WO2022194399A1 - Macrocycles en tant que modulateurs de cftr - Google Patents

Macrocycles en tant que modulateurs de cftr Download PDF

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WO2022194399A1
WO2022194399A1 PCT/EP2021/069292 EP2021069292W WO2022194399A1 WO 2022194399 A1 WO2022194399 A1 WO 2022194399A1 EP 2021069292 W EP2021069292 W EP 2021069292W WO 2022194399 A1 WO2022194399 A1 WO 2022194399A1
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alkyl
independently
substituted
mono
unsubstituted
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PCT/EP2021/069292
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English (en)
Inventor
Martin Bolli
Christine Brotschi
Malgorzata COMMANDEUR
John Gatfield
Thierry Kimmerlin
Hervé SIENDT
Jasper SPRINGER
Clemens Wagner
Anita Wegert
Jodi T. Williams
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Idorsia Pharmaceuticals Ltd
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Priority to IL305881A priority Critical patent/IL305881A/en
Priority to MX2023010924A priority patent/MX2023010924A/es
Priority to KR1020237032544A priority patent/KR20230170906A/ko
Priority to EP21742129.6A priority patent/EP4308575A1/fr
Priority to CA3212388A priority patent/CA3212388A1/fr
Priority to AU2021434528A priority patent/AU2021434528A1/en
Priority to BR112023018642A priority patent/BR112023018642A2/pt
Priority to JP2023556965A priority patent/JP2024511752A/ja
Priority to CN202180095810.8A priority patent/CN116981672A/zh
Publication of WO2022194399A1 publication Critical patent/WO2022194399A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids

Definitions

  • the present invention relates to novel macrocyclic compounds of formula (I) and their use as pharmaceuticals in the treatment of CFTR-related diseases and disorders such as especially cystic fibrosis.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and their use as modulators of CFTR.
  • Cystic Fibrosis (CF; mucoviscidosis, sometimes also called fibrocystic disease of pancreas or pancreatic fibrosis) is an autosomal recessive genetic disease caused by a dysfunctional epithelial chloride/bicarbonate channel named Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).
  • CFTR dysfunction leads to dysregulated chloride, bicarbonate and water transport at the surface of secretory epithelia causing accumulation of sticky mucus in organs including lung, pancreas, liver and intestine and, as a consequence, multi-organ dysfunction.
  • Fluman CFTR is a multidomain protein of 1480 amino acids. Many different mutations causing CFTR dysfunction have been discovered in CF patients leading e.g.
  • CFTR2 database http://cftr2.org; data retrieved 06.07.2021) currently contains information on 360 disease-causing mutations.
  • F508del phenylalanine at position 508
  • allele frequency 0.697 in the CFTR2 database phenylalanine at position 508
  • the residual F508del-CFTR that is trafficked to the cell surface is functional, however less than wildtype CFTR, i.e. F508del-CFTR also harbours a gating defect (Dalemans, 1991).
  • CF is currently treated by a range of drugs addressing the various organ symptoms and dysfunctions.
  • Intestinal and pancreatic dysfunction are treated from diagnosis by food supplementation with pancreatic digestive enzymes.
  • Lung symptoms are mainly treated with hypertonic saline inhalation, mucolytics, anti-inflammatory drugs, bronchiodilators and antibiotics (Elborn, 2016).
  • CFTR modulators In addition to symptomatic treatments, CFTR modulators have been developed and approved for patients with certain CFTR mutations. These compounds directly improve CFTR trafficking to the cell surface (CFTR correctors) or improve CFTR function at the cell surface (CFTR potentiators). CFTR modulators can also enhance function of non-mutated (i.e. wildtype) CFTR and are therefore being studied in disorders where increasing wildtype CFTR function would have beneficial effects in non-CF disorders such as chronic bronchitis/CO PD (Le Grand, J Med Chem. 2021, 64(11):7241- 7260. Patel, Eur Respir Rev. 2020, 29(156): 190068) and dry eye disease (Flores, FASEB J. 2016, 30(5): 1789-1797).
  • CFTR correctors directly improve CFTR trafficking to the cell surface
  • CFTR potentiators CFTR modulators
  • CFTR modulators can also enhance function of non-mutated (i.e. wildtype)
  • CFTR modulators and their combinations can be discovered and optimized by assessing their ability to promote trafficking and function of mutated CFTR in in vitro cultivated recombinant and primary cellular systems. Activity in such systems is predictive of activity in CF patients.
  • W02019/161078 discloses macrocycles as modulators of cystic fibrosis, wherein said macrocycles generally are 15- membered macrocycles comprising a (pyridine-carbonyl)-sulfamoyl moiety that is linked to a further aromatic group.
  • Macrocyclic tetrapeptides (12- or 13-membered) including the compound Apicidin (CAS: 183506-66-3) have been proposed as potential agents for treating CF (Hutt DM et al. ACS Med Chem Lett. 2011;2(9):703-707. doi: 10.1021/ml200136e).
  • W02020/128925 discloses macrocycles capable of modulating the activity of CFTR, wherein said macrocycles comprise an optionally substituted divalent N-(pyridine-2-yl)pyridinyl-sulfonamide moiety.
  • Non macrocyclic CFTR correctors and/or potentiators of CFTR have been disclosed for example in WO2011/119984, W02014/015841 , W02007/134279, WO2010/019239, WO2011/019413, WO2012/027731, WO2013/130669, WO2014/078842 and WO2018/227049, WO2010/037066, WO2011/127241, WO2013/112804, WO2014/071122, and W02020/128768.
  • particular macrocycles can be found as screening compounds, wherein the phenylene group which is part of said macrocycles is always unsubstituted (CAS registry number : CAS-2213100-89- 9, CAS-2213100-96-8, CAS-2213100-99-1 , CAS-2213101 -02-9, CAS-2213101-04-1 , CAS-2213101 -06-3, CAS- 2213101-08-5, CAS-2213101 -09-6, CAS-2213101 -19-8, CAS-2213101 -24-5, CAS-2215788-95-5, CAS-2215788-98- 8, CAS-2215789-01-6, CAS-2215789-02-7, CAS-2215789-09-4, CAS-2215789-15-2, CAS-2215789-20-9, CAS- 2215789-24-3, CAS-2215789-35-6, CAS-2215789-37-8, CAS-2215946-94-2, CAS-2215947-04-7, CAS-2215947-13- 8, CAS-2215947-24
  • a first aspect of the invention relates to compounds of the Formula (I) wherein ⁇ X represents -CR X1 R X2 , wherein ⁇ R X1 and R X2 together with the carbon atom to which they are attached form a ring which is: ⁇ C3-6-cycloalkan-1,1-diyl (especially cyclopropan-1,1-diyl, cyclobutan-1,1-diyl, cyclopentane-1,1- diyl); ⁇ C 5-6 -cycloalkan-1,1-diyl which is fused to a benzene ring (especially 1,3-dihydro-2H-indene-2,2- diyl); ⁇ C 3-6 -cycloalkan-1,1-diyl, wherein said C 3-6 -cycloalkan-1,1-diyl, wherein said C 3-6 -cycloalkan-1,1-diyl, wherein said C 3-6 -cycloalkan
  • ⁇ a partially aromatic bicyclic ring, which is or ⁇ -L X2 -Ar ⁇ L X2 independently represents a direct bond, C 1-3 -alkylene, -C 1-3 -alkylene-O-*, or -C 1-3 -alkylene-O-C 1-2 -alkylene-*; wherein the asterisks indicate the bond that is attached to the group Ar X2 ; and ⁇ Ar X2 independently represents aryl (especially phenyl, or napthyl), or 5- to 10- membered heteroaryl (especially oxadiazolyl, triazolyl, isoxazolyl, pyridinyl, or quinolinyl); wherein said group Ar X2 independently is unsubstituted, or mono-
  • Ar 2 represents • phenyl or naphthyl (especially phenyl), wherein said phenyl or naphthyl independently is unsubstituted, mono- or di-substituted wherein the substituents are independently selected from C 1-4 -alkyl, C 1-3 -fluoroalkyl, halogen, cyano, C 1-6 -alkoxy, and C 1-3 -fluoroalkoxy; • 5- or 6-membered heteroaryl (especially pyridinyl), wherein said 5- or 6-membered heteroaryl independently is unsubstituted or mono-substituted wherein the substituents are independently selected from C 1-4 -alkyl, C 1- 3 -fluoroalkyl, halogen, cyano, C 1-6 -alkoxy, and C 1-3
  • a further embodiment relates to compounds of the Formula (I) according to embodiment 1), wherein ⁇ X represents -CR X1 R X2 , wherein ⁇ R X1 and R X2 together with the carbon atom to which they are attached form a ring which is: ⁇ C 3-6 -cycloalkan-1,1-diyl- (especially cyclopropan-1,1-diyl, cyclobutan-1,1-diyl, cyclopentane- 1,1-diyl); ⁇ C 5-6 -cycloalkan-1,1-diyl- which is fused to a benzene ring (especially 1,3-dihydro-2H-indene- 2,2-diyl); ⁇ C 3-6 -cycloalkan-1,1-diyl-, wherein said C 3-6 -cycloalkan-1,1-diyl group is mono-substituted with C 1-3 -alkoxy, or di-sub
  • ⁇ -L X2 -Ar X2 wherein - ⁇ L X2 independently represents a direct bond, C 1-3 -alkylene, -C 1-3 -alkylene-O-*, or -C 1-3 -alkylene-O-C 1-2 -alkylene-*; wherein the asterisks indicate the bond that is attached to the group Ar X2 ; and ⁇ Ar X2 independently represents aryl (especially phenyl, or napthyl), or 5- to 10- membered heteroaryl (especially oxadiazolyl, triazolyl, isoxazolyl, pyridinyl, or quinolinyl); wherein said group Ar X2 independently is unsubstituted, or mono-, or di- substituted wherein said group Ar X2 independently is unsubstituted, or mono-, or di- substituted wherein said group Ar X2 independently is unsubstituted, or mono-, or di- substituted where
  • HET 2 represents 9- or 10-membered bicyclic heteroaryl (especially benzoxazolyl, benzisoxazolyl, benzofuranyl, benzo[d][1,2,3]triazolyl or [1 ,2,4]triazolo[1 ,5-a]pyrimidinyl), wherein said HET 2 is unsubstituted or mono-substituted with Ci4-alkyl;
  • HCy 1 represents a partially aromatic bicyclic ring system consisting of a phenyl ring which is fused to a 5- to 7-membered saturated heterocyclic ring containing one or two heteroatoms independently selected from oxygen and nitrogen, wherein, if present, said nitrogen when having a free valency is unsubstituted or mono-substituted with Ci4-alkyl (especially methyl); and wherein the phenyl ring of said partially aromatic bicyclic ring system is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are indepently Ci4-alkyl (especially methyl), Ci4-alkoxy (especially methoxy), Cu-fluoroalkyl, Ci-3-fluoroalkoxy, halogen (especially chloro), or cyano;
  • HCy 2 represents a partially aromatic bicyclic ring system consisting of a 5- membered heteroaryl which is fused to a 5- to 7-membered saturated carbocyclic ring;
  • HCy 3 represents a partially aromatic bicyclic ring system consisting of a phenyl ring which is fused to a 5- to 7-membered saturated heterocyclic ring containing one oxygen atom; wherein said group HCy 3 is bound to the nitrogen of the -CO-NH- group at a carbon atom which is part of said 5- to 7-membered saturated heterocyclic ring; and wherein the phenyl ring of said partially aromatic bicyclic ring system is unsubstituted, or mono-substituted with Ci4-alkyl (especially methyl), or Ci4-alkoxy (especially methoxy);
  • 5- or 6-membered heteroarylene wherein said 5- or 6-membered heteroarylene is unsubstituted (especially pyridin-3,4-diyl, thiophen-2,3-diyl);
  • phenylene, or 5- or 6-membered heteroarylene wherein said phenylene, or 5- or 6-membered heteroarylene independently is mono-, di- or tri-substituted, wherein the substituents are independently selected from C14- alkyl (especially methyl), Ci4-alkoxy (especially methoxy, ethoxy), Ci-3-fluoroalkyl, C 1 -3-f I u 0 ro a I k oxy , cyano, and halogen (especially fluoro, chloro);
  • phenylene wherein said phenylene is fused to a 5- or 6-membered saturated heterocyclic ring containing one or two oxygen atoms, wherein said 5- or 6-membered saturated heterocyclic ring independently is unsubstituted or di-substituted with fluoro; or
  • bicyclic aromatic ring selected from naphthylene and 8- to 10-membered bicyclic heteroarylene; wherein said bicyclic aromatic ring independently is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from Ci4-alkyl (especially methyl) and halogen (especially fluoro, chloro); or
  • Ar 1 the groups linking Ar 1 to the rest of the molecule are attached in ortho arrangement to aromatic ring carbon atoms of Ar 1 as depicted in Formula (I)]; and Ar 2 represents • phenyl or naphthyl (especially phenyl); • 5- or 6-membered heteroaryl (especially pyridinyl); or • 9- or 10-membered heteroaryl (especially benzothiophenyl).
  • a second aspect relates to compounds of Formula (I) according to embodiment 1) or 2), wherein the compounds are compounds of Formula (I E ): 4)
  • Another embodiment relates to compounds according to any one of embodiments 1) to 3), wherein ⁇ X represents -CR X1 R X2 , wherein ⁇ R X1 and R X2 together with the carbon atom to which they are attached form a ring which is: ⁇ C 3-6 -cycloalkan-1,1-diyl- (especially cyclopropan-1,1-diyl, cyclobutan-1,1-diyl, cyclopentane- 1,1-diyl); ⁇ C 5-6 -cycloalkan-1,1-diyl- which is fused to a benzene ring (especially 1,3-dihydro-2H-indene- 2,2-diyl); or ⁇ C 3-6 -cycloalkan-1,1-diyl-, wherein said C 3-6
  • ⁇ -L X2 -Ar X2 wherein - ⁇ L X2 independently represents a direct bond, C 1-3 -alkylene, -C 1-3 -alkylene-O-*, or -C 1-3 -alkylene-O-C 1-2 -alkylene-*; wherein the asterisks indicate the bond that is attached to the group Ar X2 ; and ⁇ Ar X2 independently represents aryl (especially phenyl, or napthyl), or 5- to 10- membered heteroaryl (especially oxadiazolyl, triazolyl, isoxazolyl, pyridinyl, or quinolinyl); wherein said group Ar X2 independently is unsubstituted, or mono-, or di- substituted wherein
  • such group X representing -CR X1 R X2 wherein R X1 represents hydrogen is methylene, or ethan-1,1-diyl); or ⁇ R X1 and R X2 together with the carbon atom to which they are attached form a ring which is C 3-5 - cycloalkan-1,1-diyl- (especially cyclopropan-1,1-diyl); and R 1 independently represents ⁇ -C 4-6 -alkyl (especially 3,3-dimethyl-butyl); ⁇ -C 2-6 -alkyl, wherein said C 2-6 -alkyl is mono-substituted with C 1-4 -alkoxy (especially methoxy, tert- butoxy) (in particular such group is 2-methoxy-ethyl, 3-methoxy-propyl, 3-methoxy-3-methyl-butyl, 2-(tert-butoxy)-ethyl); ⁇ -C 3-6 -alkyl,
  • ⁇ X represents -CR X1 R X2 , wherein ⁇ R X1 and R X2 together with the carbon atom to which they are attached form a ring which is: ⁇ C 3-6 -cycloalkan-1,1-diyl- (especially cyclopropan-1,1-diyl, cyclobutan-1,1-diyl, cyclopentane- 1,1-diyl); ⁇ C 5-6 -cycloalkan-1,1-diyl- which is fused to a benzene ring (especially 1,3-dihydro-2H-indene- 2,2-diyl); ⁇ C 3-6 -cycloalkan-1,1-diyl-, wherein said C 3-6 -cycloalkan-1,1-diyl group is mono-substituted with C 1-3 -alkoxy, or di-sub
  • Ar X2 represents phenyl, wherein said phenyl independently is unsubstituted, or mono-, or di-substituted wherein the substituents are independently selected from o C 1-4 -alkyl; o C 1-3 -alkoxy; o halogen; o C 3-6 -cycloalkyl; and o
  • Another embodiment relates to compounds according to any one of embodiments 1) to 3), wherein the fragment represents a group selected from: A) • C 1-4 -alkyl; • C3-4-cycloalkyl; • C 1-4 -alkyl, wherein said C 1-4 -alkyl is mono-substituted with C 3-4 -cycloalkyl; • C 1-4 -alkyl, wherein said C 1-4 -alkyl is mono-substituted with hydroxy, or C 1-3 -alkoxy; • phenyl; • 6-membered heteroaryl (especially pyridinyl), wherein said 6-membered heteroaryl is unsubstituted or mono-substituted with halogen (especially fluoro); , wherein R SX1 represents -CO-O-C 1-4 -alkyl; r -SO 2 -R OX1 ; wherein R OX1 independently represents ⁇ C 1-4 -alkyl; ⁇ C
  • Anather particular sub-embodiment is formed by the groups A), D), E), F) and G).
  • Another embodiment relates to compounds according to any one of embodiments 1) to 6), wherein R 2 represents methyl.
  • Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein R 3 represents isobutyl.
  • R 4 represents a group -CO-NH-R 41 ; wherein R 41 represents • C2-6-alkyl, which is mono-substituted with C1-4-alkoxy (especially methoxy), or C1-4-fluoroalkoxy (especially difluoromethoxy, or trifluoromethoxy); • C 1-3 -alkoxy-C 2-3 -alkylene-O-CH 2 -CH 2 -; • -CH 2 -CH 2 -C 5-6 -heterocycloalkyl, wherein said C 5-6 -heterocycloalkyl contains one ring oxygen atom, wherein said C 5-6 -heterocyclyl is unsubstituted, mono- or di-substituted with C 1-4 -alkyl (especially methyl); • -L 1 -aryl; wherein L 1 represents -CH 2 -CH 2 -, -CH 2
  • R 4 represents a group -CO-NH-R 41 ; wherein R 41 represents • -L 1 -aryl; wherein L 1 represents -CH 2 -CH 2 -, or -CH 2 -CH 2 -O-*; wherein asterisks indicate the bond with which L 1 is attached to the aryl; wherein aryl represents phenyl; wherein said aryl independently is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently C 1-4 -alkyl (especially methyl, ethyl, tert-butyl), C 1-4 -alkoxy (especially methoxy, ethoxy), C 1-3 -fluoroalkyl, C 1-3 -fluoroalkoxy, halogen (especially fluoro, chloro, bromo), hydroxy-C 1-3 -alkyl, 5- or 6-membere
  • Another embodiment relates to compounds according to any one of embodiments 1) to 11), wherein Ar 2 represents phenyl.
  • phenylene, or 5- or 6-membered heteroarylene wherein said phenylene, or 5- or 6-membered heteroarylene independently is mono-, or di-substituted, wherein the substituents are independently selected from Ci-4-alkyl (especially methyl), Cu-alkoxy (especially methoxy, ethoxy), and halogen (especially fluoro, chloro);
  • phenylene wherein said phenylene is fused to a 5- or 6-membered saturated heterocyclic ring containing one or two oxygen atoms, wherein said 5- or 6-membered saturated heterocyclic ring independently is unsubstituted;
  • bicyclic aromatic ring selected from naphthylene and 8- to 10-membered bicyclic heteroarylene; wherein said bicyclic aromatic ring independently is unsubstituted, or mono-substituted, wherein the substituents are independently selected from Ci_ 4 -alkyl (especially methyl), and halogen (especially fluoro, chloro);
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 12), wherein Ar 1 represents a group selected from
  • a second aspect of the invention relates to compounds of the Formula (II) for use in the treatment of cystic fibrosis; wherein X, R 1 , R 2 , R 3 , R 4 , Ar 2 independently are as defined for the compounds of Formula (I) in any one of embodiments 1), 2) or 4) to 12); and
  • 5- or 6-membered heteroarylene wherein said 5- or 6-membered heteroarylene is unsubstituted (especially pyridin-3,4-diyl, thiophen-2,3-diyl);
  • phenylene, or 5- or 6-membered heteroarylene wherein said phenylene, or 5- or 6-membered heteroarylene independently is mono-, di- or tri-substituted, wherein the substituents are independently selected from C1-4- alkyl (especially methyl), Cu-alkoxy (especially methoxy, ethoxy), Ci- 3 -fluoroalkyl, C 1 -3-f I u 0 ro a I k oxy , cyano, and halogen (especially fluoro, chloro);
  • phenylene wherein said phenylene is fused to a 5- or 6-membered saturated heterocyclic ring containing one or two oxygen atoms, wherein said 5- or 6-membered saturated heterocyclic ring independently is unsubstituted or di-substituted with fluoro; or
  • bicyclic ring selected from naphthylene and 8- to 10-membered bicyclic heteroarylene; wherein said bicyclic ring independently is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from Ci_ 4 -alkyl (especially methyl), Ci- 3 -fluoroalkyl, Ci- 4 -alkoxy, Ci- 3 -fluoroalkoxy, cyano, and halogen (especially fluoro, chloro); or
  • Another embodiment relates to compounds of the Formula (II) according to embodiment 15), for use in the treatment of cystic fibrosis; wherein Ar 1 represents unsubstituted phenylene; or represents a group as defined in embodiment 13) or 14). 17) A further embodiment relates to compounds of Formula (II) for use according to embodiment 15) or 16), wherein the compounds are compounds of Formula (HE):
  • the compounds of formula (I) / formula (II) contain at least three stereogenic or asymmetric centers, which are present in (R)- or (S)-configuration as defined in the respective embodiment defining such compound of formula (I) / formula (II).
  • the compounds of formula (I) / formula (II) may contain one or more further stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms.
  • the compounds of formula (I) / formula (II) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • any stereogenic or asymmetric center in a given chemical name is designated as being in (RS)-configuration
  • the compound (3S,7S,10RS,13R)-13-benzyl-10-(tert-butoxymethyl)-7-isobutyl-N-(3- methoxyphenethyl)-6,9-dimethyl-1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydronaphtho[1 ,2- p][1 ]oxa[4,7, 10, 14]tetraazacycloheptadecine-3-carboxamide comprises (3S.7S, 1 OR, 13R)-13-benzyl-10-(tert- butoxymethyl)-7-isobutyl-N-(3-methoxyphenethyl)-6,9-dimethyl-1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10,11,12,13,14- tetradecahydronaphtho[1 ,2-p][
  • a stereogenic or asymmetric center indicated as “abs” represents said stereogenic or asymmetric center in the respective ( R )- or (S)-configuration.
  • a stereogenic or asymmetric center indicated as “&” represents said stereogenic or asymmetric center in the respective (RS)-configuration, i.e. comprising the respective (R)- or ( S) -conf i gu rati o n or any mixture of epimers at such center.
  • the compounds of formula (I) / formula (II) may further encompass compounds with one or more double bonds which are allowed to be present in Z- as well as E-configuration and/or compounds with substituents at a ring system which are allowed to be present, relative to each other, in cis- as well as trans-configuration.
  • a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer, such designation is to be understood as referring to the respective compound (or generic structure) in enriched enantiomeric form, especially in essentially pure enantiomeric form.
  • a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure form with regard to the respective configuration of said asymmetric center.
  • c/s- or frans-designations are to be understood as referring to the respective stereoisomer of the respective relative configuration in enriched, especially essentially pure form.
  • enriched when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
  • essentially pure when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
  • the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) / formula (II) according to embodiments 1) to 21), which compounds are identical to the compounds of formula (I) / formula (II) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • Isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) / formula (II) and salts thereof are within the scope of the present invention.
  • a certain substituent is specifically indicated as representing hydrogen, it is understood to refer to all isotopes of the atom "H", i.e.
