group may be unsubstituted or substituted.

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen substituents. Haloalkyl is also called "alkylene-halo". By way of example, C ₁ -C ₆ haloalkyl refers to C ₁ -C 6 alkyl substituted with one or more halogen atoms, such as 1, 2, 3, 4, 5 or ₆ halogen atoms. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl and trichloromethyl. 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.

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

As used herein, the term "pendant oxy" refers to a =O substituent, for example, a carbon may be substituted with a pendant oxy group to form a carbonyl group (C=O).

As used herein, the term "carbocycle" or "carbocyclyl" refers to a ring containing three to eleven carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or 11 carbon atoms) cyclic hydrocarbon group. The term "n-membered carbocycle" means a carbocyclic group having "n" carbon atoms. For example, a 5-membered carbocyclic ring refers to a carbocyclic group having 5 carbon atoms in the ring. 6- to 8-membered carbon rings are those with carbon atoms that cover the entire range (e.g., 6 to 8 carbon atoms) and all subgroups (e.g., 6-7, 6-8, 7-8, 6, 7 and 8 A carbocyclic group with the number of carbon atoms). Non-limiting examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise indicated, a carbocyclic group may be an unsubstituted carbocyclic group or a substituted carbocyclic group. The carbocyclic groups described herein may be alone or fused with another carbocyclic group. In particular, the carbocyclic rings described herein may have fused, bridged or spiro ring structures.

As used herein, the term "heterocycle" is defined similarly to a carbocycle, except that the ring contains one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur. Specifically, the term "heterocycle" refers to a ring containing a total of four to twelve (e.g., four to six or six to eight) atoms, in which 1, 2, 3 or 4 of those atoms The atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, and the remaining atoms in the ring are carbon atoms. Heterocycles as disclosed herein can be in the form of monocyclic, fused (eg, bicyclic), bridged, or spirocyclic rings, but still exhibit 4 to 12 ring members and heteroatoms as discussed herein. Non-limiting examples of heterocyclic groups include azetidine, pyridine, pipera , Pyrazolidine, tetrahydrofuran, tetrahydropyran, dihydrofuran, phyline, Ridine and similar groups. Heterocyclyl may be a saturated or partially unsaturated ring system, which is optionally substituted with, for example, one to three groups, such as halo, C _1-6 alkyl, C _1-6 haloalkyl, OH, C _1-6 extension Alkyl-OH, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkoxy-C _1-6 alkyl, -NR ^a R ^b (such as -NH ₂ or -NHMe) , C _1-6 alkylene-NR ^a R ^b (such as C _1-6 alkylene-NH ₂ or C _1-6 alkylene-NHMe), SC _1-6 alkyl, C _2-6 olefin, C(O)-C _1-6 haloalkyl or SO ₂ -C _1-6 alkyl. Other contemplated substituents on heterocycles are discussed elsewhere in this disclosure.

As used herein, the term "substituted" when used to modify a chemical functional group means that at least one hydrogen group on that functional group has been replaced by a substituent. Unless otherwise stated for a particular part, substituents may include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, oxy , alkoxy, heteroalkoxy, ester, thioester, carboxyl, cyano, nitro, amine, amide, acetylamine and halo (such as fluorine, chlorine, bromine or iodine). When the chemical functionality includes more than one substituent, the substituents may be bonded to the same carbon atom or to two or more different carbon atoms.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms having one or more asymmetric carbon atoms. This invention contemplates such forms, including cis and trans isomers, R- and S-enantiomers, diastereomers, racemic mixtures thereof and other mixtures thereof, as being among the disclosed compounds. within the scope. 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.

As used herein, the term "pharmaceutically acceptable" means that the substance referred to (such as a compound of the invention) or a formulation or specific excipient containing the compound is safe and suitable for administration to a patient or individual. The term "pharmaceutically acceptable excipient" means a medium that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

The compounds disclosed herein may be in the form of pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" means salts that are suitable, within the scope of reasonable medical judgment, for use in contact with tissues of humans and lower animals without unusual toxicity, irritation, allergic reactions and the like. and commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino acids with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (such as acetic acid, trifluoroacetic acid, oxalic acid, cis salts formed from butenedioic acid, tartaric acid, citric acid, succinic acid or malonic acid) or by using other methods used in this technology (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphor sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, formate, fumarate, glucoheptanate Glycolate, glycerophosphate, gluconate, glutamate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxyethane sulfonate, lactobionate, lactate , laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, grass Acid, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate , succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and similar salts. Salts of compounds containing carboxylic acid or other acidic functionality can be prepared by reaction with a suitable base. Such salts include, but are not limited to, alkali metal salts, alkaline earth metal salts, aluminum salts, ammonium salts, N ⁺ (C _1-4 alkyl) ₄ salts, and organic bases such as trimethylamine, triethylamine, Phenoline, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-diphenylmethylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-( 2-Hydroxyethyl)amine, procaine, diphenylmethylpiperidine, dehydroabidamine, N,N'-didehydroabidamine, glucosamine, N-methylglucamine , trimethylpyridine, quinine, quinoline) and salts of basic amino acids (such as lysine and arginine). The present invention also contemplates quaternary ammonization of any basic nitrogen-containing groups of the compounds disclosed herein. Water- or oil-soluble or dispersible products can be obtained by such quaternary ammonization. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include the use of counter ions (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and arylsulfonates) where appropriate. Non-toxic ammonium, quaternary ammonium and amine cations formed. Pharmaceutical formulations, dosages and routes of administration

Pharmaceutical formulations (also referred to throughout this document as compositions) are also provided, comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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 compounds can be administered all at once, in multiple doses, or delivered generally evenly over a period of time. It should also be noted that the dosage of the compound may vary over time.

The specific dosing regimen for a particular individual will depend in part on the compound, the amount of the compound administered, the route of administration, and the cause and extent of any side effects. The amount of compound administered to an individual (eg, a mammal, such as a human) according to the present invention should be sufficient to affect the desired response within a reasonable time frame. Dosage usually depends on the route, timing and frequency of administration. Therefore, the clinician adjusts the dosage and adjusts the route of administration to obtain optimal therapeutic effect, and conventional range determination techniques are known to those skilled in the art.

By way of illustration only, methods include, for example, administering from about 0.1 mg/kg to about 100 mg/kg or more of the compound, depending on the factors noted above. In other embodiments, the dosage range is 1 mg/kg to about 100 mg/kg; or 5 mg/kg to about 100 mg/kg; or 10 mg/kg to about 100 mg/kg. Some conditions require long-term treatment, which may or may not require the administration of lower doses of the compound over multiple administrations. If necessary, a dose of the compound is administered in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, as appropriate in unit dosage form. The treatment period will depend on the specific condition and type of pain and can last from one day to several months.

Suitable methods of administering physiologically acceptable compositions, such as pharmaceutical compositions containing compounds disclosed herein, are well known in the art. Although more than one route may be used to administer a compound, certain routes may provide a more direct and efficient response than other routes. As appropriate, pharmaceutical compositions containing the compounds are administered or instilled into a body cavity, absorbed through the skin or mucous membranes, ingested, inhaled and/or introduced into the circulation. For example, in some cases, it is desirable to deliver a pharmaceutical composition containing an agent: orally; intravenously, intraperitoneally, intracerebrate (brain parenchyma), intracerebroventricularly, intramuscularly, intraocularly , intraarterial, intraportal vein, intralesional, intramedullary, intrathecal, intraventricular, transcutaneous, subcutaneous, intraperitoneal, intranasal, enteral, local, sublingual, transurethral, transvaginal or transrectal injection; by injection Sustained release systems; or via implanted devices. If desired, the compound is administered topically to deliver to the region of interest via intrathecal administration, intracerebral (brain parenchymal) administration, intracerebroventricular administration, or intraarterial or intravenous administration. Alternatively, the composition is administered topically via implantation of a membrane, sponge, or other suitable material onto which the desired compound has been absorbed or encapsulated. Where an implanted device is used, in one aspect, the device is implanted in any suitable tissue or organ and the desired compound is delivered, for example, via diffusion, timed release bolus injection, or continuous administration.

To facilitate administration, in various aspects, the compounds are formulated into physiologically acceptable compositions including a carrier, such as a vehicle, adjuvant, or diluent. The particular carrier used is limited only by physico-chemical factors, 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 injection include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (see, eg, U.S. Patent No. 5,466,468). Injectable formulations are further described in, for example, Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Injections ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pp. 622-630 (1986)). In one aspect, a pharmaceutical composition comprising a compound is placed in a container with packaging material that provides instructions for the use of such pharmaceutical composition. Generally, such instructions include physical expressions describing the concentration of the reagents and, in certain embodiments, the relative amounts of excipient ingredients or diluents (e.g., water, normal saline, or PBS) that may be necessary to reconstitute the pharmaceutical composition. quantity.

Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution to sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin and similar alcohols), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper flowability can be maintained, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

These compositions may 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 and the like. It may also be necessary to include isotonic agents such as sugar, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical compositions can be brought about by the use of agents which delay absorption, such as aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) a filler or extender, For example, starch, lactose, sucrose, mannitol and silicic acid; (b) Binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates and sodium carbonate; (a) dissolution delaying agents, such as paraffin; (f) absorption enhancers, For example, quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or mixtures thereof. In the case of capsules and tablets, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose/milk sugar and high molecular weight polyethylene glycols and the like.

Solid dosage forms, such as tablets, dragees, capsules, pills and granules, may be prepared with coatings and shells such as enteric coatings and other coatings well known in the art. Solid dosage forms may also contain devitrification agents. Additionally, solid dosage forms may be entrapped compositions such that they release one or more active compounds in a certain portion of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, optionally with one or more excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame seed oil; glycerin, tetrahydrofurfuryl alcohol , polyethylene glycol and sorbitan fatty acid esters, or mixtures of these substances, and their analogs.

Besides such inert diluents, the compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active compounds, suspensions may also contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and Tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administration are preferably suppositories, which may be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or suppository wax, Such excipients or carriers are solid at normal room temperature, but liquid at body temperature, and therefore melt in the rectal or vaginal cavity and release the active ingredient.

Compositions for use in the methods of the present invention may be formulated in micellar or liposome form. Such formulations include sterically stabilized micelles or liposomes and sterically stabilized mixed micelles or liposomes. Such formulations may facilitate intracellular delivery since the lipid bilayers of liposomes and micelles are known to fuse with the cytoplasmic membrane and deliver the coated contents into the intracellular compartment.

When formulated, the solution is administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The formulations are readily administered in a variety of dosage forms, such as injectable solutions, drug release capsules, and the like. For example, for parenteral administration in the form of aqueous solutions, the solution should be appropriately buffered if necessary, and the liquid diluent first made isotonic with sufficient saline or glucose. These specific aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.

The frequency of dosing will depend on the pharmacokinetic parameters of the agent and the route of administration. Those skilled in the art will determine the optimal pharmaceutical formulation based on the route of administration and dosage required. See, eg, Remington's Pharmaceutical Sciences, 18th Edition (1990) Mack Publishing Co., Easton, PA, pages 1435-1712, which is incorporated herein by reference. Such formulations can affect the physical state, stability, in vivo release rate, and in vivo clearance rate of the administered agent. Depending on the route of administration, the appropriate dosage may be calculated based on body weight, body surface area, or organ size. Those skilled in the art can usually make further refinements in the calculations required to determine appropriate therapeutic doses without undue experimentation, particularly based on the dosing information and analytical methods disclosed herein and observations in animal or human clinical trials. available pharmacokinetic data.

The precise dosage used will depend on a number of factors, including the host, the application in veterinary or human medicine, the nature and severity of the condition (e.g., disease or disorder) being treated, the mode of administration and the specific active substance used. The compounds may be administered by any conventional route, in particular enterally, and in one aspect, orally in the form of tablets or capsules. Where appropriate, the compounds administered may be in free form or pharmaceutically acceptable salt form for pharmaceutical use, particularly for the prophylactic or therapeutic treatment of a disease of interest. These measures will slow the progression of the disease condition and help the body naturally reverse the direction of progression.

It should be understood that the pharmaceutical compositions and treatment methods of the present invention can be used in the fields of human and veterinary medicine. Thus, in one aspect, the individual to be treated is a mammal. In another aspect, the mammal is a human.

In jurisdictions that prohibit the patenting of methods for practice on the human body, the meaning of "administering" a composition to a human subject should be limited to prescribing a controlled substance that is to be administered by the human subject Self-administer by any technique (e.g., oral, inhalation, topical application, injection, infusion, etc.). The broadest reasonable interpretation consistent with the law or regulation defining patentable subject matter is contemplated. In jurisdictions that do not prohibit the patenting of methods of practice on the human body, "administering" a composition includes methods of practice on the human body as well as the foregoing activities. Instructions

Compounds disclosed herein (eg, compounds of Formula I and as shown in Table A) increase the amount of granulin precursors or granulin in an individual. In some cases, the compound increases the amount of progranulin in an individual. In some cases, the compound increases the amount of granule protein in an individual. In some cases, the compounds affect cells to increase progranulin secretion. Therefore, compounds disclosed herein (e.g., compounds of Formula I and as shown in Table A) may be useful in the treatment of conditions associated with abnormal (e.g., reduced) progranulin secretion or activity.

In particular, methods of modulating progranulin (eg, increasing progranulin secretion) using a therapeutically effective amount of a compound disclosed herein as a therapeutic agent in an individual are contemplated. As used herein, the term "therapeutically effective amount" means ameliorating, alleviating, or eliminating one or more symptoms of a particular disease or condition (e.g., progranulin or granulin-related disorder) or preventing or delaying a particular disease or condition. An amount of a compound or combination of therapeutically active compounds (eg, a progranulin modulator or a combination of modulators) that is responsible for the onset of one or more symptoms.

The therapeutically effective amount will vary depending on the intended use or individual and disease condition being treated (e.g., desired biological endpoint), the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, and may be readily determined by It is generally determined by those who are familiar with this technology. The term also applies to doses that induce a specific response in the target cell (eg, increased secretion of progranulin). The specific dosage will vary depending on factors such as: the specific compound selected, the species and age of the individual and/or existing health conditions or risks to health conditions, the dosing regimen followed, the severity of the disease, whether the compound is combined with other agents The combination of administration, timing of administration, tissue to which the compound is administered, and the physical delivery system carrying the compound.

As used herein, the terms "patient" and "individual" are used interchangeably and mean animals such as dogs, cats, cattle, horses, and sheep (eg, non-human animals) as well as humans. The particular patient or individual is a mammal (eg, a human). The terms patient and subject include males and females.

Covered diseases related to abnormal progranulin activity include Alzheimer's disease (AD), Parkinson's disease (PD) and PD-related disorders, amyotrophic lateral sclerosis (ALS), frontotemporal lobar type Dementia (FTD), Lewy Body Dementia (LBD), Prion Disease, Motor Neurone Disease (MND), Huntington's Disease (HD), Spinocerebellar Disorders (SCA), Spinal Muscle Disease amyotrophic syndrome (SMA) and other neurodegenerative diseases. Other conditions covered include conditions of lysosomal dysfunction or dysfunction, such as lysosomal storage diseases (e.g., Paget's disease, Gaucher's disease, Niemann-Pick's disease). Nieman's Pick disease, Tay-Sachs Disease, Fabry Disease, Pompes disease, or Naso-Hakula disease) . Other diseases covered include those associated with inclusion bodies and/or C9orf72, TDP-43, FUS, UBQLN2, VCP, CHMP28 and/or MAPT dysfunction. Other diseases include acute neurological conditions, such as stroke, cerebral hemorrhage, traumatic brain injury and other head injuries, and brain diseases, such as glioblastoma and neuroblastoma.

In some cases, progranulin related disorders are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) , Frontotemporal dementia-granulin isoform (FTD-GRN), Lewy body dementia (LBD), prion disease, motor neuron disease (MND), Huntington's disease (HD), Spinocerebellar disorders (SCA), spinal muscular atrophy (SMA), lysosomal storage diseases, nephropathy, and inclusion bodies and/or C9orf72, TDP-43, FUS, UBQLN2, VCP, CHMP28 and/or MAPT Disorders related to functional impairment, acute neurological conditions, glioblastoma or neuroblastoma. In some cases, Parkinson's disease is Parkinson's disease with a GBA mutation. In some cases, the lysosomal storage disease is Paget's disease, Gaucher's disease, Niemann-Pick's disease, Tay-Sachs' disease, Fabry's disease, Pompe's disease, or Nasu-Harco's disease Laden disease. In some cases, the acute neurological condition is 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).

Compounds disclosed herein (eg, compounds of Formula I and as shown in Table A) can increase the content of lysosomal proteins by modulating the translocon complex. Translocators are protein complexes involved in the translocation of proteins across cell membranes, such as complexes that transport nascent polypeptides with targeting signal sequences from the cytosol to the internal (cisternal or luminal) space of the endoplasmic reticulum (ER). body. This translocation process requires proteins to span a hydrophobic lipid bilayer. The same complex is also used to integrate nascent proteins into their own membranes (membrane proteins). The translocon complex is a heterotrimeric protein complex called Sec61. It contains subunits Sec61α, Sec61β and Sec61γ. Sec61α is a large micropore subunit. During protein translocation, the channels rearrange to dislodge the α-helical "plug" and the polypeptide chain moves from the cytoplasmic funnel through the pore ring (extracellular funnel) into the extracellular space. Proteins destined for secretion are elongated through the Sec61 channel and N-glycosylated by OST on an asparagine residue, followed by final cleavage of the signal peptide by a signal peptidase.

The content 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 content. It can increase the content of intracellular lysosomal proteins, and/or can increase the secretion of lysosomal proteins, thereby increasing the extracellular content. Increase lysosomal protein content

It has been found that the content of lysosomal proteins can be increased by modulating the activity of the translocon complex. Without being bound by any particular theory, it is hypothesized that the amount of lysosomal protein is increased by one of four mechanisms or any combination of these four mechanisms. Increased migration of lysosomal proteins may be due to increased translation of mRNA subsets, facilitated translocation into the endoplasmic reticulum, increased glycosylation of lysosomal proteins (thereby increasing their stability), and/or via transmembrane proteins Enhanced migration of lysosomal proteins through mannose-6-phosphate receptor (M6PR) and/or sortilin.

The compounds disclosed herein are useful in methods of treating disorders associated with low levels of lysosomal proteins by administering to an individual suffering from the disorder a disclosed compound that modulates the translocon complex, thereby This increases the amount of lysosomal proteins and treats the condition.

Compared with the control, the lysosomal protein content can be increased by 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%, at least 150% or at least 200%.

The amount of lysosomal protein can be assessed using typical bioassays, including those described in the Examples section below. The measured lysosomal protein content can be intracellular, extracellular (i.e., secreted protein), or a combination thereof. In some cases, the amount of lysosomal proteins secreted from the cell is increased (eg, the amount of extracellular proteins is increased). In some cases, intracellular levels of lysosomal proteins are increased.

Provided herein are methods of increasing the content of lysosomal proteins in an individual by administering compounds as disclosed herein. Lysosomal proteins can be progranulin, prosaposin, β-glucocerebrosidase, galactosidase α, cathepsin B, cathepsin Z, neuraminidase 1, tripeptidyl Peptidase, α-L-fucosidase 2, mannosidase α 2B class member 2, mannosidase β, serine carboxypeptidase 1, acid ceramide, GM2 ganglioside activating factor, tissue Protease D, cathepsin S, cathepsin K, cathepsin L or hexosaminidase. Increasing the levels of lysosomal proteins can affect conditions associated with abnormal levels of lysosomal proteins. For example, the condition may be a lysosomal storage disease, a neurodegenerative disease, an inflammatory disease, or a disease selected from: stroke, Down syndrome, congenital heart disease, diabetes, common variant immunity deficiency (CVID), tubulointerstitial kidney disease (TKD), polycystic liver disease, myocarditis, dermatitis, hyperhomocysteinemia, endotoxic shock, lung injury, bone defects (e.g., inflamed periodontal disease) bone defect) or osteolysis.

In various cases, individuals suffer from lysosomal storage diseases. Lysosomal storage diseases can be mucopolysaccharidosis, sphingolipidosis, glycogen storage disease type II, glycoprotein storage disease, Hurler disease, Scheie disease disease), Hunter disease, Sanfilippo disease A (Sanfilippo disease A), Sanfilippo disease B, Sanfilippo disease C, Sanfilippo disease D, Morquio disease A (Morquio disease A), Morquio disease B, Maroteaux-Lamy disease, Sly disease, mucopolysaccharidosis type IX, mucopolysaccharidosis Syndrome plus syndrome, Fabry disease, Gaucher disease, Tay-Sachs disease, sialidosis, Niemann-Pick disease type A, Niemann-Pick disease type B, galactosialidosis , Niemann-Pick disease type C, I-cell disease, mucolipidosis type III, GM1 gangliosidosis, beta-galactosidase deficiency, alpha-mannosidosis, GM2 neuro Arthrosidosis, β-mannosidosis, Krabbe disease, fucosidosis, metachromatic leukodystrophy, asparagus glucosamineuria, polysulfate Enzyme deficiency, Schindler's disease, Farber lipogranulomatosis, Pompe disease, Wolman disease, Danon disease, free saliva Acidosis, ceroid lipofuscinosis, beta-glucuronidase hyperactivity, Sandhoff's disease, or cholesteryl ester storage disease.

In each case, the condition is a neurodegenerative disease. Neurodegenerative diseases may be Parkinson's disease (eg, 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 dementia, Alexander's disease, Alper's disease , cerebral palsy, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangle calcification disease, HIV-related dementia, Lewy body dementia, Kennedy's disease, neurospirosis, primary lateral sclerosis, Refsum's disease, Gerstmann's disease -Gerstmann-Straussler-Scheinker disease, Hallevorden-Spatz disease, hereditary diffuse leukoencephalopathy with axonal spheroids with spheroids (HDLS), inclusion body myositis, multiple systemic atrophy, myotonic dystrophy, Nasu-Hakola disease, Schilder's disease, Wobbly Hedgehog Syndrome (WHS) , Duchenne-Aran muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, HIV-related neurocognitive disorder, tauopathy, chronic traumatic encephalopathy, or cerebellar hypoplasia Nystagmus.

In each case, the condition is an inflammatory disease. The inflammatory disease may be Sjogren's disease, inflammatory arthritis, osteoarthritis, inflammatory bowel disease or immune thrombocytopenia.

As used herein, the term "treatment/treating" refers to methods of reducing, delaying or ameliorating the condition of a disease or condition before or after the occurrence of such condition. Treatment may target one or more of the effects or symptoms of the disease and/or underlying pathology. Treatment is intended to achieve beneficial or desired results, including (but not limited to) therapeutic and/or preventive benefits. Therapeutic benefit means eradication or amelioration of the underlying condition being treated. Furthermore, therapeutic benefit is achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying condition such that an improvement is observed in the patient, although the patient may still suffer from the underlying condition. To obtain preventive benefits, pharmaceutical compounds and/or compositions may be administered to patients who are at risk of developing a particular disease or to patients who report one or more physiological symptoms of the disease but who may not have been diagnosed with the disease. Treatment may be any reduction of the disease or symptoms of the disease and may be (but is not limited to) its complete removal. Such reduction or prevention to a degree of at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90% as compared to an equivalent untreated control, as measured by any standard technique %, 95% or 100%.

As used herein, the term "therapeutic effect" refers to a therapeutic benefit and/or a prophylactic benefit as described herein. Preventative action includes delaying or eliminating the appearance of a disease or condition; delaying or eliminating the onset of symptoms of a disease or condition; slowing, stopping, or reversing the progression of a disease or condition; or any combination thereof. Synthesis of compounds disclosed herein

Typical synthetic chemistry techniques may be used, using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art, or according to the teachings herein. Synthetic compounds. In general, the synthesis of the disclosed compounds can be accomplished by following a synthesis similar to that detailed in Schemes A and B and the Examples below. Process A

Compounds of structure e can be synthesized using the procedure shown in Scheme A. For example, the reaction of an optionally substituted benzoic acid derivative of structure a with an optionally substituted 2-phenylethyl-1-amine b yields an optionally substituted N - phenylethyl group of structure c Benzamide compound. Cyclization under appropriate conditions affords optionally substituted 1-phenyl-3,4-dihydroisoquinoline compounds having structure d . Subsequent reduction, followed by separation of the single stereoisomers by dissolution or chromatography as appropriate, yields the substituted tetrahydroquinoline compound having structure e .

The coupling of compounds a and b can be catalyzed by appropriate reagents selected based on the exact properties of compounds a and b . For example, when compound a is a chloride compound (that is, when Z is Cl), the coupling of compounds a and b can be catalyzed by, for example, triethylamine. Compounds a and b may be commercially available or prepared by a variety of methods from commercially available starting materials.

Cyclization of compound c can be achieved using various reactions known in the art. For example, cyclization may involve an acid-catalyzed electrophilic aromatic substitution reaction, such as cyclization under Bischler-Napieralski reaction conditions. For example, c can be cyclized by treatment with triflate in the presence of a solvent containing, for example, chloropyridine, such as dichloromethane. Alternatively, compound c can be cyclized by treatment with polyphosphoric acid (PPA).

Compound d can be reduced to form compound e with or without induction of asymmetry at the stereocenter. For example, compound d can be treated with a reducing agent such as sodium borohydride in a solvent such as methanol. The desired stereoisomer can be formed after reduction of compound d , for example by crystallization in the presence of D-tartaric acid. Alternatively, compound d can be reduced via asymmetric hydrogenation to directly yield substituted tetrahydroquinoline compound e as the desired stereoisomer. For example, compound d can be reduced with H gas in the presence of an _iridium catalyst such as [{Ir(H)[( S,S )-(f)-binaphthyl]} ₂ (μ-I ) ₃ ] ⁺ I ⁻ . Process B

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

Appropriate coupling conditions i for the reaction between compounds e and f are known to those skilled in the art. For example, carbodiimide coupling conditions (e.g., EDC/HOBt) or other peptide coupling conditions (e.g., (1-[bis(dimethylamino)methylene]-1H-1,2,3-tri Azolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and bases such as N,N-diisopropylethylamine (DIPEA) or trimethylamine (TEA), also known as HATU/ DIPEA or HATU/TEA) in an organic solvent such as dichloromethane (DCM) or dimethylformamide (DMF). Example General Method

LCMS : Equipment: Agilent 1260 binary pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315D, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, positive/negative ions 100-1000, ELSD Alltech 3300 gas flow rate: 1.5 ml/min, gas temperature: 40°C, eluent A: acetonitrile containing 0.1% formic acid, eluent B: water containing 0.1% formic acid.

Method A _{: column} ^: _{Waters _ minutes} = 98% A, dwell time: 1.3 minutes.

Method C _: ^column _{: Waters _ Minutes} =98% A, dwell time: 2 minutes.

Method AK : Column: Waters XSelect ^TM CSH C18, 50×2.1 mm, 3.5 µ, temperature: 40°C, flow: 0.8 ml/min, gradient: t ₀ =5% A, t _{4.5 minutes} = 98% A, t _{6 minutes} = 98% A, dwell time: 2 minutes.

Method BV : Column: Waters XSelect ^TM C18, 30×2.1 mm, 3.5 µ, temperature: 25°C, flow: 1 ml/min, gradient: t ₀ =5% A, t _{1.6 min} = 98% A, t _{4 minutes} = 98% A, dwell time: 1.3 minutes.

LCMS : Equipment: Agilent 1260 binary pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, positive/negative ions 100-1000, Eluent A: acetonitrile, eluent B: water containing 10 mM ammonium bicarbonate (pH=9.5).

Method B : Column: Waters XSelect ^TM CSH C18, 30×2.1 mm, 3.5 µ, temperature: 25°C, flow: 1 ml/min, gradient: t ₀ =5% A, t _{1.6 minutes} = 98% A, t _{3 minutes} = 98% A, dwell time: 1.3 minutes.

Method D : Column: Waters XSelect ^TM CSH C18, 50×2.1 mm, 3.5 µ, temperature: 25°C, flow: 0.8 ml/min, gradient: t ₀ =5% A, t _{3.5 minutes} = 98% A, t _{6 minutes} = 98% A, dwell time: 2 minutes.

Method AQ : Column: Waters XSelect ^TM CSH C18, 50×2.1 mm, 3.5 µ, temperature: 25°C, flow: 0.8 ml/min, gradient: t ₀ =5% A, t _{4.5 minutes} = 98% A, t _{6 minutes} = 98% A, dwell time: 2 minutes.

Method J : Column: Phenomenex GeminiNX C18, 50×2.0 mm, 3 µ, temperature: 25°C, flow: 0.8 ml/min, gradient: t ₀ =5% A, t _{3.5 minutes} = 98% A, t _{6 minutes} =98% A, dwell time: 2 minutes.

LCMS : Equipment: Agilent 1290 series with UV detector (220 nm, 270 nm (bandwidth 100 nm)) and HP 6130 MSD mass detector (API-ES positive ions and negative ions).

Method E _: Column: _Waters XBridge _BEH t _{3 minutes} = 0% A. Solvent A: 100% water, Solvent B: 100% methanol/acetonitrile 1:1.

Method O _: Column: _Waters XBridge _BEH t _{2 minutes} = 20% A. Eluent A: water containing 0.05% trifluoroacetic acid, eluant B: 100% acetonitrile.

Method K _: Column _{: Waters} XBridge BEH t _{4 minutes} = 0% A. Eluent A: ammonium acetate (10 mM); water/methanol/acetonitrile (90:6:4), eluent B: ammonium acetate (10 mM); water/methanol/acetonitrile (10:54:36).

LCMS : Equipment: Agilent Infinty II; Binary pump: G7120A; Multifunction injector, VTC, DAD: Agilent G7117B, 220 and 220-320 nm, PDA: 210-320 nm, MSD: Agilent G6135B ESI, positive ion/ Negative ions 100-1000, ELSD G7102A: Evap 40℃, Neb 40℃, gas flow 1.6 ml/min.

Method P _{: Column : Waters Minutes} = 98% A, residence time: 0.3 minutes, eluent A: acetonitrile containing 0.1% formic acid, eluent B: water containing 0.1% formic acid.

Method Q _{: Column : Waters minutes} = 98% A, residence time: 0.3 minutes, eluent A: acetonitrile, eluant B: water containing 10 mM ammonium bicarbonate (pH=9.5).

Method AH : Column: XBridge Shield RP C18 (50×2.1mm, 2.5 µm), temperature: 25°C, flow: 0.6 ml/min, gradient: t ₀ =5% A, t _{2 minutes} = 98% A, t _{2.7 minutes} = 98% A, residence time: 0.3 minutes, eluent A: acetonitrile containing 100 mM ammonia, eluent B: water containing 100 mM ammonia (pH=10).

Method BB : Column: Waters XBridge BEH Shield RP (50×2.1 mm; 2.5 µm), temperature: 40°C, flow: 0.6 ml/min, t ₀ =5% A, t _{2.0 min} = 98% A, t _{2.7 Minutes} = 98% A, residence time: 0.3 minutes, eluent A: acetonitrile containing 0.1% formic acid, eluent B: water containing 0.1% formic acid.

Method CA _{: Column : Waters minutes} = 98% A, t _{5 minutes} = 98% A, residence time: 0.5 minutes, eluent A: acetonitrile containing 0.1% formic acid, eluent B: water containing 0.1% formic acid.

Method CB _{: Column : Waters minutes} = 98% A, t _{5 minutes} = 98% A, residence time: 0.5 minutes, eluent A: acetonitrile, eluent B: water containing 10 mM ammonium bicarbonate (pH=9.5).

LCMS : Equipment: Waters Acquity UPLC H-Class with PDA detector and SQD mass detector (API-ES positive and negative ions).

Method R _{: Column : Waters _} =5% A, residence time: 0.5 minutes, eluent A: water containing 10 mM ammonium acetate and 5% acetonitrile, eluant B: acetonitrile.

Method BI : Column: Waters Acquity CSH C18, 100×2.1 mm, 1.7 µm, temperature: 40°C, flow: 0.45 ml/min, gradient: t ₀ =5% A, t _{5.0 minutes} = 98% A, t _{6.0 Minutes} = 98% A, residence time: 0.5 minutes, eluent A: acetonitrile containing 0.1% formic acid, eluent B: water containing 0.1% formic acid.

LCMS : Equipment: Waters Iclass; binary pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: ACQ-SQD2 ESI; ELSD: air pressure 40 psi, drift tube temperature: 50°C .

Method AV : Column: Waters Acquity Shield RP18 (50×2.1 mm; 1.7 µm), temperature: 25°C, flow: 0.5 ml/min, t ₀ =5% B, t _{2.0 min} = 98% B, t _{2.7 min} =98% B, residence time: 0.3 minutes, eluent A: water containing 10 mM ammonium bicarbonate (pH=9.5), eluent B: acetonitrile.

Chiral LC:

Equipment : Agilent 1260 quaternary pump: G1311C, degasser; autosampler, ColCom, DAD: Agilent G1315D (210 nm, 220 nm, 220-320 nm).

Method H : Column: Chiralcel OD-H (250×4.6mm, 5 µm); column temperature: 25°C; flow rate: 1.0 ml/min; containing 0.1% diethylamine in heptane/isopropyl alcohol (95/ 05) isocratic gradient.

Method I : Column: Chiralcel OD-H (250×4.6 mm, 5 µm); column temperature: 25°C; flow rate: 1.0 ml/min; heptane/ethanol (80/20) containing 0.1% diethylamine isocratic gradient.

Method L : Column: Chiralcel OD-H (250×4.6 mm, 5 µm); column temperature: 25°C; flow rate: 1.0 ml/min; containing 0.1% diethylamine in heptane/isopropyl alcohol (90/ 10) isocratic gradient.

Method AB : Column: Chiralpak AD-H (250×4.6 mm, 5 µm); column temperature: 25°C, flow rate: 0.8 ml/min, containing 0.1% diethylamine in heptane/ethanol 30/70, etc. degree gradient.

Method AC : Column: Chiralpak AD-H (250×4.6 mm, 5 µm); column temperature: 25°C, flow: 1.0 ml/min, containing 0.1% diethylamine in heptane/ethanol 70/30, etc. degree gradient.

Method AG : Column: Chiralpak AD-H (250×4.6 mm, 5 µm); column temperature: 25°C, flow rate: 1.0 ml/min, isocratic gradient of heptane/isopropyl alcohol 70/30.

SFC : Equipment: Waters Acquity UPC ² : Waters ACQ-ccBSM Binary Pump; Waters ACQ-CCM Aggregation Manager; Waters ACQ-SM Sample Manager-Fixed Loop; Waters ACQ-CM Column Manager-30S; Waters ACQ- PDA photodiode array detector (210-400 nm); Waters ACQ-ISM supply pump, Waters Acquity QDa MS detector (positive ions 100-650).

Method F : Column: Phenomenex Cellulose-2 (100×4.6 mm, 5 µm), temperature: 35°C, BPR: 170 bar, flow: 2.5 ml/min, gradient: t ₀ =5% B, t _{5 min} = 50% B, t _{6 minutes} = 50% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: methanol containing 20 mM ammonia

Method BL : Column: Phenomenex Cellulose-2 (100×4.6 mm, 5 µm), temperature: 35°C, BPR: 170 bar, flow: 2.5 ml/min, gradient: t ₀ =10% B, t _{5 min} = 40% B, t _{6 minutes} = 40% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: 2-propanol containing 20 mM ammonia

Method G : Column: PhenomenexAmylose-1 (100×4.6 mm, 5 µm), temperature: 35°C, BPR: 170 bar, flow: 2.5 ml/min, gradient: t ₀ =5% B, t _{2.5 min} = 50 % B, t _{10 minutes} = 50% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: methanol containing 20 mM ammonia

Method W : Column: PhenomenexAmylose-1 (100×4.6 mm, 5 µm), temperature: 35°C, BPR: 170 bar, flow: 2.5 ml/min, gradient: t ₀ =5% B, t _{5 minutes} = 50 % B, t _{6 minutes} = 50% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluent B: methanol containing 20 mM ammonia

Method _ _{_ _ _} % B, t _{6 minutes} = 30% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: methanol containing 20 mM ammonia

Method N : Column: Diacel Chiralpak IG-3 (3.0×150 mm, 3 µm), temperature: 40°C, BPR: 126 bar, flow: 2.0 ml/min, pump program: isocratic 30% B, eluent A : CO ₂ , solvent B: methanol containing 0.2% ammonia

Method V : Column: Phenomenex Cellulose-1 (100×4.6 mm, 5 µm), temperature: 35°C, BPR: 170 bar, flow: 2.5 ml/min, gradient: t ₀ =5% B, t _{5 min} = 50% B, t _{6 minutes} = 50% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: methanol containing 20 mM ammonia

Method AO : Column: Phenomenex Cellulose-1 (100×4.6 mm, 5 µm), temperature: 35°C, BPR: 170 bar, flow: 2.5 ml/min, gradient: t ₀ =2% B, t _{5 min} = 10% B, t _{6 minutes} = 10% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluent B: methanol containing 20 mM ammonia

Method BM : Column: Phenomenex Cellulose-1 (100×4.6 mm, 5 µm), temperature: 35°C, BPR: 170 bar, flow: 2.5 ml/min, gradient: t ₀ =10% B, t _{5 min} = 40% B, t _{6 minutes} = 40% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: methanol containing 20 mM ammonia

Method AA : Column: Phenomenex Lux Cellulose4 (3.0×150 mm, 3 µm); Temperature: 40°C, BPR: 138 bar; Flow: 2.5 ml/min, Gradient: t ₀ =2% B, t _{4 minutes} = 27 % B, residence time: 1 minute; eluent A: CO ₂ , eluant B: methanol

Method AD : Column: Diacel Chiralpak IC (4.6×100 mm, 5 µm), temperature: 35°C, BPR: 170 bar, flow: 2.5 ml/min, gradient: t ₀ =5% B, t _{5 min} = 50 % B, residence time: 0.5 minutes; eluent A: CO ₂ , eluent B: methanol containing 20 mM ammonia

Method AI : Column: Diacel Chiralpak IC (4.6×100 mm, 5 µm); Temperature: 35°C, BPR: 170 bar; Flow: 2.5 ml/min, Gradient: t ₀ =5% B, t _{5 min} = 50 % B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: 2-propanol containing 20 mM ammonia

Method AR : Column: Waters Acquity UPC2 BEH (3.0×100 mm, 1.7 µm); Temperature: 35°C, BPR: 210 bar; Flow: 1.0 ml/min, Gradient: t ₀ =2% B, t _{4 min} = 20% B, t _{6 minutes} = 20% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: methanol containing 20 mM ammonia

Method AS : Column: Waters Acquity UPC2 BEH (3.0×100 mm, 1.7 µm); Temperature: 35°C, BPR: 210 bar; Flow: 1.0 ml/min, Gradient: t ₀ =2% B, t _{4 min} = 50% B, t _{6 minutes} = 50% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: methanol containing 20 mM ammonia

Method AU : Column: Waters Acquity UPC2 Torus 2-PIC (100×3.0 mm, 1.7 µm), Temperature: 35°C, BPR: 170 bar, Flow: 1.0 ml/min, Gradient: t ₀ =2% B, t _{4 minutes} = 50% B, t _{6 minutes} = 50% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: methanol containing 20 mM ammonia

Method AZ : Column: Phenomenex iAmylose-3 (100×4.6 mm, 5 µm), temperature: 35°C, BPR: 170 bar, flow: 2.5 ml/min, gradient: t ₀ =5% B, t _{5 min} = 50% B, t _{6 minutes} = 50% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluent B: methanol containing 20 mM ammonia

Method BZ : Column: Phenomenex iAmylose-3 (100×4.6 mm, 5 µm), temperature: 35°C, BPR: 170 bar, flow: 2.5 ml/min, gradient: t ₀ =5% B, t _{5 min} = 50% B, t _{6 minutes} = 50% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluent B: ethanol containing 20 mM ammonia

Method BE : Column: Phenomenex Cellulose-1 (100×4.6 mm, 5 µm), temperature: 35°C, BPR: 120 bar, flow: 2.5 ml/min, gradient: t ₀ =10% B, t _{5 min} = 30% B, t _{6 minutes} = 30% B, residence time: 0.5 minutes; eluent A: CO ₂ , eluant B: methanol containing 20 mM ammonia

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

Method A20 : Initial temperature: 100°C; Initial time: 1.5 minutes; Solvent delay: 1.0 minutes; Rate 75°C/min; Final temperature 250°C; Final time 3.5 minutes.

Method SC_S20 : Initial temperature: 60°C; Initial time: 1.0 minutes; Solvent delay: 1.3 minutes; Rate 50°C/min; Final temperature 250°C; Final time 3.5 minutes.

Preparation method

Alkaline reversed-phase MPLC : Instrument type: Reveleris™ preparative MPLC; Eluent A: 99% acetonitrile + water containing 1% 10 mM ammonium bicarbonate (pH=9.0); Eluent B: 10 mM ammonium bicarbonate Water (pH=9.0). Unless otherwise stated, column used: Waters XSelect CSH C18 (145 × 25 mm, 10 µ); flow rate: 40 ml/min; column temperature: room temperature. Otherwise use column: Phenomenex Gemini C18 (185×25 mm, 10 µ); flow rate: 40 ml/min; column temperature: room temperature.

Acidic reversed-phase MPLC : Instrument type: Reveleris™ preparative MPLC; Column: Phenomenex LUNA C18(3) (150×25 mm, 10 µ); Flow rate: 40 ml/min; Column temperature: room temperature; Eluent A : Acetonitrile containing 0.1% (v/v) formic acid, eluent B: water containing 0.1% (v/v) formic acid.

Preparative SFC : Equipment: Waters Prep 100 SFC UV/MS directional system; Waters 2998 photodiode array (PDA) detector; Waters Acquity QDa MS detector; Waters 2767 sample manager. Solvent A: CO ₂ , Solvent B: methanol containing 20 mM ammonia. Eluent C: 2-propanol containing 20 mM ammonia. Eluent D: ethanol containing 20 mM ammonia.

Method S : Column: Phenomenex Lux Cellulose-2 (250×21.2 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 minutes 10% B , t=6 minutes 50%B; Detection: PDA (210-400 nm)/TIC.

Method T : Column: Phenomenex Lux Amylose-1 (250×21 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 min 5% B , t=3 minutes 10% B; t=8.5 minutes 10% B; Detection: PDA (210-400 nm)/TIC.

Method Y : Column: Phenomenex Lux Amylose-1 (250×21 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 minutes 10% B , t=6 minutes 40% B; t=7.5 minutes 40% B; Detection: PDA (210-400 nm)/TIC.

Method Z : Column: Phenomenex Lux Amylose-1 (250×21 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 minutes 10% B , t=6 minutes 50% B; t=7.5 minutes 50% B; Detection: PDA (210-400 nm)/TIC.

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

Method U : Column: Phenomenex Lux Cellulose-1 (250×21.2 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 minutes 10% B , t=6.5 minutes 30%B; t=8 minutes 30%B; Detection: PDA (210-400 nm)/TIC.

Method AE : Column: Diacel Chiralpak IC (250×20 mm, 5 µm) for SFC; Column temperature: 35°C; Flow rate: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 min10 % B, t=6 minutes 40% B; t=7.5 minutes 40% B; detection: PDA (210-400 nm); fraction collection: PDA TIC.

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

Method AM : 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 min25 % B, t=6 minutes 50% B; detection: PDA (210-400 nm); fraction collection: PDA TIC.

Method AN : Column: Diacel Chiralpak IC (250×20 mm, 5 µm) for SFC; Column temperature: 35°C; Flow rate: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 min10 % B, t=6 minutes 50% B; t=7.5 minutes 50% B; detection: PDA (210-400 nm); fraction collection: PDA TIC.

Method AP : 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 min10 % C, t=6 minutes 50% C, t=7.5 minutes 50% C; detection: PDA (210-400 nm); fraction collection: PDA TIC.

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

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

Method BD : Column: Phenomenex Lux Cellulose-1 (250×21.2 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 min 10% B , t=6.5 minutes 40% B; t=8 minutes 40% B; Detection: PDA (210-400 nm)/TIC.

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

Method BH : Column: Waters Torus 2-PIC 130A OBD (250×19 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 min5 % B, t=4 minutes 30% B, t=7 minutes 30% B; detection: PDA (210-400 nm); fraction collection: PDA TIC.

Method BK : Column: Phenomenex Lux Cellulose-2 (250×21.2 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 min 10% C , t=6 minutes 40% C; Detection: PDA (210-400 nm)/TIC.

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

Method BO : Column: Phenomenex Lux Amylose-1 (250×21 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 min 50% B , t=4 minutes 50% B; Detection: PDA (210-400 nm)/TIC.

Method BP : 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 min20 % B, t=3.5 minutes 30% B; detection: PDA (210-400 nm); fraction collection: PDA TIC.

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

Method BR : Column: Phenomenex Lux Cellulose-1 (250×21.2 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 minutes 10% B , t=6.5 minutes 50% B; t=8 minutes 50% B; Detection: PDA (210-400 nm)/TIC.

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

Method BT : Column: Phenomenex Lux Cellulose-2 (250×21.2 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 min 5% B , t=6 minutes 50%B; Detection: PDA (210-400 nm)/TIC.

Method BW : Column: Waters Viridis BEH Prep OBD (250×19 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Isocratic method: 10% B maintained for 8 minutes ; Detection: PDA (210-400 nm); PDA TIC based fraction collection.

Method BX : Column: Phenomenex Lux iAmylose-3 (250×21 mm, 5 µm); Column temperature: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Linear gradient: t=0 min 5% C , t=5 minutes 50% C, t=7 minutes 50% C; detection: PDA (210-400 nm); fraction collection: PDA TIC.

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

Preparative chiral HPLC : Equipment: Shimadzu LC8-A preparative pump, Shimadzu SCL-10Avp system controller, Shimadzu SPD-10Avp UV-VIS detector; eluate collector: Gilson 215 liquid handler.

Method AF : Column: Diacel Chiralpak AD-H, 20×250 mm, 5 µm, flow: 18 ml/min, isocratic heptane/isopropanol. Time: 60 minutes, solvent A: 70%, solvent B: 30%.

Method AJ : Column: Diacel Chiralpak AD-H, 20×250 mm, 5 µm, flow: 18 ml/min, isocratic 0.1% diethylamine in heptane/ethanol. Time: 60 minutes, solvent A: 30%, solvent B: 70%.

Method AY : Column: Diacel Chiralcel OD, 20×250 mm, 10 µm, flow: 18 ml/min, isocratic heptane/ethanol. Time: 60 minutes, solvent A: 90%, solvent B: 10%.

Preparative LCMS : Equipment: Agilent Technologies 1290 preparative LC; MS instrument type: Agilent Technologies G6130B quadrupole; Detection: DAD (220-320 nm); MSD (ESI positive ion/negative ion) mass range: 100-800; based on MS and/or DAD fractions were collected.

Method M : Column: Xbridge Amide (150×19mm, 5 µ); Flow rate: 25 ml/min; Column temperature: room temperature; Eluent A: 100% acetonitrile; Eluent B: containing 10 mM ammonium bicarbonate Water (pH=9.0).

Preparative LCMS : Agilent Technologies G6130B quadrupole; HPLC instrument type: Agilent Technologies 1200 preparative LC; Detection: DAD (220-320 nm); Detection: MSD (ESI positive ion/negative ion) mass range: 100-1000; Fraction collection based on MS and DAD.

Method AX : Column: Xbridge Amide (150×19mm, 5 µ); Flow rate: 25 ml/min; Column temperature: room temperature; Eluent A: 100% acetonitrile; Eluent B: water containing 10mM ammonium bicarbonate (pH=9.0). Linear gradient: t=0 minutes 2% A, t=2.5 minutes 2% A, t=11 minutes 30% A, t=13 minutes 100% A, t=17 minutes 100% A.

Method BC : Column: Waters % formic acid in water; linear gradient: t=0 minutes 2% A, t=2 minutes 2% A, t=8.5 minutes 30% A, t=10 minutes 100% A, t=13 minutes 100% A.

Method BU : Column: Waters XBridge Shield (C18, 150×19mm, 5 µ); flow rate: 25 ml/min; column temperature: RT; eluent A: water containing 10mM ammonium bicarbonate, pH=9.5; elution Agent B: 100% acetonitrile; linear gradient: t=0 minutes 20% B, t=2.5 minutes 20% B, t=11 minutes 60% B, t=13 minutes 100% B, t=17 minutes 100% B.

Preparative LCMS : Agilent Technologies G6120AA quadrupole; HPLC instrument type: Agilent Technologies 1200 preparative LC; Detection: DAD (220-320 nm); Detection: MSD (ESI positive ion/negative ion) mass range: 100-1000; Fraction collection based on MS and DAD.

Method BF : Column: Waters 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.

Preparative LCMS : MS instrument type: ACQ-SQD2; HPLC instrument type: Waters modular preparative HPLC system. Detection: DAD (220-320 nm); Detection: MSD (ESI positive ion/negative ion) mass range: 100-800; collection of dissociated fractions based on MS and DAD.

Method BJ : Column: Waters Xselect (C18, 100×30mm, 10µm); flow rate: 55 ml/min; column temperature: RT; eluent A: water containing 10 mM ammonium bicarbonate, pH=9.5, eluent B: 100% acetonitrile; linear gradient: t=0 minutes 5% B, t=2.5 minutes 5% B, t=4 minutes 20% B, t=13 minutes 60% B, t=14.5 100% B, t= 17 minutes 100% B.

¹ H-NMR:

400 MHz ^H -NMR spectra were recorded on a Bruker Avance-400 ultrashield NMR spectrometer using CDCl _or DMSO- d as solvent and TMS (0.00 ppm) as internal standard reported in ppm.

300 MHz ¹ H-NMR spectra were recorded on a Varian VNMRS: 7.05 Tesla magnet from Oxford Instruments. Chemical shifts are expressed in δ (ppm), and the residual protic solvent is used as a reference.

All CP analytical SFC experiments were run on the SFC Analytical Method Development Station (Thar, Waters), column temperature: 40°C, mobile phase: _CO2 /methanol (or ethanol or isopropanol), containing 0.2% MA (MA =7M methanolic ammonia), flow rate: 4.0 ml/min, back pressure: 120 bar, detection wavelength: 214 nm;

All CP analytical chiral HPLC experiments were run 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. Preparation method:

All CP preparative SFC experiments were run on SFC-80 (Thar, Waters), column temperature: 35°C, mobile phase: CO ₂ /methanol (or ethanol or isopropyl alcohol), containing 0.2% MA (MA=7M methanolic ammonia). Flow rate: 80 g/min, back pressure: 100 bar, detection wavelength: 214 nm.

All CP preparative chiral HPLC experiments were run on 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. LCMS experiment:

All CP LCMS experiments were run on an Agilent 1200 with a column temperature of 40°C, monitoring UV absorption at 214 nm and scanning the mass range 100-1000. Individual conditions vary slightly, as described in the methods below:

LCMS CP method A : Column: ZORBAX SB-C18 3.0×50 mm, 3.5 µm; mobile phase: A: water (0.1% TFA), B: ACN (0.1% TFA); gradient: 5% B increase in 1.3 minutes to 95% B, stopping at 3 minutes. Flow rate: 1.8 ml/min

LCMS CP method B : Column: XBridge C18 50×4.6 mm, 3.5 µm; mobile phase: A: water (0.1% TFA), B: ACN (0.1% TFA); gradient: 5% B to 95 in 1.2 minutes % B, stop at 3 minutes. Flow rate: 2.0 ml/min

LCMS CP Method C : 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 to 95 in 1.2 minutes %B. Flow rate: 2.0 ml/min;

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 to 95 in 1.4 minutes %B. Flow rate: 2.0 ml/min;

LCMS CP method C2 : Column: SunFire-C18 4.6×50 mm, 3.5 µm; mobile phase: A: water (10 mM NH ₄ HCO ₃ ), B: ACN; gradient: 5% B to 95% in 1.4 minutes B. Flow rate: 2.0 ml/min;

LCMS CP method D : Column: SunFire-C18 3.0×50 mm, 3.5 µm; mobile phase: A: water (0.01% TFA), B: ACN (0.01% TFA); gradient: 5% B in 1.3 minutes to 95% B, stop at 3 minutes. Flow rate: 2.0 ml/min;

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 increase in 1.8 minutes to 95% B, stopping at 3 minutes. Flow rate: 1.8 ml/min;

LCMS CP method F : Column: XBridge C18 4.6×50 mm, 3.5 µm; mobile phase: A: water (0.1% TFA), B: ACN (0.1% TFA); gradient: 5% B to 95 in 1.7 minutes % B, stop at 3 minutes. Flow rate: 1.8 ml/min Experimental Procedure Example 1 Synthesis of ((2 R ,5 S )-5-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone (compound 5000) and ((2 S ,5 R )-5-(aminomethyl)tetrahydrofuran-2-yl)(( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5001)

Synthesis of (((2S,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)tetrahydrofuran-2-yl) Methyl)carbamic acid tertiary butyl ester and (((2R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydrofuran-2-yl)methyl)carbamic acid tertiary butyl ester.

Autocis- 5-(((tertiary butoxycarbonyl)amino)methyl)tetrahydrofuran-2-carboxylic acid (97.4 mg, 0.397 mmol) and ( S )-1-(4-fluorophenyl)- Starting from 1,2,3,4-tetrahydroisoquinoline (98.6 mg, 0.434 mmol), as specified for ( S and R )-5-(( S )-1-(4-fluorophenyl)-1, (((2 S , 5 R ) -5- (( S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl)carbamic acid tertiary butyl ester (51 mg, 28%) as the first soluble isomer and (((2 R ,5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)tetrahydrofuran-2-yl)methyl)carbamic acid tertiary butyl ester as the second soluble isomer was subjected to additional acidic treatment (aq. HCl (1 M)/dichloromethane) and Purification was performed by preparative chiral SFC (Method S). The absolute configuration of the cis -tetrahydropyran-2-methamide center is arbitrarily specified.

First soluble isomer: SFC: RT=2.89 minutes. (M+Na) ⁺ =472 (Method F). Synthesis of ((2R,5S)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H) -Methyl ketone ( compound 5000 ).

From (((2 S ,5 R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2- Starting from tert-butyl)methyl)carbamate (51 mg, 0.112 mmol), treated with alkaline (extraction with saturated _aqueous NaHCO/dichloromethane) and lyophilized from acetonitrile and water (1:1) Thereafter, ((2 R ,5 S )-5-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3 was prepared according to the procedure described for compound 5008 ,4-Dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5000 ).

LCMS: 98%, RT=1.06 minutes. (M+H) ⁺ =355 (Method P). Synthesis of ((2S,5R)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H) -Methyl ketone ( compound 5001 ).

From (((2 R ,5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2- Starting from tert-butyl)methyl)carbamate (35 mg, 0.077 mmol), treated with alkaline (extraction with saturated _aqueous NaHCO/dichloromethane) and lyophilized from acetonitrile and water (1:1) Thereafter, ((2 S ,5 R )-5-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3 was prepared according to the procedure described for compound 5008 ,4-Dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5001 ).

LCMS: 99%, RT=1.07 minutes. (M+H) ⁺ =355 (Method P). Example 2 Synthesis of ((2 R ,5 R )-5-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline -2(1 H )-yl)methanone (compound 5002)

Synthesis of (((2R,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl) Methyl)carbamic acid tertiary butyl ester.

From (2 R ,5 R )-5-(((tertiary butoxycarbonyl)amino)methyl)tetrahydrofuran-2-carboxylic acid (synthesized according to the following method as reported in: Tetrahedron Lett . )》 , 2014 , 55 , 3569, using ( R , R )-salenCo(II) as a catalyst, and "Journal of Organic Chemistry ( J. Org. Chem. )" , 2010 , 65 , 6441; 0.11 g, 0.44 mmol ) and ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.11 g, 0.48 mmol), according to the instructions for ( S and R )-5-( Procedure described for ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2 H )-one (see Compounds 5004 ), preparation of (((2 R ,5 R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran -2-yl)methyl)carbamic acid tertiary butyl ester.

LCMS: 84%, RT=2.31 minutes, (M+H) ⁺ =455 (Method K).

Synthesis of ((2R,5R)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone ( compound 5002 ) .

At room temperature, to (((2 R ,5 R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )To a solution of tert-butyl tetrahydrofuran-2-yl)methyl)carbamate (53 mg, 0.12 mmol) in 2-propanol (1 mL) was added HCl (6 M in 2-propanol, 0.25 mL , 1.5 mmol). After the reaction mixture was stirred for 6 h, additional HCl (6 M in 2-propanol, 0.25 mL, 1.5 mmol) was added and stirring was continued for 72 h. Next, the reaction mixture was diluted with aqueous K ₂ CO ₃ solution (2 M, 10 mL) and extracted with dichloromethane (2 × 25 mL). The combined organic layers were dried over _Na2SO4 and evaporated under _reduced pressure. The residue was purified 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% A; t=18 min 100 %; t=23 min 100% A; Detection: 220 nm) purified (product isolated from alkalized (saturated aqueous NaHCO ₃ ) fraction by extraction with methylene chloride and from acetonitrile to water (1:1) mixture). ((2 R ,5 R )-5-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1 H )-yl)methanone ( compound 5002 ).

LCMS: 99%, RT=1.05 minutes, (M+H) ⁺ =355 (Method P). Example 3 Synthesis of ((2 S ,5 S )-5-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline -2(1 H )-yl)methanone (compound 5003)

Synthesis of (((2S,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-yl) Methyl)carbamic acid tertiary butyl ester.

From (2 S ,5 S )-5-(((tertiary butoxycarbonyl)amino)methyl)tetrahydrofuran-2-carboxylic acid (synthesized according to the following method as reported in: Tetrahedron Lett . )》 , 2014 , 55 , 3569, using ( R , R )-salenCo(II) as a catalyst, and "Journal of Organic Chemistry ( J. Org. Chem. )" , 2010 , 65 , 6441; 0.13 g, 0.54 mmol ) and ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.14 g, 0.59 mmol), according to the instructions for ( S and R )-5-( Procedure described for ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2 H )-one (see Compounds 5004 ), preparation of (((2 S ,5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran -2-yl)methyl)carbamic acid tertiary butyl ester.

LCMS: 81%, RT=2.30 minutes, (M+H) ⁺ =455 (Method K). Synthesis of ((2S,5S)-5-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone (compound 5003 ).

From (((2 S ,5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2- ((2 S ,5 S )-5-(aminomethyl)tetrahydrofuran-2 was prepared according to the procedure described for compound 5002 , starting from tert-butyl)methyl)carbamate (66 mg, 0.15 mmol). -yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5003 ), and by acidic preparative MPLC (Linear gradient: t=0 minutes 5% A; t=1 minute 5% A; t=2 minutes 10% A; t=17 minutes 50% A; t=18 minutes 100%; t=23 minutes 100% A ; Detection: 220 nm) purification (by extraction with methylene chloride, isolation of the product from the alkalized (saturated aqueous NaHCO ₃ solution) fraction, and lyophilization from a mixture of acetonitrile and water (1:1)).

LCMS: 98%, RT=1.04 minutes, (M+H) ⁺ =355 (Method P). Example 4 Synthesis of ((2 S ,4 R )-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)methanone (compound 5004), ((2 S ,4 S )-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5005), ((2 R ,4 S )-4-(amine Methyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5006) and ((2 R ,4 R )-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5007)

Synthesis of (R)-5-((S)-1-(4-fluorophenyl)-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 .

To 4-side oxytetrahydrofuran-2-carboxylic acid (1.1 g, 8.46 mmol) and ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (1.92 g , 8.46 mmol) in dichloromethane (40 mL) were added N , N -diisopropylethylamine (3.83 mL, 22.0 mmol) and hexafluorophosphoric acid 3-oxidation 1-[bis(dimethylamine methyl)-1H-1,2,3-triazolo[4,5-b]pyridinium (HATU, 3.54 g, 9.3 mmol). After stirring at room temperature for 20 h, the reaction mixture was washed with saturated aqueous NaHCO solution (3×50 mL), _dried over _Na2SO4 , and evaporated under reduced _pressure . The residue was purified by flash column chromatography (silica, 0 to 30% ethyl acetate in heptane) to give ( R )-5-(( S )-1-(4-fluorophenyl) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2 H )-one as the first soluble isomer and ( S )-5-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3( 2H )-one as the second eluted isomer. The absolute configuration of the tetrahydropyran-2-methamide center was determined by X-ray crystallography.

First eluted isomer: LCMS: 95%, RT=2.04 min, (M+H) ⁺ =340 (Method K).

Second eluted isomer: LCMS 95%, RT=2.03 minutes, (M+H) ⁺ =340 (Method K).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S)-4-hydroxy-4-(nitromethyl) Tetrahydrofuran-2-yl)methanone.

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

LCMS: 44:54 mixture of isomers, (M+H) ⁺ =401 at RT=2.00 min and 2.04 min (Method K).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R)-4-hydroxy-4-(nitromethyl) Tetrahydrofuran-2-yl)methanone.

From ( R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2 H )- Starting from ketone (0.20 g, 0.59 mmol), according to the method for (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 S ) )-4-Hydroxy-4-(nitromethyl)tetrahydrofuran-2-yl)methanone to prepare (( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)((2 R )-4-hydroxy-4-(nitromethyl)tetrahydrofuran-2-yl)methanone was used directly in the next step.

LCMS: 48:51 mixture of isomers, (M+H) ⁺ =401 at RT=2.02 min and 2.05 min (Method K).

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

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 S )-4-hydroxy-4- To a solution of (nitromethyl)tetrahydrofuran-2-yl)methanone (70 mg, 0.17 mmol) and NiCl ₂ ·6H ₂ O (21 mg, 0.087 mmol) in methanol (15 mL), NaBH ₄ was added portionwise (0.13 g, 3.5 mmol), causing an initial severe exotherm. After stirring at room temperature for 20 hours, _saturated aqueous NaHCO (25 mL) was added and stirring was continued for 30 minutes. Ethyl acetate (50 mL) was added and the mixture was mixed well. Add brine (20 mL) and mix the mixture thoroughly. The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). _The combined organic phases were dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative chiral SFC (Method Z) and the product containing the eluate was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((2 S ,4 S )-4 -(Aminomethyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methone ( compound 5005 ) as the first soluble isomer and ((2 S ,4 R )-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4 -Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5004 ) as the second eluted isomer. The absolute configuration of tetrahydropyran-2-methamide was determined by X-ray crystallography, and the tetrahydropyran-4-hydroxy-aminomethyl center was arbitrarily assigned.

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

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

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 R )-4-hydroxy-4-(nitromethyl Starting with (( 2S , 4S and 2S , 4R )-4-(aminomethyl)-4-hydroxytetrahydrofuran) starting from tetrahydrofuran-2-yl)methanone (130 mg, 0.325 mmol) -2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see above), Preparation of ((2 R ,4 R )-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroiso Quinolin-2(1 H )-yl)methanone ( compound 5007 ) as the first soluble isomer and ((2 R ,4 S )-4-(aminomethyl)-4-hydroxytetrahydrofuran-2- yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5006 ) as the second soluble isomer, and Purification was performed by preparative chiral SFC (Method AN). The absolute configuration was determined by X -ray crystallography .

Compound 5007 : LCMS: 97%, RT=2.49 min, (M+H) ⁺ =371 (Method AK). SFC: 100%, RT=3.72 minutes, (M+H) ⁺ =371 (method AD).

Compound 500 6 : LCMS: 99%, RT=2.53 min, (M+H) ⁺ =371 (Method AK). SFC: de=97.5%, RT=4.16 minutes, (M+H) ⁺ =371 (method AD). Example 5 Synthesis of ((2 S ,4 S )-4-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline -2(1 H )-yl)methanone (compound 5008) and ((2 S ,4 R )-4-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluoro) Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5009)

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

To ( S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3 at 0°C To a solution of (2 H )-ketone (see Compound 5004 , 300 mg, 0.88 mmol) in methanol (8 mL) was added (1-diazo-2-sideoxypropyl)dimethylphosphate (0.5 g , 2.6 mmol) and K ₂ CO ₃ (512 mg, 3.7 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 phases were dried over Na ₂ SO ₄ and evaporated under reduced pressure to give (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H ) -yl)(( S )-4-(methoxymethylene)tetrahydrofuran-2-yl)methanone.

LCMS: RT=2.20 minutes, (M+H) ⁺ =368 (Method K).

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

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( S )-4-(methoxymethyl)tetrahydrofuran- To a solution of 2-yl)methanone (325 mg, 0.884 mmol) in acetonitrile (5 mL) was added aqueous HCl (2.0 M, 2.5 mL, 5.0 mmol). After 20 minutes, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over Na ₂ SO ₄ and evaporated to dryness under reduced pressure to give (5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde was used directly in the next step.

LCMS: RT=2.00 minutes, (M+H) ⁺ =354 (Method K).

Synthesis of ((2S)-4-(( phenylmethylamino ) methyl ) tetrahydrofuran - 2- yl )((S)-1-(4- fluorophenyl )-3,4- dihydroisoquinoline- 2(1H) -yl ) methanone .

To crude (5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde (0.884 To a solution of benzylamine (1.0 g, 9.3 mmol) in dichloromethane (3 mL) was added benzylamine (1.0 g, 9.3 mmol), followed by titanium tetraisopropoxide (1.0 mL, 3.5 mmol). The reaction mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was dissolved in methanol (30 mL) and _NaBH4 (981 mg, 25.9 mmol) was added portionwise. The mixture was stirred for 1 h, then aqueous NaOH (0.1 M, 25 mL) was added and the mixture was extracted with methyl tert-butyl ether (3 × 50 mL). The combined organic layers were evaporated under reduced pressure (at 60 °C) and the residue was co-evaporated from ethanol (2×20 mL) to give ((2 S )-4-((phenylmethylamino)methyl) Tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone was used directly in the next step.

LCMS: RT=2.14 minutes, (M+H) ⁺ =445 (Method K).

Synthesis of ((2S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- base) methanone.

To ((2 S )-4-((phenylmethylamino)methyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline To a solution of -2(1 H )-yl)methanone (380 mg, 0.855 mmol) in methanol (40 mL) was added palladium (10% on activated carbon, 200 mg, 0.188 mmol). The mixture was stirred under a hydrogen atmosphere for 24 hours, then flushed with nitrogen, filtered through celite, and washed with methanol (2×40 mL). The combined filtrates were evaporated under reduced pressure (at 65°C). The residue was purified by flash column chromatography (silica, dichloromethane containing 0 to 25% methanol) to give (( 2S )-4-(aminomethyl)tetrahydrofuran-2-yl)( ( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 100%, RT=1.78 minutes, (M+H) ⁺ =355 (Method K).

Synthesis of (((3R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl) Methyl)carbamic acid tertiary butyl ester and (((3S,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydrofuran-3-yl)methyl)carbamic acid tertiary butyl ester.

To ((2 S )-4-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H To a solution of )-yl)methanone (134 mg, 0.378 mmol) in dichloromethane (3 mL) was added di-tertiary butyl dicarbonate (93 mg, 0.426 mmol). After 5.5 hours, the reaction mixture was concentrated to dryness under reduced pressure and analyzed by flash column chromatography (silica, 10 to 50% ethyl acetate in heptane) and preparative chiral SFC (Method AP ) Purify the residue to obtain (((3 R ,5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydrofuran-3-yl)methyl)carbamic acid tertiary butyl ester as the first soluble isomer and (((3 S ,5 S )-5-(( S )-1-(4-fluorophenyl) -1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)methyl)carbamic acid tertiary butyl ester as the second eluted isomer. The absolute configuration of the tetrahydropyran-aminomethyl center is arbitrarily specified.

First soluble isomer: LCMS: 97%, RT=2.13 minutes, (M+Na) ⁺ =477 (Method A). SFC: de=100%, RT=3.66 minutes, (M+Na) ⁺ =477 (Method AI).

Second soluble isomer: LCMS: 97%, RT=2.12 minutes, (M+H) ⁺ =455 (Method A). SFC: de=97%, RT=3.98 minutes, (M+H) ⁺ =455 (Method AI).

((2S,4S)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H) -Methyl ketone ( compound 5008 ).

