WO2017063754A1

WO2017063754A1 - Conformationally constrained macrocyclic compounds as pin1 modulators

Info

Publication number: WO2017063754A1
Application number: PCT/EP2016/025110
Authority: WO
Inventors: Daniel Obrecht; Philipp Ermert; Jean-Frangois GOSALBES; Sachin V. Shelke
Original assignee: Polyphor Ag
Priority date: 2015-10-12
Filing date: 2016-10-12
Publication date: 2017-04-20

Abstract

Conformationally constrained macrocyclic compounds of formula (I), including substituents E, G, and Q, as defined in the description and the claims, and salts thereof, have the property to modulate the activity of the peptidyl-prolyl cis/trans isomerases Pin1. Thus, these compounds and pharmaceutical compositions containing said compounds may be useful in the treatment and/or prevention of diseases or conditions in the area of proliferative disorders and diseases, such as e.g. cancer, inflammatory diseases, transplant rejection, viral infections, osteolytic bone diseases, cardiac diseases, cardiovascular diseases, respiratory diseases, acute neurological diseases, neurodegenerative diseases, immune disorders, and lymphoproliferative theileriosis.

Description

Conformationally constrained macrocyclic compounds as Pin1 modulators

The present invention provides conformationally constrained macrocyclic compounds of formula (I), as described herein below.

These conformationally constrained macrocyclic compounds have a modulating activity on the peptidyl-prolyl cis/trans isomerase Pin1 and may thus be useful in the treatment or prevention of a variety of diseases, conditions and disorders mediated by or sustained through the activity of Pin1 , or in the support of therapeutic treatments of specific disease conditions of primarily different cause. The present invention relates to methods of using these compounds in the treatment of various diseases and disorders, and to pharmaceutical compositions and forms comprising these compounds.

Isomerization of the peptidyl-prolyl bond plays an important role in many biological processes, including protein folding and regulation of various signaling pathways. Peptidyl-prolyl cis/trans isomerases (PPIases) are able to catalyse this conformational interconversion of peptidyl-prolyl bonds, and three classes of PPIases have been identified (S. D. Hanes, Biochim. Biophys. Acta 20 5, 1850(10), 2017- 2034).

The peptidyl-prolyl isomerase Pin1 [protein interacting with NI MA 1 (K. P. Lu et al., Nature 1996, 380(6574), 544-547)], belonging to the parvulin class of PPIase, is a phosphorylation-dependent peptidyl-prolyl isomerase that shows a unique substrate specificity for phosphorylated Ser/Thr-Pro motifs. This conformational isomerization by Pin1 has been reported to be critically involved in diverse regulatory processes (K. P. Lu et a/., Nat. Chem Biol. 2007, 3(10), 619-629), affecting the function, protein- protein interactions, subcellular localization, protein phosphorylation, and stability of corresponding substrate proteins (Y.-C. Liou et al., Trends Biochem. Sci. 201 1 , 36(10), 501-514 and literature cited therein; K. P. Lu et al., Trends Cell. Biol. 2002, 12, 164-172).

Human Pin1 is a small protein of 163 amino acids, comprising an N-terminal WW domain for substrate recognition, a flexible linker, and a C-terminal catalytic peptidyl- prolyl isomerase (PPI) domain (P.-J. Lu et al, J. Biol. Chem. 2002, 277(4), 2381 - 2384). High evolutionary conservation was reported for the Pin1 enzyme among eukaryotes, including mammalian Pin1 and orthologues in yeast (S. D. Hanes et al, Yeast 1989, 5(1), 55-72) and drosophila (T. Hsu et al, Nat. Cell Biol. 2001 , 3, 538- 543). The crystal structure of human full-length Pin1 , complexed with the dipeptide Ala-Pro, was first reported by R. Ranganathan et al. (0// 1997, 89(6), 875-886). Further high- resolution crystal structures of Pin1 or mutants of Pin1 , in complex with peptidic or non-peptidic compounds, have since been published (Y. Zhang et al, ACS Chem. Biol. 2007, 2(5), 320-328; WO2004/005315 A2). Importantly, structural analysis revealed key binding interactions between Pin1 and the phosphorylated Ser/Thr-Pro motif in the substrates. These interactions include the formation of salt bridge(s) in a phosphate binding pocket and hydrophobic interactions in a proline binding pocket.

Rational design and various screening approaches have been used successfully for the discovery of Pin1 inhibitors, comprising peptidic and non-peptidic compounds.

Only recently, Pin1 was identified as target of all- trans retinoic acid (S. Wei eta/., Nat.

Med. 2015, 21 (5), 457-466) which is used in the therapy for acute promyelotic leukemia and was also applied in clinical trials for treatment of advanced breast cancer. Other known Pin1 inhibitors are less advanced. For many of these compounds, potential liabilities concerning selectivity and/or stability and/or potency and/or activity on whole cells were reported (J. D. Moore, A. Potter, Bioorg. Med.

Chem. Lett. 2013, 23, 4283-4291 and literature cited therein).

Among peptidic Pin1 inhibitors, linear pentameric peptides (D. Wildemann et al, J. Med. Chem. 2006, 49(7), 2147-2150), cyclic heptameric peptides (T. Liu et al, J. Med. Chem. 2010, 53(6), 2494-250), and disulfide-bridged nonameric peptides (K. E. Duncon et ai, J. Med. Chem. 2011 , 54(11), 3854-3865) have been described. Furthermore, a series of linear peptides, including octameric peptides, were disclosed in WO2006/019982 A2 as Pin1 modulating compounds. As a general feature, peptidic Pin1 inhibitors comprise elements that mimic the phospho-Ser/Thr and/or proline moieties of the phosphorylated Ser/Thr-Pro motif in Pin1 substrates. Mimicry of the phospho-Ser/Thr moiety was mainly achieved by phosphonic or phosphoric acid-bearing residues, and corresponding peptidic inhibitors of Pin1 were frequently reported to be inactive or only weakly active in whole cell experiments. This issue was addressed by a combination strategy based on cell-penetrating peptides (W. Lian eta/., J. Am. Chem. Soc. 2014, 136(28), 9830-9833; T. Liu eta/., J. Med. Chem. 2010, 53(6), 2494-2501 ) or masking the acidic moiety by a prodrug-type ester (WO2006/124494 A1 ).

Several small molecule Pin1 inhibitors have been published in addition to the above- mentioned a\\-trans retinoic acid, including, naphthoquinone juglone, a non-reversible Pin1 inhibitor (L. Hennig et a/., Biochemistry 1998, 37, 5953-5960), hydroxy- naphthoquinone buparvaquone, used for treatment of certain parasitic infections in animals (J. Masolier et a/, Nature 2015, 520, 378-382), compounds comprising various acidic functional groups to mimic the phosphate group of the substrate (C. Guo et a/., Bioorg. Med. Chem. Lett. 2014, 24(17), 4187-4191 and literature cited therein), compounds sharing the presence of a carboxylic acid moiety (A. Potter et a/, Bioorg. Med. Chem. Lett. 2010, 20, 6483-6488), and a series of compounds all comprising an oxalic acid moiety (C. Liu et a/., Bioorg. Med. Chem. Lett. 2012, 20, 2992-2999). To improve cell-permeability masking of a phosphoric acid moiety as prodrug-type ester was described (S. Zhao, F. A. Etzkorn, Bioorg. Med. Chem. Lett. 2007, 17(23), 6615-6618). Furthermore, inhibitors of Pin1 have been disclosed in WO2004/087720 A1 , WO2006/040646 A1 , and WO2015/032998 A1 . The majority of these compounds share the presence of an acidic functional group, including carboxylic, phosphoric, phosphonic or sulfonic acids, and corresponding esters have also been disclosed, for example in WO2004/087720 A1 .

In addition to the treatment of acute promyelotic leukemia, evidence is emerging that Pin1 modulators may be useful in the treatment or prevention of other diseases and conditions related to abnormal cell growth (Z. Lu, T. Hunter, Cell Res. 2014, 24, 1033-1049 and literature cited therein; E. S. Yeh, A. R. Means, Nat. Rev. Cancer 2007, 7, 381 -387). For example, Pin1 has been reported to control normal and cancer stem cells in the human breast (Rustighi A. et a/., Mol. Med. 2014, 6(1), 99- 1 19), including effects mediated through the p53 pathway (J. E. Giardini et a/., Cancer Cell 2011 , 12, 79-91 ; F. Mantovani et a/., Biochim. Biophys. Acta 2015, 1850(10), 2048-2060). Evidence on the role of Pin1 in tumorigenesis of breast cancer has also been obtained from studies in in vivo models (G. Wulf eta/., EMBO J. 2004, 23, 3397-3407).

Furthermore, overexpression of Pin1 has been reported in many cancers (L. Bao et a/, Am. J. Pathol. 2004, 164, 1727-1737), and the use of Pin1 inhibitors has been suggested for the treatment or prevention of diverse cancers, including breast cancer (J. Z. Wang et ai, Pharmacol. Res. 2015, 93, 28-35), prostate cancer (A. Ryo et ai, Clin. Cancer Res. 2005, 11(20), 7523-7531 ; S.-Y. Chen et ai, Mol. Cell. Biol. 2006, 26(3), 929-939), cervical cancer (H. Li et ai, Oncol Rep. 2006, 16, 491-496), liver cancer (R. W. Pang et ai, J. Pathol. 2006, 210, 19-25; G. Kim et ai, Biol. Pharm. Bull. 2015, 38(7), 975-979), lung cancer (X. Tan et ai, Cancer Biol. Ther. 2010, 9(2), 1 1 1 -1 19), esophageal cancer (H. Jin etai, Oncol. Lett. 201 1 , 2(6), 1 191-1 196), colon cancer (C. J. Wim et ai, World J. Gastroenterol. 2005, 11(32), 5006-5009), gastric cancer (M. Shi et ai, Cell Biochem. Biophys. 2015, 71(2), 857-864), and lymphoma, such as non-Hodgkin lymphoma (G. Fan et ai, Cancer Res. 2009, 69(11), 4589- 4597).