  • the term hydrogen as used for a certain substituent is understood as comprising the isotope 2 H (deuterium); preferably it refers to the isotope 1 H (hydrogen). Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile.
  • the compounds of formula (I) / formula (II) are not isotopically labelled, or they are labelled only with one or more deuterium atoms.
  • the compounds of formula (I) / formula (II) are not isotopically labelled at all.
  • Isotopically labelled compounds of formula (I) / formula (II) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • a bond drawn as a dotted line shows the point of attachment of the radical drawn.
  • the radical drawn below is the 2,3-dihydrobenzofuran-2-yl group.
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • substituent Whenever a substituent is denoted as optional, it is understood that such substituent may be absent (i.e. the respective residue is unsubstituted with regard to such optional substituent), in which case all positions having a free valency (to which such optional substituent could have been attached to; such as for example in an aromatic ring the ring carbon atoms and / or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate.
  • substituent optionally is used in the context of (ring) heteroatom(s)
  • the term means that either the respective optional heteroatom(s), or the like, are absent (i.e. a certain moiety does not contain heteroatom(s) / is a carbocycle / or the like), or the respective optional heteroatom(s), or the like, are present as explicitly defined.
  • halogen means fluorine/fluoro, chlorine/chloro, or bromine/bromo; preferably fluorine/fluoro or chlorine/chloro.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group containing one to six carbon atoms.
  • C x-y -alkyl (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms.
  • a Ci_6-alkyl group contains from one to six carbon atoms.
  • Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl and 3,3-dimethyl-butyl.
  • a group is referred to as e.g. propyl or butyl, it is meant to be n-propyl, respectively n-butyl.
  • R X2 represents a Ci-6-alkyl group, the term especially refers to Ci -alkyl, in particular to methyl, ethyl, isopropyl, or isobutyl; preferably methyl.
  • R 1 represents -Ci_s- alkyl
  • the term especially means methyl, or 3,3-dimethylbut-1-yl; preferably methyl.
  • R x represents Ci-4-alkyl, the term especially means methyl, ethyl, isopropyl, or isobutyl.
  • R 0X1 representing Ci_4-alkyl the term especially means methyl or isobutyl.
  • R 0X2 representing Ci_4-alkyl the term especially means methyl or ethyl.
  • R 2 representing Ci_4-alkyl the term especially means methyl, or ethyl; preferably methyl.
  • R 3 represents -Ci-6-alkyl, the term especially means methyl, or isobutyl; preferably isobutyl.
  • Ci-6-alkyl group wherein said Ci-6-alkyl is mono- substituted with R 11 especially refers to -(CF ⁇ m- groups wherein m represents the integer 1 or 2, or to a C3-6-alkyl group, said groups being mono-substituted with R 11 as explicitly defined.
  • -C x-y -alkylene- refers to bivalently bound alkyl group as defined before containing x to y carbon atoms.
  • the points of attachment of a -Ci_ y -alkylene group are in 1,1-diyl, in 1,2- diyl, or in 1,3-diyl arrangement.
  • an alkylene group (or a substituted alkyl group) that links two heteroatoms preferably will distance such heteroatoms by at least 2 carbon atoms.
  • alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined before.
  • C x-y -alkoxy (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a C ⁇ -alkoxy group means a group of the formula Ci_4-alkyl-0- in which the term “Ci-4-alkyl” has the previously given significance.
  • Representative examples of alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.
  • fluoroalkyl refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • C x. y -fluoroalkyl (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms.
  • a Ci-3-fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • fluoroalkyl groups include especially Ci- fluoroalkyl groups such as trifluoromethyl, and difluoromethyl, as well as 2-fluoroethyl, 2, 2-d if I uoroethyl and 2,2,2- trifluoroethyl.
  • R X2 represents C 1-4-f I uoroal kyl
  • the term especially means 2, 2-difl uoroethyl or 2,2, 2-trif I uoroethyl .
  • -C x-y -fluoroalkylene- used alone or in combination, refers to bivalently bound fluoroalkyl group as defined before containing x to y carbon atoms.
  • fluoroalkoxy refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • C x.y -fluoroalkoxy (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
  • a Ci-3-fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy.
  • alkynyl refers to a straight or branched hydrocarbon chain containing two to four carbon atoms and one carbon-carbon triple bond.
  • C x-y -alkynyl (x and y each being an integer), refers to an alkynyl group as defined before containing x to y carbon atoms.
  • a C2-4-alkynyl group contains from two to four carbon atoms.
  • R 3 represents -C2-4-alkynyl
  • An example of C2-3-alkynyl is ethynyl.
  • cycloalkyl refers to a saturated monocyclic hydrocarbon ring containing three to six carbon atoms.
  • C x-y cycloalkyl refers to a cycloalkyl group as defined before containing x to y carbon atoms.
  • a C3-6-cycloalkyl group contains from three to six carbon atoms.
  • Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R X2 represents C3-6-cycloalkyl
  • the term preferably means cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 11 represents C3-6- cycloalkyl
  • the term especially means cyclobutyl or cyclohexyl.
  • -C x-y -cycloalkylene- refers to bivalently bound cycloalkyl group as defined before containing x to y carbon atoms.
  • the points of attachment of any bivalently bound cycloalkyl group are in 1,1-diyl arrangement. Examples are cyclopropan-1, 1-diyl, cyclobutan-1 ,1-diyl, and cyclopentan-1 , 1 -diyl; preferred is cyclopropan-1, 1-diyl.
  • C3-6-cycloalkan-1, 1-diyl- are cyclopropan-1, 1-diyl, cyclobutan-1, 1-diyl and cyclopentane-1, 1-diyl.
  • An example of a C5-6-cycloalkan-1,1-diyl- group which is fused to a benzene ring is 1 ,3-dihydro-2H-indene-2,2-diyl.
  • heterocycloalkyr used alone or in combination, and if not explicitly defined in a broader or more narrow way, refers to a saturated monocyclic hydrocarbon ring containing one or two ring heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • C x-y -heterocycloalkyr refers to such a heterocycle containing x to y ring atoms. Examples are tetrahydrofuranyl, terahydropyranyl, and piperidnyl. Heterocycloalkyl groups are unsubstituted or substituted as explicitly defined.
  • R 11 represents a saturated 5- or 6-membered heterocycloalkyl containing one or two ring heteroatoms
  • the term especially means tetrahydropyranyl and tetrahydrofuranyl.
  • An example of a C5- 6-heterocycloalkyl group containing one ring oxygen atom is especially tetrahydropyranyl.
  • C4-6-heterocycloalkan-diyl wherein said C4-6-heterocycloalkan-diyl contains one ring oxygen atom refers to a bivalently bound heterocycloalkyl group containing one ring oxygen atom and the remaining ring carbon atoms.
  • An example of “C4-6-heterocycloalkan-diyl wherein said C4-6-heterocycloalkan-diyl contains one ring oxygen atom” is tetrahyd ropy ran-4, 4-d iy I .
  • C4-6-heterocycloalkan-diyl wherein said C4-6-heterocycloalkan-diyl contains one ring nitrogen atom refers to a bivalently bound heterocycloalkyl group containing one ring nitrogen atom and the remaining ring carbon atoms.
  • An example of “C4-6-heterocycloalkan-diyl wherein said C4-6-heterocycloalkan-diyl contains one ring nitrogen atom” is piperidin-4,4-diyl.
  • aryl used alone or in combination, means phenyl or naphthyl, especially phenyl.
  • the above-mentioned aryl groups are unsubstituted or substituted as explicitly defined. It is understood that a heterocyclic ring, for example "containing one or two heteroatoms independently selected from oxygen and nitrogen” or " containing one oxygen atom”, contains exactly the number and type of heteroatoms indicated, the remaining ring atoms being carbon atoms if not explicitly indicated otherwise.
  • Examples of the substituent “HCy 1 representing a partially aromatic bicyclic ring system consisting of a phenyl ring which is fused to a 5- to 7-membered saturated heterocyclic ring containing one or two heteroatoms independently selected from oxygen and nitrogen” are benzodioxolyl, dihydrobenzofuranyl, dihydrobenzodioxinyl, chromanyl, tetrahydrobenzooxepinyl, dihydrobenzooxazinyl; more particularly benzo[d][1,3]dioxol-5-yl, 1,3-dihydroisobenzofuran- 5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3- dihydrobenzo[b][1,4]dioxin-2-yl, chro
  • HCy 2 representing a partially aromatic bicyclic ring system consisting of a 5- membered heteroaryl which is fused to a 5- to 7-membered saturated carbocyclic ring” is 5,6-dihydro-4H- cyclopenta[d]thiazol-2-yl.
  • HCy 3 representing a partially aromatic bicyclic ring system consisting of a phenyl ring which is fused to a 5- to 7-membered saturated heterocyclic ring containing one oxygen atom” is chroman- 3-yl.
  • phenylene or 5- or 6-membered heteroarylene such as thiophene-diyl, thiazole-diyl, or pyridine-diyl;
  • phenylene wherein said phenylene is is fused to a 5- or 6-membered saturated heterocyclic ring containing one or two oxygen atoms, such as benzo[d][1,3]dioxole-diyl, or 2,3-dihydrobenzofuran-diyl;
  • quinoline-diyl wherein such quinoline-diyl is present in form of the respective N-oxide, such as quinoline-1 -oxide- diyl.
  • Examples of the group Ar 1 are especially those, notably as listed above, with the -CO- group and the oxygen (i.e. the groups linking Ar 1 to the rest of the molecule) attached in ortho arrangement to aromatic ring carbon atoms of Ar 1 .
  • said groups Ar 1 are unsubstituted or substituted as explicitly defined.
  • Particular examples of the fragment: are:
  • phenylene or 5- or 6-membered heteroarylene such as 1,2-phenylene, thiophene-2, 3-diyl, thiazole-4,5-diyl, pyridine-3, 4-diyl, or pyridine-2, 3-diyl;
  • phenylene wherein said phenylene is is fused to a 5- or 6-membered saturated heterocyclic ring containing one or two oxygen atoms, such as benzo[d][1,3]dioxole-4,5-diyl, benzo[d][1,3]dioxole-5,6-diyl, 2,3-dihydrobenzofuran- 6,7-diyl, or 2 , 3-d i hyd ro be n zof u ran-4 , 5-d iy I ;
  • quinoline-diyl wherein such quinoline-diyl is present in form of the respective N-oxide, such as quinoline-1 -oxide- 3, 4-diyl or quinoline-1-oxide-5, 6-diyl.
  • heteroaryl used alone or in combination, and if not explicitly defined in a broader or more narrow way, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms, each independently selected from oxygen, nitrogen and sulfur.
  • heteroaryl groups are 5-membered heteroaryl groups such asfuranyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; and 8- to 10-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazoly
  • R 0X1 represents 5- or 6-membered heteroaryl
  • the term especially means 6-membered heteroaryl containing one or two nitrogen atoms such as pyrazinyl or pyridinyl.
  • substituent HET 1 representing a "5- or 6-membered heteroaryl”
  • the term especially means the above- mentioned 5- or 6-membered groups such as especially pyridinyl, pyrimidinyl, pyrazinyl, furanyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiophenyl.
  • the term refers to 5-membered groups such as especially thiophen-2-yl, thiazol-2-yl, thiazol-4-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, furan-2-yl, isothiazol-5- yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-
  • the term especially means pyridinyl, in particular pyridine-2-yl.
  • substituent HET 2 representing a "9- or 10-membered bicyclic heteroaryl" the term especially refers to benzoxazolyl, benzisoxazolyl, and benzofuranyl; as well as benzo[d][1,2,3]triazolyl or [1 ,2,4]triazolo[1,5-a]pyrimidinyl.
  • the above groups are unsubstituted or substituted as explicitly defined.
  • Particular examples are benzofuran-6-yl, benzisoxazol-3-yl, benzoxazol-2-yl, and, in addition, 2H-benzo[d][1 ,2,3]triazol-2-yl and [1 ,2,4]triazolo[1 ,5-a]pyrimidin- 2-yl.
  • substitutent Ar 2 representing “9- or 10-membered heteroaryl”
  • the term especially means benzothiophenyl, in particular benzothiophen-3-yl.
  • the term especially means 5- or 6-membered heteroaryl groups, or 8- to 10-membered bicyclic heteroaryl groups as defined before; especially pyridinyl, pyrimidinyl, pyrazinyl, furanyl, pyrazolyl, triazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiophenyl, or benzoxazolyl, benzisoxazolyl, benzofuranyl; or, in addition, benzo[d][1,2,3]triazolyl or [1 ,2,4]triazolo[1 ,5-a]pyrimidinyl.
  • the above groups are unsubstituted or substituted as explicitly defined.
  • heteroaryl is as defined before; especially it represents mono-cyclic 5- or 6-membered heteroaryl [notably 5-membered heteroaryl containing one to three heteroatoms selected from oxygen and nitrogen (especially oxadiazolyl, triazolyl, or isoxazolyl); or 6-membered heteroaryl containing one or two nitrogen atoms (especially pyridinyl)], wherein such mono-cyclic heteroaryl is unsubstituted or substituted as explicitly defined; or it represents bicyclic 8- to 10-membered heteroaryl [notably 10- membered heteroaryl containing one nitrogen atom (especially quinolinyl)], wherein such bicyclic heteroaryl is notably unsubstituted, or substituted as explicitly defined.
  • mono-cyclic 5- or 6-membered heteroaryl notably 5-membered heteroaryl containing one to three heteroatoms selected from oxygen and nitrogen (especially oxadiazolyl, triazolyl, or isoxazolyl); or 6-membered heteroaryl
  • Particular examples of the substitutent Ar X2 representing 5- to 10- membered heteroaryl are 3-phenyl-[1 ,2,4]-oxadiazol-5-yl, 3-(5-fluoro-pyridin-2-yl)-[1 ,2,4]-oxadiazol-5-yl, or 3- trifluoromethyl-[1,2,4]-oxadiazol-5-yl.
  • heteroaryl notably represents 6-membered heteroaryl containing one or two nitrogen atoms, especially pyridinyl; wherein such 5- or 6-membered heteroaryl heteroaryl is unsubstituted or substituted as explicitly defined.
  • a particular example is 5-fluoro-pyridin-2-yl.
  • fragment examples include the 4-methyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-7-yl and 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl.
  • cyano refers to a group -CN.
  • the compounds of formula (I) / formula (II) may contain tautomeric forms.
  • Such tautomeric forms are encompassed in the scope of the present invention.
  • the other tautomeric form(s) are understood to be encompassed in such disclosed residue.
  • 2-oxo-2,3-dihydrobenzo[d]oxazol-yl group is to be understood as also encompassing its tautomeric form (2-hydroxybenzo[d]oxazol-yl).
  • the term “about” placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature ⁇ ” refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C.
  • room temperature refers to a temperature of about 25°C.
  • Another embodiment relates to compounds of Formula (I) according to embodiment 1), wherein said compounds are selected from the compounds of example (as disclosed in the experimental part below):
  • Another embodiment relates to compounds of Formula (I) according to embodiment 1), wherein said compounds are selected from the compounds of example (as disclosed in the experimental part below):
  • the compound of example 724 (3R,6RS,9S, 13S)-3-benzyl-6-((benzyloxy)methyl)-N-(2-(3-cyclopropyl-1 ,2,4- oxadiazol-5-yl)ethyl)-9-isobutyl-16-methoxy-7, 10-dimethyl-5,8, 11,15-tetraoxo-2,3,4,5,6,7,8,9, 10,11,12,13,14,15- tetradecahydropyrido[3,4-p][1 ]oxa[4,7, 10, 14]tetraazacycloheptadecine-13-carboxamide has the structure depicted in
  • the compound of example 769 (9S,13S,19aR,22R)-22-benzyl-5-fluoro-13-isobutyl-N-(2-(3- methoxyisoxazol-5-yl)ethyl)-12-methyl-7, 11,14,20-tetraoxo-7,8,9, 10, 11 , 12, 13, 14, 17, 18, 19, 19a, 20, 21 ,22,23- hexadecahydro-16H-pyrido[2', 1 ':6,7][1 ]oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-9-carboxamide has the structure depicted in Table 4, wherein said compound is in absolute configuration as drawn:
  • the compound of example 820 (3R,6R,9S,13S)-3-benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-9- isobutyl-16-methoxy-7,10,18-trimethyl-5, 8, 11,15-tetraoxo-6-((3-(trifluoromethyl)-1, 2, 4 -ox ad i azo I -5 -y I ) m ethy I ) - 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15-tetradecahydropyrido[3,4-p][1 ]oxa[4,7, 10, 14]tetraazacycloheptadecine-13- carboxamide has the structure depicted in Table 4, wherein said compound is in absolute configuration as drawn:
  • the compounds of formula (I) / formula (II) according to embodiments 1) to 21) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral e.g. in form of a tablet or a capsule) or parenteral administration (including topical application or inhalation).
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) / formula (II) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the present invention also relates to a method for the prevention / prophylaxis or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) / formula (II) according to embodiments 1) to 21).
  • the compounds of formula (I) / formula (II) according to embodiments 1) to 21) are useful for the treatment of CFTR- related diseases and disorders, especially cystic fibrosis.
  • CFTR-related diseases and disorders may be defined as including especially cystic fibrosis, as well as further CFTR- related diseases and disorders selected from:
  • CBAVD congenital bilateral absence of the vas deferens
  • ABPA allergic bronchopulmonary aspergillosis
  • liver disease coagulation-fibrinolysis deficiencies, such as protein C deficiency
  • diabetes mellitus
  • idiopathic pancreatitis pancreatitis
  • hereditary emphysema hereditary hemochromatosis
  • lysosomal storage diseases such as especially l-cell disease pseudo-FI urler; mucopolysaccharidoses; Sandhoff/Tay-Sachs; osteogenesis imperfecta; Fabry disease; Sjogren's disease; osteoporosis; osteopenia; bone healing and bone growth (including bone repair, bone regeneration, reducing bone resorption and increasing bone deposition); chloride channelopathies, such as myotonia congenita (Thomson and Becker forms); Bartter's syndrome type 3; epilepsy; lysosomal storage disease; Primary Ciliary Dyskinesia (PCD) - a term for inherited disorders of the structure and or function of cilia (including PCD with situs inversus also known as Kartagener syndrome, PCD without situs inversus, and ciliary aplasia); generalized epilepsy with
  • treatment of cystic fibrosis refers to any treatment of cystic fibrosis and includes especially treatment that reduces the severity of cystic fibrosis and/or reduces the symptoms of cystic fibrosis.
  • cystic fibrosis refers to any form of cystic fibrosis, especially to a cystic fibrosis that is associated with one or more gene mutation(s).
  • cystic fibrosis is associated with an CFTR trafficking defect (class II mutations) or reduced CFTR stability (class VI mutations) [in particular, an CFTR trafficking defect / class II mutation], wherein it is understood that such CFTR trafficking defect or reduced CFTR stability may be associated with another disease causing mutation of the same or any other class.
  • Such further disease causing CFTR gene mutation comprises class I mutations (no functional CFTR protein), (a further) class II mutation (CFTR trafficking defect), class III mutations (CFTR regulation defect), class IV mutations (CFTR conductance defect), class V mutations (less CFTR protein due to splicing defects), and/or (a further) class VI mutation (less CFTR protein due to reduced CFTR stability).
  • Said one or more gene mutation(s) may for example comprise at least one mutation selected from F508del, A561 E, and N1303K, as well as I507del, R560T, R1066C and V520F; in particular F508del.
  • CFTR gene mutations comprise for example G85E, R347P, L206W, and M1101 K.
  • Said gene mutation(s) may be heterozygous, homozygous or compound hetereozygous. Especially said gene mutation is heterozygous comprising one F508del mutation.
  • Further CFTR gene mutations (which are especially class III and/or IV mutations) comprise G551D, R117H, D1152H, A455E, S549N, R347H, S945L, and R117C.
  • the severity of cystic fibrosis / of a certain gene mutation associated with cystic fibrosis as well as the efficacy of correction thereof may generally be measured by testing the chloride transport effected by the CFTR. In patients, for example average sweat chloride content may be used for such assessment.
  • cystic fibrosis refers especially to elevated chloride concentration in the sweat; symptoms of cystic fibrosis further comprise chronic bronchitis; rhinosinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility caused by congenital bilateral absence of the vas deferens (CBAVD); mild pulmonary disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolysis deficiencies such as protein C deficiency; and/or diabetes mellitus.
  • CBAVD congenital bilateral absence of the vas deferens
  • ABPA allergic bronchopulmonary aspergillosis
  • liver disease coagulation-fibrinolysis deficiencies such as protein C deficiency
  • diabetes mellitus if compounds are described as useful for the treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the treatment of said diseases. Likewise, such compounds are also suitable in a method for the
  • subject refers to a mammal, especially a human.
  • the present invention further relates to a method of treating cystic fibrosis, comprising the administration of an effective amount of a macrocycle (especially of a 17- or 18-membered macrocycle), or of a pharmaceutically acceptable salt thereof; to a subject in need thereof; wherein the cyclic core of said macrocycle comprises one aromatic moiety (such as an arylene or 5- to 10-membered heteroarylene, wherein said aromatic moiety especially is bound to the rest of the molecule / the ring members of said macrocycle (i) through a carbonyl group and (ii) through an oxygen atom, wherein notably said carbonyl group and said oxygen atom are attached to said aromatic moiety in a 1,2-diyl, or in a 1,3-diyl relationship), at least one beta-amino acid (wherein especially said beta-amino acid is bound through its amino group to the carbonyl group attached to said aromatic moiety), and at least one N-alkylated alpha-amino acid (wherein especially said N-
  • any preferences and (sub-)embodiments indicated for the compounds of formula (II) (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, or uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of formula (I).
  • the compounds of formula (I), formula (II), formula (l E ), formula (ll E ) can be prepared by well-known literature methods, by the methods given below, by the methods given in the experimental part below or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures. In some cases, the order of carrying out the following reaction schemes, and/or reaction steps, may be varied to facilitate the reaction or to avoid unwanted reaction products. In the general sequence of reactions outlined below, the generic groups R 1 , R 2 , R 3 , R 4 , Ar 1 and Ar 2 are as defined for formula (I), formula (II), formula (l E ), formula (ll E ).
  • manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis and transition-metal catalysed cross-coupling reactions which are commonly known to those skilled in the art.
  • the compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts, in a manner known perse.
  • Reaction Scheme A Syntheses can be performed with racemic or enantiomerically enriched amino acid building blocks.
  • Suitably protected amine building block A and acid B-Acid prepared following procedures well described in the literature or in Reaction Schemes I and J respectively, are treated with a peptide coupling reagent such as HATU, COMU, T3P, PyBop or EDCI/HOBt in a solvent like THF, DMF or NMP in the presence of a base such as TEA or DIPEA at a temperature between -20°C and +75°C, preferably at RT, to generate the corresponding amide intermediate AB.
  • a peptide coupling reagent such as HATU, COMU, T3P, PyBop or EDCI/HOBt
  • a solvent like THF, DMF or NMP in the presence of a base such as TEA or DIPEA at a temperature between -20°C and +75°C, preferably at RT, to generate the
  • Deprotection of the amine function of the intermediate AB is achieved according to known methodologies by those skilled in the art, e.g. by treatment with 4M HCI in dioxane or preferably with TFA in the case of a Boc protecting group, or with piperidine ordiethylamine in the case of an Fmoc protecting group, or the appropriate treatment in case of other protecting groups such as Cbz or Alloc protecting groups.
  • the deprotected intermediate AB-Amine is then reacted with the suitably protected acid C, prepared following procedures described in the literature or in the experimental section, according to the peptide coupling conditions already described above for the formation of the AB intermediate.
  • the obtained linear intermediate ABC is then deprotected before the final peptide coupling macrolactamisation.