To (((3 R ,5 R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3- To a solution of tert-butyl)methyl)carbamate (22.3 mg, 0.049 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.1 mL). After stirring at room temperature for 4.5 h, 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). ((2 R ,4 R )-4-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H )-yl)methanone. The absolute configuration of the tetrahydropyran-aminomethyl center is arbitrarily specified.

LCMS: 99%, RT=2.54 minutes, (M+H) ⁺ =355 (Method AK).

((2S,4R)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H) -Methyl ketone ( compound 5009 ).

From (((3 R ,5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3- ((2 S ,4 R )-4-(aminomethyl)tetrahydrofuran-2-yl was prepared as described for compound 5008 , starting with tert-butyl)methyl)carbamate (18.6 mg, 0.041 mmol) )(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5009 ), desalted (SCX-2 (1 g) Ion exchange chromatography) and lyophilized from a mixture of acetonitrile and water (1:1). The absolute configuration of the tetrahydropyran-aminomethyl center is arbitrarily specified.

LCMS: 99%, RT=2.54 minutes, (M+H) ⁺ =355 (Method AK). Example 6 Synthesis of ((2 S ,4 R )-4-aminotetrahydrofuran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone (compound 5010) and ((2 S ,4 S )-4-aminotetrahydrofuran-2-yl) (( S )-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5011)

Synthesis of ((2S)-4-(phenylmethylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H) -base) methanone.

From ( S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2 H )- Ketone (see Compound 5004 , 290 mg, 0.855 mmol) starting as for ((2 S )-4-((phenylmethylamino)methyl)tetrahydrofuran-2-yl)(( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone was prepared as described (see compound 5008 ) ((2 S )-4-(phenylmethylamino) )tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (368 mg). Use as is.

LCMS: 63%, RT=2.22 minutes, (M+H) ⁺ =431 (Method K).

Synthesis of ((2S)-4-(phenylmethylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H) -base) methanone.

From ((2 S )-4-(phenylmethylamino)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 Starting with H )-yl)methanone (368 mg, 0.855 mmol), as for ((2 S )-4-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluoro) ((2 S ) -4-( phenylmethylamino ) tetrahydrofuran- 2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone and was used without purification.

LCMS: 81%, RT=1.79 minutes, (M+H) ⁺ =341 (Method K).

Synthesis of ((3R,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)amine Tertiary butyl formate and ((3S,5S)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran- 3-yl)tertiary butyl carbamate.

To ((2 S )-4-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H To a suspension of )-yl)methanone (178 mg, 0.523 mmol) in dichloromethane (5 mL) was added di-tertiary butyl dicarbonate (131 mg, 0.600 mmol). After 5.5 hours, the reaction mixture was diluted with dichloromethane (10 mL) and saturated _aqueous NaHCO (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 to 50% ethyl acetate in heptane) and preparative chiral SFC (Method S) to give ((3 S ,5 S )-5 -(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamic acid tertiary butyl ester as the first elution Isomers and ((3 R ,5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran- 3-yl)tertiary butylcarbamic acid as the second eluted isomer. The absolute configuration of the tetrahydropyran-amine center is arbitrarily specified.

First soluble isomer: LCMS: 98%, RT=2.17 minutes, (M+Na) ⁺ =463 (Method A). SFC: de=100%, RT=2.64 minutes, (M+Na) ⁺ =463 (Method F).

Second eluted isomer: LCMS: 98%, RT=2.12 minutes, (M+H) ⁺ =441 (Method A). SFC: de=98%, RT=3.14 minutes, (M+H) ⁺ =441 (Method F).

Synthesis of ((2S,4R)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Methyl ketone ( compound 5010 ).

From ((3 R ,5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl ) ((2 S , 4 R )-4- aminotetrahydrofuran -2-yl)(( S )-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5010 ), desalted (SCX-2 (1 g) ion exchange chromatography), and Lyophilize from a mixture of acetonitrile and water (1:1). The absolute configuration of the tetrahydropyran-amine center is arbitrarily specified.

LCMS: 98%, RT=2.50 min, (M+H) ⁺ =341 (Method AK).

Synthesis of ((2S,4S)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Methyl ketone ( compound 5011 ).

From ((3 S ,5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl ) ((2 S , 4 S )-4- aminotetrahydrofuran -2-yl)(( S )-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5011 ), desalted (SCX-2 (1 g) ion exchange chromatography), and Lyophilize from a mixture of acetonitrile and water (1:1). The absolute configuration of the tetrahydropyran-amine center is arbitrarily specified.

LCMS: 100%, RT=2.54 minutes, (M+H) ⁺ =341 (Method AK). Example 7 Synthesis of ((2 R ,4 R )-4-aminotetrahydrofuran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone (compound 5012) and ((2 R ,4 S )-4-aminotetrahydrofuran-2-yl) (( S )-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5013)

Synthesis of ((2R)-4-(phenylmethylamino)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H) -base) methanone.

From ( R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2 H )- Ketone (see Compound 5005 , 290 mg, 0.855 mmol) starting as for ((2 S )-4-((phenylmethylamino)methyl)tetrahydrofuran-2-yl)(( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone was prepared as described (see compound 5008 ) ((2 R )-4-(phenylmethylamino) )tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone and it was used directly in the next step.

LCMS: 64%, RT=2.24 minutes, (M+H) ⁺ =431 (Method K).

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

From ((2 R )-4-(phenylmethylamino)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 Starting with H )-yl)methanone (368 mg, 0.855 mmol), as for ((2 S )-4-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluoro) ( (2 R ) -4-( phenylmethylamino ) tetrahydrofuran- 2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone was used directly in the next step.

LCMS: 83%, RT=1.80 min, (M+H) ⁺ =341 (Method K).

Synthesis of ((3S,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)amine Tertiary butyl formate and ((3R,5R)-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran- 3-yl)tertiary butyl carbamate.

To ((2 R )-4-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H To a suspension of )-yl)methanone (270 mg, 0.793 mmol) in dichloromethane (5 mL) was added di-tertiary butyl dicarbonate (194 mg, 0.889 mmol). After 5.5 hours, the reaction mixture was diluted with dichloromethane (10 mL) and saturated _aqueous NaHCO (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 to 50% ethyl acetate in heptane) and preparative chiral SFC (Method AN) to give ((3 S ,5 R )-5 -(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl)carbamic acid tertiary butyl ester as the first elution Isomers and ((3 R ,5 R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran- 3-yl)tertiary butylcarbamic acid as the second eluted isomer. The absolute configuration of the tetrahydropyran-amine center is arbitrarily specified.

First soluble isomer: LCMS: 91%, RT=2.17 minutes, (M+Na) ⁺ =463 (Method A). SFC: de=100%, RT=2.66 minutes, (M+a) ⁺ =463 (Method AD).

Second eluted isomer: LCMS: 98%, RT=2.12 minutes, (M+H) ⁺ =441 (Method A). SFC: de=96.5%, RT=3.30 minutes, (M+H) ⁺ =441 (Method AD).

Synthesis of ((2R,4R)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Methyl ketone ( compound 5012 ).

From ((3 R ,5 R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl )(( 2R , 4R )-4- Aminotetrahydrofuran -2-yl)(( S ) -1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5012 ), desalted (SCX-2 (1 g) ion exchange chromatography), and Lyophilize from a mixture of acetonitrile and water (1:1). The absolute configuration of the tetrahydropyran-amine center is arbitrarily specified.

LCMS: 97%, RT=2.50 minutes, (M+H) ⁺ =341 (Method AK).

Synthesis of ((2R,4S)-4-aminotetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl) Methyl ketone ( compound 5013 ).

From ((3 S ,5 R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-yl )(( 2R , 4S )-4- Aminotetrahydrofuran -2-yl)(( S ) -1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5013 ), desalted (SCX-2 (1 g) ion exchange chromatography), and Lyophilize from a mixture of acetonitrile and water (1:1). The absolute configuration of the tetrahydropyran-amine center is arbitrarily specified.

LCMS: 100%, RT=2.55 minutes, (M+H) ⁺ =341 (Method AK). Example 8 Synthesis of (( 2R )-4-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1 H )-yl)methanone (compound 5014)

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

From (1-diazo-2-side-oxypropyl)dimethylphosphate (270 mg, 1.41 mmol) and ( R )-5-(( S )-1-(4-fluorophenyl)-1, Starting from 2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3( 2H )-one (see compound 5005 , 40 mg, 0.12 mmol), as for (( S )-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( S )-4-(methoxymethylene)tetrahydrofuran-2-yl)methanone is described (See compound 5008 ), preparation of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) (( R )-4-(methoxy Methyl)tetrahydrofuran-2-yl)methanone.

LCMS: E/Z mixture, RT=2.20 and 2.22 minutes, (M+H) ⁺ =368 (Method K).

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

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) (( R )-4-(methoxymethyl)tetrahydrofuran- Starting with 2-yl)methanone (40 mg, 0.11 mmol) as for (5 S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde was prepared as described (see compound 5008 ) for (5 R )-5-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde. used directly in the next step.

LCMS: RT=2.02 minutes, (M+H) ⁺ =354 (Method K).

Synthesis of ((2R)-4-((phenylmethylamino)methyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline- 2(1H)-yl)methanone product.

From crude (5 R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbaldehyde (0.11 mmol), as for ((2 S )-4-((phenylmethylamino)methyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4 Preparation of ((2 R )-4-((phenylmethylamino)methyl)tetrahydrofuran-2-yl) -dihydroisoquinolin -2(1 H )-yl)methanone (see compound 5008 ) )(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone product. used directly in the next step.

LCMS: RT=2.17 minutes, (M+H) ⁺ =445 (Method K).

Synthesis of ((2R)-4-(aminomethyl)tetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)- base) methanone.

From ((2 R )-4-((phenylmethylamino)methyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline -2(1 H )-yl)methanone (50 mg, 0.11 mmol) starting as for ((2 S )-4-(aminomethyl)tetrahydrofuran-2-yl)(( S )-1- ((2 R )-4-(aminomethyl ) was prepared as described for (4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5008 ) )tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5014 ) and purified to Derivatives with Boc protecting group (di-tertiary butyl dicarbonate (18.3 mg, 0.084 mmol), dichloromethane (3 mL) containing N,N -diisopropylethylamine (0.080 mL, 0.458 mmol) ), 1 day; flash column chromatography (silica, 10 to 70% ethyl acetate in heptane), and removal of protecting groups (trifluoroacetic acid (0.5 mL), dichloromethane (2 mL), 1.5 h; SCX-2 (1 g)) was subsequently lyophilized from acetonitrile to water (1:1).

LCMS: 95%, RT=1.02 minutes, (M+H) ⁺ =355 (Method P). Example 9 Synthesis of ((2 S ,5R)-5-aminotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroiso Quinolin-2(1 H )-yl)methanone (Compound 5015)

Synthesis of ((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran -3-yl)tertiary butyl carbamate.

From (2 S ,5 R )-5-{[(tertiary butoxy)carbonyl]amine} Starting from alkane-2-carboxylic acid (1.00 g, 4.08 mmol) and ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.927 g, 4.08 mmol) , as for ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -Piran-3-yl)carbamic acid tertiary butyl ester was prepared as described (see compound 5042 ) (( 3R , 6S )-6-(( S )-1-(4-fluorophenyl) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester, and by flash column chromatography (di Silica, purified from 0 to 50% ethyl acetate in heptane).

LCMS: 99%, RT=2.14 minutes, (M+H) ⁺ =455 (Method A).

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

To ((3 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H To a solution of -pyran-3-yl)carbamic acid tertiary butyl ester (1.71 g, 3.76 mmol) in 2-propanol (30 mL) was added HCl (5-6 M in 2-propanol, 15 mL , 75 mmol) and stir overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with water (40 mL) and aqueous HCl (1 M, 4.0 mL (pH<3)) and the mixture was extracted with ethyl acetate (20 mL). The aqueous phase was basified by adding saturated aqueous K ₂ CO ₃ (20 mL) and extracted with ethyl acetate (50 mL). The latter organic layer was dried over Na ₂ SO ₄ and evaporated under reduced pressure to give ((2 S ,5 R )-5-amine after lyophilization from a mixture of acetonitrile and water (1:1, 30 mL) Tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5015 ).

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =355 (Method P). Example 10 Synthesis of Compound 5016 and Compound 5017

Step 1 : Add 5-(tertiary butoxycarbonylamino)-tetrahydro- 2H -piran-2-carboxylic acid (200 mg, 0.8 mmol) in DMF (4 mL) at 0°C. Add ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (185 mg, 0.8 mmol), HATU (372 mg, 1.0 mmol) and Et ₃ N to the solution. (0.2 mL, 1.6 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours and 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), dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography to obtain 6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-tetrahydro -2H -Pyran-3-ylcarbamic acid tertiary butyl ester.

LCMS: (M+H) ⁺ =455; residence time = 1.933 minutes. LCMS CP Method A

Step 2 : Add 6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-tetrahydro- 2H at 0°C. -Pyran-3-ylcarbamate tertiary butyl ester (300 mg, 0.7 mmol) in 2 To a solution in alkane (2 mL), add HCl alkane (4N, 2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give (5-amino-tetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1 H )-yl)methanone.

LCMS: (M+H) ⁺ =355; residence time = 1.381 minutes. LCMS CP Method E

The diastereoisomers were separated by chiral SFC on an EnantioPak® AD column (20×250 mm 10µm) with 0.2% MA dissolved in CO ₂ /MeOH to obtain compound 5016 (retention time = 3.332 min), compound 5017 (residence time = 1.193 minutes). The stereochemical assignment of the 1 position (S) of tetrahydroisoquinoline is based on enantiomerically pure starting materials; the configuration of the chiral center of tetrahydropyran is compared with related analogues of known configurations Specified based on chromatographic elution order.

Compound 5016 : LCMS: (M+H) ⁺ =355; Purity = 100% (214 nm); Retention time = 1.490 minutes. LCMS CP Method F

Chiral SFC: CO ₂ /MeOH (65%:35%) containing 0.2% MA, on CHIRALPAK® IG column (4.6*100mm 5µm), retention time = 3.086 minutes, 100% ee.

Compound 5017 : LCMS: (M+H) ⁺ =355; Purity = 97.36% (214 nm); Retention time = 1.489 minutes. LCMS CP Method F Example 11 Synthesis of Compound 5018 and Compound 5019

Step 1 : Add 1-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline (300 mg, 1.2 mmol) in DMF (5 mL) at 0 °C. (2R,5S)-5-((tertiary butoxycarbonyl)amino)tetrahydro-2H-piran-2-carboxylic acid (223 mg, 0.99 mmol) and HATU (480 mg, 1.26 mmol) were added to the solution. and TEA (0.3 mL, 2 mmol). The resulting reaction mixture was stirred at room temperature for 2 h, diluted with EA (10 mL) and washed with saturated _NH4Cl (2×10 mL), followed by brine (2×10 mL). The organic phase was dried _{over Na2SO4} and concentrated in vacuo. The residue was purified by preparative HPLC to obtain ((3S,6R)-6-(1-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

LCMS: (M+H) ⁺ =473.1; Purity = 100% (214 nm); Retention time = 1.68 minutes. Method C1

Step 2 : Add HCl to the Add ((3S,6R)-6-(1-(2,4-difluorophenyl)-1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)tetrahydro-2H-piran-3-yl)carbamic acid tert-butyl ester (320 mg, 0.68 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give a residue which was purified by preparative HPLC to give ((2R,5S)-5-aminotetrahydro-2H-piran-2-yl)((R)-1-(2,4- Difluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

LCMS: (M+H) ⁺ =373.1; Purity = 100% (214 nm); Retention time = 1.42 minutes. Method C1

The non-mirror image isomers were separated on a Daicel® IG column (20×250 mm, 10µm) by chiral SFC dissolving with CO2/MeOH (0.2% methanolic ammonia) = 45/55 to obtain compound 5018 and compound 5019. The configuration of the stereogenic center on the pyran ring is based on commercially available starting materials; the stereochemical configuration of the tetrahydroisoquinoline is arbitrarily assigned based on the chromatographic elution order of related analogs.

Compound 5018 : LCMS: (M+H) ⁺ =373.0, purity = 100% (214 nm); retention time = 1.49 minutes. Method C1

Chiral SFC: CO ₂ /MeOH =60:40 containing 0.2% methanolic ammonia, on Daicel® IG column (20×250 mm, 10um), retention time = 2.698 minutes, 98.7% ee.

Compound 5019 : LCMS: (M+H) ⁺ =373.0; Purity = 100% (214 nm); Retention Time = 1.43 minutes. Method C1

Chiral SFC: CO ₂ /MeOH = 60:40 containing 0.2% methanolic ammonia, on Daicel® IG column (20×250 mm 10µm), retention time = 1.503 minutes, 100% ee. Example 12 Synthesis of Compound 5020, Compound 5021, Compound 5022 and Compound 5023

Step 1 : Add 4-((tertiary butoxycarbonyl)amino)-2-oxabicyclo[2.2.1]heptane-1-carboxylic acid (150 mg, 0.58 mmol) and TEA at room temperature. To a solution of DMF (0.16 mL, 0.17 mmol) in DMF (2 mL) was added HATU (266 mg, 0.7 mmol). After stirring at room temperature for 30 minutes, (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (145 mg, 0.64 mmol) was added and stirred at room temperature Reaction mixture for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain a residue which was purified by preparative HPLC to obtain (1-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)-2-oxabicyclo[2.2.1]heptan-4-yl)carbamic acid tertiary butyl ester.

LCMS: (M + 1) ⁺ =467.0; residence time = 1.78 minutes. LCMS CP Method C2

Step 2 : At 0°C, add (1-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2-oxa To a solution of bicyclo[2.2.1]heptan-4-yl)carbamic acid tertiary butyl ester (62 mg, 0.13 mmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated and the residue redissolved in water. The mixture was basified with 1 N NaOH and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a residue, which was purified by preparative HPLC to obtain (4-amino-2-oxabicyclo [2.2.1] Heptan-1-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

LCMS: (M+H) ⁺ =367.0; residence time = 1.47 minutes. LCMS CP Method C2

The diastereoisomers (26 mg) were separated by chiral SFC on a Daicel® IG column (20 × 250 mm, 10 µm) with CO2/MEOH (0.2% methanolic ammonia) = 50/50 to obtain compound 5020 , compound 5021 , compound 5022 and compound 5023 . The stereochemical designation of the tetrahydroisoquinoline 1 position (S) is based on the starting material designation, while the stereochemical designation of the bicyclic center is arbitrary.

Compound 5020 : LCMS: (M+H) ⁺ =367.0; retention time = 1.79 minutes. LCMS CP Method C

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

Compound 5021 : LCMS: (M+H) ⁺ =367.2; retention time = 1.53 minutes. LCMS CP Method A1

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

Compound 5022 : LCMS: (M+H) ⁺ =367.0; retention time = 1.76 minutes. LCMS CP Method C

Chiral SFC: CO ₂ /IPA (60%:40%) containing 1% ammonia, on CHIRALPAK® IG column (4.6×100 mm, 5µm), retention time = 1.843 minutes), 95.5% ee.

Compound 5023 : LCMS: (M+H) ⁺ =367.0; retention time = 1.78 minutes. LCMS CP Method C

Chiral SFC: CO ₂ /IPA (60%:40%) containing 1% ammonia, on CHIRALPAK® IG column (4.6×100 mm, 5µm), retention time = 2.947 minutes), 96.64% ee. Example 13 Synthesis of ((2 S ,4 S )-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5024)

Synthesis of ((2S,4S)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5024 ).

To ((2 S ,4 S )-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroiso To a solution of quinolin-2(1 H )-yl)methanone ( Compound 5005 , 32 mg, 0.086 mmol) in ethanol (1.5 mL) was added acetaldehyde (10 wt% in ethanol, 73.0 µL, 0.130 mmol). After stirring the mixture for 1 hour, 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 to 10% (3.5 M ammonia in methanol)/dichloromethane) to give ((2 S ,4 S )-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5024 ). The absolute configuration of tetrahydropyran-2-methamide was determined by X-ray, and the stereochemistry of the tetrahydropyran-4-hydroxy-aminomethyl center was arbitrarily assigned.

LCMS: 96%, RT=2.56 minutes, (M+H) ⁺ =399 (Method AK). SFC: RT=2.78 minutes. Example 14 Synthesis of Compound 5027 and Compound 5027

To a solution of 4-aminotetrahydro-2H-piran-2-carboxylic acid hydrochloride (362 mg, 2 mmol) in DCM (50 mL) under nitrogen was added SOCl _{2 (} 1 mL, excess) . The resulting reaction mixture was stirred at room temperature for 1 hour and subsequently concentrated to afford a white solid, which was added to (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (454 mg, The solid was added to another solution of TEA (404 mg, 4 mmol) and TEA (404 mg, 4 mmol) in DCM (10 mL). The resulting mixture was stirred for 3 hours and then quenched with water (10 mL). The mixture was extracted with DCM (3 _× 10 mL) and the combined organic phases were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated to give a residue. The residue was purified by preparative HPLC to give (4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroiso Quinolin-2(1H)-yl)methanone.

LCMS: (M+H) ⁺ =355.1, Purity=100% (214 nm), Retention Time=1.38 minutes. LCMS CP Method C

The diastereoisomers were separated by chiral SFC on an EnantioPak® OX-H column (20×250 mm 10µm) with CO ₂ /MEOH (0.2% methanolic ammonia) = 65/35 to obtain compound 5028 (retentive time = 2.32 minutes) and compound 5027 (retention time = 3.07 minutes). The stereochemical assignment of tetrahydroisoquinolines was based on enantiomerically pure starting materials, and the stereochemistry of tetrahydropyran was determined by X-ray crystallography of related analogues.

Compound 5028 : LCMS: ((M+H) ⁺ =355.1, Purity=100% (214 nm), Retention Time=1.38 min. LCMS CP Method C

Chiral SFC: CO ₂ /MeOH = 65:35 containing 0.2% methanolic ammonia, on CHIRALPAK® IG column (4.6×100mm 5µm), retention time = 1.73 minutes, 100% ee.

Compound 5027 : LCMS: ((M+H) ⁺ =355.1, Purity=100% (214 nm), Retention Time=1.38 min. LCMS CP Method C

Chiral SFC: CO ₂ /MeOH = 65:35 containing 0.2% methanolic ammonia, on CHIRALPAK® IG column (4.6×100mm 5µm), retention time = 1.67 minutes, 100% ee. Example 15 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 S ,5 S )-5-((2 -Methoxyethyl)amino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5029)

Synthesis of ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran -3-yl)tertiary butyl carbamate.

From (2 S ,5 S )-5-((tertiary butoxycarbonyl)amino)tetrahydro-2 H -piran-2-carboxylic acid (241 mg, 0.983 mmol) and ( S )-1- Starting from (4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (213 mg, 0.937 mmol), as for ((3 S ,6 R )-6-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester is described (see Compound 5042 ), preparation of ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydroisoquinoline-2-carbonyl Hydrogen- 2H -pyran-3-yl)carbamic acid tertiary butyl ester. White foam.

LCMS: 97%, RT=2.15 minutes, (M+Na) ⁺ =477 (Method A).

Synthesis of ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran -3-yl)(2-methoxyethyl)carbamic acid tertiary butyl ester.

From ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H Starting from -tert-butyl-pyran-3-yl)carbamate (76.6 mg, 0.169 mmol), as for ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)(2-methoxyethyl)carbamic acid tertiary butyl ester is described (See compound 5030 ), preparation of ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )tetrahydro- 2H -piran-3-yl)(2-methoxyethyl)carbamic acid tertiary butyl ester and by acidic preparative MPLC (linear gradient: t=0 min 10% A; t= 1 minute 10% A; t=2 minutes 40% A; t=17 minutes 80% A; t=18 minutes 100%; t=23 minutes 100% A; Detection: 220 nm) purification.

LCMS: 100%, RT=2.27 minutes, (M+H) ⁺ =513 (Method A).

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

From ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H Starting from -tert-butyl-pyran-3-yl)(2-methoxyethyl)carbamate (44.8 mg, 0.087 mmol), as for (( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-((2-methoxyethyl)amino)tetrahydro-2 H -pyran ( ( S )-1-(4- fluorophenyl )-3,4-dihydroisoquinolin-2(1 H )-yl)(( 2 S ,5 S )-5-((2-methoxyethyl)amino)tetrahydro-2 H -pyran-2-yl)methanone ( compound 5029 ) without additional purification.

LCMS: 99%, RT=1.09 minutes, (M+H) ⁺ =413 (Method P). Example 16 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 R ,5 S )-5-((2 -Methoxyethyl)amino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5030)

Synthesis of ((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran -3-yl)(2-methoxyethyl)carbamic acid tertiary butyl ester.

Under nitrogen atmosphere, to ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5042 , 100 mg, 0.220 mmol) in N , N -dimethylformamide (anhydrous, 1.5 mL) Add sodium hydride (60% dispersion in oil, 11.4 mg, 0.286 mmol). After 15 minutes, 2-bromoethyl methyl ether (38 µL, 0.396 mmol) was added and stirring was continued overnight. The reaction mixture was diluted with ethyl acetate ₍ 25 mL), washed with brine (4 × 10 mL), dried over _Na2SO4 , and evaporated under reduced pressure to give (( 3S , 6R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-3-yl)(2-methoxy Ethyl)tert-butylcarbamate and this was used directly in the next step.

LCMS: 79%, RT=2.27 minutes, (M+H) ⁺ =513 (Method A).

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

To ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H To a solution of -pyran-3-yl)(2-methoxyethyl)carbamic acid tertiary butyl ester (102 mg (79 wt%), 0.157 mmol) in dichloromethane (2.7 mL) was added trifluoro Acetic acid (0.307 mL, 3.98 mmol). After 1 hour, the reaction mixture was diluted with dichloromethane (15 mL) and washed with saturated _aqueous NaHCO (10 mL). The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over _Na2SO4 and evaporated under reduced pressure _. The residue was dissolved in dimethylsulfoxide (2 mL) and analyzed by 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) purification. The products containing the isolated fractions were combined, diluted with a mixture of brine, NaHCO ₃ saturated aqueous solution and Na ₂ CO ₃ saturated aqueous solution (1:1:1, 15 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic phases were dried over Na ₂ SO ₄ and evaporated under reduced pressure to give (( S )-1-(4-) after lyophilization from a mixture of acetonitrile and water (3:2, 2 mL) Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-((2-methoxyethyl)amino)tetrahydro- 2H -Piran-2-yl)methanone ( Compound 5030 ).

LCMS: 99%, RT=1.07 minutes, (M+H) ⁺ =413 (Method P). SFC: RT=3.84 minutes. Example 17 Synthesis of ((2 S ,4 R )-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5031)

Synthesis of ((2S,4R)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5031 ).

To ((2 S ,4 R )-4-(aminomethyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroiso To a solution of quinolin-2(1 H )-yl)methanone ( Compound 5004 , 51 mg, 0.138 mmol) in ethanol (1.5 mL) was added acetaldehyde (10 wt% in ethanol, 120 µL, 0.207 mmol). After stirring the mixture for 1 hour, 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 analyzed by flash column chromatography (silica, 0 to 10% (7M ammonia in methanol)/dichloromethane) and acidic preparative MPLC (linear gradient: t=0 min 10 % A; t=1 minute 5% A; t=16 minutes 50% A; t=17 minutes 100%; t=22 minutes 100% A; detection: 220 nm) The purified residue was separated from acetonitrile and water. After lyophilization in the mixture (1:1, 4 mL), ((2 S ,4 R )-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)(( S ) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5031 ). The absolute configuration of tetrahydropyran-2-methamide was determined by X-ray, and the stereochemistry of the tetrahydropyran-4-hydroxy-aminomethyl center was arbitrarily assigned.

LCMS: 98%, RT=1.03 minutes, (M+H) ⁺ =399 (Method P). Example 18 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 S ,5 R )-5-((2 -Hydroxyethyl)amino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5032)

Synthesis of ((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)carbamic acid tertiary butyl ester.

From ((3 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -tert-butyl-3-yl)carbamate (see Compound 5015 , 100 mg, 0.220 mmol) and 2-(2-bromoethoxy)tetrahydro- 2H -piran (53 µL, 0.352 mmol) ) starting from ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tetrahydro- 2H -piran-3-yl)(2-methoxyethyl)carbamic acid tertiary butyl ester was prepared as described (see compound 5030 ) (( 3R , 6S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)(2-((tetrahydroisoquinoline-2-carbonyl) Hydrogen- 2H -pyran-2-yl)oxy)ethyl)carbamic acid tertiary butyl ester by alkaline 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) Purification.

LCMS: 98%, RT=2.26 minutes, (M-THP+H) ⁺ =499 (Method A).

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

From ((3 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H Starting from -tert-butyl-piran-3-yl)(2-((tetrahydro-2 H -piran-2-yl)oxy)ethyl)carbamic acid (70 mg, 0.120 mmol) as specified for (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-((2-methoxy Preparation of (( S )-1-(4 - fluorophenyl )-3,4 - di Hydroisoquinolin-2(1 H )-yl)((2 S ,5 R )-5-((2-hydroxyethyl)amino)tetrahydro-2 H -pyran-2-yl)methanone ( Compound 5032 ). Two more portions of trifluoroacetic acid were added after 2 hours and 4 hours respectively.

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =399 (Method P). SFC: RT=5.19 minutes, (M+H) ⁺ =399 (Method F). Example 19 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 S ,5 S )-5-((2 -Hydroxyethyl)amino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5033)

Synthesis of ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran -3-yl)(2-methoxyethyl)carbamic acid tertiary butyl ester.

From ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H Tertiary butyl-pyran-3-yl)carbamate (see compound 5029 , 75.7 mg, 0.167 mmol) and 2-(2-bromoethoxy)tetrahydro- 2H -piran (30.2 µl, 0.200 mmol ) starting from ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tetrahydro- 2H -pyran-3-yl)(2-methoxyethyl)carbamic acid tertiary butyl ester was prepared as described (see compound 5030 ) (( 3S , 6S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)(2-((tetrahydroisoquinoline-2-carbonyl) Hydrogen- 2H -pyran-2-yl)oxy)ethyl)carbamate tertiary butyl ester by 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) purification.

LCMS: 100%, RT=2.34 minutes, (M+Na) ⁺ =605 (Method A).

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

From ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H Starting from -tert-butyl-piran-3-yl)(2-((tetrahydro-2 H -piran-2-yl)oxy)ethyl)carbamic acid (21.1 mg, 0.036 mmol) as for ((2 R ,5 S )-5-aminotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline Preparation of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )- as described for -2 ( 1 H )-yl)methanone ( compound 5042 ) yl)((2 S ,5 S )-5-((2-hydroxyethyl)amino)tetrahydro-2 H -pyran-2-yl)methanone ( compound 5033 ).

LCMS: 99%, RT=2.57 minutes, (M+H) ⁺ =399 (Method AK). Example 20 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 R ,5 S )-5-((2 -Hydroxyethyl)amino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5034)

Synthesis of ((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)carbamic acid tertiary butyl ester.

From ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -tert-butyl-3-yl)carbamate (see compound 5042 , 100 mg, 0.220 mmol) and 2-(2-bromoethoxy)tetrahydro- 2H -piran (60 µL, 0.396 mmol) ) starting from ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tetrahydro- 2H -piran-3-yl)(2-((tetrahydro- 2H -piran-2-yl)oxy)ethyl)carbamic acid tertiary butyl ester is described (see compound 5030 ) , preparation of ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-3-yl)(2-((tetrahydro-2 H -piran-2-yl)oxy)ethyl)carbamic acid tertiary butyl ester by alkaline preparative MPLC (linear Gradient: t=0 minutes 10% A; t=1 minute 10% A; t=2 minutes 40% A; t=17 minutes 80% A; t=18 minutes 100% A; t=23 minutes 100% A; Detection: 220 nm) purification.

LCMS: 99%, RT=2.27 minutes, (M-THP+H) ⁺ =499 (Method A).

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

From ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H Starting from -tert-butyl-piran-3-yl)(2-((tetrahydro-2 H -piran-2-yl)oxy)ethyl)carbamic acid (68 mg, 0.117 mmol) as for (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-((2-methoxy Preparation of (( S )-1-(4 - fluorophenyl )-3,4 - di Hydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-((2-hydroxyethyl)amino)tetrahydro-2 H -pyran-2-yl)methanone ( Compound 5034 ).

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =399 (Method P). SFC: RT=4.34 minutes, (M+H) ⁺ =399 (Method AD). Example 21 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 S ,5 R )-5-((2 -Methoxyethyl)amino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5035)

Synthesis of ((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran -3-yl)(2-methoxyethyl)carbamic acid tertiary butyl ester.

From ((3 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H Starting from -tertiary butyl-pyran-3-yl)carbamate (see compound 5015 , 100 mg, 0.209 mmol), as for ((3 S ,6 R )-6-(( S )-1-(4 -Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)(2-methoxyethyl)carbamic acid tertiary Preparation of ((3 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline) as described for butyl ester (see compound 5030 ) -2-Carbonyl)tetrahydro- 2H -piran-3-yl)(2-methoxyethyl)carbamic acid tertiary butyl ester was used directly in the next step.

LCMS: 70%, RT=2.21 minutes, (M-tBu) ⁺ =455 (Method A).

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

From ((3 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H Starting from -tert-butyl-pyran-3-yl)(2-methoxyethyl)carbamate (99 mg (70 wt%), 0.135 mmol), as for (( S )-1-(4- Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-((2-methoxyethyl)amino)tetrahydro- (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H ) was prepared as described for 2 H -pyran-2-yl ) methanone ( Compound 5030 ) -yl)((2 S ,5 R )-5-((2-methoxyethyl)amino)tetrahydro-2 H -pyran-2-yl)methanone ( compound 5035 ).

LCMS: 99%, RT=1.07 minutes, (M+H) ⁺ =413 (Method P). SFC: RT=4.33 minutes, (M+H) ⁺ =413 (Method F). Example 22 Synthesis of ((2 R ,4 S )-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5036)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-methyltetrahydrofuran-2-yl)methyl ketone.

To a suspension of methyltriphenylphosphonium bromide (1054 mg, 2.95 mmol) in tetrahydrofuran (anhydrous, 15.0 mL) was added dropwise potassium tertiary butoxide (in tetrahydrofuran) at 0°C under a nitrogen atmosphere. 1 M solution, 2.53 mL, 2.53 mmol) solution. After 30 minutes, ( R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran- was added dropwise A solution of 3(2 H )-ketone (see compound 5004 , 715 mg, 2.107 mmol) in tetrahydrofuran (anhydrous, 7.5 mL). 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 to 30% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)(( R )-4-methylenetetrahydrofuran-2-yl)methanone.

LCMS: 99%, RT=2.14 minutes, (M+H) ⁺ =338 (Method B).

Synthesis of ((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)methanone.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) (( R )-4-methyltetrahydrofuran-2-yl) To a solution of methanone (585 mg, 1.734 mmol) in dichloromethane (6.0 mL) was added m-chloroperbenzoic acid (70%, 513 mg, 2.081 mmol). After stirring the reaction overnight, the mixture was purified by flash column chromatography (silica, 0 to 60% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)((3 R ,6 R )-1,5-dioxaspiro[2.4]heptan-6-yl)methanone as the first Isolated isomers and (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 S ,6 R )-1,5 -dioxaspiro[2.4]heptan-6-yl)methanone as the second lysate isomer.

First eluted isomer: LCMS: 95%, RT=2.00 min, (M+H) ⁺ =354 (Method A).

Second soluble isomer: LCMS: 96%, RT=1.97 min, (M+H) ⁺ =354 (Method A).

Synthesis of ((2R,4S)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5036 ).

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 S ,6 R )-1,5-dioxa To a solution of spiro[2.4]heptan-6-yl)methanone (58 mg, 0.164 mmol) in tetrahydrofuran (anhydrous, 1.0 mL) was added ethylamine (2.0 M in tetrahydrofuran, 1.026 mL, 2.052 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 analyzed by 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) purified residue. The products containing the isolated fractions were combined, basified with saturated _aqueous NaHCO solution (2.5 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organics were washed with brine (15 mL), dried over _Na2SO4 , and evaporated under reduced pressure. After lyophilization from _a mixture of acetonitrile and water (1:1, 4 mL), ((2 R ,4 S )-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroiso Quinolin-2(1 H )-yl)methanone ( compound 5036 ).

LCMS: 99%, RT=1.05 minutes, (M+H) ⁺ =399 (Method P). Example 23 Synthesis of ((2 R ,4 R )-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5037)

Synthesis of ((2R,4R)-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5037 ).

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 R ,6 R )-1,5-dioxa Starting from spiro[2.4]heptan-6-yl)methanone (see compound 5036 , 53 mg, 0.150 mmol), as for (( 2R , 4S )-4-((ethylamino)methyl) -4-Hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone is described ( compound 5036 ), preparing ((2 R ,4 R )-4-((ethylamino)methyl)-4-hydroxytetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5037 ).

LCMS: 97%, RT=1.03 minutes, (M+H) ⁺ =399 (Method P). Example 24 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 S ,4 R )-4-hydroxy-4 -(((2-Hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone (Compound 5038)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-methyltetrahydrofuran-2-yl)methyl ketone.

From ( R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2 H )- ketone (see Compound 5004 , 285 mg, 0.840 mmol) starting as for (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Preparation of (( R )-1-(4-fluorophenyl)-3,4-dihydroisoquine as described for (( R )-4-methyltetrahydrofuran-2-yl)methanone (see compound 5036 ) Phin-2(1 H )-yl)(( S )-4-methyltetrahydrofuran-2-yl)methanone.

LCMS: 99%, RT=2.17 minutes, (M+H) ⁺ =338 (Method B).

Synthesis of ((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.

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) (( S )-4-methyltetrahydrofuran-2-yl) Starting with methanone (145 mg, 0.430 mmol) as for (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 R ,6 R )-1,5-dioxaspiro[2.4]heptan-6-yl) methanone was prepared (( S )-1-(4- fluorophenyl )- 3,4-Dihydroisoquinolin-2(1 H )-yl)((3 S ,6 S )-1,5-dioxaspiro[2.4]heptan-6-yl)methanone as the first Isolated isomers and (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 R ,6 S )-1,5 -dioxaspiro[2.4]heptan-6-yl)methanone as the second lysate isomer. The configuration of the spiro epoxide is arbitrary.

First eluted isomer: LCMS: 98%, RT=1.99 min, (M+H) ⁺ =354 (Method A).

Second eluted isomer: LCMS: 99%, RT=1.97 min, (M+H) ⁺ =354 (Method A).

Synthesis of ((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 ).

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 R ,6 S )-1,5-dioxa Starting from spiro[2.4]heptan-6-yl)methanone (30 mg, 0.085 mmol) as for (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline- 2(1 H )-yl)((2 R ,4 R )-4-hydroxy-4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone ( Compound 5040 ) As described, the preparation of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 S ,4 R )-4-hydroxy- 4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone ( compound 5038 ). The configuration of the tetrahydrofuran-hydroxyl moiety is arbitrary.

LCMS: 97%, RT=1.02 minutes, (M+H) ⁺ =415 (Method P). Example 25 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 S ,4 S )-4-hydroxy-4 -(((2-Hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone (Compound 5039)

Synthesis of ((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 ).

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 S ,6 S )-1,5-dioxa Starting from spiro[2.4]heptan-6-yl)methanone (see compound 5038 , 71 mg, 0.201 mmol), after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL), as for ( ( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 R )-4-hydroxy-4-((( Preparation of (( S )-1-(4- fluorophenyl )-3,4- dihydroiso- Quinolin-2(1 H )-yl)((2 S ,4 S )-4-hydroxy-4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone ( Compound 5039 ). The configuration of the tetrahydrofuran-hydroxyl moiety is arbitrary.

LCMS: 99%, RT=1.00 min, (M+H) ⁺ =415 (Method P). Example 26 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 R )-4-hydroxy-4 -(((2-Hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone (Compound 5040)

Synthesis of ((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 ).

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 R ,6 R )-1,5-dioxa To a solution of spiro[2.4]heptan-6-yl)methanone (see compound 5036 , 64 mg, 0.181 mmol) in dichloromethane (1.8 mL) was added ethanolamine (0.055 mL, 0.906 mmol). The reaction vial was sealed and heated at 35°C overnight. The reaction mixture was concentrated to dryness under reduced pressure and analyzed by 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) purified residue. The products containing the isolated fractions were combined, basified with saturated _aqueous NaHCO solution (2.5 mL), and extracted with ethyl acetate (2 × 20 mL). _The combined organics were washed with brine (15 mL), dried over _Na2SO4 and evaporated under reduced pressure to give (( S ) after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 R )-4-hydroxy-4-(((2-hydroxy Ethyl)amino)methyl)tetrahydrofuran-2-yl)methanone ( compound 5040 ).

LCMS: 99%, RT=1.01 min, (M+H) ⁺ =415 (Method P). Example 27 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S )-4-hydroxy-4 -(((2-Hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone (Compound 5041)

Synthesis of ((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 ).

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 S ,6 R )-1,5-dioxa Starting from spiro[2.4]heptan-6-yl)methanone (see compound 5036 , 55 mg, 0.156 mmol), as for (( S )-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1 H )-yl)((2 R ,4 R )-4-hydroxy-4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone ( S )-1-(4-fluorophenyl)-3,4 -dihydroisoquinolin-2(1H)-yl)((2R , 4S )-4 was prepared as described in ( Compound 5040 ) -Hydroxy-4-(((2-hydroxyethyl)amino)methyl)tetrahydrofuran-2-yl)methanone ( Compound 5041 ).

LCMS: 99%, RT=1.02 minutes, (M+H) ⁺ =415 (Method P). Example 28 Synthesis of ((2 R ,5 S )-5-aminotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1 H )-yl)methanone (Compound 5042)

Synthesis of ((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran -3-yl)tertiary butyl carbamate.

Under a nitrogen atmosphere, add (2 R ,5 S )-5-((tertiary butoxycarbonyl)amino)tetrahydro-2 H -piran-2-carboxylic acid (289 mg, 1.178 mmol), N -(3-Dimethylaminopropyl) -N′ -carbodiimide hydrochloride (248 mg, 1.296 mmol) and 1-hydroxy-7-azabenzotriazole (32.1 mg, 0.236 mmol) in N , N -dimethylformamide (anhydrous, 5.5 mL) was added ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroiso Quinoline (281 mg, 1.237 mmol) and N,N -diisopropylethylamine (0.514 mL, 2.95 mmol), and the mixture was 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 _× 15 mL), dried over _Na2SO4 , and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 45% ethyl acetate in heptane) to give ((3 S ,6 R )-6-(( S )-1-(4 -Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.16 minutes, (M+H) ⁺ =455 (Method A).

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

To ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -Pyran-3-yl)carbamic acid tert-butyl ester (694 mg, 1.526 mmol) was added with HCl (5-6 M in 2-propanol, 4.5 mL, 112 mmol). After 2 hours, the reaction mixture was diluted with dichloromethane (25 mL) and washed with saturated _{aqueous Na2CO3} solution (10 mL). The aqueous layer was extracted with dichloromethane ( ₃ ×15 mL), and the combined organic phases were dried over _Na2SO4 and evaporated under reduced pressure. The residue was dissolved in methanol, introduced onto a SCX-2 column (5 g), and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:2, 30 mL) to give ((2 R ,5 S )-5-aminotetrahydro-2 H -piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5042 ).

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =355 (Method P). SFC: RT=5.32 minutes, (M+H) ⁺ =355 (Method W). Example 29 Synthesis of ((2 S ,4 R ,5 S )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5043)

Synthesis of ((3S,6S)-4-(benzyloxy)-6-(((tertiary butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl) Tertiary butyl carbamate.

To ((3 S ,6 S )-6-(((tertiary butyldimethylsilyl)oxy)methyl)-4-hydroxytetrahydro-2 H -piran-3-yl)carbamic acid To a solution of tertiary butyl ester (0.70 g, 1.936 mmol), tetrabutylammonium hydrogen sulfate (1.972 g, 5.81 mmol) and toluene bromide (0.576 mL, 4.84 mmol) in dichloromethane (20 mL) was added NaOH Aqueous solution (50%, 20 mL). The mixture was stirred for 5 hours, diluted with ice-cold water (50 mL) and extracted with dichloromethane (3×30 mL). _The combined phases were dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 35% ethyl acetate in heptane) to give ((3S,6S)-4-(benzyloxy)-6-(( (tertiary butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 85%, RT=2.69 minutes, (M-Boc+H) ⁺ =352 (Method B).

Synthesis of ((3S,6S)-4-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

To ((3 S ,6 S )-4-(benzyloxy)-6-((tertiary butyldimethylsilyl)oxy)methyl) at 0°C under an argon atmosphere To a solution of tertiary butyl tetrahydro- 2H -piran-3-yl)carbamate (0.623 g, 1.379 mmol) in tetrahydrofuran (anhydrous, 10 mL) was added dropwise tetrabutylammonium fluoride (in tetrahydrofuran) 1.0 M solution, 4.14 mL, 4.14 mmol). The reaction mixture was allowed to reach room temperature and stirred for 4 hours. The reaction mixture was quenched with saturated aqueous _NH4Cl (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine (20 mL), dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 80% ethyl acetate in heptane) to give (( 3S , 6S )-4-(benzyloxy)-6- (Hydroxymethyl)tetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 95%, RT=1.91 minutes, (M+Na) ⁺ =360 (Method A)

Synthesis of (2S,5S)-4-(benzoyloxy)-5-((tertiary butoxycarbonyl)amine)tetrahydro-2H-piran-2-carboxylic acid.

To ((3 S ,6 S )-4-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2 H -piran-3-yl)carbamic acid tertiary butyl ester (460 mg, 1.363 mmol) in a mixture of dichloromethane (6 mL), acetonitrile (6 mL) and water (9 mL) were added sodium periodate (875 mg, 4.09 mmol) and ruthenium trichloride hydrate (30.7 mg, 0.136 mmol). After stirring overnight, the _mixture was cooled in an ice/water bath and diluted with saturated _{aqueous Na2S2O3} solution. After warming to room temperature, the pH was adjusted to approximately 6-7 by adding aqueous HCl (1 M), and the mixture was extracted with ethyl acetate (3 × 25 mL). The combined _organic phases were washed with brine (10 mL), dried over _Na2SO4 and evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A, t=1 minute 5% A; t=16 minutes 60% A; t=17 minutes 100%; t=22 minutes 100% A; Detection (Measurement: 220 nm) The residue was purified to obtain (2 S , 5 S )-4-(benzyloxy)-5-((tertiary butoxycarbonyl)amine)tetrahydro- 2H -piran -2-carboxylic acid.

LCMS: 68%, RT=1.88 minutes, (MH) ^- =364 (Method A).

Synthesis of benzoic acid (2S,5S)-5-((tertiary butoxycarbonyl)amine)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetra Hydroisoquinolin-2-carbonyl)tetrahydro-2H-pyran-4-yl ester.

Under an argon atmosphere, to (2 S ,5 S )-4-(benzoyloxy)-5-((tertiary butoxycarbonyl)amine)tetrahydro- 2H -piran-2- To a solution of carboxylic acid (43.4 mg, 0.119 mmol) in N , N -dimethylformamide (anhydrous, 1 mL) was added N -(3-dimethylaminopropyl)- N ′-carboamide Diimine hydrochloride (23.91 mg, 0.125 mmol) and 1-hydroxy-7-azabenzotriazole (3.23 mg, 0.024 mmol), 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). After stirring for 3 days, the mixture was diluted with ethyl acetate (10 mL) and washed with saturated _aqueous NaHCO (5 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL), and the combined organics were _washed with brine (15 mL), dried over _Na2SO4 , and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give benzoic acid ( 2S , 5S )-5-((tertiary butoxycarbonyl )Amino)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4 - base ester.

LCMS: 95%, RT=2.25 minutes, (M+H) ⁺ =575 (Method A).

Synthesis of ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro- 2H-Pyran-3-yl)carbamic acid tertiary butyl ester.

To benzoic acid (2 S ,5 S )-5-((tertiary butoxycarbonyl)amino)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4 -Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl ester (40 mg, 0.070 mmol) was added to a solution in a mixture of water and methanol (1:1, 0.5 mL) Aqueous NaOH solution (1 M, 0.139 mL, 0.139 mmol). After 4 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and extracted with dichloromethane (2×10 mL). The organic layers were combined and passed through a phase separator. The filtrate was evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A, t=1 minute 5% A; t=16 minutes 60% A; t=17 minutes 100%; t=22 minutes 100% A; Measured: 220/254 nm), the residue was purified to obtain ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phinolin-2-carbonyl)-4-hydroxytetrahydro-2H-piran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 100%, RT=2.07 minutes, (M+H) ⁺ =471 (Method A).

Synthesis of ((2S,4R,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5043 ).

To ((3S,4R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetra To a solution of tert-butylhydro-2H-pyran-3-yl)carbamate (20 mg, 0.043 mmol) in 2-propanol (0.5 mL) was added HCl (5-6 M in 2-propanol , 83 µL, 0.46 mmol) and stir overnight. After one, two, and three days of stirring, three portions of HCl (5-6 M in 2-propanol, 83 µL, 0.46 mmol) were added. After stirring for a further three days, the reaction mixture was diluted with dichloromethane (10 mL) and saturated aqueous K ₂ CO ₃ (5 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3×10 mL). _The combined phases were dried over _Na2SO4 and evaporated under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (7 M). The basic fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ((2 S , 4 R , 5 S )-5-amino -4-Hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methyl ketone ( compound 5043 ).

LCMS: 100%, RT=1.01 min, (M+H) ⁺ =371 (Method P). Example 30 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( S )-1,4-oxazaheterocycle Heptan-7-yl)methanone (compound 5044) and (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) (( R )-1,4-oxaazepan-7-yl)methanone (compound 5045)

Synthesis of (S)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxazaheterocycle Heptane-4-carboxylic acid tertiary butyl ester and (R)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )-1,4-oxaazepine-4-carboxylate.

To a solution of 4-(tertiary butoxycarbonyl)-1,4-oxazepan-7-carboxylic acid (90 mg, 0.367 mmol) in dichloromethane (5 mL) was added N, N -Diisopropylethylamine (80 µl, 0.459 mmol) and hexafluorophosphoric acid 3-oxyl-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[ 4,5-b]pyridinium (153 mg, 0.404 mmol). After 10 minutes, ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (92 mg, 0.404 mmol) was added and the mixture was stirred for 2 hours. Subsequently, the reaction mixture was washed with aqueous HCl (1 M, 5 mL), saturated _aqueous NaHCO (5 mL) and brine (5 mL), dried over _Na2SO4 , and evaporated under reduced pressure _. The residue was purified by preparative LCMS (Method BF) and by preparative chiral SFC (Method Y) to give ( S )-7-(( S )-1-(4-fluorophenyl)-1,2 ,3,4-Tetrahydroisoquinoline-2-carbonyl)-1,4-oxaazepine-4-carboxylic acid tertiary butyl ester as the first eluted SFC isomer and ( R )-7 -(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxaazepine-4-carboxy The acid tertiary butyl ester was used as the second eluting SFC isomer. The configuration of the oxazepine stereocenter is arbitrarily specified.

First eluting SFC isomer: LCMS: 97%, RT=2.18 minutes, (M-tBu+H) ⁺ =399 (Method A). SFC: RT=2.60 minutes, (M-tBu+H) ⁺ =399 (Method W).

Second eluted SFC isomer: LCMS: 99%, RT=2.17 minutes, (M-tBu+H) ⁺ =399 (Method A). SFC: RT=3.14 minutes, (M-tBu+H) ⁺ =399 (Method W).

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

To ( S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxazacyclo To a solution of heptane-4-carboxylic acid tertiary butyl ester (10 mg, 0.022 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL, 6.53 mmol). After 4 hours, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (3 M). The alkaline 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 was obtained ,4-dihydroisoquinolin-2(1H)-yl)(( S )-1,4-oxaazepan-7-yl)methanone ( compound 5044 ). The configuration of the oxazepine stereocenter is arbitrarily specified.

LCMS: 100%, RT=1.05 minutes, (M+H) ⁺ =355 (Method P). SFC: RT=4.16 minutes, (M+H) ⁺ =355 (Method W).

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

From ( R )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxazacyclo Starting from heptane-4-carboxylic acid tertiary butyl ester (10 mg, 0.022 mmol), as for (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( Preparation of ( ( S ) -1-(4- fluorophenyl ) -3,4-Dihydroisoquinolin-2(1H)-yl)(( R )-1,4-oxaazepan-7-yl)methanone ( Compound 5045 ). The configuration of the oxazepine stereocenter is arbitrarily specified.

LCMS: 100%, RT=1.04 minutes, (M+H) ⁺ =355 (Method P). SFC: RT=4.63 minutes, (M+H) ⁺ =355 (Method W). Example 31 Synthesis of ((2 S ,5 S )-5-(aminomethyl)-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5046) and ((2 R ,5 R )-5-(aminomethyl)-5-hydroxytetrahydro -2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5047)

Synthesis of trans-1,5-dioxaspiro[2.5]octane-6-carboxylic acid ethyl ester.

To a solution of trimethylstyrene iodide (179 mg, 0.813 mmol) in dimethylstyrene (2.0 mL) was added sodium hydride (60% dispersion in oil, 32.5 mg, 0.813 mmol). After 0.5 h, a solution of ethyl 5-pentoxytetrahydro-2H-piran-2-carboxylate (100 mg, 0.581 mmol) in 1,2-dimethoxyethane (1.0 mL) was added. After stirring for another 2 hours, the reaction mixture was poured into a mixture of saturated aqueous NH ₄ Cl solution and (20 mL), and the resulting mixture was extracted with diethyl ether (2 × 15 mL) and ethyl acetate (15 mL). _The combined organic phases were washed with water, dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 10 to 50% ethyl acetate in heptane) to give trans -1,5-dioxaspiro[2.5]octane-6-carboxylic acid ethyl ester.

GCMS: 99%, RT=3.06 min, (M-CO ₂ Et) ⁺ =113 (Method A20).

Synthesis of trans-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2-carboxylic acid ethyl ester.

To trans -1,5-dioxaspiro[2.5]octane-6-carboxylic acid ethyl ester (30 mg, 0.161 mmol) was added sodium azide (52.4 mg, 0.806 mmol) in acetic acid (0.15 mL ) and water (0.26 mL). After 3 hours, the reaction mixture was diluted with dichloromethane (10 mL) and a mixture of saturated aqueous K ₂ CO ₃ (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 to 70% ethyl acetate in heptane) to give trans -5-(azidomethyl)-5-hydroxytetrahydro- 2H -Ethyl piperan-2-carboxylate.

LCMS: 99%, RT=1.76 minutes (Method B).

Synthesis of trans-5-(azidomethyl)-5-hydroxytetrahydro-2H-piran-2-carboxylic acid.

To a solution of trans - 5-(azidomethyl)-5-hydroxytetrahydro- 2H -piran-2-carboxylic acid ethyl ester (30 mg, 0.131 mmol) in methanol (0.3 mL) was added NaOH Aqueous solution (2 M, 0.079 mL, 0.157 mmol). After 1 hour, the mixture was diluted with dichloromethane and acidified with aqueous HCl (1 M) to a pH of about 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). Use a phase separator to separate each layer, 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 -piper Pyran-2-carboxylic acid.

Synthesis of (trans-5-(azidomethyl)-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1H)-yl)methanone

To ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (21.46 mg, 0.094 mmol) and trans - 5-(azidomethyl)-5- To a solution of hydroxytetrahydro- 2H -piran-2-carboxylic acid (19 mg, 0.094 mmol) in acetonitrile (0.5 mL) was added 1-hydroxy-7-azabenzotriazole (2.57 mg, 0.019 mmol) and N- (3-dimethylaminopropyl) -N′ -carbodiimide hydrochloride (21.73 mg, 0.113 mmol). After stirring overnight, the mixture was diluted with water and acetonitrile (1:1, 1 mL) and analyzed by 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) purification. The product containing fractions were combined and the volatiles were removed under reduced pressure. The aqueous residue was diluted with _saturated aqueous NaHCO (5 mL) and dichloromethane (5 mL) and stirred for 2 h. 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 give ((2 S ,5 S )-5-(azidomethyl)-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S ) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone as the first eluted SFC isomer and ((2 R ,5 R )-5 -(azidomethyl)-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2 ( 1H )-yl)methanone serves as the second eluting SFC isomer. The configuration of the pyran stereoisomeric center is arbitrarily specified.

First eluted isomer: LCMS: 99%, RT=2.07 minutes, (M+H) ⁺ =411 (Method C). SFC: RT=3.73 minutes, (M+H) ⁺ =411 (Method W).

Second eluted isomer: LCMS: 99%, RT=2.07 minutes, (M+H) ⁺ =411 (Method C). SFC: RT=4.94 minutes, (M+H) ⁺ =411 (Method W).

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

To ((2 S ,5 S )-5-(azidomethyl)-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- To a solution of 3,4-dihydroisoquinolin-2(1 H )-yl)methanone (12.2 mg, 0.030 mmol) was added palladium on carbon (10 wt%, containing 50% water, scrape a little). The mixture was hydrogenated at room temperature and ambient pressure for 4 h, diluted with methanol, filtered through nylon (0.45 µm filter) and the filtrate was evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=2 minutes 10% A; t=17 minutes 50% A; t=18 minutes 100%; t=23 minutes 100% A; (measured at 210 nm) purified residue. The products containing the eluates were combined, diluted with saturated _aqueous NaHCO solution (4 mL), and extracted with dichloromethane. The organic layer was passed through a phase separator and evaporated under reduced pressure to give (( 2S , 5S )-5-(aminomethyl) after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL) yl)-5-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H )- base) methanone ( compound 5046 ). The configuration of the pyran stereoisomeric center is arbitrarily specified.

LCMS: 99%, RT=2.57 minutes, (M+H) ⁺ =385 (Method AK).

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

To ((2 R ,5 R )-5-(azidomethyl)-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- To a solution of 3,4-dihydroisoquinolin-2(1 H )-yl)methanone (12.2 mg, 0.030 mmol) was added palladium on carbon (10 wt%, containing 50% water, scrape a little). The mixture was hydrogenated at room temperature and ambient pressure for 4 h, diluted with methanol, filtered through nylon (0.45 µm filter) and the filtrate was evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=2 minutes 10% A; t=17 minutes 50% A; t=18 minutes 100%; t=23 minutes 100% A; (measured at 210 nm) purified residue. The products containing the eluates were combined, diluted with saturated _aqueous NaHCO solution (4 mL), and extracted with dichloromethane. The organic layer was passed through a phase separator and the filtrate was evaporated under reduced pressure to give (( 2S , 5S )-5-(amine) after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL) Methyl)-5-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) -Methyl ketone ( compound 5047 ). The configuration of the pyran stereoisomeric center is arbitrarily specified.

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =385 (Method P). Example 32 Synthesis of (trans-5-amino-1,3-di Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5048)

Synthesis of ethyl 5-methylene-1,3-bis Alkane-2-carboxylate.

To a refluxed solution of boron trifluoride etherate (ca. 48% BF ₃ , 9.33 mL, 73.6 mmol) in chloroform (20 ml) was added 2,2-diethoxyacetic acid dropwise over 15 minutes. A suspension of ethyl ester (6.58 mL, 36.8 mmol) and 2-methylpropane-1,3-diol (3 mL, 36.8 mmol) in chloroform (10 mL). After stirring at reflux for 1.5 hours, the reaction mixture was cooled to room _temperature , washed successively with water, saturated aqueous _Na2CO3 and water, dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give 5-methyl-1,3-di Alkane-2-carboxylic acid ethyl ester.

GCMS: 96%, RT=2.67 min, (M-CO ₂ Et) ⁺ =99 (Method A20).

Synthesis of 5-Pendant Oxy-1,3-Di Alkane-2-carboxylic acid ethyl ester.

5-methyl-1,3-bis Alkane-2-carboxylic acid ethyl ester (2.09 g, 12.14 mmol) and ruthenium trichloride hydrate (0.109 g, 0.486 mmol) in acetonitrile (20 mL), dichloromethane (20 mL) and water (20 mL) Sodium periodate (10.39 g, 48.6 mmol) was added to the mixture). 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 filtrate was washed with brine. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give 5-side oxy-1,3-di Alkane-2-carboxylic acid ethyl ester.

GCMS: RT=2.54 minutes, (M-CO ₂ Et) ⁺ =101 (Method A20).

Synthesis of cis-5-(diphenylmethylamino)-1,3-di Alkane-2-carboxylic acid ethyl ester and (trans)-5-(diphenylmethylamino)-1,3-di Alkane-2-carboxylic acid ethyl ester.

To the 5-side oxy-1,3-bis To a solution of alkane-2-carboxylic acid ethyl ester (200 mg, 1.148 mmol) in dichloromethane (3 mL) was added benzylamine (0.222 mL, 1.148 mmol). After 15 minutes, sodium triacetyloxyborohydride (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 allowed to warm to 40°C. After 2 hours, the reaction mixture was cooled to room temperature and diluted with water and dichloromethane. The layers were separated, and the aqueous phase was diluted with saturated aqueous _NaHCO3 solution and extracted twice with dichloromethane. The combined organic phases were dried over _Na2SO4 and evaporated _under reduced pressure. By acidic 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) purified residue. The product fractions were combined and lyophilized. After lyophilizing the product containing the fractions, cis-5-(diphenylmethylamino)-1,3-bis was obtained. Alkane-2-carboxylic acid ethyl ester as the first soluble isomer and trans-5-(diphenylmethylamino)-1,3-di Alkane-2-carboxylic acid ethyl ester as the second lytic isomer.

Cis isomer: LCMS: RT=1.76 min, (M+H) ⁺ =356 (Method A).

Trans isomer: LCMS: RT=2.15 min, (M+H) ⁺ =356 (Method A).

Synthesis of trans-5-(diphenylmethylamino)-1,3-di Alkane-2-carboxylic acid lithium salt.

To trans-5-(diphenylmethylamino)-1,3-di To a solution of alkane-2-carboxylic acid ethyl ester (32 mg, 0.090 mmol) in a mixture of water (2 mL) and tetrahydrofuran (2 mL) was added lithium hydroxide monohydrate (5.67 mg, 0.135 mmol). After 1 hour, the reaction mixture was concentrated to dryness under reduced pressure to obtain trans-5-(diphenylmethylamino)-1,3-di Alkane-2-carboxylic acid lithium salt and it was used as received.

LCMS: RT=1.73 min, (M-Li) ^- =326 (Method B).

Synthesis of (trans-5-(diphenylmethylamino)-1,3-di Alk-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

To trans-5-(diphenylmethylamino)-1,3-di To a solution of alkane-2-carboxylic acid lithium salt (0.090 mmol) in N , N -dimethylformamide (anhydrous, 3 mL) was added ( S )-1-(4-fluorophenyl)-1, 2,3,4-Tetrahydroisoquinoline (20.46 mg, 0.090 mmol), N- (3-dimethylaminopropyl) -N′ -carbodiimide hydrochloride (20.70 mg, 0.108 mmol) ) and 1-hydroxy-7-azabenzotriazole (1.225 mg, 9.00 µmol). After the reaction mixture was stirred overnight, aqueous HCl (1 M, a few drops) and N -(3-dimethylaminopropyl)- N ′-carbodiimide hydrochloride (8.63 mg, 0.045 mmol) were added and Continue stirring for 1 hour. The mixture was diluted with water and extracted 3 times with dichloromethane. The combined organic phases were dried over _Na2SO4 and evaporated _under reduced pressure. By alkaline 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 minutes 100% A; detection: 210/220/270 nm) The purified residue, after concentration and lyophilization of the product containing the eluate, gave (trans-5-(diphenylmethylamino) -1,3-two Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 100%, RT=2.48 minutes, (M+H) ⁺ =537 (Method B).

Synthesis (trans-5-amino-1,3-di Alk-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5048 ).

(trans-5-(diphenylmethylamino)) in the presence of palladium (10 wt% on carbon, 50% water, 8 mg, 3.76 µmol) at 50°C and atmospheric hydrogen pressure -1,3-two Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (27 mg, 0.050 mmol) in methanol (5 mL) was hydrogenated. After 5 hours, the reaction mixture was filtered and analyzed by alkaline 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 minutes 100% A; t=23 minutes 100% A; detection: 210/220/270 nm) purified filtrate, after concentration and freeze-drying of the product containing the eluate, (trans-5-amine base-1,3-bis Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5048 ).

LCMS: 100%, RT=1.03 minutes, (M+H) ⁺ =357 (Method P). Example 33 Synthesis of (cis-5-amino-1,3-di Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5049) and (cis- 5-(ethylamino)-1,3-di Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5050)

Synthesis of cis-5-(diphenylmethylamino)-1,3-di Alkane-2-carboxylic acid lithium salt.

To cis-5-(diphenylmethylamino)-1,3-bis To a solution of alkane-2-carboxylic acid ethyl ester (56 mg, 0.158 mmol) in a mixture of water (2 mL) and tetrahydrofuran (2 mL) was added lithium hydroxide monohydrate (13.22 mg, 0.315 mmol). After 1 hour, the reaction mixture was diluted with aqueous HCl (1 M, 0.150 mL, 0.150 mmol) and concentrated to dryness under reduced pressure to give cis-5-(diphenylmethylamino)-1,3-di Alkane-2-carboxylic acid lithium salt and it was used as received.

LCMS: RT=1.73 min, (M-Li) ^- =326 (Method B).

Synthesis of (cis-5-(diphenylmethylamino)-1,3-di Alk-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

From ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (36.1 mg, 0.159 mmol) and cis-5-(diphenylmethylamino)- 1,3-two Starting from lithium alkane-2-carboxylate (0.159 mmol), as for (trans-5-(diphenylmethylamino)-1,3-di Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone, prepared as described (see compound 5048 ) (cis-5-(diphenylmethylamino)-1,3-di Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 100%, RT=2.48 minutes, (M+H) ⁺ =537 (Method B).

Synthesis (cis-5-amino-1,3-di Alk-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5049 ) and (cis-5 -(ethylamino)-1,3-di Alk-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5050 ).

(cis-5-(diphenylmethylamino)) in the presence of palladium (10 wt% on carbon, 50% water, 8 mg, 3.76 µmol) at 45°C and atmospheric hydrogen pressure -1,3-two Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (24 mg, 0.045 mmol) in ethanol (5 mL) was hydrogenated. After 5 hours, the reaction mixture was filtered and analyzed by alkaline 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 minutes 100% A; t=23 minutes 100% A; detection: 210/220/270 nm) Purify the filtrate, after concentration and lyophilization of the product containing the eluate, obtain (cis-5- Amino-1,3-bis Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5049 ) and (cis- 5-(ethylamino)-1,3-di Alk-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5050 ).

Compound 5049 : LCMS: 100%, RT=1.03 min, (M+H) ⁺ =357 (Method P).

Compound 5050 : LCMS: 97%, RT=1.06 min, (M+H) ⁺ =385 (Method P). Example 34 Synthesis of ((2 R ,4 S ,5 S )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5051)

Synthesis of ((2R,4S,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5051 ).

From ((2 R ,4 S ,5 S )-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -Hydroxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5052 , 53 mg, 0.113 mmol) starting as for (( S )-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-((2-methoxyethyl)amino)tetrahydro-2 H - Preparation of ((2 R ,4 S ,5 S )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl) as described for pyran-2-yl)methanone ( compound 5030 ) (( S )-1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5051 ) without additional purification.

LCMS: 98%, RT=1.03 minutes, (M+H) ⁺ =371 (Method P). SFC: RT=4.64 minutes, (M+H) ⁺ =371 (Method F). Example 35 Synthesis of ((2 R ,4 S ,5 R )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5052)

Synthesis of ((3R,4S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrakis Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester, ((3S,4R,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester, ((2R,4S,5S)-2-((S) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H-piran-4-yl)carbamic acid tert-butanyl Esters and ((2R,4R,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy Tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

From (( R )-3,6-dihydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( Starting from 1 H )-yl)methanone (2.45 g, 7.26 mmol) as for ((3 S ,4 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester was prepared as described (see compound 5053 ). product. The crude product was purified by flash column chromatography (silica, 0 to 70% ethyl acetate in heptane), crystallized from 2-propanol and further purified by chiral preparative SFC (Method S) After mixing the fractions, ((3 R ,4 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)-4-hydroxytetrahydro-2 H -pyran-3-yl)carbamate tertiary butyl ester was used as the first eluted isomer on silica by chiral preparative SFC (Method BG) After further purification, ((3 S ,4 R ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)-4-hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester was used as the second soluble isomer on silica to obtain ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro- 2H -pyran -4-yl)carbamate tertiary butyl ester as the third eluted isomer on silica, and after further purification by chiral preparative SFC (Method AI), ((2 R ,4 R , 5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro- 2H -piper Perran-4-yl)carbamic acid tertiary butyl ester as the fourth soluble isomer on silica.