From other studies it was also suggested that Pin1 inhibitors may be useful for the treatment and/or prevention of other diseases or conditions, including asthma (P. Anders, Nat. Immunol. 2005, 6, 121 1-1212), allergic pulmonary eosinophilia (S. Esnaut etai, J. Allergy Clin. Immunol. 2007, 120, 1082-1088), pulmonary fibrosis, for example caused by chronic asthma (Z.-J. Shen et ai, J. Clin. Invest. 2008, 118(2), 479-490), stroke (S. H. Baik et ai, Ann. Neurol. 2015, 77(3), 504-517), viral infections, for example HIV/AIDS (H. Hou et ai, <Se/7e 2015, 656{\ ), 9-14), infections with intracellular and extracellular pathogens, for example infections by intracellular pathogen Chlamydia trachomatis (A J. Olive et ai, Cell Host Microb. 2014, 15(1), 1 13-124), osteolytic bone diseases, for example periodontitis (Y.-A. Cho et ai, J. Dent. Res. 2015, 94(2), 371-380), cardiovascular diseases, for example diabetic vascular disease (F. Paneni et ai, Eur. Heart J. 2015, 36(13), 817-828), diabetic restenosis (L. Lv et ai, J. Cell Mol. Med. 2013, 17(8), 989-1005), nonalcoholic steatohepatitis (Y. Nakatsu et ai, J. Biol. Chem. 2012, 287(53), 44526-44535), and cardiac hypertrophy (H. Toko et ai, Circ. Res. 2013, 112(9), 1244-1252; S. Sakai et ai, Life Sci. 2014, 102(2), 98-104). Results from recent studies indicate that Pin1 may be implicated in additional inflammatory diseases (T. Boussetta et al, Blood 2010, 116(25), 5795-5802), including rheumatoid arthritis, inflammatory bowel diseases, and acute respiratory distress syndrome. Immunosuppressive effects of a Pin1 inhibitor were reported from animal studies of organ transplantation (S. Esnault et al, PLoS One 2007, 2(2), e226). Accordingly, important roles for Pin1 were also suggested in immune disorders like diabetes, multiple sclerosis and lupus, macrophage mediated tissue damage, gastritis, and myeloproliferative syndromes (Z.-H. Shen, J. S. Malter, Biomolecules 2015 , 5, 412-434) .

In addition to cell-cycle-regulated proteins and transcription factors, Alzheimer's disease-related proteins have been identified as substrates of Pin1 . Recent studies support a neuroprotective role of Pin1 with opposite directions of Pin1 dysregulation in Alzheimer's disease as compared to cancer (J. A. Driver et al, Biochim Biphys. Acta 2015, 1850(10), 2069-2076; J. A. Driver et al, Discov. Med. 2014, 17(92), 93- 99). Pin1 is also suggested to be involved in other neurodegenerative diseases, including Huntington's disease (M. T. Lin, M. F. Beal, Nature 2006, 443, 787-795; A. Grison et al, /VAS 2011 , 108(44), 17979-17984) and frontotemporal dementia that is associated with a mutation in the tau gene (J. Lim et al, J. Clin. Invest. 2008, 118(5), 1877-1889).

Pin1 inhibitors may also be useful for the treatment or prevention of certain parasite infections in animals, including infections of cattle with Theileria parasites (J. Masolier et al, Nature 2015, 520, 378-382). Importantly, the homologue of Pin1 in Theileria annulata was demonstrated to play a key role in maintaining bovine leukocyte transformation, and Pin1 inhibitor buparvaquone was able to reverse transformed phenotypes.

The present invention provides chemical entities as modulators of Pin1 . These compounds contain a macrocyclic backbone with appended substituents, including E, G, and Q. Substituent E, for example, is involved in the mimicry of the phospho- Ser/Thr moiety of Pin1 substrates. Additionally, it is essential that compounds of the invention comprise an aromatic group in substituents G and/or Q, as described herein below. Compounds based on macrocyclic scaffolds and modular approaches for their synthesis have been described in the literature and also in patent applications WO201 1/014973 A2, WO201 1/015241 A1 and WO2013/139697 A1 . The three latter publications contain versatile methods to generate macrocyclic compounds using combinatorial and parallel synthesis strategies.

In a first embodiment (1), the present invention relates to compounds of formula (I)

(I)

wherein

L is -C(O)-; or -S(0)₂-;

X is 0; S; -S(0)-; or -S(0)₂-; t is an integer of 0-1 ;

i and p are independently an integer of 0-3 with the proviso that 1≤ i+p≤ 3;

R¹ is H; CH₃; or CH₂CH₃;

R², R³, R⁴, R⁵, and R⁶ are independently H; F; or CH₃;

with the proviso that

at most three substituents of R², R³, R⁴, R⁵, and R⁶ are F; or CH₃;

R⁷ is H; or F;

R⁸ is H; F; CF₃; or Ci-₃-alkyl;

R⁹, R¹⁰, R¹¹ , R¹², and R¹³ are independently H; F; or Ci_-3 alkyl;

with the proviso that

at most three substituents of R⁹, R¹⁰, R¹¹ , R¹², and R¹³ are F; or Ci_-3 alkyl; R¹⁴ is H; or Ci_-3 alkyl;

R ⁵ is H; F; or CH₃; E is a group of one of the formulae

R¹⁷ is -C(0)OH; -S(0)₂OH; or -P(0)(OH)₂;

R¹⁸ is a group of one of the formulae

R¹⁹ is H; Ci-2-alkyl; -(CHR²²)₀C(0)OR²¹; -(CHR²²)₀S(0)₂OH;

-(CHR²²)₀P(0)(OR² )₂; -(CHR²²)₀OH; -(CHR²²)₀C(0)NH₂;

-(CHR²²)oNHC(0)NH₂; -(CHR²²)₀S(0)₂NH₂; or -(CHR²²)₀OC(0)NH₂; R²¹ is H; or Ci-4-alkyl;

R²² is H; F; or CH₃;

R²³ and R²⁴ are independently H; or CH3;

Z is -C(O)-; -S(0)₂-; -OC(O)-; -OS(0)₂-; -NR²⁴C(0)-; or -NR²⁴S(0)₂-; Z² is -C(O)-; -S(0)₂-; -(CHR²²)-; -OC(O)-; -OS(0)₂-; -NR² C(0)-; -NR² S(0) -C(0)NR²⁴-; or -S(0)₂NR²⁴-; d is an integer of 0-1 ;

if E is E1 , o is an integer of 1 -3; if E is E2, o is an integer of 0-2;

if E is E3, o is an integer of 1 -2;

if E is E4; E5; E6; E7; or E8; o is an integer of 0-1 ; with the proviso that

in E at most three substituents R²² are different from H;

G is H; Ci-6-alkyl; C2-6-alkenyl; C3-6-cycloalkyl; C3-6-heterocyclyl; C6-io-aryl;

C5-io-heteroaryl; or a group of one of the formulae

R²⁵ is H; F; CH₃; CF₃; OCH₃; OCF₃; or OCHF₂;

R²⁶ is H; F; CI; CF₃; OCF₃; OCHF₂; Ci_-2-alkyl; Ci_-2-alkoxy; or Ci_-2-thioalkoxy; R²⁷ is H; F; CI; CF₃; OCF₃; OCHF₂; CN; Ci_-3-alkyl; Ci_-3-alkoxy;

Ci-₃-thioalkoxy; -C(0)NR³ R³²; or -S(0)₂NR³ R³²;

R²⁸ is H; F; CI; CF₃; CN; OCF₃; OCHF₂; Ci_-3-alkyl; Ci_-3-alkoxy; or

Ci_-3-thioalkoxy; R²⁹ is H; F; CF₃; OCF₃; OCHF₂; Ci_-3-alkyl; Ci_-3-alkoxy; or Ci_-3-thioalkoxy; R³⁰ is H; F; CI; CF₃; OH; OCF₃; OCHF₂; N0₂; Ci_-3-alkyl; Ci_-3-alkoxy;

Ci-₃-thioalkoxy; or -NR³ R³²;

R³¹ and R³² are independently H; or CH₃;

R³³ is H; Ci-3-alkyl; or -C(0)-Ci_-3-alkyl;

T is N; or CR²⁵;

M is 0; S; or NR³³; with the proviso that

in each of G1 to G4 at least two of the substituents are H;

in each of G5 to G10 at least one the substituents is H; and with the proviso that,

if Q is O; S; -S(O)-; or -S(0)₂-; or

if R³⁴ in Q1 is H; F; CF₃; OH; SH; Ci_-8-alkyl; C_2-8-alkenyl; C_2-8-alkynyl;

Ci-8-alkoxy; Ci-e-thioalkoxy; C_3-8-cycloalkyl; C_3-8-heterocyclyl; or

-NR⁴⁸C(0)C(0)OR⁴⁸;

then G is C6-io-aryl; Cs-io-heteroaryl; or a group of one of the formulae G1 to G14;

Q is O; S; -S(O)-; -S(0)₂-; or a group of one of the formulae

Z³ is -(CHR⁴⁷)-; O; -C(O)-; -C(0)NR⁴⁸-; -NR⁴⁸C(0)-; -NR⁴⁸C(0)NR⁴⁸-;

-NR ⁸C(0)0-; -OC(0)NR⁴⁸-; -NR ⁸S(0)₂-; -S(0)₂NR⁴⁸-; or

-NR ⁸S(0)₂NR⁴⁸-;

R³⁴ is H; F; CF₃; OH; SH; Ci_-8-alkyl; C_2-8-alkenyl; C_2-8-alkynyl; Ci_-8-alkoxy;

Ci-e-thioalkoxy; C_3-8-cycloalkyl; C_3-8-heterocyclyl; C6-io-aryl;

Cs-io-heteroaryl; or -NR ⁸C(0)C(0)OR⁴⁸;

R³⁵ is H; or CH₃;

R³⁶ is a group of one of the formulae

R³⁷ is H; F; CI; CH₃; 0CH₃; CF₃; 0CF₃; or 0CHF₂;

R³⁸ is H; F; CI; CF₃; 0CF₃; 0CHF₂; Ci-4-alkyl; C_2-4-alkenyl; Ci_-4-alkoxy;

Ci_-4-thioalkoxy; or C_3-4-cycloalkyl;

R³⁹ is H; F; CI; Br; I; CF₃; OH; 0CF₃; 0CHF₂; N0₂; CN; Ci_-6-alkyl; Ci_-6-alkoxy;

Ci-6-thioalkoxy; C_3-6-cycloalkyl; C_3-6-heterocyclyl; -C(0)OH;

-C(O)NR⁴⁰R⁴¹; or -S(O)₂NR⁴⁰R⁴¹;

R⁴⁰ and R⁴¹ are independently H; or Ci_-3-alkyl;

R⁴² is C6-aryl-Ci-₄-alkyl; C5-6-heteroaryl-Ci_-4-alkyl; or a group of formula

H16

R⁴³ is C6-aryl; Cs-6-heteroaryl; or a group of one of the formulae

H17 H18 H19 R⁴⁴ is H; F; CI; CF₃; OH; OCF₃; OCHF₂; N0₂; CN; d-4-alkyl; d-4-alkoxy;

Ci-4-thioalkoxy; or C3-4-cycloalkyl;

R⁴⁵ is H; F; CI; CF₃; OCF₃; OCHF₂; Ci-4-alkyl; Ci-4-alkoxy; or Ci_-4-thioalkoxy; R⁴⁶ is H; Ci-e-alkyl; -C(0)-Ci_-6-alkyl; or -C(0)-C₃-₆-cycloalkyl;

R⁴⁷ is H; F; CI; CH₃; or CF₃;

R ⁸ is H; or Ci_-3 alkyl;

M' is O; S; or NR⁴⁶;

T' is N; or CR³⁷;