  • the protecting groups PG1 and PG3 are sequentially removed, but they are preferably removed simultaneously in one single step.
  • a Bu ester and Boc protecting groups are removed by treatment with 4M HCI in dioxane or preferably TFA, or alternatively Allyl ester and Alloc protecting groups can be removed by palladium catalyst treatment as extensively reported in the literature.
  • the linear ABC deprotected intermediate is then cylised under standard conditions, i.e. the intermediate can be treated with a coupling reagent such as COMU, T3P, PyBop, EDCI/HOBt, or preferably HATU in diluted conditions such as less than 0.1 M soln. of the ABC starting material in a solvent like DMF or NMP or a mix.
  • Reaction Scheme B In a modified version of Reaction Scheme A, the C moiety can be introduced stepwise, one amino acid at a time.
  • Selective deprotection of the amine function of ABD-1 such as removing an Fmoc group by treatment with piperidine or diethylamine, or removing a Cbz protecting group by hydrogenolysis over a catalyst such as Pd/C or Pd(OH)2/C in a solvent like EtOAc, THF or dioxane, or preferably removing a Boo protecting group by treatment with 4M HCI in dioxane or with TFA, affords the free amine or its ammonium salt respectively, ready to be coupled with the second amino acid D-2 in a similar peptide coupling step.
  • the three described coupling/deprotection/coupling steps yield the same linear intermediate ABC as the one previously described in Reaction Scheme A.
  • the remaining steps of the synthesis to furnish the desired macrocycle cABC are the same as described above.
  • Reaction Scheme C In an alternative approach, the sequence for building the linear intermediate ABC can be modified.
  • Suitably protected building block C and the amine B-Amine prepared following procedures described in the literature or in Reaction Schemes K and J respectively, are treated according to the peptide coupling conditions already described above, with a reagent such as HATU, COMU, T3P, PyBop or EDCI/HOBt in a solvent like THF, DMF or NMP in the presence of a base such as TEA or DIPEA at a temperature between -20°C and +75°C, preferably at RT.
  • a reagent such as HATU, COMU, T3P, PyBop or EDCI/HOBt
  • a solvent like THF, DMF or NMP in the presence of a base such as TEA or DIPEA at a temperature between -20°C and +75°C, preferably at RT.
  • a base such as TEA or DIPEA
  • Reaction Scheme D As it is the case when moving from Reaction Scheme A to Reaction Scheme B, the C moiety in Reaction Scheme C can be similarly introduced stepwise, one amino acid at a time.
  • Reaction Scheme E In another variation of Reaction Scheme C, the building block A-Amine is doubly protected with suitable orthogonal protecting groups on the 2 carboxylic acid functions, such as the a-benzyl ester or a-methyl ester in the presence of a b-tiutyl ester. Following the sequence described in Reaction Scheme C then yields the corresponding linear intermediate ABC. Double deprotection of the aspartic acid side chain and the Boo amine using TFA and subsequent cyclisation by a method already described previously yields the cyclised intermediate cABC, still protected on A. Deprotection of the aspartic acid backbone carboxylic acid, i.e.
  • removal of PG6 can be accomplished by treatment with NaOFI or LiOH in methanol/water at a temperature ranging from 0°C to 50°C for methyl or ethyl esters or preferably by hydrogenolysis of the benzyl ester over a catalyst such as Pd/C or Pd(OH)2/C in a solvent like EtOAc, THF or dioxane.
  • a catalyst such as Pd/C or Pd(OH)2/C in a solvent like EtOAc, THF or dioxane.
  • the deprotected intermediate cABC-Acid is then coupled according to peptide coupling conditions already described above with an amine AM, either commercially available or prepared following a procedure described in the literature or in the experimental section to yield the target compound. This strategy is especially efficient for preparation of libraries for the exploration of the AM moiety.
  • Reaction Scheme F The strategy described in Reaction Scheme E, introducing the A moiety stepwise, can be applied in a different sequence to give the same cABC-Acid intermediate, as illustrated in Reaction Scheme F.
  • the protected A-Amine, doubly protected with suitable orthogonal protecting groups on the 2 carboxylic acid functions, such as the a-benzyl ester or a-methyl ester in the presence of a b-allyl ester can be coupled with the required B- Acid and C building blocks in the same sequence as described in Reaction Scheme A to furnish the corresponding linear intermediate ABC.
  • Reaction Scheme G In a variation of Reaction Scheme F a and in close similarity to Reaction Schemes B and D, moiety C can be introduced stepwise, one amino acid at a time. Moreover, the amino acid D-1 can itself be built stepwise, by introducing the desired side-chain R1 on an already assembled ABD1 precursor.
  • the amine deprotected AB intermediate already described in Reaction Scheme F can be coupled with an unsubstituted amino acid precursor of D-1 such as the NH-Boc or preferably the NH-nosyl-amino acid according to already described peptide coupling conditions.
  • the NH-Nosyl function can then either be alkylated by treatment with the desired alkyl halide such as the bromide or preferably iodide in the presence of a base, such as K2CO3 or preferably, via a Mitsunobu reaction with the desired alcohol, performed according to standard conditions well known to those skilled in the art, e.g. by treatment with DEAD or DIAD with a phosphine ligand like triphenylphosphine at a temperature ranging from -80°C up to 60°C in a solvent such asTHF ordioxane.
  • the desired alkyl halide such as the bromide or preferably iodide
  • a base such as K2CO3
  • Mitsunobu reaction with the desired alcohol, performed according to standard conditions well known to those skilled in the art, e.g. by treatment with DEAD or DIAD with a phosphine ligand like triphenylphosphine at a temperature
  • the Nosyl activating/protecting group can then be removed by standard treatment with thiophenol in the presence of a base such as K2CO3 in a solvent like DMF to afford the corresponding deprotected intermediate.
  • the amino acid D-2 can be coupled to this intermediate according to the conditions illustrated in Reaction Scheme B.
  • the three described coupling/deprotection/coupling steps yield the same deprotected linear intermediate ABC as the one previously described in Reaction Scheme F.
  • the remaining steps of the synthesis to furnish the desired macrocycle cABC are the same as already described above.
  • the a-carboxylic acid protecting group of the A- Amine building block can be solid phase such as a polymer-linked support, enabling the stepwise solid phase peptide synthesis of the cyclised macrocycle precursor according to established methodologies well known to those skilled in the art of polymer supported peptide synthesis.
  • the amino acid A-Acid suitably orthogonally protected on the amine function by for example an Fmoc protecting group and on the b-carboxylic acid function by for example an allylester, can be introduced on Wang resin by treatment with HOBt and DMAP and a coupling reagent such as DCC or DIC in a solvent mix.
  • Cyclisation under standard peptide coupling conditions can be accomplished in these circumstances without risk of oligomer formation.
  • the macrocycle cABC-Acid already described in Reaction Scheme F can then be released from the polymer support by acidic treatment such as with a mix. of TFA/H2O (95/5).
  • the liberated cABC-Acid can then be coupled with the appropriate AM amine using coupling conditions as described above to furnish the target compound.
  • a suitably orthogonally protected A-Acid such as the b-tiutylester of the N-Fmoc or the b-allylester of the N-Boc aspartic acid, is coupled with the desired AM amine according to standard peptide coupling conditions, by treatment with COM U or T3P, HATU, PyBop or another peptide coupling reagent, in a solvent like THF, DMF or NMP in the presence of a base such as TEA or DIPEA at a temperature between -20°C and +75°C, preferably at RT.
  • a base such as TEA or DIPEA
  • the resulting intermediate can then be selectively deprotected on the amine functionality without removing the b-ester protecting group PG1 , under standard conditions well established in the field of protecting group chemistry.
  • Specific treatment with piperidine or diethylamine to remove the N-Fmoc in the presence of the b-tiutylester or with TFA or 4M HCI in dioxane to remove the N-Boc in the presence of the b-allylester gives access to the target building block A as its free base or its ammonium salt respectively.
  • the building blocks B, B-Acid or B-Amine are either prepared as described in the literature or may be prepared as illustrated in Reaction Scheme J.
  • An appropriate salicylic acid derivative, protected as an ester on the carboxylic acid function, such as a methyl, ethyl, or benzyl ester, are either commercially available or prepared as described in the literature, or may be prepared as described in the experimental section.
  • the amino alcohol protected on the amine function by the Boc or Cbz groups are either commercially available or readily prepared from the corresponding amino acid, as described in the literature, or may also be prepared as described in the experimental section.
  • the alcohol function of the amino alcohol can be activated upon treatment with methanesulfonyl chloride ortoluenesulfonyl chloride or a similar activating agent, in the presence of a base such as DIPEA or TEA and reacted with the phenol function of the salicylic acid ester derivative in a solvent such as THF or DMF to furnish the doubly protected B building block.
  • a base such as DIPEA or TEA
  • the two building blocks can be reacted together according to Mitsunobu methodology, by treatment with a phosphine ligand like triphenylphosphine and the DEAD or DIAD reagents in a solvent such as THF or dioxane at a temperature ranging from -20°C up to 60°C.
  • the resulting orthogonally protected intermediate can then be selectively deprotected on the acid function or on the amine function to access the corresponding building blocks B- Acid or B-Amine respectively.
  • saponification of a methyl ester with aq. NaOFI or LiOH soln. or hydrogenolysis of a benzyl ester over a palladium catalyst such as charcoal supported Pd or Pd(OH)2 gives access to the corresponding B-Acid.
  • Boc deprotection by treatment with TFA or hydrogenolysis of a Cbz protected amine in the case of a methyl ester leads to the corresponding B-Amine.
  • Building blocks C may be prepared as illustrated in Reaction Scheme K from the key intermediate D-1Amine.
  • the intermediate D-1 is either commercially available or prepared as described in the literature or may be prepared as illustrated in this scheme.
  • a suitably PG8 protected bromoacetic acid ester derivative, such as methyl, ethyl or benzyl ester can be reacted with the appropriate amine R1 NH 2 , in a solvent like MeCN, acetone or DMF in the presence of a base such as K2CO 3 or DIPEA at a temperature ranging from RT up to 80°C to yield the amine D-1.
  • a suitably PG8 protected amino acid ester derivative such as methyl, ethyl or benzyl ester
  • nitrosulfonylbenzene chloride in the presence of a catalytic amount of DMAP, in a solvent such as DCM or THF to yield the corresponding N-Nosyl protected amine.
  • Alkylation of the sulfonamide nitrogen can then be accomplished by Mitsunobu methodology as already described above, i.e.
  • HPLC pump Binary gradient pump, Agilent G4220A or equivalent Autosampler: Gilson LH215 (with Gilson 845z injector) or equivalent Column compartment: Dionex TCC-3000RS or equivalent Degasser: Dionex SRD-3200 or equivalent Make-up pump: Dionex HPG-3200SD or equivalent DAD detector: Agilent G4212A or equivalent
  • MS detector Single quadrupole mass analyzer, Thermo Finnigan MSQPIus or equivalent
  • ELS detector Sedere SEDEX 90 or equivalent
  • Method A Column: Zorbax SB-aq (3.5 mhh, 4.6 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B] Gradient: 95% B — > 5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis + MS.
  • Method B Column: Zorbax RRHD SB-aq (1.8 mhh, 2.1 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B] Gradient: 95% B — > 5% B over 2.0 min (flow: 0.8 mL/min). Detection: UV/Vis + MS.
  • Method C Column: Waters XBridge C18 (5 mhh, 4.6 x 30 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B] Gradient: 95% B — > 5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis + MS.
  • Method D Column: Waters BEH C18 (2.1 x 50mm, 2.5mhi). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B] Gradient: 95% B — > 5% B over 2.0 min (flow: 0.8 mL/min). Detection: UV/Vis + MS.
  • Method E Column: Waters XBridge C18 (2.5 mhi, 4.6 x 30 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B] Gradient: 95% B — > 5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis + MS.
  • Method F Column: Waters XSelect CSH C18 (3.5 mhi, 2.1 x 30 mm). Conditions: MeCN + 0.1% formic acid [eluent
  • Method G Column: Waters Atlantis T3 (3.0 mhi, 2.1 x 50 mm). Conditions: MeCN + 0.1% formic acid [eluent A]; water + 0.1% formic acid [eluent B] Gradient: 95% B — > 2% B over 5 min (flow 0.8 mL/min). Detection: UV/Vis + MS.
  • Method H Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector or Xevo TQD or SYNAPT G2 MS, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD.
  • Dionex ISO-3100A make-up pump Dionex DAD-3000 DAD detector, Single quadrupole mass analyzer MS detector, Thermo Finnigan MSQ Plus, MRA100-000 flow splitter, Polymer Laboratories PL-ELS1000 ELS detector
  • desired diastereoisomers can be isolated or purified by standard preparative scale HPLC according to standard methods well-known to those skilled in the art.
  • the use of a chiral chromatography column is advisable to separate complex mixtures of diastereoisomers. Best results are obtained using Chiral Stationary Phase columns, such as Chiralpak IA, IB, or IC columns based on an immobilised amylose or cellulose chiral phase, with an isocratic eluent based on a mix. of MeCN with EtOH or MeOH, in a ratio varying from 9:1 to 1:9.
  • modifiers can be added to the solvent mix.
  • HATU (1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate Hept heptane(s) Hex hexane(s)HOBT 1-hydroxybenzotriazol HPLC high performance liquid chromatography HV high vacuum conditions i Bu isobutyl i Pr isopropyl iPrOH isopropyl alcohol i PrOAc isopropyl acetate KO t Bu potassium tert-butoxide LAH Lithium aluminium hydride LC-MS liquid chromatography – mass spectrometry Lit.
  • Non-commercial amines are synthesised as described below.
  • Step 1 Potassium ferf-butyl A/-[2-(trifluoroboranuidyl)ethyl]carbamate (693 mg, 2.76 mmol) is added to a RT soln. of 6-bromochroman (600 mg, 2.73 mmol) and CS2CO3 (2.67 g, 8.19 mmol) in PhMe (9.2 mL) and water (3 mL). After degassing the RM by bubbling argon through the soln., RuPhos 95% (134 mg, 0.273 mmol) and Pd(OAc)2 (30.7 mg, 0.137 mmol) are added and the resulting mix. is stirred at 95°C for 18 h. The mix.
  • Step 2 4 M HCI in dioxane (4 mL) is added to a RT soln. of (2-chroman-6-yl-ethyl)-carbamic acid ferf-butyl ester (540 mg, 1.95 mmol) in dioxane (0.5 mL). The RM is stirred at RT for 4 h, then the mix. is concentrated in vacuo to give AM-2.1 (412 mg, 99%) as a white solid.
  • Table AM-2 Listed in Table AM-2 below are amines that are prepared from the corresponding starting materials in analogy to the 2-step sequence described for AM-2.1.
  • Step 1 A mix. of 1-bromo-3-(1,1-difluoroethyl)benzene (200 mg, 0.91 mmol) and potassium (2 -((ferf- butoxycarbonyl)amino)ethyl)trifluoroborate (273 mg, 1.09 mmol) in PhMe (7 mL) and H2O (2 mL) is degassed with Ar for 10 min before CS2CO3 (884 mg, 2.71 mmol) and Pd(dppf)Cl2.DCM (74 mg, 0.09 mmol) are added. The RM is degassed with Ar for a further 2 min and then heated to 100°C for 2 h.
  • Step 2 The title compound is prepared from ferf-butyl (3-(1,1-difluoroethyl)phenethyl)carbamate in analogy to the procedure described for AM-2.1 step 2.
  • Step 1 CU(OAC)2 (1.23 g, 6.61 mmol) is added to a mix. of 4, 5-dibromo-2H-1, 2, 3-triazole (1.5 g, 6.61 mmol), cyclopropyl boronic acid (1.17 g, 13.2 mmol), is ⁇ CCh (1.4 g, 13.2 mmol), and 2,2’-bipyridine (1.04 g, 6.61 mmol) in DCE (15 mL) and 2-methylfuran (15 mL) and the RM is heated to 80°C for 48 h. The RM is filtered and the filter cake is rinsed with EtOAc.
  • Step 2 ferf-Butyl (2-(5-bromo-2-cyclopropyl-2/-/-1,2,3-triazol-4-yl)ethyl)carbamate is prepared from 4,5-dibromo-2- cyclopropyl-2H-1, 2, 3-triazole following the procedure described for AM-2.1 step 1.
  • Step 3 A soln. of ferf-butyl (2-(5-bromo-2-cyclopropyl-2/-/-1,2,3-triazol-4-yl)ethyl)carbamate (110 mg, 0.33 mmol) in EtOH (3 mL) is evacuated/purged with N2 (3x) before 10% Pd/C (23 mg, 5 mol%) is added. The RM is evacuated/purged with H2 (3x) and stirred under a H2 atm for 16 h.
  • Step 4 The title compound is prepared from ferf-butyl (2-(2-cyclopropyl-2/-/-1,2,3-triazol-4-yl)ethyl)carbamate in analogy to the procedure described for AM-2.1 step 2.
  • Step 1 Di-ferf-butyl dicarbonate (2.33 g, 10.5 mmol) is added to a RT suspension of dopamine hydrochloride (2.0 g, 10.5 mmol) and NaHCCh (886 mg, 10.5 mmol) in THF (50 mL) and the mix. is stirred at RT for 2 h. The product is extracted with EtOAc (3x) and the combined org. layers are dried (MgSCU), filtered, and concentrated. Purification by FC (eluting with 5% MeOFI in DCM) yields ferf-butyl (3,4-dihydroxyphenethyl)carbamate (2.34 g, 88%) as a white solid.
  • Step 2 1,3-Dibromopropane (1.01 mL, 9.75 mmol) is added to a RT suspension of ferf-butyl (3,4- dihydroxyphenethyl)carbamate (2.24 g, 8.86 mmol) and K2CO3 (3.13 g, 22.2 mmol) in DMF (10 mL) and the resulting mix. is stirred at RT overnight.
  • the RM is directly purified by prep. HPLC (basic) to give ferf-butyl (2-(3,4-dihydro-2H- benzo[b][1,4]dioxepin-7-yl)ethyl)carbamate (1.25 g, 48%) as a slightly brownish oil.
  • Step 3 4 M HCI in dioxane (5.4 mL) is added to a RT soln. of ferf-butyl (2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7- yl)ethyl)carbamate (1.25 g, 4.28 mmol) in dioxane (20 mL). The RM is stirred at RT for 18 h, then the mix. is concentrated in vacuo to give AM-3.1 (931 mg, 100%) as a white solid.
  • Step 1 CD3I (0.25 mL, 4.0 mmol) is added to a RT mix. of ferf-butyl (3-hydroxyphenethyl)carbamate (638 mg, 2.7 mmol) and K2CO3 (557 mg, 4.0 mmol) in DMF (5 mL) and the RM is heated to 50°C for 36 h. The RM is cooled to RT and partitioned between H2O and EtOAc and extracted. The layers are separated and the aq. phase is re-extracted with EtOAc (2x). The combined org.
  • Step 2 The title compound is prepared from ferf-butyl (3-(methoxy-d3)phenethyl)carbamate in analogy to the procedure described for AM-2.1 step 2.
  • Step 1 Molecular sieves 4A (100 mg) are added to a RT soln. of 2-fluoro-4-methoxybenzaldehyde (1.25 g, 7.95 mmol) in nitromethane (16 mL), then butylamine (0.1 mL, 0.938 mmol) and acetic acid (0.01 mL, 1.62 mmol) are added and the mix. is heated to 90°C for 1 h. The RM is concentrated and the residue is partitioned between EtOAc and water. The org. layer is washed with water and brine and concentrated in vacuo.
  • Step 2 Boron trifluoride diethyl etherate (4.19 mL, 32.3 mmol) is added to a 0°C soln. of NaBFL (996 mg, 25.8 mmol) in THF (40 mL). The mix. is stirred at 0°C for 10 min, then at RT for 15 min before a soln. of 2-fluoro-4-methoxy-1-2- nitro-vinyl-benzene (1.06 g, 5.38 mmol) in THF (10 mL) is added dropwise and the mix. refluxed at 70°C for 3 h, then allowed to reach RT overnight.
  • the RM is cooled to 0°C before 2 N HCI (35 mL, 69.9 mmol) is added dropwise. After addition, the mix. is stirred at 0°C for 10 min, then at RT for 15 min, before the mix. is heated to 80°C for 1 h. The RM is cooled to RT and the org. solvent is evaporated, and the remaining aq. layer is cooled to 0°C, before being basified with 10% aq. NaOH. The product is extracted with EtOAc (3x), and the combined org. layers are washed with brine, dried (MgSCU), filtered, and concentrated.
  • 2 N HCI 35 mL, 69.9 mmol
  • Step 1 Ammonium acetate (179 mg, 2.28 mmol) is added to a RT soln. of 2,6-difluoro-4-methoxybenzaldehyde (1.0 g, 5.69 mmol) in nitromethane (7 mL) and the resulting mix. is refluxed for 40 min. The RM is evaporated and the residue partitioned between water and DCM. The aq. layer is extracted with DCM (2x) and the combined org.
  • Step 2 The title compound is prepared from 1,3-difluoro-5-methoxy-2-(2-nitro-vinyl)-benzene in analogy to the procedure described for AM-4.1 step 2.
  • Step 1 1,2-Difluoro-4-(2-nitro-vinyl)-benzene is prepared in analogy to the procedure described for AM-4.1, step 1.
  • LC-MS C: t R 0.75 min; No ionisation.
  • Step 2 Concentrated H2SO4 (0.710 mL) is added to a 0°C suspension of UAIH4 (1.06 g, 26.65 mmol) in THF (35 mL). After stirring for 20 min, a soln. of 1,2-difluoro-4-(2-nitro-vinyl)-benzene (1.10 g, 5.97 mmol) in THF (5 mL) is added dropwise and stirring is continued for 10 min before the cooling bath is removed and the RM is slowly heated to a gentle reflux. After 5 min, the mix. is cooled to 0°C and carefully hydrolised by dropwise addition of 'PrOH (4.4 mL), followed by 2 M aq. NaOH soln. (3.1 mL).
  • Step 1 In a Dean Stark Apparatus, pTsOH monohydrate (11.1 mg, 0.06 mmol) is added to a RT soln. of ethyl acetoacetate (1.46 mL, 11.4 mmol) and pyrrolidine (1.92 mL, 22.8 mmol) in PhMe (50 mL) and the resulting mix. is refluxed for 2 h. The volatiles are removed and 3-pyrrolidin-1 -yl-but-2-enoic acid ethyl ester (2.03 g, 97%) as an orange oil is used as such in the next step.
  • Step 2 A soln. of SO3 Pyridine complex (11 .0 g, 69.2 mmol) in DMSO (39.3 mL) is added dropwise to 0°C soln. of 3- (Boc-amino)-l -propanol (4.88 mL, 27.7 mmol) and DIPEA (14.2 mL, 083 mmol) in DCM (83.1 mL).
  • the RM is stirred at 0°C for 1 h, then at RT for 1 h.
  • the mix. is diluted with HCI and water, then extracted with DCM (3x). The combined org.
  • Step 3 A soln. of hydroxylamine hydrochloride (3.90 g, 0.06 mol) in H2O (25 mL) and a soln. of sodium acetate (9.20 g, 0.11 mol) in H2O (25 mL) are added to a vigorously stirred soln. of (3-oxo-propyl)-carbamic acid ferf-butyl ester (4.81 g, 0.028 mol) in EtOH (100 mL). The resulting suspension is stirred at RT for 18 h and then another 3 h at 50°C. The volatiles are removed, and the residue is partitioned between EtOAc and water. The layers are separated and the aq. layer is further extracted with EtOAc.