First soluble isomer on silica: LCMS: 100%, RT=2.07 minutes, (M+H) ⁺ =471 (Method A). SFC: RT=3.59 minutes, (M+H) ⁺ =471 (Method F).

Second soluble isomer on silica: LCMS: 95%, RT=2.06 min, (M+H) ⁺ =471 (Method A). SFC: RT=3.06 minutes, (M+H) ⁺ =471 (Method F).

Third soluble isomer on silica: LCMS: 100%, RT=2.06 min, (M+H) ⁺ =471 (Method A). SFC: RT=3.32 minutes, (M+H) ⁺ =471 (Method F).

Fourth soluble isomer on silica: LCMS: 93%, RT=2.05 min, (M-Boc+H) ⁺ =371 (Method A). SFC: RT=3.07 minutes, (M-Boc+H) ⁺ =371 (Method F).

Synthesis of ((2R,4S,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5052 ).

From ((3 R ,4 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 -Hydroxytetrahydro- 2H -pyran-3-yl)carbamic acid tert-butyl ester (30 mg, 0.064 mmol) starting as for (( 2S , 4R , 5S )-5-amino- 4-Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl (( 2R , 4S , 5R )-5-amino-4-hydroxytetrahydro- 2H -piran-2 - yl )(( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5052 ).

LCMS: 99%, RT=1.00 min, (M+H) ⁺ =371 (Method P). SFC: RT=4.47 minutes, (M+H) ⁺ =371 (Method F). Example 36 Synthesis of ((2 S ,4 S ,5 R )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5053) Synthesis of ((R)-3,6-dihydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone and ((S)-3,6-dihydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroiso Quinolin-2(1H)-yl)methanone.

To a solution of 3,6-dihydro-2 H -piran-2-carboxylic acid (10 g, 78 mmol) in dichloromethane (150 mL) was added hexafluorophosphoric acid 3-oxyl-[bis(di Methylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium (32.6 g, 86 mmol) and N,N -diisopropylethylamine (20.45 mL, 117 mmol). After 10 minutes, ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (19.51 g, 86 mmol) was added and stirring was continued for 1 hour. The reaction mixture was diluted with dichloromethane (120 mL), washed with saturated _aqueous NaHCO ₍ 2 × 50 mL) and aqueous HCl (1 M, 2 × 50 mL), dried over _NaSO and evaporated under reduced pressure . The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give (( R )-3,6-dihydro- 2H -piran-2- base) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone as the first soluble isomer and (( S )- 3,6-Dihydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methyl ketone as the second soluble isomer.

First eluted isomer: LCMS: 87%, RT=2.12 minutes, (M+H) ⁺ =338 (Method A). SFC: 100%, RT=3.18 minutes, (M+H) ⁺ =338 (Method F).

Second soluble isomer: LCMS: 95%, RT=2.12 minutes, (M+H) ⁺ =338 (Method A). SFC: 100%, RT=2.72 minutes, (M+H) ⁺ =338 (Method F).

Synthesis of ((3S,4R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetra Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester, ((3R,4S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester, ((2S,4S,5S)-2-((S) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro-2H-piran-4-yl)carbamic acid tert-butanyl Esters and ((2S,4R,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy Tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

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) was added dichloroisocyanuric acid Sodium (1.29 g, 5.84 mmol). After 15 minutes, a fine suspension formed, and freshly prepared hydroquinidine 1,4-naphthyridine ((DHQD) ₂ PHAL, 76 mg, 0.097 mmol) and (( S )-3, 6-Dihydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (657 mg, 1.95 mmol) in 1-propanol (13 mL). After stirring the reaction mixture for an additional 2 minutes, 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, a saturated aqueous solution of sodium metabisulfite (10 mL) was added 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 volatiles from the filtrate were removed under reduced pressure and the aqueous residue was extracted with dichloromethane (2×20 mL). The combined organic _phases were washed with brine, dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane). After further purification of propanol (heptane), ((3 S ,4 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)-4-hydroxytetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester was used as the first isomer to dissolve on silica. The fraction of the second elution on silica was further purified by chiral preparative SFC (method BH) to obtain ((3 R ,4 S ,6 S )-6-(( S )-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester was used as the The first soluble isomer, ((2 S ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)-5-hydroxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester as the second soluble isomer on SFC, and ((2 S , 4 R , 5 R ) -2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro- 2H -piran-4 -tertiary butyl carbamate as the third soluble isomer on SFC.

First soluble isomer on silica: LCMS: 85%, RT=2.07 minutes, (M+H) ⁺ =471 (Method A). SFC: RT=2.31 minutes, (M+H) ⁺ =471 (method AU).

Second eluted fraction on silica; first eluted isomer on SFC: SFC: RT=1.97 min, (M+H) ⁺ =471 (Method AU).

Second eluted fraction on silica; second eluted isomer on SFC: SFC: RT=2.10 min, (M-Boc+H) ⁺ =371 (Method AU).

Second eluted fraction on silica; third eluted isomer on SFC: SFC: RT=2.31 min, (M+H) ⁺ =471 (Method AU).

Synthesis of ((2S,4S,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5053 ).

From ((3 R ,4 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 -Hydroxytetrahydro- 2H -pyran-3-yl)carbamic acid tert-butyl ester (16 mg, 0.034 mmol) starting as for (( 2S , 4R , 5S )-5-amino- 4-Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl (( 2S , 4S , 5R )-5-amino-4-hydroxytetrahydro- 2H -piran-2 - yl )(( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5053 ).

LCMS: 99%, RT=1.01 minutes, (M+H) ⁺ =371 (Method P). SFC: RT=3.94 minutes, (M+H) ⁺ =371 (Method W). Example 37 Synthesis of ((2 S ,4 R ,5 R )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5054)

Synthesis of ((2S,4R,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5054 ).

From ((2 S ,4 R ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -Hydroxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5053 , 33 mg, 0.070 mmol) starting as for (( 2S , 4R , 5S )-5 -Amino-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) (( 2S , 4R , 5R )-4-amino-5-hydroxytetrahydro- 2H -pyran-2-yl)(( S )) as described for methanone ( compound 5043 ) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5054 ).

LCMS: 99%, RT=1.02 minutes, (M+H) ⁺ =371 (Method P). SFC: RT=4.48 minutes, (M+H) ⁺ =371 (Method AD). Example 38 Synthesis of ((2 R ,4 S ,5 R )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5055)

Synthesis of 4-nitrobenzoic acid (3R,4S,6R)-4-((tertiary butoxycarbonyl)amine)-6-((S)-1-(4-fluorophenyl)-1,2 ,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl ester.

From ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -Hydroxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5052 , 50 mg, 0.106 mmol) starting as for 4-nitrobenzoic acid ( 2S , 4S , 5 S )-5-((tertiary butoxycarbonyl)amine)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro- 2H -piran-4-yl ester was prepared as described (see compound 5056 ), 4-nitrobenzoic acid ( 3R , 4S , 6R )-4-((tertiary butanyl Oxycarbonyl)amino)-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piper Perran-3-yl ester, and after 2 days triphenylphosphine and diisopropyl azodicarboxylate were added again and used directly in the next step.

LCMS: 93%, RT=2.30 minutes, (M+Na) ⁺ =642 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrakis Hydrogen-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

From benzoic acid (3 R ,4 S ,6 R )-4-((tertiary butoxycarbonyl)amino)-6-(( S )-1-(4-fluorophenyl)-1,2, Starting from 3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl 4-nitroester (67 mg crude, 0.106 mmol), as for ((3 S , 4 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro-2 H -Piran-3-yl)carbamic acid tertiary butyl ester was prepared as described (see compound 5056 ) ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorobenzene) tertiary butyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro- 2H -piran-4-yl)carbamate.

LCMS: 100%, RT=2.05 minutes, (M+H) ⁺ =471 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5055 ).

From ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -Hydroxytetrahydro- 2H -pyran-4-yl)carbamic acid tert-butyl ester (11 mg, 0.023 mmol) starting as for (( 2S , 4R , 5S )-5-amino- 4-Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl ((2 R ,4 S ,5 R )-4-amino-5-hydroxytetrahydro - 2 H -piran-2-yl)(( S ) -1- ( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5055 ).

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =371 (Method P). SFC: RT=3.68 minutes, (M+H) ⁺ =371 (Method AD). Example 39 Synthesis of (( 2S , 4S , 5S )-5-amino-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5056)

Synthesis of 4-nitrobenzoic acid (2S,4S,5S)-5-((tertiary butoxycarbonyl)amine)-2-((S)-1-(4-fluorophenyl)-1,2 ,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl ester.

To ((3 S ,4 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro) at 0°C under an argon atmosphere Isoquinoline-2-carbonyl)-4-hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5053 , 40 mg, 0.085 mmol), triphenylphosphine (33.4 mg, To a solution of 4-nitrobenzoic acid (21.3 mg, 0.128 mmol) and anhydrous tetrahydrofuran (0.4 mL) was added diisopropyl azodicarboxylate (0.025 mL, 0.128 mmol). The reaction mixture was allowed to warm 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 ×5 mL) and the combined phases were dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 35% ethyl acetate in heptane) to give 4-nitrobenzoic acid ( 2S , 4S , 5S )-5-( (tertiary butoxycarbonyl)amino)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2 H -pyran-4-yl ester and was used as received.

LCMS: 98%, RT=2.27 minutes, (M+H) ⁺ =620 (Method A).

Synthesis of ((3S,4S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrakis Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

To 4-nitrobenzoic acid (2 S ,4 S ,5 S )-5-((tertiary butoxycarbonyl)amine)-2-(( S )-1-(4-fluorophenyl)- To a solution of 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl ester (40 mg, 0.065 mmol) in tetrahydrofuran (0.5 mL) was added a single A solution of lithium hydroxide hydrate (2.98 mg, 0.071 mmol) in water (0.5 mL). After stirring for 1 hour, the mixture was diluted with dichloromethane (10 mL) and saturated _aqueous NaHCO (10 mL). The aqueous layer was extracted with dichloromethane (2×10 mL) and the combined phases were dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 0 to 70% ethyl acetate in heptane) to give (( 3S , 4S , 6S )-6-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester .

LCMS: 100%, RT=2.03 minutes, (M+H) ⁺ =471 (Method A).

Synthesis of ((2S,4S,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5056 ).

From ((3 S ,4 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 -Hydroxytetrahydro- 2H -pyran-3-yl)carbamic acid tert-butyl ester (15 mg, 0.032 mmol) starting as for (( 2S , 4R , 5S )-5-amino- 4-Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl (( 2S , 4S , 5S )-5-amino-4-hydroxytetrahydro- 2H -piran-2- yl )(( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5056 ).

LCMS: 98%, RT=1.01 min, (M+H) ⁺ =371 (Method P). SFC: RT=4.55 minutes, (M+H) ⁺ =371 (Method F). Example 40 Synthesis of ((2 R , 4 R , 5 R )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5057)

Synthesis of ((3R,4R,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrakis Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

From ((3 R ,4 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 -Hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5052 , 40 mg, 0.085 mmol) starting as for 4-nitrobenzoic acid ( 2S , 4S , 5 S )-5-((tertiary butoxycarbonyl)amine)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-carbonyl)tetrahydro- 2H -piran-4-yl ester (see compound 5056 ) and (( 3S , 4S , 6S )-6-(( S )-1-(4-fluorophenyl )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5056 ) , prepare ((3 R ,4 R ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)- 4-Hydroxytetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester. LCMS: 100%, RT=2.03 minutes, (M+H) ⁺ =471 (Method A).

Synthesis of ((2R,4R,5R)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5057 ).

From ((3 R ,4 R ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 -Hydroxytetrahydro- 2H -pyran-3-yl)carbamic acid tert-butyl ester (29 mg, 0.062 mmol) starting as for (( 2S , 4R , 5S )-5-amino- 4-Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl ((2 R ,4 R ,5 R )-5-amino-4-hydroxytetrahydro - 2 H -piran-2 - yl)(( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5057 ).

LCMS: 99%, RT=2.51 minutes, (M+H) ⁺ =371 (Method AK). SFC: RT=5.31 minutes, (M+H) ⁺ =371 (Method F). Example 41 Synthesis of ((2 S ,4 S ,5 S )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5058)

Synthesis of ((2S,4S,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5058 ).

From ((2 S ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -Hydroxytetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester (see compound 5053 , 35 mg, 0.074 mmol) starting as for (( 2S , 4R , 5S )-5 -Amino-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) (( 2S , 4S , 5S )-4-amino-5-hydroxytetrahydro- 2H -pyran-2-yl)(( S )) as described for methanone ( compound 5043 ) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5058 ). LCMS: 99%, RT=1.01 minutes, (M+H) ⁺ =371 (Method P). SFC: RT=4.00 minutes, (M+H) ⁺ =371 (Method AD). Example 42 Synthesis of ((2 S ,4 S ,5 S )-5-amino-4-fluorotetrahydro-2 H -pyran-2-yl) ((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5059)

Synthesis of ((3S,4S,6S)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydroisoquinoline-2-carbonyl Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

From ((3 S ,4 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 -Hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5053 , 76 mg, 0.162 mmol) starting as for (( 2R , 4S , 5R )-5 -Fluoro-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl ) tertiary butyl carbamate as described (see compound 5069 at 80°C) to prepare (( 3S , 4S , 6S )-4-fluoro-6-(( S )-1-(4-fluoro Phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 100%, RT=2.15 minutes, (M+H) ⁺ =473 (Method A).

Synthesis of ((2S,4S,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5059 ).

From ((3 S ,4 S ,6 S )-4-fluoro-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Starting from tert-butylcarbonyltetrahydro- 2H -piran-3-yl)carbamate (34 mg, 0.072 mmol), as for (( 2S , 4R , 5S )-5-amino- 4-Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl (( 2S , 4S , 5S )-5-amino-4-fluorotetrahydro- 2H -piran-2 - yl )(( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5059 ) and purified by preparative chiral SFC (Method AN).

LCMS: 100%, RT=1.05 minutes, (M+H) ⁺ =373 (Method P). SFC: RT=3.56 minutes, (M+H) ⁺ =373 (method AD). Example 43 Synthesis of ((2 S ,5 S )-5-amino-4,4-difluorotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5060)

Synthesis of ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-side oxytetrakis Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

At 0°C, to ((3 S ,4 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 To a solution of -carbonyl)-4-hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5053 , 50 mg, 0.106 mmol) in dichloromethane (1 mL) was added 1,1,1-Shen(acetyloxy)-1,1-dihydro-1,2-benzeniodolide-3-(1 H )-one (Dess-Martin periodinane) ), 49.6 mg, 0.117 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with _a mixture of saturated _{aqueous Na2S2O3} and saturated aqueous _NaHCO3 solutions (1:1, 2 mL) and stirred for 1 hour. 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 to 35% ethyl acetate in heptane) to give ((3 S ,6 S )-6-(( S )-1-(4 -Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-side oxytetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 82%, RT=2.15 min, (M+Na) ⁺ =491, and 18% as hydrate: RT =2.03 min, (M+Na) ⁺ =509 (Method A).

Synthesis of ((3S,6S)-4,4-difluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

To a solution of [bis(2-methoxyethyl)amino]sulfide trifluoride (2.6 M in toluene, 0.072 mL, 0.188 mmol) in dichloromethane (0.20 mL) at 0 °C was added ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-side oxy group Tetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester (42 mg, 0.090 mmol) in dichloromethane (0.5 mL) followed by ethanol (0.523 µL, 8.96 µmol). After adding ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-side oxy group A solution of tertiary butyl tetrahydro-2H-pyran-3-yl)carbamate (42 mg, 0.090 mmol) in dichloromethane (0.5 ml) was followed by the addition of ethanol (0.523 µl, 8.96 µmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 days. The reaction mixture was diluted with dichloromethane (1 mL), cooled in an ice bath and quenched with saturated aqueous _NaHCO (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 to 30% ethyl acetate in heptane) to give (( 3S , 6S )-4,4-difluoro-6-((( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester .

LCMS: 100%, RT=2.20 minutes, (M+Na) ⁺ =513 (Method A).

Synthesis of ((2S,5S)-5-amino-4,4-difluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5060 ).

From ((3 S ,6 S )-4,4-difluoro-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Starting from tert-butylcarbonyltetrahydro- 2H -piran-3-yl)carbamate (23 mg, 0.047 mmol), as for (( 2S , 4R , 5S )-5-amino- 4-Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl ((2 S ,5 S )-5 - amino-4,4-difluorotetrahydro- 2 H -pyran-2-yl)(( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5060 ).

LCMS: 99%, RT=1.09 minutes, (M+H) ⁺ =391 (Method P). SFC: RT=4.64 minutes, (M+H) ⁺ =371 (Method F). Example 44 Synthesis of ((2 R , 4 R , 5 R )-5-amino-4-fluorotetrahydro-2 H -piran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5061)

Synthesis of ((3R,4R,6R)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydroisoquinoline-2-carbonyl Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

From ((3 R ,4 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 -Hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5052 , 100 mg, 0.213 mmol) starting as for (( 2R , 4S , 5R )-5 -Fluoro-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl ) tertiary butyl carbamate as described (see compound 5069 ), preparation of ((3 R ,4 R ,6 R )-4-fluoro-6-(( S )-1-(4-fluorophenyl)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.16 minutes, (M+H) ⁺ =473 (Method A).

Synthesis of ((2R,4R,5R)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5061 ).

From ((3 R ,4 R ,6 R )-4-fluoro-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Starting from tert-butylcarbonyltetrahydro- 2H -piran-3-yl)carbamate (86 mg, 0.182 mmol), as for (( 2S , 4R , 5S )-5-amino- 4-Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl ((2 R ,4 R , 5 R )-5-amino-4-fluorotetrahydro-2 H -piran-2 - yl)(( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5061 ) and analyzed by flash column chromatography (silica, 0 to 2% ( Purified with 7 M ammonia in methanol/methylene chloride.

LCMS: 99%, RT=1.04 minutes, (M+H) ⁺ =373 (Method P). SFC: RT=3.37 minutes, (M+H) ⁺ =373 (method AD). Example 45 Synthesis of ((2 R ,4 S ,5 S )-4-amino-5-methoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorobenzene) methyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone (compound 5062)

Synthesis of ((2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxy Tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 S )-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of tert-butyl -hydroxytetrahydro- 2H -piran-4-yl)carbamate (see compound 5052 , 70 mg, 0.149 mmol) in toluene (1.2 mL) was added tetrabutylammonium hydrogen sulfate ( 15 mg, 0.043 mmol), followed by aqueous NaOH (50 wt%, 119 µL, 2.23 mmol) and methane iodide (14.9 µL, 0.238 mmol). After stirring for 3 hours, additional amounts of aqueous NaOH (50 wt%, 119 µL, 2.23 mmol) and methane iodide (14.9 µL, 0.238 mmol) were added and stirring was continued overnight. Dilute the reaction mixture 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 to 50% ethyl acetate in heptane) to give (( 2R , 4S , 5S )-2-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.18 minutes, (M+H) ⁺ =485 (Method A).

Synthesis of ((2R,4S,5S)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5062 ).

From ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -Methoxytetrahydro- 2H -pyran-4-yl)carbamic acid tert-butyl ester (69 mg, 0.142 mmol) starting as for (( 2S , 4R , 5S )-5-amine Base-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl )(( 2R , 4S , 5S )-4-amino-5-methoxytetrahydro- 2H -piran-2-yl)(( S )) as described for methanone ( compound 5043 ) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5062 ).

LCMS: 99%, RT=1.06 minutes, (M+H) ⁺ =385 (Method P). SFC: RT=3.97 minutes, (M+H) ⁺ =385 (Method AD). Example 46 Synthesis of ((2 R ,4 S ,5 S )-4-amino-5-ethoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5063)

Synthesis of ((2R,4S,5S)-5-ethoxy-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

From ((2 R ,4 S ,5 S )-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 Starting with tert-butyl -hydroxytetrahydro- 2H -piran-4-yl)carbamate (see compound 5052 , 70 mg, 0.149 mmol) and ethane iodide (19.0 µL, 0.238 mmol), as for ( (2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methyl Preparation of ( ( 2R ,4S , 5S ) -5 - ethoxy -2- (( S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.24 minutes, (M+H) ⁺ =485 (Method A).

Synthesis of ((2R,4S,5S)-4-amino-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5063 ).

From ((2 R ,4 S ,5 S )-5-ethoxy-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- Starting from tert-butyl 2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamate (69 mg, 0.142 mmol) as for (( 2S , 4R , 5S )-5-amine Base-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl )(( 2R , 4S , 5S )-4-amino-5-ethoxytetrahydro - 2H -pyran-2-yl)(( S ) - 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5063 ).

LCMS: 99%, RT=1.10 minutes, (M+H) ⁺ =399 (Method P). SFC: RT=3.91 minutes, (M+H) ⁺ =399 (Method F). Example 47 Synthesis of ((2 R ,4 S ,5 R )-5-amino-4-fluorotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5064)

Synthesis of ((3R,4S,6R)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydroisoquinoline-2-carbonyl Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

From ((3 R ,4 R ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 -Hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5057 , 114 mg, 0.242 mmol) starting as for (( 2R , 4S , 5R )-5 -Fluoro-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl ) tertiary butyl carbamate as described (see compound 5069 ) to prepare ((3 R ,4 S ,6 R )-4-fluoro-6-(( S )-1-(4-fluorophenyl)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 95%, RT=2.19 minutes, (M+H) ⁺ =473 (Method A).

Synthesis of ((2R,4S,5R)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5064 ).

From ((3 R ,4 S ,6 R )-4-fluoro-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Starting with tert-butylcarbonyltetrahydro- 2H -piran-3-yl)carbamate (50 mg, 0.106 mmol), methanol, and dichloromethane (to dissolve the starting material), as for ((2 S ,4 R ,5 S )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydro Preparation of ((2 R ,4 S , 5 R )-5-amino-4-fluorotetrahydro-2 H -pyran as described for isoquinolin-2(1 H )-yl)methanone ( compound 5043 ) -2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5064 ) and via flash column Purification by chromatography (silica, 0 to 2% (7 M ammonia in methanol)/dichloromethane).

LCMS: 98%, RT=1.04 minutes, (M+H) ⁺ =373 (Method P). SFC: RT=3.43 minutes, (M+H) ⁺ =373 (Method AD). Example 48 Synthesis of ((2 R ,4 R ,5 S )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5065)

Synthesis of ((2R,4R,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5065 ).

From ((3 S ,4 R ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 -Hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5052 , 50 mg, 0.106 mmol) starting as for (( 2S , 4R , 5S )-5 -Amino-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) (( 2R , 4R , 5S )-5-amino-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )) as described for methanone ( compound 5043 ) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5065 ).

LCMS: 99%, RT=1.00 min, (M+H) ⁺ =371 (Method P). SFC: RT=4.70 minutes, (M+H) ⁺ =371 (Method F). Example 49 Synthesis of (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 S ,4 R )-4-((2 -Hydroxyethyl)amino)tetrahydrofuran-2-yl)methanone (compound 5066) and (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)((2 S ,4 S )-4-((2-hydroxyethyl)amino)tetrahydrofuran-2-yl)methanone (compound 5067)

Synthesis of ((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-hydroxyethyl)amino)tetrahydrofuran-2-yl)methanone ( compound 5067 ).

Under nitrogen atmosphere, to ( S )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3 To a solution of ( 2H )-ketone (see compound 5004 , 150 mg, 0.442 mmol) in ethanol (anhydrous, 3.0 mL) was added ethanolamine (0.029 mL, 0.486 mmol). After 3.5 hours, _NaBH4 (21.74 mg, 0.575 mmol) was added and stirring was continued for a further 1.5 hours. Dilute the reaction mixture with water (1 mL), ethyl acetate (15 mL), and brine (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic phases were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 1 to 7% (7M ammonia in methanol)/dichloromethane). The product (109 mg) was combined with the product of a similar reaction (64 mg) and purified by preparative chiral SFC (Method BN) after lyophilization from a mixture of water and acetonitrile (1:3, 3 mL). Obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 S ,4 R )-4-((2-hydroxy Ethyl)amino)tetrahydrofuran-2-yl)methanone ( compound 5066 ) was used as the first soluble isomer, and after lyophilization from a mixture of water and acetonitrile (1:3, 3 mL), (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 S ,4 S )-4-((2-hydroxyethyl) Amino)tetrahydrofuran-2-yl)methanone ( compound 506 7 ) as the second eluted isomer.

First eluted isomer: LCMS: 96%, RT=1.00 min, (M+H) ⁺ =385 (Method P). SFC: RT=3.73 minutes, (M+H) ⁺ =385 (Method AD).

Second eluted isomer: LCMS: 97%, RT=1.01 min, (M+H) ⁺ =385 (Method P). SFC: RT=4.31 minutes, (M+H) ⁺ =385 (Method AD). Example 50 Synthesis of ((2 S ,4 R ,5 S )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5068)

Synthesis of ((2S,4R,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5068 ).

From ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3 Starting from ,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5072 , 75 mg, 0.212 mmol), as for ((2 S ,4 R ,5 R )-5-amine Base-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl ) (( 2S , 4R , 5S )-4-amino-5-hydroxytetrahydro- 2H -pyran-2-yl)(( S ) - 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5068 ) without additional purification by preparative chiral SFC.

LCMS: 98%, RT=1.03 minutes, (M+H) ⁺ =371 (Method P). SFC: RT=3.65 minutes, (M+H) ⁺ =371 (Method W). Example 51 Synthesis of ((2 R ,4 S ,5 R )-4-amino-5-fluorotetrahydro-2 H -piran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5069)

Synthesis of ((2R,4S,5R)-5-fluoro-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydroisoquinoline-2-carbonyl Hydrogen-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

In a microwave vial under an argon atmosphere, add ((2 R ,4 S ,5 S )-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)-5-hydroxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5052 , 100 mg, 0.213 mmol) and triethylamine (0.196 mL, To a solution of 1.407 mmol) in anhydrous acetonitrile (1.5 mL), triethylamine trihydrofluoride (0.076 mL, 0.468 mmol) and perfluoro-1-butylsulfonyl fluoride (0.084 mL, 0.468 mmol) were added. The vial was sealed, transferred to a preheated 60°C oil bath, and stirred for 3.5 hours. After the mixture was cooled to room temperature, it was poured into a mixture of saturated _aqueous NaHCO and ice (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined phases were dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 0 to 35% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-5-fluoro-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester .

LCMS: 99%, RT=2.18 minutes, (M+H) ⁺ =473 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5069 ).

From ((2 R ,4 S ,5 R )-5-fluoro-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Starting from tert-butylcarbonyltetrahydro- 2H -pyran-4-yl)carbamate (36 mg, 0.076 mmol), as for (( 2S , 4R , 5S )-5-amino- 4-Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl ((2 R ,4 S , 5 R ) -4 -amino-5-fluorotetrahydro-2 H -piran-2-yl)(( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5069 ).

LCMS: 99%, RT=1.07 minutes, (M+H) ⁺ =373 (Method P). SFC: RT=3.15 minutes, (M+H) ⁺ =373 (method AD). Example 52 Synthesis of ((2 R ,4 S ,5 S )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5070)

Synthesis of ((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-dihydroisoquinolin-2(1H)-yl)methanone.

To (( R )-3,6-dihydro-2 H -piran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( To a mixture of 1 H )-yl)methanone (see compound 5053 , 2.8 g, 8.30 mmol) and NaHCO ₃ (2.091 g, 24.90 mmol) in dichloromethane (50 mL), m-chloroperbenzoic acid (50 mL) was added portionwise. 70%, 4.09 g, 16.60 mmol). After the mixture was stirred for 3 days, it was diluted with dichloromethane (300 mL) and washed with saturated _aqueous NaHCO solution. The aqueous phase was extracted with dichloromethane, and the combined organic layers were washed with saturated aqueous _NaHCO3 solution and brine, dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give ((1 R ,4 R ,6 S )-3,7-dioxabis Cycl[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone is used as the One soluble isomer and ((1 S ,4 R ,6 R )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone as the second eluted isomer.

First eluted isomer: LCMS: 88%, RT=2.01 min, (M+H) ⁺ =354 (Method A).

Second eluted isomer: LCMS: 95%, RT=1.96 min, (M+H) ⁺ =354 (Method A).

Synthesis of ((2R,4S,5S)-5-amino-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5070 ).

To ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3 ,4-Dihydroisoquinolin-2(1 H )-yl)methanone (302 mg, 0.855 mmol) in ethanol (12 mL) was added ammonia (32% in water, 517 µL, 8.55 mmol) And the mixture was stirred at 60°C overnight. The reaction mixture was concentrated to dryness under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 10% A; t=16 minutes 50% A; t=17 minutes 100%; t=22 minutes 100% A; The residue was purified by preparative chiral SFC (Measurement: 220 nm) and preparative chiral SFC (Method AN), and after lyophilization from a mixture of acetonitrile and water (1:1), ((2 R , 4 S , 5 S )-5 was obtained -Amino-4-hydroxytetrahydro-2H-pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )- base) methanone ( compound 5070 ).

LCMS: 99%, RT=1.00 min, (M+H) ⁺ =371 (Method P). SFC: RT=3.23 minutes, (M+H) ⁺ =371 (Method AD). Example 53 Synthesis of ((2 R ,4 S )-4-amino-4-(hydroxymethyl)tetrahydrofuran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)methanone (Compound 5071)

Synthesis of (3S,5R)-3-amino-5-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3 -Carbonitrile.

To ( R )-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dihydrofuran-3(2 H )- To a solution of the ketone (see compound 50004 , 104 mg, 0.306 mmol) in a mixture of methanol (extra dry, 2 mL) and ammonia-containing methanol (7 M, 2 mL) was added titanium tetraisopropoxide (0.109 mL, 0.368 mmol). After stirring for 4 hours, trimethylsilyl cyanide (0.041 mL, 0.306 mmol) was added and stirring was continued for 16 hours. The reaction mixture was diluted with saturated _aqueous NaHCO 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 to 100% ethyl acetate in heptane) to give ( 3S , 5R )-3-amino-5-(( S )- 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbonitrile as the first soluble isomer and (3 R ,5 R )- 3-Amino-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-3-carbonitrile as second elution isomers. The configuration of the tetrahydrofuran-amine stereocenter is arbitrarily specified.

First soluble isomer: LCMS: 98%, RT=1.87 minutes, (M+H) ⁺ =366 (Method A), SFC: 99%, RT=3.49 minutes, (M+H) ⁺ =366 (Method A) W).

Second soluble isomer: LCMS: 87%, RT=1.86 min, (M+H) ⁺ =366 (Method A). SFC: 99%, RT=4.06 minutes, (M+H) ⁺ =366 (Method W).

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

To (3 S ,5 R )-3-amino-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran -To a solution of 3-carbonitrile (78 mg, 0.213 mmol) in a mixture of methanol and water (1:1, 2 mL) was added sodium hydroxide (85 mg, 2.14 mmol) and the mixture was stirred at 65°C for 4 hours. The volatiles were removed under reduced pressure and aqueous HCl (1 M) was added until the pH was approximately 5. The mixture was extracted with ethyl acetate (4 mL) _, dried over _Na2SO4 and evaporated 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. The configuration of the tetrahydrofuran-amine stereocenter is arbitrarily specified.

LCMS: 89%, RT=1.72 minutes, (M+H) ⁺ =385 (Method A).

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

At 0°C, to (3 R ,5 R )-3-amino-5-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- To a solution of 2-carbonyl)tetrahydrofuran-3-carboxylic acid (45 mg, 0.117 mmol) in tetrahydrofuran (anhydrous, 4 mL) was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 0.293 mL, 0.293 mmol). After 4 hours, aqueous NaOH (3 M, 1 mL) was added and stirring was continued for 16 hours. The reaction mixture was saturated with _Na2CO3 , and _the product was extracted with ethyl acetate (10 mL). The organic layer was dried over _Na2SO4 and evaporated _under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 5% A; t=16 minutes 40% A; t=17 minutes 100%; t=22 minutes 100% A; (measurement: 220/216 nm) purified residue. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (3 M). 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 ((2 R ,4 S )-4-amino-4 -(Hydroxymethyl)tetrahydrofuran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5071 ). The configuration of the tetrahydrofuran-amine stereocenter is arbitrarily specified.

LCMS: 95%, RT=1.01 minutes, (M+H) ⁺ =371 (Method P). SFC: 97%, RT=3.45 minutes, (M+H) ⁺ =371 (Method W). Example 54 Synthesis of ((2 S ,4 R ,5 R )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5072)

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

From (( S )-3,6-dihydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( Starting from 1 H )-yl)methanone (2.71 g, 8.03 mmol) as for ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptane-4 -yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone and ((1 S ,4 R ,6 R ) -3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 ((1 S ,4 S ,6 R )-3,7-dioxabicyclo[4.1.0]heptan-4 - yl)(( S )-1 -(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone as the first soluble isomer on silica and ((1 R ,4 S , 6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline- 2(1 H )-yl)methanone as the second soluble isomer on silica.

First eluted isomer: LCMS: 84%, RT=2.00 min, (M+H) ⁺ =354 (Method A).

Second soluble isomer: LCMS: 96%, RT=1.97 min, (M+H) ⁺ =354 (Method A).

Synthesis of ((2 S ,4 R ,5 R )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5072 ).

((1 S ,4 S ,6 R )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3 ,4-Dihydroisoquinolin-2(1 H )-yl)methanone (200 mg, 0.447 mmol) was dissolved in ammonia (7 M in methanol, 10 mL, 70 mmol). The reaction vial was sealed and warmed 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 to 8% (7M ammonia in methanol)/dichloromethane) and part of the product (45 mg of 145 mg) was dissolved in methanol. Introduce onto SCX-2 column (6 g) and elute with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The product (35 mg) was combined with a similarly prepared batch (53 mg) and purified by preparative chiral SFC (Method AN) after lyophilization from a mixture of acetonitrile and water (1:3, 3 mL) , obtaining ((2 S ,4 R ,5 R )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5072 ).

LCMS: 98%, RT=1.01 min, (M+H) ⁺ =371 (Method P). SFC: RT=3.35 minutes, (M+H) ⁺ =371 (Method AD). Example 55 Synthesis of ((2 R , 4 R , 5 R )-4-amino-5-methoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorobenzene) methyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone (compound 5073)

Synthesis of ((2R,4R,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxy Tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

From ((2 R ,4 R ,5 R )-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -Hydroxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5052 , 35 mg, 0.074 mmol) starting as for (( 2R , 4S , 5S )-2 -(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro- 2H -piran-4 ( ( 2 R ,4 R ,5 R )-2-(( S )-1-(4-fluorophenyl) -1,2 ,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 95%, RT=2.15 minutes, (M+Na) ⁺ =507 (Method A).

Synthesis of ((2R,4R,5R)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5073 ).

From ((2 R ,4 R ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -Methoxytetrahydro- 2H -pyran-4-yl)carbamic acid tert-butyl ester (34 mg, 0.070 mmol) starting as for (( 2S , 4R , 5S )-5-amine Base-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl )(( 2R , 4R , 5R )-4-amino-5-methoxytetrahydro- 2H -pyran-2-yl)(( S )) as described for methanone ( compound 5043 ) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5073 ).

LCMS: 99%, RT=1.05 minutes, (M+H) ⁺ =385 (Method P). Example 56 Synthesis of ((2 R ,4 R ,5 R )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5074)

Synthesis of ((2R,4R,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5074 ).

From ((2 R ,4 R ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -Hydroxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5052 , 22 mg, 0.047 mmol) starting as for (( 2S , 4R , 5S )-5 -Amino-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) (( 2R , 4R , 5R )-4-amino-5-hydroxytetrahydro- 2H -pyran-2-yl)(( S )) as described for methanone ( compound 5043 ) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5074 ).

LCMS: 99%, RT=1.00 min, (M+H) ⁺ =371 (Method P). Example 57 Synthesis of ((2 R ,4 R )-4-aminotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1 H )-yl)methanone (compound 5028) and ((2 R ,4 S )-4-aminotetrahydro-2 H -piran-2-yl) (( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5080)

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

To ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (2.5 g, 11.00 mmol) and glycolic acid (0.725 mL, 12.10 mmol) were dissolved in dichloromethane ( 20 mL), add N- (3-dimethylaminopropyl) -N′ -carbodiimide hydrochloride (2.320 g, 12.10 mmol) and 1-hydroxy-7-azepine Triazole (0.150 g, 1.100 mmol). After 2 hours, the mixture was diluted with water and the layers separated on a phase separation filter. The organic layer was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 10 to 60% ethyl acetate in heptane) to give ( S )-1-(1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1 H )-yl)-2-hydroxyethan-1-one.

LCMS: 99%, RT=1.90 minutes, (M+H) ⁺ =286 (Method A).

Synthesis of (S)-2-(1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-side oxyacetaldehyde.

To a solution of oxalate chloride (0.685 mL, 7.98 mmol) in dichloromethane (anhydrous, 7.5 mL) at -78°C under a nitrogen atmosphere, dimethylsulfoxide (0.850 mL, 11.97 mmol) was added dropwise. solution in dichloromethane (15.0 mL). After 20 minutes, ( S )-1-(1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)-2-hydroxyethane-1 was added dropwise - A solution of ketone (1.138 g, 3.99 mmol) in dichloromethane (7.5 mL) and after a further 30 min, triethylamine (2.77 mL, 19.94 mmol) was added. After 30 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was partitioned between water (50 mL) and dichloromethane (50 mL), and the aqueous phase was extracted with dichloromethane (15 mL). The combined _organic phases were washed with brine (30 mL), dried over _Na2SO4 and evaporated under reduced pressure. By alkaline 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=18 min 100% A ; t=23 minutes 100% A; detection: 220 nm) Purify part of the residue, and after lyophilizing the product containing the eluate, obtain ( S )-2-(1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)-2-pentanoxyacetaldehyde.

LCMS: 97%, RT=1.93 min, (M+H ₂ O (ketone hydrate)+H) ⁺ =302 (Method B).

Synthesis of (R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H- Pyran-4-one.

In a microwave vial under nitrogen atmosphere, add ( S )-2-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)phenol (45.3 mg, 0.106 mmol) and triethylamine (0.015 mL, 0.106 mmol) in cyclopentyl methyl ether (8.0 mL) was added copper(II) trifluoromethanesulfonate (38.3 mg, 0.106 mmol) . The reaction vial was sealed with a septum and stirred for 1 hour. Add ( S )-2-(1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)-2-side oxyacetaldehyde (200 mg, 0.706 mmol ) and powdered 4Å molecular sieve (400 mg), and the reaction mixture was cooled to -18°C and stirred for 30 minutes. (E)-((4-methoxybut-1,3-dien-2-yl)oxy)trimethylsilane (0.241 mL, 1.235 mmol) was then 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 adding trifluoroacetic acid (0.135 mL, 1.765 mmol) dropwise. 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 pad of celite. The residue was rinsed with ethyl acetate (2 x 5 mL) and the combined filtrate was washed with saturated _{aqueous Na2CO3} (12.5 mL). The aqueous phase was extracted with ethyl acetate (12.5 mL). The combined organics were washed with brine (12.5 mL), dried over _Na2SO4 , and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to obtain a small amount of ( S )-2-(( S )-1-(4-fluorobenzene). (R ) -2-( (S ) - 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-2,3-dihydro- 4H -pyran-4-one.

LCMS: 95%, RT=1.99 minutes, (M+H) ⁺ =352 (Method A).

Synthesis of (R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-4H-piran-4- ketone.

To ( R )-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4 H -To a solution of -pyran-4-one (240 mg, 0.683 mmol) in 2,2,2-trifluoroethanol (7.5 mL) was added palladium on carbon (10 wt% with 50% water, 72.7 mg, 0.068 mmol ). The mixture was hydrogenated at room temperature and ambient pressure for 1 hour. The reaction mixture was filtered through nylon (0.45 µm filter) and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) and preparative chiral SFC (Method AM) to give ( R )-2-(( S ) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 4H -pyran-4-one.

LCMS: 99%, RT=2.01 minutes, (M+H) ⁺ =354 (Method A). SFC: RT=3.79 minutes, (M+H) ⁺ =354 (method AD)

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

To ( R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 4H -piran-4 -To a solution of ketone (120 mg, 0.340 mmol) in 2,2,2-trifluoroethanol (4.0 mL) was added ammonium acetate (262 mg, 3.40 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 hour, sodium cyanoborohydride (64.0 mg, 1.019 mmol) was added. After continuing to stir for 1 hour, the liquid was analyzed by acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 5% A; t=2 minutes 10% A; t=17 minutes 50% A; t= 18 min 100%; t=23 min 100% A; Detection: 220 nm) and preparative chiral SFC (Method AL) purified reaction mixture in a mixture of acetonitrile and water (3:2, 2.5 mL) After lyophilization, ((2 R ,4 R )-4-aminotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4- is obtained Dihydroisoquinolin-2(1 H )-yl)methanone (compound 5028 ) as the first eluting SFC isomer and ((2 R ,4 S )-4-aminotetrahydro-2 H -pyran -2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5080 ) as the second eluted SFC iso conformation.

Compound 5028 : LCMS: 99%, RT=1.06 min, (M+H) ⁺ =355 (Method P). SFC: RT=4.24 minutes, (M+H) ⁺ =355 (Method F).

Compound 5080 : LCMS: 99%, RT=1.04 min, (M+H) ⁺ =355 (Method P). SFC: RT=4.58 minutes, (M+H) ⁺ =355 (Method F). Example 58 Synthesis of ((2 S ,4 S )-4-aminotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1 H )-yl)methanone (compound 5027) and ((2 S ,4 R )-4-aminotetrahydro-2 H -piran-2-yl) (( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5081)

Synthesis of (S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4H- Pyran-4-one.

From ( R )-2-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)phenol (74.4 mg, 0.175 mmol) and ( S ) Starting from -2-(1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)-2-pentoxyacetaldehyde (330 mg, 1.165 mmol), For example, for ( R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro-4 H -pyran-4-one is as described (see compound 5028 ), prepared as ( R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro ( S )-2-((S)-1-(4-fluorophenyl ) -1 of a mixture of isoquinoline-2-carbonyl)-2,3-dihydro- 4H -piran-4-one ,2,3,4-Tetrahydroisoquinolin-2-carbonyl)-2,3-dihydro- 4H -pyran-4-one (207 mg).

LCMS: 98%, RT=1.98 minutes, (M+H) ⁺ =352 (Method A).

Synthesis of (S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-4H-piran-4- ketone.

Since it is related to ( R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2,3-dihydro- ( S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro , a mixture of 4H-pyran-4-one (205 mg, 0.583 mmol) Starting from isoquinolin-2-carbonyl)-2,3-dihydro- 4H -pyran-4-one, as for ( R )-2-(( S )-1-(4-fluorophenyl) Preparation of (S ) -2-( ( S ) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 4H -pyran-4-one.

LCMS: 99%, RT=2.00 minutes, (M+H) ⁺ =354 (Method A). SFC: RT=3.48 minutes, (M+H) ⁺ =354 (Method AD).

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

From ( S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 4H -piran-4 -ketone (80 mg, 0.226 mmol) starting as for ((2 R ,4 R )-4-aminotetrahydro-2 H -pyran-2-yl)(( S )-1-(4- ((2 S ,4 S)-4 - aminotetrahydro-2 was prepared as described for fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5028 ) H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5027 ) One soluble SFC isomer and ((2 S ,4 R )-4-aminotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5081 ) served as the second eluting SFC isomer.

Compound 5027 : LCMS: 99%, RT=1.06 min, (M+H) ⁺ =355 (Method P). SFC: RT=3.84 minutes, (M+H) ⁺ =355 (method AD).

Compound 5081 : LCMS: 99%, RT=1.04 min, (M+H) ⁺ =355 (Method P). SFC: RT=4.11 minutes, (M+H) ⁺ =355 (Method F). Example 59 Synthesis of Compound 5090 and Compound 5091

Step 1 : Add (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (470 mg, 1.6 mmol) in DMF (5 mL) at 0 °C. 4-(tertiary 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). The resulting reaction mixture was stirred at room temperature for 2 h, diluted with EA (10 mL) and washed with saturated _NH4Cl (2×10 mL), followed by brine (2×10 mL). The organic phase was dried over _Na2SO4 , filtered _and concentrated in vacuo. The residue was purified by preparative HPLC to give 2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4- Oxaazepan-4-carboxylic acid tertiary butyl ester.

LCMS: (M+H) ⁺ =455.1; Purity = 100% (214 nm); Retention time = 1.77 minutes. Method C1

Step 2 : Add HCl to the second Add 2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- to a round-bottomed flask containing a solution in alkane (4.0M, 10 mL). Carbonyl)-1,4-oxazepan-4-carboxylic acid tertiary butyl ester (320 mg, 0.70 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give a residue, which was purified by preparative HPLC to give ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)( 1,4-Oxaazepan-2-yl)methanone.

LCMS: (M+H) ⁺ =355.1; Purity = 100% (214 nm); Retention time = 1.47 minutes. Method C1

The diastereoisomers eluted with CO2/IPA (0.2% methanolic ammonia) = 50/50 were separated by chiral SFC on a Daicel® OZ column (20×250 mm, 10µm) to obtain compound 5091 and compound 5090 . The stereochemical designation of the 1-position (S) of tetrahydroisoquinoline is based on enantiomerically pure starting materials; the configuration of the chiral center on the 7-membered ring is arbitrarily assigned.

Compound 5090 : LCMS: (M+H) ⁺ =355.0, purity = 100% (214 nm); retention time = 1.74 minutes. Method C1. Chiral SFC: CO ₂ /MeOH 0.2%MA=60/40, on Daicel® OZ column (4.6×100mm, 3um), residence time = 2.009 minutes, 100% ee.

Compound 5091 : LCMS: (M+H) ⁺ =355.0; Purity=100% (214 nm); Retention Time=1.73 minutes. Method C1. Chiral SFC: CO ₂ /MeOH 0.2%MA=60/40, on Daicel® OZ column (4.6×100mm, 3um), residence time = 1.935 minutes, 100 % ee. Example 60

((2 R ,4 R ,5 S )-5-amino-4-fluorotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5075)

Synthesis of ((2R,4S,5S)-5-azido-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone.

To ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3 To a solution of 4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070 , 0.80 g, 2.264 mmol) in a mixture of methanol (100 mL) and water (12.5 mL), chlorine was added Ammonium chloride (0.605 g, 11.32 mmol) and sodium azide (1.472 g, 22.64 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 (2×). _The combined organics were washed with brine, dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 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(1 H )-yl)methanone.

LCMS: 92%, RT=2.04 minutes, (M+H) ⁺ =397 (Method A).

Synthesis of ((2R,4R,5S)-5-azido-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone.

Under an argon atmosphere, to ((2 R ,4 S ,5 S )-5-azido-4-hydroxytetrahydro-2 H -piran-2-yl) (( S )-1-(4 -Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (75 mg, 0.189 mmol) in acetonitrile (anhydrous, 2 mL) was added triethylamine ( 0.174 mL, 1.249 mmol), triethylamine trihydrofluoride (0.068 mL, 0.416 mmol) and perfluoro-1-butylsulfonate fluoride (0.075 mL, 0.416 mmol). The reaction mixture was warmed to 60°C and stirred for 2 hours. Subsequently, the mixture was allowed to cool to room temperature and stirred overnight. Add additional triethylamine (0.087 mL, 0.624 mmol), triethylamine trihydrofluoride (0.034 mL, 0.208 mmol), and perfluoro-1-butylsulfonate fluoride (0.037 mL, 0.208 mmol). The reaction mixture was warmed to 60°C and stirred for 2 hours. The reaction mixture was poured into ice-cold saturated aqueous _NaHCO solution, and the mixture was extracted with ethyl acetate (twice). The combined organic layers were dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give ((2 R , 4 R , 5 S )-5-azido-4- Fluorotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Purity 50%, 50 mg).

LCMS: 91%, RT=2.19 minutes, (M+H) ⁺ =399 (Method A). SFC: 50%, RT=2.10 minutes, (M+H) ⁺ =399 (method AD).

Synthesis of ((2R,4R,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5075 ).

((2 R ,4 R ,5 S )-5-azido-4 in the presence of palladium (10 wt% on carbon, 50% water, 26.7 mg, 0.013 mmol) and atmospheric hydrogen pressure -Fluorotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Purity 50%, 50 mg, 0.063 mmol) in methanol (extra dry, 5 mL) was hydrogenated. After 3 days, the reaction mixture was filtered and evaporated under reduced pressure. By alkaline 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) The residue was purified to obtain ((2 R , 4 R , 5 S )-5-amino-4-fluorotetrahydro-2 H -pyran-2 -yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5075 ).

LCMS: 97%, RT=1.22 minutes, (M+H) ⁺ =373 (Method P). SFC: 92%, RT=3.20 minutes, (M+H) ⁺ =373 (Method W). Example 61

((2 S ,4 R ,5 R )-5-amino-4-methyltetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5084) and ((2 S ,4 S ,5 R )-5-amino-4-methyltetrahydro-2 H -Pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5076)

Synthesis of ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-side oxytetrakis Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

At 0°C, to ((3 S ,4 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 A solution of -carbonyl)-4-hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5053, 200 mg, 0.409 mmol) in dichloromethane (anhydrous, 4.0 mL) Dess-Martin periodane (191 mg, 0.450 mmol) was added. The reaction mixture was stirred at room temperature overnight. Subsequently, the mixture was diluted with _a mixture of _NaHCO3 saturated aqueous solution and _{Na2S2O3 saturated} aqueous solution (1/1 (v/v), 5 mL) and stirred vigorously for 15 minutes. The mixture was further diluted with dichloromethane (10 mL) and a mixture of NaHCO ₃ saturated aqueous solution and Na ₂ S ₂ O ₃ saturated aqueous solution (1/1 (v/v), 5 mL), and the layers were separated. Extract the aqueous layer with dichloromethane (5 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 1 to 35% ethyl acetate in heptane) to give ((3 S ,6 S )-6-(( S )-1-(4 -Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-side oxytetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 83%, RT=2.16 minutes, (M+Na) ⁺ =491 and 16% hydrated product, RT=2.03 minutes, (M+Na) ⁺ =509 (Method A).

Synthesis of ((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methylenetetrakis Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester

To a suspension of methyltriphenylphosphonium bromide (176 mg, 0.493 mmol) in tetrahydrofuran (anhydrous, 2.4 mL) was added potassium tert. butoxide (1.0 M solution in tert. butanol) at 0 °C. , 0.423 mL, 0.423 mmol). After 30 minutes, ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl was added dropwise )-4-Pendantoxytetrahydro- 2H -piran-3-yl)carbamate tertiary butyl ester (165 mg, 0.352 mmol) in tetrahydrofuran (anhydrous, 1.2 mL), and the mixture was stirred 75 minute. Subsequently, the reaction mixture was 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 to 45% ethyl acetate in heptane) to give ((3 R ,6 S )- 6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methyltetrahydro- 2H -piran- 3-yl)tertiary butyl carbamate.

LCMS: 93%, RT=2.20 minutes, (M+H) ⁺ =467 (Method A).

Synthesis of ((3R,4R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methyl Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl tertiary butyl ester and ((3R,4S,6S)-6-((S)-1-(4-fluorophenyl)-1 , 2,3,4-Tetrahydroisoquinoline-2-carbonyl)-4-methyltetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

((3 R ,6 S )-6-(( S )-1-( 4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methyltetrahydro- 2H -pyran-3-yl)carbamate (133 mg, 0.285 mmol) in ethanol (2.0 mL) was hydrogenated. 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 to 35% ethyl acetate in heptane) to give (( 3R , 4R , 6S )-6-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methyltetrahydro- 2H -piran-3-yl)carbamic acid tert-butyl Ester as the first soluble isomer and ((3 R ,4 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)-4-methyltetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester was used as the second eluted isomer.

First eluted isomer: LCMS: 99%, RT=2.26 minutes, (M+H) ⁺ =469 (Method A).

Second eluted isomer: LCMS: 97%, RT=2.20 min, (M+H) ⁺ =469 (Method A).

Synthesis of ((2S,4R,5R)-5-amino-4-methyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5084 ).

To ((3 R ,4 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 To a solution of -methyltetrahydro- 2H -pyran-3-yl)carbamic acid tert-butyl ester (9.0 mg, 0.019 mmol) in 2-propanol (0.2 mL) was added HCl (5-6 M in 2-propanol, 83 µL, 0.46 mmol) and stir for 24 hours. Dilute _the reaction mixture with dichloromethane (2 mL) and saturated aqueous _Na2CO3 solution (1 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2×2 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The basic fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ((2 S , 4 R , 5 R )-5-amino- 4-Methyltetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methyl ketone ( compound 5084 ).

LCMS: 99%, RT=1.06 minutes, (M+H) ⁺ =369 (Method P). SFC: RT=3.76 minutes, (M+H) ⁺ =369 (Method W).

Synthesis of ((2S,4S,5R)-5-amino-4-methyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5076 ).

At 0°C, to ((3 R ,4 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 To tert-butyl -carbonyl)-4-methyltetrahydro- 2H -pyran-3-yl)carbamate (44.0 mg, 0.094 mmol) was added HCl (5-6 M in 2-propanol, 0.854 mL, 4.70 mmol). After 5 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. Dilute the reaction mixture with dichloromethane (7 mL) and saturated aqueous _Na2CO3 solution ₍ 4 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2×3 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (6 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ((2 S , 4 S , 5 R )-5-amino-4 -Methyltetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methyl Ketone (compound 5076 ).

LCMS: 99%, RT=1.06 minutes, (M+H) ⁺ =369 (Method P). SFC: RT=3.79 minutes, (M+H) ⁺ =369 (Method W). Example 62

((2 R ,4 S ,5 R )-4-amino-5-methoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5077)

Synthesis of ((2R,4S,5R)-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone.

To ((1 S ,4 R ,6 R )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3 To a solution of ,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 0.427 g, 1.208 mmol) in a mixture of methanol (50 mL) and water (6.25 mL), chlorine was added Ammonium chloride (0.103 g, 6.04 mmol) and sodium azide (0.786 g, 12.1 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 (2×). _The combined organics were washed with brine, dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 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(1 H )-yl)methanone.

LCMS: 100%, RT=2.04 minutes, (M+H) ⁺ =397 (Method A).

Synthesis of ((2R,4S,5R)-4-azido-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1H)-yl)methanone.

Under an argon atmosphere, to ((2 R ,4 S ,5 R )-4-azido-5-hydroxytetrahydro-2 H -piran-2-yl) (( S )-1-(4 -Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (70 mg, 0.177 mmol) in tetrahydrofuran (anhydrous, 6 mL) was added sodium hydride (60 % dispersion in oil, 17.7 mg, 0.443 mmol), followed by methyl iodide (22.1 µL, 0.354 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with aqueous KHSO ₄ solution (0.1 M) and extracted with ethyl acetate (twice). The combined organic layers were dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 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)methyl ketone.

LCMS: 99%, RT=2.18 minutes, (M+H) ⁺ =411 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5077 ).

((2 R ,4 S ,5 R )-4-azido-5 in the presence of palladium (10 wt% on carbon, 50% water, 26.8 mg, 0.013 mmol) and atmospheric hydrogen pressure -Methoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) A solution of methanone (51.7 mg, 0.126 mmol) in methanol (extra dry, 5 mL) was hydrogenated. After 3 days, the reaction mixture was filtered and evaporated under reduced pressure. By alkaline 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) The residue was purified to obtain ((2 R , 4 S , 5 R )-4-amino-5-methoxytetrahydro-2 H -pyran -2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5077 ).

LCMS: 99%, RT=1.25 minutes, (M+H) ⁺ =385 (Method P). Example 63

((2 R ,4 S ,5 R )-4-amino-5-ethoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5078)

Synthesis of ((2R,4S,5R)-4-azido-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone.

Under an argon atmosphere, to ((2 R ,4 S ,5 R )-4-azido-5-hydroxytetrahydro-2 H -piran-2-yl) (( S )-1-(4 -Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5077 , 50 mg, 0.126 mmol) in tetrahydrofuran (anhydrous, 4 mL) was added Sodium hydride (60% dispersion in oil, 12.6 mg, 0.315 mmol), followed by ethyl iodide (20 µL, 0.252 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. Subsequently, another portion of sodium hydride (60% dispersion in oil, 12.6 mg, 0.315 mmol) and ethyl iodide (20 µL, 0.252 mmol) were added and stirring was continued for a further 2 hours. The reaction mixture was diluted with aqueous KHSO ₄ solution (0.1 M) and extracted with ethyl acetate (twice). The combined organic layers were dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-4-azido-5- Ethoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone .

LCMS: 98%, RT=2.25 minutes, (M+H) ⁺ =425 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5078 ).

((2 R ,4 S ,5 R )-4-azido-5 in the presence of palladium (10 wt% on carbon, 50% water, 26.8 mg, 0.013 mmol) and atmospheric hydrogen pressure -Ethoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methane A solution of the ketone (53 mg, 0.126 mmol) in methanol (extra dry, 5 mL) was hydrogenated. After 3 days, the reaction mixture was filtered and evaporated under reduced pressure. By alkaline 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) The residue was purified to obtain ((2 R , 4 S , 5 R )-4-amino-5-ethoxytetrahydro-2 H -pyran- 2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5078 ).

LCMS: 99%, RT=1.21 minutes, (M+H) ⁺ =399 (Method P). Example 64

(3a S ,6 R ,7a S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro-2 H -pirano[4,3-d] Azol-2-one (compound 5079)

To ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of tert-butyl -hydroxytetrahydro- 2H -piran-4-yl)carbamate (see compound 5052, 300 mg, 0.638 mmol) in tetrahydrofuran (anhydrous, 15 mL) was added sodium hydride (in mineral 60 wt% dispersion in oil, 25.5 mg, 0.638 mmol) and the mixture was stirred at 40°C overnight. Dilute the mixture with dichloromethane (25 mL) and saturated aqueous NH ₄ Cl solution (20 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2 x 25 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 40 to 100% ethyl acetate in heptane) to give ( 3aS , 6R , 7aS )-6-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro- 2H -pirano[4,3-d] Azol-2-one.

LCMS: 100%, RT=1.51 minutes, (M+H) ⁺ =397 (Method P). Example 65

((2 R ,4 S ,5 R )-5-amino-4-methoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5082)

Synthesis of ((3R,4S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methoxy Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

To ((3 R ,4 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 To a solution of tert-butyl -hydroxytetrahydro- 2H -piran-3-yl)carbamate (see compound 5052, 35 mg, 0.074 mmol) in toluene (3 mL) was added tetrabutylammonium hydrogen sulfate ( 7.3 mg, 0.022 mmol), followed by aqueous NaOH (50 wt%, 11.7 µL, 0.223 mmol) and methane iodide (21 µL, 0.335 mmol). After stirring for 3 days, additional amounts of aqueous NaOH (50 wt%, 11.7 µL, 0.223 mmol) and methane iodide (21 µL, 0.335 mmol) were added and stirring was continued for 7 days. Dilute the reaction mixture with dichloromethane (5 mL) and saturated _aqueous NaHCO (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 to 50% ethyl acetate in heptane) to give (( 3R , 4S , 6R )-6-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methoxytetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.24 minutes, (M+H) ⁺ =485 (Method A).

Synthesis of ((2R,4S,5R)-5-amino-4-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5082 ).

To ((3 R ,4 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 To a solution of tert-butyl-methoxytetrahydro- 2H -piran-3-yl)carbamate (34 mg, 0.070 mmol) in 2-propanol (2.0 mL) was added HCl (5-6 M in 2-propanol, 0.2 mL, 1.1 mmol). After 3 days, additional HCl (5-6 M in 2-propanol, 0.2 mL, 1.1 mmol) was added and stirring was continued for another 1 day. The reaction mixture was diluted with dichloromethane (10 mL) and neutralized with saturated _aqueous NaHCO solution. The _layers were separated and the organic phase was washed with brine, dried over _Na2SO4 and evaporated under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:3, 3 mL) to give ((2 R , 4 S , 5 R )-5-amino-4-methoxytetrahydro-2 H - Piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5082 ).

LCMS: 99%, RT=1.05 minutes, (M+H) ⁺ =385 (Method P). Example 66

((2 S ,4 S ,5 R )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5083)

Synthesis of ((2S,4S,5R)-4-azido-5-((trimethylsilyl)oxy)tetrahydro-2H-piran-2-yl)((S)-1-(4 -Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

To ( R , R ) -N , N ′-bis(3,5 di-tertiary butylsulfylidene)-1,2-cyclohexanediamine chromium(III) chloride (10.91 mg) under nitrogen atmosphere , 0.017 mmol) was added to a dark red suspension in diethyl ether (anhydrous, 1.2 mL) ((1 S ,4 S ,6 R )-3,7-dioxabicyclo[4.1.0]heptane- 4-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5072, 305 mg, 0.863 mmol) . After stirring the resulting thick orange suspension for 15 minutes, trimethylsilyl azide (0.127 mL, 0.906 mmol) was added. After stirring the reaction mixture overnight, another portion of trimethylsilyl azide (0.089 mL, 0.636 mmol) was added. Continue stirring for 5 days. The reaction mixture was concentrated under reduced pressure at room temperature. The residue was purified by flash column chromatography (silica, 6 to 16% ethyl acetate in heptane) to give (( 2S , 4S , 5R )-4-azido-5- ((Trimethylsilyl)oxy)tetrahydro-2 H -piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2 (1 H )-yl)methanone.

LCMS: 62%, RT=2.34 minutes, (M+H) ⁺ =469 and 38% TMS product, RT=2.00 minutes, (M+H) ⁺ =397 (Method A).

Synthesis of ((2S,4S,5R)-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone.

To ((2 S ,4 S ,5 R )-4-azido-5-((trimethylsilyl)oxy)tetrahydro-2 H -piran-2-yl)(( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (91.5 mg, 0.193 mmol) in methanol (3.0 mL) and water (0.375 mL) Potassium carbonate (80 mg, 0.578 mmol) was added to the solution in the mixture. 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 dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 15 to 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(1 H )-yl)methanone.

LCMS: 100%, RT=2.03 minutes, (M+H) ⁺ =397 (Method A).

Synthesis of ((2S,4S,5R)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5083 ).

((2 S ,4 S ,5 R )-4-azido-5 in the presence of palladium (10 wt% on carbon, 50% water, 14.35 mg, 6.74 µmol) and atmospheric hydrogen pressure -Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (27.0 mg, 0.067 mmol) in tetrahydrofuran (500 µL) was hydrogenated. 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) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (7 M). The basic fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ((2 S , 4 S , 5 R )-4-amino- 5-Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl Ketone ( compound 5083 ).

LCMS: 98%, RT=1.01 min, (M+H) ⁺ =371 (Method P). SFC: 100%, RT=3.77 minutes, (M+H) ⁺ =371 (method AD). Example 67

((2 S ,4 S ,5 R )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5085)

Synthesis of ((2R,4S,5R)-5-(dimethylamino)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5085 ).

To ((2 R ,4 S ,5 R )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3 To a solution of ,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5052, 60 mg, 0.162 mmol) in dichloromethane (1 mL) was added formaldehyde (37 wt in water % solution, stabilized with 10-15% methanol, 8.5 µL, 0.113 mmol), followed by sodium triacetyloxyborohydride (34.3 mg, 0.162 mmol). After 30 minutes, add another portion of formaldehyde (37 wt% solution in water, stabilized with 10-15% methanol, 0.037 mL, 0.486 mmol) and sodium triacetyloxyborohydride (103 mg, 0.486 mmol). After 15 minutes, the reaction mixture was partitioned between dichloromethane (5 mL) and _saturated aqueous NaHCO (5 mL). The organic layer was _separated , washed with brine (5 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was dissolved in methanol (2 mL), loaded onto an SCX-2 column and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:2, 3 mL) to obtain ((2 R , 4 S , 5 R )-5-(dimethyl methylamino)-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone ( compound 5085 ).

LCMS: 99%, RT=1.01 min, (M+H) ⁺ =399 (Method P). Example 68

((2 S ,4 R ,5 S )-5-amino-4-fluorotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5086)

Synthesis of ((2S,4R,5R)-4-fluoro-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1H)-yl)methanone.

In a microwave vial, add ((1 R ,4 S ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluoro To phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5072, 175 mg, 0.495 mmol) was added triethylamine trihydrofluoride (363 µL, 2.228 mmol ). The vials were capped and placed in a preheated 120°C sand bath. After 2.5 hours, the reaction mixture was diluted with ice-cold water (approximately 1 mL) and dichloromethane (2 mL), and then a saturated _aqueous NaHCO solution (4 mL) was slowly added. The mixture was further diluted with dichloromethane (10 mL) and saturated _aqueous NaHCO (2 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 15 to 55% ethyl acetate in heptanes) and preparative chiral SFC (Method Y) to give ((2 S , 4 R , 5 R )-4-fluoro-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone.

LCMS: 99%, RT=2.01 minutes, (M+H) ⁺ =374 (Method A).

Synthesis of trifluoromethanesulfonic acid (3R,4R,6S)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro-2H-pyran-3-yl ester.

To ((2 S ,4 R ,5 R )-4-fluoro-5-hydroxytetrahydro-2 H -piran-2-yl)(( S )-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (55.0 mg, 0.147 mmol) and pyridine (35.7 µL, 0.442 mmol) in dichloromethane (anhydrous , 750 µL), trifluoromethanesulfonic anhydride (36.7 µL, 0.221 mmol) was added dropwise. After 45 min, the reaction mixture was diluted with dichloromethane (6 mL) and washed with aqueous citric acid (0.5 M, 2 mL), saturated _aqueous NaHCO (2 mL), and brine (2 mL). The organic layer was dried over Na ₂ SO ₄ and evaporated under reduced pressure to give trifluoromethanesulfonic acid (3 R , 4 R , 6 S )-4-fluoro-6-(( S )-1 as an orange solid) -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl ester (76 mg) and was used as received.

LCMS: 99%, RT=2.28 minutes, (M+H) ⁺ =506 (Method A).

Synthesis of ((2S,4R,5S)-5-azido-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone.

Under an argon atmosphere, to trifluoromethanesulfonic acid (3 R ,4 R ,6 S )-4-fluoro-6-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl ester (74.5 mg, 0.147 mmol) in N , N -dimethylformamide (anhydrous, 750 µL) Tetrabutylammonium azide (46.1 mg, 0.162 mmol) was added to the solution and stirred overnight. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with a mixture of saturated aqueous NaHCO and brine (1:1, ₄ mL), and subsequently with brine (3 × 2 mL). The organic layer was dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 1 to 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.

LCMS: 100%, RT=2.16 minutes, (M+H) ⁺ =399 (Method A).

Synthesis of ((2S,4R,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5086 ).

((2 S ,4 R ,5 S )-5-azido-4 in the presence of palladium (10 wt% on carbon, 50% water, 24.5 mg, 0.011 mmol) and atmospheric hydrogen pressure -Fluorotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (46 mg, 0.115 mmol) in tetrahydrofuran (1 mL) was hydrogenated. 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) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water to obtain ((2 S , 4 R , 5 S )-5-amino-4-fluorotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5086 ).

LCMS: 99%, RT=1.04 minutes, (M+H) ⁺ =373 (Method P). SFC: RT=3.38 minutes, (M+H) ⁺ =373 (method AD). Example 69

((2 R ,4 S ,5 S )-4-amino-5-fluorotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5087)

Synthesis of ((2R,4S,5S)-4-azido-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone.