U is 0; S; or CHR⁴⁷; m and n are independently an integer of 0-4 with the proviso that n+m<4;

e is an integer of 0-1 ;

g is an integer of 0-2; with the proviso that,

if G is H; C1-6 alkyl; C2-6-alkenyl; C_3-6-cycloalkyl; or C_3-6-heterocyclyl;

then Q is Q1 ; or Q2; R³⁴ in Q1 is C6-io-aryl; or Cs-io-heteroaryl; and with the proviso that,

if i is 1 ; or p is 0;

then Q is Q1 ; or Q2;

and with the further proviso that,

if G is H; C1-6 alkyl; C2-6-alkenyl; C_3-6-cycloalkyl; or C₃.

then R³⁴ in Q1 is C6-io-aryl; or Cs-io-heteroaryl; and with the proviso that,

in Q at most 3 substituents R⁴⁷ are different from H;

an aromatic 5-membered (t=0) or 6-membered (t=1 ) ring system is positioned between functional moieties L and X; if t=0,

Y¹ is CR⁴⁹; NR⁵⁵; N; O; or S;

Y² is CR⁵⁰; NR⁵⁵; N; O; or S;

Y³ is CR⁵¹ ; NR⁵⁵; N; O; or S; with the proviso that

the aromatic 5-membered ring system is a group of one of the formulae

wherein Y' is NR⁵⁵; O; or S; if t=1 ,

Y¹ is CR⁴⁹; or N

Y² is CR⁵⁰; or N

Y³ is CR⁵¹ ; or N

Y⁴ is CR⁵²; or N with the proviso that

the aromatic 6-membered ring system is a group of one of the formulae

and with the further proviso that

in H29 two of the substituents are H;

in each of H30 to H33 one of the substituents is H; R⁴⁹ and R⁵⁰ are independently H; F; CI; CH₃; CH₂CH₃; CF₃; OCH₃;

OCF₃; or OCHF₂;

R⁵¹ is H; F; CI; CF₃; OCF₃; OCHF₂; N0₂; NH₂; OH; CN; d-4-alkyl; C_2-4-alkenyl;

C_2-4-alkynyl; C_3-4-cycloalkyl; Ci-4-alkoxy; Ci-4-thioalkoxy; or -NR⁵³R⁵⁴; R⁵² is H; F; CI; CH₃; CF₃; OCF₃; OCHF₂; or OCH₃;

R⁵³ and R⁵⁴ are independently H; or Ci_-2-alkyl;

R⁵³ and R⁵⁴ together with the nitrogen atom to which they are connected can form C_3-5-heterocyclyl moieties;

R⁵⁵ is H; or CH₃; and wherein

in each such compound at most 12 halogen substituents are present; or stereoisomers; or tautomers or rotamers thereof; or a salts; or a pharmaceutically acceptable salts; or a solvates thereof.

A bond drawn as dotted line indicates the point of attachment of the corresponding radical or substituent. For example, the drawing below

represents the 5-hydroxy-naphth-2-yl substituent.

For the avoidance of doubt, some of the aforementioned substituents, for example, but not limited to, R⁹, R¹⁰, R¹¹ , R¹², R²¹ , R²², R⁴⁷, and R⁴⁸; as well as some of the indices (for example o, and g) may occur several times within the same molecular entity. In such a case each of them shall be selected independently from others specified by the same symbol, unless otherwise indicated. "Salts" as understood herein are especially, but not limited to, the pharmaceutically acceptable salts of compounds of formula (I). Such salts are formed, for example, as acid addition salts with organic or inorganic acids, from macrocyclic compounds of the invention with a basic nitrogen atom. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids; like acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantine-carboxylic acid, benzoic acid, salicylic acid, 4 aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxy-ethanesulfonic acid, ethane-1 ,2- disulfonic acid, benzene-sulfonic acid, 2-naphthalenesulfonic acid, 1 ,5-naphthalene- disulfonic acid, 2-, 3- or 4-methyl-benzene-sulfonic acid, methylsulfuric acid, ethyl- sulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.

As used in this description, the term "alkyl", taken alone or in combinations (i.e. as part of another group, such as "aryl-Ci-6-alkyl"), designates saturated, straight-chain or branched hydrocarbon radicals and, unless otherwise indicated, may be optionally substituted with at most 2 substituents selected from the group of F and CI. The term "Cx-y-alkyl" (x and y each being an integer) refers to an alkyl group as defined above containing x to y carbon atoms. For example a Ci-6-alkyl group contains one to six carbon atoms. Representative examples of alkyl groups include methyl, ethyl, n- propyl, /so-propyl, /7-butyl, /so-butyl, sec-butyl, fe -butyl, /7-pentyl, /7-hexyl and the like.

The term "alkenyl", taken alone or in combinations, designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four olefinic double bonds. Such alkenyl moieties, unless otherwise indicated, may be optionally substituted with at most 2 substituents selected from the group of F and CI, and can independently exist as E or Z configurations per double bond, which are all part of the invention. The term "C_x-y-alkenyl" (x and y each being an integer) refers to an alkenyl group as defined above, containing x to y carbon atoms. Examples of this moiety include, but are not limited to, vinyl, prop-1-en-1-yl, 2- methylprop-1 -en-1 -yl, and allyl.

The term "alkynyl" designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four triple bonds. The term "C_x-y-alkynyl" (x and y each being an integer) refers to an alkynyl group as defined above, containing x to y carbon atoms. Examples of this moiety include, but are not limited to, prop-2-yn-1 -yl.

The term "cycloalkyi" refers to a saturated or partially unsaturated alicyclic moiety having from three to eight carbon atoms and, unless otherwise indicated, may be optionally substituted with at most 2 substituents selected from the group of F and CI. The term "C_x-_y-cycloalkyl" (x and y each being an integer) refers to a cycloalkyi group as defined above, containing x to y carbon atoms. Examples of this moiety include, but are not limited to, cyclobutyl, cyclohexyl, norbornyl and the like. The term "heterocyclyl" describes a saturated or partially unsaturated mono- or bicyclic moiety having from one to seven ring carbon atoms and one or more ring heteroatoms selected from oxygen, sulphur or nitrogen, provided the nitrogen is forming an aromatic amino group, or is part of an amide, urea, urethane, or sulfonamide group within the heterocyclyl moiety. The term "C_x-_y-heterocyclyl" (x and y each being an integer) refers to a heterocyclyl group as defined above, containing x to y ring atoms. Examples of this moiety include, but are not limited to, morpholino, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and the like.

The term "aryl", taken alone or in combinations, designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings. The term "C6-aryl" refers to phenyl. The term "C6-io-aryl" refers to phenyl or naphthyl, which, unless otherwise indicated, may be optionally substituted with at most 3 substituents selected from the group of F, CI, CF3, OCF3, and OCF2. The term "heteroaryl", taken alone or in combinations, designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to four heteroatoms selected from the group consisting of O, S and N and whereby the heteroaryl radicals or tautomeric forms thereof may be attached via any suitable atom. The term "C_x-y-heteroaryl" (x and y each being an integer) refers to a heteraryl group as defined above, containing x to y ring atoms. Said heteroaryl ring(s) are optionally substituted, e.g. as indicated above for "aryl". Examples of the term "C5-6-heteroaryl" include, but are not limited to, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, pyrimidinyl, pyridyl and the like. Examples of the term "Cs-io-heteroaryl" include, but are not limited to, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, pyrimidinyl, pyridyl, quinolinyl, benzothiofuranyl and the like.

The term "-C(0)-C_x-_y-alkyl", as used herein, refers to an C_x-y-alkyl group as defined above, connected to a carbonyl group. Representative examples of -C(0)-C_x-y-alkyl moieties include, but are not limited to, acetyl, propanoyl, /so-butanoyl and the like.

The term "-C(0)-C3-6-cycloalkyl", as used herein, refers to an C_x-y-cycloalkyl group as defined above, connected to a carbonyl group. Representative examples of -C(0)-C3-6-cycloalkyl moieties include, but are not limited to, cyclopropyl-methanoyl, cyclobutyl-methanoyl and the like.

The term "C₆-aryl-C_x-_y-alkyl", as used herein, refers to an C_x-y-alkyl group as defined above, substituted by an C6-aryl group, as defined above. Representative examples of C6-aryl-C_x-y-alkyl moieties include, but are not limited to, benzyl, 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.

The term "C5-6-heteroaryl-C_x-y-alkyl", as used herein, refers to an C_x-y-alkyl group as defined above, substituted by a Cs-6-heteroaryl group, as defined above. Examples of C5-6-heteroaryl-C_x-y-alkyl groups, for example, include pyridin-3-ylmethyl, (1 H-pyrrol-2- yl)ethyl and the like.

The terms "alkoxy" and "aryloxy", taken alone or in combinations, refer to the groups of -O-alkyl and -O-aryl respectively, wherein an alkyl group or an aryl group is as defined above. The term "C_x-y-alkoxy" (x and y each being an integer) refers to an -O- alkyl group as defined above containing x to y carbon atoms attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, n- propoxy, /so-propoxy, /7-butoxy, fe -butoxy and the like. Examples of aryloxy include e.g. phenoxy.

The term "thioalkoxy", taken alone or in combinations, refers to an -S-alkyl group, wherein an alkyl group is as defined above. The term "C_x-y-thioalkoxy" (x and y each being an integer) refers to an -S-alkyl group as defined above containing x to y carbon atoms attached to an sulfur atom. Representative examples of thioalkoxy groups include methlythio, ethylthio and the like. The term "halogen" refers to a fluorine substituent (F), a chlorine substituent (CI), a bromine substituent (Br) or an iodine substituent (I).

"Amino" designates primary, secondary or tertiary amine groups. Particular secondary and tertiary amine groups are alkylamine, dialkylamine, arylamine, diarylamine, arylalkylamine and diarylamine groups wherein the alkyl or aryl is as herein defined and optionally substituted.

For the avoidance of doubt the term "heteroatom" refers to any atom that is not carbon or hydrogen.