  • Step 4 NCS (2.23 g, 16.4 mmol) is added to a RT soln. of (3-hydroxyimino-propyl)-carbamic acid ferf-butyl ester (2.80 g, 14.9 mmol) in DCM (80 mL) and the resulting mix. is stirred at RT for 2 h. The mix. is evaporated and directly purified by FC (eluting with 50% EtOAc in hept) to give ferf-butyl (3-chloro-3-(hydroxyimino)propyl)carbamate (2.02 g, 61%) as an orange oil.
  • Step 5 A soln. of 3-pyrrolidin-1-yl-but-2-enoic acid ethyl ester (1.83 g, 10 mmol) in DCM (15 mL) followed by TEA (2.56 mL, 0.0181 mol) is added to a RT soln. of ferf-butyl (3-chloro-3-(hydroxyimino)propyl)carbamate (2.02 g, 9.07 mmol) in DCM (15 mL) and the resulting mix. is stirred for 15 min.
  • the RM is concentrated and the residue directly purified by FC (eluting with 50% EtOAc in hept) to yield 3-(2-ferf-butoxycarbonylamino-ethyl)-5-methyl-isoxazole-4- carboxylic acid ethyl ester (1 .60 g) still containing starting material, therefore the product is dissolved in DCM and washed with 2 M aq. HCI. The org. layer is washed with brine, dried (Na2S04), filtered, and concentrated to give 3-(2- ferf-butoxycarbonylamino-ethyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (1.25g, 46%) as slightly yellow oil.
  • Step 6 LAH (76 mg, 2.01 mmol) in Et20 (15 mL) is added dropwise to a 0°C soln. of 3-(2-ferf-butoxycarbonylamino- ethyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (500 mg, 1 .68 mmol) in Et20 (5 mL). After addition, the resulting mix. is warmed to RT and stirred for 1 .5 h. The mix. is cooled to 0°C and very carefully quenched with EtOAc followed by addition of a saturated aq. Rochelle's salt soln. The resulting mix.
  • Step 7 4 M HCI in dioxane (1 mL, 3.99 mmol) is added to a RT soln. of [2-(4-hydroxymethyl-5-methyl-isoxazol-3-yl)- ethylj-carbamic acid ferf-butyl ester (100 mg, 0.39 mmol) in dioxane (2 mL) and the resulting mix. is stirred at RT for 6 d. The mix. is concentrated to yield 2-(4-chloromethyl-5-methyl-isoxazol-3-yl)-ethylamine (HCI salt) (77 mg, 93%) as a colourless oil which is used as such in the next step.
  • HCI salt 2-(4-chloromethyl-5-methyl-isoxazol-3-yl)-ethylamine
  • Step 1 A soln. of DIAD (61.7 mL, 318 mmol) in THF (350 mL) is added dropwise to a 0°C soln. of but-3-yn-1 -ol (22.9 mL, 318 mmol), isoindoline-1 ,3-dione (44.5g, 302 mmol) and PPfi3 (83 g, 318 mmol) in THF (1500 mL) and the RM is stirred for 1 h. The RM is concentrated in vacuo and the residue is dissolved in hot PhMe (370 mL) before MeOH (210 mL) is slowly added. The RM is cooled to RT and MeOH is added until a white solid precipitates.
  • Step 2 Na2C03 (22.7 g, 214 mmol) is carefully added to a RT soln. of hydroxylamine.HCI (37.2 g, 535 mmol) in H2O (125 mL) followed by the slow addition of a soln. of cyclopropanecarbaldehyde (26.7 mL, 357 mmol) in EtOH (100 mL). The RM is stirred for 1 h and then partitioned between H2O and EtOAc and extracted. The layers are separated and the aq. phase is re-extracted with EtOAc (2x). The combined org.
  • Step 3 NCS (34.3 g, 257 mmol) is added portion wise to a 0°C soln. of cyclopropanecarbaldehyde oxime (19.3 g, 226 mmol) and pyridine (0.83 mL, 10.3 mmol) in DMF (100 mL) and the RM is stirred for 3 h.
  • a soln. of 2-(but-3-yn-1- yl)isoindoline-1 ,3-dione (21.0 g, 103 mmol) in DMF (100 mL) followed by TEA (28.7 mL, 206 mmol) are added and the RM is stirred for 3 h.
  • the RM is partitioned between H 2 0 and DCM and extracted. The layers are separated and the aq. phase is re-extracted with DCM (2x). The combined org. layers are washed with brine, dried over Na2S04, filtered and evaporated in vacuo to give the crude product that is triturated with MeOH to give 2-(2-(3- cyclopropylisoxazol-5-yl)ethyl)isoindoline-1 ,3-dione as a white solid.
  • Step 4 Hydrazine.
  • H2O (9.44 mL, 194 mmol) is added to a RT suspension of 2-(2-(3-cyclopropylisoxazol-5- yl)ethyl)isoindoline-1 ,3-dione (28.0 g, 97 mmol) in EtOH (100 mL) and the RM is heated to 80°C for 5 h. The RM is cooled to RT and filtered washing with EtOH. The filtrate is concentrated in vacuo and the residue is suspended in Et20 and re-filtered washing with Et20.
  • Step 1 Imidazole (1.94 g, 28.5 mmol) is added to a RT soln. of but-3-yn-1-ol (1.0 mL, 14.3 mmol) in THF (25 mL) followed by TBDMSCI (2.58 g, 17.1 mmol) and the RM is stirred for 16 h. 'Pr20 (25 mL) is added and the precipitate is filtered and washed with additional 'Pr20. The filtrate is washed with sat. aq.
  • Step 3 Hydroxylamine hydrochloride (0.71 g, 10.2 mmol) followed by CuO (121 mg, 0.85 mmol) are added to a RT soln. of 6-((tert-butyldimethylsilyl)oxy)-1,1-difluorohex-3-yn-2-one (2.22 g, 8.5 mmol) in THF (20 mL) and the RM is stirred for 16 h. NaHCO 3 (0.85 g, 10.2 mmol) is added and the RM is stirred for 1 h before the RM is filtered over a short pad of silica gel (eluting with 1:1 Et 2 O:THF) to give a mix.
  • Step 4 TBAF (1.0 M in THF, 6.0 mL, 6.0 mmol) is added to a RT soln.
  • Step 6 Hydrazine.H 2 O (380 ⁇ L, 0.77 mmol) is added to a RT suspension of 2-(2-(3-(difluoromethyl)isoxazol-5- yl)ethyl)isoindoline-1,3-dione (113 mg, 0.39 mmol) in EtOH (4 mL) and the RM is heated to 80°C for 2 h. The RM is cooled to RT and filtered washing with EtOH. The filtrate is concentrated in vacuo and the residue is suspended in Et 2 O and re-filtered washing with Et 2 O. The filtrate is concentrated in vacuo to give the title compound as a white solid.
  • Step 1 NaHC03 (1.55 g, 18.4 mmol), followed by hydroxylamine hydrochloride (1.29 g, 18.4 mmol) are added to a RT soln. of 3-methoxybenzonitrile (1 .0 g, 7.36 mmol) in MeOH (15 mL) and the resulting white suspension is refluxed (70°C) overnight. The mix. is concentrated and the residue is diluted with EtOAc and washed with brine, dried (MgSO ⁇ , filtered, and concentrated to yield A/-hydroxy-3-methoxy-benzamidine (1.67 g, 137%) as a yellow oil which is used as such in the next step.
  • Step 2 TBTU (3.49 g, 10.9 mmol) is added to a 0°C soln. of Boc-beta-ala-OH (1.73 g, 9.06 mmol), A/-hydroxy-3- methoxy-benzamidine (1 .67 g, 9.06 mmol) and DIPEA (4.65 mL, 27.2 mmol) in DCM (45 mL). The ice bath is removed and the mix. is stirred at RT for 18 h.
  • the RM is concentrated and the residue is partitioned between EtOAc (50 mL) and water (50 mL) and the resulting solid is filtered off to yield the intermediate (2- ⁇ [[hydroxyimino]-(3-methoxy-phenyl)- methyl]-carbamoyl ⁇ -ethyl)-carbamic acid ferf-butyl ester (1.856 g, 61%).
  • dioxane 50 mL
  • the RM is refluxed (90°C) for 24 h. The mix.
  • Step 3 TFA (4.59 mL,60 mmol) is added to a RT soln. of ⁇ 2-[3-(3-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl ⁇ - carbamic acid ferf-butyl ester (1.915 g, 6.0 mmol) in DCM (40 mL) and the mix. is stirred at RT for 1 d. The mix. is neutralised with a saturated aq. soln. of NaHC03 (50 mL), then DCM (50mL) is added. The two layers are separated and the aq. layer is extracted with DCM (50 mL). The combined org. layers are dried (MgSO ⁇ , filtered, and concentrated to yield AM-7.1 (1.14 g, 86%) as a yellow oil.
  • Steps 1&2 The title compound is prepared from 3,2-trifluoromethoxy-benzonitrile following the synthesis described for AM-7.1, steps 1&2 to yield ⁇ 2-[3-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl ⁇ -carbamic acid ferf-butyl ester.
  • Step 3 4 M HCI in dioxane (6 mL) is added to a RT soln.
  • Step 1 K2CO3 (487 mg, 3.53 mmol) is added to a RT soln. of ferf-butyl A/-(2-cyanoethyl)carbamate (1.20 g, 7.05 mmol) and 2-(trifluoromethoxy)benzoic acid hydrazide (1.55 g, 7.05 mmol) in n-butanol (50 mL) and the resulting suspension is heated to 120°C for 6.5 h, then stirred at RT overnight, and re-heated to 120°C for another 4.5 h. The mix. is concentrated, and the residue is diluted with DCM and acidified with 1 N HCI. The two layers are separated and the aq. layer is extracted with DCM.
  • Step 2 4 M HCI in dioxane (30 mL, 30 mmol) is added dropwise to a 0°C soln. of ⁇ 2-[5-(2-trifluoromethoxy-phenyl)- 4H-[1,2,4]triazol-3-yl]-ethyl ⁇ -carbamic acid ferf-butyl ester (678 mg, 1.82 mmol) in DCM (20 mL).
  • the resulting RM is stirred at RT for 2 h, then the RM is concentrated to yield AM-8.1 (515 mg, 104%) as a yellow oil, which is used as such in the next step.
  • Step 1 1 H-1 ,2,3-T riazole (5.0 g, 0.072 mmol) is diluted with water (35 mL) and heated to 50°C before Br2 (23.1 g, 0.145 mmol) is added dropwise (exothermic). The oil bath is replaced with a water bath to keep the internal temperature below 50°C. After 15 min the resulting orange suspension is quenched with 2 M aq. NaOH (5 mL) and 40% sodium bisulfite soln. (2 mL). A 32% aq. NaOH soln. is then added until pH 7 followed by additional 40% sodium bisulfite soln. (10 mL). Due to the exotherm the suspension is cooled to RT before it is filtered. The cake is rinsed with water (3 x 10 mL) and the filtrate is concentrated to yield 4,5-dibromo-2/-/-[1,2,3]triazole (14.86 g, 90%) as a slightly yellowish solid.
  • Step 2 K2CO3 (3.96 g, 28.6 mmol) and 4,5-dibromo-2H-[1,2,3]triazole (6.50 g, 28.6 mmol) are added to a RT soln. of 2-fluoro-5-nitroanisole (5.00 g, 28.6 mmol) in DMF (40 mL) and the mix. is stirred at 45°C for 3 d. The mix.
  • Step 3 Pd(OH)2 (20%, 1.04 g, 1.96 mmol) is added to a RT soln. (degassed) of 4,5-dibromo-2-(2-methoxy-4-nitro- phenyl)-2H-[1,2,3]triazole (7.4 g, 0.020 mol) in MeOH (70 mL) and the resulting mix. is stirred at RT for 2 h under a H2 atm. The mix. is filtered over celite which is then copiously washed with MeOH. The filtrate is concentrated and purified by FC (eluting first with EtOAc/hept, then with 100% EtOAc and eventually with 10% MeOH in DCM.
  • FC eluting first with EtOAc/hept, then with 100% EtOAc and eventually with 10% MeOH in DCM.
  • Step 5&6 The title compound is prepared from 2-(4-bromo-2-methoxyphenyl)-2H-1, 2, 3-triazole following the 2- step sequence described for AM-2.1.
  • Step 1 K2CO32 M in water (2 mL) is added to a RT soln. of 4-(2-nitroethyl)phenylboronic acid (200 mg, 1.03 mmol) and 2-bromopyrazine (168 mg, 1.03 mmol) in dioxane (8 mL).
  • the soln. is degassed for 2 min with argon, then Pd(PPh3)4 (35.6 mg, 0.0308 mmol) is added and the mix. heated to 80°C for 18 h.
  • To the mix. is added water and EtOAc.
  • the layers are separated and the aq. layer is re-extracted with EtOAc.
  • the combined org. layers are dried (MgS04), filtered, and concentrated.
  • Step 2 Pd/C (10%, 13.5 mg, 0.019 mmol) is added to a RT soln. of 2-[4-(2-nitro-ethyl)-phenyl]-pyrazine (88 mg, 0.384 mmol) in EtOH/THF and the mix. is stirred at RT for 18 h under a H2 atm. The mix. is filtered and concentrated. Purification by prep. HPLC (basic) gives AM-10.1 (65 mg, 85%) as a yellow solid.
  • Step 1 NBS (8.89 g, 50 mmol) is added portionwise to a RT soln. of 2,3-dihydro-1,4-benzodioxin-6-ol (8.0 g, 50 mmol) in DMF (80 mL) and the mix. is stirred for 2 h, before additional NBS (3.0 g) is added and the mix. is stirred for another 30 min. The mix. is diluted with water and extracted with EtOAc (3x). The combined org. extracts are washed with water (2x), brine, dried over a phase separator and concentrated.
  • Step 2 Mel (3.26 mL, 51.8 mmol) is added to a RT soln. of 7-bromo-2,3-dihydro-benzo[1,4]dioxin-6-ol (5.981 g, 25.9 mmol) and CS2CO3 (10.12 g, 31.1 mmol) in DMF (60 mL) and the mix. is stirred for 1.5 h. The mix. is diluted with water and extracted with Et20 (3x). The combined org. layers are washed with water, brine, dried over a phase separator, and concentrated.
  • Step 1 1,2-Dibromoethane (8.85 mL, 101 mmol) is added to a RT soln. of 3-methylcatechol (5.0 g, 40.3 mmol) and K 2 CO 3 (22.27 g, 161 mmol) in DMF (70 mL) and the resulting mix. is stirred for 18 h. The mix. is diluted with water and the extracted with Et20 (3x). The combined org. layers are washed with water and brine, dried over a phase separator, and concentrated.
  • Step 2 NBS (3.39 g, 19.1 mmol) is added portionwise to 0°C soln. of 5-methyl-2,3-dihydro-benzo[1,4]dioxine (2.864 g, 19.1 mmol) in THF (60 mL) and the RM is stirred at RT for 18 h. To the mix. is added NBS (286 mg) and stirring is continued for another 30 min. The mix. is diluted with water and extracted with EtOAc (3x). The combined org. extracts are washed with water (2x), brine, dried over a phase separator, and concentrated.
  • Step 3 [2-(5-Methyl-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-ethyl]-carbamic acid ferf-butyl ester is prepared from 6-bromo- 5-methyl-2,3-dihydro-benzo[1,4]dioxine following the reaction described for AM-2.1, step 1.
  • LC-MS B: tR 0.95 min; No ionisation.
  • Step 4 NCS (307 mg, 2.25 mmol) is added portionwise to a RT soln. of [2-(5-methy I-2, 3-d i hyd ro-ben zo[ 1 , 4]d i oxi n-6- yl)-ethyl]-carbamic acid ferf-butyl ester (600 mg, 2.05 mmol) in DMF (10 mL) and the mix. is heated to 50°C for 18 h. The mixute is diluted with water and extracted with EtOAc (3x). The combined org. extracts are washed with water, brine, dried over a phase separator, and concentrated.
  • Step 5 The title compound is prepared from [2-(7-chloro-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-carbamic acid ferf-butyl ester following the reaction described for AM-2.1, step 2.
  • Step 1 DPPA (1.32 mL, 6.1 mmol) is added dropwise to a RT soln. of 3-(3-methoxyisoxazol-5-yl)propanoic acid (1.0 g, 5.55 mmol) and TEA (0.93 mL, 6.66 mmol) in PhMe (25 mL) and the RM is heated to 100°C for 1.5 h.
  • 2- Methylpropan-2-ol (1.06 mL, 11.1 mmol) is added and the RM is heated to reflux for 16 h.
  • the RM is cooled to RT and partitioned between sat. aq. NaFICOa and EtOAc and the layers are separated. The aq.
  • Step 2 The title compound is prepared from ferf-butyl (2-(3-methoxyisoxazol-5-yl)ethyl)carbamate in analogy to the procedure described for AM-2.1 step 2.
  • Step 1 H2SO4 (136 m ⁇ , 2.55 mmol) is added to a RT soln. of pent-4-ynoic acid (5.0 g, 51 mmol) in EtOH (50 mL) and the RM is heated to 70°C for 2 h. The RM is partitioned between water and EtOAc and the layers are separated. The org. phase is washed with H2O (2x) before a soln. of KFICO3 (10.21 g, 102 mmol) in H2O (25 mL) is added followed by the dropwise addition of a soln. of hydroxycarbonimidic dibromide (10.34 g, 51 mmol) in EtOAc (200 mL).
  • the RM is stirred at RT for 48 h and then washed with H2O, brine, dried over Na2S04, filtered and evaporated in vacuo.
  • the crude product is purified by FC (eluting with 1% to 15% EtOAc in hept) to give ethyl 3-(3-bromoisoxazol-5- yl)propanoate as a white solid.
  • Step 2 Na (1.15 g, 50 mmol) is added portionwise to methanol-d3 (11.53 mL, 285 mmol) in an ice bath and when all solids are dissolved, ethyl 3-(3-bromoisoxazol-5-yl)propanoate (1.0 g, 4.0 mmol) is added and the resulting soln. is irradiated in a MW oven at 110°C for 75 min. The RM is diluted with H2O and then poured into 2M HCI (35 mL) and extracted with EtOAc (3x). The combined org. extracts are washed with brine, dried over Na2S04, filtered and evaporated in vacuo.
  • Steps 3-4 The title compound is prepared from 3-(3-(methoxy-d3)isoxazol-5-yl)propanoic acid in analogy to the procedure described for AM-13.1.
  • Step 1 A mix. of carbamic acid, A/-[2-(4-bromo-1 H-pyrazol-1 -yljethyl]-, 1 , 1 -dimethylethyl ester (300 mg, 1.03 mmol) and trans-3-methoxy-1-propenylboronic acid pinacol ester (0.71 mL, 1.07 mmol) in dioxane (3 mL) and H2O (3 mL) is degassed with Ar for 10 min before CS2CO3 (1.18 g, 3.62 mmol) and Pd(dppf)Cl2.DCM (25.3 mg, 0.03 mmol) are added.
  • the RM is degassed with Ar for a further 2 min and then irradiated in a MW oven at 90°C for 20 min (cooling function on). After cooling to RT the RM is partitioned between water and DCM and extracted. The layers are separated, and the aq. phase is re-extracted with DCM (2x). The combined org. extracts are washed with brine, dried (Mg2S04), filtered and evaporated in vacuo. The crude product is purified by prep.
  • Step 2 Pd/C (10%, 34 mg, 0.032 mmol) is added to a RT soln. of ferf-butyl (2-(4-(3-methoxyprop-1 -en-1 -yl)-1 H- pyrazol-1 -yl)ethyl)carbamate (180 mg, 0.64 mmol) in MeOFI and the mix. is stirred at RT for 1 h under a H2 atm. The mix. is filtered and concentrated to yield ferf-butyl (2-(4-(3-methoxypropyl)-1 H-pyrazol-1 -yl)ethyl)carbamate (180 mg, 99%) as a colourless oil.
  • Step 1 A mix. of carbamic acid, N-[2-(4-bromo-1 H-pyrazol-1 -yl)ethyl]-, 1 , 1 -dimethylethyl ester (500 mg, 1.72 mmol) and cyclopropylboronic acid (459 mg, 5.34 mmol) in THF (10 mL) is degassed with Arfor 10 min before CS2CO3 (1.97 g, 6.03 mmol) and Pd(dppf)Cl2.DCM (42.2 mg, 0.052 mmol) are added. The RM is degassed with Ar for a further 2 min and then irradiated in a MW oven at 70°C for 30 min (cooling function on).
  • Step 2 5 M HCI in 'PrOH (2.3 mL, 11.5 mmol) is added to ferf-butyl (2-(4-cyclopropyl-1 H-pyrazol-1 -yl)ethyl)carbamate (580 mg, 2.31 mmol) at RT and the RM is stirred for 30 min. The RM is concentrated in vacuo to yield the title compound AM-15.1 (157 mg, 99%) as a colourless oil.
  • Step 1 ferf-Butyl A/-(2-bromoethyl)carbamate (1.61 g, 7.06 mmol) is added to a RT suspension of 4-methoxy-1H- pyrazole hydrochloride (1.00 g, 7.06 mmol) and Cs2C03 (6.97 g, 21.2 mmol) in MeCN (16.3 mL) and the RM is heated to 80°C for 18 h. The RM is allowed to reach RT, then it is filtered and the filter cake rinsed with DCM.
  • Step 2 4 M HCI in dioxane (13.8 mL, 55.3 mmol) is added to a0°C suspension of ferf-butyl (2-(4-methoxy-1H-pyrazol-
  • Step 1 ferf-Butyl (3-bromophenethyl)carbamate is prepared from 2-(3-bromophenyl)ethan-1 -amine in analogy to the procedure described for AM-3.1 step 1.
  • Step 2 A degassed mix. of ferf-butyl (3-bromophenethyl)carbamate (10.51 g, 35 mmol), trimethylsilylacetylene (14.8 mL, 105 mmol), XPhos Pd G2 (1.38 g, 1.75 mmol) and TEA (14.6 mL, 105 mmol) in DMF (120 mL) is stirred at 60°C for 18 h. The RM is partitioned between water and Et 2 O and the layers are separated. The aq. phase is re-extracted with Et 2 O (2x) and the combined org. extracts are washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo.
  • Step 3 4 M HCl in dioxane (0.62 mL, 2.47 mmol) is added to a RT solution of tert-butyl (2-(3-methoxy-1,2,4-oxadiazol- 5-yl)ethyl)carbamate (150 mg, 0.62 mmol) in DCM (2 mL) and the RM is stirred for 4 days at RT, then at 50°C for 6 h. The mixture is evaporated to yield the title compound A-18.1 (79 mg, 71%) as a white solid.
  • Step 2 4 M HCl in dioxane (4.9 mL, 19.6 mmol) is added to a RT solution of tert-butyl (2-(4-cyclopropyl-2H-1,2,3- triazol-2-yl)ethyl)carbamate (550 mg, 1.96 mmol) in DCM (3.4 mL).
  • the RM is stirred at RT for 30 min, then the RM is concentrated to give title compound AM-19.1 (432 mg, 98%) as a white solid which is used as such in the next step.
  • Step 2 KMnO 4 (401 mg, 1.0 mmol) is added to a RT soln. of tert-butyl (2-(4-vinyl-2H-1,2,3-triazol-2-yl)ethyl)carbamate (118 mg, 0.50 mmol) in a 1:1 mix. of water:acetone (6 mL) and the RM is stirred for 18 h. The RM is filtered and evaporated in vacuo and the crude product is purified by prep. HPLC (acidic) to give 2-(2-((tert- butoxycarbonyl)amino)ethyl)-2H-1,2,3-triazole-4-carboxylic acid as a white solid.