Under an argon atmosphere, to ((2 R ,4 S ,5 R )-4-azido-5-hydroxytetrahydro-2 H -piran-2-yl) (( S )-1-(4 -Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5077, 50 mg, 0.126 mmol) in acetonitrile (anhydrous, 2 mL) was added Triethylamine (0.116 mL, 0.832 mmol), triethylamine trihydrofluoride (0.045 mL, 0.277 mmol), and perfluoro-1-butylsulfonate fluoride (0.050 mL, 0.277 mmol). The reaction mixture was warmed to 50°C and stirred for 18 hours. Subsequently, the mixture was cooled to room temperature and additional triethylamine (0.058 mL, 0.416 mmol), triethylamine trihydrofluoride (0.023 mL, 0.139 mmol) and perfluoro-1-butylsulfonyl fluoride (0.025 mL, 0.139 mmol). The mixture was warmed to 50°C and stirred for 2 hours. The reaction mixture was poured into ice-cold saturated aqueous _NaHCO solution, and the mixture was extracted with ethyl acetate (twice). The combined organic layers were dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 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.

LCMS: 99%, RT=2.20 minutes, (M+H) ⁺ =399 (Method A).

Synthesis of ((2R,4S,5S)-4-amino-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5087 ).

((2 R ,4 S ,5 S )-4-azido-5 in the presence of palladium (10 wt% on carbon, 50% water, 25.1 mg, 0.012 mmol) and atmospheric hydrogen pressure -Fluorotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (38.7 mg, 0.063 mmol) in methanol (extra dry, 4 mL) was hydrogenated. After stirring overnight, the reaction mixture was filtered and evaporated under reduced pressure. The residue was purified by preparative LCMS (Method BU).

Obtain ((2 R ,4 S ,5 S )-4-amino-5-fluorotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5087 ).

LCMS: 99%, RT=1.57 minutes, (M+H) ⁺ =373 (Method Q). Example 70

((2 R ,4 S ,5 R )-5-amino-4-ethoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5088)

Synthesis of ((3R,4S,6R)-4-ethoxy-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

To ((3 R ,4 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4 To a solution of -hydroxytetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester (50 mg, 0.106 mmol) in toluene (4 mL) was added tetrabutylammonium hydrogen sulfate (10.5 mg, 0.031 mmol), followed by aqueous NaOH (50 wt%, 5.6 µL, 0.106 mmol) and ethane iodide (31 µL, 0.383 mmol). After stirring for 3 days, additional amounts of aqueous NaOH (50 wt%, 5.6 µL, 0.106 mmol) and ethane iodide (31 µL, 0.383 mmol) were added, and after a further 5 days aqueous NaOH (50 wt%, 22.4 µL, 0.425 mmol) and ethane iodide (92 µL, 1.15 mmol). After stirring for an additional 5 days, 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 to 50% ethyl acetate in heptane) to give (( 3R , 4S , 6R )-4-ethoxy-6- (( S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.27 minutes, (M+Na) ⁺ =521 (Method A).

Synthesis of ((2R,4S,5R)-5-amino-4-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5088 ).

To ((3 R ,4 S ,6 R )-4-ethoxy-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- To a solution of tertiary butyl 2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamate (38 mg, 0.076 mmol) in 2-propanol (1 mL) was added HCl (5-6 M in 2-propanol, 0.167 mL, 0.919 mmol) and stir overnight. Another portion of HCl (5-6 M in 2-propanol, 0.167 mL, 0.919 mmol) was added and stirring was continued for another day. Dilute the reaction mixture with dichloromethane (5 mL) and saturated _aqueous NaHCO (5 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3×10 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (7 M). The basic fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ((2 R , 4 S , 5 R )-5-amino- 4-Ethoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methyl ketone ( compound 5088 ).

LCMS: 100%, RT=1.09 minutes, (M+H) ⁺ =399 (Method P). Example 71

((2 R ,4 S ,5 R )-5-amino-4-(difluoromethoxy)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5089)

Synthesis of ((3R,4S,6R)-4-(difluoromethoxy)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

Under an argon atmosphere, a solution containing ((3 R ,4 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)-4-hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5052, 50 mg, 0.106 mmol) and copper(I) iodide (5.1 mg, 0.027 mmol) degassed acetonitrile (2 mL) was added to the vial. The suspension was heated to 50°C and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.033 mL, 0.319 mmol) in degassed acetonitrile (0.2 mL) was added portionwise over 2 hours. solution. After addition, continue heating for 30 minutes. The reaction mixture was diluted with dichloromethane (4 mL) and washed with saturated aqueous NaHCO ( ₃ 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 to 50% ethyl acetate in heptane) to give (( 3R , 4S , 6R )-4-(difluoromethoxy )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl) Tertiary butyl carbamate.

LCMS: 100%, RT=2.24 minutes, (M+H) ⁺ =521 (Method A).

Synthesis of ((2R,4S,5R)-5-amino-4-(difluoromethoxy)tetrahydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5089 ).

To ((3 R ,4 S ,6 R )-4-(difluoromethoxy)-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro To a solution of tertiary butyl isoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamate (19 mg, 0.036 mmol) in 2-propanol (2.0 mL) was added HCl ( 5-6 M in 2-propanol, 0.2 mL, 1.1 mmol). The mixture was stirred at room temperature for 5 days. The reaction mixture was diluted with dichloromethane (20 mL) and neutralized with saturated _aqueous NaHCO solution. The layers were separated by phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:2, 3 mL) to obtain ((2 R , 4 S , 5 R )-5-amino-4-(difluoromethoxy)tetrahydrogen -2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone ( Compound 5089 ) . LCMS: 97%, RT=1.09 minutes, (M+H) ⁺ =421 (Method P). Example 72

((2 R ,4 R ,5 S )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5092)

Synthesis of ((2R,4R,5S)-4-azido-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone.

To (1 S ,2 S )-(+)-[1,2-cyclohexanediamine- N , N '-bis(3,5-di-tertiary butylsulfenyl)] chromium(III) chloride ) (catalyst, 16.5 mg, 0.026 mmol) in diethyl ether (anhydrous, 2 mL) was added ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0 ]Heptan-4-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 230 mg , 0.651 mmol) in diethyl ether (anhydrous, 4 mL). After 15 minutes, trimethylsilyl azide (0.090 mL, 0.683 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give a mixture of the title compound and its regioisomers. This mixture was crystallized from methanol and the mother liquor was purified by preparative SFC (Method BR) to give (( 2R , 4R , 5S )-4-azido-5-hydroxytetrahydro- 2H -piper Pran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS SFC: RT=2.79 minutes, (M+H) ⁺ =396 (Method V).

Synthesis of ((2R,4R,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5092 ).

((2 R ,4 R ,5 S )-4-azido-5 in the presence of palladium (10 wt% on carbon, 50% water, 10.7 mg, 5 µmol) and atmospheric hydrogen pressure -Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (10 mg, 0.025 mmol) in methanol (extra dry, 2 mL) was hydrogenated. After 18 hours, the reaction mixture was filtered and evaporated under reduced pressure. The residue was purified by preparative LCMS (method BU) to give

((2R,4R,5S)-4-amino-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1H)-yl)methanone ( Compound 5092 ).

LCMS: 99%, RT=1.01 minutes, (M+H) ⁺ =371 (Method P). Example 73

((2 R ,5 R )-5-(bis(2-hydroxyethyl)amino)tetrahydro-2 H -pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5093)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-hydroxytetrahydro-2H-pyran -2-yl)methanone and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5R)-5-hydroxy Tetrahydro-2H-pyran-2-yl)methanone.

(( R )-3,4-dihydro-2 H -piran-2-yl) (( S )-1-(4-fluorophenyl)) was added via syringe under an argon atmosphere at 0°C. To a solution of -3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5213, 1.57 g, 4.65 mmol) in tetrahydrofuran (anhydrous, 20 mL) was added borane-methyl Thioether complex (2M, 2.91 mL, 5.82 mmol). After 1 hour, aqueous NaOH (1 M, 13.96 mL, 13.96 mmol) was slowly added, followed by aqueous hydrogen peroxide (30% (w/v), 2.377 mL, 23.27 mmol). After 30 minutes, the mixture was diluted with water and extracted with ethyl acetate (twice). The combined organic layers were _washed with brine, dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 30 to 100% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-hydroxytetrahydro-2 H -pyran-2-yl)methanone (first soluble isomer) and ( ( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 R )-5-hydroxytetrahydro-2 H - Piran-2-yl)methanone (second soluble isomer).

First soluble isomer: SFC: 99%, RT=2.99 minutes, (M+H) ⁺ =356 (Method AD).

Second soluble isomer: SFC: 60%, RT=3.51 minutes, (M+H) ⁺ =356 (Method AD).

Synthesis of methanesulfonic acid (3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H- Piran-3-yl ester.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 To a solution of S )-5-hydroxytetrahydro-2 H -pyran-2-yl)methanone (300 mg, 0.844 mmol) and triethylamine (0.235 mL, 1.688 mmol) in dichloromethane was added methane sulfonate Chloride (0.099 mL, 1.266 mmol). After 30 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. Additional triethylamine (0.082 mL, 0.591 mmol) and methanesulfonyl chloride (0.033 mL, 0.422 mmol) were added and the mixture was stirred for an additional 1 hour. Aqueous KHSO ₄ solution (1 M) was added and the layers were separated on a phase separation filter. The organic filtrate was concentrated under reduced pressure to obtain methanesulfonic acid (3 S , 6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)tetrahydro- 2H -pyran-3-yl ester.

LCMS: 95%, RT=2.07 minutes, (M+H) ⁺ =434 (Method A).

Synthesis of ((2R,5R)-5-azidotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2 (1H)-yl)methanone.

Methanesulfonic acid (3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- A solution of 2 H -pyran-3-yl ester (366 mg, 0.844 mmol) and sodium azide (165 mg, 2.53 mmol) in N , N -dimethylformamide was heated at 80°C with stirring. Overnight. Additional sodium azide (54.9 mg, 0.844 mmol) was added and heating was continued at 90°C for 6 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (twice). The combined organic layers were washed with brine (2×), dried _{over Na2SO4} and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 50% ethyl acetate in heptane) to give ((2 R ,5 R )-5- after co-evaporation from dichloromethane) Azidetetrahydro- 2H -piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone .

LCMS: 99%, RT=2.13 minutes, (M+H) ⁺ =381 (Method A).

Synthesis of ((2R,5R)-5-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2 (1H)-yl)methanone.

((2 R ,5 R )-5-tetrazide in the presence of palladium (10 wt% on carbon, 50% water, 150 mg, 0.070 mmol) at 45°C and atmospheric hydrogen pressure Hydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (222 mg , 0.584 mmol) in 2,2,2-trifluoroethanol (5 mL) was hydrogenated. After 1 hour, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give (( 2R , 5R )-5-aminotetrahydro- 2H -piran-2-yl)(( S )-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone was used as received.

LCMS: 96%, RT=1.63 minutes, (M+H) ⁺ =355 (Method A).

Synthesis of ((2R,5R)-5-(bis(2-((tertiary butyldimethylsilyl)oxy)ethyl)amino)tetrahydro-2H-piran-2-yl)(( S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

To ((2 R ,5 R )-5-aminotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquin To a solution of pholin-2(1 H )-yl)methanone (66 mg, 0.186 mmol) in dichloromethane (3 mL) was added (tertiary butyldimethylsiloxy)acetaldehyde (0.053 mL, 0.279 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 20 min. Sodium triacetylborohydride (59 mg, 0.279 mmol) was added and stirring continued for 1 hour. _Saturated aqueous NaHCO solution (5 mL) was added and the mixture was stirred for 15 min. Separate the layers on a phase separation filter. The organic filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica, 5 to 50% ethyl acetate in heptane) to obtain ((2 R ,5 R )-5- (bis(2-((tertiary butyldimethylsilyl)oxy)ethyl)amino)tetrahydro- 2H -piran-2-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 98%, RT=3.76 minutes, (M+H) ⁺ =672 (Method BV).

Synthesis of ((2R,5R)-5-(bis(2-hydroxyethyl)amino)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5093 ).

To ((2 R ,5 R )-5-(bis(2-((tertiary butyldimethylsilyl)oxy)ethyl)amino)tetrahydro- 2H -piran-2-yl )(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (44 mg, 0.066 mmol) in methanol (1 mL) Cesium fluoride (60 mg, 0.393 mmol) was added to the solution. The mixture was stirred at room temperature for 5 days and then at 40°C for 3 days. The mixture was introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((2 R ,5 R )-5-(bis(2-hydroxyethyl)amino)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5093 ).

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =443 (Method P). Example 74

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 R )-5-((2-methoxy Ethyl)amino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5212)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5R)-5-((2-methoxyethyl) yl)amino)tetrahydro-2H-pyran-2-yl)methanone ( compound 5212 ).

To ((2 R ,5 R )-5-aminotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquin To a suspension of pholin-2(1 H )-yl)methanone (see compound 5093, 40 mg, 0.113 mmol) and potassium carbonate (47 mg, 0.339 mmol) in acetonitrile (2 mL) was added 2-bromoethyl Methyl ether (0.021 mL, 0.226 mmol). The mixture was heated at 80°C for 6 hours. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 20% A; t=16 minutes 60% A; t=17 minutes 100%; t=22 minutes 100% A; detection Measurement: 214/264 nm) purified mixture. The product fractions were concentrated under reduced pressure. The residue was dissolved in methanol (5 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)((2 R ,5 R )-5-((2-methoxyethyl)amino)tetrahydro-2 H -pyran-2-yl)methanone ( compound 5212 ).

LCMS: 98%, RT=1.07 minutes, (M+H) ⁺ =413 (Method P). Example 75

((2 S ,4 S )-4-amino-2-methyltetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1 H )-yl)methanone (compound 5238) and ((2 S ,4 R )-4-amino-2-methyltetrahydro-2 H -piran-2- base)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5237)

Synthesis of 2-methyl-4-side oxytetrahydro-2H-pyran-2-carboxylic acid lithium salt.

A solution of 2-methyl-4-pendantoxytetrahydro- 2H -piran-2-carboxylic acid methyl ester (903 mg, 5.24 mmol) in tetrahydrofuran (30 mL) at 0°C over 1 hour Add aqueous LiOH solution (1.0 M, 4.98 mL, 4.98 mmol) dropwise. After 30 minutes, the reaction mixture was concentrated to dryness under reduced pressure to obtain lithium salt of 2-methyl-4-pentoxytetrahydro- 2H -pyran-2-carboxylate.

Synthesis of (R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2-methyltetrahydro-4H- Piran-4-one and (S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2-methyl Tetrahydro-4H-pyran-4-one.

To 2-Methyl-4-pendantoxytetrahydro- 2H -piran-2-carboxylic acid lithium salt (1.07 g, 6.55 mmol) in N,N -dimethylformamide (anhydrous, 12.5 mL) Hexafluorophosphoric acid 3-oxyl-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium (HATU, 3.11 g, 8.18 mmol), followed by triethylamine (1.36 mL, 9.82 mmol). After 10 minutes, ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (1.49 g, 6.55 mmol) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated _aqueous NaHCO (100 mL). Extract the aqueous layer with ethyl acetate (50 mL). The combined organics were washed with half-saturated brine (3 _x 25 mL) and brine (25 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) and the diastereoisomers separated by preparative SFC (Method BR) to give ( R ) -2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2-methyltetrahydro- 4H -piran- 4-one as the first soluble isomer on SFC and ( S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)-2-methyltetrahydro- 4H -pyran-4-one as the second eluted isomer on SFC. The stereochemistry of the pyran ring is arbitrary.

The first soluble isomer on SFC: LCMS: 99%, RT=2.08 minutes, (M+H) ⁺ =368 (Method A, 40°C). SFC: 99%, RT=1.93 minutes (there is a small plateau between peaks at 1.64 minutes), (M+H) ⁺ =368 (Method V).

Second soluble isomer on SFC: LCMS: 100%, RT=2.08 minutes, (M+H) ⁺ =368 (Method A, 40°C). SFC: 98%, RT=2.31 minutes, (M+H) ⁺ =368 (Method V).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-4-(hydroxyimino)-2-methyl Tetrahydro-2H-pyran-2-yl)methanone.

To a suspension of hydroxylamine hydrochloride (76 mg, 1.09 mmol) and sodium acetate (89 mg, 1.09 mmol) in ethanol (anhydrous, 4.0 mL) was added ( S )-2-(( S )-1-( 4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2-methyltetrahydro- 4H -pyran-4-one (200 mg, 0.544 mmol). The reaction vial was sealed and heated at 50°C for 2 hours. After cooling to room temperature, the mixture was diluted with dichloromethane (15 mL) and washed with water (10 mL). The organic layer was passed through a phase separator and evaporated under reduced pressure to give (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( S )-4-(hydroxyimino)-2-methyltetrahydro- 2H -pyran-2-yl). The stereochemistry of the pyran ring is arbitrary.

LCMS: 99%, RT=2.03 minutes, (M+H) ⁺ =383 (Method A, 40°C).

Synthesis of ((2S,4S)-4-amino-2-methyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1H)-yl)methanone ( compound 5238 ) and ((2S,4R)-4-amino-2-methyltetrahydro-2H-piran-2-yl)((S) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5237 ).

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( S )-4-(hydroxyimine) in an autoclave To a stirred solution of (148 mg , 0.387 mmol)-2-methyltetrahydro-2H-piran-2-yl)methanone (148 mg, 0.387 mmol) in methanol (10 mL) was added 50% Raney nickel ®-Nickel) in water (0.50 mL). The reaction mixture was stirred under hydrogen atmosphere (3 bar) for 1.5 hours. The reaction mixture was diluted with methanol (10 mL) and filtered through a nylon filter. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 5% (7M NH in _methanol )/dichloromethane) and the diastereomers separated by preparative SFC (Method BS) , after freeze-drying both from a mixture of acetonitrile and water (1:1, 4 mL), gave ((2 S ,4 S )-4-amino-2-methyltetrahydro-2 H -pyran- 2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5238 ) as the first elution on SFC Isomers, and ((2 S ,4 R )-4-amino-2-methyltetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5237 ) (second soluble isomer on SFC). The stereochemistry of the pyran ring is arbitrary.

Compound 5238 : LCMS: 99%, RT=2.77 min, (M+H) ⁺ =369 (Method AK, 40°C). SFC: 99%, RT=2.39 minutes, (M+H) ⁺ =369 (Method AS).

Compound 5237 : LCMS: 98%, RT=2.78 min, (M+H) ⁺ =369 (Method AK, 40°C). SFC: 95%, RT=2.59 minutes. (M+H) ⁺ =369 (Method AS). Example 76

((2 R ,4 S )-4-amino-2-methyltetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1 H )-yl)methanone (compound 5235) and ((2 R ,4 R )-4-amino-2-methyltetrahydro-2 H -piran-2- base)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5236)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-(hydroxyimino)-2-methyl Tetrahydro-2H-pyran-2-yl)methanone.

From ( R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-2-methyltetrahydro-4 H -pyran-4-one (see compound 5238 , 200 mg, 0.544 mmol) starting as for (( S )-4-(hydroxyimino)-2-methyltetrahydro- 2H -pyran- 2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H ) -yl ) methanone was prepared (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( R )-4-(hydroxyimino)-2-methyltetrakis Hydrogen- 2H -pyran-2-yl).

LCMS: 99%, RT=2.03 minutes, (M+H) ⁺ =383 (Method A, 40°C).

Synthesis of ((2R,4S)-4-amino-2-methyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1H)-yl)methanone ( compound 5235 ) and ((2R,4R)-4-amino-2-methyltetrahydro-2H-piran-2-yl) ((S) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5236 ).

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( R )-4-(hydroxyimino)-2- Starting from methyltetrahydro- 2H -pyran-2-yl)methanone (134 mg, 0.350 mmol), as for (( 2S , 4S )-4-amino-2-methyltetrahydro- 2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5238 ) Description, preparation of ((2 R ,4 S )-4-amino-2-methyltetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5235 ) as the first eluted SFC (BEH column) isomer and ((2 R ,4 R )-4-amino -2-Methyltetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl ) methanone ( compound 5236 ) as the second eluting SFC (BEH column) isomer and purified by preparative chiral SFC (methods BS and BT). The stereochemistry of the pyran ring is arbitrary.

Compound 5235 : white solid; LCMS: 99%, RT=2.82 min, (M+H) ⁺ =369 (Method AK, 40°C). SFC: 97%, RT=4.36 minutes, (M+H) ⁺ =369 (Method F).

Compound 5236 : white solid. LCMS: 99%, RT=2.78 minutes, (M+H) ⁺ =369 (Method AK, 40°C). SFC: 99%, RT=4.07 minutes, (M+H) ⁺ =369 (Method F). Example 77

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 R )-5-((2-hydroxyethyl) yl)amino)tetrahydro- 2H -pyran-2-yl)methanone (compound 5211)

Synthesis of formic acid ((2R,5R)-5-((2-((tertiary butyldimethylsilyl)oxy)ethyl)amine)tetrahydro-2H-piran-2-yl)(( S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ester.

To ((2 R ,5 R )-5-aminotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquin To a suspension of pholin-2(1 H )-yl)methanone (see compound 5093, 50 mg, 0.141 mmol) and potassium carbonate (59 mg, 0.423 mmol) in acetonitrile (2 mL) was added (2-bromoethyl Oxy)-tertiary butyldimethylsilane (0.061 mL, 0.282 mmol). The mixture was heated at 80°C for 20 hours. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 20% A; t=16 minutes 60% A; t=17 minutes 100%; t=22 minutes 100% A; detection Measurement: 214/264 nm) purified mixture. Concentrate the product fraction under reduced pressure to obtain formic acid ((2 R , 5 R )-5-((2-((tertiary butyldimethylsilyl)oxy)ethyl)amine in the form of a slurry) )tetrahydro-2H-pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ester ( 43 mg). LCMS: 81%, RT=1.94 minutes, (M+H) ⁺ =513 (Method B).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5R)-5-((2-hydroxyethyl) Amino)tetrahydro-2H-pyran-2-yl)methanone ( compound 5211 ).

Formic acid ((2 R ,5 R )-5-((2-((tertiary butyldimethylsilyl)oxy)ethyl)amino)tetrahydro- 2H -piran-2-yl )(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ester (43 mg, 0.077 mmol) was suspended in methanol (5 mL )middle. Cesium fluoride (50 mg, 0.329 mmol) was added and the mixture was heated at 45°C for 3 hours. The mixture was introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. By alkaline preparative MPLC (linear gradient: t=0 min 5% A; t=1 min 20% A; t=16 min 60% A; t=17 min 100% A; t=22 min 100% A ;Detection: 214/264 nm) purified residue. The product fractions were combined and concentrated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)((2 R ,5 R )-5-((2-hydroxyethyl)amino)tetrahydro-2H-pyran-2-yl)methanone ( compound 5211 ).

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =399 (Method P). Example 78

((2 S ,5 S )-5-amino-5-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5213) and ((2 S ,5 R )-5-amino-5-(hydroxymethyl)tetrahydro-2 H -Pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5214)

Synthesis of ((S)-3,4-dihydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H )-yl)methanone and ((R)-3,4-dihydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroiso Quinolin-2(1H)-yl)methanone.

To ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (2.154 g, 9.48 mmol) and 3,4-dihydro-2 H -pyran-2 -To a suspension of potassium carboxylate (1.5 g, 9.02 mmol) in a mixture of dichloromethane (30 mL) and N , N -dimethylformamide (anhydrous, 7.5 mL) was added N -(3- Dimethylaminopropyl) -N′ -carbodiimide hydrochloride (1.816 g, 9.48 mmol) and 1-hydroxy-7-azabenzotriazole (0.123 g, 0.902 mmol). After 20 hours, the reaction mixture was partially concentrated under reduced pressure. The residue was diluted with aqueous HCl (0.5 M, 50 mL) and extracted with ethyl acetate (250 mL). The organic layer was washed with water (50 mL) and saturated _aqueous NaHCO solution (50 mL), dried over _Na2SO4 and concentrated under reduced pressure to dryness _. The residue was purified by flash column chromatography (silica, 0 to 15% ethyl acetate in heptane) to give (( R )-3,4-dihydro- 2H -piran-2- base) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone as the first soluble isomer and (( S )- 3,4-Dihydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methyl ketone as the second soluble isomer.

First soluble isomer: LCMS: 99%, RT=2.14 minutes, (M+H) ⁺ =338 (Method A). SFC: 99%, RT=2.79 minutes, (M+H) ⁺ =338 (Method F).

Second soluble isomer: LCMS: 99%, RT=2.14 minutes, (M+H) ⁺ =338 (Method A). SFC: 99%, RT=2.61 minutes, (M+H) ⁺ =338 (Method F)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-5-nitro-3,4-dihydro- 2H-pyran-2-yl)methanone.

To (( S )-3,4-dihydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3, A solution of 4-dihydroisoquinolin-2(1 H )-yl)methanone (314 mg, 0.931 mmol) and tetrabutylammonium nitrate (312 mg, 1.024 mmol) in dichloromethane (5 mL) Add trifluoroacetic anhydride (0.142 mL, 1.024 mmol). The reaction mixture was allowed to reach room temperature and stirred for 3 hours. The reaction mixture was cooled to 0 °C and triethylamine (0.129 mL, 0.931 mmol) was added dropwise. After 15 minutes, the reaction mixture was diluted with ice/water (10 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 to 100% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)(( S )-5-nitro-3,4-dihydro-2 H -pyran-2-yl)methanone.

LCMS: 84%, RT=2.10 minutes, (M+H) ⁺ =383 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5R)-5-nitrotetrahydro-2H-piper Pyran-2-yl)methanone and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5S)-5- Nitrotetrahydro-2H-pyran-2-yl)methanone.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( S )-5-nitro-3,4-dihydro To a solution of -2H -pyran-2-yl)methanone (150 mg, 0.392 mmol) in a mixture of tetrahydrofuran (anhydrous, 10 mL) and methanol (anhydrous, 1 mL) was added sodium borohydride (18.6 mg, 0.490 mmol). After 1 hour, water (1 mL) was added and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (5 mL) and washed with brine (3 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)((2 S ,5 R )-5-nitrotetrahydro-2 H -pyran-2-yl)methanone as the first soluble isomer and ( ( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 S ,5 S )-5-nitrotetrahydro-2 H -pyran-2-yl)methanone as the second eluted isomer. Stereochemistry The 5-nitro-pyran stereocenter is arbitrarily assigned.

First eluted isomer: LCMS: 99%, RT=2.11 minutes, (M+H) ⁺ =385 (Method A).

Second eluted isomer: LCMS: 99%, RT=2.07 minutes, (M+H) ⁺ =385 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2S,5S)-5-(hydroxymethyl)-5- Nitrotetrahydro-2H-pyran-2-yl)methanone and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)( (2S,5R)-5-(hydroxymethyl)-5-nitrotetrahydro-2H-pyran-2-yl)methanone.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 S ,5 R )-5-nitrotetrahydro- 2 H -pyran-2-yl)methanone (37 mg, 0.096 mmol) and (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H ) A mixture of -yl)((2 S ,5 S )-5-nitrotetrahydro-2 H -pyran-2-yl)methanone (48 mg, 0.125 mmol) in acetonitrile (4 ml) Formaldehyde (37% wt solution in _H2O , 0.050 mL, 0.663 mmol) and triethylamine (0.031 mL, 0.221 mmol) were added. After 16 hours, the reaction mixture was concentrated under reduced pressure, and the residue was co-evaporated from methanol (2 mL). The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)((2 S ,5 R )-5-(hydroxymethyl)-5-nitrotetrahydro-2 H -pyran-2-yl)methanone as The first soluble isomer, and (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 S ,5 S )- 5-(hydroxymethyl)-5-nitrotetrahydro- 2H -pyran-2-yl)methanone as the second eluted isomer. Stereochemistry The 5-nitro-pyran stereocenter is arbitrarily assigned.

First eluted isomer: LCMS: 99%, RT=2.03 minutes, (M+H) ⁺ =415 (Method A).

Second soluble isomer (silica): LCMS: 99%, RT=1.99 minutes, (M+H) ⁺ =415 (Method A).

Synthesis of ((2S,5R)-5-amino-5-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5214 ).

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 S ,5 R )-5-(hydroxymethyl) To a solution of -5-nitrotetrahydro- 2H -pyran-2-yl)methanone (33 mg, 0.080 mmol) in methanol (6 mL) was added nickel(II) chloride hexahydrate (19.9 mg, 0.084 mmol). The reaction mixture was cooled to 0°C and sodium borohydride (26.3 mg, 0.695 mmol) was added in two portions. The mixture was then warmed to room temperature. After 2 hours water (1.5 mL) was added and stirring was continued for 30 minutes. The mixture was diluted with methanol (5 mL) and filtered on a nylon 0.45 µm filter. Rinse the filter with a mixture of methanol and dichloromethane (1:1, 2 × 5 mL). The combined filtrates were concentrated to dryness under reduced pressure. The residue was stirred in a mixture of dichloromethane (5 mL) and water (2 mL) for 5 min. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. By alkaline preparative MPLC (linear gradient: t=0 min 5% A; t=1 min 5% A; t=16 min 60% A; t=17 min 100% A; t=22 min 100% A ; Detection: 251/210nm) purify the residue, and freeze-dry the product containing the eluate from a mixture of acetonitrile and water (1:1, 6 mL) to obtain ((2 S ,5 R )-5-amino -5-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone ( compound 5214 ). Stereochemistry The 5-amino-pyran stereocenter is arbitrarily assigned.

LCMS: 99%, RT=1.01 min, (M+H) ⁺ =385 (Method P). SFC: 99%, RT=4.70 minutes, (M+H) ⁺ =385 (Method F).

Synthesis of ((2S,5S)-5-amino-5-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5213 ).

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 S ,5 S )-5-(hydroxymethyl) Starting from -5-nitrotetrahydro- 2H -pyran-2-yl)methanone (36 mg, 0.087 mmol), as for (( 2S , 5R )-5-amino-5-(hydroxy Methyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl ((2 S ,5 S )-5 - amino-5-(hydroxymethyl)tetrahydro-2 H -pyran - 2-yl)(( S )-1 -(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5213 ). Stereochemistry The 5-amino-pyran stereocenter is arbitrarily assigned.

LCMS: 99%, RT=1.02 minutes, (M+H) ⁺ =385 (Method P). SFC: 99%, RT=4.35 minutes, (M+H) ⁺ =385 (Method F). Example 79

((6 S ,7 S )-6-fluoro-1,4-oxazepan-7-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1H)-yl)methanone (compound 5418) and ((2 R ,3 R )-3-(fluoromethyl) Phin-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5420)

Synthesis of (6S,7S)-6-fluoro-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4 -Oxaazepine-4-carboxylic acid tertiary butyl ester and tertiary butyl ((2R,3R)-3-(fluoromethyl) Phin-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

At 0°C, to (6 S ,7 R )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)- To a solution of 6-hydroxy-1,4-oxazepan-4-carboxylic acid tertiary butyl ester (see compound 5243, 118 mg, 0.251 mmol) in dichloromethane (2 mL) was added Deoxofluor ( 0.102 mL, 0.276 mmol). The reaction mixture was allowed to warm and stir at room temperature for 30 minutes. Dilute the reaction mixture with dichloromethane (10 mL) and saturated _aqueous NaHCO (10 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 to 30% ethyl acetate in heptane) to give tertiary butyl ((2 R ,3 R )-3-(fluoromethyl) Phin-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone as the first elution agent on silica Product and (6 S ,7 R )-6-fluoro-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)- 1,4-Oxaazepine-4-carboxylic acid tertiary butyl ester was used as the second elution product on silica. The stereochemistry of pholines and oxazepanes is arbitrary.

First eluted product: LCMS: 100%, RT=2.23 minutes, (M+Na) ⁺ =495 (Method A).

Second eluted product: LCMS: 100%, RT=2.21 minutes, (M+Na) ⁺ =495 (Method A).

Synthesis of ((2R,3R)-3-(fluoromethyl) Phin-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5420 ).

To tertiary butyl ((2 R ,3 R )-3-(fluoromethyl) Phin-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (28 mg, 0.059 mmol) in 2 -To a solution in propanol (5 mL), add HCl (5-6 M in 2-propanol, 1.0 mL, 6.00 mmol). The mixture was stirred at room temperature for 24 hours. Dilute the mixture with dichloromethane (5 mL) and saturated _aqueous NaHCO (5 mL). The layers were separated on a phase separator and the organic filtrate was concentrated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((6 R ,7 S )-6-fluoro-1,4-oxaazepan-7-yl )(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5420 ). The stereochemistry of the pholine is arbitrary.

LCMS: 97%, RT=1.07 minutes, (M+H) ⁺ =373 (Method P).

Synthesis of ((6S,7S)-6-fluoro-1,4-oxaazepan-7-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroiso Quinolin-2(1H)-yl)methanone ( compound 5418 ).

To (6 S ,7 S )-6-fluoro-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 ,To a solution of tertiary butyl 4-oxazepane-4-carboxylate (58 mg, 0.123 mmol) in 2-propanol (5 mL) was added HCl (5-6 M in 2-propanol) in alcohol, 1.0 mL, 6.00 mmol). The mixture was stirred at room temperature for 24 hours. HCl (5-6 M in 2-propanol, 1.0 mL, 6.00 mmol) was added and the mixture was stirred at room temperature for 6 h. Dilute the mixture with dichloromethane (5 mL) and saturated _aqueous NaHCO (5 mL). The layers were separated on a phase separator and the organic filtrate was concentrated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((6 S ,7 S )-6-fluoro-1,4-oxaazepan-7-yl )(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5418 ). The stereochemistry of the oxazepanes is arbitrary.

LCMS: 97%, RT=1.06 minutes, (M+H) ⁺ =373 (Method P). Example 80

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((6 R ,7 S )-6-hydroxy-1,4- Oxaazepan-7-yl)methanone (compound 5246) and (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )- base)((6 S ,7 R )-6-hydroxy-1,4-oxaazepan-7-yl)methanone (compound 5243)

Synthesis of cis-6-hydroxy-1,4-oxazepane-4,7-dicarboxylic acid 7-ethyl 4-(tertiary butyl) ester.

To 6-side oxy-1,4-oxazepane-4,7-dicarboxylic acid 7-ethyl 4-(tertiary butyl) ester (2.00 g, 6.96 mmol) at 0°C ) to a solution in ethanol (100 mL, heating required) was added sodium borohydride (263 mg, 6.96 mmol). After 30 min at 0°C, the mixture was diluted with saturated aqueous _NH4Cl (20 mL), brine (50 mL) and ethyl acetate (300 mL) and the layers separated. The organic layer was washed with brine (50 mL), dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 20 to 100% ethyl acetate in heptane) to give cis - 6-hydroxy-1,4-oxaazepine-4 , 7-ethyl 4-(tertiary butyl) 7-dicarboxylate (543 mg) as the first eluted diastereoisomer, and trans - 6-hydroxy-1,4-oxazacyclo Heptane-4,7-dicarboxylic acid 7-ethyl 4-(tertiary butyl) ester as the second eluted diastereoisomer. The relative stereochemistry of oxazepanes is arbitrary and is a racemic mixture.

First eluted diastereomer: LCMS: 99%, RT=1.70 minutes, (2M+Na) ⁺ =601 (Method A).

Second eluted diastereomer: LCMS: 99%, RT=1.65 minutes, (2M+Na) ⁺ =601 (Method A).

Synthesis of cis-4-(tertiary butoxycarbonyl)-6-hydroxy-1,4-oxazepine-7-carboxylic acid.

To cis - 6-hydroxy-1,4-oxazepan-4,7-dicarboxylic acid 7-ethyl 4-(tertiary butyl) ester (700 mg, 2.419 mmol) in ethanol ( To a solution of lithium hydroxide monohydrate (152 mg, 3.63 mmol) in water (7 mL) was added. After 30 min, the reaction mixture was diluted with a mixture of chloroform and 2-propanol (2:1, 120 mL) and acidified with a mixture of aqueous HCl (1 M) and water (1:1, 30 mL). The organic layer was collected, and the aqueous layer was extracted with a mixture of chloroform and 2-propanol (2:1, 2 × 60 mL). The combined organic phases were dried over Na ₂ SO ₄ and evaporated under reduced pressure to give cis - 4-(tertiary butoxycarbonyl)-6-hydroxy-1,4-oxazepane- 7-carboxylic acid. The relative stereochemistry of oxazepanes is arbitrary and is a racemic mixture.

LCMS: 100%, RT=1.51 minutes, (M-tBu+H) ⁺ =206 (Method A).

Synthesis of (6R,7S)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1,4 -Oxaazepine-4-carboxylic acid tertiary butyl ester and (6S,7R)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetra Hydroisoquinoline-2-carbonyl)-6-hydroxy-1,4-oxaazepan-4-carboxylic acid tertiary butyl ester.

To cis - 4-(tertiary butoxycarbonyl)-6-hydroxy-1,4-oxazepan-7-carboxylic acid (630 mg, 2.41 mmol) and ( S )-1-( To a solution of 4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (603 mg, 2.65 mmol) in dichloromethane (7 mL) was added 1-ethyl-3-(3- Dimethylaminopropyl)carbodiimide hydrochloride (462 mg, 2.411 mmol). The reaction mixture was stirred for 2 minutes, hydroxybenzotriazole hydrate (73.9 mg, 0.482 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (30 mL) and washed with saturated _aqueous NaHCO (20 mL), aqueous HCl (1 M, 20 mL) and brine ( ₁₅ mL), dried over _Na2SO4 and dried in reduced Concentrate under pressure. The residue was purified twice by flash column chromatography (silica, 10 to 30% ethyl acetate in heptane) to give (6 R ,7 S )-7-(( S )-1-( 4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1,4-oxaazepine-4-carboxylic acid tertiary butyl ester As the first eluted diastereomer and (6 S ,7 R )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)-6-hydroxy-1,4-oxazepane-4-carboxylic acid tertiary butyl ester as the second eluted diastereoisomer. The stereochemistry of the oxazepanes is arbitrary.

First eluted diastereomer: LCMS: 100%, RT=2.11 minutes, (M-tBu+H) ⁺ =415 (Method A).

Second eluted diastereomer: LCMS: 100%, RT=2.10 minutes, (M-tBu+H) ⁺ =415 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((6R,7S)-6-hydroxy-1,4-oxa Azepan-7-yl)methanone ( compound 5246 ).

To (6 R ,7 S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1 ,To a solution of tertiary butyl 4-oxazepan-4-carboxylate (50 mg, 0.106 mmol) in 2-propanol (2 mL) was added HCl (5-6 M in 2-propanol) in alcohol, 1.0 mL, 6.00 mmol). After 24 hours, the mixture was diluted with dichloromethane (10 mL) and saturated _aqueous NaHCO (15 mL). The layers were separated on a phase separator and the organic filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The basic fraction was concentrated to dryness under reduced pressure, and the residue was lyophilized from a mixture of acetonitrile and water (1:2, 3 mL) to obtain (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)((6 R ,7 S )-6-hydroxy-1,4-oxaazepan-7-yl)methanone ( Compound 5246 ). The stereochemistry of the oxazepanes is arbitrary.

LCMS: 99%, RT=1.02 minutes, (M+H) ⁺ =371 (Method P).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((6S,7R)-6-hydroxy-1,4-oxa Azepan-7-yl)methanone ( compound 5243 ).

To (6 S ,7 R )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1 ,To a solution of tertiary butyl 4-oxazepane-4-carboxylate (36 mg, 0.077 mmol) in 2-propanol (1 mL) was added HCl (5-6 M in 2-propanol) in alcohol, 1.0 mL, 6.00 mmol). After 24 hours, the mixture was diluted with dichloromethane (10 mL) and saturated _aqueous NaHCO (10 mL). The layers were separated on a phase separator and the organic filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The basic fraction was concentrated to dryness under reduced pressure, and the residue was lyophilized from a mixture of acetonitrile and water (1:2, 3 mL) to obtain (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)((6 S ,7 R )-6-hydroxy-1,4-oxaazepine-7-yl)methanone ( Compound 5243 ). The stereochemistry of the oxazepanes is arbitrary.

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =371 (Method P). Example 81

((2 R ,5 R )-5-amino-5-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5215) and ((2 R ,5 S )-5-amino-5-(hydroxymethyl)tetrahydro-2 H -Pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5216)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-5-nitro-3,4-dihydro- 2H-pyran-2-yl)methanone.

From (( R )-3,4-dihydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( Starting from 1 H )-yl)methanone (see compound 5213, 1.1 g, 3.26 mmol), as for (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2 The preparation of (( S ) - 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( R )-5-nitro-3,4-dihydro-2 H -pyran -2-yl)methanone (673 mg). White solid.

LCMS: 68%, RT=2.11 minutes, (M+H) ⁺ =383 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5S)-5-nitrotetrahydro-2H-piper Pyran-2-yl)methanone and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5R)-5- Nitrotetrahydro-2H-pyran-2-yl)methanone

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( R )-5-nitro-3,4-dihydro Starting from -2H -pyran-2-yl)methanone (673 mg, 1.760 mmol), as for (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline- Preparation of ( ( S ) - 1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-nitrotetrahydro-2 H -piran- 2-yl)methanone as the first soluble isomer on silica (0-100% ethyl acetate in heptane) and (( S )-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1 H )-yl)((2 R ,5 R )-5-nitrotetrahydro-2 H -pyran-2-yl)methanone as the first compound on silicon dioxide Two soluble isomers (containing 0-100% ethyl acetate in heptane). The stereochemistry of 5-nitro-pyran is arbitrary.

First eluted isomer: LCMS: 99%, RT=2.11 minutes, (M+H) ⁺ =385 (Method A).

Second eluted isomer: LCMS: 99%, RT=2.07 minutes, (M+H) ⁺ =385 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,5R)-5-(hydroxymethyl)-5- Nitrotetrahydro-2H-pyran-2-yl)methanone and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)( (2R,5S)-5-(hydroxymethyl)-5-nitrotetrahydro-2H-pyran-2-yl)methanone.

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-nitrotetrahydro- 2 H -pyran-2-yl)methanone (139 mg, 0.362 mmol) and (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H ) -yl)((2 R ,5 R )-5-nitrotetrahydro-2 H -pyran-2-yl)methanone (207 mg, 0.538 mmol) starting from a mixture of (( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 S ,5 R )-5-(hydroxymethyl)-5-nitrotetrakis Preparation of (( S )-1-(4- fluorophenyl )-3,4-dihydroisoquinoline - 2( 1 H )-yl) ((2 R ,5 R )-5-(hydroxymethyl)-5-nitrotetrahydro-2 H -pyran-2-yl)methanone as the first silicon dioxide Soluted isomers (containing 0-100% ethyl acetate in heptane) and (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl )((2 R ,5 S )-5-(hydroxymethyl)-5-nitrotetrahydro-2 H -pyran-2-yl)methanone as the second soluble isomer on silica ( Containing 0-100% ethyl acetate in heptane). The stereochemistry of 5-nitro-pyran is arbitrary.

First eluted isomer: LCMS: 99%, RT=2.03 minutes, (M+H) ⁺ =415 (Method A).

Second soluble isomer: LCMS: 99%, RT=1.99 min, (M+H) ⁺ =415 (Method A).

Synthesis of ((2R,5R)-5-amino-5-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5215 ).

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 R )-5-(hydroxymethyl) Starting from -5-nitrotetrahydro- 2H -pyran-2-yl)methanone (51.1 mg, 0.123 mmol), as for (( 2S , 5S )-5-amino-5-(hydroxy Methyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl ((2 R ,5 R )-5-amino-5-(hydroxymethyl)tetrahydro - 2 H -pyran-2 - yl)(( S )-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5215 ). The stereochemistry of 5-amino-pyran is arbitrary.

LCMS: 99%, RT=1.02 minutes, (M+H) ⁺ =385 (Method P). SFC: 99%, RT=4.21 minutes, (M+H) ⁺ =385 (Method F).

Synthesis of ((2R,5S)-5-amino-5-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5216 ).

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,5 S )-5-(hydroxymethyl) Starting from -5-nitrotetrahydro- 2H -pyran-2-yl)methanone (51.9 mg, 0.125 mmol), as for (( 2S , 5S )-5-amino-5-(hydroxy Methyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl ((2 R ,5 S )-5-amino-5-(hydroxymethyl)tetrahydro-2 H -pyran-2 - yl)(( S )-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5216 ). The stereochemistry of 5-amino-pyran is arbitrary.

LCMS: 99%, RT=1.02 minutes, (M+H) ⁺ =385 (Method P, 40°C). SFC: 99%, RT=4.45 minutes, (M+H) ⁺ =385 (Method F). Example 82

((2 R ,4 S ,5 S )-5-amino-4-fluorotetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5210)

Synthesis of ((1R,4R,6R)-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone.

Under a nitrogen atmosphere, to ((2 R ,4 S ,5 S )-5-azido-4-hydroxytetrahydro-2 H -piran-2-yl) (( S )-1-(4- To a suspension of fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (150 mg, 0.378 mmol) in acetonitrile (anhydrous, 3.8 mL) was added triphenylphosphine ( 119 mg, 0.454 mmol). After 30 minutes, the mixture was warmed to 75°C and stirred for 3.5 hours. Subsequently, the reaction mixture was concentrated to dryness under reduced pressure. By flash column chromatography (silica, 0 to 80% ethyl acetate in heptane) and acidic preparative MPLC (linear gradient: t=0 min 5% A; t=1 min 5% A; t=17 minutes 50% A; t=18 minutes 100%; t=23 minutes 100% A; detection: 220 nm) Purify the residue to obtain ((1 R , 4 R , 6 R )-3-oxa -7-Azabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl ) methyl ketone.

LCMS: 99%, RT=1.61 minutes, (M+H) ⁺ =353 (Method A).

Synthesis of (1R,4R,6R)-4-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-oxa- 7-Azabicyclo[4.1.0]heptane-7-carboxylic acid tertiary butyl ester.

To ((1 R ,4 R ,6 R )-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)- To a solution of 3,4-dihydroisoquinolin-2(1 H )-yl)methanone (47.0 mg, 0.133 mmol) in dichloromethane (0.5 mL) was added triethylamine (0.022 mL, 0.160 mmol) and di-tertiary butyl dicarbonate (34.9 mg, 0.160 mmol). After 4 days, additional triethylamine (0.022 mL, 0.160 mmol) was added and stirring was continued for 2.5 hours. Subsequently, the mixture was purified by flash column chromatography (silica, 0 to 45% ethyl acetate in heptane) to give (1 R , 4 R , 6 R )-4-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-oxa-7-azabicyclo[4.1.0]heptane-7-carboxylic acid Tertiary butyl ester.

LCMS: 19%, RT=2.16 minutes, (M+H) ⁺ =453 and 81%, RT=2.06 minutes, (M+H) ⁺ =471 (product in hydrate form) (Method A).

Synthesis of ((3S,4S,6R)-4-fluoro-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydroisoquinoline-2-carbonyl Hydrogen-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

Under an argon atmosphere, in a microwave vial sealed with a septum, add (1 R ,4 R ,6 R )-4-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)-3-oxa-7-azabicyclo[4.1.0]heptane-7-carboxylic acid tertiary butyl ester (50.0 mg, 0.110 mmol) in acetonitrile (anhydrous , 0.50 mL), add triethylamine trihydrofluoride (144 µL, 0.884 mmol). The mixture was placed in a sand bath preheated to 90°C and stirred overnight. After cooling to room temperature, the mixture was partitioned between ethyl acetate (5 mL) and a mixture of brine and saturated aqueous NaHCO (1:1, ₃ mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 2.5 mL). The combined organic layers were dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 35% ethyl acetate in heptanes) and preparative SFC (Method V) to give (( 3S , 4S , 6R )- 4-Fluoro-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3- base) tertiary butyl carbamate.

LCMS: 99%, RT=2.33 min, (M+H) ⁺ =473 (Method A=scan acid). SFC: 99%, RT=1.89 minutes, (M+H) ⁺ =473 (Method BR).

Synthesis of ((2R,4S,5S)-5-amino-4-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5210 ).

To ((3 S ,4 S ,6 R )-4-fluoro-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- To a solution of tert-butylcarbonyltetrahydro- 2H -piran-3-yl)carbamate (29.2 mg, 0.062 mmol) in 2-propanol (0.62 mL) was added HCl (5-6 M in 2 -Propanol, 339 µL, 1.862 mmol). After stirring overnight, the mixture was

Dilute with dichloromethane ( ₅ mL) and wash with saturated aqueous _Na2CO3 solution (2 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:3, 2 mL) to give (( 2R , 4S , 5S )-5-amino-4-fluorotetrahydro- 2H -piran -2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 99%, RT=1.07 minutes, (M+H) ⁺ =373 (Method P). SFC: 99%, RT=3.21 minutes, (M+H) ⁺ =373 (Method W). Example 83

((2 R ,4 R ,5 R )-4-amino-5-ethoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5248)

Synthesis of ((2R,4S,5S)-5-ethoxy-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone.

To ethanol (anhydrous, 1.2 mL) was added sodium hydride (60% in mineral oil, 24.2 mg, 0.604 mmol). After stopping foaming, add ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4- Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 1.0 g, 2.83 mmol), and the mixture was warmed to 60 °C for 2 h. After cooling to room temperature, the mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous _NH4Cl (2 mL). Extract the aqueous phase with dichloromethane (5 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 40 to 80% ethyl acetate in heptane) and preparative SFC (Method AW) to give ((2 R ,4 S ,5 S )- 5-ethoxy-4-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone.

LCMS: 99%, RT=1.98 minutes, (M+H) ⁺ =400 (Method A), SFC: 99%, RT=4.79 minutes, (M+H) ⁺ =400 (Method W).

Synthesis of (2R,5S)-5-ethoxy-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro -4H-pyran-4-one.

To ((2 R ,4 S ,5 S )-5-ethoxy-4-hydroxytetrahydro-2 H -piran-2-yl)(( S )-1-(4- To a solution of fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (95 mg, 0.238 mmol) in dichloromethane (anhydrous, 2.4 mL) was added Des- Martin periodane (111 mg, 0.262 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with a mixture of saturated aqueous _NaHCO3 solution and saturated _{aqueous Na2S2O3} solution (1:1, 2 mL) and stirred _vigorously for 15 minutes. Subsequently, the mixture was further diluted with dichloromethane (4 mL) and _a mixture of saturated aqueous _NaHCO3 solution and saturated _{aqueous Na2S2O3} solution (1:1, 2 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (4 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 20 to 60% ethyl acetate in heptane) to give ( 2R , 5S )-5-ethoxy-2-(( S ) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 4H -pyran-4-one.

LCMS: 99%, there is a plateau between the two peaks at RT=1.86 and 2.04 minutes, (M+H) ⁺ =398 (Method A).

Synthesis of ((2R,4R,5R)-4-(phenylmethylamino)-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone.

Under nitrogen atmosphere, to (2 R ,5 S )-5-ethoxy-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline To a solution of -2-carbonyl)tetrahydro- 4H -pyran-4-one (85.0 mg, 0.214 mmol) in dichloromethane (anhydrous, 2.1 mL) was added benzylamine (0.047 mL, 0.428 mmol). After 35 minutes, sodium triacetyloxyborohydride (113 mg, 0.535 mmol) was added. After stirring overnight, the _mixture was diluted with dichloromethane (3 mL) and washed with saturated aqueous NaHCO (2 mL). The aqueous _layer was extracted with dichloromethane (3 mL), and the combined organic layers were dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 1 to 3.5% (7M ammonia in methanol)/dichloromethane) to give ((2 R , 4 S , 5 R ) as a yellow solid -4-(phenylmethylamino)-5-ethoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroiso Quinolin-2(1 H )-yl)methanone (22.5 mg, 22%) as the first soluble isomer and ((2 R ,4 R ,5 R )-4-(benzyl) as an off-white solid methylamino)-5-ethoxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone (71.8 mg) as the second lysate isomer.

First eluted isomer: LCMS: 93%, RT=1.92 min, (M+H) ⁺ =489 (Method A). SFC: 99% (de), RT=1.75 minutes, (M+H) ⁺ =489 (Method AS).

Second eluted isomer: LCMS: 99%, RT=1.89 min, (M+H) ⁺ =489 (Method A). SFC: 99%, RT=2.36 minutes, (M+H) ⁺ =489 (Method AS).

Synthesis of ((2R,4R,5R)-4-amino-5-ethoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5248 ).

((2 R ,4 R ,5 R )-4-(phenylmethyl Amino)-5-ethoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H A solution of )-yl)methanone (69 mg, 0.141 mmol) in 2,2,2-trifluoroethanol (4.0 mL) was hydrogenated. After 6 hours, the reaction mixture was filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 1 to 6% (7M ammonia in methanol)/dichloromethane) and preparative SFC (Method BS) to give ((2 R , 4 R , 5 R )-4-amino-5-ethoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline -2(1 H )-yl)methanone ( compound 5248 ).

LCMS: 99%, RT=1.09 minutes, (M+H) ⁺ =399 (Method P). SFC: 99%, RT=2.72 minutes, (M+H) ⁺ =399 (Method AS). Example 84

((2 R ,4 S ,5 S )-4-(dimethylamino)-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorobenzene yl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone (compound 5447)

Synthesis of ((2R,4S,5S)-4-(dimethylamino)-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1H)-yl)methanone.

To ((2 R ,4 S ,5 S )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3 To a solution of ,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5051, 79 mg, 0.213 mmol) in dichloromethane (1 mL) was added formaldehyde (in H ₂ O 37% wt solution (stabilized with 7-8% MeOH), 0.016 mL, 0.213 mmol) and sodium triacetyloxyborohydride (45.2 mg, 0.213 mmol). After 10 minutes, add additional formaldehyde (37% wt solution in H ₂ O (stabilized with 7-8% MeOH), 0.226 mL, 0.427 mmol) and sodium triacetyloxyborohydride (181 mg, 0.853 mmol ). The reaction mixture was stirred for 30 min, diluted with dichloromethane (5 mL) and quenched with saturated _aqueous NaHCO (5 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:2, 3 mL) to give ((2 R , 4 S , 5 S )-4-(dimethylamino)-5-hydroxytetrahydro- 2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 99%, RT=1.12 minutes, (M+H) ⁺ =399 (Method P). Example 85

((2 R ,4 R ,5 R )-4-amino-5-fluorotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5250)

Synthesis of ((2R,4S,5S)-5-fluoro-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1H)-yl)methanone.

In a microwave vial under an argon atmosphere, add ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1 -(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 1.0 g, 2.83 mmol) was added with triethylamine trihydrofluoride ( 2.076 mL, 12.73 mmol). The vials were capped and placed in a preheated 120°C sand bath. After 2.5 hours, the mixture was cooled to room temperature, diluted with dichloromethane (10 mL) and poured into a mixture of ice and saturated _{aqueous Na2CO3} (1:2, 30 mL). Once gas evolution ceased, the mixture was further diluted with dichloromethane (30 mL) and the layers separated. The aqueous phase was extracted with dichloromethane (20 mL), and the combined organic layers were washed with aqueous citric acid solution (0.5M, 20 mL) and a mixture of aqueous citric acid solution (0.5M) and brine (1:1, 40 mL) , dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 30 to 50% ethyl acetate in heptane) to give (( 2R , 4S , 5S )-5-fluoro-4-hydroxytetrakis Hydrogen- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone is used as the The first soluble isomer after methanol crystallization and ((2 R , 4 R , 5 R )-5-fluoro-4-hydroxytetrahydro-2 H -piran-2-yl) (( S )-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone serves as the second soluble isomer.

First eluted isomer: LCMS: 100%, RT=1.94 min, (M+H) ⁺ =374 (Method A). SFC: 98%, RT=2.34 minutes, (M+H) ⁺ =374 (Method V).

Second eluted isomer: LCMS: 100%, RT=2.09 min, (M+H) ⁺ =374 (Method A). SFC: 98%, RT=2.50 minutes, (M+H) ⁺ =374 (Method V).

Synthesis of ((2R,5S)-5-fluoro-4,4-dihydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone.

To ((2 R ,4 S ,5 S )-5-fluoro-4-hydroxytetrahydro-2 H -piran-2-yl)(( S )-1-(4-fluorobenzene) at 0°C To a solution of methyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (168 mg, 0.450 mmol) in dichloromethane (anhydrous, 4.5 mL) was added Dess-Martin solution Iodane (210 mg, 0.495 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. Subsequently, the mixture was diluted with a _mixture of saturated aqueous _NaHCO3 solution and saturated _{aqueous Na2S2O3} solution (1:1, 4 mL) and stirred vigorously. After 15 minutes, the mixture was diluted with dichloromethane (10 mL) and a mixture of saturated aqueous NaHCO ₃ and saturated aqueous Na ₂ S ₂ O ₃ solutions (1:1, 4 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 35 to 95% ethyl acetate in heptane) to give (( 2R , 5S )-5-fluoro-4,4-dihydroxytetrakis Hydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone.

LCMS: 99%, RT=2.03 minutes, (M+H) ⁺ =390 (Method A).

Synthesis of ((2R,4R,5R)-4-(phenylmethylamino)-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1H)-yl)methanone.

Under nitrogen atmosphere, to (2 R ,5 S )-5-fluoro-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro- 4H -pyran-4-one (139 mg, 0.374 mmol) in dichloromethane (anhydrous, 3.7 mL) was added benzylamine (0.082 mL, 0.749 mmol). After 35 minutes, sodium triacetyloxyborohydride (198 mg, 0.936 mmol) was added and the resulting suspension was stirred overnight. The mixture was diluted with dichloromethane (6 mL) and washed with saturated _aqueous NaHCO (4 mL). The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over _Na2SO4 and evaporated under reduced pressure _. By flash column chromatography (silica, 1 to 6% (7M ammonia in methanol)/dichloromethane) and 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: 210 nm) Purification residue. The product fractions were combined, diluted with a mixture of brine and saturated aqueous Na ₂ CO ₃ solution (1:1, 10 mL) and extracted with dichloromethane (3 × 20 mL). The combined organics were dried over _Na2SO4 and evaporated under reduced pressure to give (( 2R , 4R _, 5R )-4-(phenylmethylamino)-5-fluorotetrahydro- 2H- Piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 99%, RT=1.72 minutes, (M+H) ⁺ =463 (Method A). SFC: 99%, RT=4.62 minutes, (M+H) ⁺ =463 (Method F).

Synthesis of ((2R,4R,5R)-4-amino-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5250 ).

((2 R ,4 R ,5 R )-4-(phenylmethyl Amino)-5-fluorotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H ) A solution of -yl)methanone (75 mg, 0.162 mmol) in 2,2,2-trifluoroethanol (4.0 mL) was hydrogenated. After 1 day, the reaction mixture was filtered and evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:2, 3 mL) to give (( 2R , 4R , 5R )-4-amino-5-fluorotetrahydro- 2H -piran -2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5250 ).

LCMS: 99%, RT=1.04 minutes, (M+H) ⁺ =373 (Method P). Example 86

((2 R ,4 S ,5 R )-4-amino-5-(2,2,2-trifluoroethoxy)tetrahydro-2 H -pyran-2-yl)(( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5475)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S,5S)-4-hydroxy-5-(2 ,2,2-trifluoroethoxy)tetrahydro-2H-pyran-2-yl)methanone.

To 2,2,2-trifluoroethanol (5 mL) was added sodium hydride (60 wt% dispersion in oil, 56.6 mg, 1.415 mmol) under nitrogen atmosphere. Then ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 250 mg, 0.707 mmol) and the mixture was stirred at 60 °C overnight. The mixture was diluted with dichloromethane, washed with saturated aqueous _NH4Cl solution, dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 40 to 100% ethyl acetate in heptane) and preparative SFC (Method Z) to give (( S )-1-(4-fluorobenzene) base)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-4-hydroxy-5-(2,2,2-trifluoroethoxy yl)tetrahydro- 2H -pyran-2-yl)methanone.

LCMS: 97%, RT=2.06 minutes, (M+H) ⁺ =454 (Method A). SFC: 99%, RT=3.55 minutes, (M+H) ⁺ =454 (Method Z).

Synthesis of methane sulfonic acid (2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- (2,2,2-Trifluoroethoxy)tetrahydro-2H-pyran-4-yl ester.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-4-hydroxy- To a solution of 5-propoxytetrahydro- 2H -piran-2-yl)methanone (75 mg, 0.165 mmol) in dichloromethane (5 mL) was added triethylamine (0.069 mL, 0.496 mmol) and methane sulfonyl chloride (0.026 mL, 0.331 mmol). After 1 hour, the mixture was washed with citric acid aqueous solution (0.5M) and NaHCO saturated aqueous solution, passed through a phase separator and evaporated _under reduced pressure to obtain methane sulfonic acid (2 R , 4 S , 5 S )-2-( ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(2,2,2-trifluoroethoxy)tetrahydro -2H -pyran-4-yl ester.

LCMS: 99%, RT=1.91 minutes, (M+H) ⁺ =532 (Method P).

Synthesis of ((2R,4S,5R)-4-azido-5-(2,2,2-trifluoroethoxy)tetrahydro-2H-piran-2-yl)((S)-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

To methanesulfonic acid (2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -5-(2,2,2-trifluoroethoxy)tetrahydro- 2H -pyran-4-yl ester (0.165 mmol) in N , N -dimethylformamide (6 mL) Sodium azide (33.0 mg, 0.508 mmol) was added to the solution and the mixture was heated to 80°C. After stirring overnight, the reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-4-azido-5- (2,2,2-trifluoroethoxy)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline -2(1 H )-yl)methanone.

LCMS: 96%, RT=2.24 minutes, (M+H) ⁺ =479 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-(2,2,2-trifluoroethoxy)tetrahydro-2H-pyran-2-yl)((S)-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5475 ).

((2 R ,4 S ,5 R )-4-azido-5 in the presence of palladium (10 wt% on carbon, 50% water, 20.46 mg, 0.019 mmol) and atmospheric hydrogen pressure -(2,2,2-trifluoroethoxy)tetrahydro-2 H -piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquine A solution of pholin-2(1 H )-yl)methanone (46 mg, 0.096 mmol) in tetrahydrofuran (5 mL) was hydrogenated. After stirring overnight, the reaction mixture was filtered and evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ((2 R ,4 S ,5 R )-4-amino-5-(2,2,2-trifluoro Ethoxy)tetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methyl ketone ( compound 5475 ).

LCMS: 99%, RT=1.20 minutes, (M+H) ⁺ =453 (Method P). Example 87

((2 R ,4 S ,5 R )-4-amino-5-propoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5502)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S,5S)-4-hydroxy-5-propoxy Tetrahydro-2H-pyran-2-yl)methanone.

From ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 240 mg, 0.679 mmol) and 1-propanol (5 mL), as specified for (( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-4-hydroxy-5-(2,2,2- (( S )-1-(4-fluorophenyl)-3,4 - di Hydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-4-hydroxy-5-propoxytetrahydro-2 H -pyran-2-yl)methanone.

LCMS: 99%, RT=2.03 minutes, (M+H) ⁺ =414 (Method A). SFC: 99%, RT=4.53 minutes, (M+H) ⁺ =414 (Method Z).

Synthesis of methane sulfonic acid (2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- Propoxytetrahydro-2H-pyran-4-yl ester.

From (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 R ,4 S ,5 S )-4-hydroxy- Starting with 5-propoxytetrahydro- 2H -pyran-2-yl)methanone (160 mg, 0.387 mmol), as for methanesulfonic acid ( 2R , 4S , 5S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(2,2,2-trifluoroethoxy)tetrahydro- Methanesulfonic acid (2 R ,4 S ,5 S )-2-(( S )-1- ( 4-fluorophenyl)- was prepared as described for 2 H -pyran-4-yl ester (see compound 5475). 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-5-propoxytetrahydro- 2H -pyran-4-yl ester (170 mg).

LCMS: 98%, RT=2.18 minutes, (M+H) ⁺ =492 (Method A).

Synthesis of ((2R,4S,5R)-4-azido-5-propoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1H)-yl)methanone.

From methanesulfonic acid (2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Starting from -5-propoxytetrahydro- 2H -pyran-4-yl ester (170 mg, 0.346 mmol), as for (( 2R , 4S , 5R )-4-azido-5 -(2,2,2-trifluoroethoxy)tetrahydro-2 H -piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquine ((2 R ,4 S ,5 R )-4-azido-5-propoxytetrahydro-2 H - was prepared as described for pholin-2 ( 1 H )-yl)methanone (see compound 5475). Piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 99%, RT=2.14 minutes, (M+H) ⁺ =439 (Method P).

Synthesis of ((2R,4S,5R)-4-amino-5-propoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5502 ).

From ((2 R ,4 S ,5 R )-4-azido-5-propoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) )-3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (120 mg, 0.274 mmol) starting as for ((2 R ,4 S ,5 R )-4-amino -5-(2,2,2-trifluoroethoxy)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydro ((2 R ,4 S ,5 R )-4- amino -5-propoxytetrahydro-2 H - was prepared as described for isoquinolin-2(1 H )-yl)methanone (compound 5475). Piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5502 ).

LCMS: 95%, RT=1.20 minutes, (M+H) ⁺ =413 (Method P). Example 88

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 R )-5-methoxy -4-(methylamino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5503)

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxy Tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-4-amino-5-methoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5077 , 53 mg, 0.138 mmol) and triethylamine (0.023 mL, 0.166 mmol) in dichloromethane Add di-tertiary butyl dicarbonate (36.2 mg, 0.166 mmol). After 1.5 hours, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-2-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 100%, RT=2.13 minutes, (M+H) ⁺ =485 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxy Tetrahydro-2H-pyran-4-yl)(methyl)carbamic acid tertiary butyl ester.

Under nitrogen atmosphere, to ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)-5-methoxytetrahydro- 2H -piran-4-yl)carbamate tertiary butyl ester (40.0 mg, 0.083 mmol) in N , N -dimethylformamide (anhydrous, 0.415 mL), add sodium hydride (60% dispersion in mineral oil, 3.96 mg, 0.099 mmol). After 15 minutes, methyl iodide (18 µL, 0.289 mmol) was added and the mixture was stirred for 50 minutes. Subsequently, the mixture was diluted with ethyl acetate (5 mL) and washed with brine (2 mL). Extract the aqueous layer with ethyl acetate (1 mL). The combined organic layers were _washed with brine (4 x 2 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 10 to 60% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-2-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro- 2H -pyran-4-yl)(methyl) Tertiary butyl carbamate.

LCMS: 100%, RT=2.25 minutes, (M+H) ⁺ =499 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S,5R)-5-methoxy-4- (Methylamino)tetrahydro-2H-pyran-2-yl)methanone ( Compound 5503 ).

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of -methoxytetrahydro- 2H -pyran-4-yl)(methyl)carbamic acid tert-butyl ester (32.4 mg, 0.065 mmol) in 2-propanol (0.650 mL) was added dropwise HCl (5-6 M in 2-propanol, 0.354 mL, 1.949 mmol) and the mixture was stirred overnight. The mixture was diluted with dichloromethane (4 mL) and washed with saturated _{aqueous Na2CO3} solution (1.5 mL). _The aqueous phase was extracted with dichloromethane (2 mL) and the combined organics were dried over _Na2SO4 and evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:2, 2 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)((2 R ,4 S ,5 R )-5-methoxy-4-(methylamino)tetrahydro-2 H -pyran-2-yl)methanone ( compound 5503 ) . LCMS: 99%, RT=1.11 minutes, (M+H) ⁺ =399 (Method P). SFC: 100%, RT=2.54 minutes, (M+H) ⁺ =399 (Method AS). Example 89

((2 R ,4 S ,5 R )-4-(ethylamino)-5-methoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5504)

Synthesis of ethyl ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- Methoxytetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

From ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 Starting from tert-butyl -methoxytetrahydro- 2H -piran-4-yl)carbamate (see compound 5503, 38.4 mg, 0.079 mmol) and ethane iodide (22.2 µL, 0.277 mmol), as For ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 Ethyl ((2 R ,4 S , 5 R )- 2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxytetrahydro-2 H -pyran- 4-yl)tertiary butyl carbamate.

LCMS: 99%, RT=2.49 minutes, (M+H) ⁺ =513 (Method A).

Synthesis of ((2R,4S,5R)-4-(ethylamino)-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone.