The term "isomer" comprises species of identical chemical formula, constitution and thus molecular mass, such as but not limited to C=C-double bond or amide cis/trans isomers, rotamers, conformers and diastereomers. All possible stereoisomers - explicitly including atropisomers - conformers and rotamers as well as salts, solvates, clathrates, N-oxides, or isotopically enriched or enantiomerically enriched versions of macrocyclic compounds of formula (I) are part of this invention. A further embodiment (2) of the invention relates to compounds of formula (I) according to embodiment (1 ),

wherein

2 stereocenters are further defined as in formula (II)

(II)

if Q is Q1 ;

then, in the moiety comprising Q1 , one further stereocenter is defined formula (III)

if Q is Q2;

then, in the moiety comprising Q2, one further stereocenter is defined formula (IV)

or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof. A further embodiment (3) of the invention relates to compounds of formula (I) according to embodiment (2),

wherein

L is -C(O)-;

X is O; t is 0;

i is 1 , and p is 1 ; or

i is 2, and p is 1 ;

R is CH₃; or CH₂CH₃;

or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (4) of the invention relates to compounds of formula (I) according to embodiment (2),

wherein

L is -C(O)-;

X is O; t is 1 ;

i is 1 , and p is 1 ; or

i is 2, and p is 1 ;

R¹ is CH₃; or CH₂CH₃;

A further embodiment (5) of the invention relates to compounds of formula (I) according to embodiment (4),

wherein

E is E1 ; E2; E3; E5; or E7;

G is Ci-3-alkyl; C_6-io-aryl; C₅-io-heteroaryl; G1; G2; G3; G4; G5; G6; G7; G8;

G9; G10; orG13;

R³⁰is H; OH; or-NR³R³²;

R³ and R³² are H; with the proviso that,

if Q is O; orS; or

if R³⁴in Q1 is H; F; CF₃; OH; SH; Ci_-8-alkyl; C₂-₈-alkenyl; C₂-8-alkynyl;

Ci-8-alkoxy; Ci-s-thioalkoxy; C3-8-cycloalkyl; C3-s-heterocyclyl; or

-NR⁴⁸C(0)C(0)OR⁴⁸;

then G is C₆-io-aryl; C₅-io-heteroaryl; G1; G2; G3; G4; G5; G6; G7; G8; G9;

G10; orG13;

Qis 0;S;Q1;orQ2;

R³⁶is H6; H7; H8; orH9;

R³is H18;

R⁴⁴ is H; F; CI; CF₃; OCF₃; OCHF₂; Ci_-4-alkyl; Ci-4-alkoxy; Ci-4-thioalkoxy; or C3-4-cycloalkyl;

R⁴⁵is H; F; CI; or CH₃;

R⁴⁷ and R⁴⁸ are H;

m and n are 0;

e is 0;or1;

g is 0;or1; with the proviso that,

if G is Ci-₃alkyl;

then Q is Q1 ; or Q2; R³⁴ in Q1 is C₆-io-aryl; or C₅-io-heteroaryl; and with the proviso that,

if i is 1; or p is 0;

then Q is Q1; orQ2;

and with the further proviso that,

if G is C_1-3alkyl;

then R³⁴ in Q1 is C₆-io-aryl; or C₅-io-heteroaryl; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (6) of the invention relates to compounds of formula (I) according to embodiment (5),

wherein

E is E1 ; E2; E3; or E5;

R¹⁹ is H; -(CHR22)oC(0)OR²¹ ; -(CHR²²)oS(0)₂OH;

-(CHR²²)₀P(0)(OR² )₂; -(CHR²²)₀OH; -(CHR²²)₀C(0)NH₂;

-(CHR²²)oNHC(0)NH₂; -(CHR²²)₀S(0)₂NH₂; or -(CHR²²)₀OC(0)NH₂; R² is H; CH₃; CH₂CH₃; or -CH(CH₃)₂;

Z is -C(O)-; or -S(0)₂-;

Z² is -C(O)-; -S(0)₂-; -(CHR²²)-; -C(0)NR²⁴-; or -S(0)₂NR²⁴-; d is 0;

if E is E1 , o is an integer of 1 -2;

if E is E2, o is an integer of 0-1 ;

if E is E3, o is 1 ;

if E is E5, o is 0;

G is Ci-3-alkyl; G5; or G13;

R³⁰ is H; OH; or -NR³¹R³²;

R³¹ and R³² are H;

T is N; or CH; with the proviso that

G13 is a group of one of the formulae

G13¹ G13" and with the proviso that,

if Q is O; S; or if R³⁴ in Q1 is H; F; CF₃; OH; Ci-4-alkyl; C₂-4-alkenyl; or Ci_-4-alkoxy;

or-NR⁴⁸C(0)C(0)OR⁴⁸;

then G isG5; G13'; orG13"; Qis 0; S; Q1; orQ2;

Z³ is -NR⁴⁸C(0)-; -NR⁴⁸C(0)NR⁴⁸-; or -NR⁴⁸S(0)₂-;

R³⁴is H; F; CF₃; OH; Ci_-4-alkyl; C₂-₄-alkenyl; or Ci_-4-alkoxy; or

-NR⁴⁸C(0)C(0)OR⁴⁸;

R³⁶ is H6; H7; or H8;

R³⁷is H; F; CI; CH₃; OCH₃; CF₃; OCF₃; orOCHF₂;

R³⁸ is H; F; CI; CF₃; OCF₃; OCHF₂; Ci-4-alkyl; C_2-4-alkenyl; Ci_-4-alkoxy;

Ci_-4-thioalkoxy; or C_3-4-cycloalkyl;

R³⁹ is H; F; CI; Br; I; CF₃; OH; OCF₃; OCHF₂; CN; Ci_-6-alkyl; Ci_-6-alkoxy;

Ci-6-thioalkoxy; C_3-6-cycloalkyl; or C_3-6-heterocyclyl;

R⁴³is H18;

R⁴⁴ is H; F; CI; CF₃; OCF₃; OCHF₂; Ci_-4-alkyl; Ci-4-alkoxy; Ci-4-thioalkoxy; or

C_3-4-cycloalkyl;

R ⁵is H; F; CI; or CH₃;

R⁴⁷ and R⁴⁸ are H; m and n are 0;

e is 1 ;

g is 0; or1;

U is 0; orCHR⁴⁷; with the proviso that,

if i is 1, and p is 1;

then Q is Q1; orQ2;

and with the further proviso that,

if G is Ci_-3alkyl;

then Q is Q2; and with the proviso that,

if i is 2, and p is 1 ;

then Q is O; S; or Q1 ; R³⁴ in Q1 is H; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (7) of the invention relates to compounds of formula (I) according to embodiment (6),

wherein

t is 1 ;

E is E1 ; E2; E3; or E5;

R ⁸ is H1 ;

R ⁹ is H; -(CHR²²)oC(0)OR²¹ ; or -(CHR²²)oP(0)(OR² )2; the 6-membered (t=1) ring system positioned between functional moieties L and X is H29; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (8) of the invention relates to compounds of formula (I) according to embodiment (7),

wherein

for substituent E

R¹⁷ is -C(0)OH; or -P(0)(OH)₂;

R¹⁹ is H; or -(CHR²²)₀C(0)OR²¹;

R² is H; CH₃; or CH₂CH₃;

Z is -C(O)-;

Z² is -C(0)NH-;

G is Ci-3-alkyl; G5; G13¹; or G13";

R²⁵ is H;

R²⁶, R²⁷, and R²⁸ are independently H; F; CI; CH₃; CF₃; OCH₃; OCF₃; or OCHF₂;

R²⁹ is H; F; CH₃; or CF₃; with the proviso that,

if R³⁴ in Q1 is H; F; CF₃; OH; Ci-4-alkyl; C₂-4-alkenyl; or Ci-4-alkoxy;

then G is G5; G13' or G13"; Q is Q1 ; or Q2;

R³⁴ is H; F; CF₃; OH; Ci_-4-alkyl; C_2-4-alkenyl; or Ci_-4-alkoxy;

R³⁶ is is a group of one of the formulae

H6¹ H7¹

R³⁷ and R³⁸ are independently H; F; CI; CH₃; OCH₃; CF₃; OCF₃; or OCHF₂; R³⁹ is H; F; CI; CF₃; OH; OCF₃; OCHF₂; d-4-alkyl; d-4-alkoxy;

or Ci-4-thioalkoxy;

M' is 0; or S; with the proviso that,

if i is 1 , and p is 1 ;

then Q is Q1 ; or Q2;

and with the further proviso that,

if G is Ci_-3 alkyl;

then Q is Q2; and with the proviso that,

if i is 2, and p is 1 ;

then Q is Q1 ; R³⁴ in Q1 is H; for H29 positioned between functional moieties L and X

R⁴⁹, R⁵⁰ and R⁵² are independently H; F; CI; CH₃; CF₃; OCH₃; OCF₃; or OCHF₂;

R⁵¹ is H; F; CI; CF₃; OCF₃; OCHF₂; NH₂; Ci_-3-alkyl; or Ci_-3-alkoxy; with the proviso that in H29 two of the substituents are H; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (9) of the invention relates to compounds of formula (I) according to embodiment (7),

wherein

for substituent E R¹⁹ is H; -(CHR²²)oC(0)OR²¹; or -(CHR²²)₀P(0)(OR¹)₂;

R²¹ is H; CH₃; or CH₂CH₃;

Z is -C(O)-;

Z² is -C(0)NH-;

G is Ci-3-alkyl; G5; G13¹; or G13";

R²⁵is H;

R²⁶, R²⁷, and R²⁸ are independently H; F; CI; CH₃; CF₃; OCH₃; OCF₃; or OCHF₂; R²⁹ is H; F; CH₃; or CF₃; with the proviso that,

if Q is O; S; or

if R³⁴in Q1 is H; F; CF₃; OH; Ci-4-alkyl; C₂-4-alkenyl; or Ci-4-alkoxy;

then GisG5;G13' orG13";

Qis 0;S;Q1;orQ2;

R³⁴is H; F; CF₃; OH; Ci_-4-alkyl; C_2-4-alkenyl; or Ci_-4-alkoxy;

R³⁶ is is a group of one of the formulae

R³⁷ and R³⁸are independently H; F; CI; CH₃; OCH₃; CF₃; OCF₃; or OCHF₂; R³⁹ is H; F; CI; CF₃; OH; OCF₃; OCHF₂; Ci-4-alkyl; Ci-4-alkoxy;

or Ci-4-thioalkoxy;

M'is 0;orS; with the proviso that,

if i is 1, and p is 1;

then Q is Q1 ; or Q2;

and with the further proviso that,

if G is Ci_-3alkyl;

then Q is Q2; and with the proviso that,

if i is 2, and p is 1 ; then Q is O; S; or Q1 ; R³⁴ in Q1 is H; for H29 positioned between functional moieties L and X

R⁴⁹, R⁵⁰ and R⁵² are independently H; F; CI; CH₃; CF₃; OCH₃; OCF₃; or OCHF₂; R⁵¹ is H; F; CI; CF₃; OCF₃; OCHF₂; NH₂; Ci_-3-alkyl; or Ci_-3-alkoxy; with the proviso that in H29 two of the substituents are H; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (10) of the invention relates to compounds of formula (I) according to embodiment (9),

wherein

R is CH₃;

E is E1 ; E2; or E5;

R ⁷ is -C(0)OH;

R ⁹ is H; -(CH₂)oC(0)OH; for substituent Q

R³⁶ is H7'; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof

A further embodiment (1 1) of the invention relates to compounds of formula (I) according to embodiment (10),

wherein

for substituent E

if E is E1 , o is 2; for substituent Q

Z³ is -NHC(O)-; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof. A further embodiment (12) of the invention relates to compounds of formula (I) according to embodiment (1 1 ),

wherein

for substituent E

R¹⁹ is H; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (13) of the invention relates to compounds of formula (I) according to embodiment (1 1 ),

wherein

E is E1 ; or E5; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (14) of the invention relates to compounds of formula (I) according to embodiment (1 1 ),

wherein

E is E5;

R¹⁹ is -C(0)OH; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (15) of the invention relates to compounds of formula (I) according to embodiment (9),

wherein

R is CH₃;

E is E1 ; E2; or E5;

R¹⁷ is -P(0)(OH)₂;

R¹⁹ is H; for substituent Q Z³ is -NHC(O)-;