  • the RM is poured into water, diluted with DCM and extracted. The layers are separated and the aq. phase is re-extracted with DCM (2x). The combined org. extracts are washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The crude product is purified by prep. HPLC (acidic) to give tert-butyl (2-(4-cyano-2H-1,2,3-triazol-2-yl)ethyl)carbamate as a colourless oil.
  • Step 5 The title compound is prepared from tert-butyl (2-(4-cyano-2H-1,2,3-triazol-2-yl)ethyl)carbamate in analogy to the procedure described for AM-17.1 step 3.
  • Step 1 NaH 60% dispersion in mineral oil (1.48 g, 37 mmol) is added portionwise to a 0°C soln.
  • Step 2 ZnMe2 (2 M in PhMe, 0.50 mL, 1.0 mmol) is added dropwise to a RT soln. of 2-(2-(4,5-dibromo-2H-1,2,3- triazol-2-yl)ethyl)isoindoline-1 ,3-dione (500 mg, 1.25 mmol), and Pd(dppf)Cl2.DCM (10 mg, 0.013 mmol) in dioxane (2 mL) and the RM is heated to 70°C and stirred for 3 h. The RM is concentrated in vacuo and the residue is partitioned between water and EtOAc and extracted. The layers are separated, and the aq.
  • Step 3 A degassed mix. of 2-(2-(4-bromo-5-methyl-2H-1, 2, 3-triazol-2-yl)ethyl)isoindoline-1 ,3-dione (85 mg, 0.25 mmol), (tert-butyldimethylsilyl)acetylene (73 mg, 0.51 mmol), XPhos Pd G2 (20 mg, 0.03 mmol) and KOAc (75 mg, 0.76 mmol) in DMF (2 mL) is stirred at70°C for30 min. The RM is filtered through a Whatman filter and directly purified by prep.
  • Step 4 Hydrazine monohydrate (0.18 mL, 2.43 mmol) is added to a RT solution of 2-(2-(4-((tert- butyldimethylsilyl)ethynyl)-5-methyl-2H-1, 2, 3-triazol-2-yl)ethyl)isoindoline-1 ,3-dione (32 mg, 0.08 mmol) in EtOH (1 mL) and the RM is heated to reflux for 2.5 h. The RM is cooled to RT and MeCN is added. The resulting suspension is filtered and the filter cake is discarded.
  • Step 5 1 M aq. NaOH (0.25 mL, 0.25 mmol) is added to a RT soln. of 2-(4-((tert-butyldimethylsilyl)ethynyl)-5-methyl- 2H-1 ,2,3-triazol-2-yl)ethan-1 -amine (26 mg, 0.1 mmol) in EtOH (0.75 mL) and the RM is heated to 60°C for 3 h. The RM is concentrated before water and DCM are added. The layers are separated and the aq. phase is extracted with DCM (1x). The combined org. layers are dried over a phase separator and concentrated in vacuo to give the title compound as a yellow oil.
  • Step 1 In a microwave tube, phthalic anhydride (354 mg, 2.36 mmol) is added to a RT suspension of AM-13.1 (402 mg, 2.25 mmol) and DIPEA (0.47 mL, 2.7 mmol) in dioxane (12 mL). The tube is sealed and heated to 100°C for 48 h. Water is added to the RM, the mixture is acidified with 1 M HCI and the product extracted with EtOAc, dried (MgSO ⁇ , filtered, and concentrated to yield 2-(2-(3-methoxyisoxazol-5-yl)ethyl)isoindoline-1 ,3-dione (718 mg) as a white solid which was used as such in the next step.
  • Step 2 Selectfluor (1.07 g, 2.87 mmol) is added to a 40°C solution of 2-(2-(3-methoxyisoxazol-5-yl)ethyl)isoindoline- 1 ,3-dione (710 mg, 2.61 mmol) in tetramethylene sulfone (21.7 mL, 226 mmol) and the RM is heated to 120°C for 18 h. The resulting dark brown solution is allowed to cool down to around 50°C, then the RM is poured into pre-stirred H2O (30 mL), followed by EtOAc (10 mL). The two layers are separated and the inorg. layer is extracted with EtOAc (5 mL). The comb.
  • Step 3 Hydrazine monohydrate (0.222 mL, 2.93 mmol) is added to a RT solution of 2-(2-(4-fluoro-3-methoxyisoxazol- 5-yl)ethyl)isoindoline-1 ,3-dione (85 mg, 0.293 mmol) in EtOH (3 mL) and the RM is heated to 80°C for 1 h. The RM is cooled down to RT and a white precipitate is formed. Ether is added and the solid (sideproduct) is triturated before filtered off. The filtrate is concentrated to yield title compound AM-20.1 (40 mg, 85%) as a colorless oil which was used as such in the next step.
  • Step 1 HATU (4.53 g, 11.9 mmol) is added to a RT soln. of Fmoc-L-aspartic acid beta-ferf-butyl ester (5.0 g, 11.9 mmol), 3-methoxyphenethylamine (AM-1.4, 2.0 g, 13.1 mmol) and DIPEA (4.08 mL, 23.8 mmol) in DMF (40 mL) and the RM is stirred for 1 h. The RM is partitioned between water and EtOAc and the layers are separated. The aq. phase is re-extracted with EtOAc (2x) and the combined org.
  • Fmoc-L-aspartic acid beta-ferf-butyl ester 5.0 g, 11.9 mmol
  • 3-methoxyphenethylamine AM-1.4, 2.0 g, 13.1 mmol
  • DIPEA 4.08 mL, 23.8 mmol
  • Step 2 Piperidine (4.95 mL, 49.5 mmol) is added to a RT soln. of ferf-butyl (S)-3-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-4-((3-methoxyphenethyl)amino)-4-oxobutanoate (5.45 g, 9.9 mmol) in DCM (60 mL) and the RM is stirred for 2 h. The RM is concentrated in vacuo and the residue directly purified by FC (eluting with 100:2:0.5 DCM:MeOH:NH3) to give the title compound as a colourless oil.
  • Table A-1 Listed in Table A-1 below are building blocks A that are prepared in analogy to the 2-step sequence described above for A-1.1.
  • Step 1 Benzyl bromide (2.15 mL, 17.7 mmol) is added to a RT mix. of Boc-L-aspartic acid-beta-allyl ester (5.0 g, 17.7 mmol) and KHCO3 (1 .8 g, 17.7 mmol) in DMF (30 mL) and the RM is stirred for 16 h. The RM is concentrated in vacuo and the residue is partitioned between H2O and EtOAC and extracted. The layers are separated and the aq. phase is re-extracted with EtOAc (2x). The combined org.
  • Step 1 Allyl (S)-4-((2-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-((ferf-butoxycarbonyl)amino)-4-oxobutanoate is prepared from (S)-4-(allyloxy)-2-((ferf-butoxycarbonyl)amino)-4-oxobutanoic acid in analogy to the procedure described for A-1.1 step 1 .
  • Step 2 The title compound is prepared from (S)-4-(allyloxy)-2-((ferf-butoxycarbonyl)amino)-4-oxobutanoic acid in analogy to the procedure described for A-2.1 step 2.
  • Table A-2 Listed in Table A-2 below are building blocks A that are prepared in analogy to the 2-step sequence described above for A-2.2.
  • Step 1 KHCO3 (1.6 g, 15.8 mmol) and benzyl bromide (2.1 mL, 17.3 mmol) are added to a soln. of 2-hydroxy-4,6- dimethoxybenzoic acid (3 g, 14.4 mmol) in DMF (40 mL) and the RM is stirred for 16 h. The RM is filtered and the filtrate concentrated in vacuo. The residue is partitioned between water and EtOAc and extracted. The layers are separated, and the aq. phase is re-extracted with EtOAc (2x). The combined org. extracts are washed with brine, dried over Na2S04, filtered and evaporated in vacuo.
  • Step 2 DIAD (3.0 mL, 15 mmol) is added to a 0°C mix. of 2-hydroxy-4,6-dimethoxybenzoate (3.16 g, 10.7 mmol), ferf-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate (4.12 g, 16.1 mmol), and PPti3 (4.27 g, 16.1 mmol) in THF (40 mL) and the RM is stirred for 16 h at RT. The mix.
  • Step 3 4M HCI in dioxane (21 mL, 86.3 mmol) is added to a soln. of benzyl (R)-2-(2-((ferf-butoxycarbonyl)amino)-3- phenylpropoxy)-4,6-dimethoxybenzoate (4.64 g, 8.63 mmol) in dioxane (40 mL) and the RM is stirred for 5 h at RT. The volatiles are removed in vacuo and the residue is triturated with Et20 (3x) to give the title compound as a white solid.
  • Table B-1 Listed in Table B-1 below are building blocks B that are prepared in analogy to the 3-step sequence described above for B-1 .1.
  • the amine is subjected to a basic workup to liberate its free base.
  • Step 1 Benzyl bromide (0.92 mL, 7.6 mmol) is added to a RT mix. of 2,6-dihydroxybenzoic acid (1 .0 g. 6.3 mmol) and NaHCCh (582 mg, 6.9 mmol) in DMF (16 mL) and the RM is heated to 60°C for 6 h. The RM is partitioned between water and EtOAc and extracted. The layers are separated, and the aq. phase is re-extracted with EtOAc (2x). The combined org. extracts are washed with brine, dried over Na2S04, filtered and evaporated in vacuo.
  • Steps 3-4 The title compound is prepared from benzyl 2-ethoxy-6-hydroxybenzoate following steps 2&3 described for B-1.1.
  • Step 1 CDI (615 mg, 3.8 mmol) is added to a soln. of 4-hydroxy-2-methoxynicotinic acid (452 mg, 2.7 mmol) in DMF (5 mL) and the RM is heated to 60°C for 2 h. After cooling to 0°C, additional DMF (5 mL), benzyl alcohol (0.5 mL, 4.8 mmol), and NaH (118 mg, 2.95 mmol) are added and the RM is warmed to RT and stirred for 16 h. The RM is partitioned between 1 N HCI and DCM and the layers are separated. The aq. phase is re-extracted with DCM (1x) and the combined org.
  • Step 2 Benzyl (R)-4-(2-((ferf-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxynicotinate is prepared from benzyl 4-hydroxy-2-methoxynicotinate and ferf-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B-1.1 step 2.
  • Step 3 TFA (3.65 mL, 4.77 mmol) is added to a 0°C soln. of benzyl (R)-4-(2-((ferf-butoxycarbonyl)amino)-3- phenylpropoxy)-2-methoxynicotinate (235 mg, 0.48 mmol) in DCM (6 mL) and the RM is warmed to RT and stirred for 3 h. The RM is concentrated in vacuo and the residue partitioned between DCM and sat. aq. NaFICOa and the layers are separated. The aq. phase is re-extracted with DCM (1x) and the combined org. layers are washed with brine, dried over Na2S04, filtered and evaporated in vacuo to give the title compound as a yellow oil.
  • Step 1 Benzyl 2-hydroxy-1-naphthoate is prepared from 2-hydroxy-1 -naphthoic acid in analogy to the procedure described for B-1.1 step 1 .
  • Step 2 (R)-2-((ferf-Butoxycarbonyl)amino)-3-(pyridin-2-yl)propanoic acid (500 mg, 1.8 mmol) is added to a 0°C suspension of LAH (85 mg, 2.2 mmol) in Et20 (13 mL) and the RM is warmed to RT and stirred for 1 h. The RM is cooled to 0°C and quenched with EtOAc before a sat. aq. Rochelle’s salt soln. is added and vigorous stirring is maintained for 30 min after which the layers are separated. The aq. phase is re-extracted with EtOAc (3x) and the combined org.
  • Step 4 A soln. of benzyl (R)-2-(2-((ferf-butoxycarbonyl)amino)-3-(pyridin-2-yl)propoxy)-1-naphthoate (108 mg, 0.17 mmol) in MeOH (3 mL) is evacuated/purged with N2 (3x) before 10% Pd/C (18 mg, 10 mol%) is added. The RM is evacuated/purged with H2 (3x) and stirred under a H2 atm for 2 h. The RM is filtered through a pad of celite and the filtrate concentrated in vacuo to give the title compound as a white solid.
  • Step 1 A soln. of TMS-diazomethane (2 M in Et20, 0.6 mL, 1.2 mmol) is added to a 0°C soln. of (R)-3- (benzo[b]thiophen-3-yl)-2-((ferf-butoxycarbonyl)amino)propanoic acid (128 mg, 0.4 mmol) in MeOH (2 mL) and the RM is warmed to RT and stirred for 2 h. The RM is subsequently purified by prep.
  • Step 2 NaBH4 (30 mg, 0.78 mmol) is added to a 0°C mix. of methyl (R)-3-(benzo[b]thiophen-3-yl)-2-((ferf- butoxycarbonyl)amino)propanoate (130 mg, 0.39 mmol) in EtOH (1 mL) and H2O (1 mL) and the RM is warmed to RT and stirred for 16 h. The RM is subsequently purified by prep. HPLC (basic) to furnish ferf-butyl (R)-(1- (benzo[b]thiophen-3-yl)-3-hydroxypropan-2-yl)carbamate as a colourless oil.
  • Step 3 Benzyl 3-hydroxyquinoline-4-carboxylate is prepared from 3-hydroxyquinoline-4-carboxylic acid in analogy to the procedure described for B-1 .1 step 1.
  • Step 4 Benzyl (R)-3-(3-(benzo[b]thiophen-3-yl)-2-((ferf-butoxycarbonyl)amino)propoxy)quinoline-4-carboxylate is prepared from the products of steps 2&3 above in analogy to the procedure described for B-1 .1 step 2.
  • Step 5 UOH.H2O (20 mg, 0.48 mmol) is added to a mix. of benzyl (R)-3-(3-(benzo[b]thiophen-3-yl)-2-((ferf- butoxycarbonyl)amino)propoxy)quinoline-4-carboxylate (136 mg, 0.24 mmol) in 2:1 THF:H20 (3 mL) and the RM is heated to 50°C for 16 h. The RM is concentrated in vacuo and the residue is partitioned between 1M aq. HCI and EtOAc and extracted. The layers are separated, and the aq. phase is re-extracted with EtOAc (2x). The combined org. extracts are washed with brine, dried over Na2S04, filtered and evaporated in vacuo to give the title compound as a yellow solid.
  • Step 1 4-Fluoroindoline-2,3-dione (4.8 g, 27.6 mmol) is added to a RT soln. of KOH (18.6 g, 331 mmol) in water (80 mL) followed by bromopyruvic acid (6.47 g, 38 mmol) and the RM is stirred for 16 h. Additional KOH (4.6 g, 83 mmol) and bromopyruvic acid (2.88 g, 17.3 mmol) are added and stirring is continued for another 16 h. The RM is poured into 1 M aq.
  • Step 1 Methyl (R)-2-(2-((ferf-butoxycarbonyl)amino)-3-phenylpropoxy)-6-fluorobenzoate is prepared from methyl 2- fluoro-6-hydroxybenzoate and ferf-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B-1.1 step 2.
  • Table B-2 Listed in Table B-2 below are building blocks B that are prepared in analogy to the 2-step sequence described above for B-2.1.
  • the amine is subjected to a basic workup to liberate its free base.
  • Step 2 4M HCl in dioxane (1.45 mL, 5.8 mmol) is added to a suspension of methyl 2,6-dihydroxy-3-nitrobenzoate (500 mg, 2.3 mmol) in triethyl ortho acetate (13.5 mL, 72 mmol) and the RM is evacuated/purged with N2 (3x) before 10% Pd/C (173 mg, 7 mol%) is added.
  • the RM is evacuated/purged with H 2 (3x) and stirred under a H 2 atm for 16 h.
  • Step 1 Methylamine (2 M in MeOH, 7.9 mL, 15.8 mmol) is added to a RT soln. of methyl 2,6-difluoro-3-nitrobenzoate (5.0 g, 22.6 mmol) in MeOH (40 mL) and the RM is stirred for 1 h. The RM is concentrated in vacuo and the residue suspended in a mix. of i PrOH and water before being filtered.
  • Ethyl (R)-2-(2-amino-3-phenylpropoxy)imidazo[1,2-a]pyridine-3-carboxylate dihydrochloride (B-2.10) Step 1: 2-Aminopyridine (7.08 g, 75 mmol) is suspended in diethyl bromomalonate (38.5 mL, 226 mmol) and heated to 100 °C for 1.5 h. The RM is partitioned between water and EtOAc and the layers are separated. The org. phase is discarded and the aq. phase is freeze dried to give the crude product that is purified by prep. HPLC (basic) to give ethyl 2-hydroxyimidazo[1,2-a]pyridine-3-carboxylate as a cream solid.
  • Steps 1-2 A suspension of methyl 2,5-dihydroxybenzoate (1.02 g, 6.1 mmol) and MgSO 4 (2.1 g, 17.5 mmol) in Et 2 O (10 mL) is purged with argon for 10 min before Ag 2 O (3.46 g, 14.9 mmol) is added and the RM is stirred for 16 h.
  • the RM is filtered over a pad of celite and the filtrate is concentrated in vacuo to give the crude poduct methyl 3,6- dioxocyclohexa-1,4-diene-1-carboxylate that is re-dissolved in PhMe (50 mL) before n-butyl vinyl ether (1.7 mL, 13.1 mmol) is added and the RM is heated to 45°C for 19 h.
  • the RM is poured into water and the phases are separated. The aq. phase is extracted with EtOAc (3x) and the combined org. phases are washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo.
  • Step 4 A soln. of methyl 5-hydroxybenzofuran-4-carboxylate (395 mg, 2.06 mmol) and AcOH (1 .3 mL, 22.5 mmol) in EtOAc (20 mL) is evacuated/purged with N2 (3x) before 10% Pd/C (109 mg, 5 mol%) is added.
  • the RM is evacuated/purged with H2 (3x) and stirred under a H2 atm for 21 h.
  • the RM is filtered through a pad of celite and the filtrate concentrated in vacuo to give methyl 6-hydroxy-2-methylbenzo[d]oxazole-7-carboxylate as a white solid.
  • Steps 5-6 The title compound is prepared from methyl 5-hydroxy-2,3-dihydrobenzofuran-4-carboxylate in analogy to the procedure described for B-2.1.
  • Step 1 Cs2C03 (2.4 g, 7.4 mmol) and BnBr (1 .31 mL, 11.1 mmol) are added to a RT soln. of methyl 3-hydroxypicolinate (0.94 g, 6.1 mmol) in DMF (20 mL) and the RM is heated to 70°C for 2 h. The RM is concentrated in vacuo and the residue is partitioned between water and EtOAc and extracted. The layers are separated, and the aq. phase is reextracted with EtOAc (2x). The combined org. extracts are washed with brine, dried over Na2S04, filtered and evaporated in vacuo.
  • Step 2 mCPBA (1.51 g, 6.1 mmol) is added to a 0°C soln. of methyl 3-(benzyloxy)picolinate (1.19 g, 4.9 mmol) in DCM (10 mL) and the RM is warmed to RT and stirred for 16 h.
  • the RM is partitioned between sat. aq. NaHS03 and DCM and extracted. The layers are separated, and the aq. phase is re-extracted with DCM (2x).
  • the combined org. extracts are washed with sat. aq.
  • Step 3 AC2O (7.0 mL, 74.2 mmol) is added to 3-(benzyloxy)-2-(methoxycarbonyl)pyridine 1 -oxide (1.27 g, 4.9 mmol) and the RM is heated to 100°C for 1 h. Additional AC2O (7 mL, 74.2 mmol) is added and heating continued for 2 h. EtOH (10 mL) is added and the RM is heated to reflux for 1 h before being cooled to RT overnight. The RM is concentrated in vacuo and the residue azeotroped with PhMe (1x) before 2M NaOFI in MeOFI (10 mL) is added and the RM is heated to 80°C for 3 h.
  • Step 4 Ag2C03 (4.5 g, 16.3 mmol) and Mel (0.56 mL, 9.0 mmol) are added to a suspension of 3-(benzyloxy)-6- hydroxypicolinic acid (1 .0 g, 4.1 mmol) in acetone (60 mL) and the RM is heated to reflux for 2 h.
  • the RM is cooled to RT and acidified with 1 M HCI before being concentraed in vacuo.
  • the residue is partitioned between water and DCM and extracted. The layers are filtered and separated, and the aq. phase is re-extracted with DCM (2x). The combined org.
  • the RM is evacuated/purged with H2 (3x) and stirred under a H2 atm for 2 h.
  • the RM is filtered through a pad of celite and the filtrate concentrated in vacuo to give methyl 3-hydroxy-6-methoxypicolinate as a white solid.
  • LC-MS J: tR 1.48 min; No ionisation.
  • Steps 6-7 The title compound is prepared from methyl 3-hydroxy-6-methoxypicolinate in analogy to the procedure described for B-2.1 .
  • Step 1 NBS (1.30 g, 7.3 mmol) is added portionwise to a 0°C soln. of isoquinolin-3-amine (1.0 g, 6.9 mmol) in DCM (20 mL) and EtOH (10 mL) and the RM is stirred for 30 min before being warmed to RT overnight. The RM is concentrated in vacuo and the residue is triturated with DCM and filtered. The filtrate is concentrated in vacuo and the residue purified by FC (eluting with 25% to 40% EtOAc in hept) to give 4-bromoisoquinolin-3-amine as a brown solid. Subsequent trituration with 'Pr20 further enhances its purity.
  • Step 2 A soln. of 4-bromoisoquinolin-3-amine (796 mg, 3.6 mmol) and DIPEA (1.87 mL, 10.7 mmol) in DMF (10 mL) and MeOH (5 mL) is evacuated/purged with CO (3x) before Pd(dppf)Cl2 (261 mg, 0.36 mmol) is added.
  • the RM is evacuated/purged with CO (3x) and stirred under a CO atm at 75°C for 20 h.
  • the RM is cooled to RT and concentrated in vacuo and the residue is partitioned between water and EtOAc and extracted. The layers are separated, and the aq. phase is re-extracted with EtOAc (2x). The combined org.
  • Step 3 A soln. of NaN02 (135 mg, 2.0 mmol) in H2O (0.6 mL) is added to a 0°C suspension of methyl 3- aminoisoquinoline-4-carboxylate (330 mg, 1.63 mmol) in 2.5M aq. H2SO4 (4 mL, 10 mmol) and the RM is stirred for 1.5 h.
  • the RM is neutralised by the addition of 2M aq. NaOH and extracted with EtOAc (4x). The combined org. extracts are washed with brine, dried over Na2S04, filtered and evaporated in vacuo to give methyl 3- hydroxyisoquinoline-4-carboxylate as a yellow solid.
  • Steps 4-5 The title compound is prepared from methyl 3-hydroxyisoquinoline-4-carboxylate following the sequence of reactions described for B-2.1.
  • Step 1 Br2 (0.81 mL, 15.7 mmol) is added dropwise to a 0°C soln. of methyl-3-hydroxypicolinate (2.41 g, 15.7 mmol) in water (110 mL) and the RM is warmed to RT and stirred overnight. The RM is quenched with 40% aq. sodium bisulfite soln. and extracted with DCM (2x). The combined org. extracts are washed with brine, dried over Na2S04, filtered and evaporated in vacuo to give methyl 6-bromo-3-hydroxypicolinate as a white solid.
  • Step 2 Methyl (R)-6-bromo-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate is prepared from methyl 6- bromo-3-hydroxypicolinate and ferf-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B-1.1 step 2.
  • Step 3 Pd2(dba)3 (483 mg, 0.53 mmol) and XPhos (201 mg, 0.42 mmol) are added to a RT mix.
  • Step 4 A soln. of methyl (R)-6-(((benzyloxy)carbonyl)amino)-3-(2-((tert-butoxycarbonyl)amino)-3- phenylpropoxyjpicolinate (1.43 g, 2.19 mmol) in EtOH (20 mL) is purged with ish/vacuum (3x) before 10% Pd/C (70 mg, 0.07 mmol) is added. After inertising another three times a H2 balloon is connected and the RM is stirred at 55°C for 1 h. The mix. is filtered over a celite plug rinsing with EtOH.