From ethyl ((2 R ,4 S ,5R)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)- Starting from tert-butyl 5-methoxytetrahydro- 2H -pyran-4-yl)carbamate (31.8 mg, 0.062 mmol) as for (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 R )-5-methoxy-4-(methylamino)tetrahydro-2 H ((2 R ,4 S ,5 R )-4-(ethylamino)-5-methoxytetrahydro-2 H - was prepared as described for -pyran-2-yl)methanone ( compound 5503 ). Piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5504 ).

LCMS: 98%, RT=1.14 minutes, (M+H) ⁺ =413 (Method P). SFC: 99%, RT=2.33 minutes, (M+H) ⁺ =413 (Method AU). Example 90

((2 S ,5 S )-5-amino-5-(methoxymethyl)tetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5217)

Synthesis of ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(hydroxymethyl )Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

To crude ((2 S ,5 S )-5-amino-5-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl) To a solution of )-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5213 , 0.145 mmol) in dichloromethane (4 mL) was added di-tertiary butyl dicarbonate (47.5 mg, 0.218 mmol). After 20 hours, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give ((3 S ,6 S )-6-(( S )-1-(4 -Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(hydroxymethyl)tetrahydro- 2H -piran-3-yl)carbamic acid tert-butan ester.

LCMS: 95%, RT=2.05 minutes, (M+H) ⁺ =485 (Method A).

Synthesis of ((3S,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(methoxy Methyl)tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

To ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(hydroxy Methyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (27 mg, 0.056 mmol) and tetrabutylammonium hydrogen sulfate (5.7 mg, 0.017 mmol) in toluene (2 mL) To the solution, sodium hydroxide (50 wt% solution in water, 0.063 mL, 1.67 mmol) and methane iodide (0.014 mL, 0.223 mmol) were added. After 4 days, the reaction mixture was diluted with dichloromethane (5 mL) and water (1 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was taken up in toluene (2 mL) and washed with tetrabutylammonium hydrogen sulfate (11.4 mg, 0.033 mmol), sodium hydroxide (50 wt% in water, 0.126 mL, 3.34 mmol), and methane iodide. (0.035 mL, 0.557 mmol) for 3 days. Dilute the reaction mixture with dichloromethane (5 mL) and water (1 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 30% A; t=16 minutes 70% A; t=17 minutes 100%; t=22 minutes 100% A; Measured: 220/292 nm), the purified residue was lyophilized to obtain ((3 S , 6 S )-6-(( S )-1-(4-fluorophenyl)-1 as a white solid, 2,3,4-Tetrahydroisoquinoline-2-carbonyl)-3-(methoxymethyl)tetrahydro- 2H -pyran-3-yl)carbamic acid tertiary butyl ester (10.7 mg).

LCMS: 99%, RT=2.19 minutes, (M+H) ⁺ =499 (Method A).

Synthesis of ((2S,5S)-5-amino-5-(methoxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5217 ).

To ((3 S ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(methyl To a solution of tert-butyloxymethyl)tetrahydro- 2H -piran-3-yl)carbamate (9 mg, 0.018 mmol) in 2-propanol (1 mL) was added HCl (6 M in in 2-propanol, 0.283 mL, 1.697 mmol). After 4 days, the reaction mixture was diluted with dichloromethane ₍ 10 mL) and washed with saturated aqueous _K2CO3 solution (3 mL). The organic layer was dried over _Na2SO4 and filtered _by evaporation under reduced pressure. The residue was dissolved in methanol (1.5 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2.3 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was dissolved in a mixture of acetonitrile and water (1:1, 4 mL) and lyophilized to give (( 2S , 5S )-5-amino-5-(methoxymethyl)tetrahydro- 2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5217 ).

LCMS: 99%, RT=1.08 minutes, (M+H) ⁺ =399 (Method P). SFC: 99%, RT=2.51 minutes, (M+H) ⁺ =399 (Method AS). Example 91

((2 S ,5 R )-5-amino-5-(methoxymethyl)tetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5218)

Synthesis of ((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(hydroxymethyl )Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

From ((2 S ,5 R )-5-amino-5-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- Starting from 3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5214, 56.1 mg, 0.146 mmol), as for ((3 S ,6 S )-6-(( S ) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-3-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl) Preparation of ((3 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrabutyl carbamate) as described for tertiary butyl carbamate (see compound 5214) Hydroisoquinolin-2-carbonyl)-3-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl)carbamate.

LCMS: 94%, RT=2.08 minutes, (M+H) ⁺ =485 (Method A).

Synthesis of ((3R,6S)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(methoxy Methyl)tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

From ((3 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(hydroxy Starting with tert-butyl methyl)tetrahydro- 2H -piran-3-yl)carbamate (28 mg, 0.058 mmol) as for ((3S,6S)-6-((S)-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(methoxymethyl)tetrahydro-2H-piran-3-yl)carbamic acid The preparation of ((3 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroiso Quinoline-2-carbonyl)-3-(methoxymethyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.22 minutes, (M+H) ⁺ =499 (Method A).

Synthesis of ((2S,5R)-5-amino-5-(methoxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5218 ).

From ((3 R ,6 S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(methyl Starting from tert-butyloxymethyl)tetrahydro- 2H -pyran-3-yl)carbamate (11 mg, 0.022 mmol), as for (( 2S , 5S )-5-amino- 5-(methoxymethyl)tetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 (( 2S , 5R )-5-amino-5-( methoxymethyl )tetrahydro- 2H -piran-2- yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5218 ).

LCMS: 99%, RT=1.07 minutes, (M+H) ⁺ =399 (Method P). Example 92

((2 R ,4 S ,5 R )-5-(allyloxy)-4-aminotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorobenzene methyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone (compound 5476)

Synthesis of ((2R,4S,5R)-5-(allyloxy)-4-azidotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1H)-yl)methanone.

Under a nitrogen atmosphere, to ((2 R ,4 S ,5 R )-4-azido-5-hydroxytetrahydro-2 H -piran-2-yl) (( S )-1-(4- Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5077, 90 mg, 0.227 mmol) in N , N -dimethylformamide (anhydrous, To the solution in 4 mL), add sodium hydride (60% dispersion in mineral oil, 13.1 mg, 0.272 mmol). After 10 minutes, propylene bromide (0.030 mL, 0.341 mmol) was added. After 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-5-(allyloxy) -4-Azidetetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl ) methyl ketone.

LCMS: 98%, RT=2.24 minutes, (M+H) ⁺ =437 (Method A).

Synthesis of ((2R,4S,5R)-5-(allyloxy)-4-aminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5476 ).

Under a nitrogen atmosphere, to ((2 R ,4 S ,5 R )-5-(allyloxy)-4-azidetetrahydro-2 H -piran-2-yl)(( S )-1 To a solution of -(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (65 mg, 0.149 mmol) in tetrahydrofuran (anhydrous, 4 mL) was added trimethyl Phosphine (1.0 M in THF, 0.149 mL, 0.149 mmol). After stirring over the weekend, another portion of trimethylphosphine (1.0 M in THF, 0.179 mL, 0.179 mmol) was added and stirring was continued for an additional 4 hours. Subsequently, aqueous NaOH solution (1 M, 3 mL) was added. The mixture was stirred vigorously and extracted with dichloromethane. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto a SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure, and after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL), ((2 R , 4 S , 5 R )-5-(ene Propoxy)-4-aminotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone.

LCMS: 95%, RT=1.17 minutes, (M+H) ⁺ =411 (Method P). Example 93

((2 R ,4 S ,5 S )-4-amino-5-(difluoromethoxy)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5443)

Synthesis of ((2R,4S,5S)-5-(difluoromethoxy)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

Within 5 minutes, to the solution containing ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)-5-hydroxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5052, 100 mg, 0.213 mmol) and potassium acetate (83 mg, 0.850 mmol) in 2 To a mixture of methyl chloride (0.2 mL) and water (0.2 mL) was added portionwise trimethyl(bromodifluoromethyl)silane (0.066 mL, 0.425 mmol). Additional amounts of potassium acetate (83 mg, 0.850 mmol) and trimethyl(bromodifluoromethyl)silane (0.066 mL, 0.425 mmol) were added daily for 4 consecutive days. Stirring was continued for an additional 3 days, and the mixture was then diluted with dichloromethane (8 mL) and water (8 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (silica, 0 to 40% ethyl acetate in heptane) to give (( 2R , 4S , 5S )-5-(difluoro) as a white solid Methoxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4 -tert-butylcarbamic acid (33.8 mg).

LCMS: 81%, RT=2.21 minutes, (M+H) ⁺ =521 (Method A).

Synthesis of ((2R,4S,5S)-4-amino-5-(difluoromethoxy)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5443 ).

To ((2 R ,4 S ,5 S )-5-(difluoromethoxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro To a solution of isoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (43 mg, 0.083 mmol) in 2-propanol (4 mL) was added HCl of 2-propanol (5.5 M, 0.452 mL, 2.486 mmol). After stirring for 3 days, the reaction mixture was diluted with dichloromethane (20 mL) and neutralized with saturated _aqueous NaHCO solution. The layers were separated by phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (7 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give (( 2R , 4S , 5S )-4-amino-5-(difluoromethoxy)tetrahydrogen -2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone ( Compound 5443 ) .

LCMS: 95%, RT=1.112 minutes, (M+H) ⁺ =421 (Method P). Example 94

((2 R ,4 S ,5 S )-4-(ethylamino)-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl )-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5508)

Synthesis of (3aS,6R,7aS)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro-2H-piper Nand[4,3-d] Azol-2-one.

Under an argon atmosphere, to ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- A solution of 2-carbonyl)-5-hydroxytetrahydro-2 H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5052, 100 mg, 0.213 mmol) in tetrahydrofuran (anhydrous, 5 mL) Add sodium hydride (60 wt% in mineral oil, 8.50 mg, 0.213 mmol). The reaction mixture was warmed to 40°C and stirred overnight. Subsequently, the mixture was diluted with dichloromethane (15 mL) and saturated aqueous NH ₄ Cl solution (10 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (silica, 30 to 100% ethyl acetate in heptane) to give ( 3aS , 6R , 7aS )-6-(( S )-1-(4 -Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro- 2H -pirano[4,3-d] Azol-2-one.

LCMS: 99%, RT=1.87 minutes, (M+H) ⁺ =397 (Method A).

Synthesis of (3aS,6R,7aS)-1-ethyl-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexa Hydro-2H-pirano[4,3-d] Azol-2-one.

To (3a S ,6 R ,7a S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroiso Quinoline-2-carbonyl)hexahydro- 2H -pirano[4,3-d] To a solution of azole-2-one (57.2 mg, 0.144 mmol) in N , N -dimethylformamide (anhydrous, 1.5 mL) was added sodium hydride (60 wt% in mineral oil, 6.93 mg, 0.173 mmol ). After 15 minutes, ethane iodide (0.058 mL, 0.721 mmol) was added. After 1 hour, the reaction mixture was quenched with water (4 mL) and diluted with ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 5 mL). _The combined organics were washed with brine (5 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography (silica, 30 to 100 ethyl acetate in heptane) to give ( 3aS , 6R , 7aS )-1-ethyl-6-(( S )- 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro- 2H -pirano[4,3-d] Azol-2-one.

LCMS: 98%, RT=1.98 minutes, (M+H) ⁺ =425 (Method A).

Synthesis of ((2R,4S,5S)-4-(ethylamino)-5-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5508 ).

To (3a S ,6 R ,7a S )-1-ethyl-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)hexahydro- 2H -pirano[4,3-d] To a solution of azole-2-one (48.2 mg, 0.114 mmol) in ethanol (3 mL) was added aqueous NaOH (2 M, 0.568 mL, 1.136 mmol), and the mixture was warmed to 70 °C. After stirring overnight, the mixture was concentrated to dryness under reduced pressure. Dilute the residue with dichloromethane (5 mL) and saturated _aqueous NaHCO (5 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was purified by preparative SFC (Method BS) to give ((2 R ,4 S ,5 S )-4- after lyophilization of the mixture from a mixture of acetonitrile and water (1:1, 4 mL) (Ethylamino)-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H )-yl)methanone.

LCMS: 99%, RT=1.05 minutes, (M+H) ⁺ =399, (Method P). SFC: 99%, RT=2.78 minutes, (M+H) ⁺ =399, (Method AS). Example 95

((2 R ,4 S ,5 R )-4-amino-5-(trifluoromethoxy)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5507)

Synthesis of ((2R,4S,5R)-4-azido-5-(trifluoromethoxy)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

((2 R ,4 S ,5 R )-4-azido-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5075, 313 mg, 0.790 mmol) was concentrated from ethyl acetate (10 mL), placed under argon, and transferred into the glove box. Add Selectfluor (420 mg, 1.184 mmol), silver triflate (609 mg, 2.369 mmol), and potassium fluoride (anhydrous, 138 mg, 2.369 mmol). Cover the reaction flask with aluminum foil. Subsequently, ethyl acetate (anhydrous, 4 mL), 2-fluoropyridine (0.272 mL, 3.16 mmol) and (trifluoromethyl)trimethylsilane (0.376 mL, 2.369 mmol) were added continuously, and the mixture was stirred overnight. Subsequently, the mixture was diluted with ethyl acetate (10 mL), filtered through a layer of celite and rinsed with ethyl acetate (3×10 mL). The combined filtrates were diluted with saturated _aqueous NaHCO solution (40 mL), and the resulting mixture was filtered through celite. Rinse the residue with ethyl acetate (3 x 5 mL). The combined filtrate layers were separated and the organic layer was washed with brine (30 mL), dried over _Na2SO4 and concentrated under reduced pressure _. The residue was dissolved in toluene, coated on a hydromatrix, and purified by flash column chromatography (silica, 5 to 60% ethyl acetate in heptane) to give (( 2R , 4S ,5 R )-4-azido-5-(trifluoromethoxy)tetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 95%, RT=2.26 minutes, (M+H) ⁺ =465 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-(trifluoromethoxy)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5507 ).

((2 R ,4 S ,5 R )-4-azido-5- in the presence of palladium (10 wt% on carbon, 50% water, 50 mg, 0.023 mmol) at atmospheric hydrogen pressure (Trifluoromethoxy)tetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) A solution of -yl)methanone (154 mg, 0.332 mmol) in tetrahydrofuran (5 mL) was hydrogenated. After 3 hours, the reaction mixture was diluted with methanol (10 mL), filtered and evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 10% A; t=2 minutes 10% A; t=17 minutes 50% A; t=18 minutes 100%; t=23 minutes 100% A; detection (measurement: 215/254 nm) purified residue. The product fractions were combined, diluted with saturated aqueous _NaHCO3 , partially concentrated to remove acetonitrile, and extracted with dichloromethane. The organic layer was passed through a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in a mixture of acetonitrile and water (1:1, 15 mL), filtered through nylon (0.45 μm) and lyophilized to give 2 R , 4 S , 5 R )-4-amino-5- (Trifluoromethoxy)tetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) -Methanone ( compound 5507 ).

LCMS: 99%, RT=2.95 min, (M+H) ⁺ =439 (Method AK). Example 96

((2 R ,5 R )-5-amino-5-(methoxymethyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5219)

Synthesis of ((3R,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(hydroxymethyl )Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

From crude ((2 R ,5 R )-5-amino-5-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5215, 0.145 mmol), as for ((3 S ,6 S )-6-(( S ) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-3-(hydroxymethyl)tetrahydro- 2H -pyran-3-yl) Preparation of ((3 R ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrabutyl carbamate) as described for tertiary butyl carbamate (see compound 5217) Hydroisoquinoline-2-carbonyl)-3-(hydroxymethyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester. The stereochemistry of the 5-amino-pyran center is arbitrary.

LCMS: 98%, RT=2.09 minutes (M+H) ⁺ =485 (Method A).

Synthesis of ((3R,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(methoxy Methyl)tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

From ((3 R ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(hydroxy Starting with tert-butyl methyl)tetrahydro- 2H -piran-3-yl)carbamate (34 mg, 0.070 mmol), as for ((3 S ,6 S )-6-(( S )- 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-3-(methoxymethyl)tetrahydro- 2H -piran-3-yl ) tertiary butyl carbamate as described (see compound 5217), preparation of ((3 R ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinolin-2-carbonyl)-3-(methoxymethyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester. The stereochemistry of the 5-amino-pyran center is arbitrary.

LCMS: 99%, RT=2.23 minutes, (M+H) ⁺ =499 (Method A).

Synthesis of ((2R,5R)-5-amino-5-(methoxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5219 ).

From ((3 R ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(methyl Starting from tert-butyloxymethyl)tetrahydro- 2H -pyran-3-yl)carbamate (13 mg, 0.026 mmol), as for (( 2S , 5S )-5-amino- 5-(methoxymethyl)tetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 (( 2R , 5R )-5-amino-5-( methoxymethyl )tetrahydro- 2H -piran-2- base) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5219 ). The stereochemistry of the 5-amino-pyran center is arbitrary.

LCMS: 99%, RT=1.08 minutes, (M+H) ⁺ =399 (Method P). Example 97

((2 R ,5 S )-5-amino-5-(methoxymethyl)tetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5220)

Synthesis of ((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(hydroxymethyl )Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester

From crude ((2R,5S)-5-amino-5-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 , starting from 4-dihydroisoquinolin-2(1H)-yl)methanone (see compound 5216, 0.145 mmol), as for ((3S,6S)-6-((S)-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(hydroxymethyl)tetrahydro-2H-piran-3-yl)carbamic acid tertiary butyl ester Description (see compound 5217), preparation of ((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -3-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester. The stereochemistry of the 5-amino-pyran center is arbitrary.

LCMS: 99%, RT=2.06 minutes (M+H) ⁺ =485 (Method A).

Synthesis of ((3S,6R)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(methoxy Methyl)tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

From ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(hydroxy Starting with tert-butyl methyl)tetrahydro- 2H -piran-3-yl)carbamate (17 mg, 0.035 mmol), as for ((3 S ,6 S )-6-(( S )- 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-3-(methoxymethyl)tetrahydro- 2H -piran-3-yl ) tertiary butyl carbamate as described (see compound 5217) to prepare ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinolin-2-carbonyl)-3-(methoxymethyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester. The stereochemistry of the 5-amino-pyran center is arbitrary.

LCMS: 99%, RT=2.21 minutes, (M+H) ⁺ =499 (Method A).

Synthesis of ((2R,5S)-5-amino-5-(methoxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5220 ).

From ((3 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(methyl Starting from tert-butyloxymethyl)tetrahydro- 2H -pyran-3-yl)carbamic acid (6 mg, 0.012 mmol), as for ((2 S ,5 S )-5-amino- 5-(methoxymethyl)tetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 (( 2R , 5S )-5-amino-5-( methoxymethyl )tetrahydro- 2H -piran-2- yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5220 ). The stereochemistry of the 5-amino-pyran center is arbitrary.

LCMS: 94%, RT=1.08 minutes, (M+H) ⁺ =399 (Method P, 40°C). Example 98

((2 R ,4 S ,5 S )-4-amino-5-(methylthio)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5425)

Synthesis of thioacetic acid S -((3 S ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro Isoquinolin-2-carbonyl)tetrahydro- 2H -piran-3-yl)ester.

To a solution of triphenylphosphine (298 mg, 1.14 mmol) in tetrahydrofuran (5 mL) at 0 °C under an argon atmosphere was added diisopropyl azodicarboxylate (0.221 mL, 1.135 mmol). The mixture was warmed to 30°C, stirred for 1 hour, and cooled to 0°C again. Add ((2 R ,4 S ,5 R )-4-azido-5-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)- A solution of 3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5077, 300 mg, 0.757 mmol) and thioacetic acid (0.082 mL, 1.135 mmol) in tetrahydrofuran (5 mL) , and after 1 hour, the mixture was allowed to warm to room temperature and stirred overnight. To a solution of triphenylphosphine (298 mg, 1.135 mmol) in tetrahydrofuran (5 mL) in a separate flask under an argon atmosphere at 0 °C was added diisopropyl azodicarboxylate (0.221 mL, 1.135 mmol) and stir at 0°C for 1 hour. Subsequently, the first reaction mixture was added, followed by thioacetic acid (0.054 mL, 0.757 mmol). The mixture was allowed to warm to room temperature and stirred for another day. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica, 5 to 35% ethyl acetate in heptane) to give thioacetic acid S -(( 3S , 4S , 6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-3-yl) ester.

LCMS: 79%, RT=2.25 minutes, (M+H) ⁺ =455 (Method B).

Synthesis of ((2R,4S,5S)-4-azido-5-(methylthio)tetrahydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1H)-yl)methanone.

Thioacetic acid S -((3 S ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro To a solution of isoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)ester (106 mg, 0.205 mmol) in methanol (4 mL) was added potassium carbonate (85 mg, 0.616 mmol). The resulting suspension was stirred at room temperature for 30 minutes. Methyl iodide (0.030 mL, 0.480 mmol) was added and stirring was continued for 1 hour. The mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (3 mL) and water (3 mL). The organic phase was passed through a phase separator and the organic filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 30% ethyl acetate in heptane) to give (( 2R , 4S , 5S )-4-azido-5- (Methylthio)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl ) methyl ketone.

LCMS: 100%, RT=2.20 minutes, (M+H) ⁺ =427 (Method A).

Synthesis of ((2R,4S,5S)-4-amino-5-(methylthio)tetrahydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5425 ).

((2 R ,4 S ,5 S )-4-azido was dissolved in the presence of palladium (10 wt% on carbon, 50% water, 60 mg, 0.045 mmol) under atmospheric hydrogen pressure. -5-(Methylthio)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H A solution of )-yl)methanone (30 mg, 0.070 mmol) in tetrahydrofuran (1 mL) was hydrogenated. After 1 hour, the mixture was filtered on a 45 µm nylon filter and the filtrate was concentrated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 10% A; t=16 minutes 50% A; t=17 minutes 100%; t=22 minutes 100% A; (measurement: 220/264 nm) purified residue. The product fractions were combined and concentrated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 2 mL) to give ((2 R , 4 S , 5 S )-4-amino-5-(methylthio)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5425 ).

LCMS: 100%, RT=1.11 minutes, (M+H) ⁺ =401 (Method P). Example 99

((2 R ,4 S ,5 S )-4-amino-5-(methylsulfonyl)tetrahydro-2 H -piran-2-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5426)

Synthesis of ((2R,4S,5S)-4-azido-5-(methylsulfonyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

To ((2 R ,4 S ,5 S )-4-azido-5-(methylthio)tetrahydro-2 H -piran-2-yl)(( S )-1-(4-fluoro To a solution of phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5425, 39 mg, 0.091 mmol) in dichloromethane (2 mL) was added m-chlorine Peroxybenzoic acid (70 wt%, 49.6 mg, 0.201 mmol). The mixture was stirred at room temperature for 1 hour. Dilute the mixture with dichloromethane (5 mL) and a mixture of saturated aqueous Na ₂ S ₂ O ₃ , saturated aqueous NaHCO ₃ and water (1:1:1, 10 mL). The mixture was stirred at room temperature for 10 minutes. Separate the layers on a phase separation filter. The organic filtrate was concentrated under reduced pressure to obtain ((2 R , 4 S , 5 S )-4-azido-5-(methylsulfonyl)tetrahydro-2 H -piran-2-yl) ( ( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 96%, RT=2.05 minutes, (M+H) ⁺ =459 (Method A).

Synthesis of ((2R,4S,5S)-4-amino-5-(methylsulfonyl)tetrahydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5426 ).

(( 2R , 4S , 5S )-4-azido-5- (Methylsulfonyl)tetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) A solution of -yl)methanone (40 mg, 0.087 mmol) in tetrahydrofuran (3 mL) was hydrogenated. After 1 hour, the mixture was filtered on a 45 µm nylon filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 2 mL) to obtain ((2 R , 4 S , 5 S )-4-amino-5-(methylsulfonyl)tetrahydro -2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone ( Compound 5426 ) .

LCMS: 99%, RT=2.86 minutes, (M+H) ⁺ =433 (Method AK). Example 100

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a S ,7 R ,8a S )-octahydropirano [3,4-b][1,4] -7-yl)methanone (compound 5448)

Synthesis of (4aS,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydropirano[ 3,4-b][1,4] -2(3H)-one.

To ((2 R ,4 S ,5 S )-4-amino-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-Dihydroisoquinolin-2(1 H )-yl)methanone (200 mg, 0.540 mmol) and N,N -diisopropylethylamine (0.283 mL, 1.620 mmol) in tetrahydrofuran (5 mL) To the solution in , add a solution of bromoacetyl chloride (0.050 mL, 0.594 mmol) in tetrahydrofuran (5 mL). After 30 minutes, sodium hydride (60 wt% dispersion in mineral oil, 64.8 mg, 1.620 mmol) was added and the mixture was stirred overnight. During the day, additional portions of sodium hydride (60 wt% dispersion in mineral oil, 13 mg, 0.325 mmol and 6.5 mg, 0.163 mmol) were added and stirring was continued overnight. Molecular sieves and more sodium hydride (60 wt% dispersion in mineral oil, 13 mg, 0.325 mmol) were added and stirring was continued for another day. Dilute the reaction mixture with saturated aqueous ammonium chloride solution (15 mL) and dichloromethane (30 mL). The organic layer _was collected, washed with brine (20 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give ( 4aS , 7R , 8aS )-7-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydropirano[3,4-b][1,4] -2(3 H )-ketone.

LCMS: 98%, RT=1.89 minutes, (M+H) ⁺ =411 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aS,7R,8aS)-octahydropirano[3, 4-b][1,4] -7-yl)methanone ( compound 5448 ).

To ((4a S ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro Pirano[3,4-b][1,4] To a solution of -2(3 H )-one (93 mg, 0.227 mmol) in THF (anhydrous, 1 mL) was added borane-dimethyl sulfide complex (2 M in THF, 0.453 mL, 0.906 mmol ). After 6 hours, the reaction mixture was diluted with a mixture of methanol and aqueous HCl (1 M) (1:1, 6 mL). After 36 hours, the reaction mixture was diluted with dichloromethane (15 mL) and saturated _aqueous NaHCO (15 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was combined with the crude product of the same reaction (starting from 31 mg, 0.076 mmol), dissolved in methanol (2 mL), introduced onto the SCX-column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was purified by preparative SFC (Method AW) to give (( S )-1-(4-fluorophenyl)-3 after lyophilization from a mixture of acetonitrile and water (1:1, 3 mL) ,4-dihydroisoquinolin-2(1 H )-yl)((4a S ,7 R ,8a S )-octahydropirano[3,4-b][1,4] -7-yl)methanone ( compound 5448 ).

LCMS: 99%, RT=1.06 minutes, (M+H) ⁺ =397 (Method P). SFC: 98%, RT=3.55 minutes, (M+H) ⁺ =397 (Method W). Example 101

((2 R ,4 S ,5 R )-4-amino-5-isopropoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5267)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S,5S)-4-hydroxy-5-isopropyl Oxytetrahydro-2H-pyran-2-yl)methanone.

To a suspension of sodium hydride (60 wt% in mineral oil, 67.9 mg, 1.698 mmol) in 2-propanol (3 mL) was added ((1 R , 4 R , 6 S ) under an argon atmosphere. -3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 A hot solution of H )-yl)methanone (see compound 5070, 300 mg, 0.849 mmol) in 2-propanol (1.5 mL). After stirring at 60 °C for 3 hours, the reaction mixture was poured into saturated aqueous NH ₄ Cl solution (10 mL) and the resulting mixture was extracted with ethyl acetate (20 mL). The layers were separated and the organic phase was washed with brine (10 mL), dried over _Na2SO4 and concentrated under reduced pressure _. The residue was purified by flash column chromatography (silica, 20 to 70% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-4-hydroxy-5-isopropoxytetrahydro-2 H -pyran-2-yl)methanone .

LCMS: 96%, RT=2.01 minutes, (M+H) ⁺ =414 (Method A). SFC: 96%, RT=2.14 minutes, (M+H) ⁺ =414 (Method V).

Synthesis of methane sulfonic acid (2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- Isopropoxytetrahydro-2H-pyran-4-yl ester.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-4-hydroxy- To a solution of 5-isopropoxytetrahydro- 2H -pyran-2-yl)methanone (215 mg, 0.520 mmol) in dichloromethane (3 mL) was added triethylamine (0.145 mL, 1.040 mmol) ), followed by methanesulfonate chloride (0.061 mL, 0.780 mmol). After 2 hours, additional triethylamine (5 drops) and methanesulfonate chloride (2 drops) were added and stirring was continued for another hour. Subsequently, the mixture was diluted with saturated _aqueous NaHCO solution and stirred for 0.5 h. The layers were separated using a phase separator and the organic filtrate was concentrated under reduced pressure to give methanesulfonic acid ( 2R , 4S , 5S )-2-(( S )-1-(4-fluorophenyl)-1,2 ,3,4-Tetrahydroisoquinoline-2-carbonyl)-5-isopropoxytetrahydro- 2H -pyran-4-yl ester.

LCMS: 98%, RT=2.09 minutes, (M+H) ⁺ =492 (Method B).

Synthesis of ((2R,4S,5R)-4-azido-5-isopropoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone.

To methanesulfonic acid (2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) To a solution of -5-isopropoxytetrahydro- 2H -pyran-4-yl ester (250 mg, 0.509 mmol), sodium azide (116 mg, 1.780 mmol) was added, and the mixture was stirred at 80°C Overnight. _Subsequently , the reaction mixture was diluted with ethyl acetate (10 mL), washed with a mixture of saturated aqueous _NaHCO3 and water (1:1, 10 mL) and brine (3 × 10 mL), dried over _Na2SO4 and Evaporate under reduced pressure. The residue was dissolved in toluene, loaded onto a hydromatrix and purified by flash column chromatography (silica, 10 to 50% ethyl acetate in heptane) to give (( 2R , 4S ,5 R )-4-azido-5-isopropoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroiso Quinolin-2( 1H )-yl)methanone.

LCMS: 99%, RT=2.32 minutes, (M+H) ⁺ =439 (Method B).

Synthesis of ((2R,4S,5R)-4-amino-5-isopropoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5267 ).

((2 R ,4 S ,5 R )-4-azido-5 in the presence of palladium (10 wt% on carbon, 50% water, 30 mg, 0.014 mmol) and atmospheric hydrogen pressure -Isopropoxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl ) A solution of methanone (114 mg, 0.260 mmol) in tetrahydrofuran (3 mL) was hydrogenated. After 4 hours, the reaction mixture was diluted with methanol (10 mL) and filtered through a nylon filter (0.45 μm). The filtrate was evaporated under reduced pressure and analyzed by acidic preparative MPLC (linear gradient: t=0 min 10% A; t=2 min 10% A; t=17 min 50% A; t=18 min 100%; t =23 min 100% A; detection: 215 nm) purified residue. The products containing the eluates were combined, diluted with saturated _aqueous NaHCO solution (until the pH paper became alkaline), and partially concentrated to remove acetonitrile. After stirring the aqueous phase with dichloromethane for 0.5 hours, the layers were separated using a phase separator. The organic filtrate was evaporated under reduced pressure and after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL), ((2R,4S,5R)-4-amino-5-isopropoxytetrakis was obtained Hydrogen-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5267 ).

LCMS: 99%, RT=1.18 minutes, (M+H) ⁺ =413 (Method P). Example 102

((2 R ,4 R ,5 S )-4-amino-5-fluorotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5251)

Synthesis of ((2R,4R,5S)-5-fluoro-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydroisoquinoline-2-carbonyl Hydrogen-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

Under nitrogen atmosphere, to ((2R,4R,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tertiary butyl-5-hydroxytetrahydro-2H-piran-4-yl)carbamate (see compound 5259, 200 mg, 0.425 mmol) and triethylamine (0.391 mL, 2.81 mmol) in acetonitrile (anhydrous, 10 mL), add triethylamine trihydrofluoride (0.208 mL, 1.275 mmol) and perfluoro-1-butylsulfonyl fluoride (0.229 mL, 1.275 mmol). The mixture was warmed to 60°C and stirred overnight. Add additional triethylamine (0.118 mL, 0.850 mmol), triethylamine trihydrofluoride (0.069 mL, 0.425 mmol) and perfluoro-1-butylsulfonate fluoride (0.076 mL, 0.425 mmol) and incubate at 60°C Continue stirring for another 5 days. Subsequently, after cooling the mixture to room temperature, it was poured into cold saturated _aqueous NaHCO solution (10 mL) and extracted with ethyl acetate (twice). _The combined organics were washed with brine, dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 40% ethyl acetate in heptane) and preparative SFC (Method AN) to give ((2 R , 4 R , 5 S )- 5-Fluoro-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4- base) tertiary butyl carbamate.

LCMS: 99%, RT=2.16 minutes, (M+Na) ⁺ =495 (Method B).

Synthesis of ((2R,4R,5S)-4-amino-5-fluorotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone ( Compound 5251 ).

To ((2 R ,4 R ,5 S )-5-fluoro-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- To a solution of tert-butylcarbonyltetrahydro- 2H -piran-4-yl)carbamate (18 mg, 0.038 mmol) in 2-propanol (3 mL) was added HCl (5-6 M in 2 -Propanol, 0.5 mL, 2.75 mmol). After 2 days, the mixture was partitioned between dichloromethane (25 mL) and a mixture of saturated _aqueous NaHCO and water (1:1, 20 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (25 mL). The combined organic layers were passed through a phase separator and evaporated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (1 g), and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give (( 2R , 4R , 5S )-4-amino-5-fluorotetrahydro- 2H -piran -2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5251 ).

LCMS: 99%, RT=1.06 minutes, (M+H) ⁺ =373 (Method P). Example 103

((2 R ,4 S ,5 R )-5-ethoxy-4-(ethylamino)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5510)

Synthesis of ((2R,4S,5R)-5-ethoxy-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-4-yl)(ethyl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-ethoxy-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5501, 80 mg, 0.160 mmol) in N , N -dimethylformamide (3 mL) Sodium hydride (60 wt% dispersion in mineral oil, 7.7 mg, 0.193 mmol) was added to the solution. After 10 minutes, ethyl iodide (0.038 mL, 0.481 mmol) was added. After 1 hour, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 20 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-5-ethoxy-2- (( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-4-yl) (ethyl) Tertiary butyl carbamate.

LCMS: 99%, RT=2.38 minutes, (M+H) ⁺ =527 (Method A).

Synthesis of ((2R,4S,5R)-5-ethoxy-4-(ethylamino)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5510 ).

To ((2 R ,4 S ,5 R )-5-ethoxy-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- To a solution of tertiary butyl 2-carbonyl)tetrahydro- 2H -piran-4-yl)(ethyl)carbamate (75 mg, 0.142 mmol) in 2-propanol (4 mL) was added HCl ( 6 M in 2-propanol, 1 mL, 6.00 mmol). After stirring overnight, the mixture was partitioned between dichloromethane and saturated _{aqueous Na2CO3} solution. _The organic layer was separated, dried over _Na2SO4 and evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1) to obtain ((2 R ,4 S ,5 R )-5-ethoxy-4-(ethylamino)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5510 ).

LCMS: 99%, RT=1.19 minutes, (M+H) ⁺ =427 (Method P). Example 104

((2 R ,4 S ,5 R )-5-ethoxy-4-(methylamino)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5509)

Synthesis of ((2R,4S,5R)-5-ethoxy-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-4-amino-5-ethoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- To a solution of 3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5078, 150 mg, 0.376 mmol) in dichloromethane (3 mL) was added triethylamine (0.063 mL , 0.452 mmol) and di-tertiary butyl dicarbonate (99 mg, 0.452 mmol). After 2.5 hours, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica, 20 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-5-ethoxy-2- (( S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.20 minutes, (M+H) ⁺ =499 (Method A).

Synthesis of ((2R,4S,5R)-5-ethoxy-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-4-yl)(methyl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-ethoxy-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- To a solution of tertiary butyl 2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamate (80 mg, 0.160 mmol) in N , N -dimethylformamide (3 mL) was added Sodium hydride (60 wt% dispersion in mineral oil, 7.7 mg, 0.193 mmol). After 10 minutes, methyl iodide (0.030 mL, 0.481 mmol) was added. After 1 hour, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 20 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-5-ethoxy-2- (( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-4-yl) (methyl) Tertiary butyl carbamate.

LCMS: 98%, RT=2.31 minutes, (M+H) ⁺ =513 (Method A).

Synthesis of ((2R,4S,5R)-5-ethoxy-4-(methylamino)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5509 ).

To ((2 R ,4 S ,5 R )-5-ethoxy-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- To a solution of tertiary butyl 2-carbonyl)tetrahydro- 2H -piran-4-yl)(methyl)carbamate (80 mg, 0.156 mmol) in 2-propanol (4 mL) was added HCl ( 6 M in 2-propanol, 1 mL, 6.00 mmol). After stirring overnight, the mixture was partitioned between dichloromethane and saturated _{aqueous Na2CO3} solution. The organic layer _was separated, dried over _Na2SO4 and evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1) to obtain ((2 R , 4 S , 5 R )-5-ethoxy-4-(methylamino)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5509 ).

LCMS: 98%, RT=1.16 minutes, (M+H) ⁺ =413 (Method P). Example 105

((2 R ,4 R ,5 S )-4-amino-5-methoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5247)

Synthesis of 4-nitrobenzoic acid (3S,4R,6R)-4-((tertiary butoxycarbonyl)amine)-6-((S)-1-(4-fluorophenyl)-1,2 ,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl ester.

To a solution of 4-nitrobenzoic acid (42.6 mg, 0.255 mmol) and triphenylphosphine (84 mg, 0.319 mmol) in tetrahydrofuran (anhydrous, 5 mL) at 0°C under a nitrogen atmosphere was added ((2 R ,4 R ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro -2H -Piran-4-yl)carbamic acid tertiary butyl ester (see compound 5052, 100 mg, 0.213 mmol) and diisopropyl azodicarboxylate (0.050 mL, 0.255 mmol) in tetrahydrofuran (anhydrous, 4 mL) solution. After addition, the mixture was allowed to warm to room temperature and stirred overnight. Additional triphenylphosphine (84 mg, 0.319 mmol) and diisopropyl azodicarboxylate (0.050 mL, 0.255 mmol) were added and stirring was continued for 4 days. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), washed with _saturated aqueous NaHCO (10 mL), dried over _Na2SO4 and evaporated under _reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 40% ethyl acetate in heptane) to afford 4- as a mixture with hydrazine-1,2-dicarboxylic acid diisopropyl ester. Nitrobenzoic acid (3 S ,4 R ,6 R )-4-((tertiary butoxycarbonyl)amine)-6-(( S )-1-(4-fluorophenyl)-1,2 ,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl ester).

LCMS: 97%, RT=2.28 minutes, (M-Boc+H) ⁺ =520 (Method B).

Synthesis of ((2R,4R,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrakis Hydrogen-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To a solution of lithium hydroxide monohydrate (4.99 mg, 0.119 mmol) in water (2 mL) was added 4-nitrobenzoic acid (3) as a mixture with hydrazine-1,2-dicarboxylic acid diisopropyl ester. S ,4 R ,6 R )-4-((tertiary butoxycarbonyl)amine)-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetra A solution of hydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl ester (127 mg, 29 wt%, 0.059 mmol) in tetrahydrofuran (2 mL). After stirring overnight, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous _NaHCO (2 mL). The organic layer was dried over _Na2SO4 and evaporated under reduced _pressure . The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give ((2 R , 4 R , 5 S )-2-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxytetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester .

LCMS: 98%, RT=2.11 minutes, (M+Na) ⁺ =493 (Method A).

Synthesis of ((2R,4R,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methoxy Tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 R ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of tert-butyl -hydroxytetrahydro- 2H -piran-4-yl)carbamate (14 mg, 0.030 mmol) in toluene (1.5 mL) was added sodium hydroxide (50 wt% solution in water , 0.067 mL, 1.27 mmol), tetrabutylammonium hydrogen sulfate (5.05 mg, 0.015 mmol) and methane iodide (5.56 µL, 0.089 mmol). After stirring overnight, additional methane iodide (1.85 µL, 0.030 mmol) was added. After another 3 days, the reaction mixture was diluted with water (1 mL) and dichloromethane (5 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 30% A; t=16 minutes 70% A; t=17 minutes 100%; t=22 minutes 100% A; (Measurement: 220/292 nm) The residue was purified to obtain ((2 R ,4 R ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydrofuran) Hydroisoquinoline-2-carbonyl)-5-methoxytetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 98%, RT=2.18 minutes, (M+Na) ⁺ =507 (Method A).

Synthesis of ((2R,4R,5S)-4-amino-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5247 ).

To ((2 R ,4 R ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of tert-butyl-methoxytetrahydro- 2H -piran-4-yl)carbamate (8 mg, 0.017 mmol) in 2-propanol (3 mL) was added HCl (5-6 M in 2-propanol, 0.5 mL, 2.75 mmol). After 2 days, the mixture was partitioned between dichloromethane (25 mL) and a mixture of saturated _aqueous NaHCO and water (1:1, 20 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (25 mL). The combined organic layers were passed through a phase separator and evaporated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (1 g), and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((2 R , 4 R , 5 S )-4-amino-5-methoxytetrahydro-2 H - Piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5247 ).

LCMS: 99%, RT=1.06 minutes, (M+H) ⁺ =385 (Method P). Example 106

((2 R ,4 S ,5 R )-4-amino-5-(prop-2-yn-1-yloxy)tetrahydro-2 H -piran-2-yl)(( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5541)

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(propanyl) -2-yn-1-yloxy)tetrahydro-2H-piran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of tert-butyl -hydroxytetrahydro- 2H -piran-4-yl)carbamate (see compound 5055, 106 mg, 0.225 mmol) in toluene (2 mL) was added tetrabutylammonium hydrogen sulfate ( 22.95 mg, 0.068 mmol), sodium hydroxide (50 wt% in water, 0.180 mL, 3.38 mmol), and 3-bromoprop-1-yne (80 wt% in toluene, 0.036 mL, 0.338 mmol). After stirring overnight, add additional sodium hydroxide (50 wt% in water, 0.180 mL, 3.38 mmol) and 3-bromoprop-1-yne (80 wt% in toluene, 0.036 mL, 0.338 mmol) and continue Stir for 5 days. Subsequently, the mixture was diluted with water (10 mL) and saturated _aqueous NaHCO solution (2 mL) and extracted with toluene (10 mL). The organic layer was dried over _Na2SO4 and evaporated under reduced _pressure . The residue was purified by flash column chromatography (silica, 10 to 50% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-2-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(prop-2-yn-1-yloxy)tetrahydro- 2H -piper Phenyl-4-yl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.13 minutes, (M+H) ⁺ =509 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-(prop-2-yn-1-yloxy)tetrahydro-2H-piran-2-yl)((S)-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5541 ).

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl in the dark )-5-(prop-2-yn-1-yloxy)tetrahydro-2 H -piran-4-yl)carbamic acid tertiary butyl ester (86.8 mg, 0.171 mmol) in 2-propanol (10 mL) was added HCl (5 M in 2-propanol, 2.5 mL, 12.50 mmol). The mixture was stirred for 1.5 days and subsequently diluted with water (10 mL) and saturated aqueous _K2CO3 solution until the _pH was approximately 10-12 on pH paper. The volatiles were removed under reduced pressure and the aqueous residue was stirred with dichloromethane. After 0.5 hours, the layers were separated using a phase separator and the organic filtrate was concentrated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((2 R , 4 S , 5 R )-4-amino-5-(prop-2-yne-1- (oxy)tetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methyl ketone ( compound 5541 , 70 mg).

LCMS: 99%, RT=1.13 minutes, (M+H) ⁺ =409 (Method P). Example 107

N -((3 S ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro- 2H -piran-3-yl)acetamide (Compound 5427)

Synthesis of 2-((3S,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro-2H-pyran-3-yl)isoindoline-1,3-dione.

To ((2 R ,4 S ,5 R )-4-azido-5-hydroxytetrahydro-2 H -piran-2-yl)(( S )-1 -(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (300 mg, 0.757 mmol), triphenylphosphine (238 mg, 0.908 mmol) and o-benzene To a solution of dimethylimide (134 mg, 0.908 mmol) in tetrahydrofuran (anhydrous, 6 mL) was added diisopropyl azodicarboxylate (0.177 mL, 0.908 mmol) dropwise. After 10 minutes, the mixture was allowed to warm to room temperature and stirred for 2 hours. Subsequently, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica, 10 to 35% ethyl acetate in heptane) to give 2-(( 3S , 4S , 6R )-4-azido- 6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-3-yl)isoindole Doline-1,3-dione. LCMS: 98%, RT=2.22 minutes, (M+H) ⁺ =526 (Method A).

Synthesis of ((2R,4S,5S)-5-amino-4-azidotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone.

To 2-((3 S ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro- 2H -piran-3-yl)isoindoline-1,3-dione (258 mg, 70 wt%, 0.344 mmol), as compared with hydrazine-1,2- To a mixture of diisopropyl dicarboxylate in ethanol (5 mL) was added hydrazine monohydrate (0.036 mL, 0.736 mmol). The mixture was stirred at 90°C overnight. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 2.5 to 10% methanol in dichloromethane) to give (( 2R , 4S , 5S )-5-amino-4-azide Tetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone.

LCMS: 96%, RT=1.67 minutes, (M+H) ⁺ =396 (Method A).

Synthesis of N-((3S,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro-2H-piran-3-yl)acetamide.

To ((2 R ,4 S ,5 S )-5-amino-4-azidotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- A solution of 3,4-dihydroisoquinolin-2(1 H )-yl)methanone (40 mg, 0.101 mmol) and triethylamine (0.015 mL, 0.106 mmol) in dichloromethane (1 mL) Add acetic anhydride (0.012 mL, 0.126 mmol). After stirring overnight, the mixture was diluted with water (2 mL) and extracted with dichloromethane (3×1 mL). The combined extracts were passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 2 to 6% methanol in dichloromethane) to give N -(( 3S , 4S , 6R )-4-azido-6 -(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)acetamide And it is used as is.

LCMS: 99%, RT=1.99 minutes, (M+H) ⁺ =438 (Method B).

Synthesis of N-((3S,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro-2H-piran-3-yl)acetamide ( compound 5427 ).

N -((3 S ,4 S ,6 R )-4-azido in the presence of palladium (10 wt% on carbon, 50% water, 23.84 mg, 0.011 mmol) and atmospheric hydrogen pressure -6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)ethyl A solution of amide (49 mg, 0.112 mmol) in a mixture of tetrahydrofuran (1 mL) and water (0.2 mL) was hydrogenated. After stirring overnight, the reaction mixture was filtered and washed with dichloromethane. The combined filtrate and washings were evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 1 to 6% methanol in dichloromethane). The product was dissolved in methanol and introduced onto an SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2.5 M). The alkaline fraction was concentrated to dryness under reduced pressure, and after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL), N -((3 S , 4 S , 6 R )-4- was obtained. Amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl )acetamide ( compound 5427 ).

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =412 (Method P). Example 108

N -((3 S ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro- 2H -pyran-3-yl)methanesulfonamide (Compound 5428)

Synthesis of N-((3S,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro-2H-pyran-3-yl)methanesulfonamide.

Under an argon atmosphere, to ((2 R ,4 S ,5 S )-5-amino-4-azidetetrahydro-2 H -piran-2-yl) (( S )-1-(4 -Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5247, 50 mg, 0.126 mmol) and triethylamine (0.070 mL, 0.506 mmol) in di To a solution in methyl chloride (2.5 mL), methane sulfonyl chloride (0.020 mL, 0.253 mmol) was added dropwise. After 2 hours, the mixture was basified with saturated aqueous _NaHCO and extracted with dichloromethane (3 × 2 mL). The combined organics were passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 10 to 60% ethyl acetate in heptane) to give N -(( 3S , 4S , 6R )-4-azido- 6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)methanesulfonamide .

LCMS: 99%, RT=2.06 minutes, (M+H) ⁺ =474 (Method A).

Synthesis of N-((3S,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro-2H-pyran-3-yl)methanesulfonamide ( compound 5428 ).

N -((3 S ,4 S ,6 R )-4-azido in the presence of palladium (10 wt% on carbon, 50% water, 36.9 mg, 0.017 mmol) and atmospheric hydrogen pressure -6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-3-yl)methane A solution of sulfonamide (41 mg, 0.087 mmol) in a mixture of tetrahydrofuran (1.5 mL) and water (0.3 mL) was hydrogenated. After stirring overnight, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. 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% A; t=18 min 100%; t =23 min 100% A; detection: 220 nm) purified residue. The product was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure, and after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL), N -((3 S , 4 S , 6 R )-4- was obtained. Amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl )methanesulfonamide ( compound 5428 ).

LCMS: 99%, RT=1.02 minutes, (M+H) ⁺ =448 (Method P). Example 109

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-5-hydroxy-4 -(Methylamino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5444)

Synthesis of (3aS,6R,7aS)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro-2H-piper Nand[4,3-d] Azol-2-one.

Under an argon atmosphere, to ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- A solution of 2-carbonyl)-5-hydroxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5052, 300 mg, 0.638 mmol) in tetrahydrofuran (anhydrous, 15 mL) Sodium hydride (60 wt% dispersion in mineral oil, 25.5 mg, 0.638 mmol) was added, and the reaction mixture was warmed to 40 °C. After stirring overnight, it was added with dichloromethane (25 mL) and a saturated aqueous solution of NH ₄ Cl ( 20 mL) to dilute the reaction mixture. The layers were separated and the aqueous phase was extracted with dichloromethane (2 x 25 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 40 to 100% ethyl acetate in heptane) to give ( 3aS , 6R , 7aS )-6-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro- 2H -pirano[4,3-d] Azol-2-one.

LCMS: 99%, RT=2.07 minutes, (M+H) ⁺ =397 (Method A).

Synthesis of (3aS,6R,7aS)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylhexane Hydro-2H-pirano[4,3-d] Azol-2-one.

To (3a S ,6 R ,7a S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroiso Quinoline-2-carbonyl)hexahydro- 2H -pirano[4,3-d] To a solution of azole-2-one (185 mg, 0.467 mmol) in N , N -dimethylformamide (anhydrous, 4.5 mL) was added sodium hydride (60 wt% dispersion in mineral oil, 22.40 mg ,0.560 mmol). After 15 minutes, methyl iodide (0.157 mL, 2.52 mmol) was added. After 5 hours, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×15 mL). _The combined organics were washed with brine (10 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 30 to 100% ethyl acetate in heptane). The product was dissolved in ethyl acetate ₍ 5 mL), washed with brine (5 mL), dried over _Na2SO4 and evaporated under reduced pressure to give ( 3aS , 6R , 7aS )-6-( ( S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylhexahydro- 2H -pirano[4,3 -d] Azol-2-one. LCMS: 99%, RT=1.99 minutes, (M+H) ⁺ =411 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S,5S)-5-hydroxy-4-(methane) (Amino)tetrahydro-2H-pyran-2-yl)methanone ( Compound 5444 ).

To (3a S ,6 R ,7a S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1- Methylhexahydro- 2H -pirano[4,3-d] To a solution of azole-2-one (155 mg, 0.378 mmol) in methanol (17 mL) was added aqueous NaOH (2 M, 1.89 mL, 3.78 mmol), and the mixture was warmed to 70°C. After 4 days, at reduced temperature The reaction mixture was concentrated under pressure. Dilute the residue with dichloromethane (15 mL) and saturated _aqueous NaHCO (20 mL). The aqueous layer was separated and extracted with dichloromethane (3 x 15 mL). The combined organics were dried over _Na2SO4 and _evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 5% (7M ammonia in methanol)/dichloromethane) and preparative SFC (Method BW) in a mixture of acetonitrile and water (1 :1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((2 R , 4 S ,5 S )-5-hydroxy-4-(methylamino)tetrahydro-2 H -pyran-2-yl)methanone.

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =385 (Method P). SFC: 100%, RT=3.00 minutes, (M+H) ⁺ =385 (Method AU). Example 110

((2 R ,4 S ,5 R )-4-amino-5-(tertiary butoxy)tetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5511)

Synthesis of ((2R,4S,5R)-4-azido-5-(tertiary butoxy)tetrahydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

To ((2 R ,4 S ,5 R )-4-azido-5-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5077, 100 mg, 0.252 mmol) in tert-butyl acetate (2 mL, 14.98 mmol) and dichloromethane (3 mL) was added perchloric acid (0.017 mL, 0.202 mmol). After 2 hours, the mixture was diluted with dichloromethane (4 mL) and saturated _aqueous NaHCO (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 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-4-azido-5- (Tertiary butoxy)tetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H ) -base) methanone.

LCMS: 99%, RT=2.40 minutes, (M+H) ⁺ =453 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-(tertiary butoxy)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5511 ).

((2 R ,4 S ,5 R )-4-azido-5 in the presence of palladium (10 wt% on carbon, 50% water, 24.9 mg, 0.012 mmol) and atmospheric hydrogen pressure -(tertiary butoxy)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H A solution of )-yl)methanone (53 mg, 0.117 mmol) in tetrahydrofuran (3 mL) was hydrogenated. After stirring overnight, the reaction mixture was filtered and washed with methanol. The combined filtrate and washings were evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ((2 R , 4 S , 5 R )-4-amino-5-(tertiary butoxy)tetrahydro -2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone ( Compound 5511 ) .

LCMS: 97%, RT=1.22 minutes, (M+H) ⁺ =427 (Method P). Example 111

(( S )-1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-octahydropirano [3,4-b][1,4] -7-yl)methanone (compound 5266)

Synthesis of 2-(((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-3-yl)oxy)acetaldehyde.

A mixture of ozone and oxygen was bubbled through (( 2R , 4S , 5R )-5-(allyloxy)-4-azidotetrahydro- 2H -pyran-2 at -78°C. -yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5474, 400 mg, 0.916 mmol) in solution in dichloromethane (20 mL) until the reaction mixture turns light blue (2 min). After 5 minutes, the reaction mixture was purged with argon for 5 minutes. Subsequently, dimethyl sulfide (0.339 mL, 4.58 mmol) was added and after 1 hour, the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was combined with the reaction mixture of the same conversion (starting from 0.206 mmol) and evaporated under reduced pressure.

The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give 2-(((3 R ,4 S ,6 R )-4-azido -6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-3-yl)oxy base) acetaldehyde.

LCMS: 97%, plateau between RT=1.9-2.2 minutes, (M+H) ⁺ =439 (Method B).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-octahydropirano[3, 4-b][1,4] -7-yl)methanone ( compound 5266 ).

2-(((3 R ,4 S ,6 R )-4-azide Base-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl) A solution of (oxy)acetaldehyde (320 mg, 0.73 mmol) in ethanol (35 mL) was hydrogenated. After 5 hours, the reaction mixture was filtered and washed with ethanol. The combined filtrate and washings were evaporated under reduced pressure. By flash column chromatography (silica, 0.5 to 5% (7M ammonia in methanol)/dichloromethane) and 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) Purification residue. The product containing fractions were combined, diluted with saturated aqueous K ₂ CO ₃ solution (2.5 mL) and partially concentrated to remove acetonitrile. Extract the aqueous residue with dichloromethane (2 × 10 mL). The combined extracts were dried over Na ₂ SO ₄ and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give (( S )-1-(4- Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-octahydropirano[3,4-b][1, 4] -7-yl)methanone ( compound 5266 ).

LCMS: 96%, RT=2.75 minutes, (M+H) ⁺ =397 (Method AK). Example 112

N -((3R,4S,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro- 2H -piran-3-yl)acetamide (Compound 5512)

Synthesis of ((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

To (1 R ,4 R ,6 R )-4-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3- Oxa-7-azabicyclo[4.1.0]heptane-7-carboxylic acid tertiary butyl ester (see compound 5210, 1.20 g, 2.65 mmol) in N , N -dimethylformamide (anhydrous, 13 mL), add ammonium chloride (0.284 g, 5.30 mmol) and sodium azide (0.517 g, 7.96 mmol). The mixture was warmed to 60°C and stirred overnight. Subsequently, the mixture was diluted with brine (20 mL) and extracted with ethyl acetate (2×60 mL). The combined _organic layers were washed with brine (3×20 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 10 to 40% ethyl acetate in heptane) to give (( 3R , 4S , 6R )-4-azido-6- (( S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.26 minutes, (M+H) ⁺ =496 (Method A).

Synthesis of ((2R,4S,5R)-5-amino-4-azidotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone.

At 0°C, to ((3 R ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydrofuran) To a solution of tert-butyl hydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamate (550 mg, 1.110 mmol) in 2-propanol (11 mL) was added HCl (5-6 M in 2-propanol, 6.05 mL, 33.3 mmol). After 10 minutes, the cooling bath was removed and the reaction mixture was stirred for 1 day. _The mixture was diluted with saturated aqueous _Na2CO3 (18 mL) and brine (30 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with a mixture of saturated aqueous Na ₂ CO ₃ and brine (1:1, 30 mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give ((2 R , 4 S , 5 R )- 5-Amino-4-azidotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone.

LCMS: 98%, RT=1.88 minutes, (M+H) ⁺ =396 (Method A).

Synthesis of N-((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro-2H-piran-3-yl)acetamide.

Under a nitrogen atmosphere, to ((2 R ,4 S ,5 R )-5-amino-4-azidetetrahydro-2 H -pyran-2-yl) (( S )-1-(4- Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (80 mg, 0.202 mmol) and triethylamine (0.037 mL, 0.263 mmol) in dichloromethane (anhydrous, Acetic anhydride (0.023 mL, 0.243 mmol) was added to the solution in 1 mL). After 1 hour, the mixture was purified by flash column chromatography (silica, 10 to 60% ethyl acetate in heptane) to give N -(( 3R , 4S , 6R )-4-azide Nitrogen-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl )acetamide.

LCMS: 99%, RT=2.03 minutes, (M+H) ⁺ =438 (Method A).

Synthesis of N-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro-2H-piran-3-yl)acetamide ( compound 5512 ).

N -((3 R ,4 S ,6 R )-4-stacked in the presence of palladium (10 wt% on carbon, 50% water, 37.0 mg, 0.017 mmol) under atmospheric hydrogen pressure. Nitrogen-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl ) A solution of acetamide (76 mg, 0.174 mmol) in tetrahydrofuran (1.7 mL) was hydrogenated. After 2 hours, the mixture was filtered on a 45 µm nylon filter and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:4, 2 mL) to obtain N -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)acetamide ( Compound 5512 ).

LCMS: 99%, RT=1.04 minutes, (M+H) ⁺ =412 (Method P). Example 113

N -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro- 2H -pyran-3-yl) -N -methylacetamide (Compound 5516)

Synthesis of ((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-3-yl)(methyl)carbamic acid tertiary butyl ester.

Under nitrogen atmosphere, to ((3 R ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydrofuran) Hydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5512 , 400 mg, 0.807 mmol) in N , N -dimethylformamide (anhydrous, 4.0 mL) was added sodium hydride (60 wt% dispersion in mineral oil, 38.7 mg, 0.969 mmol). After 15 minutes, methane iodide (0.176 mL, 2.83 mmol) was added. After 1 hour, the mixture was partitioned between ethyl acetate (30 mL) and brine (10 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (3×10 mL), dried over _Na2SO4 and evaporated under _reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 25% ethyl acetate in heptane) to give (( 3R , 4S , 6R )-4-azido-6- (( S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-3-yl) (methyl) Tertiary butyl carbamate.

LCMS: 99%, RT=2.35 minutes, (M+H) ⁺ =510 (Method A).

Synthesis of ((2R,4S,5R)-4-azido-5-(methylamino)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone.

To ((3 R ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-piran-3-yl)(methyl)carbamic acid tertiary butyl ester (234 mg, 0.459 mmol) in 2-propanol (8 mL) and dichloromethane (3 mL) To a solution of the mixture was added HCl (5-6 M in 2-propanol, 2.51 mL, 13.82 mmol). After 3 days, the reaction mixture was diluted with dichloromethane (15 mL) and washed with saturated _aqueous NaHCO (25 mL). The aqueous phase was extracted with dichloromethane (3×20 mL) and the combined organics were dried over _Na2SO4 and evaporated under reduced pressure _. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (7 M). The alkaline fraction was concentrated to dryness under reduced pressure to obtain ((2 R , 4 S , 5 R )-4-azido-5-(methylamino)tetrahydro- 2H -pyran-2 -yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 99%, RT=1.76 minutes, (M+H) ⁺ =410 (Method A).

Synthesis of N-((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro-2H-pyran-3-yl)-N-methylacetamide.

Under a nitrogen atmosphere, to ((2 R ,4 S ,5 R )-4-azido-5-(methylamino)tetrahydro-2 H -piran-2-yl)(( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (85 mg, 0.201 mmol) and triethylamine (0.039 mL, 0.282 mmol) were dissolved in di To a solution in methyl chloride (anhydrous, 1 mL) was added acetic anhydride (0.028 mL, 0.302 mmol). After 1 hour, the mixture was purified by flash column chromatography (silica, 25 to 65% ethyl acetate in heptane) to give N -(( 3R , 4S , 6R )-4-azide Nitrogen-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl ) -N -methylacetamide.

LCMS: 98%, RT=2.03 minutes, (M+H) ⁺ =452 (Method A).

Synthesis of N-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro-2H-piran-3-yl)-N-methylacetamide ( compound 5516 ).

N -((3 R ,4 S ,6 R )-4-stacked in the presence of palladium (10 wt% on carbon, 50% water, 43.6 mg, 0.020 mmol) under atmospheric hydrogen pressure Nitrogen-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl A solution of )- N -methylacetamide (92.5 mg, 0.205 mmol) in tetrahydrofuran (2.0 mL) was hydrogenated. After 2 hours, the mixture was filtered on a 45 µm nylon filter and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (3:1, 3 mL) to obtain N -(( 3R , 4S , 6R )-4-amino-6-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl) -N -methylacetamide ( Compound 5516 ).

LCMS: 99%, RT=1.06 minutes. (M+H) ⁺ =426 (Method P). Example 114

N -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro- 2H -pyran-3-yl)-2,2,2-trifluoroacetamide (Compound 5514)

Synthesis of N-((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro-2H-pyran-3-yl)-2,2,2-trifluoroacetamide.

To ((2 R ,4 S ,5 R )-5-amino-4-azidetetrahydro-2 H -piran-2-yl)(( S )-1 -(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5512 , 80 mg, 0.202 mmol) and triethylamine (0.037 mL, 0.263 mmol ) to a solution in dichloromethane (anhydrous, 1.0 mL) was added trifluoroacetic anhydride (0.034 mL, 0.243 mmol). After 5 minutes, the reaction mixture was warmed to room temperature and stirred for 2.5 hours. Subsequently, another portion of triethylamine (0.018 mL, 0.131 mmol) and trifluoroacetic anhydride (0.017 mL, 0.121 mmol) were added and stirring was continued for 0.5 h. The mixture was diluted with dichloromethane (4 mL), washed with saturated _aqueous NaHCO (1 mL), dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 05 to 40% ethyl acetate in heptane) to give N -(( 3R , 4S , 6R )-4-azido- 6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-3-yl)-2 ,2,2-trifluoroacetamide.

LCMS: 99%, RT=2.36 minutes, (M+H) ⁺ =492 (Method A).

Synthesis of N-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro-2H-piran-3-yl)-2,2,2-trifluoroacetamide ( compound 5514 ).

N -((3 R ,4 S ,6 R )-4-stacked in the presence of palladium (10 wt% on carbon, 50% water, 40.3 mg, 0.019 mmol) under atmospheric hydrogen pressure Nitrogen-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl A solution of )-2,2,2-trifluoroacetamide (93 mg, 0.189 mmol) in tetrahydrofuran (1.9 mL) was hydrogenated. After 2 hours, the mixture was filtered on a 45 µm nylon filter and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (3:2, 3 mL) to give N -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)-2,2,2-trifluoroacetyl Amine ( compound 5514 ).

LCMS: 97%, RT=1.15 minutes, (M+H) ⁺ =466 (Method P). Example 115

N -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro- 2H -pyran-3-yl)propanamide (Compound 5513)

Synthesis of N-((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro-2H-piran-3-yl)propanamide.

Under a nitrogen atmosphere, to ((2 R ,4 S ,5 R )-5-amino-4-azidetetrahydro-2 H -pyran-2-yl) (( S )-1-(4- Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5512 , 80 mg, 0.202 mmol) and triethylamine (0.039 mL, 0.283 mmol) in dichloro To a solution in methane (anhydrous, 1.0 mL) was added propionic anhydride (0.034 mL, 0.263 mmol). After 1 hour, the mixture was purified by flash column chromatography (silica, 5 to 60% ethyl acetate in heptane) to give N -(( 3R , 4S , 6R )-4-azide Nitrogen-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl )propamide.

LCMS: 99%, RT=2.25 minutes, (M+H) ⁺ =452 (Method A).

Synthesis of N-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro-2H-piran-3-yl)propanamide ( compound 5513 ).

N -((3 R ,4 S ,6 R )-4-stacked in the presence of palladium (10 wt% on carbon, 50% water, 38.7 mg, 0.018 mmol) under atmospheric hydrogen pressure Nitrogen-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl ) A solution of propamide (82 mg, 0.182 mmol) in tetrahydrofuran (1.8 mL) was hydrogenated. After 2 hours, the mixture was filtered on a 45 µm nylon filter and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 3 mL) to give N -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)propanamide ( compound 5513 ).

LCMS: 99%, RT=1.07 minutes, (M+H) ⁺ =426 (Method P). Example 116

N -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro- 2H -pyran-3-yl) -N -methylpropanamide (Compound 5517)

Synthesis of N-((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro-2H-pyran-3-yl)-N-methylpropanamide.

Under a nitrogen atmosphere, to ((2 R ,4 S ,5 R )-4-azido-5-(methylamino)tetrahydro-2 H -piran-2-yl)(( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5516 , 85 mg, 0.201 mmol) and triethylamine (0.039 mL, 0.282 To a solution of dichloromethane (anhydrous, 1 mL) was added propionic anhydride (0.034 mL, 0.262 mmol). After 1 hour, the mixture was purified by flash column chromatography (silica, 15 to 55% ethyl acetate in heptane) to give N -(( 3R , 4S , 6R )-4-azide Nitrogen-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl ) -N -Methylpropamide.

LCMS: 99%, RT=2.10 minutes, (M+H) ⁺ =466 (Method A).

Synthesis of N-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro-2H-piran-3-yl)-N-methylpropanamide ( compound 5517 ).

N -((3 R ,4 S ,6 R )-4-stacked in the presence of palladium (10 wt% on carbon, 50% water, 37.7 mg, 0.018 mmol) under atmospheric hydrogen pressure Nitrogen-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl A solution of )- N -methylpropamide (82.5 mg, 0.177 mmol) in tetrahydrofuran (1.8 mL) was hydrogenated. After 1.5 hours, the mixture was filtered on a 45 µm nylon filter and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (6:1, 3 mL) to give N -(( 3R , 4S , 6R )-4-amino-6-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl) -N -methylpropanamide ( Compound 5517 ).

LCMS: 99%, RT=1.10 minutes, (M+H) ⁺ =440 (Method P). Example 117

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3a S ,6 R ,7a S )-1,3a,4 ,6,7,7a-hexahydropirano[3,4-d]imidazol-6-yl)methanone (compound 5430)

Synthesis of trifluoromethanesulfonic acid (3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)tetrahydro-2H-pyran-3-yl ester.

To ((2 R ,4 S ,5 R )-4-azido-5-hydroxytetrahydro-2 H -piran-2-yl)(( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5077 , 0.50 g, 1.26 mmol) and pyridine (0.306 mL, 3.78 mmol) To a solution in dichloromethane (11 mL) was added trifluoromethanesulfonic anhydride (0.314 mL, 1.892 mmol). After 30 minutes, the reaction mixture was diluted with dichloromethane (10 mL), washed with aqueous citric acid (0.5 M, 10 mL) and saturated _aqueous NaHCO (10 mL), dried over _Na2SO4 and under reduced _pressure Evaporate to obtain trifluoromethanesulfonic acid (3 R , 4 S , 6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydrofuran Hydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl ester.

LCMS: 99%, RT=2.35 minutes, (M+H) ⁺ =529 (Method A).

Synthesis of ((2R,4S,5S)-4,5-diazidetetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1H)-yl)methanone.