R³⁶ is H7¹; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (16) of the invention relates to compounds of formula (I) according to embodiment (15),

wherein

E is E1 ; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (17) of the invention relates to compounds of formula (I) according to embodiment (5),

wherein

t is 1 ;

R¹ is CH₃; or CH₂CH₃; a group of one of the formulae

G is CH3; phenyl; 1 -naphthyl; 2-naphthyl; or a group of one of the formulae

with the proviso that,

if Q is O; orQ1;

then G is phenyl; 1-naphthyl; 2-naphthyl; G5'; G5"; G5^m; G5^IV; G5^V; G5^VI; G5^V";

G5^vm; G5^IX; G5^X; G13¹"; or G13^IV;

Qis 0;Q1;orQ2;

Z³is -NHC(O)-; or -NHC(0)NH-;

R³⁴ is H; OH; OCH₃; or -NHC(0)C(0)OH; 3⁶ is a group of one of the formulae

with the proviso that,

if i is 1, and p is 1;

then Q is Q1; orQ2;

and with the further proviso that,

if G is CH₃;

then Q is Q2; and with the proviso that,

if i is 2, and p is 1 ;

then Q is O; orQ1; R³⁴ in Q1 is H; the 6-membered (t=1) ring system positioned between functional moieties L and X is H29;

R⁴⁹, R⁵⁰, R⁵¹, and R⁵²are H; or

R⁴⁹ is F, R⁵⁰ is H, R⁵¹ is H, and R⁵²is F; or

R⁴⁹ is F, R⁵⁰ is F, R⁵¹ is H, and R⁵²is H; or R⁴⁹ is H, R⁵⁰ is H, R⁵¹ is H, and R⁵² is CI; or

R⁴⁹ is CI, R⁵⁰ is H, R⁵¹ is H, and R⁵² is H; or

R⁴⁹ is OCH3, R⁵⁰ is H, R⁵¹ is H, and R⁵² is H; or

R⁴⁹ is H, R⁵⁰ is H, R⁵¹ is H, and R⁵² is OCH₃; or

R⁴⁹ is H, R⁵⁰ is H, R⁵¹ is NH₂, and R⁵² is H; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof. A further embodiment (18) of the invention relates to compounds of formula (I) according to embodiment (17),

wherein

i is 1 , and p is 1 ; E is a group of one of the formulae E1¹; E1 »; E1¹"; E2¹; E2"; E5¹; or E5";

G is CH3; phenyl; 1 -naphthyl; 2-naphthyl; or a group of one of the formulae G5'; G5"; G5'"; G5^IV; G5^V; G5^VI; G5^VM; G5^vm; G5^IX; G5^X; or G13¹"; with the proviso that,

if Q is Q1 ;

then G is phenyl; 1 -naphthyl; 2-naphthyl; G5'; G5"; G5'"; G5^IV; G5^V; G5^VI; G5^VM;

G5^vm; G5^IX; G5^X; or G13^m; Q is Q1 ; or Q2;

Z³ is -NHC(O)-; or -NHC(0)NH-;

R³ is -NHC(0)C(0)OH;

R³⁶ is a group of one of the formulae H7»; H7'"; H7^IV; H7^V; H7^VI; H7^V"; H7^VI";

H7^IX; H7^X; H7^XI; H6"; or H8'; with the proviso that,

if G is CH₃;

then Q is Q2; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; solvates thereof. A further embodiment (19) of the invention relates to compounds of formula (I) according to embodiment (18),

wherein

E is E1 "; or E1'"; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (20) of the invention relates to compounds of formula (I) according to embodiment (18),

wherein

E is E1¹; E2¹; E2^M; E5¹; or E5"; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (21) of the invention relates to compounds of formula (I) according to embodiment (18),

wherein

E is E5'; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof. A further embodiment (22) of the present invention may also include compounds, which are identical to the compounds of formula (I), except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in ²H (D), ³H, ¹¹C, ¹⁴C, ¹²⁷l etc. These isotopic analogs and their pharmaceutical salts and formulations are considered useful agents in the therapy and/or diagnostic, for example, but not limited to, where a fine-tuning of in vivo half-life time could lead to an optimized dosage regimen.

A further embodiment (23) of the invention relates to compounds of formula (I) according to embodiment (1 ) which are selected from the group consisting of Ex.1 to Ex.50, the lUPAC names of which are shown in Table 01 b; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (24) of the invention relates to compounds of formula (I) according to embodiment (23) which are selected from the group consisting of Ex.1 to Ex.12, Ex.14 to Ex.16, Ex.18 to Ex.23, Ex.25 to Ex.28, Ex.30 to Ex.38, and Ex.40 to Ex.50, the lUPAC names of which are shown in Table 01 b; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

A further embodiment (25) of the invention relates to compounds of formula (I) according to embodiment (23) which are selected from the group consisting of Ex.14, Ex.20, Ex.46, and Ex.49, the lUPAC names of which are shown in Table 01 b; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.

General approach for the preparation of macrocyclic compounds of the invention Constituent building blocks

The macrocyclic compounds of the invention can formally be dissected into building blocks A, B, and C. Additionally, building block C can be divided into two appropriately substituted subunits c1 and c2.

Scheme 1 : Building blocks

Buildin block A Building block B

Building block C

Substituted subunits c1 and c2 Building block A is based on appropriately substituted and protected divalent phenol or thiophenol derivatives. Building block B is corresponding to appropriately substituted and protected secondary aminoalcohols. For building block C, appropriately substituted subunits c1 and c2 are derived from suitably substituted and protected precursors, like, but not limited to, appropriately substituted and protected amino acids derivatives.

Synthesis of the building blocks

For access to building blocks A, B, and C a plethora of literature precedents exists, and corresponding synthetic approaches have also been described in WO201 1/014973 A2, WO201 1/015241 A1 and WO2013/139697 A1 , disclosing macrocyclic compounds. Functional groups not involved in the formation of the macrocydic backbone can be diversified by standard methods of organic synthesis, preferably by parallel/ combinatorial chemistry. These derivatization methods are well-known to those skilled in the art (selected references: A. R. Katritzky et al. (eds), Comprehensive Functional Group Transformations, Pergamon, 1995; S. Patai, Z. Rappoport (eds), Chemistry of Functional Groups, Wiley, 1999; J. March, Advanced Organic Chemistry, 4 ed., Wiley, 1992; D. Obrecht, J.M. Villalgordo (eds), Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Pergamon, 1998; W. Bannwarth et al. (eds), Combinatorial Chemistry: From Theory to Application, 2 ed., Wiley-VCH 2006).

General processes for the synthesis of macrocydic compounds of formula (I)

General procedures for the synthesis of libraries of macrocydic compounds of formula (I) are described below. It will be immediately apparent to those skilled in the art how these procedures have to be modified for the synthesis of individual macrocydic compounds.

The macrocydic compounds of the invention can be obtained by cyclization of suitable linear precursors which are derived from optionally substituted bifunctional phenols or thiophenols A, substituted amino alcohols B, and two building blocks forming C. If needed, further transformations can be performed.

Variable substituents can be introduced by pre- or postcyclative derivatization of one or more orthogonally protected attachment points (e.g. amino groups, carboxyl groups, hydroxyl groups) on B, C or A. Variable R-groups may also be introduced as side chain motifs of the subunits of building block C.

The macrocydic products of the invention can be prepared either in solution or on solid support.

The essential ring closure reaction may be performed between any of the building blocks; for example, macrocycles of formula (I) may be obtained by

Macrolactamization between C and B;

- Macrolactamization between A and C;

Sulfonamide formation between A and C;

Macrolactamization between two subunits of C;

Arylether or arylthioether formation between A and B; Properties and usefulness

The macrocyclic compounds of the invention can be used in a wide range of applications in order to modulate Pin1 activity, leading to the desired therapeutic effect in man or in other mammals. Especially, the compounds of the invention can be used as agents for treating and/or preventing and/or delaying the onset of diseases, disorders or conditions related to abnormal cell growth, such as various cancers, such as breast cancer, prostate cancer, cervical cancer, lung cancer, liver cancer, esophageal cancer, and gastric cancer; or lymphoma, such as non-Hodgkin lymphoma; or leukemia, such as promyelotic leukemia; inflammatory diseases, such as asthma, allergic pulmonary eosinophilia, acute respiratory distress syndrome, rheumatoid arthritis or inflammatory bowel diseases; or acute neurological disorders, such as stroke; or neurodegenerative diseases, such as Huntington's disease and frontotemporal dementia; or viral infections, such as HIV/AIDS; or infection with intracellular and extracellular pathogens, such as infections by Chlamydia trachomatis, or osteolytic bone diseases, such as periodontitis; nonalcoholic steatohepatitis; or nonalcoholic steatohepatitis; or cardivascular diseases, such as diabetic vascular disease or diabetic restenosis; or cardiac hypertrophy; or immune diseases or disorders, such as diabetes, multiple sclerosis, lupus, macrophage mediated tissue damage, gastritis, or myeloproliferative syndromes; or transplant rejection; or parasitic diseases, such as Theileriosis, such as lymphoproliferative Theileriosis caused by Theileria annulata or Theileria parva.

They can be administered singly, as mixtures of several macrocyclic compounds of the invention, in combination with other anti cancer agents, or antiviral (e.g. anti-HIV) agents, or in combination with other pharmaceutically active agents. The macrocyclic compounds can be administered per se or as pharmaceutical compositions.

The macrocyclic compounds of the invention may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well known in the art.

Pharmaceutical compositions comprising macrocyclic compounds of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active macrocyclic compounds into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.

For topical administration the macrocyclic compounds of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well known in the art.

Systemic formulations include those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

For injections, the macrocyclic compounds of the invention may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hink's solution, Ringer's solution, or physiological saline buffer. The solutions may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the macrocyclic compounds of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen free water, before use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.

For oral administration, the compounds can be readily formulated by combining the active macrocyclic compounds of the invention with pharmaceutically acceptable carriers well known in the art. Such carriers enable the macrocyclic compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated. For oral formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents. If desired, desintegrating agents may be added, such as cross linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate. If desired, solid dosage forms may be sugar coated or enteric coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In addition, flavoring agents, preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets, lozenges, etc. formulated as usual. For administration by inhalation, the macrocyclic compounds of the invention are conveniently delivered in form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol the dose unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the macrocyclic compounds of the invention and a suitable powder base such as lactose or starch.

The compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the macrocyclic compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the macrocyclic compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts.

Other pharmaceutical delivery systems may be employed such as liposomes and emulsions well known in the art. Certain organic solvents such as dimethylsulfoxide may also be employed. Additionally, the macrocyclic compounds of the invention may be delivered using a sustained release system, such as semipermeable matrices of solid polymers containing the therapeutic agent (e.g. for coated stents). Various sustained release materials have been established and are well known by those skilled in the art. Sustained release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed.

As the macrocyclic compounds of the invention may contain charged residues, they may be included in any of the above described formulations as such or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than are the corresponding free forms.

In addition, the compounds of the present invention and their pharmaceutical acceptable salts may be used per se or in any appropriate formulation in morphological different solid state forms, which may or may not contain different amounts of solvent, e.g. hydrate.