  • Step 5 50% aq. 2-Chloroacetaldehyde (0.475 mL, 3.74 mmol) is added to a mix. of methyl (R)-6-amino-3-(2-((tert- butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (0.50 g, 1.25 mmol) and NaFICOs (209 mg, 2.49 mmol) in EtOH (15 mL) and the RM is heated to 70°C and stirred for 5 h. The RM is concentrated in vacuo and the residue is partitioned between water and EtOAc and extracted. The layers are separated, and the aq. phase is re-extracted with EtOAc (2x). The combined org.
  • Step 1 H 2 SO 4 (1.86 mL, 34.9 mmol) is added dropwise to a 0°C soln. of 4-hydroxynicotinic acid (5.0 g, 34.9 mmol) in EtOH (50 mL) and the RM is heated to reflux for 3 d. After concentration in vacuo, sat. aq. NaHCCh is carefully added to the residue and the solid filtered off and dried to give ethyl 4-hydroxynicotinate as an off-white solid.
  • Step 2 Ethyl (R)-4-(2-((ferf-butoxycarbonyl)amino)-3-phenylpropoxy)nicotinate is prepared from ethyl 4- hydroxynicotinate and ferf-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B-1.1 step 2.
  • Step 3 The title compound is prepared in analogy to the procedure described for B-1.1 step 3.
  • Table B-3 Listed in Table B-3 below are building blocks B that are prepared in analogy to the 3-step sequence described above for B-3.1.
  • the amine is subjected to a basic workup to liberate its free base.
  • Step 1 A soln. of 3-(trifluoromethoxy)phenol (5.0 g, 28.1 mmol) in THF (40 mL) is added dropwise to a RT suspension of NaH (1 .35 g, 33.7 mmol) in THF (50 mL) and the resulting mix. is stirred for 15 min before methoxymethyl bromide (2.98 mL, 36.5 mmol) is added dropwise. After stirring for 1 h the RM is quenched by the addition of sat. aq. is ⁇ CCh, diluted with some water, and extracted with 'Pr20. The org.
  • Step 2 A soln. of 1-(methoxymethoxy)-3-(trifluoromethoxy)benzene (3.0 g, 13.5 mmol) in THF (7 mL) is added dropwise to a -78°C soln. of sBuLi (1.4 M in cyclohexane, 12.54 mL, 17.55 mmol) in a mix. of THF (10 mL) and cyclohexane (15 mL) and the RM is stirred for 1.5 h. The RM is quenched onto freshly ground dry ice and then warmed to RT. After stirring for 15 min, a few drops of MeOH are added before the RM is concentrated in vacuo.
  • the intermediate lithium carboxylate is dissolved in DMF (20 mL) before KHCO3 (0.41 g, 4.1 mmol) and benzyl bromide (1.93 mL, 16.2 mmol) are added and the RM is stirred for 18 h.
  • the RM is filtered and the filtrate concentrated in vacuo.
  • the residue is partitioned between water and EtOAc and extracted. The layers are separated, and the aq. phase is re-extracted with EtOAc (2x).
  • the combined org. extracts are washed with brine, dried over Na2S04, filtered and evaporated in vacuo.
  • Step 3 TFA (2 mL, 26.1 mmol) is added to a soln. of benzyl 2-(methoxymethoxy)-6-(trifluoromethoxy)benzoate (1.39 g, 3.9 mmol) in DCM (20 mL) and the resulting mix. is stirred for 1 h. The RM is concentrated in vacuo and the residue is co-evaporated with DCM (2x) to give benzyl 2-hydroxy-6-(trifluoromethoxy)benzoate as a white solid.
  • Step 4 Benzyl (R)-2-(2-((ierf-butoxycarbonyl)amino)-3-phenylpropoxy)-6-(trifluoromethoxy)benzoate is prepared from benzyl 2-hydroxy-6-(trifluoromethoxy)benzoate and ferf-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B-1.1 Step 2.
  • Table B-4 Listed in Table B-4 below are building blocks B that are prepared in analogy to the 5-step sequence described above for B-4.1.
  • the amine is subjected to a basic workup to liberate its free base.
  • Step 1 NaH (370 mg, 9.26 mmol) is added to a 0°C soln. of 2-chloro-4-hydroxypyridine (1.0 g, 7.72 mmol) in DMF (20 mL) and the RM is warmed to RT and stirred for 15 min before being cooled back to 0°C. Chloromethyl methyl ether (1.17 mL, 15.4 mmol) is added and the RM is warmed to RT and stirred for 1 h. The RM is quenched by the addition of sat. aq. Na2C03, diluted with some water, and extracted with Et20. The org.
  • Step 2 nBuLi (2.5 M in hex, 1.18 mL, 2.94 mmol) is added to a -78°C soln. of 2-chloro-4-(methoxymethoxy)pyridine (413 mg, 2.36 mmol) in THF (7 mL) and after stirring for 30 min the RM is added via cannula to a -78°C soln. of ethyl chloroformate (0.23 mL, 2.36 mmol) in THF (4 mL) and stirred for 1h at -78°C. The RM is warmed to RT and stirred for 2h before being quenched with NaFiC0 3 and extracted with EtOAc (3x). The combined org.
  • Step 3 ZnMe2 (2 M in PhMe, 0.46 mL, 0.93 mmol) is added dropwise to a RT soln. of ethyl 2-chloro-4- (methoxymethoxy)nicotinate (120 mg, 0.46 mmol), and Pd(dppf)Cl2.DCM (3.8 mg, 0.005 mmol) in dioxane (2 mL) and the RM is heated to 90°C and stirred for 1 h. The RM is concentrated in vacuo and the residue is partitioned between water and EtOAc and extracted. The layers are separated, and the aq. phase is re-extracted with EtOAc (2x). The combined org.
  • Step 4 4M HCI in dioxane (0.55 mL) is added to a RT soln. of ethyl 4-(methoxymethoxy)-2-methylnicotinate (50 mg, 0.22 mmol) in dioxane (1 mL) and the RM is stirred for 16 h. The volatiles are removed in vacuo and the residue is suspended in Et20 and concentrated to give ethyl 4-hydroxy-2-methylnicotinate hydrochloride as a white solid.
  • Step 5 Ethyl (R)-4-(2-((ferf-butoxycarbonyl)amino)-3-phenylpropoxy)-2-methylnicotinate is prepared from ethyl 4- hydroxy-2-methylnicotinate hydrochloride and ferf-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B-1.1 Step 2.
  • Step 6 The title compound is prepared in analogy to the procedure described for B-1.1 Step 3.
  • Step 1 Benzyl bromide (8.9 mL, 74.6 mmol) and K2CO3 (14.7 g, 107 mmol) are added to a RT soln. of 6- hydroxybenzofuran-3(2H)-one (8.0 g, 53.3 mmol) in DMF (80 mL) and the RM is stirred for 2 h. The RM is poured into cold water and the precipitate is collected by filtration and dried at 40°C in a vacuum oven for 48 h. 6- (benzyloxy)benzofuran-3(2FI)-one is isolated as an orange solid.
  • Step 2 6-(benzyloxy)Benzofuran-3(2FI)-one (11 .25 g, 46.8 mmol) is added portionwise to a 0°C soln. of AICI3 (6.87 g, 51.5 mmol) and LiAIH4 (19.5 mL, 46.8 mmol, 2.4M in THF) in THF (200 mL) and the RM is warmed to RT and stirred for 2 h. The RM is cooled to 0°C and quenched with 0.5M aq. NaOFI (400 mL) and extracted with EtOAc (3x). The combined org.
  • Step 3 2,3-Dihydrobenzofuran-6-ol is prepared from 6-(benzyloxy)benzofuran following the procedure described for B-2.11 step 4.
  • Steps 4-8 The title compound is prepared from 2,3-dihydrobenzofuran-6-ol in analogy to the procedure described for B-4.1.
  • Step 1 A soln. of Efo (0.37 mL, 7.2 mmol) in AcOH (5 mL) is added to a RT soln. of quinolin-6-ol (1.0 g, 6.9 mmol) and NaOAc (0.62 g, 7.6 mmol) in AcOH (15 mL) and the RM is stirred for 30 min. The RM is quenched with sat. aq. NaHS03 and neutralised with 2M aq. NaOH and Na2C03 before being extracted with EtOAc (2x). The combined org. extracts are washed with brine and concentrated in vacuo. The residue is taken up in PhMe and concentrated in vacuo (2x) to give 5-bromoquinolin-6-ol as a brown solid.
  • Step 2 5-Bromo-6-(methoxymethoxy)quinoline is prepared from 5-bromoquinolin-6-ol in analogy to the procedure described for B-4.1 step 1.
  • Step 3 nBuLi (1.6 M in hex, 5.7 mL, 9.1 mmol) is added dropwise to a -78°C soln. of 5-bromo-6- (methoxymethoxy)quinoline (2.45 g, 9.1 mmol) in THF (50 mL) and the RM is stirred for 30 min.
  • the RM is quenched with freshly ground dry ice (12 g, 273 mmol) and then warmed to RT and stirred for 30 min.
  • the RM is concentrated in vacuo and the intermediate lithium carboxylate is dissolved in DMF (30 mL) before benzyl bromide (1.3 mL, 11 mmol) is added and the RM is heated to 60°C for 10 min.
  • the RM is cooled to RT and partitioned between sat. aq. NaHC03 and EtOAc and extracted. The layers are separated, and the aq. phase is re-extracted with EtOAc (2x). The combined org. extracts are washed with brine, dried over Na2S04, filtered and evaporated in vacuo.
  • the crude product is purified by FC (eluting with 30% to 100% EtOAc in hept) to give benzyl 6-(methoxymethoxy)quinoline-5-carboxylate as a yellow oil.
  • FC eluting with 30% to 100% EtOAc in hept
  • Steps 4-6 The title compound is prepared from benzyl 6-(methoxymethoxy)quinoline-5-carboxylate in analogy to the procedure described for B-4.1 steps 3-5.
  • Step 1 DCM (40 mL) is added to a soln. of quinolin-7-ol (10 g, 68.9 mmol) in AcOH (20 mL) and the resulting suspension is cooled to 0°C before a soln. of Br2 (3.87 mL, 75 mmol) in AcOH (20 mL) is added slowly and the RM is stirred for 2 h. The suspension is diluted with EtOAc and filtered and the filter residue is washed with EtOAc and Et20 and dried in vacuo at 40°C to give 8-bromoquinolin-7-ol hydrobromide as a brown solid.
  • Steps 2-6 The title compound is prepared from 8-bromoquinolin-7-ol hydrobromide in analogy to the procedure described for B-4.7 steps 2-6.
  • Step 1 Benzyl 2-fluoro-4-methoxynicotinate is prepared from 2-fluoro-4-methoxypyridine in analogy to the procedure described for B-4.7 step-3.
  • Step 2 A soln. of KOBu (258 mg, 2.3 mmol) in THF (3.5 mL) is added to a 0°C soln.
  • Step 3 The title compound is prepared from benzyl (R)-2-(2-((ferf-butoxycarbonyl)amino)-3-phenylpropoxy)-4- methoxynicotinate in analogy to the procedure described for B-1 .1 step 3.
  • Step 1 2-Methoxy-5-(methoxymethoxy)pyridine is prepared from 6-methoxypyridin-3-ol in analogy to the procedure described for B-4.1 step 1.
  • Steps 2-5 The title compound is prepared from 2-methoxy-5-(methoxymethoxy)pyridine in analogy to the procedure described for B-4.7 steps 3-6 substituting HCI for TFA in the Boo cleavage step.
  • Step 1 4-(Benzyloxy)-6-methylpyridin-2-ol is prepared from 6-methylpyridine-2,4-diol following the procedure described for B-4.6 step 1.
  • Step 2 Mel (0.438 mL, 6.97 mmol) is added to a RT mix. of 4-(benzyloxy)-6-methylpyridin-2-ol (500 mg, 2.32 mmol) and Ag2C03 (1.29 g, 4.65 mmol) in DCM (20 mL) and the RM is irradiated in a MW oven at 100°C for 1 h. The RM is filtered and the solids washed with DCM before the filtrate is concentrated in vacuo and the residue is purified by FC (eluting with 20% to 100% EtOAc in hept) to give 4-(benzyloxy)-2-methoxy-6-methylpyridine as a colourless oil.
  • Step 3 nBuLi (2.5 M in hex, 3.63 mL, 9.1 mmol) is added dropwise to a -78°C soln. of 4-(benzyloxy)-2-methoxy-6- methylpyridine (1.66 g, 7.3 mmol) in THF (25 mL) and the RM is stirred for 30 min before ethyl chloroformate (0.70 mL, 7.3 mmol) is added dropwise.
  • the RM is warmed to RT and quenched by addition of sat. aq. NaHC03 and extracted with EtOAc. The layers are separated and the aq. phase is re-extracted with EtOAc (2x) and the combined org.
  • Steps 4-6 The title compound is prepared from ethyl 4-(benzyloxy)-2-methoxy-6-methylnicotinate in analogy to the procedure described for B-2.12 steps 5-7. Note: Boc-cleavage is performed using TFA instead of HCI and the title compound is isolated as its free base after a basic workup.
  • Step 1 Meldrum’s acid (6.04 g, 41.1 mmol) and triethyl orthoformate (6.06 mL, 35.7 mmol) are added to a RT soln. of 4-methoxy-2-methylaniline (5.0 g, 35.7 mmol) in EtOH (50 mL) and the RM is heated to 80°C for 2h. The RM is cooled to RT and the precipitate is collected by filtration washing with EtOH and dried under HV to give 5-(((4-methoxy- 2-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as a white solid.
  • Step 2 5-(((4-Methoxy-2-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.19 g, 28.1 mmol) is dissolved in Dowtherm A (50 mL) and heated to 250°C for 5 min. The RM is cooled to RT and diluted with Et20 and the precipitate is collected by filtration and washed with Et20 before being dried under HV to give 6-methoxy-8- methylquinolin-4-ol as a brown solid.
  • Step 3 Phosphorous tribromide (2.16 mL, 22.7mmol) is added to a RT soln. of 6-methoxy-8-methylquinolin-4-ol (3.91 g, 20.7 mmol) in DMF (75 mL) and the RM is heated to 45°C for 1h. The RM is cooled to RT, diluted with water and the pH is adjusted to 8 by the addition of sat. aq. NaHC03 soln. The precipitate is collected by filtration and dissolved in EtOAc, washed with brine, dried over Na2S04, filtered and evaporated in vacuo.
  • Step 4 nBuLi (1.6 M in hex, 35.7 mL, 57.1 mmol) is added dropwise to a -78°C soln. of 4-bromo-6-methoxy-8- methylquinoline (7.2 g, 28.5 mmol) in THF and the RM is stirred for 30 min. The reaction is quenched with sat. aq. NH 4 CI soln. and extracted with EtOAc (3x). The combined org. extracts are washed with brine, dried over Na 2 S0 4 , filtered and evaporated in vacuo. The crude product is purified by FC (eluting with 20% EtOAc in hept) to give 6- methoxy-8-methylquinoline as a yellow oil.
  • Step 5 5-Bromo-6-methoxy-8-methylquinoline is prepared from 6-methoxy-8-methylquinoline in analogy to the procedure described for B-4.7 step 1 .
  • Step 6 BBr3 (1 M in DCM, 42.5 mL, 42.5 mmol) is added dropwise to a 0°C soln. of 5-Bromo-6-methoxy-8- methylquinoline (3.57 g, 14.2 mmol) in DCM (70 mL). The cooling bath is removed and the RM is stirred at RT for 2 h. The RM is carefully quenched into cold MeOH and concentrated in vacuo. The residue is co-evaporated with PhMe, EtOAc and DCM to give 5-bromo-8-methylquinolin-6-ol as a yellow solid.
  • Step 7 tert-Butyl (R)-(1-((5-bromo-8-methylquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate is prepared from 5- bromo-8-methylquinolin-6-ol and ferf-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B-1.1 Step 2.
  • Step 8 nBuLi (1 .6 M in hex, 0.54 mL, 0.86 mmol) is added dropwise to a -78°C soln. of tert-butyl (R)-(1-((5-bromo-8- methylquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate (185 mg, 0.39 mmol) in THF (2 mL) and the RM is stirred for 30 min before benzyl chloroformate (0.058 mL, 0.41 mmol) is added dropwise. The RM is warmed to RT and quenched by addition of sat. aq. NaHC03 and extracted with EtOAc.
  • Step 9 TFA (4.0 mL, 52.2 mmol) is added to a RT soln. of benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3- phenylpropoxy)-8-methylquinoline-5-carboxylate (550 mg, 1.04 mmol) in DCM (5 mL) and the RM is stirred for 1 h. The RM is concentrated in vacuo and the residue is co-evaporated with DCM (2x) before being purified by prep. HPLC (Basic) to give the title compound as a yellow oil.
  • Step 1 NaOH 16% aq. soln. (100 mL, 472 mmol) is added to a RT soln. of ethyl (R)-4-(2-((tert-butoxycarbonyl)amino)- 3-phenylpropoxy)-2-methoxy-6-methylnicotinate (B-4.12, step 5) (42 g, 94.5 mmol) in MeOH (300 mL) and heated to 90°C for 4 h. The RM is cooled to RT and concentrated in vacuo. The remaining aq. phase is extracted with 'PrOAc (3x) and the org. phases are discarded. The aq.
  • Step 2 K2CO3 (1.33 g, 9.6 mmol) and BnBr (0.51 mL, 4.3 mmol) are added to a RT soln. of (R)-4-(2-((tert- butoxycarbonyl)amino)-3-phenylpropoxy)-2-methoxy-6-methylnicotinic acid (2.0 g, 4.8 mmol) in DMF (8 mL) and the RM is heated to 40°C and stirred for 4 h. The RM is poured into water and extracted with TBME (2x). The combined org.
  • Step 3 The title compound is prepared from benzyl (R)-4-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2- methoxy-6-methylnicotinate in analogy to the procedure described for B-1.1 step 3. Note: Boc-cleavage is performed using TFA instead of HCI and the title compound is isolated as its free base after a basic workup.
  • Step 1 nBuLi (1.6 M in hex, 34.5 mL, 55.2 mmol) is added dropwise to a -78°C soln. of DIPEA (7.74 mL 55.2 mmol) in THF (35 mL) and the RM is stirred for 5 min.
  • a soln. of 4,6-dichloro-2-methylpyrimidine (5.0 g, 30.7 mmol) in THF (40 mL) is added dropwise to the freshly prepared LDA and stirring is continued at -78°C for 1 h.
  • the RM is quenched with freshly ground dry ice (20 g, 454 mmol) and stirred for 5 min before being warmed to RT over 20 min and stirred for a further 15 min.
  • Step 2 KHCO3 (6.15 g, 61.4 mmol) and BnBr (10.95 mL, 92 mmol) are added to a RT soln. of lithium 4,6-dichloro-2- methylpyrimidine-5-carboxylate (6.54 g, 30.7 mmol) in DMF (50 mL) and the RM is stirred for 18 h. The RM is quenched by the addition of H2O and brine and extracted with EtOAc (3x). The combined org. extracts are washed with brine, dried over is ⁇ SCU, filtered and evaporated in vacuo.
  • Step 3 NaOMe (30% soln. in MeOH, 1.0 mL, 5.41 mmol) is added dropwise to a 0°C soln. of benzyl 4,6-dichloro-2- methylpyrimidine-5-carboxylate (2.68 g, 5.41 mmol) in THF (15 mL) and the RM is stirred for 1 h. The RM is quenched with 1 M aq. HCI and extracted with EtOAc (3x). The combined org. extracts are washed with brine, dried over Na2S04, filtered, and evaporated in vacuo.
  • Step 4 NaH (60% dispersion in mineral oil, 128 mg, 3.21 mmol) is added to a 0°C soln. of allyl alcohol (0.21 mL, 3.1 mmol) in THF (10 mL) and the resulting suspension is stirred for 10 min before being slowly added to a -10°C soln. of benzyl 4-chloro-6-methoxy-2-methylpyrimidine-5-carboxylate in THF (15 mL) and the RM is stirred for 1 h. The RM is quenched with 1 M aq. HCI and extracted with EtOAc (3x). The combined org. extracts are washed with brine, dried over Na2S04, filtered, and evaporated in vacuo.
  • Step 5 Pd(PPh3)4 (43.7 mg, 0.038 mmol) is added to a RT soln. (degassed) of benzyl 4-(allyloxy)-6-methoxy-2- methylpyrimidine-5-carboxylate (170 mg, 0.54 mmol) and 1,3-dimethylbarbituric acid (127 mg, 0.81 mmol) in MeCN (10 mL) and the RM is heated to 50°C for 2.5 h. The RM is filtered and concentrated to give benzyl 4-hydroxy-6- methoxy-2-methylpyrimidine-5-carboxylate as a grey solid.
  • Steps 6&7 The title compound is prepared from benzyl 4-hydroxy-6-methoxy-2-methylpyrimidine-5-carboxylate in analogy to the procedure described for B-1 .1 steps 2&3 substituting HCI for TFA in the Boo cleavage step.
  • Step 1 A soln. of benzyl alcohol (0.82 mL, 7.85 mmol) and KO3 ⁇ 4u (867 mg, 7.5 mmol) in DMF (4 mL) is added to a - 78°C soln. of 2,4, 6-trif I u oro py ri d i n e (1.0 g, 7.14 mmol) in DMF (4 mL) and the RM is stirred for 10 min. The RM is quenched with water and warmed to 0°C before being filtered. The filter residue is re-crystallised from hept to give 4- (benzyloxy)-2,6-difluoropyridine as a white solid.
  • Step 2 A suspension of 4-(benzyloxy)-2,6-difluoropyridine (1.71 g, 7.56 mmol) in NaOMe (25 wt. % in MeOH, 6.9 mL, 30.2 mmol) is heated to 60°C for 18 h. The RM is concentrated in vacuo and the residue is partitioned between water and TBME and the layers are separated. The aq. phase is re-extracted with TBME (2x) and the combined org. extracts are washed with brine, dried over Na2S04, filtered and evaporated in vacuo to give 4-(benzyloxy)-2,6- dimethoxypyridine as a colourless oil.
  • Step 1 DMAP (120 mg, 0.99 mmol) is added to a 0°C soln. of 2,6-dihydroxybenzoic acid (3.0 g, 19.7 mmol) in 1,2- dimethoxyethane (15 mL) followed by the dropwise addition of acetone (1.9 mL, 25.8 mmol) and thionyl chloride (1.85 mL, 25.2 mmol) and the RM is stirred for 30 min before being warmed to RT and stirred for 16 h. The RM is quenched by the addition of sat. aq. NaHCCh and extracted with Et20 (4x). The combined org.
  • Step 2 CD3I (0.8 mL, 12.9 mmol) is added to a soln. of 5-hydroxy-2,2-dimethyl-4H-benzo[d][1 ,3]dioxin-4-one (1.76 g, 8.6 mmol) and K2CO3, (1.79 g, 12.9 mmol) in DMF (25 mL) and the RM is heated to 50°C for 1 h. The RM is partitioned between water and EtOAc and the layers are separated. The aq. phase is re-extracted with EtOAc (1x) and the combined org. layers are washed with brine, dried over Na2S04, filtered and evaporated in vacuo.
  • Step 3 NaH (0.65 g, 16.3 mmol) is added to a soln. of benzyl alcohol (1.7 mL, 16.3 mmol) in DMF (45 mL) and the RM is stirred for 30 min before a soln. of 5-(methoxy-d3)-2,2-dimethyl-4H-benzo[d][1 ,3]dioxin-4-one (1 .72 g, 8.1 mmol) in DMF (5 mL) is added and stirring continued for 1 h. The RM is partitioned between 1N HCI and EtOAc and the layers are separated. The aq. phase is re-extracted with EtOAc (1x) and the combined org.