Under an argon atmosphere, to trifluoromethanesulfonic acid (3 R ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl ester (200 mg, 0.378 mmol) in N , N -dimethylformamide (anhydrous, 1.8 mL ), add sodium azide (86 mg, 1.325 mmol) to the solution. The reaction mixture was warmed to 80°C and stirred for 3 hours. After cooling to room temperature, the mixture was diluted with brine (10 mL) and extracted with ethyl acetate (3×15 mL). _The combined organics were washed with brine (20 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 40% ethyl acetate in heptane) to give (( 2R , 4S , 5S )-4,5-tetrazidediazide Hydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone.

LCMS: 87%, RT=2.27 minutes, (M+H) ⁺ =422 (Method A).

Synthesis of ((2R,4S,5S)-4,5-diaminotetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1H)-yl)methanone.

((2 R ,4 S ,5 S )-4,5-dihydrogen was dissolved in the presence of palladium (10 wt% on carbon, 50% water, 0.083 g, 0.039 mmol) under atmospheric hydrogen pressure. Azidetetrahydro- 2H -piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone (0.164 g, 0.389 mmol) in tetrahydrofuran (3 mL) was hydrogenated. After 1.5 hours, the mixture was filtered on a 0.22 µm nylon filter and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (7 M). The alkaline fraction was concentrated to dryness under reduced pressure to obtain ((2 R , 4 S , 5 S )-4,5-diaminotetrahydro-2 H -piran-2-yl) (( S ) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 88%, RT=1.45 minutes, (M+H) ⁺ =370 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3aS,6R,7aS)-1,3a,4,6, 7,7a-Hexahydropirano[3,4-d]imidazol-6-yl)methanone.

To ((2 R ,4 S ,5 S )-4,5-diaminotetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3, To a solution of 4-dihydroisoquinolin-2(1 H )-yl)methanone (90 mg, 0.244 mmol) in hexafluoroisopropanol (1.975 mL, 18.76 mmol) was added trimethyl orthoformate (0.030 mL, 0.270 mmol). After 1 hour, the reaction mixture was concentrated under reduced pressure and analyzed by acidic 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) purified residue. The product was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (7 M). The alkaline fraction was concentrated to dryness under reduced pressure. The product was further purified by preparative SFC (Method AT) and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give (( S )-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1 H )-yl)((3a S ,6 R ,7a S )-1,3a,4,6,7,7a-hexahydropirano[3,4-d ]imidazol-6-yl)methanone ( compound 5430 ).

LCMS: 98%, RT=1.01 min, (M+H) ⁺ =380 (Method P). Example 118

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 R )-4-hydroxy-5 -(Methylamino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5431)

Synthesis of (3aR,6R,7aS)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-4H-piper Nand[3,4-d] Azol-2(3H)-one.

Under an argon atmosphere, to ((3 R ,4 S ,6 R )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)-4-hydroxytetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5052, 300 mg, 0.638 mmol) in tetrahydrofuran (anhydrous, 15 mL) Sodium hydride (60 wt% dispersion in mineral oil, 25.5 mg, 0.638 mmol) was added. The reaction mixture was warmed to 40°C and stirred overnight. Subsequently, the mixture was cooled to room temperature and diluted with dichloromethane (15 mL) and saturated aqueous _NH4Cl (20 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2 x 15 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 30 to 100% ethyl acetate in heptane) to give (3a R , 6 R , 7a S )-6-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 4H -pirano[3,4-d] Azol-2( 3H )-one.

LCMS: 99%, RT=2.07 minutes, (M+H) ⁺ =397 (Method A).

Synthesis of (3aR,6R,7aS)-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methyltetrakis Hydro-4H-pirano[3,4-d] Azol-2(3H)-one.

To (3a R ,6 R ,7a S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine at 0°C under nitrogen atmosphere Phino-2-carbonyl)tetrahydro- 4H -pirano[3,4-d] To a solution of azole-2(3 H )-one (0.16 g, 0.404 mmol) in N , N -dimethylformamide (anhydrous, 4 mL) was added sodium hydride (60 wt% dispersion in mineral oil liquid, 19.4 mg, 0.484 mmol). After 30 minutes, methyl iodide (0.136 mL, 2.180 mmol) was added and the reaction mixture was slowly warmed to room temperature. After stirring overnight, the mixture was diluted with a mixture of water and brine (1:1). The precipitate formed was collected by filtration, washed with water and dried on the filter by air flow to give (3a R , 6 R , 7a S )-6-(( S )-1-(4-fluorophenyl)- 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-3-methyltetrahydro- 4H -pirano[3,4-d] Azol-2( 3H )-one.

LCMS: 100%, RT=1.95 minutes, (M+H) ⁺ =411 (Method B).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S,5R)-4-hydroxy-5-(methane) (Amino)tetrahydro-2H-pyran-2-yl)methanone (Compound 5431 )

To (3a R ,6 R ,7a S )-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3- Methyltetrahydro- 4H -pirano[3,4-d] To a solution of azole-2(3 H )-one (108 mg, 0.263 mmol) in methanol (15 mL) was added aqueous sodium hydroxide (2 M, 1.316 mL, 2.63 mmol), and the mixture was warmed to 70 °C. After stirring overnight, additional sodium hydroxide (solid, 105 mg, 2.63 mmol) was added and stirring was continued for 5 days. Subsequently, the mixture was warmed to 80°C and stirred for another day. After cooling to room temperature, the solvent was partially removed under reduced pressure, and the residue was diluted with water and aqueous HCl (1 M, 5 mL). The resulting suspension was extracted (twice) with dichloromethane, and the combined organic layers were dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by preparative SFC (method BT) to give (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 R )-4-hydroxy-5-(methylamino)tetrahydro-2 H -pyran-2-yl)methanone ( compound 5431 ).

LCMS: 97%, RT=1.00 min, (M+H) ⁺ =385 (Method P). SFC: 96%, RT=4.43 minutes, (M+H) ⁺ =385 (Method F). Example 119

((2 R ,4 S ,5 R )-4-amino-5-methyltetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5518) and ((2 R ,4 S ,5 S )-4-amino-5-methyltetrahydro-2 H -Pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5519)

Synthesis of ((2R,4S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-side oxytetrakis Hydrogen-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

At 0°C, to ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 To a solution of -carbonyl)-5-hydroxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5052, 1000 mg, 2.125 mmol) in dichloromethane (20 mL) was added Dess-Martin periodane (992 mg, 2.338 mmol). The resulting mixture was allowed to warm to room temperature. After 3 hours, the reaction mixture was diluted with a mixture of saturated aqueous Na ₂ S ₂ O ₃ solution and saturated aqueous NaHCO ₃ solution (1:1, 40 mL) and stirred for 30 minutes. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 40 mL). The combined organic layers were washed with _brine (40 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give ((2 R ,4 S )-2-(( S )-1-(4 -Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-side oxytetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 100%, RT=2.02 minutes + 2.11-2.14 minutes, (M-( t -Bu) + H) ⁺ =413 (Method A).

Synthesis of ((2R,4S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methyltetrakis Hydrogen-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To a suspension of methyltriphenylphosphonium bromide (427 mg, 1.195 mmol) in tetrahydrofuran (anhydrous, 5 mL) was added potassium tert. butoxide (1.0 M in THF, 1.024 mL) at 0 °C. 1.024 mmol). After 30 minutes, ((2 R ,4 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl was added dropwise )-5-Pendantoxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (400 mg, 0.854 mmol) in tetrahydrofuran (anhydrous, 2.5 mL). After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. Dilute the mixture with saturated aqueous ammonium chloride (5 mL) and methylene chloride (30 mL). The organic layer was _separated , washed with brine (10 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) and preparative SFC (Method BR) to give ((2 R ,4 S )-2-( (S)-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-5-methyltetrahydro- 2H -piran-4-yl ) tertiary butyl carbamate as the first eluted SFC isomer and ((2 S ,4 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)-5-methyltetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester was used as the second eluting SFC isomer.

First eluting SFC isomer LCMS: 99%, RT=2.22 minutes, (M+H) ⁺ =467 (Method A). SFC: 99%, RT=2.13 minutes, (M+H) ⁺ =467 (Method V).

Second eluting SFC isomer LCMS: 92%, RT=2.19 minutes, (M+H) ⁺ =467 (Method A). SFC: 97%, RT=2.36 minutes, (M+H) ⁺ =467 (Method V).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methyl Tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

((2 R ,4 S )-2-(( S )-1-(4-fluoro) in the presence of palladium (10 wt% on carbon, 23.27 mg, 0.022 mmol) under atmospheric hydrogen pressure Phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methyltetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester (102 mg , 0.219 mmol) in ethanol (2 mL) was hydrogenated. After stirring overnight, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative SFC (method BT) to give ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4 -Tetrahydroisoquinoline-2-carbonyl)-5-methyltetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester as the first eluting SFC isomer and ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-methyltetrahydro-2 H -pyran-4-yl)carbamate tertiary butyl ester as the second eluting SFC isomer.

The first eluted SFC isomer. LCMS: 99%, RT=2.25 minutes, (M+H) ⁺ =469 (Method A). SFC: 100%, RT=2.58 minutes, (M+H) ⁺ =469 (Method F).

The second eluted SFC isomer. LCMS: 94%, RT=2.21 minutes, (M+H) ⁺ =469 (Method A). SFC: 95%, RT=2.83 minutes, (M+H) ⁺ =469 (Method F).

Synthesis of ((2R,4S,5R)-4-amino-5-methyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5518 ).

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of -methyltetrahydro- 2H -pyran-4-yl)carbamic acid tert-butyl ester (59 mg, 0.126 mmol) in 2-propanol (3 mL) was added HCl (6 M in 2- in propanol, 0.3 mL, 1.80 mmol). After 4 days, the reaction mixture was diluted with dichloromethane (10 mL) and saturated _aqueous NaHCO (10 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:2, 3 mL) to give (( 2R , 4S , 5R )-4-amino-5-methyltetrahydro- 2H -piper Pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5518 ).

LCMS: 99%, RT=2.77 minutes, (M+H) ⁺ =369 (Method AK).

Synthesis of ((2R,4S,5S)-4-amino-5-methyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5519 ).

To ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of -methyltetrahydro- 2H -pyran-4-yl)carbamic acid tert-butyl ester (17 mg, 0.036 mmol) in 2-propanol (1 mL) was added HCl (6 M in 2- in propanol, 0.1 mL, 0.60 mmol). After 4 days, the reaction mixture was diluted with dichloromethane (5 mL) and saturated _aqueous NaHCO (5 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:2, 3 mL) to give (( 2R , 4S , 5S )-4-amino-5-methyltetrahydro- 2H -piper Pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5519 ).

LCMS: 93%, RT=2.73 minutes, (M+H) ⁺ =369 (Method AK). Example 120

((2 R ,4 S ,5 R )-4-amino-5-(ethylthio)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5521)

Synthesis of N-((2R,4S,5R)-5-(ethylthio)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonamide.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((1 S ,4 R ,6 S )-7-methyl Benzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (see compound 5520, 200 mg, 0.395 mmol) in 1,4-di To the suspension in alkanes (6 mL) was added sodium ethyl mercaptide (66.4 mg, 0.790 mmol). After stirring overnight, additional sodium ethethiolate (33.2 mg, 0.395 mmol) was added and the mixture was warmed to 40°C. After stirring overnight, additional sodium ethyl mercaptide (266 mg, 3.16 mmol) was added and stirring was continued for a further 3 days. Subsequently, the mixture was diluted with dichloromethane (10 mL), washed with saturated _aqueous NaHCO solution, passed through a hydrophobic glass frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 40% ethyl acetate in heptane) to give N -(( 2R , 4S , 5R )-5-(ethylthio) )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-4-yl) -4-Toluenesulfonamide.

LCMS: 98%, RT=2.40 minutes, (M+H) ⁺ =569 (Method A).

Synthesis of ((2R,4S,5R)-5-(ethylthio)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro-2H-piran-4-yl)(toluenesulfonyl)carbamic acid tertiary butyl ester.

To N -((2 R ,4 S ,5 R )-5-(ethylthio)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro To a solution of isoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)-4-methylbenzenesulfonamide (70 mg, 0.123 mmol) in tetrahydrofuran (5 mL) was added triethyl Amine (0.034 mL, 0.246 mmol), 4-dimethylaminopyridine (1.504 mg, 0.012 mmol), and di-tertiary butyl dicarbonate (53.7 mg, 0.246 mmol). After the reaction mixture was stirred for 3 hours, additional di-tertiary butyl dicarbonate (26.9 mg, 0.123 mmol) was added and stirring was continued for another hour. Subsequently, the mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica, 20 to 100% ethyl acetate in heptane) to give ((2 R , 4 S , 5 R )-5-(ethylthio)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -Pyran-4-yl)(methylbenzenesulfonyl)carbamic acid tertiary butyl ester.

LCMS: 98%, RT=2.43 minutes, (M+H) ⁺ =669 (Method A).

Synthesis of ((2R,4S,5R)-5-(ethylthio)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carboyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-(ethylthio)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine A solution of tertiary butyl pholin-2-carbonyl)tetrahydro- 2H -piran-4-yl)(toluenesulfonyl)carbamate (60 mg, 0.090 mmol) in methanol (5 mL) Magnesium (109 mg, 4.49 mmol) and ammonium chloride (48.0 mg, 0.897 mmol) were added. After stirring overnight, additional magnesium was added and the reaction was stirred for an additional hour. Subsequently, the mixture was diluted with a saturated aqueous solution of NH ₄ Cl and after stirring for a few minutes, the mixture was extracted with dichloromethane. The organic layer was passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-5-(ethylthio)- 2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-4-yl)carbamic acid Tertiary butyl ester.

LCMS: 96%, RT=2.26 minutes, (M+H) ⁺ =515 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-(ethylthio)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5521 ).

To ((2 R ,4 S ,5 R )-5-(ethylthio)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine To a solution of tertiary butyl pholin-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamate (23 mg, 0.045 mmol) in 2-propanol (3 mL) was added HCl (6 M in 2-propanol, 2 mL, 12.00 mmol). After stirring for 2 h, additional HCl (6 M in 2-propanol, 2 mL, 12.00 mmol) was added. After 1 hour, the reaction mixture was diluted with saturated aqueous _NaHCO3 solution and extracted with dichloromethane. The organic layer was passed through a phase separator and evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto the SCX-2 column and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water to give (( 2R , 4S , 5R )-4-amino-5-(ethylthio)tetrahydro- 2H -piran-2-yl )(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5521 ).

LCMS: 97%, RT=1.18 minutes, (M+H) ⁺ =415 (Method P). Example 121

((2 R ,4 S ,5 R )-4-amino-5-(methylthio)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5520)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((1S,4R,6S)-7-methylbenzenesulfonyl -3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone.

To (( R )-3,6-dihydro-2 H -piran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( To a solution of 1 H )-yl)methanone (see compound 5053, 1.0 g, 2.96 mmol) in acetonitrile (12.5 mL) was added chloramine-T hydrate (801 mg, 3.26 mmol) and phenyltrimethyltrimethyl Ammonium bromide (111 mg, 0.296 mmol). After 1 day, the white precipitate was filtered out, washed with acetonitrile, and dried on the filter by air flow to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline- 2(1 H )-yl)((1 S ,4 R ,6 S )-7-methylbenzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl ) methyl ketone.

LCMS: 96%, RT=2.18 minutes, (M+H) ⁺ =507 (Method A).

Synthesis of N-((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- (Methylthio)tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonamide.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((1 S ,4 R ,6 S )-7-methyl Benzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (200 mg, 0.395 mmol) in 1,4-di To a solution in alkanes (6 mL) was added sodium methylthiolate (55.3 mg, 0.790 mmol). After stirring overnight, the mixture was diluted with dichloromethane (10 mL), washed with saturated aqueous NaHCO solution, passed through a _hydrophobic glass frit, and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 40% ethyl acetate in heptane) to give N -((2 R ,4 S ,5 R )-2-(( S ) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(methylthio)tetrahydro- 2H -piran-4-yl) -4-Toluenesulfonamide.

LCMS: 99%, RT=2.20 minutes, (M+H) ⁺ =555 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(methyl Thio)tetrahydro-2H-piran-4-yl)(toluenesulfonyl)carbamic acid tertiary butyl ester.

To N -((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) To a solution of -5-(methylthio)tetrahydro- 2H -piran-4-yl)-4-methylbenzenesulfonamide (70 mg, 0.126 mmol) in tetrahydrofuran (5 mL) was added triethyl amine (0.035 mL, 0.252 mmol), 4-dimethylaminopyridine (1.5 mg, 0.013 mmol), and di-tertiary butyl dicarbonate (55.1 mg, 0.252 mmol). After 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 20 to 100% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-2-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(methylthio)tetrahydro- 2H -piran-4-yl)(methyl Benzene sulfonyl) tertiary butyl carbamate.

LCMS: 99%, RT=2.40 minutes, (M+H) ⁺ =655 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(methyl Thio)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(Methylthio)tetrahydro- 2H -piran-4-yl)(toluenesulfonyl)carbamic acid tertiary butyl ester (80 mg, 0.122 mmol) in methanol (5 mL) Magnesium (120 mg, 4.94 mmol) and ammonium chloride (65.3 mg, 1.22 mmol) were added. After stirring overnight, additional magnesium (50 mg, 1.24 mmol) and ammonium chloride (20 mg, 0.37 mmol) were added and stirring was continued for 2 hours. Subsequently, the mixture was diluted with saturated aqueous NH ₄ Cl solution, stirred for a few minutes and extracted with dichloromethane. The combined organics were passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-2-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(methylthio)tetrahydro- 2H -piran-4-yl)carbamic acid tris grade butyl ester.

LCMS: 94%, RT=2.21 minutes, (M+H) ⁺ =501 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-(methylthio)tetrahydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5520 ).

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of tert-butyl -(methylthio)tetrahydro- 2H -piran-4-yl)carbamate (36 mg, 0.072 mmol) in 2-propanol (3 mL) was added HCl (6 M in 2-propanol, 3 mL, 18.0 mmol). After 2 hours, additional HCl (6 M in 2-propanol, 2 mL, 12.0 mmol) was added and stirring was continued overnight. Dilute the reaction mixture with dichloromethane and saturated _aqueous NaHCO solution. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto the SCX-2 column and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water to give (( 2R , 4S , 5R )-4-amino-5-(methylthio)tetrahydro- 2H -piran-2-yl )(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5520 ).

LCMS: 97%, RT=1.13 minutes, (M+H) ⁺ =401 (Method P). Example 122

((2 R ,4 S ,5 R )-4-amino-5-(methylsulfonyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5523)

Synthesis of N-((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- (Methylsulfonamide)tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonamide.

At 0°C, to N -((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-carbonyl)-5-(methylthio)tetrahydro- 2H -piran-4-yl)-4-methylbenzenesulfonamide (see compound 5520 , 70 mg, 0.126 mmol) in dichloromethane (4 mL) was added m-chloroperbenzoic acid (70 wt%, 78 mg, 0.315 mmol). After 1 hour, the reaction mixture was diluted with a mixture of saturated _aqueous NaHCO, aqueous NaOH (1 M) and water (1:1:1). The organic layer was separated using a phase separator and evaporated under reduced pressure to give N -(( 2R , 4S , 5R )-2-(( S )-1-(4-fluorophenyl)-1,2 ,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(methylsulfonyl)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide.

LCMS: 93%, RT=2.07 minutes, (M+H) ⁺ =587 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(methyl Tertiary butyl methylbenzenesulfonyl)tetrahydro-2H-pyran-4-yl)(methylbenzenesulfonyl)carbamate.

To N -((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) To a solution of -5-(methylsulfonyl)tetrahydro- 2H -piran-4-yl)-4-methylbenzenesulfonamide (70 mg, 0.119 mmol) in tetrahydrofuran (5 mL) was added Triethylamine (0.033 mL, 0.239 mmol), 4-dimethylaminopyridine (1.458 mg, 0.012 mmol), and di-tertiary butyl dicarbonate (52.1 mg, 0.239 mmol). After 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 20 to 100% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-2-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-5-(methylsulfonyl)tetrahydro- 2H -piran-4-yl) (Toluenesulfonyl)carbamic acid tertiary butyl ester.

LCMS: 96%, RT=2.28 minutes, (M+H) ⁺ =687 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(methyl Tertiary butyl sulfonyl)tetrahydro-2H-pyran-4-yl)carbamate.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(methylsulfonyl)tetrahydro- 2H -piran-4-yl)(methylbenzenesulfonyl)carbamic acid tertiary butyl ester (75 mg, 0.109 mmol) in methanol (5 mL) Magnesium (133 mg, 5.46 mmol) and ammonium chloride (58.4 mg, 1.092 mmol) were added to the solution. After stirring overnight, the mixture was diluted with saturated aqueous _NH4Cl solution and the reaction was stirred for a few minutes. Subsequently, the mixture was extracted with dichloromethane. The combined organics were passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-2-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-5-(methylsulfonyl)tetrahydro- 2H -piran-4-yl) Tertiary butyl carbamate.

LCMS: 99%, RT=2.08 minutes, (M+H) ⁺ =533 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-(methylsulfonyl)tetrahydro-2H-piran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5523 ).

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of tert-butyl -(methylsulfonyl)tetrahydro- 2H -piran-4-yl)carbamate (45 mg, 0.084 mmol) in 2-propanol (3 mL) was added HCl ( 6 M in 2-propanol, 2 mL, 12.0 mmol). After 2 hours, additional HCl (6 M in 2-propanol, 2 mL, 12.0 mmol) was added, and after the mixture was stirred overnight, another portion of HCl (6 M in 2-propanol, 2 mL , 12.0 mmol). After 3 hours, the mixture was basified with _NaHCO3 and extracted with dichloromethane. The combined organics were passed through a phase separator and evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 10% A; t=1 minute 10% A; t=16 minutes 50% A; t=17 minutes 100%; t=22 minutes 100% A; (measured at 220 nm) purified residue. The products containing the fractions were combined, basified with saturated aqueous NaHCO ₃ and the volatiles were removed under reduced pressure. The aqueous residue was extracted with dichloromethane and the combined organics were passed through a phase separator and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water to give (( 2R , 4S , 5R )-4-amino-5-(methylsulfonyl)tetrahydro- 2H -piran-2 -yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5523 ).

LCMS: 99%, RT=1.06 minutes, (M+H) ⁺ =433 (Method P). Example 123

((2 R ,4 S ,5 R )-4-amino-5-(ethylsulfonyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluoro Phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5524)

Synthesis of N-((2R,4S,5R)-5-(ethylsulfonyl)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroiso Quinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonamide.

At 0°C, to N -((2 R ,4 S ,5 R )-5-(ethylthio)-2-(( S )-1-(4-fluorophenyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)-4-methylbenzenesulfonamide (see compound 5521, 70 mg, 0.123 mmol) in dichloromethane (4 mL) was added m-chloroperbenzoic acid (70 wt%, 76 mg, 0.308 mmol). After 1 hour, the reaction mixture was diluted with a mixture of saturated _aqueous NaHCO, aqueous NaOH (1 M) and water (1:1:1). The organic layer was separated using a phase separator and evaporated under reduced pressure to give N -(( 2R , 4S , 5R )-5-(ethylsulfonyl)-2-(( S )-1-( 4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide.

LCMS: 96%, RT=2.10 minutes, (M+H) ⁺ =601 (Method A).

Synthesis of ((2R,4S,5R)-5-(ethylsulfonyl)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)tetrahydro-2H-pyran-4-yl)(methylbenzenesulfonyl)carbamic acid tertiary butyl ester.

To N -((2 R ,4 S ,5 R )-5-(ethylsulfonyl)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4- To a solution of tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)-4-methylbenzenesulfonamide (70 mg, 0.117 mmol) in tetrahydrofuran (5 mL) was added Triethylamine (0.032 mL, 0.233 mmol), 4-dimethylaminopyridine (1.424 mg, 0.012 mmol), and di-tertiary butyl dicarbonate (50.9 mg, 0.233 mmol). After 2 and 3 hours respectively, additional portions of di-tertiary butyl dicarbonate (50.9 mg, 0.233 mmol and 25.4 mg, 0.117 mmol) were added and stirring was continued for another hour. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica, 20 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )- 5-(ethylsulfonyl)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -Pyran-4-yl)(methylbenzenesulfonyl)carbamic acid tertiary butyl ester.

LCMS: 94%, RT=2.31 minutes, (M+H) ⁺ =701 (Method A).

Synthesis of ((2R,4S,5R)-5-(ethylsulfonyl)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-(ethylsulfonyl)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)(toluenesulfonyl)carbamate tertiary butyl ester (69 mg, 0.098 mmol) in methanol (5 mL) Magnesium (120 mg, 4.92 mmol) and ammonium chloride (52.7 mg, 0.985 mmol) were added to the solution. After stirring overnight, the mixture was diluted with saturated aqueous _NH4Cl solution and the reaction was stirred for a few minutes. Subsequently, the mixture was extracted with dichloromethane. The combined organics were passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give tris(( 2R , 4S , 5R )-5-(ethylsulfonate) base)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl ) carbamate grade butyl ester.

LCMS: 100%, RT=2.12 minutes, (M+H) ⁺ =547 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-(ethylsulfonyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5524 ).

To ((2 R ,4 S ,5 R )-5-(ethylsulfonyl)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro To a solution of tertiary butyl isoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid (39 mg, 0.071 mmol) in 2-propanol (3 mL) was added HCl ( 6 M in 2-propanol, 2 mL, 12.0 mmol). After 5 hours, additional HCl (6 M in 2-propanol, 2 mL, 12.0 mmol) was added, and after the mixture was stirred overnight, another portion of HCl (6 M in 2-propanol, 2 mL , 12.0 mmol). After 3 hours, the mixture was basified with _NaHCO3 and extracted with dichloromethane. The combined organics were passed through a phase separator and evaporated under reduced pressure. The residue was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 10% A; t=1 minute 10% A; t=16 minutes 50% A; t=17 minutes 100%; t=22 minutes 100% A; (measured at 220 nm) purified residue. The products containing the fractions were combined, basified with saturated aqueous NaHCO ₃ and the volatiles were removed under reduced pressure. The aqueous residue was extracted with dichloromethane and the combined organics were passed through a phase separator and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water to obtain (( 2R , 4S , 5R )-4-amino-5-(ethylsulfonyl)tetrahydro- 2H -piran-2 -yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5524 ).

LCMS: 99%, RT=1.09 minutes, (M+H) ⁺ =447 (Method P). Example 124

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-hexahydro-2 H ,5 H -pirano[4,3-b][1,4] -7-yl)methanone (compound 5432)

Synthesis of (4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H,5H -pirano[4,3-b][1,4] -3(4H)-one.

To ((2 R ,4 S ,5 R )-5-amino-4-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5052, 145 mg, 0.391 mmol) and N,N -diisopropylethylamine (0.205 mL, 1.174 mmol) in tetrahydrofuran To a solution of bromoacetyl chloride (0.036 mL, 0.431 mmol) in tetrahydrofuran (3.5 mL) was added. After 1 hour, sodium hydride (60 wt% dispersion in mineral oil, 47.0 mg, 1.174 mmol) was added. After stirring overnight, the reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and diluted with dichloromethane (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 10 mL). The combined organics were passed through a phase separator and evaporated under reduced pressure. The residue was suspended in a mixture of methanol and acetonitrile (approximately 1:1, 5 mL) and filtered. By acidic 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 minutes 100% A; detection: 220 nm) purify the filtrate to obtain (4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H , 5H -pirano[4,3-b][1,4] -3(4 H )-ketone.

LCMS: 95%, RT=1.86 minutes, (M+H) ⁺ =411 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-hexahydro-2H,5H-piper Nand[4,3-b][1,4] -7-yl)methanone ( compound 5432 ).

To (4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2 H ,5 H -pirano[4,3-b][1,4] To a solution of -3(4 H )-one (7 mg, 0.017 mmol) in tetrahydrofuran (anhydrous, 1 mL) was added borane-methyl sulfide complex (2 M, 0.034 mL, 0.068 mmol). After 3 hours, another portion of borane-methyl sulfide complex (2 M, 0.017 mL, 0.034 mmol) was added and stirring was continued for 2 hours. Subsequently, a mixture of aqueous HCl (1 M) and methanol (1:1, 1 mL) was added, and after the reaction mixture was stirred for 3 days, the mixture was diluted with dichloromethane (5 mL) and _saturated aqueous NaHCO (5 mL). reaction mixture. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. 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% A; t=18 min 100%; t =23 min 100% A; detection: 220 nm) purified residue. The product was dissolved in methanol and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl) ((4a R ,7 R ,8a S )-hexahydro-2 H ,5 H -pirano[4,3-b][1,4] -7-yl)methanone ( compound 5432 ).

LCMS: 99%, RT=1.05 minutes, (M+H) ⁺ =397 (Method P). Example 125

((2 R ,4 S ,5 R )-4-amino-5-(benzyloxy)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorobenzene methyl)-3,4-dihydroisoquinoline-2(1 H )-yl)methanone (compound 5531)

Synthesis of ((2R,4S,5S)-5-(benzyloxy)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone.

To benzyl alcohol (1 mL, 9.66 mmol) was added sodium hydride (60 wt% dispersion in mineral oil, 0.050 g, 1.245 mmol). After 5 minutes, add ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorobenzene yl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 0.20 g, 0.566 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous _NH4Cl (5 mL). The aqueous layer (2×5 mL) was extracted with dichloromethane and the combined organic layers were passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 30 to 70% ethyl acetate in heptane) to give (( 2R , 4S , 5S )-5-(benzyloxy) -4-Hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methone.

LCMS: 98%, RT=2.10 minutes, (M+H) ⁺ =462 (Method A).

Synthesis of methanesulfonic acid (2R,4S,5S)-5-(benzyloxy)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro-2H-pyran-4-yl ester.

To ((2 R ,4 S ,5 S )-5-(benzyloxy)-4-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1- To a solution of (4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (150 mg, 0.325 mmol) in dichloromethane (10 mL) was added triethyl amine (0.136 mL, 0.975 mmol), followed by methanesulfonyl chloride (0.038 mL, 0.488 mmol). After 2 hours, another portion of triethylamine (0.091 mL, 0.650 mmol) was added, followed by methanesulfonyl chloride (0.025 mL, 0.325 mmol). After 0.5 h, the mixture was diluted with saturated aqueous _NaHCO3 solution and the layers were separated. The organic layer was washed with NH ₄ Cl saturated aqueous solution, passed through a phase separator, and evaporated under reduced pressure to obtain methane sulfonic acid (2 R , 4 S , 5 S )-5-(benzyloxy) as a white solid )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-4-yl ester (174 mg).

LCMS: 97%, RT=2.20 minutes, (M+H) ⁺ =540 (Method A).

Synthesis of ((2R,4S,5R)-4-azido-5-(benzyloxy)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone.

To methanesulfonic acid (2 R ,4 S ,5 S )-5-(benzyloxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4- To a solution of tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl ester (173 mg, 0.321 mmol) in N , N -dimethylformamide (4 mL) was added After adding sodium azide (62.5 mg, 0.962 mmol), the reaction mixture was warmed to 80 °C. After stirring overnight, the mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over _Na2SO4 and evaporated under reduced _pressure . The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-4-azido-5- (Benzyloxy)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )- base) methanone.

LCMS: 99%, RT=2.31 minutes, (M+H) ⁺ =487 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-(benzyloxy)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5531 ).

To ((2 R ,4 S ,5 R )-4-azido-5-(benzyloxy)tetrahydro-2 H -piran-2-yl)(( S )-1-(4- To a solution of fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (120 mg, 0.247 mmol) in THF was added trimethylphosphine (1.0 M in THF, 370 µL ,0.370 mmol). After stirring overnight, another portion of trimethylphosphine (1.0 M in THF, 247 µL, 0.247 mmol) was added and the reaction was stirred for an additional 4 hours. Subsequently, the reaction mixture was diluted with aqueous NaOH solution (1 M) and stirred for 5 min. The mixture was extracted with dichloromethane and the combined organics were passed through a phase separator and evaporated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column, and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water to give (( 2R , 4S , 5R )-4-amino-5-(benzyloxy)tetrahydro- 2H -piran-2- yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5531 ).

LCMS: 99%, RT=1.27 minutes, (M+H) ⁺ =461 (Method P). Example 126

((2 R ,4 S ,5 R )-4-amino-5-cyclopropoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-

Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5530)

Synthesis of ((2R,4S,5S)-5-cyclopropoxy-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone.

To cyclopropanol (574 µL, 9.07 mmol) was added sodium hydride (60 wt% dispersion in mineral oil, 32.2 mg, 0.805 mmol) portionwise at 0°C. After 5 minutes, add ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorobenzene yl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 115 mg, 0.325 mmol) and the reaction mixture was warmed to 60°C. After 1 hour, the mixture was cooled to room temperature, diluted with dichloromethane (3 mL) and washed with saturated aqueous NH ₄ Cl (3 mL). The organic layer was passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give ((2 R , 4 S , 5 S )-5-cyclo as a colorless oil Propoxy-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) -methyl)methanone (impure, 99 mg) and it was used as received.

LCMS: 93%, RT=1.97 minutes, (M+H) ⁺ =412 (Method A).

Synthesis of methanesulfonic acid (2R,4S,5S)-5-cyclopropoxy-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-4-yl ester.

To ((2 R ,4 S ,5 S )-5-cyclopropoxy-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) To a solution of -3,4-dihydroisoquinolin-2(1 H )-yl)methanone (impure, 98 mg, 0.238 mmol) in dichloromethane (4 mL) was added triethylamine (0.099 mL, 0.715 mmol), followed by methane sulfonyl chloride (0.028 mL, 0.357 mmol). After 1 hour, another portion of methanesulfonate chloride (9.22 µL, 0.119 mmol) was added and stirring was continued overnight. Wash the reaction mixture with aqueous citric acid solution (0.5 M, 4 mL) and saturated _aqueous NaHCO solution (4 mL). The organic layer was passed through a phase separator and evaporated under reduced pressure to give methanesulfonic acid ( 2R , 4S , 5S )-5-cyclopropoxy-2-(( S )- as a yellow foam/oil) 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl ester (impure, 101 mg) and its Use as is.

LCMS: 91%, RT=2.16 minutes, (M+H) ⁺ =490 (Method B).

Synthesis of ((2R,4S,5R)-4-azido-5-cyclopropoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone.

To methanesulfonic acid (2 R ,4 S ,5 S )-5-cyclopropoxy-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro To a solution of isoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl ester (101 mg, 0.206 mmol) in N , N -dimethylformamide (4 mL) was added azide After adding sodium (40.2 mg, 0.619 mmol), the reaction mixture was warmed to 80 °C. After stirring overnight, another portion of sodium azide (40.2 mg, 0.619 mmol) was added and stirring continued overnight. Subsequently, the mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-4-azido-5- Cyclopropoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methone.

LCMS: 96%, RT=2.24 minutes, (M+H) ⁺ =437 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-cyclopropoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5530 ).

((2 R ,4 S ,5 R )-4-azido in the presence of palladium (10 wt% on carbon, 50% water, 19.50 mg, 9.16 µmol) under atmospheric hydrogen pressure -5-cyclopropoxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) A solution of -yl)methanone (40 mg, 0.092 mmol) in tetrahydrofuran (4 mL) was hydrogenated. After stirring for 2 hours, the mixture was filtered on a 0.22 µm nylon filter. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, loaded onto an SCX-2 column (1 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure to obtain ((2 R , 4 S , 5 R )-4-amino-5-cyclopropoxytetrahydro-2 H -piran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5530 ).

LCMS: 97%, RT=1.15 minutes, (M+H) ⁺ =411 (Method P). Example 127

((2 R ,4 S ,5 R )-4-amino-5-phenoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5527)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S,5S)-4-hydroxy-5-phenoxy Tetrahydro-2H-pyran-2-yl)methanone.

To phenol (666 mg, 7.07 mmol) was added sodium hydride (60 wt% dispersion in mineral oil, 28.3 mg, 0.707 mmol). After 5 minutes, add ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorobenzene yl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 100 mg, 0.283 mmol) and the reaction mixture was warmed to 60 °C. After 1 hour, the mixture was diluted with tetrahydrofuran (anhydrous, 1 mL). After another hour, the mixture was cooled to room temperature, diluted with dichloromethane (3 mL) and washed with saturated aqueous _NH4Cl (3 mL). The organic layer was passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-4-hydroxy-5-phenoxytetrahydro-2 H -pyran-2-yl)methanone.

LCMS: 96%, RT=2.11 minutes, (M+H) ⁺ =448 (Method A).

Synthesis of methane sulfonic acid (2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- Phenoxytetrahydro-2H-pyran-4-yl ester.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-4-hydroxy- To a solution of 5-phenoxytetrahydro- 2H -piran-2-yl)methanone (100 mg, 0.223 mmol) in dichloromethane (4 mL) was added triethylamine (0.105 mL, 0.754 mmol) , followed by methanesulfonate chloride (0.029 mL, 0.377 mmol). After 1 hour, the reaction mixture was washed with aqueous citric acid solution (0.5 M, 4 mL) and saturated _aqueous NaHCO solution (4 mL). The organic layer was passed through a phase separator and evaporated under reduced pressure to give methanesulfonic acid ( 2R , 4S , 5S )-2-(( S )-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinolin-2-carbonyl)-5-phenoxytetrahydro- 2H -pyran-4-yl ester.

LCMS: 96%, RT=2.20 minutes, (M+H) ⁺ =526 (Method A).

Synthesis of ((2R,4S,5R)-4-azido-5-phenoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1H)-yl)methanone.

To methanesulfonic acid (2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl To a solution of )-5-phenoxytetrahydro- 2H -pyran-4-yl ester (102 mg, 0.194 mmol) in N , N -dimethylformamide (4 mL) was added azide After adding sodium (25.2 mg, 0.388 mmol), the reaction mixture was warmed to 80 °C. After stirring overnight, another portion of sodium azide (25.2 mg, 0.388 mmol) was added and stirring was continued for another hour. Subsequently, the mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-4-azido-5- Phenoxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methyl ketone.

LCMS: 99%, RT=2.31 minutes, (M+H) ⁺ =473 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-phenoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5527 ).

((2 R ,4 S ,5 R )-4-azido was dissolved in the presence of palladium (10 wt% on carbon, 50% water, 27.0 mg, 0.013 mmol) under atmospheric hydrogen pressure. -5-phenoxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H )- A solution of methyl ketone (60 mg, 0.127 mmol) in tetrahydrofuran (4 mL) was hydrogenated. After stirring overnight, the mixture was filtered on a 0.22 µm nylon filter. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, loaded onto an SCX-2 column (1 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure, and after freeze-drying from a mixture of acetonitrile and water, ((2 R , 4 S , 5 R )-4-amino-5-phenoxytetrahydro was obtained -2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone ( Compound 5527 ) .

LCMS: 99%, RT=1.26 minutes, (M+H) ⁺ =447 (Method P). Example 128

((2 R ,4 S ,5 R )-4-amino-5-cyclobutoxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5525)

Synthesis of ((2R,4S,5S)-5-cyclobutoxy-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone.

To cyclobutanol (554 µL, 7.07 mmol) was added sodium hydride (60 wt% dispersion in mineral oil, 28.3 mg, 0.707 mmol). After 5 minutes, add ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorobenzene yl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 100 mg, 0.283 mmol) and the reaction mixture was warmed to 60 °C. After 2 hours, the mixture was cooled to room temperature, diluted with dichloromethane (3 mL) and washed with saturated aqueous _NH4Cl (3 mL). The organic layer was passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5S )-5-cyclobutoxy-4 -Hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone .

LCMS: 97%, RT=2.04 minutes, (M+H) ⁺ =426 (Method A).

Synthesis of methanesulfonic acid (2R,4S,5S)-5-cyclobutoxy-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-4-yl ester.

To ((2 R ,4 S ,5 S )-5-cyclobutoxy-4-hydroxytetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl) To a solution of -3,4-dihydroisoquinolin-2(1 H )-yl)methanone (107 mg, 0.251 mmol) in dichloromethane (4 mL) was added triethylamine (0.105 mL, 0.754 mmol) ), followed by methanesulfonate chloride (0.029 mL, 0.377 mmol). After 1 hour, the reaction mixture was washed with aqueous citric acid solution (0.5 M, 4 mL) and saturated _aqueous NaHCO solution (4 mL). The organic layer was passed through a phase separator and evaporated under reduced pressure to give methanesulfonic acid ( 2R , 4S , 5S )-5-cyclobutoxy-2-(( S )-1-(4-fluorobenzene) (yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl ester.

LCMS: 95%, RT=2.18 minutes, (M+H) ⁺ =504 (Method A).

Synthesis of ((2R,4S,5R)-4-azido-5-cyclobutoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone.

To methanesulfonic acid (2 R ,4 S ,5 S )-5-cyclobutoxy-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro To a solution of isoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl ester (112 mg, 0.222 mmol) in N , N -dimethylformamide (4 mL) was added azide After adding sodium (28.9 mg, 0.445 mmol), the reaction mixture was warmed to 80 °C. After stirring overnight, the mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-4-azido-5-cyclo Butoxytetrahydro- 2H -piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methyl ketone.

LCMS: 100%, RT=2.29 minutes, (M+H) ⁺ =451 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-cyclobutoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1H)-yl)methanone ( compound 5525 ).

((2 R ,4 S ,5 R )-4-azido in the presence of palladium (10 wt% on carbon, 50% water, 6.14 mg, 2.89 µmol) under atmospheric hydrogen pressure -5-cyclobutoxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) A solution of -yl)methanone (65 mg, 0.144 mmol) in tetrahydrofuran (4 mL) was hydrogenated. After stirring overnight, the mixture was filtered on a 0.22 µm nylon filter. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, loaded onto an SCX-2 column (1 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure, and after freeze-drying from a mixture of acetonitrile and water, ((2 R , 4 S , 5 R )-4-amino-5-cyclobutoxytetrakis was obtained Hydrogen-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5525 ).

LCMS: 98%, RT=1.20 minutes, (M+H) ⁺ =425 (Method P). Example 129

((2 R ,4 S ,5 R )-4-amino-5-ethyltetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5526)

Synthesis of ((2R,4S)-5-ethylene-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydroisoquinoline-2-carbonyl Hydrogen-2H-pyran-4-yl)carbamic acid tertiary butyl ester and ((2S,4S)-5-ethylene-2-((S)-1-(4-fluorophenyl)-1, 2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To a suspension of (ethyl)triphenylphosphonium bromide (1054 mg, 2.84 mmol) in tetrahydrofuran (anhydrous, 10 mL) was added potassium tert. butoxide (1.0 M in tetrahydrofuran, 2.433 mL, 2.433 mmol). After 30 minutes, ((2 R ,4 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl was added dropwise )-5-Pendantoxytetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5518, 950 mg, 2.028 mmol) in tetrahydrofuran (anhydrous, 5 mL) and continue stirring Overnight. Subsequently, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and diluted with ethyl acetate (50 mL). The mixture was filtered and the layers separated. The organic phase was dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) and preparative SFC (method BT) to give ((2 S ,4 S )-5-substituted Ethyl-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl ) carbamate as the first soluble isomer on silica and SFC and ((2 R ,4 S )-5-ethylene-2-(( S )-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-4-yl)carbamate as a second lytic isomer on silica and SFC body.

The first soluble isomer. SFC: 100%, RT=2.66 minutes, (M+H) ⁺ =481 (Method F). LCMS: 94%, RT=2.28 minutes, (M+Na) ⁺ =503 (Method A).

Second soluble isomer. SFC: 100%, RT=3.38 minutes, (M+H) ⁺ =481 (Method F). LCMS: 100%, RT=2.19 minutes, (M+H) ⁺ =481 (Method A).

Synthesis of ((2R,4S,5R)-5-ethyl-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

((2 R ,4 S )-5-ethylene-2-(( S )- 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester (91 mg , 0.189 mmol) in ethanol (3 mL) was hydrogenated. After stirring overnight, the mixture was filtered on a 0.22 µm nylon filter and the filtrate was concentrated under reduced pressure. The residue was purified by preparative SFC (Method AE) to give ((2 R ,4 S ,5 R )-5-ethyl-2-(( S )-1-(4-fluorophenyl)-1, 2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester as the first soluble isomer and ((2 R ,4 S ,5 S )-5-ethyl-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -Pyran-4-yl)carbamic acid tertiary butyl ester as the second eluted isomer.

First soluble isomer: SFC: 100%, RT=2.57 minutes, (M+H) ⁺ =483 (Method AD). LCMS: 100%, RT=2.25 minutes, (M+H) ⁺ =483 (Method A).

Second soluble isomer: SFC: 90%, RT=2.81 minutes, (M+H) ⁺ =483 (Method AD). LCMS: 80%, RT=2.21 minutes, (M+H) ⁺ =483 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-ethyltetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4- Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5526 ).

To ((2 R ,4 S ,5 R )-5-ethyl-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 To a solution of tert-butyl -carbonyl)tetrahydro- 2H -piran-4-yl)carbamate (33 mg, 0.068 mmol) in 2-propanol (1.5 mL) was added HCl (6 M in 2- in propanol, 0.15 mL, 0.90 mmol). After stirring for 4 days, the reaction mixture was diluted with dichloromethane (10 mL) and saturated _aqueous NaHCO (10 mL). The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (2 mL), introduced onto the SCX-2 column (2 g), and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:2, 3 mL) to obtain ((2 R , 4 S , 5 R )-4-amino- 5-Ethyltetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) Methyl ketone ( compound 5526 ).

LCMS: 99%, RT=1.14 minutes, (M+H) ⁺ =383 (Method P). Example 130

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3aS,6R,7aS)-3-methyl-3,3a ,4,6,7,7a-hexahydropyrano[3,4-d]imidazol-6-yl)methanone hydrochloride (compound 5528)

Synthesis of trifluoromethanesulfonic acid (3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)tetrahydro-2H-pyran-3-yl ester.

To ((2 R ,4 S ,5 R )-4-azido-5-hydroxytetrahydro-2 H -piran-2-yl)(( S )- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5077, 0.35 g, 0.883 mmol) in dichloromethane (8 mL) To the solution was added pyridine (0.214 mL, 2.65 mmol), followed by trifluoromethanesulfonic anhydride (0.220 mL, 1.324 mmol). After 0.5 h, the reaction mixture was diluted with dichloromethane (10 mL) and washed with aqueous citric acid (0.5 M, 10 mL) and saturated _aqueous NaHCO (10 mL). The organic layer was separated, dried over _Na2SO4 and evaporated under reduced pressure to give trifluoromethanesulfonic acid ( 3R , 4S , 6R )-4 _- azido-6-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl ester.

LCMS: 100%, RT=2.28 minutes, (M+H) ⁺ =529 (Method A).

Synthesis of ((2R,4S,5S)-4-azido-5-(methylamino)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) -3,4-Dihydroisoquinolin-2(1H)-yl)methanone.

Trifluoromethanesulfonate (3 R ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl ester (0.425 g, 0.804 mmol) was dissolved in a solution of methylamine in tetrahydrofuran (2 M, 5.54 mL, 11.09 mmol). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (5 g) and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (7 M). The alkaline fraction was concentrated to dryness under reduced pressure to obtain ((2 R , 4 S , 5 S )-4-azido-5-(methylamino)tetrahydro- 2H -pyran-2 -yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 92%, RT=1.64 minutes, (M+H) ⁺ =410 (Method A).

Synthesis of ((2R,4S,5S)-4-amino-5-(methylamino)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1H)-yl)methanone.

((2 R ,4 S ,5 S )-4-azido was dissolved in the presence of palladium (10 wt% on carbon, 50% water, 7.5 mg, 0.035 mmol) under atmospheric hydrogen pressure. -5-(methylamino)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 A solution of H )-yl)methanone (0.144 g, 0.352 mmol) in tetrahydrofuran (3.5 mL) was hydrogenated. After stirring overnight, the mixture was filtered on a 0.22 µm nylon filter. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (1 mL) and introduced onto an SCX-2 column (2 g) and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (7 M). The alkaline fraction was concentrated to dryness under reduced pressure to obtain ((2 R , 4 S , 5 S )-4-amino-5-(methylamino)tetrahydro- 2H -piran-2- base) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 94%, RT=1.44 minutes, (M+H) ⁺ =384 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3aS,6R,7aS)-3-methyl-3,3a ,4,6,7,7a-hexahydropyrano[3,4-d]imidazol-6-yl)methanone hydrochloride ( compound 5528 ).

To ((2 R ,4 S ,5 S )-4-amino-5-(methylamino)tetrahydro-2 H -piran-2-yl)(( S )-1-(4-fluoro To a solution of phenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (0.192 g, 0.501 mmol) in hexafluoroisopropanol (4.06 mL, 38.6 mmol) was added the original Trimethylformate (0.061 mL, 0.554 mmol). After 4 hours, the reaction mixture was concentrated under reduced pressure to give the product as the free base (ca. 250 mg; degrades over time). To a solution of the free base (50 mg) was added HCl (4 M in 1,4-bis in alkane, 0.063 mL, 0.250 mmol) until the pH value on the pH test paper is acidic. The mixture was concentrated under reduced pressure, and the residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)((3a S ,6 R ,7a S )-3-methyl-3,3a,4,6,7,7a-hexahydropirano[3, 4-d]imidazol-6-yl)methanone hydrochloride.

LCMS: 92%, RT=1.04 minutes, (M+H) ⁺ =394 (Method P). Example 131

(( S )-1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( R )-3-methyl-3,4,6,7 -Tetrahydropirano[3,4-d]imidazol-6-yl)methanone (Compound 5529)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-3-methyl-3,4,6,7 -Tetrahydropirano[3,4-d]imidazol-6-yl)methanone ( compound 5529 ).

In a screw-capped reaction vial under an argon atmosphere, add (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3a) S ,6 R ,7a S )-3-methyl-3,3a,4,6,7,7a-hexahydropyrano[3,4-d]imidazol-6-yl)methanone (see compound 5528 , 50 mg, 0.127 mmol) in chloroform- d (3 mL) was added manganese(IV) oxide (110 mg, 1.271 mmol). Transfer the reaction vial to a preheated reaction block (62°C) and stir overnight. An additional amount of manganese(IV) oxide (110 mg, 1.271 mmol) was added and stirring was continued for 5 hours. After cooling to room temperature, the reaction mixture was filtered through a 0.45 μm filter, and the filtrate was concentrated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 min 5% A, t=1 min 5% A; t=16 min 50% A; t=17 min 100%; t=22 min 100% A; detection (Measuring: 220/254 nm), the residue was purified and after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL), (( S )-1-(4-fluorophenyl)-3,4 was obtained -Dihydroisoquinolin-2(1 H )-yl)(( R )-3-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-6-yl ) methyl ketone.

LCMS: 100%, RT=1.07 minutes, (M+H) ⁺ =392 (Method P). Example 132

(4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methyl Hexahydro- 2H -pirano[3,4-b]pyra -3(4 H )-ketone (compound 5533)

Synthesis of ((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-3-yl)(methyl)carbamic acid tertiary butyl ester.

Under nitrogen atmosphere, to ((3 R ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5532 , 400 mg, 0.807 mmol) in N , N -dimethylformamide To a solution of the amine (anhydrous, 4 mL) was added sodium hydride (60% dispersion in mineral oil, 38.7 mg, 0.969 mmol). After 15 minutes, methane iodide (0.176 mL, 2.83 mmol) was added dropwise and continued. Stir for 1 hour. Subsequently, the reaction mixture was diluted with ethyl acetate (30 mL) and brine (15 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organics were washed with _brine (2 x 10 mL), dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 40% ethyl acetate in heptane) to give (( 3R , 4S , 6R )-4-azido-6- (( S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-3-yl) (methyl) Tertiary butyl carbamate.

LCMS: 99%, RT=2.30 minutes, (M+H) ⁺ =510 (Method A).

Synthesis of ((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tetrahydro-2H-pyran-3-yl)(methyl)carbamic acid tertiary butyl ester.

((3 R ,4 S ,6 R )-4-azido was dissolved in the presence of palladium (10 wt% on carbon, 50% water, 80 mg, 0.038 mmol) under atmospheric hydrogen pressure -6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)( A solution of tert-butyl methyl)carbamate (156 mg, 0.306 mmol) in tetrahydrofuran (4 mL) was hydrogenated. After stirring overnight, the mixture was diluted with ethyl acetate and filtered on a 0.22 µm nylon filter. The filtrate was concentrated under reduced pressure and co-evaporated with dichloromethane to give (( 3R , 4S , 6R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)(methyl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=1.77 minutes, (M+H) ⁺ =484 (Method A).

Synthesis of ((2R,4S,5R)-5-((tertiary butoxycarbonyl)(methyl)amino)-2-((S)-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)glycinate methyl ester.

To ((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro- 2H -pyran-3-yl)(methyl)carbamic acid tertiary butyl ester (148 mg, 0.306 mmol) and potassium carbonate (127 mg, 0.918 mmol) in acetonitrile (2.5 mL) Add methyl bromoacetate (0.058 mL, 0.612 mmol) to the suspension. After stirring overnight, the mixture was diluted with dichloromethane and water, and the layers were separated on a phase separation filter. The organic filtrate was concentrated under reduced pressure and purified by flash column chromatography (silica, 10 to 100% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-5-((tertiary butoxycarbonyl)(methyl)amino)-2-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)glycinate methyl ester.

LCMS: 97%, RT=1.82 minutes, (M+H) ⁺ =556 (Method A).

Synthesis of (4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-methylhexane Hydro-2H-pirano[3,4-b]pyra -3(4H)-one ( compound 5533 ).

To ((2 R ,4 S ,5 R )-5-((tertiary butoxycarbonyl)(methyl)amino)-2-(( S )-1-(4-fluorophenyl)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)glycinate methyl ester (110 mg, 0.198 mmol) in 2-propanol (2 mL ), add HCl (5-6 M in 2-propanol, 0.5 mL, 3.00 mmol). After stirring overnight, the mixture was diluted with dichloromethane (10 mL) and saturated _aqueous NaHCO (10 mL) and stirred for 1 h. The layers were separated on a phase separation filter and the organic filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of methanol (32 mL) and dichloromethane (1 mL), and triethylamine (0.041 mL, 0.297 mmol) was added. After stirring for 1 hour, the mixture was concentrated to dryness under reduced pressure. Purify the residue by flash column chromatography (silica, 1 to 10% (7 M NH ₃ ) methanol/dichloromethane) and freeze in a mixture of acetonitrile and water (1:1, 4 mL). After drying, (4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -4-Methylhexahydro- 2H -pirano[3,4-b]pyra -3(4 H )-one ( compound 5533 ).

LCMS: 97%, RT=1.07 minutes, (M+H) ⁺ =424 (Method P). Example 133

(4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro-2 H -pirano[3,4-b]pyra -3(4 H )-ketone (compound 5532)

Synthesis of ((1R,4R,6R)-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone.

To (( R )-3,6-dihydro-2 H -piran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( To a solution of 1 H )-yl)methanone (see compound 5053, 2.15 g, 6.37 mmol) in hexafluoro-2-propanol (32.25 mL) was added pyridine (1.031 mL, 12.74 mmol), hydroxylamine- O -sulfonate acid (0.865 g, 7.65 mmol) and bis [rhodium (α,α,α′,α′-tetramethyl-1,3-phenylenedipropionic acid)] (0.097 g, 0.127 mmol). After stirring for 3 hours, the reaction mixture was diluted with saturated aqueous _NaHCO solution (20 mL) and extracted with dichloromethane (3 × 30 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 5% (7 M ammonia in methanol)/dichloromethane) to give ((1 R ,4 R ,6 R )-3-oxo Hetero-7-azabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )- base) methanone.

LCMS: 99%, RT=1.59 minutes, (M+H) ⁺ =353 (Method A).

Synthesis of (1R,4R,6R)-4-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-oxa- 7-Azabicyclo[4.1.0]heptane-7-carboxylic acid tertiary butyl ester.

To ((1 R ,4 R ,6 R )-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorophenyl)- To a solution of 3,4-dihydroisoquinolin-2(1 H )-yl)methanone (1.300 g, 3.69 mmol) in tetrahydrofuran (35 mL) was added di-tertiary butyl dicarbonate (1.61 g, 7.38 mmol). After 1 hour, the mixture was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give (1 R , 4 R , 6 R )-4-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-oxa-7-azabicyclo[4.1.0]heptane-7-carboxylic acid tris grade butyl ester.

LCMS: 99%, RT=2.15 minutes, (M+H) ⁺ =453 (Method B).

Synthesis of ((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

Under an argon atmosphere, to (1 R ,4 R ,6 R )-4-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)-3-oxa-7-azabicyclo[4.1.0]heptane-7-carboxylic acid tertiary butyl ester (1.25 g, 2.76 mmol) in N , N -dimethylformamide (anhydrous , 20 mL) was added ammonium chloride (0.296 g, 5.52 mmol), followed by sodium azide (0.539 g, 8.29 mmol). After the reaction mixture was stirred over the weekend, it was diluted with brine (40 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with brine (25 mL), dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 35% ethyl acetate in heptane) to give (( 3R , 4S , 6R )-4-azido-6- (( S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 100%, RT=2.23 minutes, (M+H) ⁺ =496 (Method A).

Synthesis of ((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tetrahydro-2H-pyran-3-yl)carbamic acid tertiary butyl ester.

((3 R ,4 S ,6 R )-4-azido was dissolved in the presence of palladium (10 wt% on carbon, 50% water, 0.129 g, 0.061 mmol) under atmospheric hydrogen -6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-3-yl)amine A solution of tertiary butyl formate (0.30 g, 0.605 mmol) in tetrahydrofuran (6 mL) was hydrogenated. After stirring for 2 hours, the mixture was filtered on a 0.22 µm nylon filter. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (5 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (7 M). The alkaline fraction was concentrated to dryness under reduced pressure to obtain ((3 R , 4 S , 6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1, 2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester.

LCMS: 97%, RT=1.82 minutes, (M+H) ⁺ =470 (Method A).

Synthesis of ((2R,4S,5R)-5-((tertiary butoxycarbonyl)amine)-2-((S)-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-piran-4-yl)glycinate methyl ester.

To ((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 A suspension of tert-butyl -carbonyl)tetrahydro- 2H -piran-3-yl)carbamate (120 mg, 0.256 mmol) and potassium carbonate (70.6 mg, 0.511 mmol) in acetonitrile (0.5 mL) Add methyl bromoacetate (0.024 mL, 0.256 mmol). After 2 hours, additional potassium carbonate (35.3 mg, 0.256 mmol) and methyl bromoacetate (0.024 mL, 0.256 mmol) were added and stirring continued overnight. Subsequently, the mixture was diluted with dichloromethane and water, and the layers were separated on a phase separation filter. The organic filtrate was concentrated under reduced pressure and purified by flash column chromatography (silica, 10 to 75% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-5-((tertiary butoxycarbonyl)amine)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro Isoquinolin-2-carbonyl)tetrahydro- 2H -pyran-4-yl)glycinate methyl ester.

LCMS: 98%, RT=2.13 minutes, (M+H) ⁺ =542 (Method B).

Synthesis of (4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydro-2H-piper Pyro[3,4-b]pyra -3(4H)-one ( compound 5532 ).

To ((2 R ,4 S ,5 R )-5-((tertiary butoxycarbonyl)amino)-2-(( S )-1-(4-fluorophenyl)-1,2,3 , A solution of 4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)glycinate methyl ester (86 mg, 0.159 mmol) in 2-propanol (1.5 mL) Add HCl (5-6 M in 2-propanol, 0.3 mL, 1.800 mmol). After stirring overnight, the mixture was diluted with dichloromethane (10 mL) and saturated _aqueous NaHCO (10 mL) and stirred for 10 min. The layers were separated on a phase separation filter and the organic filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of methanol (2 mL) and dichloromethane (1 mL), and triethylamine (0.022 mL, 0.159 mmol) was added. After the mixture was stirred for 1 hour, the dichloromethane was removed under reduced pressure until a precipitate began to form. Let the mixture sit for about 30 minutes. The solid formed was filtered off and lyophilized from a mixture of acetonitrile and water to give ( 4aR , 7R , 8aS )-7-(( S )-1-(4-fluorophenyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)hexahydro- 2H -pirano[3,4-b]pyra -3(4 H )-one ( compound 5532 ).

LCMS: 99%, RT=1.02 minutes, (M+H) ⁺ =410 (Method P). Example 134

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-4-methylocta Hydro- 2H -pirano[3,4-b]pyra -7-yl)methanone (compound 5462)

Synthesis of N-((2R,4S,5R)-5-amino-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro-2H-piran-4-yl)-4-methylbenzenesulfonamide.

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((1 S ,4 R ,6 S )-7-methyl Benzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (see compound 5520, 550 mg, 1.086 mmol) in ammonia (7 M in methanol, 9 mL, 63 mmol) was heated to 60°C. After stirring overnight, the reaction mixture was concentrated under reduced pressure to obtain N -((2 R ,4 S ,5 R )-5-amino-2-(( S )-1-(4-fluorophenyl)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide.

LCMS: 86%, RT=1.72 minutes, (M+H) ⁺ =524 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-1-methylbenzenesulfonyl Octahydro-2H-pirano[3,4-b]pyra -7-yl)methanone.

To N -((2 R ,4 S ,5 R )-5-amino-2-(( S )-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)-4-methylbenzenesulfonamide (480 mg, 0.917 mmol) in dichloromethane (anhydrous, To the suspension in 40 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.274 mL, 1.833 mmol), followed by vinyldiphenylsulfonate trifluoromethanesulfonate. (0.415 mL, 1.146 mmol). After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred overnight. Subsequently, the mixture was washed with aqueous HCl solution (1 M, 20 mL) and saturated _aqueous NaHCO solution (20 mL) and passed through a hydrophobic glass frit. The filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% (ethyl acetate:methanol=9:1)/heptane) to obtain (( S )-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-1-methylbenzenesulfonyloctahydro-2 H -pirano[ 3,4-b]pyridine -7-yl)methanone.

LCMS: 94%, RT=1.78 minutes, (M+H) ⁺ =550 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-4-methyl-1-methyl Benzene sulfonyl octahydro-2H-pirano[3,4-b]pyra -7-yl)methanone.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-1-methyl Benzenesulfonyloctahydro- 2H -pirano[3,4-b]pyra To a solution of -7-yl)methanone (75 mg, 0.136 mmol) in tetrahydrofuran (1.5 mL) was added formaldehyde (37 wt% solution in water, stabilized with 5-15% methanol, 0.031 mL, 0.409 mmol), Sodium triacetylborohydride (87 mg, 0.409 mmol) and acetic acid (3.94 µL, 0.068 mmol). After stirring overnight, the mixture was combined with the reaction mixture of the same reaction (0.045 mmol), diluted with dichloromethane (15 mL) and washed with saturated _aqueous NaHCO solution. Extract the aqueous layer with dichloromethane (10 mL). The combined organic layers were passed through a hydrophobic glass frit, and the filtrate was evaporated under reduced pressure to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)((4a R ,7 R ,8a S )-4-methyl-1-methylbenzenesulfonyloctahydro- 2H -pirano[3,4-b]pyra -7-yl)methanone.

LCMS: 93%, RT=1.87 minutes, (M+H) ⁺ =564 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-4-methyloctahydro-2H -Pirano[3,4-b]pyra -7-yl)methanone ( compound 5462 ).

To a solution of naphthalene (500 mg, 3.90 mmol) in tetrahydrofuran (anhydrous, 8 mL) under an argon atmosphere was added sodium block (90 mg, 3.90 mmol). The mixture was stirred for 2 hours until all sodium dissolved, yielding a solution of sodium naphthide (0.5 M in tetrahydrofuran). To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R , 7 R ,8a S )-4-methyl-1-methylbenzenesulfonyloctahydro- 2H -pirano[3,4-b]pyra To a suspension of -7-yl)methanone (92 mg, 0.163 mmol) in tetrahydrofuran (anhydrous, 1.25 mL) was added sodium naphthide (0.5 M in tetrahydrofuran, 0.653 mL, 0.326 mmol). After 15 minutes, another portion of sodium naphthide (0.5 M in tetrahydrofuran, 0.653 mL, 0.326 mmol) was added and after 15 minutes, the reaction mixture was stored in the freezer overnight. Subsequently, the mixture was diluted with dichloromethane (10 mL) and saturated aqueous NH ₄ Cl solution (5 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2 x 5 mL). The combined organic layers were passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 10% (7M NH in _methanol )/dichloromethane) and preparative SFC (Method S). The product was dissolved in methanol (1 mL), introduced onto an SCX-2 column (1 g), and eluted with methanol (volume of approximately 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline 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 was obtained ,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-4-methyloctahydro-2 H -pirano[3,4-b]pyra -7-yl)methanone ( compound 5462 ).

LCMS: 97%, RT=1.02 minutes, (M+H) ⁺ =410 (Method P). Example 135

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-octahydro-2 H -Pirano[3,4-b]pyra -7-yl)methanone (compound 5461)

Synthesis of (4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylbenzene Sulfooctahydro-4H-pirano[3,4-b]pyra -4-Carboxylic acid tertiary butyl ester.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-1-methyl Benzenesulfonyloctahydro- 2H -pirano[3,4-b]pyra To a solution of -7-yl)methanone (see compound 5462, 115 mg, 0.209 mmol) in dichloromethane (1.0 mL) was added di-tertiary butyl dicarbonate (50.2 mg, 0.230 mmol). After 3 hours, the reaction mixture was concentrated to dryness under reduced pressure to obtain (4a R , 7 R , 8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)-1-methylbenzenesulfonyloctahydro- 4H -pirano[3,4-b]pyra -4-carboxylic acid tertiary butyl ester and was used as received.

Synthesis of (4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)octahydro-4H-piper Pyro[3,4-b]pyra -4-Carboxylic acid tertiary butyl ester.

To a solution of naphthalene (500 mg, 3.90 mmol) in tetrahydrofuran (anhydrous, 8 mL) under an argon atmosphere was added sodium block (90 mg, 3.90 mmol). The mixture was stirred for 2 hours until all sodium dissolved, yielding a solution of sodium naphthide (0.5 M in tetrahydrofuran). To (4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro at -78°C under an argon atmosphere Isoquinoline-2-carbonyl)-1-methylbenzenesulfonyloctahydro- 4H -pirano[3,4-b]pyra To a solution of tertiary butyl-4-carboxylate (120 mg) in tetrahydrofuran (anhydrous, 1.0 mL) was added sodium naphthide (0.5 M in tetrahydrofuran, 0.739 mL, 0.369 mmol). After 15 minutes, the reaction mixture was stored in the freezer overnight. Subsequently, the mixture was diluted with dichloromethane (10 mL) and saturated aqueous NH ₄ Cl solution (5 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2 x 5 mL). The combined organic layers were passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 10% (7M NH in _methanol )/dichloromethane) and preparative SFC (Method S) and preparative SFC (Method S). The product was dissolved in methanol (1 mL), introduced onto an SCX-2 column (1 g), and eluted with methanol (volume ~ 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure to obtain (4a R , 7 R , 8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)octahydro-4H-pirano[3,4-b]pyra -4-Carboxylic acid tertiary butyl ester.

LCMS: 96%, RT=1.97 minutes, (M+H) ⁺ =496 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-octahydro-2H-pirano [3,4-b]pyridine -7-yl)methanone ( compound 5461 ).

To (4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)octahydro- 4H-Pirano[3,4-b]pyra To a solution of -4-carboxylic acid tertiary butyl ester in 2-propanol (1.5 mL) was added HCl (6 M in 2-propanol, 0.5 mL, 3.00 mmol). After 2.5 hours, the reaction mixture was diluted with a mixture of chloroform- d (0.7 mL) and dichloromethane (1 mL) and stirring was continued overnight. Another portion of HCl (6 M in 2-propanol, 0.25 mL, 1.50 mmol) was added and stirring was continued for a further 3 days. Subsequently, the mixture was partitioned between dichloromethane (25 mL) and saturated _aqueous NaHCO solution (10 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was dissolved in a minimal amount of methanol, introduced onto an SCX-2 column (1 g), and eluted with methanol (volume of approximately 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline 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 was obtained ,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-octahydro-2 H -pirano[3,4-b]pyra -7-yl)methanone ( compound 5461 ).