The macrocyclic compounds of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. It is to be understood that the amount used will depend on a particular application. For the use of treating or preventing diseases, disorders, or conditions with an etiology comprising, or associated with Pin1 , the macrocyclic compounds of the invention or compositions thereof, are administered or applied in a therapeutically effective amount. Determination of a therapeutically effective amount is well within the capacities of those skilled in the art, especially in view of the detailed disclosure provided herein.

For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating macrocyclic compounds concentration range that includes the I C50 as determined in an enzymatic assay. Such information can be used to more accurately determine useful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data. Dosage amounts for applications as agents for Pin1 modulation may be adjusted individually to provide plasma levels of the macrocyclic compounds of the invention which are sufficient to maintain the therapeutic effect. Therapeutically effective serum levels may be achieved by administering multiple doses each day.

In cases of local administration or selective uptake, the effective local concentration of the macrocyclic compounds of the invention may not be related to plasma concentration. One having the ordinary skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

The amount of macrocyclic compounds of the invention administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgement of the prescribing physician.

Normally, a therapeutically effective dose of the macrocyclic compounds of the invention described herein will provide therapeutic benefit without causing substantial toxicity.

Toxicity of the macrocyclic compounds of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) or the LD100 (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these animal studies can be used in formulating a dosage range that is not toxic for use in humans. The dosage of the macrocyclic compounds of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within the range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (see, e.g. E. Fingl etal. 1975, In: The Pharmacological Basis of Therapeutics, Ch.1 , p.1 ).

The effective dosage of the active ingredients employed may vary depending on the particular compound or pharmaceutical preparation employed, the mode of adminis- tration and the severity and type of the condition treated. Thus, the dosage regimen is selected in accordance with factors including the route of administration and the clearance pathway, e.g. the renal and hepatic function of the patient. A physician, clinician or veterinarian skilled in the art can readily determine and prescribe the amount of the single active ingredients required to prevent, ameliorate or arrest the progress of the condition or disease. Optimal precision in achieving concentration of active ingredients without toxicity requires a regimen based on the kinetics of the active ingredients' availability to the target sites. This involves a consideration of the distribution, equilibrium, and elimination of the active ingredients.

Examples

The following examples illustrate the invention in more detail but are not intended to limit its scope in any way. Before specific examples are described in detail the used abbreviations and applied general methods are listed.

Abbreviations

addn: addition, additional

ADDP: 1 ,1 '-(azodicarbonyl)dipiperidine

Alloc: allyloxycarbonyl

aq.: aqueous

Bn: benzyl

Boc: tert.-butoxycarbonyl

br.: broad

Bu: butyl; t-Bu: tert. butyl

Cbz: benzyloxycarbonyl

CMBP: cyanomethylenetributyl-phosphorane

d: day(s) or doublet (spectral)

DBU: 1 ,8-diazabicyclo[5.4.0]undec-7-ene

DCE: 1 ,2-dichloroethane

DIAD: diisopropyl azodicarboxylate

DIC: Λ,Λ '-diisopropylcarbodiimide

DMBA: 1 ,3-dimethylbarbituric acid

DME: 1 ,2-dimethoxyethane

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

DTT: 1 ,4-dithio-DL-threitol

DVB: divinylbenzene

equiv.: equivalent

Et: ethyl

Et₃N: triethylamine

Et₂0: diethyl ether

EtOAc: ethyl acetate

EtOH: ethanol

FC: flash chromatography

FDPP: pentafluorophenyl diphenylphosphina FI-MS: flow injection mass spectrometry

Fmoc: 9-fluorenylmethoxycarbonyl

h: hour(s)

HATU: C>-(7-azabenzotriazol-1 -yl)-/V,/V,/V',/V-tetramethyluronium hexa- fluorophosphate

Hepes: 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid

HFIP: Hexafluoroisopropanol (1 ,1 ,1 ,3,3,3-hexafluoro-2-propanol)

HOAt: 1 -hydroxy-7-azabenzotriazole

i-PrOH: 2-Propanol, isopropanol

i-Pr20: diisopropyl ether

i.v.: in vacuo

m: multiplet (spectral)

MeCN: acetonitrile

MeOH: methanol

Me: methyl

MOPS: 3-(4-morpholinyl)-1 -propanesulfonic acid

Nosyl: nitrobenzenesulfonyl

Ns: 2-nitrobenzenesulfonyl; 4-nitrobenzenesulfonyl

Pd(PPh3)₄: tetrakis(triphenylphosphine)palladium(0)

Ph: phenyl

PPh3: triphenylphosphine

prep.: preparative

i-Pr: isopropyl

i-Pr2NEt: Nethyl-A/,/V-diisopropylamine

i-PrOH: isopropanol

PyBOP: (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate q: quartet (spectral)

quant.: quantitative

quint: quintet (spectral)

rt: room temperature

s: singlet (spectral)

sat.: saturated

soln: solution

TBAF: tetrabutylammonium fluoride

TBAI: tetrabutylammonium iodide

t: triplet (spectral) trityl: triphenylmethyl

Teoc: 2-(trimethylsilyl)ethoxycarbonyl

tert.: tertiary

TFA: trifluoroacetic acid

THF: tetrahydrofuran

TLC: thin layer chromatography

Tris-HCI: tris(hydroxymethyl)aminomethane hydrochloride

T3P = T3P™ propanephosphonic acid cyclic anhydride

General Methods

TLC: Merck (silica gel 60 F254).

Flash chromatography (FC): Fluka silica gel 60 (0.04-0.063 mm) and Interchim Puriflash IR 60 silica gel (0.04-0.063 mm).

I. Analytical HPLC-MS methods:

Retention time (R_t) in minutes (purity at 220 nm in %), m/z [M+H]⁺

UV wave length 220 nm, 254 nm

MS: Electrospray Ionization

Volume of injection: 5 μΙ_

Method 1

LC-MS: Agilent HP1 100 (DAD detector)

Column: Ascentis Express™ C18 2.7 pm, 3x50 mm (5381 1-U - Supelco Inc.) Mobile Phases: A: 0.1 % TFA in Water; B: 0.085% TFA in MeCN

Column temperature: 55°C

Flow rate: 1 .3 mL/min

Gradient: 0-0.05 min: 97% A, 3% B; 2.95 min: 3% A, 97% B; 2.95-3.15 min: 3% A, 97% B; 3.17 min: 97% A, 3% B; 3.17-3.20 min: 97% A, 3% B.

Method 1a: m/z 95 - 1800, 2 sec; centroid mode, positive mode 20V

Method 1 b: m/z 95 - 1800, 2 sec; centroid mode, positive mode 80V

Method 1c: m/z 95 - 1800, 2 sec; profile mode, positive mode 40V

Method 1d: m/z 95 - 1800, 2 sec; centroid mode, positive mode 40V

Method 1e: m/z 95 - 1800, 2 sec; profile mode, positive mode 80V

Method 1f: m/z 95 - 1800, 2 sec; centroid mode, positive mode 20V

Method 1g: m/z 95 - 1800, 2 sec; profile mode, positive mode 20V Method 2

LC-MS: Agilent HP1 100 (DAD detector)

Column: Ascentis Express™ C18 2.7 pm, 3x50 mm (5381 1 -U - Supelco Inc.) Mobile Phases: A: Ammonium Bicarbonate 1 mM in Water - pH=10 in Water; B: MeCN

Column temperature: 55°C

Flow rate: 1 .3 mL/min Gradient: 0-0.05 min: 97% A, 3% B; 2.95 min: 3% A, 97% B; 2.95-3.15 min: 3% A, 97% B; 3.17 min: 97% A, 3% B; 3.17-3.20 min: 97% A, 3% B.

Method 2a: m/z 95 - 800, 2 sec; centroid mode, positive mode 40V

Method 2b: m/z 95 - 1800, 2 sec; profile mode, positive mode 40V

Method 2c: m/z 95 - 1800, 2 sec; centroid mode, positive mode 40V

Method 2d: m/z 95 - 1800, 2 sec; centroid mode, negative mode 40V

Method 2e: m/z 95 - 800, 2 sec; centroid mode, negative mode 40V

Method 3

LC-MS: Dionex Ultimate 3000 RS (DAD detector)

Column: Ascentis Express™ C18 2.7 pm, 2.1x50 mm (53822-U - Supelco Inc.) Mobile Phases: A: 0.1 % TFA in Water; B: 0.085% TFA in MeCN

Column temperature: 55°C

Flow rate: 1 .4 mL/min

Gradient: 0-0.05 min: 97% A, 3% B; 2.80 min: 3% A, 97% B; 2.80-3.18 min: 3% A, 97% B; 3.20 min: 97% A, 3% B; 3.20-3.30 min: 97% A, 3% B.

Method 3a: m/z 95 - 1800, 2 sec; centroid mode, positive mode 40V

Method 3b: m/z 95 - 1800, 2 sec; profile mode, positive mode 40V Method 4

LC-MS: Agilent HP1 100 (DAD detector)

Column: Ascentis Express™ F5 2.7 pm, 3x50 mm (53576-U - Supelco Inc.) Mobile Phases: A: 0.1 % TFA in Water; B: 0.085% TFA in MeCN

Column temperature: 55°C

Flow rate: 1 .3 mL/min

Gradient: 0-0.05 min: 70% A, 30% B; 2.95 min: 3% A, 97% B; 2.95-3.15 min: 3% A, 97% B; 3.17 min: 70% A, 30% B; 3.17-3.20 min: 70% A, 30% B.

Method 4a: m/z 95 - 1800, 2 sec; centroid mode, positive mode 40V

Method 4c: m/z 95 - 1800, 2 sec; centroid mode, positive mode 20V

Method 4b: m/z 95 - 800, 2 sec; centroid mode, positive mode 40V

Method 4d: m/z 95 - 1800, 2 sec; profile mode, positive mode 40V

Method 4e: m/z 95 - 1800, 2 sec; centroid mode, positive mode 40V Method 5

LC-MS: Agilent HP1 100 (DAD detector)

Column: Atlantis™ T3 3 μττι, 2.1 x50 mm (186003717 - Waters AG)

Mobile Phases: A: 0.1 % TFA in Water; B: 0.085% TFA in MeCN

Column temperature: 55 °C

Flow rate: 0.8 mL/min

Gradient: 0-0.1 min: 100% A, 0% B; 2.90 min: 50% A, 50% B; 2.95 min: 3% A, 97% B; 2.95-3.20 min: 3% A, 97% B; 3.22 min: 100% A, 0% B; 3.22-3.30 min: 100% A, 0% B.

Method 5a: m/z 95 - 1800, 2 sec; centroid mode, positive mode 40V Method 6

LC-MS: Agilent HP1 100 (DAD detector)

Column: Ascentis Express™ C8 2.7 pm, 3x100 mm (53852-U - Supelco Inc.) Mobile Phases: A: 0.1 % TFA in Water; B: 0.085% TFA in MeCN

Column temperature: 55°C

Flow rate: 0.75 mL/min

Gradient: 0-0.1 min: 95% A, 5% B; 1 1.0 min: 15% A, 85% B; 1 1 .02 min: 3% A, 97% B; 1 1.02-12.5 min: 3% A, 97% B; 12.55 min: 95% A, 5% B; 12.55-13.45 min: 95% A, 5% B.