  • Step 4 Benzyl (R)-2-(2-((ferf-butoxycarbonyl)amino)-3-phenylpropoxy)-6-(methoxy-d3)benzoate is prepared from benzyl 2-hydroxy-6-(methoxy-d3)benzoate and ferf-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B-1.1 Step 2.
  • Step 5 The title compound is prepared in analogy to the procedure described for B-1.1 Step 3.
  • Step 1 A soln. of KOH (4.57 g, 81 mmol) in water (12 mL) is added to a 0°C soln. of 5-hydroxy-2,2-dimethyl-4H- benzo[d][1,3]dioxin-4-one (B-5.1 Step 1,1.58 g, 8.1 mmol) in MeCN (12 mL) and the biphasic RM is stirred for 5 min before bromodifluoromethyl diethylphosphonate (2.0 mL, 11.4 mmol) is added dropwise. After stirring for 1 .5 h EtOAc (25 mL) is added and the phases are separated. The aq. phase is re-extracted with EtOAc (1x) and the combined org.
  • Steps 2-4 The title compound is prepared from 5-(difluoromethoxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one following the sequence of reactions described for B-5.1 .
  • Step 1 K2CO3 (2.38 g, 17.2 mmol) and 3-bromopropyne (80% soln. in PhMe, 1.67 mL, 15.5 mmol) are added to a RT soln. of 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (B-5.1 Step 1, 3.0 g, 15.4 mmol) in acetone (60 mL) and the RM is heated to 55°C for 21 h. The mix. is concentrated, and the residue partitioned between water and EtOAc. The layers are separated and the aq. layer re-extracted with EtOAc (2x). The combined org.
  • Step 2 NaOMe (30% soln. in MeOH, 1.9 mL, 10.1 mmol) is added to a 0°C soln. of 2,2-dimethyl-5-(prop-2-yn-1- yloxy)-4H-benzo[d][1,3]dioxin-4-one (1.53 g, 6.6 mmol) in DMF (15 mL) and the RM is warmed to RT and stirred for 1 h. The RM is quenched with 1 M aq. HCI and extracted with EtOAc (3x). The combined org.
  • Step 3 A mix. of methyl 2-hydroxy-6-(prop-2-yn-1-yloxy)benzoate (1.33 g, 6.5 mmol), CsF (1.5 g, 9.9 mmol), and diethylaniline (18 mL) is purged with N2 before being irradiated in a MW oven at 200°C for 55 min.
  • the RM is diluted with EtOAc and washed with 1 M aq. HCI.
  • the aq. phase is extracted with EtOAc (2x) and the combined org. extracts are washed with 1 M HCI, brine, dried over Na2S04, filtered, and evaporated in vacuo.
  • Steps 4-5 The title compound is prepared from methyl 6-hydroxy-2-methylbenzofuran-7-carboxylate in analogy to the procedure described for B-1.1 steps 2-3.
  • Step 2 2-Methyl-2-butene (7.33 mL, 69.2 mmol) is added in one portion to a RT soln. of 6-hydroxy-3- methylbenzo[d]isoxazole-7-carbaldehyde (1.09 g, 6.1 mmol) in THF (40 mL) and tert-butanol (12 mL) followed by a soln. of NaClO 2 (2.06 g, 18.2 mmol) and NaH 2 PO 4 .2H 2 O (4.3 g, 27.3 mmol) in H 2 O (12 mL) and the RM is stirred at RT for 30 min. The solids are collected by filtration, washed with cold 1M aq.
  • Step 2 tert-Butyl (R)-(1-((5-bromoisoquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate is prepared from 5- bromoisoquinolin-6-ol and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B-1.1 Step 2.
  • Step 3 A soln. of DIPEA (0.76 mL, 4.4 mmol) in MeOH (3 mL) is purged with Ar before Pd(OAc) 2 (74 mg, 0.33 mmol) and Xantphos (190 mg, 0.33 mmol) are added and the catalyst mix. is heated to 70°C for 20 min. In a separate flask a soln.
  • the RM is filtered through a pad of celite and the filtrate partially concentrated in vacuo before being diluted with EtOAc and washed successively with 1M KHSO 4 soln. and brine and concentrated in vacuo.
  • the crude product is purified by FC (eluting with 0% to 30% EtOAc in hept) to give 4-methoxy-2-(prop-1-yn-1-yl)benzaldehyde as a yellow solid.
  • Step 4 BBr 3 (1 M in DCM, 55.4 mL, 55.4 mmol) is added dropwise to a -78°C soln. of 6-methoxy-3-methylisoquinoline (5.0 g, 27.7 mmol) in DCM (100 mL). The cooling bath is removed and the RM is stirred at RT for 30 h. The RM is carefully quenched into cold MeOH and concentrated in vacuo. The residue is co-evaporated with PhMe, EtOAc and DCM to give 3-methylisoquinolin-6-ol as a brown solid.
  • Steps 5-6 tert-Butyl (R)-(1-((5-bromo-3-methylisoquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate is prepared from 3-methylisoquinolin-6-ol following steps 1&2 described for B-7.1.
  • Step 7 A RT soln.
  • Step 2 Benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxole-5-carboxylate is prepared from benzyl 6-hydroxybenzo[d][1,3]dioxole-5-carboxylate in analogy to the procedure described for B-1.1 step 2.
  • Step 3 The title compound is prepared from benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3- phenylpropoxy)benzo[d][1,3]dioxole-5-carboxylate in analogy to the procedure described for B-1.24 step 4.
  • the title compound is prepared from 2-hydroxy-4,5-dimethoxybenzoic acid following the 3-step sequence as described for B-Acid-1.
  • Step 1 Benzyl (R)-6-(2-((((benzyloxy)carbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxole-5-carboxylic acid (B-Acid-4) Step 1: Benzyl (R)-6-(2-(((benzyloxy)carbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxole-5-carboxylate is prepared from benzyl 6-hydroxybenzo[d][1,3]dioxole-5-carboxylate in analogy to the procedure described for B-1.1 step 2 substituting tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate by benzyl (R)-(1-hydroxy-3- phenylpropan-2-yl)carbamate.
  • Step 2 A soln. of benzyl (R)-6-(2-(((benzyloxy)carbonyl)amino)-3-phenylpropoxy)benzo[d][1,3]dioxole-5-carboxylate (2.4 g, 4.45 mmol) in THF (40 mL) is evacuated/purged with N 2 (3x) before 10% Pd/C (473 mg, 10 mol%) is added. The RM is evacuated/purged with H 2 (3x) and stirred under a H 2 atm for 2 h.
  • Step 2 (R)-6-(2-Amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylic acid (436 mg, 1.28 mmol) is taken up in THF (10 mL) and water (10 mL). To the resulting light suspension is added NaHCO 3 (430 mg, 5.12 mmol) followed by allyl chloroformate (0.155 mL, 1.41 mmol). The reaction mixture is stirred for 1 h at RT. The reaction mixture is diluted/partitionned between water and EtOAc and acidified carefully with some HCl (2N) down to pH ⁇ 3. The layers are separated and the inorg. layer is extracted further with EtOAc (2x).
  • Step 2-5 The title compound is prepared from 1-(tert-butoxycarbonyl-methyl-amino)-cyclopropanecarboxylic acid following the sequence of reactions described for C-1.1, steps 1-4.
  • Step 1 H 2 SO 4 (92 ⁇ L, 1.72 mmol) is added to a 0°C soln.
  • Steps 2&3 The title compound is prepared from Boc-N-methyl-L-leucine and (S)-1,2,3,6-tetrahydropyridine-2- carboxylate following the sequence of reactions described for C-2.1.
  • Steps 2-5 The title compound is prepared from N-(tert-butoxycarbonyl)-N-methyl-D-alanine following the 4-step sequence of reactions described for C-1.1, steps 1-4.
  • Step 2 2 M aq. NaOH (11 .7 mL, 22.6 mmol) is added to a RT soln. of methyl (R)-4-(A/-(ferf-butoxycarbonyl)-A/-methyl- L-leucyl)morpholine-3-carboxylate (4.37 g, 11.7 mmol) in MeOH (55 mL) and the mix. is stirred at RT for 4.5 h. The volatiles are removed in vacuo and the aq. residue is neutralised with 2 M aq. HCI before being extracted with DCM (3x). The combined org. layers are dried (is ⁇ SCU), filtered, and evaporated in vacuo to give the title compound as a white solid.
  • Table C-2 Listed in Table C-2 below are building blocks C that are prepared from the corresponding starting materials in analogy to the 2-step sequence described above for C-2.1. Table C-2
  • Step 1 (T rimethylsilyl)diazomethane soln. (2.0 M in hex, 0.75 mL, 1.49 mmol) is added to a 0°C soln. of commercially available 6-azaspiro[2.5]octane-5-carboxylic acid hydrochloride in MeOH (2 mL). The RM is warmed to RT and stirred for 30 min. The mix. is concentrated to yield rac-6-aza-spiro[2.5]octane-5-carboxylic acid methyl ester which is used as such in the next step.
  • Steps 2&3 The title compound is prepared from rac-6-aza-spiro[2.5]octane-5-carboxylic acid methyl ester following the 2-step procedure described for C-2.1.
  • Step 1 Thionyl chloride is added to a 0°C solution of O-benzyl-N-methyl-DL-serine (3.10 g, 14.8 mmol) in DCM (20 mL) and the RM is stirred at 60°C for 16 h. The mix. is poured into ice water and extracted with DCM (3x). The combined organic layers are washed with brine, dried (MgS04), filtered, and concentrated in vacuo.
  • Step 2 Methyl (R)-4-methylpiperazine-2-carboxylate dihydrochloride is prepared from 1 -(ferf-butyl) 2-methyl (R)-4- methylpiperazine-1,2-dicarboxylate in analogy to the procedure described for C-1.1, step 2.
  • Steps 3&4 The title compound is prepared from Boc-A/-methyl-L-leucine and methyl (R)-4-methylpiperazine-2- carboxylate dihydrochloride following the 2-step sequence of reactions described for C-2.1.
  • Step 1 (1-Ethoxycyclopro poxy) trimethylsilane (2.6 mL, 12.80 mmol), NaBhhCN (0.66 g, 9.98 mmol), and AcOH (0.5 mL, 8.74 mmol) are added to a RT soln. of methyl (R)-1-Boc-piperazine-2-carboxylate (1.54 g, 6.30 mmol) in MeOH (30 mL) and THF (30 mL) and the resulting mix. is heated to 60°C for 16 h. Water (5 mL) is added to the cooled mix. followed by 1 M aq. NaOH (10 mL) and after stirring for 15 min the volatiles are removed under reduced pressure.
  • Steps 2-4 The title compound is prepared from l-(ferf-butyl) 2-methyl (R)-4-cyclopropylpiperazine-1 ,2-dicarboxylate following 3-step sequence as described for C-3.1, steps 2 to 4.
  • Step 1 HATU (219 mg, 0.58 mmol) is added to a RT soln. of Boc-A/-methyl-L-leucine (135 mg, 0.55 mmol), IM-1.3 (155 mg, 0.5 mmol), and DIPEA (0.34 mL, 2 mmol) in DMF (2 mL) and the resulting mix. is stirred for 1 h.
  • the RM is directly purified by prep. HPLC (basic) to yield benzyl A/-(A/-(ferf-butoxycarbonyl)-A/-methyl-L-leucyl)-A/-((chroman-3- yl)methyl)glycinate (218 mg, 81%).
  • Step 2 LiOH (52.9 mg, 1.26 mmol) is added to a RT soln. of benzyl A/-(A/-(ferf-butoxycarbonyl)-A/-methyl-L-leucyl)-A/- ((chroman-3-yl)methyl)glycinate (218 mg, 0.4 mmol) in THF/H2O (2:1) (2 mL) and the mix. is stirred at RT overnight. The volatiles are removed in vacuo and the aq. residue is acidified with 2 M aq. HCI before being extracted with EtOAc (3x). The combined org. layers are dried (MgSCU), filtered, and evaporated to give the title compound C-4.1 (200 mg, 71%) as a white solid.
  • Table C-4 Listed in Table C-4 below are building blocks C that are prepared from the corresponding starting materials in analogy to the 2-step sequence described above for C-4.1. Table C-4
  • the RM is stirred at RT for 1 h, then diluted with water (20 mL) and DCM (50 mL). The layers are separated and the aq. layer is extracted with DCM (2x 50 mL). The combined org. layers are washed with brine (20 mL), dried (MgSCU), filtered, and concentrated.
  • Step 3 4 M NaOFI soln. (21 mL, 83.2 mmol) is added to a RT soln. of methyl (S)-2-(2-((ferf-butoxycarbonyl)amino)- A/,4-dimethylpentanamido)-2,3-dihydro-1H-indene-2-carboxylate (90 mg, 2.08 mmol) in MeOFI (30 mL), and the RM is stirred at 50°C for 4 h. The RM is cooled to RT, then the mix. is diluted with DCM (100 mL) and acidified with a 2 M HCI soln. (10 mL). The layers are separated and the aq.
  • Step 1 K2CO3 (1.66 g, 12 mmol) is added to a RT soln. of l-(ferf-butyl) 2-methyl (R)-piperazine-l ,2-dicarboxylate (1.0 g, 4.01 mmol) and benzyl 3-bromopropyl ether (0.95 mL, 5.22 mmol) in MeCN (10 mL) and the resulting mix. is stirred at 60°C for 17 h. Water (20 mL) and DCM (75 mL) are added to the RM, then the two layers are separated and the aq. layer is extracted with DCM (2x 50 mL). The combined org.
  • Step 2 4 M HCI in dioxane (5 mL, 20 mmol) is added to a RT soln. of (R)-4-(3-benzyloxy-propyl)-piperazine-1 ,2- dicarboxylic acid 1-ferf-butyl ester 2-methyl ester (1 .57 g, 4 mmol) in dioxane (7 mL) and the resulting mix. is stirred at 50°C for 2 h. The RM is cooled to RT, then diluted with DCM (100 mL) and sat. aq. K2CO3 (20 mL) is added. The layers are separated and the aq. layer is extracted with DCM (2 x 75 mL). The combined org.
  • Step 3 HATU (1 .36 g, 3.58 mmol) is added to a RT soln. of Boc-A/-methyl-L-leucine (880 mg, 3.58 mmol), (R)-4-(3- benzyloxy-propyl)-piperazine-2-carboxylic acid methyl ester (1.05 g, 3.58 mmol), and DIPEA (1.84 mL, 10.7 mmol) in DMF (11 mL). The resulting mix. is stirred at RT for 1 h, the RM is diluted with DCM (100 mL) and water (10 mL). The layers are separated and the aq. layer is extracted with DCM (2x 75 mL). The combined org.
  • Step 4 2 M NaOH soln. (32 mL, 63.9 mmol) is added to a RT soln. of methyl (R)-4-(3-(benzyloxy)propyl)-1-(A/-(ferf- butoxycarbonyl)-A/-methyl-L-leucyl)piperazine-2-carboxylate (1.66 g, 3.19 mmol) in MeOH (60 mL) and the RM is stirred at 50°C for 1 h. The RM is cooled to RT and the RM is diluted with DCM (100 mL) and acidified with a 25% aq. HCI soln. (10 mL). The layers are separated and the aq.
  • Step 5 A soln. of (R)-4-(3-benzyloxy-propyl)-1-[(S)-2-(ferf-butoxycarbonyl-methyl-amino)-4-methyl-pentanoyl]- piperazine-2-carboxylic acid (1.74 g, 3.21 mmol) in EtOH (20 mL) is inertised with ish/vacuum (3x) before 10% Pd/C (171 mg, 0.16 mmol) is added. After inertising another three times a H2 balloon is connected and the RM is stirred at RT for 18 h. The mix. is concentrated and filtered over a celite plug rinsing with EtOH. The filtrate is concentrated to give the title compound C-6.1 (1.14 g, 79%) as a white solid.
  • Step 1 1-Bromo-2-methoxyethane (4.31 mL, 44.9 mmol) is added to a RT soln. of 1 -(ferf-butyl) 2-methyl (R)- piperazine-1 ,2-dicarboxylate (4.00 g, 16 mmol) and DIPEA (8.41 mL, 48.1 mmol) in MeCN (87 mL). The resulting mix. is stirred at 80°C for 18 h. The mix. is concentrated, and the residue partitioned between water (10 mL) and DCM (50 mL). The layers are separated, and the aq. layer re-extracted with DCM (2x 75 mL). The combined org.
  • Steps 2 to 4 The title compound is prepared from (R)-4-(2-methoxy-ethyl)-piperazine-1 ,2-dicarboxylic acid 1 -ferf- butyl ester 2-methyl ester following the sequence of reactions described for C-6.1, steps 2 to 4.
  • Step 1 1-(3-Methoxy-propylamino)-cyclopropanecarboxylic acid methyl ester is prepared from methyl 1- aminocyclopropanecarboxylate and 1 -bromo-3-methoxypropane following the reaction described for C-6.3, step 1.
  • Steps 2&3 The title compound is prepared from 1-(3-methoxy-propylamino)-cyclopropanecarboxylic acid methyl ester following the sequence of reactions described for C-6.1, steps 3&4.
  • Step 1 2,2,2-T richloroethyl chloroformate (1.2 mL, 8.54 mmol) is added to a RT soln. of 1 -(ferf-butyl) 2-methyl (R)- piperazine-1 ,2-dicarboxylate (2.0 g, 8.02 mmol) and DIPEA (2.88 mL, 16.5 mmol) in DCM (40 mL). The resulting mix. is stirred at RT for 45 min. The RM is diluted with DCM (100 mL) and water (20 mL). The layers are separated and the aq. layer is extracted with DCM (2x 75 mL). The combined org.
  • Steps 2 to 4 The title compound is prepared from 1 -(ferf-butyl) 2-methyl 4-(2,2,2-trichloroethyl) (R)-piperazine-1 ,2,4- tricarboxyl ate following the sequence of reactions described for C-6.1, steps 2 to 4.
  • Step 1 CU(OAC)2 (749 mg, 6.2 mmol) is added to a RT soln. of 1 -(ferf-butyl) 2-methyl (R)-piperazine-l ,2-dicarboxylate (1.00 g, 4.01 mmol) and phenylboronic acid (749 mg, 4.01 mmol) in DCM (20 mL) and the resulting mix. is stirred at RT overnight.
  • the RM is diluted with DCM and washed with cold water (20 mL), and brine (20 mL).
  • the org. layer is dried (MgSC ), filtered, and evaporated. Purification by prep.
  • Step 2 TFA (0.8 mL, 10.6 mmol) is added to a soln. of (R)-4-phenyl-piperazine-1 ,2-dicarboxylic acid 1 -ferf-butyl ester 2-methyl ester (337 mg, 1 .06 mmol) in DCM (40 mL) and the resulting mix. is stirred for 24 h.
  • the RM is diluted with DCM (10 mL) and neutralised with a sat. aq. soln. of NaHC03 (30 mL). The layers are separated, and the aq. layer re-extracted with DCM (20 mL). The combined org.
  • Steps 3&4 The title compound is prepared from Boc-A/-methyl-L-leucine and (R)-4-phenyl-piperazine-2-carboxylic acid methyl ester following the sequence of reactions described for C-2.1.
  • the RM is then heated up to 100°C for 4h30 to reach complete conversion as monitored by LC-MS.
  • the solution is cooled back to RT and is filtered over a glass fiber filter. Water is added to the resulting filtrate and the org. layer is collected; the inorg. phase is then further extracted with EtOAc (2x).
  • the combined organic phase is successively washed with sat. aq. NH4CI, sat. aq. NaHC03 and brine, dried over MgS04 then concentrated under reduced pressure.
  • Step 2-4 The title compound is prepared from boc-A/-methyl-L-leucine and 1 -(tert-butyl) 2-methyl (R)-4-(5- fluoropyridin-2-yl)piperazine-1 ,2-dicarboxylate following the sequence of reactions 2 to 4 described for C-8.1. Extensive epimerization is observed at the piperazine chiral center at the end of the 4 step sequence.
  • Step 1 Pyridine-3-sulfonyl chloride (2.33 g, 12.8 mmol) is added to a RT soln. of l-(ferf-butyl) 2-methyl (R)-piperazine- 1,2-dicarboxylate (2.00 g, 8.02 mmol) and TEA (3.37 mL, 24.1 mmol) in DCM (80 mL) and the resulting mix. is stirred at RT for 1 h.
  • Step 2 4 M HCI in dioxane (9.73 mL, 38.9 mmol) is added to a RT soln. of (R)-4-(pyridine-3-sulfonyl)-piperazine-1 ,2- dicarboxylic acid 1-ferf-butyl ester 2-methyl ester (3.0 g, 7.78 mmol) in dioxane (10 mL). The resulting mix. is stirred at 50°C for 2 h.
  • Steps 3&4 The title compound is prepared from Boc-A/-methyl-L-leucine and (methyl (R)-4-(pyridin-3- ylsu Ifonyl) pi perazi ne-2-carboxyl ate dihydrochloride following the sequence of reactions described for C-2.1.
  • Step 2 4 M HCl in dioxane (84.0 mL, 336 mmol) is added to a RT suspension of 1-tert-butoxycarbonylamino- cyclopropanecarboxylic acid benzyl ester (9.97 g, 33.0 mmol) in DCM (20 mL) and the resulting mix. stirred at RT for 1.5 h.
  • the RM is concentrated and co-evaporated with DCM at HV to obtain 1-amino-cyclopropanecarboxylic acid benzyl ester HCl (7.93 g, 105%) as a white solid.
  • Step 3 2-Nitrobenzenesulfonyl chloride (8.30 g, 36.4 mmol) is added portionwise to a 0°C suspension of 1-amino- cyclopropanecarboxylic acid benzyl ester HCl (7.93 g, 33.0 mmol) and TEA (13.9 mL, 99.1 mmol) in DCM (70 mL). The ice bath is removed after 30 min and the mix. is stirred at RT for 1.5 h. The RM is partitioned between sat. NaHCO 3 and DCM and the layers are separated. The aq. layer is re-extracted with DCM and the combined org.
  • Acetaldehyde (2.33 mL, 41.2 mmol) is added again after 4 h and 6 h.
  • the mix. is cooled to RT before being partitioned between EtOAc and sat. aq. NaHCO 3 .
  • the phases are separated and the aq. phase is re-extracted with EtOAc (2x).
  • the combined org. layers are dried (Na 2 SO 4 ), filtered, and concentrated.
  • Purification by FC (eluting with 5% to 20% EtOAc in hept) yields (9H-fluoren-9-yl)methyl (4S)-4-isobutyl-(2R,S)-2-methyl-5-oxooxazolidine-3- carboxylate as a yellow oil.
  • Step 1 NaH 60% dispersion in mineral oil (374 mg, 9.76 mmol) is added to a 0°C suspension of 2 -(tert- butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propanoic acid (1.0 g, 3.25 mmol) in THF (20 mL). The RM is stirred at 0°C for 10 min, then at RT for another 10 min. The RM is cooled back to 0°C and Mel (0.614 mL, 9.76 mmol) is added dropwise and the RM is warmed to RT overnight. Water and EtOAc are added, then the two layers are separated. The aq.
  • Step 2 TFA (0.99 mL, 12.9 mmol) is added to a RT soln. of methyl-2-((ferf-butoxycarbonyl)(methyl)amino)-3-(4,4- difluorocyclohexyl)propanoate (300 mg, 0.61 mmol) in DCM (10 mL) and the RM is stirred at RT for 2 h. The volatiles are removed in vacuo, and the residue co-evaporated with DCM (3x) to give methyl-3-(4,4-difluorocyclohexyl)-2- (methylamino)propanoate 2,2,2-trifluoroacetate which is used as such in the next step.