LCMS: 98%, RT=0.83 min, (M+H) ⁺ =396 (Method P). Example 136

(( S )-1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-octahydropirano [3,4-b][1,4]thi -7-yl)methanone (compound 5534)

Synthesis of N-((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- ((2-Hydroxyethyl)thio)tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonamide.

In a screw cap vial, add (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((1 S ,4 R ,6 S )-7-methylbenzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (see compound 5520, 1.00 g, 1.974 mmol) and triethylamine To a suspension of (1.098 mL, 7.90 mmol) in methanol (5 mL) was added 2-mercaptoethanol (0.831 mL, 11.84 mmol). The vial was capped and stirred at 30°C overnight. The mixture was partially concentrated, diluted with dichloromethane (3 mL) and filtered through a 0.45 µm nylon filter. The filtrate was purified by flash column chromatography (silica, 5 to 100% ethyl acetate in heptane) to give N -((2 R ,4 S ,5 R )-2-(( S )- 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-((2-hydroxyethyl)thio)tetrahydro- 2H -pyran -4-yl)-4-methylbenzenesulfonamide.

LCMS: 99%, RT=2.08 minutes, (M+H) ⁺ =585 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-1-methylbenzenesulfonyl Octahydropirano[3,4-b][1,4]thi -7-yl)methanone.

In a 20 mL microwave vial under argon, add N -((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4 -Tetrahydroisoquinoline-2-carbonyl)-5-((2-hydroxyethyl)thio)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide (625 mg To a solution of cyanomethylenetri-n-butylphosphine (0.421 mL, 1.603 mmol) in toluene (anhydrous, 10 mL) was added. The vial was capped and heated to 100°C. After 1.5 hours, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-1-methylbenzenesulfonyloctahydropirano[3,4-b][1,4] thiophene -7-yl)methanone.

LCMS: 89%, RT=2.30 minutes, (M+H) ⁺ =567 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-octahydropirano[3, 4-b][1,4]thi -7-yl)methanone ( compound 5534 ).

To a solution of naphthalene (500 mg, 3.90 mmol) in tetrahydrofuran (anhydrous, 8 mL) under an argon atmosphere was added sodium block (90 mg, 3.90 mmol). The mixture was stirred for 2 hours until all sodium dissolved, yielding a solution of sodium naphthide (0.5 M in tetrahydrofuran). To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R , 7 R ,8a S )-1-methylbenzenesulfonyloctahydropirano[3,4-b][1,4]thi To a solution of -7-yl)methanone (135 mg, 0.238 mmol) in tetrahydrofuran (anhydrous, 6.0 mL) was added sodium naphthide (0.5 M in tetrahydrofuran, 0.715 mL, 0.357 mmol). After 15 minutes, the reaction mixture was allowed to warm to room temperature and stirred overnight. Subsequently, the mixture was cooled again to -78 °C and additional sodium naphthide (0.5 M in THF, 2.3 mL, 1.125 mmol) was added over 0.5 h until the color of the reagent (dark green) persisted. After 15 minutes, the mixture was quenched by adding saturated aqueous _NH4Cl (10 mL), warmed to room temperature and concentrated under reduced pressure to remove tetrahydrofuran. Extract the residual aqueous phase with dichloromethane (3 × 10 mL). The combined organics were passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 5% (7M NH in _methanol )/dichloromethane) and preparative SFC (Method AN) in a mixture of acetonitrile and water ( 1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-octahydropirano[3,4-b][1,4]thi -7-yl)methanone ( compound 5534 ) as the first eluting SFC isomer.

LCMS: 99%, RT=2.90 min, (M+H) ⁺ =413 (Method AK). SFC: 100%, RT=3.76 minutes, (M+H) ⁺ =413 (method AD). Example 137

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-3-(hydroxymethyl base)octahydropirano[3,4-b][1,4] -7-yl)methanone (compound 5535)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S,5S)-4-hydroxy-5-(oxygen) Heterocyclobutan-3-yloxy)tetrahydro-2H-pyran-2-yl)methanone.

To sodium hydride (60% dispersion in mineral oil, 21.22 mg, 0.531 mmol) was added 3-oxetanol (337 µL, 5.31 mmol). After 5 minutes, add ((1 R ,4 R ,6 S )-3,7-dioxabicyclo[4.1.0]heptan-4-yl)(( S )-1-(4-fluorobenzene methyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5070, 75 mg, 0.212 mmol). Stir the reaction at 60 °C. After 2 hours, the mixture was diluted with dichloromethane (1 mL) and stirring was continued for another hour. After cooling to room temperature, the mixture was diluted with dichloromethane (3 mL) and washed with saturated aqueous _NH4Cl (3 mL). The organic phase was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-4-hydroxy-5-(oxetan-3-yloxy)tetrahydro-2 H - Piran-2-yl)methanone.

LCMS: 96%, RT=1.86 minutes, (M+H) ⁺ =428 (Method A).

Synthesis of methane sulfonic acid (2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- (Oxetan-3-yloxy)tetrahydro-2H-pyran-4-yl ester.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 S )-4-hydroxy- To a solution of 5-(oxetan-3-yloxy)tetrahydro-2 H -pyran-2-yl)methanone (68 mg, 0.159 mmol) in dichloromethane (4 mL) was added Triethylamine (0.066 mL, 0.477 mmol) and methane sulfonyl chloride (0.018 mL, 0.239 mmol). After stirring overnight, additional triethylamine (0.022 mL, 0.159 mmol) and methanesulfonyl chloride (0.012 mL, 0.159 mmol) were added and stirring was continued for 0.5 h. Subsequently, the reaction mixture was washed with citric acid aqueous solution (0.5 M, 4 mL) and NaHCO _saturated aqueous solution (4 mL), and the organic phase was passed through a hydrophobic glass frit and evaporated under reduced pressure to obtain methane sulfonic acid (2 R , 4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(oxetane Alk-3-yloxy)tetrahydro- 2H -pyran-4-yl ester.

LCMS: 97%, RT=2.01 minutes, (M+H) ⁺ =506 (Method A).

Synthesis of ((2R,4S,5R)-4-azido-5-(oxetan-3-yloxy)tetrahydro-2H-piran-2-yl)((S)-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

To methanesulfonic acid (2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -5-(oxetan-3-yloxy)tetrahydro- 2H -pyran-4-yl ester (78 mg, 0.154 mmol) in N , N -dimethylformamide (4 mL Sodium azide (20.06 mg, 0.309 mmol) was added to the solution in ), and the reaction mixture was heated to 80°C. After stirring overnight, the mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-4-azido-5- (oxetan-3-yloxy)tetrahydro-2 H -pyran-2-yl) (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline -2(1 H )-yl)methanone.

LCMS: 99%, RT=2.09 minutes, (M+H) ⁺ =453 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-3-(hydroxymethyl)octa Hydropirano[3,4-b][1,4] -7-yl)methanone ( compound 5535 ).

((2 R ,4 S ,5 R )-4-azido was dissolved in the presence of palladium (10 wt% on carbon, 50% water, 3.76 mg, 1.77 µmol) under atmospheric hydrogen pressure. -5-(oxetan-3-yloxy)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydro A solution of isoquinolin-2(1 H )-yl)methanone (40 mg, 0.088 mmol) in tetrahydrofuran (4 mL) was hydrogenated. After stirring overnight, the mixture was filtered on a 0.22 µm nylon filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in a minimal amount of methanol, introduced onto an SCX-2 column (1 g), and eluted with methanol (volume of approximately 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was purified by preparative SFC (Method Z) and the first eluate product fractions on SFC were combined and lyophilized. The product was dissolved in a minimum amount of methanol, introduced onto an SCX-2 column (1 g), and eluted with methanol (the volume was approximately 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-3-(hydroxymethyl)octahydropirano[3,4-b][1, 4] -7-yl)methanone ( compound 5535 ).

LCMS: 97%, RT=1.05 minutes, (M+H) ⁺ =427 (Method P). Example 138

((4a R ,7 R ,8a S )-4,4-dioxoctahydropyrano[3,4-b][1,4]thi -7-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5542)

Synthesis of ((4aR,7R,8aS)-4,4-dioxo-1-methylbenzenesulfonyloctahydropyrano[3,4-b][1,4]thi -7-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-1-methyl Benzenesulfonyloctahydropirano[3,4-b][1,4]thiophene To a solution of -7-yl)methanone (see compound 5534, 60 mg, 0.106 mmol) in dichloromethane (anhydrous, 2.0 mL) was added m-chloroperbenzoic acid (70%, 26.1 mg, 0.106 mmol). Two additional portions of m-chloroperbenzoic acid (70%, 2 times 19.58 mg, 0.079 mmol) were added after 0.5 and 1 hour respectively. After a total reaction _time of 1.5 hours, the mixture was diluted with dichloromethane (10 mL) and saturated _{aqueous Na2S2O3} (10 mL) and stirred vigorously for 15 minutes. The layers were separated and the aqueous phase was extracted with dichloromethane (10 mL). The combined organics were dried over Na ₂ SO ₄ and evaporated under reduced pressure to obtain ((4a R , 7 R , 8a S )-4,4-dioxo-1-methylbenzene as an off-white waxy Sulfonyl octahydropirano[3,4-b][1,4]thi -7-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (55.0 mg).

LCMS: 93%, RT=2.14 minutes, (M+H) ⁺ =599 (Method A).

Synthesis of ((4aR,7R,8aS)-4,4-dioxoctahydropirano[3,4-b][1,4]thiophene -7-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5542 ).

To a solution of naphthalene (500 mg, 3.90 mmol) in tetrahydrofuran (anhydrous, 8 mL) under an argon atmosphere was added sodium block (90 mg, 3.90 mmol). The mixture was stirred for 2 hours until all sodium dissolved, yielding a solution of sodium naphthide (0.5 M in tetrahydrofuran). To ((4a R ,7 R ,8a S )-4,4-dioxo-1-methylbenzenesulfonyloctahydropirano[3,4- b][1,4]thi -7-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (55 mg, 0.092 mmol) in tetrahydrofuran ( To a solution in (anhydrous, 2.5 mL), sodium naphthide (0.5 M in tetrahydrofuran, 0.735 mL, 0.367 mmol) was added. After 15 minutes, the reaction mixture was quenched by adding methanol (0.4 mL) and stored in the freezer overnight. Subsequently, the mixture was concentrated to dryness under reduced pressure. By flash column chromatography (silica, 0 to 6% (7M NH in _methanol )/dichloromethane) and 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) Purification residue. The product fractions from the acidic preparative MPLC were combined, basified with saturated aqueous Na ₂ CO ₃ (2 mL) and extracted with dichloromethane (3 × 10 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ((4a R ,7 R ,8a S )-4,4-dioxooctahydropirano[3,4 -b][1,4]thi -7-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5542 ).

LCMS: 94%, RT=1.21 minutes, (M+H) ⁺ =445 (Method P). Example 139

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 R ,4a R ,7 R ,8a S )-3- Methyloctahydropirano[3,4-b][1,4] -7-yl)methanone (compound 5472)

Synthesis of N-((2R,4S,5R)-5-(((R)-1-(benzyloxy)prop-2-yl)oxy)-2-((S)-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonamide.

Under an argon atmosphere, to (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((1 S ,4 R ,6 S )-7-methylbenzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (see compound 5520, 360 mg, 0.711 mmol) and ( R ) -(-)-1-Benzyloxy-2-propanol (591 mg, 3.55 mmol) in 1,4-di To a suspension in alkanes (10 mL) was added sodium hydride (60% dispersion in mineral oil, 42.6 mg, 1.066 mmol) and the mixture was heated to 60 °C. After 2 hours, the mixture was cooled to room temperature, diluted with half-saturated aqueous NH ₄ Cl solution and extracted with ethyl acetate (2×25 mL). _The combined organics were washed with brine, dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 60% ethyl acetate in heptane) to give N -((2 R ,4 S ,5 R )-5-((( R )-1-(benzyloxy)prop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide.

LCMS: 97%, RT=2.56 minutes, (M+H) ⁺ =673 (Method A).

Synthesis of ((2R,4S,5R)-5-(((R)-1-(benzyloxy)prop-2-yl)oxy)-2-((S)-1-(4-fluorobenzene) tertiary butyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)(toluenesulfonyl)carbamate.

To N -((2 R ,4 S ,5 R )-5-((( R )-1-(benzyloxy)prop-2-yl)oxy)-2-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide (235 mg, 0.349 mmol) in tetrahydrofuran (anhydrous, 4 mL) were added triethylamine (0.097 mL, 0.699 mmol), di-tertiary butyl dicarbonate (0.162 mL, 0.699 mmol) and 4-dimethyl Aminopyridine (4.27 mg, 0.035 mmol). After 30 minutes, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 40% ethyl acetate in heptane) to give (( 2R , 4S , 5R ) after co-evaporation from dichloromethane) -5-((( R )-1-(benzyloxy)propan-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)(toluenesulfonyl)carbamic acid tertiary butyl ester.

LCMS: 89%, RT=2.58 minutes, (M+H) ⁺ =773 (Method B).

Synthesis of ((2R,4S,5R)-5-(((R)-1-(benzyloxy)prop-2-yl)oxy)-2-((S)-1-(4-fluorobenzene) (yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-((( R )-1-(benzyloxy)prop-2-yl)oxy)-2-(( S )-1-(4 -Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)(methylbenzenesulfonyl)carbamic acid tert-butyl To a solution of the ester (235 mg, 0.304 mmol) in methanol was added ammonium chloride (163 mg, 3.04 mmol) and magnesium (369 mg, 15.20 mmol). After 3 hours, the mixture was diluted with saturated aqueous _NH4Cl (50 mL) and dichloromethane and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 50% ethyl acetate in heptane) to give (( 2R , 4S , 5R ) after co-evaporation from dichloromethane) -5-((( R )-1-(benzyloxy)propan-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 97%, RT=2.34 minutes, (M+Na) ⁺ =641 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(( (R)-1-Hydroxyprop-2-yl)oxy)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

((2 R ,4 S ,5 R )-5-(((( R )-1-(benzyloxy)prop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Hydrogenation of a solution of tertiary butyl pholin-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamate (145 mg, 0.234 mmol) in 2,2,2-trifluoroethanol (3 mL) . After stirring for 1 hour, the mixture was filtered on a 0.45 µm nylon filter. The filtrate was concentrated under reduced pressure to obtain ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)-5-((( R )-1-hydroxyprop-2-yl)oxy)tetrahydro-2 H -pyran-4-yl)carbamic acid tertiary butyl ester.

Synthesis of methane sulfonate (R)-2-(((3R,4S,6R)-4-((tertiary butoxycarbonyl)amine)-6-((S)-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)oxy)propyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -((( R )-1-hydroxyprop-2-yl)oxy)tetrahydro-2 H -pyran-4-yl)carbamic acid tert-butyl ester (117 mg, 0.221 mmol) in dichloromethane Add triethylamine (0.093 mL, 0.664 mmol) and methane sulfonyl chloride (0.034 mL, 0.443 mmol) to the solution. After 45 minutes, the mixture was diluted with saturated _aqueous NaHCO solution (4 mL) and stirred for 15 minutes. The layers were separated on a phase separation filter and the organic filtrate was evaporated under reduced pressure to give methanesulfonic acid ( R )-2-((( 3R , 4S , 6R )-4-((tertiary butoxycarbonyl )Amino)-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3 -yl)oxy)propyl ester.

LCMS: 97%, RT=2.14 minutes, (M+H) ⁺ =607 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3R,4aR,7R,8aS)-3-methyloctahydrogen Pirano[3,4-b][1,4] -7-yl)methanone ( compound 5472 ).

To methanesulfonic acid ( R )-2-(((3 R ,4 S ,6 R )-4-((tertiary butoxycarbonyl)amine)-6-(( S )-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)oxy)propyl ester (136 mg, 0.224 mmol) in di To the solution in methyl chloride was added HCl (5-6 M in 2-propanol, 1 mL, 5.50 mmol). After stirring overnight, the mixture was diluted with saturated aqueous _NaHCO3 and dichloromethane and stirred vigorously for 15 minutes. The layers were separated on a phase separation filter and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in dichloromethane and triethylamine (0.1 mL, 0.717 mmol) was added. After stirring for 1.5 hours, the mixture was warmed to 35°C and stirred for 4 days. Subsequently, the mixture was concentrated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (1 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. 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% A; t=18 min 100%; t =23 min 100% A; detection: 220 nm) purified residue. The products containing the eluate fractions were combined, neutralized with saturated aqueous NaHCO ₃ solution, and extracted twice with dichloromethane. The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl) ((3 R ,4a R ,7 R ,8a S )-3-methyloctahydropyrano[3,4-b][1,4] -7-yl)methanone ( compound 5472 ).

LCMS: 100%, RT=1.14 minutes, (M+H) ⁺ =411 (Method P). Example 140

( R )-((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro- 2H -piran-3-yl)(imino)(methyl)-λ ⁶ -sulfanone (compound 5547) and ( S )-((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-3-yl)(imino)(methyl)-λ ⁶ -sulfanone (compound 5548)

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(( R)-S-methanesulfonyl iminyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester and ((2R,4S,5R)-2-((S)-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-((S)-S-methanesulfonyl iminoyl)tetrahydro-2H-piper Phenyl-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(Methylthio)tetrahydro- 2H -piran-4-yl)carbamate tertiary butyl ester (see compound 5520, 324 mg, 0.647 mmol) and ammonium carbamate (76 mg, 0.971 mmol) in methanol ( To the suspension in 4 mL) was added iodophenylene diacetate (438 mg, 1.359 mmol). The reaction mixture was stirred in air and after 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 5% (7M ammonia in methanol)/dichloromethane) and preparative SFC (Method BX) to give ((2 R , 4 S , 5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(( R )- S -methyl Sulfoimide)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester as the first eluting SFC isomer (iAmylose column) and ((2 R , 4 S , 5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(( S )- S -methanesulfonyl Tertiary butyl imino)tetrahydro- 2H -pyran-4-yl)carbamic acid was used as the second eluting SFC isomer (iAmylose column). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

First eluted isomer: LCMS: 94%, RT=1.96 min, (M+H) ⁺ =532 (Method A). SFC: 94%, RT=2.81 minutes, (M+H) ⁺ =532 (Method V).

Second soluble isomer: LCMS: 93%, RT=1.95 min, (M+H) ⁺ =532 (Method A). SFC: 100%, RT=2.67 minutes, (M+H) ⁺ =532 (Method V).

Synthesis of (R)-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-3-yl)(imino)(methyl)-λ ⁶ -sulfanone ( compound 5547 ).

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(( R )- S -methanesulfonyl iminyl)tetrahydro-2 H -piran-4-yl)carbamic acid tert-butyl ester (50 mg, 0.094 mmol) in 2-propanol (2 mL ) and a suspension in dichloromethane (0.5 mL) was added HCl (5-6 M in 2-propanol, 0.5 mL, 2.75 mmol). After stirring for 3 days, the reaction mixture was diluted with dichloromethane (5 mL) and neutralized with saturated _aqueous NaHCO solution. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 3 mL) to obtain ( R )-((3 R ,4 S ,6 R )-4-amino-6-(( S )- 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)(imino)(methyl) -λ ⁶ -thianone ( compound 5547 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 95%, RT=2.55 minutes, (M+H) ⁺ =432 (Method AK). SFC: 95%, RT=3.92 minutes, (M+H) ⁺ =432 (Method W).

Synthesis of (S)-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-3-yl)(imino)(methyl)-λ ⁶ -sulfanone ( compound 5548 ).

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(( S )- S -methanesulfonyl iminyl)tetrahydro-2 H -piran-4-yl)carbamic acid tertiary butyl ester (40 mg, 0.075 mmol) in 2-propanol (2 mL ) and a suspension in dichloromethane (0.5 mL) was added HCl (5-6 M in 2-propanol, 0.5 mL, 2.75 mmol). After stirring for 3 days, the reaction mixture was diluted with dichloromethane (5 mL) and neutralized with saturated _aqueous NaHCO solution. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 3 mL) to obtain ( S )-(( 3R , 4S , 6R )-4-amino-6-(( S )- 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)(imino)(methyl) -λ ⁶ -thianone ( compound 5548 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 93%, RT=2.58 minutes, (M+H) ⁺ =432 (Method AK). SFC: 99%, RT=4.43 minutes, (M+H) ⁺ =432 (Method W). Example 141

( R )-((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro- 2H -piran-3-yl)(imino)(ethyl)-λ ⁶ -sulfanone (compound 5549) and ( S )-((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-3-yl)(imino)(ethyl)-λ ⁶ -sulfanone (compound 5550)

Synthesis of ((2R,4S,5R)-5-((R)-ethanesulfonyl iminyl)-2-((S)-1-(4-fluorophenyl)-1,2,3,4 -Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-piran-4-yl)carbamic acid tertiary butyl ester and ((2R,4S,5R)-5-((S)-ethanesulfonamide) Aminyl)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-piran-4- base) tertiary butyl carbamate.

To ((2 R ,4 S ,5 R )-5-(ethylthio)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Tertiary butyl pholin-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamate (508 mg, 0.987 mmol) (see compound 5521, 508 mg, 0.987 mmol) and ammonium carbamate (116 mg To a suspension of , 1.481 mmol) in methanol (6 mL) was added iodophenylene diacetate (668 mg, 2.073 mmol). The reaction mixture was stirred in air and after 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 10% (7M ammonia in methanol)/dichloromethane) and preparative SFC (method BY) to give ((2 R , 4 S , 5 R )-5-(( R )-ethanesulfonimide)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester as the first eluting SFC isomer and ((2 R ,4 S ,5 R )-5-(( S )-ethanesulfonimide)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-4-yl)carbamate tertiary butyl ester as the second eluting SFC isomer. The stereochemistry of the setrimine stereocenter is arbitrarily specified.

First eluted isomer: LCMS: 98%, RT=1.68 minutes, (M+H) ⁺ =546 (Method P). SFC: 99%, RT=4.99 minutes, (M+H) ⁺ =546 (Method BZ).

Second eluted isomer: LCMS: 96%, RT=1.68 min, (M+H) ⁺ =546 (Method A). SFC: 95%, RT=5.34 minutes, (M+H) ⁺ =546 (Method BZ).

Synthesis of (R)-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-3-yl)(imino)(ethyl)-λ ⁶ -sulfanone ( compound 5549 ).

To ((2 R ,4 S ,5 R )-5-(( R )-ethanesulfonyl iminyl)-2-(( S )-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (80 mg, 0.147 mmol) in 2-propanol (3 mL) and To a suspension in dichloromethane (1 mL) was added HCl (5-6 M in 2-propanol, 1 mL, 5.5 mmol). After stirring overnight, another portion of HCl (5-6 M in 2-propanol, 0.5 mL, 2.75 mmol) was added and stirring was continued for 2 h. The reaction mixture was diluted with dichloromethane (5 mL) and neutralized with saturated _aqueous NaHCO solution. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 3 mL). The product still contained some starting material and was resubmitted and purified according to the procedure described above to give ( R )-((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4 -Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)(imino)(ethyl)-λ ⁶ - Thianone ( compound 5549 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 97%, RT=2.61 minutes, (M+H) ⁺ =446 (Method AK). SFC: 99%, RT=3.94 minutes, (M+H) ⁺ =446 (Method W).

Synthesis of (S)-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-piran-3-yl)(imino)(ethyl)-λ ⁶ -sulfanone ( Compound 5550 ).

To ((2 R ,4 S ,5 R )-5-(( S )-ethanesulfonyl iminyl)-2-(( S )-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (80 mg, 0.147 mmol) in 2-propanol (3 mL) and To a suspension in dichloromethane (1 mL) was added HCl (5-6 M in 2-propanol, 1 mL, 5.5 mmol). After stirring overnight, another portion of HCl (5-6 M in 2-propanol, 0.5 mL, 2.75 mmol) was added and stirring was continued for 2 h. The reaction mixture was diluted with dichloromethane (5 mL) and neutralized with saturated _aqueous NaHCO solution. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 3 mL). The product still contained some starting material and was resubmitted and purified according to the above procedure to obtain ( S )-(( 3R , 4S , 6R )-4-amino-6-(( S )-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)(imino)(ethyl)-λ ⁶ -thio Alkanone ( compound 5550 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 94%, RT=1.38 minutes, (M+H) ⁺ =446 (Method Q). SFC: 96%, RT=4.37 minutes, (M+H) ⁺ =446 (Method W). Example 142

( R )-((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro- 2H -piran-3-yl)(ethyl)(methylimino)-λ ⁶ -sulfanone (compound 5551)

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(( R)-N-methylethanesulfonyl iminyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-(( R )-ethanesulfonyl iminyl)-2-(( S )-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5549 , 58 mg, 0.106 mmol), copper(II) acetate (29.0 mg, 0.159 mmol) and pyridine (0.021 mL, 0.255 mmol) in 1,4-di Molecular sieves (4 Å) were added to a solution in alkanes (1 mL). Close the reaction vessel and stir for 5 minutes. Methylboronic acid (12.72 mg, 0.213 mmol) was then added and the reaction mixture was stirred in air for 5 minutes. The reaction vessel was sealed and heated to 100°C. After 1.5 hours, the reaction mixture was cooled to room temperature, diluted with dichloromethane (4 mL) and washed with water (4 mL). The organic layer was passed through a hydrophobic glass frit, and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography twice (silica, 0 to 100% ethyl acetate in heptane) (silica, 0 to 70% ethyl acetate in heptane) to give ( (2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-( ( R ) -N -methylethanesulfonyl iminyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester. The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 99%, RT=1.97 minutes, (M+H) ⁺ =560 (Method A).

Synthesis of (R)-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-3-yl)(ethyl)(methylimino)-λ ⁶ -sulfanone ( compound 5551 ).

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(( R )- N -methylethanesulfonyl iminyl)tetrahydro-2 H -piran-4-yl)carbamic acid tert-butyl ester (50 mg, 0.089 mmol) in 2-propanol ( To the solution in 4 mL), add HCl (5-6 M in 2-propanol, 2 mL, 11.0 mmol). After stirring overnight, the reaction mixture was diluted with dichloromethane (15 mL) and neutralized with saturated _aqueous NaHCO solution. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (2 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (1.5 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 3 mL) to obtain ( R )-((3 R ,4 S ,6 R )-4-amino-6-(( S )- 1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)(ethyl)(methylimine base)-λ ⁶ -sulfanone ( compound 5551 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 97%, RT=1.48 minutes, (M+H) ⁺ =460 (Method P). SFC: 99%, RT=4.17 minutes, (M+H) ⁺ =460 (method AD). Example 143

( S )-((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro- 2H -piran-3-yl)(ethyl)(methylimino)-λ ⁶ -sulfanone (compound 5552)

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(( S)-N-methylethanesulfonyl iminyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-(( S )-ethanesulfonyl iminyl)-2-(( S )-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5550 , 68 mg, 0.125 mmol), copper(II) acetate (34.0 mg, 0.187 mmol) and pyridine (0.024 mL, 0.299 mmol) in 1,4-di Molecular sieves (4 Å) were added to a solution in alkanes (1.2 mL). Close the reaction vessel and stir for 5 minutes. Methylboronic acid (12.72 mg, 0.213 mmol) was then added and the reaction mixture was stirred in air for 5 minutes. The reaction vessel was sealed and heated to 100°C. After 1.5 hours, the reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL), and washed with water (5 mL). The organic layer was passed through a hydrophobic glass frit, and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography twice (silica, 0 to 100% ethyl acetate in heptane) and (silica, 0 to 70% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- (( S ) -N -methylethanesulfonyl iminyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester. The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 97%, RT=1.96 minutes, (M+H) ⁺ =560 (Method A).

Synthesis of (S)-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-3-yl)(ethyl)(methylimino)-λ ⁶ -sulfanone ( compound 5552 ).

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(( S )- N -methylethanesulfonyl iminyl)tetrahydro-2 H -pyran-4-yl)carbamic acid tertiary butyl ester (33 mg, 0.059 mmol) in 2-propanol ( To the solution in 3 mL), add HCl (5-6 M in 2-propanol, 1 mL, 5.5 mmol). After stirring for 3 days, the reaction mixture was diluted with dichloromethane and neutralized with saturated aqueous _NaHCO3 solution. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (2 mL) and introduced onto an SCX-2 column (1 g) and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ( S )-(( 3R , 4S , 6R )-4-amino-6-(( S )- 1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)(ethyl)(methylimine base)-λ ⁶ -sulfanone ( compound 5552 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 98%, RT=1.09 minutes, (M+H) ⁺ =460 (Method P). SFC: 95%, RT=4.36 minutes, (M+H) ⁺ =460 (method AD). Example 144

(4a R ,7 R ,8a S )-4-ethyl-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Hexahydro- 2H -pirano[3,4-b]pyra -3(4 H )-ketone (compound 5536)

Synthesis of ((3R,4S,6R)-4-azido-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )Tetrahydro-2H-pyran-3-yl)(ethyl)carbamic acid tertiary butyl ester.

Under an argon atmosphere, to ((3 R ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)carbamic acid tertiary butyl ester (see compound 5532, 200 mg, 0.371 mmol) in N , N -dimethylformamide To a solution of the amine (2 mL) was added sodium hydride (60% in mineral oil, 21 mg, 0.525 mmol). After stirring for 10 minutes, ethyl iodide (0.090 mL, 1.114 mmol) was added and stirring was continued for 1.5 hours. Subsequently, the mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed twice _with brine, dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 40% ethyl acetate in heptane) to give (( 3R , 4S , 6R ) after co-evaporation from dichloromethane) -4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran -3-yl)(ethyl)carbamic acid tertiary butyl ester.

LCMS: 99%, RT=2.34 minutes, (M+H) ⁺ =524 (Method A).

Synthesis of ((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Tetrahydro-2H-pyran-3-yl)(ethyl)carbamic acid tertiary butyl ester.

((3 R ,4 S ,6 R )-4-azido was dissolved in the presence of palladium (10 wt% on carbon, 50% water, 80 mg, 0.038 mmol) under atmospheric hydrogen pressure -6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)( A solution of tert-butylethylcarbamate (165 mg, 0.315 mmol) in tetrahydrofuran (4 mL) was hydrogenated. After stirring for 2 hours, the mixture was filtered on a 0.45 µm nylon filter. The filtrate was concentrated under reduced pressure to obtain ((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl)(ethyl)carbamic acid tertiary butyl ester.

LCMS: 97%, RT=1.79 minutes, (M+H) ⁺ =498 (Method A).

Synthesis of ((2R,4S,5R)-5-((tertiary butoxycarbonyl)(ethyl)amine)-2-((S)-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)glycinate methyl ester.

To ((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro- 2H -pyran-3-yl)(ethyl)carbamic acid tertiary butyl ester (155 mg, 0.311 mmol) and potassium carbonate (108 mg, 0.779 mmol) in acetonitrile (2.5 mL) Add methyl bromoacetate (0.044 mL, 0.467 mmol) to the suspension. After stirring for 5 hours, it was diluted with a mixture of water and dichloromethane. The layers were separated on a phase separation filter and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 10 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R ) after co-evaporation from dichloromethane) -5-((tertiary butoxycarbonyl)(ethyl)amino)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline Methyl -2-carbonyl)tetrahydro- 2H -pyran-4-yl)glycinate.

LCMS: 99%, RT=1.86 minutes, (M+H) ⁺ =570 (Method A).

Synthesis of (4aR,7R,8aS)-4-ethyl-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexa Hydro-2H-pirano[3,4-b]pyra -3(4H)-one ( compound 5536 ).

To ((2 R ,4 S ,5 R )-5-((tertiary butoxycarbonyl)(ethyl)amino)-2-(( S )-1-(4-fluorophenyl)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)glycinate methyl ester (135 mg, 0.237 mmol) in 2-propanol (3 mL ), add HCl (6 M in 2-propanol, 1 mL, 6.00 mmol). After stirring overnight, the reaction mixture was diluted with dichloromethane and saturated aqueous _NaHCO3 solution, and the mixture was stirred vigorously for 15 minutes. The layers were separated using a phase separator and the organic filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (3 mL) and triethylamine (0.066 mL, 0.474 mmol) was added. After 1 hour, another portion of triethylamine (0.033 mL, 0.237 mmol) was added and stirring was continued for 3 days. Subsequently, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 1 to 10% (7 M NH in _methanol )/dichloromethane) in a mixture of acetonitrile and water (1:1, 4 mL) After freeze-drying, (4a R , 7 R , 8a S )-4-ethyl-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroiso Quinoline-2-carbonyl)hexahydro- 2H -pirano[3,4-b]pyra -3(4 H )-one ( compound 5536 ).

LCMS: 99%, RT=1.11 minutes, (M+H) ⁺ =438 (Method P). Example 145

((2 R ,4 S ,5 S )-4-amino-5-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5537)

Synthesis of ((2R,4S,5S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(hydroxy Methyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester and ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1, 2,3,4-Tetrahydroisoquinoline-2-carbonyl)-5-(hydroxymethyl)tetrahydro-2H-piran-4-yl)carbamic acid tertiary butyl ester.

To (( 2R , 4S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline at 0°C under _N atmosphere -2-Carbonyl)-5-methyltetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5518, 100 mg, 0.214 mmol) in tetrahydrofuran (anhydrous, 2.5 mL) Add borane dimethyl sulfide complex (2 M in tetrahydrofuran, 0.134 mL, 0.268 mmol) to the solution. After 75 minutes, another portion of borane dimethyl sulfide complex (2 M in tetrahydrofuran, 0.134 mL, 0.268 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 2 h, sodium hydroxide (1 M, 1.286 mL, 1.286 mmol) was slowly added, followed by hydrogen peroxide (30% aqueous solution, 0.219 mL, 2.143 mmol). After 5 minutes, the mixture was diluted with dichloromethane (15 mL). The organic layer was passed through a hydrophobic glass frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) and preparative SFC (method AT) to give ((2 R ,4 S ,5 S )- 2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(hydroxymethyl)tetrahydro- 2H -piper Tertiary butylpyran-4-yl)carbamate (12.6 mg) as the first eluting SFC isomer and ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluoro) Phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(hydroxymethyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester as The second eluted SFC isomer.

First eluted SFC isomer: SFC: RT=2.28 minutes, (M+H) ⁺ =485 (Method AU).

Second eluted SFC isomer: SFC: RT=2.37 minutes, (M+H) ⁺ =485 (Method AU).

Synthesis of ((2R,4S,5S)-4-amino-5-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5537 ).

To ((2 R ,4 S ,5 S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of -(hydroxymethyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester (12.6 mg, 0.026 mmol) in 2-propanol (1.0 mL) was added HCl (5- 6 M in 2-propanol, 0.5 mL, 2.75 mmol). After 1 day, the mixture was partitioned between dichloromethane (15 mL) and saturated _aqueous NaHCO (5 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (1 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give (( 2R , 4S , 5S )-4-amino-5-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5537 ).

LCMS: 99%, RT=1.04 minutes, (M+H) ⁺ =385 (Method P). SFC: 94%, RT=3.15 minutes, (M+H) ⁺ =385 (Method W). Example 146

((2 R ,4 S ,5 R )-4-amino-5-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl )-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5538)

Synthesis of ((2R,4S,5R)-4-amino-5-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5538 ).

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 To a solution of -(hydroxymethyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester (see compound 5537, 18.8 mg, 0.039 mmol) in 2-propanol (1.0 mL) was added HCl (5-6 M in 2-propanol, 0.5 mL, 2.75 mmol). After 1 day, the mixture was partitioned between dichloromethane (15 mL) and saturated _aqueous NaHCO (5 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (1 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give ((2 R , 4 S , 5 R )-4-amino-5-(hydroxymethyl)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5538 ).

LCMS: 91%, RT=2.59 minutes, (M+H) ⁺ =385 (Method AK). SFC: 93%, RT=3.63 minutes, (M+H) ⁺ =385 (Method W). Example 147

((2 R ,4 R )-4-(aminomethyl)-4-hydroxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)methanone (compound 5540)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-4-methyltetrahydro-2H-pyran -2-yl)methanone.

To a suspension of methyltriphenylphosphonium bromide (167.6 mg, 0.469 mmol) in tetrahydrofuran (anhydrous, 1.5 mL) at 0 °C was added potassium tert. butoxide (1 M solution in in tetrahydrofuran, 0.445 mL, 0.445 mmol). After stirring for 30 minutes, ( R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl was added dropwise over 2 minutes ) A solution of tetrahydro- 4H -pyran-4-one (see compound 5080, 149.8 mg, 0.424 mmol) in tetrahydrofuran (anhydrous, 1.5 mL). After 1.75 hours, the reaction mixture was partitioned between a mixture of brine (10 mL), water (10 mL) and dichloromethane (15 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica: 5 to 50% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)(( R )-4-methyltetrahydro-2 H -pyran-2-yl)methanone.

SFC: 99%, RT=3.18 minutes, (M+H) ⁺ =352 (Method F).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3R,5R)-1,6-dioxaspiro[2.5 ]octane-5-yl)methanone and ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3S,5R)- 1,6-dioxaspiro[2.5]octane-5-yl)methanone.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( R )-4-methyltetrahydro-2 H - To a solution of pyran-2-yl)methanone (177 mg, 0.504 mmol) in dichloromethane (5 mL) was added sodium bicarbonate (64.5 mg, 0.768 mmol) and m-chloroperbenzoic acid) 70 wt%, 149.2 mg, 0.605 mmol). After stirring for 3 hours, the mixture was partitioned between dichloromethane (20 mL) and saturated _aqueous NaHCO (10 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica: 5 to 60% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1 H )-yl)((3 R ,5 R )-1,6-dioxaspiro[2.5]octane-5-yl)methanone as the first soluble isomer and ( ( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 S ,5 R )-1,6-dioxaspiro[ 2.5]Octan-5-yl)methanone as the second lytic isomer.

First soluble isomer: SFC: 98%, RT=2.03 minutes, (M+H) ⁺ =368 (Method V).

Second soluble isomer: SFC: 96%, RT=2.52 minutes, (M+H) ⁺ =368 (Method V).

Synthesis of ((2R)-4-(azidomethyl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1H)-yl)methanone.

To a solution of sodium azide (21.43 mg, 0.330 mmol) in water (106 µL) was added acetic acid (61 µL) and this was added to the solution containing (( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)((3 R ,5 R )-1,6-dioxaspiro[2.5]octane-5-yl)methanone (28.5 mg , 0.066 mmol) in screw-capped vials. The vial was capped and heated to 30°C. After 4 hours, the reaction mixture was partitioned between a mixture of brine and water (2:1, 5 mL) and dichloromethane (10 mL). The organic layer was separated, washed with _saturated aqueous NaHCO solution (5 mL), passed through a hydrophobic glass frit, and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 20 to 70% ethyl acetate in heptane) to give ((2 R ,4 R )-4-(azidomethyl)-4- Hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 97%, RT=1.96 minutes, (M+H) ⁺ =411 (Method A).

Synthesis of ((2R,4R)-4-(aminomethyl)-4-hydroxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl)-3,4 -Dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5540 ).

((2 R ,4 R )-4-(azidomethyl)-4-hydroxytetrakis was dissolved in the presence of palladium (10 wt% on carbon, 7.5 mg, 3.53 µmol) under atmospheric hydrogen pressure. Hydrogen- 2H -piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2( 1H )-yl)methanone in tetrahydrofuran ( 2 mL) was hydrogenated. After stirring for 1.25 hours, the mixture was diluted with dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (1 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline 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 obtain ((2 R , 4 R )-4-(amine Methyl)-4-hydroxytetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( 1H ) -Methyl ketone ( compound 5540 ).

LCMS: 94%, RT=1.01 min, (M+H) ⁺ =382 (Method P). Example 148

((2 R ,4 S ,5 R )-4-amino-5-((2,2,2-trifluoroethyl)amino)tetrahydro-2 H -piran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5539)

Synthesis of ((2R,4S,5R)-4-azido-5-((2,2,2-trifluoroethyl)amino)tetrahydro-2H-piran-2-yl)((S) -1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

To ((2 R ,4 S ,5 R )-5-amino-4-azidetetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)- 3,4-Dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5512, 92 mg, 0.233 mmol) and N,N -diisopropylethylamine (0.122 mL, 0.698 mmol) in To a solution in tetrahydrofuran (2.5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.067 mL, 0.465 mmol), and the mixture was warmed to 60°C. After stirring overnight, additional portions of 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.034 mL, 0.233 mmol) and N,N -diisopropylethylamine (0.061 mL, 0.349 mmol) were added and Continue stirring overnight. The mixture was then concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica, 5 to 40% ethyl acetate in heptane) to give ((2 R , 4 S , 5 R ) -4-azido-5-((2,2,2-trifluoroethyl)amino)tetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorobenzene yl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone.

LCMS: 100%, RT=2.21 minutes, (M+H) ⁺ =478 (Method A).

Synthesis of ((2R,4S,5R)-4-amino-5-((2,2,2-trifluoroethyl)amino)tetrahydro-2H-piran-2-yl)((S)- 1-(4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( Compound 5539 ).

((2 R ,4 S ,5 R )-4-azido was prepared under atmospheric hydrogen pressure in the presence of palladium (10 wt% on carbon, 50% water, 60 mg, 0.028 mmol) -5-((2,2,2-trifluoroethyl)amino)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4 - Hydrogenation of a solution of dihydroisoquinolin-2(1 H )-yl)methanone (95 mg, 0.199 mmol) in tetrahydrofuran (4 mL). After stirring for 1 hour, the mixture was diluted with ethyl acetate and filtered on a 0.45 µm nylon filter. The filtrate was evaporated under reduced pressure. By acidic 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 nm) purified residue. The product fractions were combined and basified with saturated aqueous NaHCO ₃ solution and then partially concentrated under reduced pressure to remove acetonitrile. The aqueous residue was extracted (twice) with dichloromethane. The combined organic layers were dried _{over Na2SO4} and concentrated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ((2 R ,4 S ,5 R )-4-amino-5-((2,2,2-tri Fluoroethyl)amino)tetrahydro- 2H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H ) -Methyl ketone ( compound 5539 ).

LCMS: 100%, RT=1.17 minutes, (M+H) ⁺ =452 (Method P). Example 149

1-((4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)octa Hydro-4H-pirano[3,4-b]pyra -4-yl)ethane-1-one (compound 5543)

Synthesis of N-((2R,4S,5R)-5-amino-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro-2H-piran-4-yl)-4-methylbenzenesulfonamide.

In a capped microwave vial, (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((1 S ,4 R ,6 S )-7-methylbenzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (see compound 5520, 1.50 g, A suspension of 2.96 mmol) in ammonia-containing methanol (7 M, 15 mL, 105 mmol) was heated overnight. Subsequently, the reaction mixture was concentrated to dryness under reduced pressure to obtain N -((2 R ,4 S ,5 R )-5-amino-2-(( S )-1-(4-) as a white solid Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)-4-methylbenzenesulfonamide (1.584 g) and It is used as is.

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-1-methylbenzenesulfonyl Octahydro-2H-pirano[3,4-b]pyra -7-yl)methanone.

To N -((2 R ,4 S ,5 R )-5-amino-2-(( S )-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)-4-methylbenzenesulfonamide (1.584 g, 3.03 mmol) in dichloromethane (anhydrous, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.905 mL, 6.05 mmol) was added to the suspension in 50 mL), followed by the vinyldiphenyl trifluoromethanesulfonate added dropwise Sulfonium salt (1.370 mL, 3.78 mmol). After 10 minutes, the mixture was slowly warmed to room temperature and stirring was continued for 3 hours. Subsequently, the reaction mixture was washed with aqueous HCl (1 M, 20 mL) and saturated _aqueous NaHCO (20 mL), dried over _Na2SO4 and evaporated under reduced pressure _. The residue was purified by flash column chromatography (silica, 5 to 100% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-1-methylbenzenesulfonyloctahydro-2 H -pirano[3,4-b]pyra -7-yl)methanone.

LCMS: 97%, RT=1.79 minutes, (M+H) ⁺ =550 (Method A).

Synthesis of 1-((4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1- Toluenesulfonyloctahydro-4H-pirano[3,4-b]pyra -4-yl)ethane-1-one.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-1-methyl Benzenesulfonyloctahydro- 2H -pirano[3,4-b]pyra To a solution of -7-yl)methanone (138 mg, 0.251 mmol) and N,N -diisopropylethylamine (0.143 mL, 0.819 mmol) in tetrahydrofuran (anhydrous, 2.5 mL) was added acetic anhydride (0.032 mL ,0.341 mmol). After 40 hours, the reaction mixture was partitioned between dichloromethane (7.5 mL) and saturated _aqueous NaHCO (7.5 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (7.5 mL). The combined organic layers were dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica (0 to 100% ethyl acetate in heptane) to give 1-(( 4aR , 7R , 8aS )-7-(( S ) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylbenzenesulfonyloctahydro- 4H -pirano[3, 4-b]pyridine -4-yl)ethane-1-one.

LCMS: 99%, RT=2.26 minutes, (M+H) ⁺ =592 (Method A).

Synthesis of 1-((4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)octahydro- 4H-Pirano[3,4-b]pyra -4-yl)ethane-1-one ( compound 5543 ).

To a solution of naphthalene (500 mg, 3.90 mmol) in tetrahydrofuran (anhydrous, 8 mL) under an argon atmosphere was added sodium block (90 mg, 3.90 mmol). The mixture was stirred for 2 hours until all sodium dissolved, yielding a solution of sodium naphthide (0.5 M in tetrahydrofuran). To 1-((4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4 at -78°C under argon atmosphere -Tetrahydroisoquinoline-2-carbonyl)-1-methylbenzenesulfonyloctahydro- 4H -pirano[3,4-b]pyra To a solution of -4-yl)ethane-1-one (118 mg, 0.199 mmol) in tetrahydrofuran (anhydrous, 2.5 mL) was added sodium naphthide (0.5 M in tetrahydrofuran, 0.735 mL, 0.367 mmol). After 15 minutes, another portion of sodium naphthide (0.5 M in THF, 0.423 mL, 0.211 mmol) was added. After 15 minutes, the reaction mixture was quenched by adding methanol (0.4 mL) and stored in the freezer overnight. Subsequently, the mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 7.5% (7M NH in _methanol )/dichloromethane) and preparative SFC (Method BA) in a mixture of acetonitrile and water ( After lyophilization in 1:1, 4 mL), 1-((4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)octahydro-4H-pirano[3,4-b]pyra -4-yl)ethane-1-one ( compound 5543 ) as the first eluting isomer on SFC.

LCMS: 97%, RT=1.05 minutes, (M+H) ⁺ =438 (Method P). SFC: 100%, RT=4.66 minutes, (M+H) ⁺ =438 (Method AD). Example 150

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-4-(2, 2,2-Trifluoroethyl)octahydro- 2H -pirano[3,4-b]pyra -7-yl)methanone (compound 5545)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-1-methylbenzenesulfonyl -4-(2,2,2-trifluoroethyl)octahydro-2H-pirano[3,4-b]pyra -7-yl)methanone.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-1-methyl Benzenesulfonyloctahydro- 2H -pirano[3,4-b]pyra To a solution of -7-yl)methanone (see compound 5462, 150 mg, 0.273 mmol) in tetrahydrofuran (anhydrous, 2.5 mL) was added N,N -diisopropylethylamine (0.143 mL, 0.819 mmol) and 2 , 2,2-trifluoroethyl trifluoromethanesulfonate (0.059 mL, 0.409 mmol), and the mixture was heated to 60°C. After 4 hours, additional amounts of N,N -diisopropylethylamine (0.143 mL, 0.819 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.059 mL, 0.409 mmol) were added and Continue stirring for 2 days. Subsequently, an additional amount of 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.059 mL, 0.409 mmol) was added. After another 1 day, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give (( S )-1-(4-fluorophenyl)-3,4-di Hydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-1-methylbenzenesulfonyl-4-(2,2,2-trifluoroethyl)octahydro -2H -pirano[3,4-b]pyra -7-yl)methanone.

LCMS: 99%, RT=2.31 minutes, (M+H) ⁺ =632 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-4-(2,2,2 -Trifluoroethyl)octahydro-2H-pirano[3,4-b]pyra -7-yl)methanone ( compound 5545 ).

To a solution of naphthalene (500 mg, 3.90 mmol) in tetrahydrofuran (anhydrous, 8 mL) under an argon atmosphere was added sodium block (90 mg, 3.90 mmol). The mixture was stirred for 2 hours until all sodium dissolved, yielding a solution of sodium naphthide (0.5 M in tetrahydrofuran). To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R , 7 R ,8a S )-1-methylbenzenesulfonyl-4-(2,2,2-trifluoroethyl)octahydro- 2H -pirano[3,4-b]pyra To a solution of -7-yl)methanone (119 mg, 0.188 mmol) in tetrahydrofuran (anhydrous, 2.5 mL) was added sodium naphthide (0.5 M in tetrahydrofuran, 0.792 mL, 0.396 mmol). After 15 minutes, another portion of sodium naphthide (0.5 M in THF, 0.396 mL, 0.198 mmol) was added. After 15 minutes, the reaction mixture was quenched by adding saturated aqueous ammonium chloride (2.0 mL), diluted with dichloromethane (5 mL) and stored in the freezer for 7 days. Subsequently, the layers were separated and the aqueous phase was extracted with dichloromethane (5 mL). The combined organic phases were passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 7.5% (7M NH in _methanol )/dichloromethane) and preparative SFC (Method AN) in a mixture of acetonitrile and water ( 1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-4-(2,2,2-trifluoroethyl)octahydro-2 H -pirano[3,4-b]pyra -7-yl)methanone ( compound 5545 ) as the first eluting isomer on SFC.

LCMS: 98%, RT=1.22 minutes, (M+H) ⁺ =478 (Method P). SFC: 99%, RT=2.70 minutes, (M+H) ⁺ =478 (Method AD). Example 151

1-((4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)octa Hydro-4H-pirano[3,4-b]pyra -4-yl)propan-1-one (compound 5544)

Synthesis of 1-((4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1- Toluenesulfonyloctahydro-4H-pirano[3,4-b]pyra -4-yl)propan-1-one.

To propionic acid (0.026 mL, 0.341 mmol) and (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-1-methylbenzenesulfonyloctahydro- 2H -pirano[3,4-b]pyra -7-yl)methanone (see compound 5462, 150 mg, 0.273 mmol) was added to a solution in a mixture of tetrahydrofuran (anhydrous, 2.5 mL) and N , N -dimethylformamide (anhydrous, 0.5 mL) N- (3-dimethylaminopropyl) -N′ -carbodiimide hydrochloride (65.4 mg, 0.341 mmol) and 1-hydroxybenzotriazole hydrate (4.18 mg, 0.027 mmol) . After 2 days, an additional amount of propionic acid (10.2 µL, 0.136 mmol) was added, followed by N -(3-dimethylaminopropyl)- N ′-carbodiimide hydrochloride (26.2 mg, 0.136 mmol) and 1-hydroxybenzotriazole hydrate (4.18 mg, 0.027 mmol) and continue stirring for 1 day. Subsequently, the reaction mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was washed with half-saturated brine (3 x 10 mL ₎ and brine (10 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 100% ethyl acetate in heptane) to give 1-((4a R , 7 R , 8a S )-7-(( S ) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylbenzenesulfonyloctahydro- 4H -pirano[3, 4-b]pyridine -4-yl)propan-1-one.

LCMS: 99%, RT=2.17 minutes, (M+H) ⁺ =606 (Method A).

Synthesis of 1-((4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)octahydro- 4H-Pirano[3,4-b]pyra -4-yl)propan-1-one ( compound 5544 ).

To a solution of naphthalene (500 mg, 3.90 mmol) in tetrahydrofuran (anhydrous, 8 mL) under an argon atmosphere was added sodium block (90 mg, 3.90 mmol). The mixture was stirred for 2 hours until all sodium dissolved, yielding a solution of sodium naphthide (0.5 M in tetrahydrofuran). To 1-((4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4 at -78°C under argon atmosphere -Tetrahydroisoquinoline-2-carbonyl)-1-methylbenzenesulfonyloctahydro- 4H -pirano[3,4-b]pyra To a solution of -4-yl)propan-1-one (125 mg, 0.206 mmol) in tetrahydrofuran (anhydrous, 2.5 mL) was added sodium naphthide (0.5 M in tetrahydrofuran, 1.783 mL, 0.891 mmol). After 15 minutes, the reaction mixture was quenched by adding methanol (0.4 mL) and stored in the freezer over the weekend. Subsequently, the mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 6% (7M NH in _methanol )/dichloromethane) and preparative SFC (Method BA) from a mixture of acetonitrile and water ( After lyophilization in 1:1, 4 mL), 1-((4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)octahydro-4H-pirano[3,4-b]pyra -4-yl)propan-1-one ( compound 5544 ) as the first eluting isomer on SFC.

LCMS: 97%, RT=1.11 minutes, (M+H) ⁺ =452 (Method P). SFC: 99%, RT=4.55 minutes, (M+H) ⁺ =452 (method AD). Example 152

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 S ,4a R ,7 R ,8a S )-3- Methyloctahydropirano[3,4-b][1,4] -7-yl)methanone (compound 5471)

Synthesis of N-((2R,4S,5R)-5-(((S)-1-(benzyloxy)prop-2-yl)oxy)-2-((S)-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonamide.

Under an argon atmosphere, to (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((1 S ,4 R ,6 S )-7-methylbenzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (see compound 5520, 300 mg, 0.592 mmol) and ( S ) -(-)-1-Benzyloxy-2-propanol (492 mg, 2.96 mmol) in 1,4-di To the suspension in alkanes (5 mL) was added sodium hydride (60% dispersion in mineral oil, 35.5 mg, 0.888 mmol). After stirring overnight, the mixture was diluted with saturated aqueous _NH4Cl solution and extracted with ethyl acetate (2x). _The combined organics were washed with brine, dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 10 to 65% ethyl acetate in heptane) to give N -((2 R ,4 S ,5 R )-5-((( S )-1-(benzyloxy)prop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide.

LCMS: 90%, RT=2.25 minutes, (M+H) ⁺ =673 (Method A).

Synthesis of ((2R,4S,5R)-5-(((S)-1-(benzyloxy)prop-2-yl)oxy)-2-((S)-1-(4-fluorobenzene) tertiary butyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)(toluenesulfonyl)carbamate.

To N -((2 R ,4 S ,5 R )-5-((( S )-1-(benzyloxy)prop-2-yl)oxy)-2-(( S )-1- (4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide (177 mg, 0.263 mmol) in tetrahydrofuran (anhydrous, 5 mL) were added triethylamine (0.073 mL, 0.526 mmol), di-tertiary butyl dicarbonate (0.115 mg, 0.526 mmol) and 4-dimethyl Aminopyridine (catalytic amount). After 45 minutes, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 40% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-5-((( S )- 1-(Benzyloxy)prop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)tetrahydro- 2H -pyran-4-yl)(toluenesulfonyl)carbamic acid tertiary butyl ester.

LCMS: 95%, RT=2.44 minutes, (M+H) ⁺ =773 (Method A).

Synthesis of ((2R,4S,5R)-5-(((S)-1-(benzyloxy)prop-2-yl)oxy)-2-((S)-1-(4-fluorobenzene) (yl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-((( S )-1-(benzyloxy)prop-2-yl)oxy)-2-(( S )-1-(4 -Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)(methylbenzenesulfonyl)carbamic acid tert-butyl To a solution of the ester (170 mg, 0.220 mmol) in methanol (5 mL) was added ammonium chloride (118 mg, 2.20 mmol) and magnesium (267 mg, 11.00 mmol). After 1.5 hours, the mixture was diluted with saturated aqueous _NH4Cl (15 mL) and stirred for 10 minutes. Subsequently, the mixture was extracted with dichloromethane (2 × 15 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 50% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-5-((( S )- 1-(Benzyloxy)prop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carboyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 95%, RT=2.27 minutes, (M+Na) ⁺ =619 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(( (S)-1-Hydroxyprop-2-yl)oxy)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

((2 R ,4 S ,5 R )-5-(((( S )-1-(benzyloxy)prop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Hydrogenation of a solution of tertiary butyl pholin-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamate (102 mg, 0.165 mmol) in 2,2,2-trifluoroethanol (3 mL) . After stirring for 45 minutes, the mixture was filtered on a 0.45 µm nylon filter. The filtrate was concentrated under reduced pressure to obtain ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline -2-Carbonyl)-5-((( S )-1-hydroxyprop-2-yl)oxy)tetrahydro-2 H -pyran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 93%, RT=2.02 minutes, (M+H) ⁺ =529 (Method A).

Synthesis of methanesulfonic acid (S)-2-(((3R,4S,6R)-4-((tertiary butoxycarbonyl)amine)-6-((S)-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)oxy)propyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -((( R )-1-hydroxyprop-2-yl)oxy)tetrahydro-2 H -pyran-4-yl)carbamic acid tertiary butyl ester (65 mg, 0.123 mmol) in dichloromethane ( 2 mL) were added triethylamine (0.051 mL, 0.369 mmol) and methanesulfonyl chloride (0.019 mL, 0.246 mmol). After 30 minutes, the mixture was diluted with saturated aqueous _NaHCO3 solution and stirred for 15 minutes. The layers were separated on a phase separation filter and the organic filtrate was evaporated under reduced pressure to yield methanesulfonic acid ( S )-2-((( 3R , 4S , 6R )-4-((tertiary butoxycarbonyl )Amino)-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3 -yl)oxy)propyl ester.

LCMS: 95%, RT=2.10 minutes, (M+H) ⁺ =607 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3S,4aR,7R,8aS)-3-methyloctahydrogen Pirano[3,4-b][1,4] -7-yl)methanone ( compound 5471 ).

To methanesulfonic acid ( S )-2-(((3 R ,4 S ,6 R )-4-((tertiary butoxycarbonyl)amine)-6-(( S )-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)oxy)propyl ester (65 mg, 0.107 mmol) in 2 -To a solution in propanol (7 mL), add HCl (5-6 M in 2-propanol, 2 mL, 11.0 mmol). After stirring for 1 day, the mixture was diluted with saturated _aqueous NaHCO (30 mL) and dichloromethane (25 mL) and stirred vigorously for 15 min. The layers were separated and the aqueous phase was extracted with dichloromethane (25 mL). The combined organics were evaporated under reduced pressure. The residue was dissolved in dichloromethane and triethylamine (0.045 mL, 0.321 mmol) was added. After stirring overnight, the mixture was warmed to 35°C and stirred for 1 day. Subsequently, the mixture was concentrated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (1 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was purified by preparative SFC (Method S) to give (( S )-1-(4-fluorophenyl)-3 after lyophilization from a mixture of acetonitrile and water (1:1, 4 mL) ,4-Dihydroisoquinolin-2(1 H )-yl)((3 S ,4a R ,7 R ,8a S )-3-methyloctahydropyrano[3,4-b][1 ,4] -7-yl)methanone ( compound 5471 ).

LCMS: 96%, RT=1.12 minutes, (M+H) ⁺ =411 (Method P). SFC: 95%, RT=3.39 minutes, (M+H) ⁺ =411 (Method G). Example 153

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 R ,4a R ,7 R ,8a S )-3- (Trifluoromethyl)octahydropirano[3,4-b][1,4] -7-yl)methanone (compound 5474)

Synthesis of N-((2R,4S,5R)-5-(((R)-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-( (S)-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-piran-4-yl)-4-methylbenzene Sulfonamides.

Under an argon atmosphere, to (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((1 S ,4 R ,6 S )-7-methylbenzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (see compound 5520, 500 mg, 0.987 mmol) and ( R ) -3-(Benzyloxy)-1,1,1-trifluoropropan-2-ol (652 mg, 2.96 mmol) in 1,4-di To a suspension in alkanes (20 mL) was added sodium hydride (60% dispersion in mineral oil, 59.2 mg, 1.480 mmol) and the mixture was heated to 60 °C. After stirring for 4.5 hours, the mixture was diluted with saturated aqueous NH ₄ Cl solution (50 mL) and water (several mL), and extracted with ethyl acetate (2×50 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 40% ethyl acetate in heptane) to give N -((2 R ,4 S ,5 R )-5-((( R )-3-(Benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide.

LCMS: 93%, RT=2.33 minutes, (M+H) ⁺ =727 (Method A).

Synthesis of ((2R,4S,5R)-5-(((R)-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-((S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)(methylbenzenesulfonyl) Tertiary butyl carbamate.

To N -((2 R ,4 S ,5 R )-5-((( R )-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)- 2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-4-yl)-4 -To a solution of toluenesulfonamide (475 mg, 0.654 mmol) in tetrahydrofuran (anhydrous, 8 mL), triethylamine (0.182 mL, 1.307 mmol) and di-tertiary butyl dicarbonate (0.285 mg, 1.307 mmol) and 4-dimethylaminopyridine (7.98 mg, 0.065 mmol). After stirring overnight, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-5-((( R )- 3-(Benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)(toluenesulfonyl)carbamic acid tertiary butyl ester.

LCMS: 97%, RT=2.48 minutes, (M+H) ⁺ =827 (Method A).

Synthesis of ((2R,4S,5R)-5-(((R)-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-((S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-((( R )-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2- (( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-4-yl) (methylbenzene To a solution of tertiary butyl sulfocarbamate (482.5 mg, 0.583 mmol) in methanol (17 mL) was added ammonium chloride (312 mg, 5.84 mmol) and magnesium (709 mg, 29.2 mmol). After stirring overnight, an additional amount of magnesium (126 mg, 5.20 mmol) was added and stirring was continued for 4 hours. Thereafter, the mixture is stored in the freezer over the weekend. Subsequently, the mixture was diluted with saturated aqueous NH ₄ Cl solution (40 mL), stirred for 10 min, and extracted with dichloromethane (2×40 mL). The combined organics were dried _{over Na2SO4} and evaporated under reduced pressure to give (( 2R , 4S , 5R )-5-((( R )-3-(benzyloxy)-1, 1,1-trifluoroprop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester and it was used as received.

LCMS: 90%, RT=2.35 minutes, (M+H) ⁺ =673 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(( (R)-1,1,1-Trifluoro-3-hydroxyprop-2-yl)oxy)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

((2 R ,4 S ,5 R )-5-(((( R )-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2 ,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (156 mg, 0.232 mmol) in 2,2,2-trifluoro A solution in ethanol (3.5 mL) was hydrogenated. After stirring overnight, the mixture was filtered on a 0.45 µm nylon filter. The filtrate was concentrated under reduced pressure to obtain ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4- as colorless oil) Tetrahydroisoquinoline-2-carbonyl)-5-((( R )-1,1,1-trifluoro-3-hydroxyprop-2-yl)oxy)tetrahydro- 2H -piran-4 -tert-butylcarbamate (131 mg).

LCMS: 84%, RT=2.14 minutes, (M+H) ⁺ =583 (Method A).

Synthesis of methane sulfonate (R)-2-(((3R,4S,6R)-4-((tertiary butoxycarbonyl)amine)-6-((S)-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)oxy)-3,3,3-trifluoropropyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -((( R )-1,1,1-trifluoro-3-hydroxyprop-2-yl)oxy)tetrahydro-2 H -pyran-4-yl)carbamic acid tertiary butyl ester (131 mg , 0.225 mmol) in dichloromethane (2.5 mL) were added triethylamine (0.094 mL, 0.674 mmol) and methane sulfonyl chloride (0.035 mL, 0.449 mmol). After stirring overnight, the reaction mixture was purified by flash column chromatography (silica, 0 to 60% ethyl acetate in heptane) to give methanesulfonic acid ( R )-2-(((3 R ,4 S ,6 R )-4-((tertiary butoxycarbonyl)amino)-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro- 2H -pyran-3-yl)oxy)-3,3,3-trifluoropropyl ester.

LCMS: 87%, RT=2.19 minutes, (M+H) ⁺ =661 (Method A).

Synthesis of methanesulfonic acid (R)-2-(((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)oxy)-3,3,3-trifluoropropyl ester.

To methanesulfonic acid ( R )-2-(((3 R ,4 S ,6 R )-4-((tertiary butoxycarbonyl)amine)-6-(( S )-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)oxy)-3,3,3-trifluoropropyl ester To a solution of (111 mg, 0.168 mmol) in 2-propanol (8 mL) was added HCl (5-6 M in 2-propanol, 1 mL, 5.5 mmol). After stirring overnight, another amount of HCl (5-6 M in 2-propanol, 1 mL, 5.5 mmol) was added and stirring continued overnight. Subsequently, the mixture was diluted with saturated _aqueous NaHCO solution (30 mL) and dichloromethane (30 mL) and stirred vigorously for 30 min. The layers were separated and the aqueous phase was extracted with dichloromethane (20 mL). The combined organics were dried over Na ₂ SO ₄ and evaporated under reduced pressure to give crude methanesulfonic acid ( R )-2-(((3 R , 4 S , 6 R )-) as a colorless glassy solid. 4-Amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3 -(yl)oxy)-3,3,3-trifluoropropyl ester (101 mg) and was used as received.

LCMS: 80%, RT=1.67 minutes, (M+H) ⁺ =561 and 15%, RT=1.72 minutes, (M+H) ⁺ =465 (product of next step) (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3R,4aR,7R,8aS)-3-(trifluoromethyl base)octahydropirano[3,4-b][1,4] -7-yl)methanone ( compound 5474 ).

To crude methanesulfonic acid ( R )-2-(((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2 ,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)oxy)-3,3,3-trifluoropropyl ester (101 mg, 0.168 mmol) in To a solution in dichloromethane (4 mL) was added triethylamine (0.099 mL, 0.714 mmol), and the mixture was warmed to 40 °C. After 8 hours, another amount of triethylamine (0.248 mL, 1.784 mmol) was added and stirring was continued at 30°C over the weekend. Subsequently, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 2.5% methanol in dichloromethane). The product was dissolved in methanol, introduced onto an SCX-2 column (2 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl) ((3 R ,4a R ,7 R ,8a S )-3-(trifluoromethyl)octahydropirano[3,4-b][1,4] -7-yl)methanone ( compound 5474 ).

LCMS: 99%, RT=1.23 minutes, (M+H) ⁺ =465 (Method P). Example 154

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 S ,4a R ,7 R ,8a S )-3- (Trifluoromethyl)octahydropirano[3,4-b][1,4] -7-yl)methanone (compound 5473)

Synthesis of N-((2R,4S,5R)-5-(((S)-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-( (S)-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-piran-4-yl)-4-methylbenzene Sulfonamides.

Under an argon atmosphere, to (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((1 S ,4 R ,6 S )-7-methylbenzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (see compound 5520, 500 mg, 0.987 mmol) and ( S ) -3-(Benzyloxy)-1,1,1-trifluoropropan-2-ol (652 mg, 2.96 mmol) in 1,4-di To a suspension in alkanes (20 mL) was added sodium hydride (60% dispersion in mineral oil, 59.2 mg, 1.480 mmol) and the mixture was heated to 60 °C. After stirring for 4.5 hours, the mixture was allowed to cool to room temperature and stirred overnight. Subsequently, the mixture was diluted with saturated aqueous NH ₄ Cl solution (35 mL) and water (10 mL) and extracted with ethyl acetate (35 + 20 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 45% ethyl acetate in heptane) to give N -((2 R ,4 S ,5 R )-5-((( S )-3-(Benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide.

LCMS: 89%, RT=2.49 minutes, (M+H) ⁺ =727 (Method A).

Synthesis of ((2R,4S,5R)-5-(((S)-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-((S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)(methylbenzenesulfonyl) Tertiary butyl carbamate.

To N -((2 R ,4 S ,5 R )-5-((( S )-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)- 2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-4-yl)-4 -To a solution of toluenesulfonamide (425 mg, 0.585 mmol) in tetrahydrofuran (anhydrous, 8 mL), triethylamine (0.163 mL, 1.170 mmol) and di-tertiary butyl dicarbonate (0.255 mg, 1.170 mmol) and 4-dimethylaminopyridine (7.15 mg, 0.059 mmol). After stirring overnight, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-5-((( S )- 3-(Benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)(toluenesulfonyl)carbamic acid tertiary butyl ester.

LCMS: 89%, RT=2.49 minutes, (M+H) ⁺ =827 (Method A).