Method 6a: m/z 95 - 2000, 2 sec; profile mode, positive mode 60V

Method 6b: m/z 95 - 2000, 2 sec; profile mode, positive mode 20V

Method 6c: m/z 95 - 2000, 2 sec; profile mode, positive mode 40V Method 7

LC-MS: Dionex Ultimate 3000 RS (DAD detector)

Column: Ascentis Express™ C18 2.7 pm, 2.1x50 mm (53822-U - Supelco Inc.) Mobile Phases: A: Ammonium Bicarbonate 1 mM in Water - pH=10 in Water; B: MeCN

Column temperature: 55°C

Flow rate: 1 .4 mL/min

Gradient: 0-0.05 min: 97% A, 3% B; 2.8 min: 3% A, 97% B; 2.8-3.18 min: 3% A, 97% B; 3.20 min: 97% A, 3% B; 3.20-3.30 min: 97% A, 3% B.

Method 7a: m/z 95 - 1800, 2 sec; profile mode, positive mode 40V

Method 7b: m/z 95 - 1800, 2 sec; centroid mode, positive mode 40V II. Preparative HPLC methods: . Reverse Phase - Acidic conditions

Method 1a

Column: XBridge™ C18 5 μηι, 30 x 150 mm (Waters AG)

Mobile phases:

A. 0.1 % TFA in Water/MeCN 98/2 (v/v)

B 0.1 % TFA MeCN 2. Reverse Phase - Basic conditions

Method 2a

Column: XBridge™ C18 5 μηι, 30 x 150 mm (Waters AG)

Mobile phases:

A. 10 mM Ammonium Bicarbonate pH 10/MeCN 98/2 (v/v)

B. MeCN

FI-MS: Agilent HP1 100 or Ultimate RS 3000; m/z [M+H]⁺

NMR Spectroscopy: Bruker Avance 300, ¹H-NMR (300 MHz) in the indicated solvent at ambient temperature. Chemical shifts δ in ppm, coupling constants J in Hz.

Specific Examples

In the examples below and if no other sources are cited, leading reference for standard conditions of protecting group manipulations (protection and deprotection) are 1 ) P.G.M. Wuts, T.W. Greene, Greene's Protective Groups in Organic Synthesis, John Wiley and Sons, 4th Edition, 2006; 2) P.J. Kocienski, Protecting Groups, 3rd Edition, Georg Thieme Verlag 2005; and 3) M. Goodman (ed.), Methods of Organic Chemistry (Houben-Weyl), Vol E22a, Synthesis of Peptides and Peptidomimetics, Georg Thieme Verlag 2004.

Starting materials and common intermediates (Scheme 2):

4-Hydroxybenzoic acid (1 ), 4-acetoxybenzoic acid (2), methyl 4-hydroxybenzoate (3), 2,3-difluoro-4-hydroxybenzoic acid (4), 2,6-difluoro-4-hydroxybenzoic acid (5),

3-chloro-4-hydroxybenzoic acid (6), 2-chloro-4-hydroxybenzoic acid (7), 3,5-dichloro- 4-hydroxybenzoic acid (8), 4-hydroxy-2-methoxybenzoic acid (9), 4-hydroxy-3- methoxybenzoic acid (10) and methyl 4-hydroxy-3-nitrobenzoate (1 1 ) are commercially available. Tert.-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate hydrochloride (12 HCI) is commercially available.

(2S,4R)-2-(Trimethylsilyl)ethyl 4-((tert.-butoxycarbonyl)amino)-2- (hydroxymethyl)pyrrolidine-l-carboxylate (13) was prepared as described in the preceding patent application WO201 1/014973 A2.

(2S,4R)-Allyl 4-((tert.-butoxycarbonyl)amino)-2-(hydroxymethyl)pyrrolidine-1 - carboxylate (14) was prepared as described in the preceding patent application WO2013/139697 A1.

Tert.-butyl ((3R,5S)-5-(hydroxymethyl)-1-((4-nitrophenyl)sulfonyl)pyrrolidin-3- yl)carbamate (15) was prepared by nosyl protection of the secondary amino group of 12 HCI with 4-nitrobenzenesulfonyl chloride in dioxane in the presence of aq. Na2CC>3 soln applying standard conditions.

Data of 15: C16H23N3O7S (401.4). LC-MS (method 1 a): R_t = 1.84 (99%), 402.0 ([M+H]⁺), 346. Allyl ((3R,5S)-5-(hydroxymethyl)-1-((2-nitrophenyl)sulfonyl)pyrrolidin-3-yl)carbamate (18)

At 0°C, 2-nitrobenzenesulfonyl chloride (8.77 g, 39.6 mmol) was added in portions to a mixture of 12 HCI (10.0 g, 39.6 mmol) and Et₃N (13.8 mL, 98.9 mmol) in CH₂CI₂ (400 mL). The mixture was stirred at 0°C for 2 h, followed by an aq. workup (CH2CI2, sat. aq. NaHCC>3 soln, sat. aq. NaCI soln; Na2S0₄). The solid product was suspended in Et₂0, sonicated and filtered to afford 16 (15.3 g, 96%).

A soln of 16 (13.3 g, 33.2 mmol) in dioxane (330 mL) was treated at rt for 15 h with 4 M HCI in dioxane (166 mL). The volatiles were evaporated. The residue was taken up in CH2CI2 and concentrated. The solid crude product was taken up in CH2CI2 (300 mL), sonicated and filtered to yield 17 HCI (10.4 g, 93%).

A mixture of 17 HCI (9.16 g, 27.0 mmol), dioxane (310 mL) and H₂0 (310 mL) was cooled to 0°C. Sat. aq. Na₂C0₃ soln (40 mL) was added. Allyl chloroformate (3.2 mL, 30 mmol) was slowly added. The mixture was stirred at rt for 2.5 h followed by partial evaporation of the volatiles, acidification to pH ca 1 by addn of 1 M aq. HCI soln and extraction with CH2CI2. The organic phase was washed (sat. aq. NaHCC>3 soln, sat. aq. NaCI soln), dried (Na2S0₄), filtered and concentrated to give 18 (9.78 g, 93%). Data of 18: C15H19N3C7S (385.4). LC-MS (method 1 a): R_t = 1.58 (97%), 386.0 ([M+H]⁺).

(S)-5-Allyl 1 -benzyl 2-(methylamino)pentanedioate hydrochloride (19 HCI) was prepared as described in the preceding patent application WO201 1/014973 A2.

(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(tert.-butoxy)-5- oxopentanoic acid (Fmoc-/V-methyl-L-glutamic acid γ-tert.-butyl ester; 20) is commercially available.

(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(benzyloxy)-5- oxopentanoic acid (Fmoc-/V-methyl-L-glutamic acid γ-benzyl ester; 24)

At 0°C, allyl bromide (10.0 mL, 1 16.0 mmol) was added drop by drop to a mixture of 20 (17.0 g, 38.7 mmol) and NaHCOs (16.2 g, 193.0 mmol) in DMF (70 mL). The mixture was allowed to warm to rt and stirring was then continued for 65 h. The mixture was diluted with EtOAc and filtered. The filtrate was washed (1 M aq. HCI soln, sat. aq. NaHCOs soln, sat. aq. NaCI soln), dried (Na2S0₄), filtered and concentrated to give 21 (18.7 g). The material was dissolved in CH2CI2 (170 mL), and cooled to 0°C. TFA (170 mL) was slowly added. The mixture was stirred at rt for 2 h. The volatiles were evaporated to give crude 22 (21 .8 g).

At 0°C, benzyl bromide (18.2 mL, 153.0 mmol) was added drop by drop to a mixture of crude 22 (21 .6 g) and NaHCOs (21 .4 g, 255 mmol) in DMF (120 mL). The mixture was allowed to warm to rt and stirring was then continued for 48 h. The mixture was diluted with EtOAc and filtered. The filtrate was washed (1 M aq. HCI soln, sat. aq. NaHCC>3 soln, sat. aq. NaCI soln), dried (Na2S0₄), filtered and concentrated. FC (hexane / EtOAc 100:0 to 80:20) afforded 23 (29 g; contaminated with benzyl alcohol).

At rt, a soln of 23 (14.5 g) in THF (150 mL) was treated for 1 h with Pd(PPh₃)₄ (1 .14 g) and phenylsilane (7.3 mL, 59 mmol) followed by evaporation of the volatiles and purification by FC (hexane / EtOAc, then CH₂CI₂ / MeOH) to yield 24 (7.9 g, 86%). Data of 24: C28H27NO6 (473.5). LC-MS (method 1 d): Rt = 2.43 (90%), 474.2 ([M+H]⁺). (S)-2-(((Benzyloxy)carbonyl)amino)-5-(tert.-butoxy)-5-oxopentanoic acid (25) is commercially available.

(S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-((3-methoxy-3- oxopropyl)amino)-5-oxopentanoic acid (27)

A mixture of 20 (10.0 g, 22.8 mmol) and methyl 3-aminopropanoate hydrochloride (28 HCI; 3.81 g, 27.3 mmol) was dissolved in DMF (100 mL). HATU (13.0 g, 34.1 mmol) and HOAt (4.65 g, 34.1 mmol) were added. The mixture was cooled to 0°C. i- Pr₂NEt (15.5 mL, 91 mmol) was added over 5 min. The mixture was stirred at rt for 2 h followed by an aq. workup (EtOAc, 1 M aq. HCI soln, H₂0, sat. aq. NaHCOs soln, sat. aq. NaCI soln; Na2S0₄) and purification by FC (hexane / EtOAc) to afford 26 (12.2 g). This material was dissolved in CH2CI2 (75 mL) and cooled to 0°C. TFA (48.2 mL) was slowly added. The solution was stirred at rt for 2 h. The volatiles were evaporated. The resdue was taken up in toluene and concentrated to give 27 (12.8 g; contained residual TFA, used without further purification).

Data of 27: C25H28N2O7 (468.5). LC-MS (method 1 d): Rt = 1 .91 (98%), 469.1 ([M+H]⁺).

Methyl 3-aminopropanoate hydrochloride (28 HCI) is commercially available. Tert. -butyl 3-aminopropanoate hydrochloride (29 HCI) is commercially available.

1 -Tert.-butyl 3,3-diethyl azetidine-1 ,3,3-tricarboxylate (30) is commercially available. Diethyl azetidine-3,3-dicarboxylate 2,2,2-trifluoroacetate (31 CF3CO2H):

At rt, a soln of 30 (4.6 g, 15.2 mmol) in CH₂CI₂ (80 mL) was treated with TFA (20 mL) for 90 min. The volatiles were evaporated. The residue was dissolved in toluene and concentrated to afford 31 CF3CO2H (5.9 g; contained residual TFA, purity ca 80%). Data of 31 CF3CO2H: C9H15NO4 CF3CO2H (201 .2+1 14.0). FI-MS: 202.0 ([M+H]⁺). ¹H- NMR (DMSO-de): 9.13 (br. s, NH₂ ⁺); 4.33 (br. s, 4 H); 4.23 (q, J = 7.1 , 4 H); 1.22 (t, J = 7.1 , 6 H).