  • Steps 3&4 The title compound is prepared from methyl-3-(4,4-difluorocyclohexyl)-2-(methylamino)propanoate 2,2,2- trifluoroacetate and Boc-A/-methyl-L-leucine, following the sequence of reactions described for C-2.1, steps 1&2.
  • T able C-18 Listed in T able C-18 below are building blocks C that are prepared from Boc-A/-methyl-L-leucine and the corresponding SM in analogy to the 4-step sequence described above for C-18.1.
  • Boc deprotection can be performed in the presence of 4 M HCI in dioxane instead of TFA.
  • Steps 3&4 The title compound is prepared from methyl-4-phenylpiperidine-2-carboxylate HCl salt and Boc-N-methyl- L-leucine, following the sequence of reactions described for C-2.1, steps 1&2.
  • Step 2 Methyl (R)-2-amino-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate HCI salt is prepared from methyl (R)-2-((ferf- butoxycarbonyl)amino)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate following the procedure described for C-19.1, step 2.
  • Steps 3 Methyl (R)-2-((S)-2-((ferf-butoxycarbonyl)(methyl)amino)-4-methylpentanamido)-4-(3-phenyl-1 ,2,4- oxadiazol-5-yl)butanoate is prepared from methyl (R)-2-amino-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate HCI salt and Boc-A/-methyl-L-leucine following the reaction described for C-2.1, step 1.
  • Step 4 NaH (216 mg, 5.65 mmol) is added to a 0°C soln. of methyl (R)-2-((S)-2-((ferf-butoxycarbonyl)(methyl)amino)- 4-methylpentanamido)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate (920 mg, 1.88 mmol) in DMF (9 mL). After 5 min stirring, Mel (0.469 mL, 7.53 mmol) is added to the 0°C soln., then the ice bath is removed, and the RM stirred at RT for 4 h.
  • Reaction control by LC/MS shows that during the methylation also saponification occurred (tR different than SM).
  • Water (15 mL) and TBME (20 mL) are added to the RM, then the layers are separated and the aq. layer is washed with TBME (1x 20 mL).
  • the aq. layer is treated with 2 M HCI (10 mL) and extracted with DCM (2x 20 mL).
  • the combined DCM layers are washed with brine (10 mL), dried (MgSO ⁇ , filtered, and concentrated to yield title compound C-20.1 (688 mg, 75%) as a yellow oil, which was used as such in the next step.
  • Table C-20 Listed in Table C-20 are building blocks C, prepared according to the 4-step sequence described above for C-20.1. In cases where saponification does not happen during methylation conditions, an extra step is added to saponify the ester to the carboxylic acid (4 N NaOH in MeOH in analogy to step 3 of C-5.1).
  • Step 2 TFA (3.29 mL, 43 mmol) is added to a RT soln. of tert-butyl (R)-(2-oxotetrahydrofuran-3-yl)carbamate (2.0 g, 8.6 mmol) in DCM (20 mL) and the RM is stirred at RT for 6 h. The volatiles are removed in vacuo, co-evaporated with DCM (3x) to give the crude (R)-3-aminodihydrofuran-2(3H)-one 2,2,2-trifluoroacetate (3.0 g, 160%) which is used as such in the next step. By LC-MS no product formation could be detected, only the disappearance of SM is followed.
  • Step 3 HATU (5.83 g, 15.3 mmol) is added to a RT soln. of (R)-3-aminodihydrofuran-2(3H)-one 2,2,2-trifluoroacetate (3.00 g), Boc-N-methyl-L-leucine (3.70 g, 14.6 mmol) and DIPEA (7.16 mL, 41.8 mmol) in DMF (20 mL) and the RM is stirred for 1 h. The mix. is partitioned between water and EtOAc and the layers are separated, and the aq. layer is re-extracted with EtOAc (2x). The combined org.
  • Step 2 4 M HCl in dioxane (57.9 mL, 240 mmol) is added to a RT solution of 4-benzyl 1-methyl (tert-butoxycarbonyl)- D-aspartate (8.19 g, 24 mmol) in dioxane (42.3 mL) and the resulting RM is heated to 50°C for 30 min. The mixture is allowed to reach RT, then concentrated to yield 4-benzyl 1-methyl D-aspartate HCl-salt (6.90 g, 92%) of a yellowish solid which is used as such in the next step.
  • Step 3 HATU (10.38 g, 26.5 mmol) is added to a RT solution of 4-benzyl 1-methyl D-aspartate HCl-salt (6.84 g, 22.1 mmol), boc-N-methyl-L-leucine (5.58 g, 22.1 mmol), and DIPEA (19.9 mL, 110 mmol) in MeCN (83 mL). The resulting mixture is stirred at RT for 10 min. Water (135 mL) and DCM (315 mL) is added to the RM, then the layers are separated and the inorg. layer is extracted with DCM. The combined org. layers are washed with brine (50 mL), dried over a phase separator and concentrated.
  • Step 4 NaH (1.02 g, 26.5 mmol) is added to a -20°C solution of 4-benzyl 1-methyl N-(tert-butoxycarbonyl)-N-methyl- L-leucyl-D-aspartate (4.53 g, 8.83 mmol) and MeI (2.22 mL, 35.3 mmol) in DMF (73 mL). The resulting solution is stirred at -20°C for 15 min, then quenched with 1 M aq. HCl soln. (224 mL) and diluted with isopropyl acetate. The layers are separated and the inorg. layer is extracted with isopropyl acetate (1x). The combined org.
  • the solvent is removed in vacuo and the residue re-dissolved in dioxane (2.8 mL).
  • the resulting mix. is heated to 100°C for 3.5 h, then to 90°C overnight. Next morning, the heating was increased to 100°C for another 8 h.
  • the RM is allowed to reach RT before concentrated in vacuo, then water and DCM is added.
  • the layers are separated and the inorg. layer is extracted with DCM (1x).
  • the combined org. layers are dried over a phase separator and concentrated.
  • step 6 (R)-3-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-4-methoxy-4- oxobutanoic acid and their corresponding hydroxyacetimidamide are used.
  • C-22.5 synthesis is performed in analogy to C-22.1, using in step 1 boc-D-Glu-OMe instead of boc-D-Asp-OMe and in step 6 the corresponding hydroxyacetimidamide as outlined in Table C-22.
  • Table C-22 No. SM Product t R [min] MS-data h drox acetimidamide* LC-MS m/z ing .
  • Step 2 K 2 CO 3 (378 mg, 3.78 mmol) is added to a solution of 3,3-difluoropyrrolidine HCl (493 mg, 3.43 mmol) in 2- propanol (0.69 mL) and water (61.8 ⁇ l, 3.43 mmol), then benzyl 2-((tert-butoxycarbonyl)(methyl)amino)acrylate (200 mg, 0.686 mmol) is added the resulting RM is heated to 60°C for 18 h. The solution is concentrated, then sat. NaHCO 3 soln. and EtOAc are added. The org. layer is collected and the inorg. layer is extracted with EtOAc (2x). The combined org.
  • Steps 4 and 5 The title compound is prepared from Boc-N-methyl-L-leucine and benzyl 3-(3,3-difluoropyrrolidin-1- yl)-2-(methylamino)propanoate TFA-salt following the sequence of reactions described for C-1.1, step 3 and 4.
  • 2-((S)-2-((tert-Butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-3-(pyrrolidin-1-yl)propanoic acid C- 23.2)
  • the title compound is prepared following the 5-step sequence described for C-23.1, using in step 2 following conditions.
  • the RM is stirred at 0°C for 1.5 h, then a solution of NaBH 4 (3.79 g, 99.2 mmol) in water (53 mL) is added dropwise at 0°C and the resulting RM stirred at 0°C for 10 min.
  • the RM is allowed to warm up to RT, then DCM is added, and the two layers are separated.
  • the inorg. layer is extracted with DCM (2x), and the combined org. layers are washed with brine, dried (over phase separator), and concentrated.
  • the RM is diluted with EtOAc and sat. aq. Na 2 CO 3 soln.
  • the layers are separated and the inorg. layer is extracted with EtOAc (1x).
  • the combined org. layers are dried (MgSO 4 ), filtered, and concentrated to yield 5-(bromomethyl)-3-methoxyisoxazole (1.65 g, 80%) as a slightly yellow oil which is used as such in the next step.
  • Step 3 n-BuLi (1.6 M in hexanes , 6.03 mL, 9.53 mmol) was added dropwise to a -75°C solution of (S)-2,5-dihydro- 3,6-dimethoxy-2-isopropylpyrazine (1.5 mL, 8.1 mmol) in THF (74 mL). The resulting solution is stirred for 30 min, then a solution of 5-(bromomethyl)-3-methoxyisoxazole (1.64 g, 8.1 mmol) in THF (60 mL) is added and the RM is stirred at -75°C for 1.5 h.1 M aq.
  • Step 4 1 M aq. HCl soln (8.1 mL, 8.21 mmol) is added to a RT solution of 5-(((2R,5S)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazin-2-yl)methyl)-3-methoxyisoxazole (1.31 g, 4.1 mmol) in MeCN (41.4 mL).
  • DCM is added to the RM and the two layers are separated.
  • the inorg. layer is extracted with DCM (1x) and the combined org.
  • Step 5 HATU (1.648 g, 4.20 mmol) is added to a RT solution of methyl (R)-2-amino-3-(3-methoxyisoxazol-5- yl)propanoate (750 mg, 3.50 mmol), boc-N-methyl-L-leucine (886 mg, 3.5 mmol), and DIPEA (1.8 mL, 10.5 mmol) in MeCN (12.8 mL). The RM is stirred at RT for 10 min, then water and DCM are added, and the layers are separated. The inorg. layers are extracted with DCM (1x) and the combined org. layers are dried (over phase separator) and concentrated.
  • Step 6 NaH (376 mg, 9.82 mmol) is added to a -20°C solution of methyl (R)-2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)-4-methylpentanamido)-3-(3-methoxyisoxazol-5-yl)propanoate (1.40 g, 3.27 mmol) and MeI (0.82 mL, 13.1 mmol) in DMF (28 mL). The RM is stirred at -20°C for 11 min, then the RM is quenched with 1 M aq. HCl soln (84 mL) followed by the addition of Et 2 O. The layers are separated and the inorg.
  • the RM is diluted with DCM and brine, the layers are separated and the org. layer is dried (with phase separator) and concentrated to yield methyl (R)-2- ((tert-butoxycarbonyl)amino)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propanoate (1.07 g, 89%) a slightly yellowish solid.
  • Step 2 4 M HCl in dioxane (7.6 mL, 30.7 mmol) is added to a RT solution of methyl (R)-2-((tert-butoxycarbonyl)amino)- 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propanoate (1.06 g, 3.07 mmol) in dioxane (5.4 mL).
  • the RM is heated to 50°C for 30 min.
  • Step 3 HATU (1.437 g, 3.67 mmol) is added to a RT solution of methyl (R)-2-amino-3-(4-phenyl-1H-1,2,3-triazol-1- yl)propanoate dihydrochloride (975 mg, 3.05 mmol), boc-N-methyl-L-leucine (773 mg, 3.05 mmol) and DIPEA (2.61 mL, 15.3 mmol) in MeCN (10.9 mL). The RM is stirred at RT for 10 min, then water and DCM are added. The layers are separated, the inorg. layer extracted with DCM (1x), and the combined org. layers are dried (over phase separator) and concentrated.
  • Step 4 NaH (381 mg, 9.95 mmol) is added to a -20°C solution of methyl (R)-2-((S)-2-(tert(- butoxycarbonyl)(methyl)amino)-4-methylpentanamido)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propanoate (1.772 g, 3.32 mmol) and MeI (0.834 mL, 13.3 mmol) in DMF (28.2 mL). The RM is stirred at -20°C for 17 min, then quenched with 1 M aq. HCl soln (84.6 mL) and Et 2 O. The layers are separated and the inorg.
  • N-(tert-butoxycarbonyl)-O-(cyclohex-2-en-1-yl)-D-homoserine (3.06g) as a brown oil which is used as such in the next step.
  • Step 3 Under N 2 , methyl N-(tert-butoxycarbonyl)-O-(cyclohex-2-en-1-yl)-D-homoserinate (900 mg, 2.87 mmol) is dissolved in MeOH (20 mL); the vessel is purged with N 2 /vacuum (3x) before 10% Pd/C (90 mg) is added. After inertising another three times a H 2 balloon is connected and the RM is stirred for 1 h under H 2 atmosphere. The heterogeneous reaction mixture is filtered over a glass fiber filter (washing with methanol/THF).
  • Step 4 Sodium hydride (60 % dispersion in mineral oil) (149 mg, 3.9 mmol) is added portionwise to a RT solution of methyl N-(tert-butoxycarbonyl)-O-cyclohexyl-D-homoserinate (820 mg, 2.6 mmol) and iodomethane (0.245 mL, 3.9 mmol) in DMF (8 mL) under argon and the resulting mixture is stirred for 1h. The RM is partitioned between water and EtOAc. The layers are separated and the inorg. layer is extracted further with EtOAc (2x). The combined org.
  • Step 5 to 7 The title compound is prepared as a colorless oil from Boc-A/-methyl-L-leucine and methyl N-(tert- butoxycarbonyl)-0-cyclohexyl-N-methyl-D-homoserinate following the sequence of reactions described for C-18.1, step 2 to 4.
  • Step 1 To a solution of (R)-4-bromo-2-[[(tert-butoxy)carbonyl]amino]butanoic acid tert-butyl ester (300 mg, 0.843 mmol) in DMF (2 mL) at RT is added phenol (0.0786 mL, 0.885 mmol) and K2CO3 (349 mg, 2.53 mmol). The RM is stirred at 60°C RT for 1 hr. Water and EtOAc are added and the 2 phases are separated. The inorg. layer is extracted further with EtOAc (2X). The combined org. layers are dried over Na2S04, filtered and concentrated.
  • Step 2 Sodium hydride (60 % dispersion in mineral oil) (43.7 mg, 1.14 mmol) is added portionwise to a RT solution of tert-butyl N-(tert-butoxycarbonyl)-0-phenyl-D-homoserinate (267 mg, 0.76 mmol) and iodomethane (0.0717 mL, 1 .14 mmol) in DMF (5 mL) under argon and the resulting mixture is stirred for 1h. The RM is partionned between water and EtOAc. The layers are separated, and the aq. phase is re-extracted with EtOAc (2x). The combined org.
  • Step 3 TFA (0.474 mL, 6.18 mmol) is added to a RT solution of tert-butyl N-(tert-butoxycarbonyl)-N-methyl-0-phenyl- D-homoserinate (226 mg, 0.618 mmol) in DCM (5 mL) and the resulting mixture is stirred at RT for 6h.
  • Step 4 Thionyl chloride (0.375 mL, 5.08 mmol) is added at rt to a solution of (R)-1-carboxy-N-methyl-3- phenoxypropan-1-aminium 2,2,2-trifluoroacetate (266 mg, 1 .27 mmol) in MeOFI (5 mL).
  • the RM is stirred at 60°C for 16 h.
  • the mixture is poured into ice water and extracted with DCM (3x).
  • the combined org. layers are washed with brine, dried over MgS04, filtered and concentrated under reduced pressure to give the crude methyl N-methyl-O- phenyl-D-homoserinate (101 mg) as a colorless oil. No purification at this stage.
  • Step 1-3 The sequence of the 3 first reactions described for C-18.2 gives the key intermediate methyl O-benzyl-N- (N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-homoserinate as a colorless oil after purification by FC (0 to 100% of EtOAc in Heptane).
  • Step 4 Under N2, methyl 0-benzyl-N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-homoserinate (5500 mg, 11.8 mmol) is dissolved in MeOH (100 mL); the vessel is purged with i h/vacuum (3x) before Pd(OH)2/C (20 wt. %) (830 mg) is added. After inertising another three times a H2 balloon is connected and the RM is stirred for 16 h under H2 atmosphere. The heterogeneous RM is filtered over a glass fiber filter (washing with methanol/THF).
  • Step 5 DIAD (0.194 mL, 0.966 mmol) is added dropwise to an ice-chilled suspension of 2-hydroxy-5-methylpyrazine (80 mg, 0.69 mmol), methyl N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-homoserinate (271 mg, 0.725 mmol), NEt3 (0.0962 mL, 0.69 mmol) and polymer supported triphenylphosphine (1.32 mmol/g) (787 mg, 1.04 mmol) in THF (30 mL). The resulting RM is stirred at RT for 1h. The polymer is filtered off.
  • Step 6 To the mixture of epimers methyl (RS)-N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-0-(5- methylpyrazin-2-yl)homoserinate (376 mg, 0.806 mmol) in dioxane (10 mL) is added NaOH 1 M (1.6 mL, 1.61 mmol). The RM is stirred at 50°C for 1 h; it is then left returning to RT and is treated with 0.5 ml of saturated NH4CI solution. The resulting mixture is concentrated to dryness. The crude residue is partitioned between DCM and Water and the DCM layer is collected. The inorg.
  • Step 1 To a pale-yellow solution of 3-methyl-D-valine methyl ester (1080 mg, 7.14 mmol) in dioxane (20 mL) is added NaOH 1 M (14.3 mL, 14.3 mmol). The resulting mixture is then treated with B0C2O (1.84 mL, 7.85 mmol) and stirred at room temperature for 24h. The mixture is concentrated under reduced pressure and the residue is partitioned between sat. aq. NH4CI solution and DCM. The inorg. layer is extracted further with DCM (2x) and the combined org. extracts are dried over MgSC and concentrated under reduced pressure.
  • Step 2 Sodium hydride (60 % dispersion in mineral oil) (253 mg, 6.6 mmol) is added portionwise, at RT, under argon, to a solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoate (1080 mg, 4.4 mmol) and iodomethane (0.415 mL, 6.6 mmol) in DMF (17 mL). The resulting mixture is stirred at RT for 1h. The RM is quenched by careful addition of sat. aq. NH 4 CI and the aq. layer is extracted with EtOAc (3x). The combined org. extracts are washed with a sat.
  • Step 1 Paraformaldehyde (579 mg, 4.5 mmol) is added to a RT soln. of Boc-D-Ser-(Bzl)-OH (271 mg, 0.9 mmol) and pTsOH (15.8 mg, 0.09 mmol) in PhMe (9 mL) and the RM is refluxed in a Dean Stark apparatus overnight. The mix. is washed with aq. NaHCCh, the org. layer is separated, dried (MgSC ) and concentrated under reduced pressure.
  • Step 2 TFA (2.0 mL, 26.1 mmol) is added to a RT soln. of ferf-butyl (R)-4-((benzyloxy)methyl)-5-oxooxazolidine-3- carboxylate (179 mg, 0.581 mmol) and triethylsilane (0.5 mL, 3.1 mmol) in CHCb (3 mL) and the RM is stirred at RT for 3 h. The mix. is concentrated, and the residue is re-dissolved in TBME and extracted with aq. NaFICOa. The aq. layer is acidified with 1 N HCI to pH 3 and extracted with TBME. The org. layer is concentrated to yield O-benzyl-A/- methyl-DL-serine as a white solid which is used as such in the next step.
  • Step 3 Di-ferf-butyl dicarbonate (128 mg, 0.581 mmol) is added to a RT soln. of 0-benzyl-A/-methyl-D-serine (122 mg, 0.581 mmol) and TEA (0.404 mL, 2.9 mmol) in THF (6 mL) and the RM is stirred at RT overnight. The mix. is concentrated and to the residue is added TBME and water. The layers are separated and the aq. layer is acidified (pH 5) with 10% citric acid. The aq. layer is extracted with TBME (3x) and the combined org.
  • Table D1-1 Listed in Table D1-1 below are building blocks D1 that are prepared from the corresponding starting materials in analogy to the sequence described above for D1-1.1.
  • Step 1 In a Dean-Stark apparatus, pTsOFI (65.3 mg, 0.336 mmol) is added to a RT suspension of Fmoc-Gly-OFI (1 .0 g, 3.36 mmol) and 3,3-dimethylbutyraldehyde (0.489 mL, 3.7 mmol) in PhMe (60 mL) and the resulting turbid mix. is refluxed at 110°C for 4 h. After cooling to RT the RM is diluted with EtOAc and the product is washed with sat. aq. NaHC03 (2x). The org.

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Abstract

La présente invention concerne : des composés macrocycliques de formule (I) dans laquelle Ar1, Ar2, R1, R2, R3, R4 et X sont tels que décrits dans la description, la préparation de ceux-ci, des sels pharmaceutiquement acceptables de ceux-ci; ainsi qu'une utilisation de ceux-ci en tant que produits pharmaceutiques, des compositions pharmaceutiques contenant au moins un composé de formule (I), et en particulier l'utilisation de ces compositions en tant que compositions modulatrices de CFTR.
PCT/EP2021/069292 2020-07-13 2021-07-12 Macrocycles en tant que modulateurs de cftr WO2022194399A1 (fr)

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IL305881A IL305881A (en) 2021-03-16 2021-07-12 Macrocycles as CFTR modulators
MX2023010924A MX2023010924A (es) 2021-03-16 2021-07-12 Macrociclos como moduladores cftr.
KR1020237032544A KR20230170906A (ko) 2021-03-16 2021-07-12 Cftr 조절제로서의 마크로사이클
EP21742129.6A EP4308575A1 (fr) 2021-03-16 2021-07-12 Macrocycles en tant que modulateurs de cftr
CA3212388A CA3212388A1 (fr) 2021-03-16 2021-07-12 Macrocycles en tant que modulateurs de cftr
AU2021434528A AU2021434528A1 (en) 2021-03-16 2021-07-12 Macrocycles as cftr modulators
BR112023018642A BR112023018642A2 (pt) 2021-03-16 2021-07-12 Composto, composição farmacêutica, e, método de tratamento de doenças e distúrbios relacionados ao regulador da condutância transmembrana da fibrose cística
JP2023556965A JP2024511752A (ja) 2021-03-16 2021-07-12 Ｃｆｔｒ調節剤としての大環状化合物
CN202180095810.8A CN116981672A (zh) 2021-03-16 2021-07-12 作为cftr调节剂的巨环

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2024056791A1 (fr) * 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Association de modulateurs de cftr macrocycliques avec des correcteurs de cftr et/ou des potentialisateurs de cftr
WO2024056779A1 (fr) * 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Forme cristalline de (3s,7s,10r,13r)-13-benzyl-20-fluoro-7-isobutyl-n-(2-(3-méthoxy-1,2,4-oxadiazol-5-yl)éthyl)-6,9-diméthyl-1,5,8,11-tétraoxo-10-(2,2,2-trifluoroéthyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tétradecahydro-[1]oxa[4,7,10,14]tétraazacycloheptadécino [16,17-f]quinoléine-3-carboxamide
WO2024056798A1 (fr) * 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Modulateurs du cftr macrocycliques

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WO2024056791A1 (fr) * 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Association de modulateurs de cftr macrocycliques avec des correcteurs de cftr et/ou des potentialisateurs de cftr
WO2024056779A1 (fr) * 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Forme cristalline de (3s,7s,10r,13r)-13-benzyl-20-fluoro-7-isobutyl-n-(2-(3-méthoxy-1,2,4-oxadiazol-5-yl)éthyl)-6,9-diméthyl-1,5,8,11-tétraoxo-10-(2,2,2-trifluoroéthyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tétradecahydro-[1]oxa[4,7,10,14]tétraazacycloheptadécino [16,17-f]quinoléine-3-carboxamide
WO2024056798A1 (fr) * 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Modulateurs du cftr macrocycliques

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