Synthesis of ((2R,4S,5R)-5-(((S)-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-((S )-1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-((( S )-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2- (( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -piran-4-yl) (methylbenzene To a solution of tertiary butyl sulfocarbamate (480 mg, 0.579 mmol) in methanol (15 mL) was added ammonium chloride (310 mg, 5.79 mmol) and magnesium (704 mg, 29.0 mmol). After stirring for 4 hours, an additional amount of magnesium (352 mg, 14.5 mmol) was added and stirring was continued over the weekend. Subsequently, the mixture was diluted with saturated aqueous NH ₄ Cl solution (40 mL), stirred for 10 min, and extracted with dichloromethane (2×40 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-5-((( S )- 3-(Benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester.

LCMS: 84%, RT=2.36 minutes, (M+H) ⁺ =673 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(( (S)-1,1,1-Trifluoro-3-hydroxyprop-2-yl)oxy)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

((2 R ,4 S ,5 R )-5-(((( S )-3-(benzyloxy)-1,1,1-trifluoroprop-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)-1,2 ,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (319 mg, 0.474 mmol) in 2,2,2-trifluoro A solution in ethanol (7.5 mL) was hydrogenated. After stirring overnight, the mixture was filtered on a 0.45 µm nylon filter and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 50% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-2-( as a white solid ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-((( S )-1,1,1-trifluoro- 3-Hydroxyprop-2-yl)oxy)tetrahydro-2 H -piran-4-yl)carbamic acid tertiary butyl ester (73 mg).

LCMS: 62%, RT=2.17 minutes, (M+H) ⁺ =583 (Method A).

Synthesis of methanesulfonic acid (S)-2-(((3R,4S,6R)-4-((tertiary butoxycarbonyl)amine)-6-((S)-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)oxy)-3,3,3-trifluoropropyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -((( S )-1,1,1-trifluoro-3-hydroxyprop-2-yl)oxy)tetrahydro-2 H -pyran-4-yl)carbamic acid tertiary butyl ester (73 mg , 0.125 mmol) in dichloromethane (3 mL) were added triethylamine (0.052 mL, 0.376 mmol) and methane sulfonyl chloride (0.020 mL, 0.251 mmol). After stirring for 1 hour, the mixture was diluted with _saturated aqueous NaHCO (4 mL) and stirred for 15 minutes. The layers were separated on a phase separation filter and the organic filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 10 to 60% ethyl acetate in heptane) to give methanesulfonic acid ( S )-2-((( 3R , 4S , 6R )-4-((tertiary butoxycarbonyl)amino)-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)tetrahydro- 2H -pyran-3-yl)oxy)-3,3,3-trifluoropropyl ester. LCMS: 91%, RT=2.21 minutes, (M+H) ⁺ =661 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3S,4aR,7R,8aS)-3-(trifluoromethyl base)octahydropirano[3,4-b][1,4] -7-yl)methanone ( compound 5473 ).

To methanesulfonic acid ( S )-2-(((3 R ,4 S ,6 R )-4-((tertiary butoxycarbonyl)amine)-6-(( S )-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)oxy)-3,3,3-trifluoropropyl ester To a solution of (45 mg, 0.068 mmol) in 2-propanol (1 mL) was added HCl (5-6 M in 2-propanol, 0.5 mL, 2.75 mmol). After stirring overnight, the mixture was diluted with saturated aqueous _NaHCO3 and dichloromethane and stirred vigorously for 15 minutes. The organic phase was passed through a hydrophobic frit and evaporated under reduced pressure. In a capped reaction vial, the residue was dissolved in dichloromethane, triethylamine (0.020 mL, 0.143 mmol) was added and the mixture was warmed to 35°C. After 2 days, another amount of triethylamine (0.10 mL, 0.717 mmol) was added and stirring was continued at 70°C for 3 hours and at 55°C over the weekend. Subsequently, the mixture was concentrated under reduced pressure. By acidic 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 nm) purified residue. The combined product fractions were basified with saturated aqueous _NaHCO3 and the acetonitrile was removed under reduced pressure. The aqueous residue was extracted (twice) with dichloromethane. The combined extracts were passed through a hydrophobic frit and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl) ((3 S ,4a R ,7 R ,8a S )-3-(trifluoromethyl)octahydropirano[3,4-b][1,4] -7-yl)methanone ( compound 5473 ). LCMS: 99%, RT=1.27 minutes, (M+H) ⁺ =465 (Method P). Example 155

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((2 R ,4 S ,5 R )-5-methoxy -4-((2-Methoxyethyl)amino)tetrahydro- 2H -pyran-2-yl)methanone (Compound 5569)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((2R,4S,5R)-5-methoxy-4- ((2-Methoxyethyl)amino)tetrahydro-2H-pyran-2-yl)methanone ( Compound 5569 ).

Under an argon atmosphere, to ((2 R ,4 S ,5 R )-4-amino-5-methoxytetrahydro-2 H -piran-2-yl) (( S )-1-( 4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5077, 400 mg, 1.040 mmol) in N , N -dimethylformamide ( Potassium carbonate (575 mg, 4.16 mmol) and 2-bromoethyl methyl ether (0.198 mL, 2.081 mmol) were added to a solution in anhydrous (8 mL), and the mixture was heated at 80°C. After stirring overnight, the mixture was diluted with ethyl acetate (30 mL) and water (15 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organics were washed with _brine (2 x 20 mL), dried over _Na2SO4 and concentrated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 5% A; t=16 minutes 50% A; t=17 minutes 100%; t=22 minutes 100% A; (measurement: 215 nm), the residue was purified and after lyophilization from a mixture of acetonitrile and water (1:1), (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquine was obtained Phinolin-2( 1H )-yl)(( 2R , 4S , 5R )-5-methoxy-4-((2-methoxyethyl)amino)tetrahydro- 2H -piper Pyran-2-yl)methanone ( compound 5569 ).

LCMS: 98%, RT=1.66 minutes, (M+H) ⁺ =443 (Method P). Example 156

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( R )- Phin-2-yl)methanone (Compound 5405)

Synthesis of (R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Phenoline-4-carboxylic acid tertiary butyl ester.

To( R )-4-(tertiary butoxycarbonyl) Phenoline-2-carboxylic acid (168 mg, 0.726 mmol) and ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (150 mg, 0.660 mmol) were dissolved in 2 To a solution in methyl chloride (5 mL) were added N- (3-dimethylaminopropyl) -N′ -carbodiimide hydrochloride (139 mg, 0.726 mmol) and 1-hydroxy-7- Azabenzotriazole (8.98 mg, 0.066 mmol). After stirring for 4 days, the reaction mixture was diluted with saturated _aqueous NaHCO solution. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 50% ethyl acetate in heptane) to give ( R )-2-(( S )-1-(4-fluorophenyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Phenoline-4-carboxylic acid tertiary butyl ester.

LCMS: 99%, RT=2.17 minutes, (M+Na) ⁺ =463 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)- Phin-2-yl)methanone ( compound 5405 ).

To ( R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) To a solution of tertiary butyl phosphine-4-carboxylate (255 mg, 0.579 mmol) in 2-propanol (5 mL) was added HCl (5-6 M in 2-propanol, 1.667 mL, 9.17 mmol) . After stirring for 2 days, the reaction mixture was diluted with saturated _aqueous NaHCO (15 mL) and dichloromethane and stirred for 15 minutes. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (2 g), and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-base)(( R )- Phin-2-yl)methanone ( compound 5405 ).

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =341 (Method P). Example 157

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( S )- Phin-2-yl)methanone (Compound 5406)

Synthesis of (S)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Phenoline-4-carboxylic acid tertiary butyl ester.

To ( S )-4-(tertiary butoxycarbonyl) Phenoline-2-carboxylic acid (168 mg, 0.726 mmol) and ( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (150 mg, 0.660 mmol) were dissolved in 2 To a solution in methyl chloride (5 mL) were added N- (3-dimethylaminopropyl) -N′ -carbodiimide hydrochloride (139 mg, 0.726 mmol) and 1-hydroxy-7- azabenzotriazole) 8.98 mg, 0.066 mmol). After stirring for 4 days, the reaction mixture was diluted with saturated _aqueous NaHCO solution. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 50% ethyl acetate in heptane) to give ( S )-2-(( S )-1-(4-fluorophenyl) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) Phenoline-4-carboxylic acid tertiary butyl ester.

LCMS: 99%, RT=2.15 minutes, (M+Na) ⁺ =463 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)- Phin-2-yl)methanone ( compound 5406 ).

To ( S )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) To a solution of tertiary butyl phosphine-4-carboxylate (260 mg, 0.590 mmol) in 2-propanol (5 mL) was added HCl (5-6 M in 2-propanol, 1.667 mL, 9.17 mmol) . After stirring for 2 days, the reaction mixture was diluted with saturated _aqueous NaHCO (15 mL) and dichloromethane and stirred for 15 minutes. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (2 g), and eluted with methanol until neutral. Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-base)(( S )- Phin-2-yl)methanone ( compound 5406 ).

LCMS: 99%, RT=1.03 minutes, (M+H) ⁺ =341 (Method P). Example 158

(S) -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro- 2H -piran-3-yl)(methyl)(methylimino)-λ ⁶ -sulfanone (compound 5555)

Synthesis of ((2R,4S,5R)-5-((S)-N,S-dimethylsulfonimide)-2-((S)-1-(4-fluorophenyl)-1, 2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(( S )- S -methanesulfonyl iminyl)tetrahydro-2 H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5547, 69 mg, 0.130 mmol), copper acetate ( II) (39.6 mg, 0.218 mmol) and molecular sieve (4 Å, 100 mg) in 1,4-di To a suspension in alkane (anhydrous, 2 mL) was added pyridine (0.025 mL, 0.311 mmol). Close the reaction vessel and stir for 5 minutes. Methylboronic acid (15.5 mg, 0.260 mmol) was then added. The reaction vessel was sealed and heated to 95°C. After 2.5 hours, the reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL), and filtered through a 0.45 μm nylon filter. The filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 30 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-5-(( S ) -N , S -dimethylsulfonimide)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro -2H -pyran-4-yl)carbamic acid tertiary butyl ester. The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 97%, RT=1.91 minutes, (M+H) ⁺ =546 (Method A).

Synthesis of (R)-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-3-yl)(methyl)(methylimino)-λ ⁶ -sulfanone ( compound 5555 ).

To ((2 R ,4 S ,5 R )-5-(( S )- N , S -dimethylsulfonyl iminyl)-2-(( S )-1-(4-fluorophenyl) -1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester (47 mg, 0.086 mmol) in 2-propanol (4 mL) was added HCl (5-6 M in 2-propanol, 1.0 mL, 5.0 mmol). After 2 days, the reaction mixture was basified with saturated aqueous _NaHCO3 solution and 2-propanol was removed under reduced pressure. The residue was extracted with dichloromethane (20 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 5% A; t=16 minutes 40% A; t=17 minutes 100%; t=22 minutes 100% A; (measured at 210 nm) purified residue. The combined product fractions were basified with saturated aqueous _NaHCO3 and the acetonitrile was removed under reduced pressure. The residue was extracted with dichloromethane. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was filtered through a 0.25 μm nylon filter and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ( R )-(( 3R , 4S , 6R )-4 -Amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3- (methyl)(methylimino)-λ ⁶ -sulfanone ( compound 5555 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 98%, RT=1.06 minutes, (M+H) ⁺ =446 (Method P). Example 159

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4 R ,4a R ,7 R ,8a S )-4- Imine-4-oxooctahydro- 2H -4λ ⁴ -pirano[3,4-b][1,4]thi -7-yl)methanone (compound 5553)

Synthesis of (4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydropirano[ 3,4-b][1,4]thi -1(5H)-Carboxylic acid tertiary butyl ester.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-octahydropyran and[3,4-b][1,4]thi To a solution of -7-yl)methanone (184 mg, 0.446 mmol) in dichloromethane (5 mL) was added di-tertiary butyl dicarbonate (135 mg, 0.619 mmol). After stirring overnight, the mixture was evaporated under reduced pressure. The residue was dissolved in a minimum amount of toluene and purified by flash column chromatography (silica, 5 to 40% ethyl acetate in heptane) to obtain combined product-containing fractions and concentrate, Obtain (4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydropipaniline Pyro[3,4-b][1,4]thi -1( 5H )-tertiary butylcarboxylate.

LCMS: 99%, RT=2.29 minutes, (M+Na) ⁺ =535 (Method A).

Synthesis of 4-oxy(4S,4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)- 4-imine hexahydro-2H-4λ ⁴ -pirano[3,4-b][1,4]thi -1(5H)-tertiary butylcarboxylate and 4-oxy(4R,4aR,7R,8aS)-7-((S)-1-(4-fluorophenyl)-1,2,3,4 -Tetrahydroisoquinoline-2-carbonyl)-4-iminehexahydro-2H-4λ ⁴ -pirano[3,4-b][1,4]thi -1(5H)-Carboxylic acid tertiary butyl ester.

To (4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)hexahydropipaniline Pyro[3,4-b][1,4]thi -To a solution of tertiary butyl 1(5 H )-carboxylate (202 mg, 0.394 mmol) and ammonium carbamate (46.1 mg, 0.591 mmol) in methanol (2.5 mL) was added iodobenzene diacetate (267 mg, 0.827 mmol). The reaction mixture was stirred in air and after 1 hour, the mixture was concentrated under reduced pressure. Purified by flash column chromatography twice (silica, 0 to 10% (7M ammonia in methanol)/dichloromethane) and (silica, 25 to 100% ethyl acetate in heptane) The residue gave 4-oxy(4 S ,4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)-4-imine hexahydro- 2H -4λ ⁴ -pirano[3,4-b][1,4]thi -1(5 H )-tertiary butylcarboxylate as the first eluted isomer from the second column and 4-oxidation (4 R , 4a R , 7 R , 8a S )-7-(( S ) -1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-iminehexahydro- 2H -4λ ⁴ -pirano[3,4 -b][1,4]thi -1( 5H )-tertiary butylcarboxylate as the second eluted isomer from the second column. The stereochemistry of the setrimine stereocenter is arbitrarily specified.

First eluted isomer: LCMS: 99%, RT=2.03 minutes, (M+H) ⁺ =544 (Method A). SFC: 99%, RT=4.94 minutes, (M+H) ⁺ =544 (Method AZ).

Second eluted isomer: LCMS: 99%, RT=2.03 min, (M+H) ⁺ =544 (Method A). SFC: 99%, RT=3.93 minutes, (M+H) ⁺ =544 (Method AZ).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4R,4aR,7R,8aS)-4-imine-4 -Oxooctahydro-2H-4λ ⁴ -pirano[3,4-b][1,4]thi -7-yl)methanone ( compound 5553 ).

To 4-oxidation (4 R ,4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)-4-imine hexahydro- 2H -4λ ⁴ -pirano[3,4-b][1,4]thi To a suspension of tertiary butyl 1(5 H )-carboxylate (64 mg, 0.118 mmol) in 2-propanol (6 mL) was added HCl (5 M in 2-propanol, 1.5 mL, 7.50 mmol). After 2 days, the reaction mixture was basified with saturated aqueous _NaHCO3 solution and 2-propanol was removed under reduced pressure. The residue was extracted with dichloromethane. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 min 5% A; t=1 min 5% A; t=3 min 15% A; t=18 min 40% A; t=19 min 100%; t =24 min 100% A; detection: 220 nm) purified residue. The combined product fractions were basified with saturated aqueous _NaHCO3 and the acetonitrile was removed under reduced pressure. The residue was extracted with dichloromethane. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl) ((4 R ,4a R ,7 R ,8a S )-4-imine-4-oxooctahydro-2 H -4λ ⁴ -pirano[3,4-b][1 ,4]thiophene -7-yl)methanone ( compound 5553 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 98%, RT=2.67 minutes, (M+H) ⁺ =444 (Method AK). SFC: 100%, RT=3.51 minutes, (M+H) ⁺ =444 (Method AS). Example 160

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4 S ,4a R ,7 R ,8a S )-4- Imine-4-oxooctahydro- 2H -4λ ⁴ -pirano[3,4-b][1,4]thi -7-yl)methanone (compound 5554)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4S,4aR,7R,8aS)-4-imine-4 -Oxooctahydro-2H-4λ ⁴ -pirano[3,4-b][1,4]thi -7-yl)methanone ( compound 5554 ).

To 4-oxidation (4 S ,4a R ,7 R ,8a S )-7-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2 -Carbonyl)-4-imine hexahydro- 2H -4λ ⁴ -pirano[3,4-b][1,4]thi -To a suspension of tertiary butyl 1(5 H )-carboxylate (64 mg, 0.118 mmol) in 2-propanol (10 mL) was added HCl (5 M in 2-propanol, 2.5 mL, 12.50 mmol). After 2 days, the reaction mixture was basified with saturated aqueous _NaHCO3 solution and 2-propanol was removed under reduced pressure. The residue was extracted with dichloromethane. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl) ((4 S ,4a R ,7 R ,8a S )-4-imine-4-oxoctahydro-2 H -4λ ⁴ -pirano[3,4-b][1 ,4]thiophene -7-yl)methanone ( compound 5554 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 99%, RT=2.67 minutes, (M+H) ⁺ =444 (Method AK). SFC: 99%, RT=3.15 minutes, (M+H) ⁺ =444 (Method AS). Example 161

(S) -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro- 2H -piran-3-yl)(ethylimino)(methyl)-λ ⁶ -sulfanone (compound 5557)

Synthesis of ((2R,4S,5R)-5-((S)-N,S-dimethylsulfonimide)-2-((S)-1-(4-fluorophenyl)-1, 2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(( S )- S -methanesulfonyl iminyl)tetrahydro-2 H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5547, 69 mg, 0.130 mmol), copper acetate ( II) (40.1 mg, 0.221 mmol) and molecular sieve (4 Å, 100 mg) in 1,4-di To a suspension in alkane (anhydrous, 2 mL) was added pyridine (0.157 mL, 1.947 mmol). Close the reaction vessel and stir for 5 minutes. Ethylboronic acid (125 mg, 1.687 mmol) was then added. The reaction vessel was sealed and heated to 95°C. After 1.5 hours, the reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL) and filtered through a 0.45 μm nylon filter. The filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 40 to 100% ethyl acetate in heptane) to give ((2 R ,4 S ,5R)-5-(( S )- N -ethyl- S -methanesulfonyl iminyl)-2-(( S )-1-(4-fluorophenyl)-1,2 ,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester. The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 99%, RT=1.94 minutes, (M+H) ⁺ =560 (Method A).

Synthesis of (S)-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-3-yl)(ethylimino)(methyl)-λ ⁶ -sulfanone ( compound 5557 ).

To ((2 R ,4 S ,5R)-5-(( S )- N -ethyl- S -methanesulfonyl iminyl)-2-(( S )-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester (50 mg, 0.089 mmol) in 2-propanol To a solution in alcohol (4 mL) was added HCl (5 M in 2-propanol, 1.0 mL, 5.0 mmol). After 2 days, the reaction mixture was basified with saturated aqueous _NaHCO3 solution and 2-propanol was removed under reduced pressure. The residue was extracted with dichloromethane (10 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 10% A; t=2 minutes 10% A; t=17 minutes 50% A; t=18 minutes 100%; t=23 minutes 100% A; detection (measured at 220 nm) purified residue. The combined product fractions were basified with saturated aqueous _NaHCO3 and the acetonitrile was removed under reduced pressure. The residue was extracted with dichloromethane (10 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was filtered through a 0.25 μm nylon filter and lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give (S) -(( 3R , 4S , 6R )-4- Amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl )(ethylimino)(methyl)-λ ⁶ -sulfanone ( compound 5557 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 98%, RT=1.10 minutes, (M+H) ⁺ =460 (Method P). Example 162

(R) -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro- 2H -piran-3-yl)(methyl)(methylimino)-λ ⁶ -sulfanone (compound 5556)

Synthesis of ((2R,4S,5R)-5-((R)-N,S-dimethylsulfonimide)-2-((S)-1-(4-fluorophenyl)-1, 2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(( R )- S -methanesulfonyl iminyl)tetrahydro-2 H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5547, 84.7 mg, 0.159 mmol), copper acetate ( II) (49.2 mg, 0.271 mmol) and molecular sieve (4 Å, 100 mg) in 1,4-di To a suspension in alkane (anhydrous, 2 mL) was added pyridine (0.032 mL, 0.398 mmol). Close the reaction vessel and stir for 5 minutes. Methylboronic acid (22 mg, 0.368 mmol) was then added. The reaction vessel was sealed and heated to 95°C. After 3 hours, the reaction mixture was cooled to room temperature, diluted with dichloromethane and a few drops of methanol, and filtered through a nylon 0.45 μm filter. The filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 50 to 100% ethyl acetate in heptane) to give (( 2R , 4S , 5R )-5-(( R ) -N , S -dimethylsulfonimide)-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro -2H -pyran-4-yl)carbamic acid tertiary butyl ester. The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 99%, RT=1.92 minutes, (M+H) ⁺ =546 (Method A).

Synthesis of (R)-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-3-yl)(methyl)(methylimino)-λ ⁶ -sulfanone ( compound 5556 ).

To ((2 R ,4 S ,5 R )-5-(( R )- N , S -dimethylsulfonyl iminyl)-2-(( S )-1-(4-fluorophenyl) -1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester (58 mg, 0.106 mmol) in 2-propanol (5 mL) was added HCl (5-6 M in 2-propanol, 1.25 mL, 6.25 mmol). After 2 days, the reaction mixture was basified with saturated aqueous _NaHCO3 solution and 2-propanol was removed under reduced pressure. The residue was extracted with dichloromethane (20 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 10% A; t=3 minutes 10% A; t=18 minutes 50% A; t=19 minutes 100%; t=24 minutes 100% A; detection (measured at 210 nm) purified residue. The combined product fractions were basified with saturated aqueous _NaHCO3 and the acetonitrile was removed under reduced pressure. The residue was extracted with dichloromethane. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ( R )-((3 R ,4 S ,6 R )-4-amino-6-(( S )- 1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)(methyl)(methylimine base)-λ ⁶ -sulfanone ( compound 5556 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 99%, RT=1.05 minutes, (M+H) ⁺ =446 (Method P). Example 163

(R) -((3 R ,4 S ,6 R )-4-amino-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquine Phenolin-2-carbonyl)tetrahydro- 2H -piran-3-yl)(ethylimino)(methyl)-λ ⁶ -sulfanone (compound 5558)

Synthesis of ((2R,4S,5R)-5-((R)-N,S-dimethylsulfonimide)-2-((S)-1-(4-fluorophenyl)-1, 2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -(( R )- S -methanesulfonyl iminyl)tetrahydro-2 H -piran-4-yl)carbamic acid tertiary butyl ester (see compound 5547, 121 mg, 0.228 mmol), copper acetate ( II) (70.3 mg, 0.387 mmol) and molecular sieve (4 Å, 200 mg) in 1,4-di To a suspension in alkane (anhydrous, 3 mL) was added pyridine (0.276 mL, 0.341 mmol). Close the reaction vessel and stir for 5 minutes. Ethylboronic acid (219 mg, 2.96 mmol) was then added. The reaction vessel was sealed and heated to 95°C. After 2 hours, the reaction mixture was cooled to room temperature, diluted with dichloromethane (20 mL) and a few drops of methanol, and filtered through a nylon 0.45 μm filter. The filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 30 to 100% ethyl acetate in heptane) to give (( 2R , 4S ,5R)-5-(( R )- N -ethyl- S -methanesulfonyl iminyl)-2-(( S )-1-(4-fluorophenyl)-1,2,3, 4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)carbamic acid tertiary butyl ester. The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 98%, RT=1.98 minutes, (M+H) ⁺ =560 (Method A).

Synthesis of (R)-((3R,4S,6R)-4-amino-6-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline- 2-Carbonyl)tetrahydro-2H-pyran-3-yl)(ethylimino)(methyl)-λ ⁶ -sulfanone ( compound 5558 ).

To ((2 R ,4 S ,5R)-5-(( R )- N -ethyl- S -methanesulfonyl iminyl)-2-(( S )-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-4-yl)carbamic acid tertiary butyl ester (91 mg, 0.163 mmol) in 2-propanol To a solution in alcohol (7.5 mL) was added HCl (5 M in 2-propanol, 1.9 mL, 9.50 mmol). After 2 days, the reaction mixture was basified with saturated aqueous _NaHCO3 solution and 2-propanol was removed under reduced pressure. The residue was extracted with dichloromethane (10 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. By acidic preparative MPLC (linear gradient: t=0 minutes 10% A; t=2 minutes 10% A; t=17 minutes 50% A; t=18 minutes 100%; t=23 minutes 100% A; detection (measured at 220 nm) purified residue. The combined product fractions were basified with saturated aqueous _NaHCO3 and the acetonitrile was removed under reduced pressure. The residue was extracted with dichloromethane (10 mL). The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to give (R) -(( 3R , 4S , 6R )-4-amino-6-(( S )- 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)(ethylimino)(methane base)-λ ⁶ -sulfanone ( compound 5558 ). The stereochemistry of the setrimine stereocenter is arbitrarily specified.

LCMS: 96%, RT=1.09 minutes, (M+H) ⁺ =460 (Method P). Example 164

((2 R ,4 S ,5 R )-4-(dimethylamino)-5-methoxytetrahydro-2 H -pyran-2-yl)(( S )-1-(4- Fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5575)

Synthesis of ((2R,4S,5R)-4-(dimethylamino)-5-methoxytetrahydro-2H-pyran-2-yl)((S)-1-(4-fluorophenyl) )-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5575 ).

To formaldehyde (37 wt% solution in water, stabilized with 10-15% methanol, 0.325 mL, 4.33 mmol) and ((2 R , 4 S , 5 R )-4-amino-5-methoxytetrahydro -2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (see compound 5077 , 333 mg, 0.866 mmol) in dichloromethane (12 ml) was added acetic acid (0.050 mL, 0.866 mmol). After 5 minutes, sodium triacetyloxyborohydride (459 mg, 2.165 mmol) was added and the mixture was stirred overnight. Subsequently, the mixture was diluted with water (10 mL), stirred until all precipitates _were dissolved, further diluted with saturated aqueous _K2CO3 solution, and stirred for 15 minutes. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 10% ammonia in methanol (7 M)/dichloromethane). The product was lyophilized from a mixture of acetonitrile and water (1:1, 20 mL) to obtain ((2 R , 4 S , 5 R )-4-(dimethylamino)-5-methoxytetrakis Hydrogen-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( Compound 5575 ).

LCMS: 98%, RT=1.99 min, (M+H) ⁺ =413 (Method CA). Example 165

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((3 R ,4a R ,7 R ,8a S )-3- Vinyl octahydropyrano[3,4-b][1,4] -7-yl)methanone (compound 5817)

Synthesis of N-((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- (((R)-1-hydroxybut-3-en-2-yl)oxy)tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonamide.

Under an argon atmosphere, to (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((1 S ,4 R ,6 S )-7-methylbenzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (see compound 5520, 2.51 g, 4.95 mmol) and ( R ) -1-((tertiary butyldimethylsilyl)oxy)but-3-en-2-ol (1.504 g, 7.43 mmol) in 1,4-di To a suspension in alkanes (100 mL) was added sodium hydride (60% dispersion in mineral oil, 0.297 g, 7.43 mmol) and the mixture was heated to 60 °C. After 1.5 hours, the mixture was cooled to room temperature, diluted with saturated aqueous _NH4Cl and some water, and extracted with ethyl acetate (2×75 mL). The combined organics were dried over _Na2SO4 and evaporated _under reduced pressure. By flash column chromatography (silica, 10 to 66% ethyl acetate in heptane) and acidic preparative MPLC (linear gradient: t=0 min 5% A; t=1 min 5% A; t=2 minutes 30% A; t=17 minutes 70% A; t=18 minutes 100%; t=23 minutes 100% A; detection: 220 nm) Purify the residue to give N -((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-((( R )- 1-Hydroxybut-3-en-2-yl)oxy)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide.

LCMS: 99%, RT=2.12 minutes, (M+H) ⁺ =595 (Method A).

Synthesis of ((2R,4S,5R)-5-(((R)-1-((tertiary butoxycarbonyl)oxy)but-3-en-2-yl)oxy)-2-(( S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-4-yl)(methylbenzenesulfonyl) ) tertiary butyl carbamate.

To N -((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -5-((( R )-1-hydroxybut-3-en-2-yl)oxy)tetrahydro-2 H -pyran-4-yl)-4-methylbenzenesulfonamide (591 mg , 0.994 mmol) in dichloromethane (30 mL) were added di-tertiary butyl dicarbonate (0.434 mg, 1.988 mmol) and 4-dimethylaminopyridine (24.28 mg, 0.199 mmol). After stirring for 1 hour, the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (15 mL) and potassium carbonate (275 mg, 1.988 mmol) was added. After stirring for 30 minutes, the mixture was diluted with water and extracted with dichloromethane (3x). The combined organic layers were passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 50% ethyl acetate in heptane) to give ((2 R , 4 S , 5 R )-5-( as a white solid (( R )-1-((tertiary butoxycarbonyl)oxy)but-3-en-2-yl)oxy)-2-(( S )-1-(4-fluorophenyl)- 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-4-yl)(toluenesulfonyl)carbamic acid tertiary butyl ester (386 mg).

LCMS: 99%, RT=2.48 minutes, (M+Na) ⁺ =817 (Method A).

Synthesis of ((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-(( (R)-1-Hydroxybut-3-en-2-yl)oxy)tetrahydro-2H-pyran-4-yl)carbamic acid tertiary butyl ester.

To ((2 R ,4 S ,5 R )-5-((( R )-1-((tertiary butoxycarbonyl)oxy)but-3-en-2-yl)oxy)-2 -(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2 H -pyran-4-yl) (methyl To a solution of benzenesulfonyl)carbamate tertiary butyl ester (386 mg, 0.486 mmol) in methanol (30 mL) was added ammonium chloride (260 mg, 4.86 mmol) and magnesium (590 mg, 24.28 mmol). After the resulting suspension was stirred in a water bath overnight, additional ammonium chloride (130 mg, 2.428 mmol) and magnesium (295 mg, 12.14 mmol) were added and stirring was continued overnight. Subsequently, the mixture was diluted with saturated aqueous _NH4Cl solution, stirred for 15 minutes and extracted with dichloromethane (3x). The combined organic layers were dried _{over Na2SO4} and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 5 to 50% ethyl acetate in heptane) to give ((2 R ,4 S ,5 R )-2-(( S )-1 -(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-((( R )-1-hydroxybut-3-en-2-yl)oxy tert-butyl)tetrahydro- 2H -pyran-4-yl)carbamate.

LCMS: 99%, RT=2.07 minutes, (M+H) ⁺ =541 (Method A).

Synthesis of methane sulfonate (R)-2-(((3R,4S,6R)-4-((tertiary butoxycarbonyl)amine)-6-((S)-1-(4-fluorophenyl) )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-yl)oxy)but-3-en-1-yl ester.

To ((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -((( R )-1-hydroxybut-3-en-2-yl)oxy)tetrahydro-2 H -pyran-4-yl)carbamic acid tertiary butyl ester (130.5 mg, 0.241 mmol) and To a solution of triethylamine (0.101 mL, 0.724 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (0.038 mL, 0.483 mmol). After stirring for 45 minutes, the mixture was diluted with saturated aqueous _NaHCO3 solution and stirred vigorously for 15 minutes. The organic layer was passed through a hydrophobic glass frit and evaporated under reduced pressure to give ( R )-2-((( 3R , 4S , 6R ))-4-(tertiary butoxycarbonyl)amine methanesulfonate base)-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl )oxy)but-3-en-1-yl ester.

LCMS: 97%, RT=2.17 minutes, (M+H) ⁺ =619 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((3R,4aR,7R,8aS)-3-vinyloctahydrogen Pirano[3,4-b][1,4] -7-yl)methanone ( compound 5817 ).

To methanesulfonic acid ( R )-2-(((3 R ,4 S ,6 R )-4-((tertiary butoxycarbonyl)amine)-6-(( S )-1-(4- Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro- 2H -pyran-3-yl)oxy)but-3-en-1-yl ester ( To a solution of 136 mg, 0.220 mmol) in 2-propanol (3 mL) was added HCl (5-6 M in 2-propanol, 1 mL, 5.50 mmol). After stirring overnight, the mixture was diluted with saturated aqueous _NaHCO3 solution and dichloromethane. The organic layer was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and triethylamine (0.092 mL, 0.659 mmol) was added and the mixture was heated at 40 °C. After 4 days, the mixture was concentrated under reduced pressure. 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% A; t=18 min 100%; t =23 minutes 100% A; detection: 220 nm) The residue was purified, and the combined product fractions were lyophilized to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydro Isoquinolin-2(1 H )-yl)((3 R ,4a R ,7 R ,8a S )-3-vinyloctahydropyrano[3,4-b][1,4] -7-yl)methanone ( compound 5817 ).

LCMS: 98%, RT=1.18 minutes, (M+H) ⁺ =423 (Method P). Example 166

((3 R ,4a R ,7 R ,8a S )-3-ethyloctahydropirano[3,4-b][1,4] -7-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (Compound 5564)

Synthesis of ((3R,4aR,7R,8aS)-3-ethyloctahydropirano[3,4-b][1,4] -7-yl)((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone ( compound 5564 ).

(( S )-1-(4-fluorophenyl)-3, 4-Dihydroisoquinolin-2(1 H )-yl)((3 R ,4a R ,7 R ,8a S )-3-vinyloctahydropirano[3,4-b][1, 4] A solution of -7-yl)methanone (see compound 5817, 47 mg, 0.111 mmol) in 2,2,2-trifluoroethanol (2 mL) was hydrogenated. After stirring for 30 minutes, the mixture was filtered on a 0.45 µm nylon filter. The filtrate was introduced onto the SCX-2 column and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (2 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain ((3 R ,4a R ,7 R ,8a S )-3-ethyloctahydropirano[3,4 -b][1,4] -7-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone ( compound 5564 ).

LCMS: 97%, RT=1.20 minutes, (M+H) ⁺ =425 (Method P). Example 167

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-4-isopropyl Octahydro- 2H -pirano[3,4-b]pyra -7-yl)methanone (compound 5602)

Synthesis of N-((2R,4S,5R)-2-((S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5- (Isopropylamino)tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonamide.

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((1 S ,4 R ,6 S )-7-methyl Benzenesulfonyl-3-oxa-7-azabicyclo[4.1.0]heptan-4-yl)methanone (see compound 5520, 250 mg, 0.493 mmol) in 1,4-di To a solution in alkanes (4 mL) was added isopropylamine (0.168 mL, 1.974 mmol) and the reaction mixture was heated to 60 °C. After 5 hours, another portion of isopropylamine (0.084 mL, 0.987 mmol) was added and stirring was continued overnight. The reaction mixture was concentrated under reduced pressure to obtain N -((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro Isoquinolin-2-carbonyl)-5-(isopropylamino)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide.

LCMS: 98%, RT=1.71 minutes, (M+H) ⁺ =566 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-4-isopropyl-1- Toluenesulfonyloctahydro-2H-pirano[3,4-b]pyra -7-yl)methanone.

To N -((2 R ,4 S ,5 R )-2-(( S )-1-(4-fluorophenyl)-1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)-5-(isopropylamino)tetrahydro- 2H -pyran-4-yl)-4-methylbenzenesulfonamide (322.8 mg, 0.571 mmol) in To a solution in dichloromethane (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.171 mL, 1.141 mmol). After 10 minutes, a solution of vinyl diphenyl sulfonate trifluoromethanesulfonate (207 mg, 0.571 mmol) in dichloromethane (2 mL) was added dropwise. After 2 hours, the reaction mixture was warmed to room temperature and stirred for a further 2 hours. Subsequently, another portion of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.085 mL, 0.571 mmol) and vinyl diphenyl sulfonate trifluoromethanesulfonate (103 mg, 0.285 mmol) in dichloromethane (1 mL). After stirring for 3 days, the mixture was diluted with saturated aqueous _K2CO3 solution (5 mL) and water (5 mL) and stirred _for 30 minutes. Extract the aqueous layer with dichloromethane (2 × 5 mL). The combined organics were passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 10% (7M ammonia in methanol)/dichloromethane) to give (( S )-1-(4-fluorophenyl)-3 ,4-dihydroisoquinolin-2(1 H )-yl)((4a R ,7 R ,8a S )-4-isopropyl-1-methylbenzenesulfonyloctahydro-2 H -piper Pyro[3,4-b]pyra -7-yl)methanone.

LCMS: 98%, RT=1.84 minutes, (M+H) ⁺ =592 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-4-isopropyloctahydro- 2H-Pirano[3,4-b]pyra -7-yl)methanone ( compound 5602 ).

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R , 7 R ,8a S )-4-isopropyl-1-methylbenzenesulfonyloctahydro- 2H -pirano[3,4-b]pyra To a solution of -7-yl)methanone (173.8 mg, 0.294 mmol) in tetrahydrofuran (anhydrous, 2 mL) was added a freshly prepared solution of sodium naphthalene-1-phenolate (0.5 M in tetrahydrofuran (anhydrous), 1.762 mL ,0.881 mmol). After 30 minutes, the reaction mixture was partitioned between a mixture of saturated aqueous _NH4Cl (5 mL) and dichloromethane (10 mL). The aqueous layer was extracted with dichloromethane (2 x 5 mL) and the combined organics were passed through a hydrophobic frit and evaporated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (2 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. The residue was purified by preparative SFC (Method BD). The product was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl)((4a R ,7 R ,8a S )-4-isopropyloctahydro-2 H -pirano[3,4-b]pyra -7-yl)methanone ( compound 5602 ).

LCMS: 97%, RT=1.87 minutes, (M+H) ⁺ =438 (Method CA). SFC: 99%, RT=2.58 minutes, (M+H) ⁺ =438 (Method V). Example 168

(( R )-1-(2,4-difluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)(( R )-1,4-oxazacyclo Heptan-7-yl)methanone (compound 5263) and (( R )-1-(2,4-difluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) (( S )-1,4-oxaazepan-7-yl)methanone (Compound 5264)

Synthesis of (R)-7-((R)-1-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxa Azepane-4-carboxylic acid tertiary butyl ester and (S)-7-((R)-1-(2,4-difluorophenyl)-1,2,3,4-tetrahydroiso Quinoline-2-carbonyl)-1,4-oxazepan-4-carboxylic acid tertiary butyl ester.

To a solution of 4-(tertiary butoxycarbonyl)-1,4-oxazepan-7-carboxylic acid (118 mg, 0.419 mmol) in dichloromethane (2.5 mL) was added hexafluoride 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium phosphate 3-oxide (159 mg, 0.419 mmol) and N, N -Diisopropylethylamine (0.110 mL, 0.628 mmol). After 10 minutes, ( R )-1-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline (103 mg, 0.419 mmol) was added and stirring was continued for 4 days. Subsequently, the mixture was diluted with dichloromethane (20 mL), washed with aqueous HCl (1 M, 2 × 10 mL) and saturated _{aqueous NaHCO} (10 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, 0 to 40% ethyl acetate in heptane) and preparative SFC (Method AE) to give ( R )-7-(( R )-1 -(2,4-Difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxaazepine-4-carboxylic acid tertiary butanyl ester as the first soluble isomer on silica and ( S )-7-(( R )-1-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquine Phosphine-2-carbonyl)-1,4-oxazepane-4-carboxylic acid tertiary butyl ester was used as the second isomer eluted on silica. The stereochemistry of the oxazepane ring is arbitrary.

First soluble isomer: LCMS: 96%, RT=2.18 minutes, (M+Na) ⁺ =495 (Method A). SFC: 99%, RT=2.85 minutes, (M+Na) ⁺ =495 (Method AD).

Second soluble isomer: LCMS: 95%, RT=2.16 minutes, (M+H) ⁺ =473 (Method A). SFC: 98%, RT=3.27 minutes, (M+Na) ⁺ =495 (Method AD).

Synthesis of ((R)-1-(2,4-difluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((R)-1,4-oxazacycle Heptan-7-yl)methanone ( compound 5263 ).

To ( R )-7-(( R )-1-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxa To a solution of azepane-4-carboxylic acid tertiary butyl ester (50 mg, 0.106 mmol) in 2-propanol (1.8 mL) was added HCl (5 M in 2-propanol, 0.60 mL, 3.00 mmol). After 1 day, _the reaction mixture was partitioned between dichloromethane (8 mL) and saturated aqueous _Na2CO3 solution (8 mL). Extract the aqueous layer with dichloromethane (8 mL). The combined organics were passed through a hydrophobic frit and evaporated under reduced pressure. 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% A; t=18 min 100%; t =23 min 100% A; detection: 220 nm) purified residue. The product fractions were combined, basified with saturated aqueous Na ₂ CO ₃ (4 mL), and extracted with ethyl acetate (4 × 10 mL). The combined organics were washed with brine ₍ 10 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( R )-1-(2,4-difluorophenyl)-3,4-dihydroisoquinoline- 2(1 H )-yl)(( R )-1,4-oxaazepan-7-yl)methanone ( compound 5263 ). The stereochemistry of the oxazepane ring is arbitrary.

LCMS: 96%, RT=2.63 min, (M+H) ⁺ =373 (Method AK).

Synthesis of ((R)-1-(2,4-difluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((S)-1,4-oxazaheterocycle Heptan-7-yl)methanone ( compound 5264 ).

To ( S )-7-(( R )-1-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,4-oxa To a solution of azepane-4-carboxylic acid tertiary butyl ester (52.6 mg, 0.112 mmol) in 2-propanol (1.8 mL) was added HCl (5 M in 2-propanol, 0.60 mL, 3.00 mmol). After 1 day, _the reaction mixture was partitioned between dichloromethane (8 mL) and saturated aqueous _Na2CO3 solution (8 mL). Extract the aqueous layer with dichloromethane (8 mL). The combined organics were passed through a hydrophobic frit and evaporated under reduced pressure. 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% A; t=18 min 100%; t =23 min 100% A; detection: 220 nm) purified residue. The product fractions were combined, basified with saturated aqueous Na ₂ CO ₃ (4 mL), and extracted with ethyl acetate (4 × 10 mL). The combined organics were washed with brine ₍ 10 mL), dried over _Na2SO4 and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( R )-1-(2,4-difluorophenyl)-3,4-dihydroisoquinoline- 2(1 H )-yl)(( S )-1,4-oxaazepan-7-yl)methanone ( compound 5264 ). The stereochemistry of the oxazepane ring is arbitrary.

LCMS: 99%, RT=2.58 min, (M+H) ⁺ =373 (Method AK). Example 169

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)((4a S ,7 R ,8a S )-4-(2- Methoxyethyl)octahydro- 2H -pirano[3,4-b]pyra -7-yl)methanone (compound 5606)

Synthesis of ((2R,4S,5S)-4-azido-5-((2-methoxyethyl)amino)tetrahydro-2H-piran-2-yl)((S)-1- (4-Fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

To trifluoromethanesulfonic acid (3 R ,4 S ,6 R )-4-azido-6-(( S )-1-(4-fluorophenyl)-1,2,3,4-tetrahydro To a solution of isoquinoline-2-carbonyl)tetrahydro- 2H -piran-3-yl ester (see compound 5430, 304.2 mg, 0.576 mmol) in tetrahydrofuran (anhydrous, 4.1 mL) was added 2-methoxy Ethylamine (0.651 mL, 7.48 mmol). After 3 days, the mixture was concentrated under reduced pressure. The residue was dissolved in methanol, introduced onto an SCX-2 column (2 g), and eluted with methanol (volume 5 columns). Subsequently, the column was eluted with ammonia-containing methanol (1 M). The alkaline fraction was concentrated to dryness under reduced pressure. 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% A; t=18 min 100%; t =23 min 100% A; detection: 220 nm) purified residue. The combined product fractions were basified with saturated aqueous NaHCO ₃ and extracted with dichloromethane. The combined extracts were dried over Na ₂ SO ₄ and evaporated under reduced pressure to give ((2 R , 4 S , 5 S )-4-azido-5-((2-methoxyethyl) Amino)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl ketone.

LCMS: 95%, RT=1.64 minutes, (M+H) ⁺ =454 (Method A).

Synthesis of ((2R,4S,5S)-4-amino-5-((2-methoxyethyl)amino)tetrahydro-2H-pyran-2-yl)((1S)-1-( 4-Fluorophenyl)-1,2,3,4-tetralin-2-yl)methanone.

((2 R ,4 S ,5 S )-4-azido was dissolved in the presence of palladium (10 wt% on carbon, 50% water, 110 mg, 0.052 mmol) under atmospheric hydrogen pressure. -5-((2-methoxyethyl)amino)tetrahydro-2 H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydro A solution of isoquinolin-2(1 H )-yl)methanone (134 mg, 0.295 mmol) in tetrahydrofuran (anhydrous, 4.6 mL) was hydrogenated. After stirring overnight, the mixture was diluted with ethanol (10 mL) and filtered through celite. The filtrate was evaporated under reduced pressure to obtain (( 2R , 4S , 5S )-4-amino-5-((2-methoxyethyl)amino)tetrahydro-2 as a light yellow juice H -pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (132 mg) and its Use as is.

LCMS: 97%, RT=1.59 minutes, (M+H) ⁺ =428 (Method A).

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aS,7R,8aS)-4-(2-methoxy) Ethyl)octahydro-2H-pirano[3,4-b]pyra -7-yl)methanone ( compound 5606 ).

To (( 2R , 4S , 5S )-4-amino-5-((2-methoxyethyl)amino)tetrahydro- 2H -piper Pyran-2-yl)(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (132 mg, 0.309 mmol) in di To a solution in methyl chloride (20.5 mL) was added triethylamine (86 µL, 0.618 mmol). After 10 minutes, a solution of vinyl diphenyl sulfonate trifluoromethanesulfonate (75.0 mg, 0.207 mmol) in dichloromethane (10.20 mL) was added dropwise over 3 minutes. After 4 hours, the reaction mixture was warmed to room temperature and stirred overnight. Subsequently, the mixture was diluted with dichloromethane (20 mL) and water (10 mL), and acidified with aqueous HCl (1 M). The layers were separated and the aqueous phase was extracted (2 x 15 mL) with dichloromethane. Subsequently, the aqueous layer was basified with saturated _aqueous NaHCO solution and extracted with dichloromethane (2 × 50 mL). The latter extracts were combined, washed with saturated aqueous NaHCO ₃ (10 mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure. By alkaline preparative MPLC (linear gradient: t=0 minutes 5% A; t=1 minute 5% A; t=2 minutes 20% A; t=17 minutes 60% A; t=18 minutes 100%; t=23 min 100% A; detection: 210 nm) The residue was purified to give (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2( after lyophilization) 1H )-yl)(( 4aS , 7R , 8aS )-4-(2-methoxyethyl)octahydro- 2H -pirano[3,4-b]pyra -7-yl)methanone ( compound 5606 ).

LCMS: 98%, RT=1.91 min, (M+H) ⁺ =454 (Method CA). Example 170

(( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-1-methyl- 4-(2,2,2-trifluoroethyl)octahydro- 2H -pirano[3,4-b]pyra -7-yl)methanone (compound 5735)

Synthesis of ((S)-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)((4aR,7R,8aS)-1-methyl-4-( 2,2,2-Trifluoroethyl)octahydro-2H-pirano[3,4-b]pyra -7-yl)methanone ( compound 5735 ).

To (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinolin-2(1 H )-yl) ((4a R ,7 R ,8a S )-4-(2 ,2,2-trifluoroethyl)octahydro- 2H -pirano[3,4-b]pyra To a solution of -7-yl)methanone (see compound 5545, 14.8 mg, 0.031 mmol) in dichloromethane (1 mL) was added formaldehyde (37 wt% in water, stabilized with 5-15% methanol, 5.82 µL, 0.077 mmol) and sodium triacetyloxyborohydride (9.85 mg, 0.046 mmol). After 2 hours, the reaction mixture was diluted with _{K2CO3 semisaturated} solution (2 mL). The aqueous phase was extracted with dichloromethane (2×2 mL) and the combined organics were passed through a hydrophobic frit and evaporated under reduced pressure. The residue was lyophilized from a mixture of acetonitrile and water (1:1, 4 mL) to obtain (( S )-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1 H )-yl) ((4a R ,7 R ,8a S )-1-methyl-4-(2,2,2-trifluoroethyl)octahydro-2 H -pirano[3,4- b]pyridine -7-yl)methanone ( compound 5735 ).

LCMS: 99%, RT=2.23 minutes, (M+H) ⁺ =492 (Method CA). Example 171

Cellular Assay: Pregranulin Induction Assay . To measure the efficacy of the compounds, progranulin-induced cell assays in mouse primary microglia (pMG), primary cortical neurons, and BV-2 cell lines were used. BV-2 cells were allowed to reach approximately 80% division one day before plating into a 96-well plate format. Cells should be plated the day before and allow for a 1 hour adhesion period and 16 hours of incubation. An ELISA-based readout can be used to quantify the amount of progranulin secreted into the cell culture medium or retained in the cell lysate, and measurements of secreted mouse PGRN in the culture medium can be assessed by the method published by Ghidoni et al. 2012 result. Standard ELISA kits for measuring PGRN are available from suppliers such as Adipogen, R&D and Biovendor.

Table B below presents the results of the progranulin induction assay as described above. Table B Compound number EC ₅₀ µM 5000 0.41 5001 0.244 5002 0.278 5003 0.509 5004 0.164 5005 0.216 5006 0.143 5007 0.14 5008 0.369 5009 0.37 5010 0.573 5011 1.660 5012 0.125 5013 0.323 5014 0.501 5015 0.090 5016 0.199 5017 0.091 5018 ＞10.0 5019 0.099 5020 1.060 5021 0.148 5022 4.160 5023 0.212 5024 0.749 5027 0.488 5028 0.042 5029 0.37 5030 0.348 5031 0.326 5032 0.213 5033 0.163 5034 0.185 5035 0.371 5036 0.356 5037 0.339 5038 0.5 5039 0.357 5040 0.173 5041 0.294 5042 0.079 5043 0.064 5044 0.163 5045 0.078 5046 0.062 5047 0.086 5048 0.575 5049 0.258 5050 0.35 5051 0.006 5052 0.018 5053 0.077 5054 0.13 5055 0.056 5056 0.127 5057 0.133 5058 0.29 5059 0.344 5060 5.850 5061 0.478 5062 0.049 5063 0.035 5064 0.102 5065 0.324 5066 0.948 5067 0.767 5068 0.376 5069 0.142 5070 0.153 5071 0.252 5072 0.081 5073 0.159 5074 0.23 5075 0.529 5076 0.321 5077 0.003 5078 0.001 5079 ＞10.0 5080 0.166 5081 0.188 5082 0.044 5083 0.084 5084 0.18 5085 0.316 5086 0.194 5087 0.0421 5088 0.074 5089 0.062 5090 0.162 5091 0.408 5092 0.184 5207 0.182 5210 0.596 5211 0.209 5212 0.314 5213 0.401 5214 0.080 5215 0.140 5216 0.295 5217 0.226 5218 0.120 5219 0.006 5220 0.081 5235 0.372 5236 0.393 5237 0.665 5238 0.105 5239 0.316 5240 0.631 5243 0.200 5244 0.091 5245 0.350 5246 0.100 5247 0.095 5248 0.032 5250 0.095 5251 0.188 5255 0.030 5256 0.100 5257 0.022 5258 0.062 5259 0.046 5261 0.079 5262 0.044 5263 0.078 5264 0.048 5266 0.036 5267 0.0001 5405 0.736 5406 0.715 5418 0.352 5420 >10 5421 0.843 5425 0.186 5426 0.441 5427 0.096 5428 >10 5430 >0.300 5431 0.029 5432 0.113 5443 0.151 5447 0.659 5448 0.044 5461 0.010 5462 0.003 5471 0.109 5472 0.013 5473 0.621 5474 1.510 5475 0.001 5476 0.001 5500 0.190 5501 3.860 5502 0.001 5503 0.005 5504 0.009 5505 0.410 5506 0.398 5507 0.001 5508 0.030 5509 0.001 5510 0.002 5511 0.0002 5512 0.005 5513 0.030 5514 0.024 5516 0.007 5517 0.012 5518 0.015 5519 0.041 5520 0.004 5521 0.008 5523 0.016 5524 0.016 5525 0.0003 5526 0.006 5527 0.274 5528 0.168 5529 1.560 5530 0.0003 5531 0.088 5532 1.680 5533 0.289 5534 0.015 5535 0.028 5536 0.150 5537 0.029 5538 0.064 5539 0.001 5540 0.210 5541 0.001 5542 4.390 5543 0.003 5544 0.019 5545 0.004 5546 0.030 5547 0.062 5548 0.071 5549 0.030 5550 0.017 5551 0.027 5552 0.011 5553 1.020 5554 4.860 5555 0.029 5556 0.070 5557 0.523 5558 0.312 5563 0.141 5564 0.004 5565 >0.300 5566 >0.300 5567 0.070 5568 0.025 5569 >0.300 5570 0.232 5575 0.028 5577 >0.300 5578 0.030 5579 0.050 5586 0.219 5587 0.194 5599 0.001 5600 0.021 5601 0.018 5603 0.008 5792 >0.300 5793 >0.300

In vivo analysis: can be performed on tissue samples or biological fluids (including blood, plasma, brain, liver, and cerebrospinal fluid (CSF) from different non-human animals (including rats, mice, dogs, and macaques) ) to detect granulin precursors. Pregranulin concentration can be detected using one or more methods, including enzyme-linked immunosorbent assay (ELISA). Compounds as disclosed herein are administered to non-human animals, including rats, mice, dogs, and cynomolgus monkeys, by one of several routes of administration, including oral, subcutaneous, and intravenous routes of administration. Samples of tissue or biological fluids are collected before and at specified times after administration of the compound. The amount of progranulin in a particular sample collected after administration of a compound is compared to the amount of progranulin detected in a sample of the same tissue or biological fluid obtained before administration of the compound. Alternatively, the amount of progranulin can be compared to equivalent samples obtained from animals that did not receive the test compound. Test compounds can be administered one or more times. When the compound is administered more than once, the number of doses and the intervals between doses can be adjusted in any combination. For example, the test compound can be administered as a single dose, the test compound can be administered 8 times at 12 hour intervals, and the test compound can be administered 4 times at 24 hour intervals. The ability of a compound to increase granulin precursors can be quantified in several ways. For example, the effect can be quantified by the progranulin concentration after administration of the compound, the effect can be quantified by the difference in the progranulin concentration between samples collected after administration and before administration, the effect can be quantified by the difference in progranulin concentration between samples collected after administration and before administration. The effect can be quantified as a ratio or percentage of sample compared to progranulin, and the effect can be quantified as a percentage change in progranulin concentration compared to the sample before administration.

Treatment with the test compound increases progranulin secretion by at least about 110% (activity level 1), at least about 130% (activity level 2), at least about 150% (activity level 3), at least about 180% compared to the control % (activity level 4), at least about 200% (activity level 5), at least about 250% (activity level 6), or at least about 300% (activity level 7).

Oral administration of the compounds of the invention at a dose of 5 mg/kg caused an increase in progranulin secretion after administration compared to the control. Table C below presents the results of the progranulin secretion assay as described above. Table C Compound number activity level 5015 7 5042 6

In view of the many possible embodiments to which the principles of the invention are applicable, it should be recognized that the illustrated embodiments are examples only and should not be construed as limiting the scope of the invention.

Claims (79)

A compound or a pharmaceutically acceptable salt thereof having the structure of formula (I): , wherein ring A is a 4- to 12-membered heterocyclic ring containing ring O or S atoms, and the heterocyclic ring further contains 0-3 additional ring heteroatoms selected from O, N and S; R ¹ is hydrogen, C _1-6 Alkyl group, halo group, C _1-3 haloalkyl group, OC _1-3 haloalkyl group, C _0-3 alkylene group-CN, C _0-3 alkylene group-NR ^N ₂ , C _0-6 alkylene group- 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 ; Each R ^N is independently hydrogen or C _1-6 alkyl, and p is 0-2; Each R ² is independently halo; Each R ³ is 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-OC _1-6 alkyl, C _{0- 6} Alkylene-NR ^a R ^b , SC _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 , 5- to 8-membered heteroaryl containing 1-4 ring N atoms, or 1-4 rings selected from O, N and S A 4- to 6-membered heterocyclic heteroatom, in which at least one ring heteroatom is N, and the heteroaryl group or heterocyclic ring is optionally selected from halo, C _1-6 alkyl, OH and C by 1 or 2 _{The 1-6} alkoxy group is substituted by a substituent, or the two simultaneous R ³ and the atom to which it is connected form a side oxygen group, and when ring A contains a ring N atom, N is substituted by R ^a , and if ring A does not Contains ring N atoms, then at least one R ³ is C _0-6 alkylene-NR ^a R ^b ; 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-OC _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 connected form a 3 to 12-membered monocyclic or bicyclic heterocyclic ring, which depends on Cases further include 1-3 additional ring heteroatoms selected from O, N and S; R ⁴ is C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-C _3-8 ring Alkyl or C _0-6 alkylene-C _6-10 aryl; each R ^d is independently H or D; each R ^e is independently H, D, halo, OH, methyl or methoxy, Or the two synposition R ^e together with the atom to which they are connected form a side oxy group or a spiro C _3-5 cycloalkyl group; m is 1-4; and n is 0-2. Such as the compound or salt of claim 1, wherein ring A is a 4- to 6-membered heterocyclic ring. For example, the compound or salt of claim 1 or 2, wherein ring A is a 6- to 8-membered heterocyclic ring. The compound or salt of any one of claims 1 to 3, wherein ring A contains ring O atoms and 0-3 additional ring heteroatoms selected from O, N and S. The compound or salt of claim 4, wherein ring A contains a tetrahydropyranyl ring. The compound or salt of any one of claims 1 to 3, wherein ring A contains ring O and N atoms. The compound or salt of any one of claims 1 to 3, wherein ring A contains ring S atoms and 0-3 additional ring heteroatoms selected from O, N and S. The compound or salt of any one of claims 1 to 3, wherein ring A is , where * indicates the point of attachment of ring A to the adjacent carbonyl moiety of formula I. Such as the compound or salt of claim 8, wherein ring A is . Such as the compound or salt of claim 8, wherein ring A is . Such as the compound or salt of claim 8, wherein ring A is or . The compound or salt of any one of claims 1 to 11, wherein m is 1. The compound or salt of claim 12, wherein R ³ is hydrogen. The compound or salt of any one of claims 1 to 11, wherein m is 3. The compound or salt of any one of claims 1 to 11, wherein m is 2. Such as the compound or salt of claim 15, wherein ring A is . The compound or salt of any one of claims 1 to 12 and 14 to 16, wherein at least one R ³ is C _0-6 alkylene-NR ^a R ^b . The compound or salt of claim 17, wherein at least one R ³ is NH ₂ . The compound or salt of claim 17, wherein at least one R ³ is NHMe. The compound or salt of any one of claims 1 to 12 and 14 to 19, wherein at least one R ³ is a halo group. The compound or salt of claim 20, wherein at least one R ³ is F. The compound or salt of any one of claims 1 to 12 and 14 to 21, wherein at least one R ³ is a C _1-6 alkoxy group. The compound or salt of claim 22, wherein at least one R ³ is methoxy. The compound or salt of claim 22, wherein at least one R ³ is ethoxy. The compound or salt of claim 21, wherein one R ³ is F and one R ³ is NH ₂ . For example, the compound or salt of claim 23, wherein one R ³ is methoxy and one R ³ is NH ₂ . For example, the compound or salt of claim 23, wherein one R ³ is methoxy and one R ³ is NHMe. The compound or salt of claim 24, wherein one R ³ is ethoxy and one R ³ is NH ₂ . The compound or salt of any one of claims 1 to 12, wherein R ³ is S ²⁺ (O) ^- (NR ^a ) ^- C _1-6 alkyl. Such as the compound or salt of claim 29, wherein R ³ is . The compound or salt of any one of claims 1 to 12, wherein R ³ is OR ⁴ . The compound or salt of claim 31, wherein R ⁴ is C _2-6 alkynyl, C _0-6 alkylene-C _3-8 cycloalkyl or C _0-6 alkylene-C _6-10 aryl . The compound or salt of claim 33, wherein R ³ is . The compound or salt of any one of claims 1 to 33, wherein n is 0. The compound or salt of any one of claims 1 to 33, wherein n is 1. The compound or salt of any one of claims 1 to 33, wherein n is 2. The compound or salt of any one of claims 1 to 28, 35 and 36, wherein R ² is F or Cl. The compound or salt of claim 37, wherein R ² is F. The compound or salt of any one of claims 1 to 38, wherein R ¹ is halo. The compound or salt of claim 39, wherein ^R1 is F. The compound or salt of any one of claims 1 to 38, wherein ^R1 is hydrogen. The compound or salt of any one of claims 1 to 41, wherein at least one R ^d is H. The compound or salt of claim 42, wherein each R ^d is H. The compound or salt of any one of claims 1 to 41, wherein at least one R ^d is D. The compound or salt of any one of claims 1 to 44, wherein at least one ^Re is H. The compound or salt of claim 45, wherein each ^Re is H. The compound or salt of any one of claims 1 to 44, wherein at least one ^Re is D. The compound or salt of any one of claims 1 to 44, wherein each ^Re is D. The compound or salt of any one of claims 1 to 44, wherein at least one ^Re is OH. The compound or salt of any one of claims 1 to 44, wherein at least one ^Re is a halo group. The compound or salt of any one of claims 1 to 44, wherein at least one ^Re is F. The compound or salt of any one of claims 1 to 44, wherein each ^Re is a halo group. The compound or salt of any one of claims 1 to 44, wherein each ^Re is F. The compound or salt of any one of claims 1 to 44, wherein the two co-positions R ^e together with the atoms to which they are connected form a pendant oxygen group. A compound or a pharmaceutically acceptable salt thereof having a structure as shown in Table A. Such as the compound or salt of claim 55, which is selected from the group consisting of compounds 5605, 5602, 5599, 5575, 5564, 5550, 5472, 5545, 5543, 5461, 5267, 5448, 5475, 5087, 5077, 5051, 5045, 5042, 5021 and 5012 and its pharmaceutically acceptable salts. For example, the compound or salt of claim 56 is selected from compounds 5599, 5564, 5472, 5077 and 5087 and pharmaceutically acceptable salts thereof. The compound or salt of any one of claims 1 to 57 is in the form of a salt. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 58 and a pharmaceutically acceptable excipient. Use of a compound or salt according to any one of claims 1 to 58 as a medicament for modulating granule protein precursors. The use of claim 60, wherein secretion of granulin precursors is increased. A method of modulating progranulin in an individual in need thereof, comprising administering to the individual any one of claims 1 to 58 in an amount effective to increase the amount of progranulin or granulin in the individual. compound or salt. A method of treating a progranulin-related disorder in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound or salt of any one of claims 1 to 58. Such as the method of claim 63, wherein the progranulin-related disease 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 disorders (SCA), spinal muscular atrophy (SMA), lysosomal storage diseases, renal disease, and inclusion bodies and/or Diseases related to C9orf72, TDP-43, FUS, UBQLN2, VCP, CHMP28 and/or MAPT dysfunction, acute neurological conditions, glioblastoma or neuroblastoma. The method of claim 64, wherein the Parkinson's disease is Parkinson's disease with a GBA mutation. Such as the method of claim 64, wherein the lysosomal storage disease is Paget's disease, Gaucher's disease, Nieman's Pick disease, Tay-Sachs disease Tay-Sachs Disease, Fabry Disease, Pompes disease or Naso-Hakula disease. The method of claim 64, wherein the acute neurological condition is stroke, cerebral hemorrhage, traumatic brain injury or head trauma. The method of claim 64, wherein the progranulin-related disorder is frontotemporal dementia (FTD). The method of claim 64, wherein the progranulin-related disorder is frontotemporal dementia-granulin subtype (FTD-GRN). A method of increasing lysosomal protein content in a cell, comprising contacting the cell with an effective amount of a compound or salt according to any one of claims 1 to 58. A method of increasing lysosomal protein content in an individual, comprising administering to the individual a therapeutically effective amount of a compound or salt of any one of claims 1 to 58. The method of claim 70 or 71, wherein the lysosomal protein is progranulin, prosaposin, β-glucocerebrosidase, galactosidase α, cathepsin B, cathepsin Z, neuron Aminosidase 1, tripeptidyl peptidase, α-L-fucosidase 2, mannosidase α class 2B member 2, mannosidase β, serine carboxypeptidase 1, acid ceramidase , GM2 ganglioside activating factor, cathepsin D, cathepsin S, cathepsin K, cathepsin L or hexosaminidase. A method of treating a lysosomal storage disease in an individual suffering from a lysosomal storage disease, comprising administering to the individual a therapeutically effective amount of a compound or salt of any one of claims 1 to 58. Such as requesting the method of item 73, wherein the lysosomal storage disease is mucopolysaccharidosis, sphingolipidosis, glycogen storage disease type II, glycoprotein storage disease, Hurler disease ), Scheie disease, Hunter disease, Sanfilippo disease A (Sanfilippo disease A), Sanfilippo disease B, Sanfilippo disease C, Sanfilippo disease Disease D, Morquio disease A, Morquio disease B, Maroteaux-Lamy disease, Sly disease, mucopolysaccharide storage Syndrome type IX, mucopolysaccharidosis plus syndrome, Fabry disease, Gaucher disease, Tay-Sachs disease, sialic acidosis, Niemann-Pick disease type A, Niemann-Pick disease type B , galactosialidosis, Niemann-Pick disease type C, I-cell disease, mucolipidosis type III, GM1 gangliosidosis, beta-galactosidase deficiency, alpha- Mannosidosis, GM2 gangliosidosis, β-mannosidosis, Krabbe disease (Krabbe), fucosidosis, metachromatic leukodystrophy, asparagine glucose Aminuria, multiple sulfatase deficiency, Schindler's disease, Farber lipogranulomatosis, Pompe disease, Wolman disease, Danon's disease Danon disease, free sialic acidosis, ceroid lipofuscinosis, beta-glucuronidase hyperactivity, Sandhoff disease, or cholesteryl ester storage disease . A method of treating an inflammatory disorder in an individual suffering from the inflammatory disorder, comprising administering to the individual a therapeutically effective amount of a compound or salt of any one of claims 1 to 58. The method of claim 75, wherein the inflammatory disorder is Sjogren's disease, inflammatory arthritis, osteoarthritis, inflammatory bowel disease, or immune thrombocytopenia. A method of treating a disorder in an individual suffering from a disorder, comprising administering to the individual a therapeutically effective amount of a compound or salt of any one of claims 1 to 58, wherein the disorder is stroke, Down syndrome (Down syndrome) syndrome), congenital heart disease, diabetes, common variable immunodeficiency (CVID), tubulointerstitial nephropathy (TKD), polycystic liver disease, myocarditis, dermatitis, hyperhomocysteinemia, endotoxin shock, lung injury, bone defects (e.g., inflammatory periodontal bone defects), or osteolysis. A method of treating a neurodegenerative disease in an individual suffering from the neurodegenerative disease, comprising administering to the individual a therapeutically effective amount of a compound or salt of any one of claims 1 to 58. Such as the method of claim 78, wherein the neurodegenerative disease is Parkinson's disease, frontotemporal dementia, Alzheimer's disease, Huntington's disease, traumatic brain injury, neuronal ceroid lipids NCL, multiple sclerosis, amyotrophic lateral sclerosis (ALS), argyrophilic dementia, Alexander's disease, Alper's disease, cerebral Paralysis, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangle calcification, HIV Related dementia, Lewy body dementia, Kennedy's disease, neurospirosis, primary lateral sclerosis, Refsum's disease, Gerstmann-Stern Gerstmann-Straussler-Scheinker disease, Hallevorden-Spatz disease, hereditary diffuse leukoencephalopathy with spheroids; HDLS), inclusion body myositis, multiple systemic atrophy, myotonic dystrophy, Nasu-Hakola disease, Schilder's disease, Wobbly Hedgehog Syndrome (WHS), Du- Duchenne-Aran muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, HIV-related neurocognitive disorder, tauopathy, chronic traumatic encephalopathy, or cerebellar downbeat nystagmus .