3-Aminopentanedioic acid (32) is commercially available.

Dimethyl 3-aminopentanedioate hydrochloride (33 HCI)

Thionyl chloride (1.5 mL) was slowly added to an ice-cold soln of 32 (500 mg, 3.4 mmol) in MeOH (10 mL). The mixture was heated to 60°C for 4 h. The volatiles were evaporated to give 33 HCI (715 mg, 99%).

Data of 33 HCI: C7H13NO4 HCI (175.2 + 36.5). FI-MS: (176.3) ([M+H]⁺). ¹H-NMR (DMSO-de): 8.33 (br. s, NH₃ ⁺); 3.77 (quint., J = 6.5, 1 H); 3.64 (s, 6 H); 2.85 - 2.70 (m, 4 H).

(R)-Di-tert. -butyl 2-aminosuccinate hydrochloride (34 HCI), (aminomethyl)phosphonic acid (35), (2-aminoethyl)phosphonic acid (36) and (1 H-tetrazole-5-yl)methanamine (37) are commercially available.

N-Phenylglycine (38a) is commercially available. 2-(((Allyloxy)carbonyl)(phenyl)amino)acetic acid (39a)

N-Phenylglycine (38a; 3.0 g, 20 mmol) was dissolved in 5 M aq. NaOH soln (10 mL) and H₂0 (4 mL) and the solution was cooled to 0°C. Allyl chloroformate (2.3 mL, 22 mmol) was added slowly. The mixture was stirred at rt for 16 h and cooled to 0°C. More 5 M aq. NaOH soln (10 mL) and allyl chloroformate (2.0 mL, 21 mmol) were added and stirring was continued for 3 h. More 5 M aq. NaOH soln (25 mL) and allyl chloroformate (2.0 mL, 21 mmol) were added and stirring was continued for 16 h. The mixture was cooled to 0°C, acidified to pH ca 4 by addn of 4 M aq. HCI soln and extracted with CH2CI2. The organic phase was dried (Na2S0₄), filtered and concentrated to yield 39a (2.85 g, 61 %).

Data of 39a: Ci₂Hi₃N0₄ (235.2). LC-MS (method 1 g): R_t = 1.59 (95%), 235.9 ([M+H]⁺). 2-(((Allyloxy)carbonyl)(naphthalen-2-yl)amino)acetic acid (39b)

At 50°C, tert.-butyl bromoacetate (2.2 mL, 14.8 mmol) was slowly added over 1 h to a soln of 2-naphthylamine (40b; 1.0 g, 6,98 mmol) and Et₃N (3.01 mL, 21 .6 mmol) in DMF 42 mL). Stirring at 50°C was continued for 1 h, followed by the addn of tert- butyl bromoacetate (1.1 mL, 7.44 mmol) over 0.5 h. Stirring was continued for 1 h. The mixture was poured into a mixture of ice / sat. aq. NaHCC>3 soln and extracted with EtOAc. The organc phase was dried (Na2S0₄), filtered and concentrated. FC (hexane / EtOAc) gave 41 b (0.69 g, 38%).

Data of 41 b: Ci₆Hi₉N0₂ (257.3). LC-MS (method 1 a): R_t = 2.47 (89%), 258.1 ([M+H]⁺).

Aq. 1 M NaHCOs soln (5.0 mL, 5 mmol) was added to a soln of 41 b (0.65 g, 2.53 mmol) in CH2CI2 (5.0 mL), followed by allyl chloroformate (0.40 mL, 3.8 mmol). The mixture was stirred at rt for 4 h. Aq. workup (CH2CI2, sat aq. NaHCC>3 soln; Na2S0₄) and purification by FC (hexane / EtOAc) afforded 42b (0.87 g, quant, yield).

Data of 42b: C2oH₂₃N0₄ (341 .4). LC-MS (method 1 a): R_t = 2.61 (92%), 342.2 ([M+H]⁺).

A soln of 42b (1.68 g, 4.9 mmol) in CH2CI2 (15 mL) was treated with TFA (5 mL) for 3 h at rt. The volatiles were evaporated. The residue was taken up in toluene and concentrated to yield 39b (1.4 g, 100%, contained residual toluene).

Data of 39b: Ci₆Hi₅N0₄ (285.3). LC-MS (method 1 a): R_t = 1.93 (84%), 286.1 ([M+H]⁺).

2-(((Allyloxy)carbonyl)(naphthalen-1-yl)amino)acetic acid (39c)

At rt, tert.-butyl bromoacetate (8.15 mL, 55.2 mmol) was slowly added to a soln of 1- naphthylamine (40c; 5.0 g, 34.9 mmol) and Et₃N (5.3 mL, 38.0 mmol) in DMF (15 mL). The soln was stirred at rt for 2 h and then at 50°C for 16 h followed by an aq. workup (EtOAc, sat. aq. NaHCOs soln, 1 M aq. HCI soln, H₂0, sat. aq. NaCI soln;

Na2S0₄). Purification by FC (hexane / EtOAc) afforded 41c (4.38 g) which was dissolved in CH2CI2 (90 mL). Sat. aq. NaHCOs soln (90 mL) and allyl chloroformate (2.9 mL, 27 mmol) were added. The mixture was stirred at rt for 16 h. Aq. workup

(CH2CI2, sat. aq. NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc) afforded 42c (4.67 g, 39%).

Data of 42c: C20H23NO4 (341.4). LC-MS (method 1 a): R_t = 2.56 (93%), 342.1 ([M+H]⁺).

At 0°C, a soln of 42c (4.1 g, 12.0 mmol) in CH₂CI₂ (20 mL) was treated with TFA (20 mL). The soln was allowed to warm to rt and stirred then for 3 h. The volatiles were evaporated. The residue was taken up in CH2CI2 and concentrated to yield 39c (3.6 g, quant, yield, contained residual solvent).

Data of 39c: Ci₆Hi₅N0₄ (285.3). LC-MS (method 1f): R_t = 1 .86 (96%), 286.1 ([M+H]⁺). Tert.-butyl 2-((3-(trifluoromethyl)phenyl)amino)acetate (41 d)

At 70°C, tert.-butyl bromoacetate (9.2 mL, 62.0 mmol) was added to a soln of 3- (trifluoromethyl)aniline (40d; 5.0 g, 31 mmol) and Et₃N (13.0 mL, 93 mmol) in DMF (1 10 mL). The mixture was stirred for 2 h at 70°C. More tert.-butyl bromoacetate (14.0 mL, 93.1 mmol) and Et₃N (17.0 mL, 124 mmol) were added and stirring at 70°C was continued for 16 h. Again, tert.-butyl bromoacetate (14.0 mL, 93.1 mmol) was added and stirring continued for 3 h followed by aq. workup (EtOAc, ice / sat aq. NaHCOs soln, H₂0, sat. aq. NaCI soln; Na₂S0₄) and FC (hexane / EtOAc) to afford 41d (5.85 g, 68%).

Data of 41d: C13H16F3NO2 (275.3). LC-MS (method 1 g): R_t = 2.42 (91 %), 317.3 ([M+H+CH₃CN]⁺), 276.3 ([M+H]⁺).

Tert.-butyl 2-((2-methyl-5-(trifluoromethyl)phenyl)amino)acetate (41 e)

In analogy, 41e (2.59 g, 52%, purified by FC (hexane / EtOAc)) was obtained from 2- methyl-5-(trifluoromethyl)benzeneamine (40e; 3.0 g, 17.1 mmol), tert.-butyl bromoacetate (18.4 mL, 137 mmol) and Et₃N (14.4 mL, 103 mmol) applying the procedure described for the synthesis of 41 d.

Data of 41e: Ci₄Hi₈F₃N0₂ (289.3). LC-MS (method 1 g): R_t = 2.55 (99%), 290.1 ([M+H]⁺). Tert.-butyl 2-((4-methyl-3-(trifluoromethyl)phenyl)amino)acetate (41f)

In analogy, 41f (4.09 g, 82%, purified by FC (hexane / EtOAc)) was obtained from 4- methyl-3-(trifluoromethyl)benzeneamine (40f; 3.0 g, 17.1 mmol), tert.-butyl bromoacetate (17.8 mL, 120 mmol) and Et₃N (14.4 mL, 103 mmol) applying the procedure described for the synthesis of 41 d.

Data of 41f: Ci₄Hi₈F₃N0₂ (289.3). LC-MS (method 1 d): Rt = 2.52 (80%), 290.2 ([M+H]⁺).

Tert.-butyl 2-((4-fluorophenyl)amino)acetate (41g)

At rt, K₂C0₃ (1 1.18 g, 80.9 mmol) was added to a soln of 4-fluoroaniline (40g; 3.0 g, 26.9 mmol) in DMF (120 mL). The mixture was cooled to 0°C. Tert.-butyl bromoacetate (4.8 mL, 32.4 mmol) was added drop by drop within 5 min. The mixture was stirred at rt for 10 min and then heated to 40°C for 6 h. H2O and half-sat. aq. NaHCC>3 soln were added. The mixture was extracted with EtOAc. The organic phase was washed (H₂0, sat. aq. NaCI soln), dried (Na2S0₄) filtered and concentrated. Purification of the crude product by FC (hexane / EtOAc) and FC (hexane / i-PrOH) afforded 41 g (4.6 g, 75%).

Data of 41g: Ci₂Hi₆FN0₂ (225.3). LC-MS (method 1 a): R_t = 2.14 (95%), 226.1 ([M+H]⁺).

Tert.-butyl 2-((3-methoxyphenyl)amino)acetate (41 h)

In analogy, 41 h (5.1 g, 87%; purified by FC (hexane / EtOAc)) was obtained from m- anisidine (40h; 3.03 g, 24.6 mmol), tert.-butyl bromoacetate (4.3 ml_, 29.2 mmol) and K2CO3 (10.1 g, 73.2 mmol) applying the procedure described for the synthesis of 41g. Data of 41 h: C13H19NO3 (237.3). LC-MS (method 1f): R_t = 2.13 (92%), 238.1 ([M+H]⁺). Tert.-butyl 2-((5-chloro-2-methylphenyl)amino)acetate (41 i)

In analogy, 41 i (2.9 g, 53%; purified by FC (hexane / EtOAc)) was obtained from 5- chloro-2-methylaniline (40i; 3.0 g, 21.2 mmol), tert.-butyl bromoacetate (3.75 ml_, 25.4 mmol) and K2CO3 (8.8 g, 63.5 mmol) applying the procedure described for the synthesis of 41g, however heating at 40 - 50°C was continued for 21 h.

Data of 41 i: Ci₃Hi₈CIN0₂ (255.7). LC-MS (method 1f): R_t = 2.57 (97%), 256.2 ([M+H]⁺).

Tert.-butyl 4-((2-(allyloxy)-2-oxoethyl)amino)-2-methylbenzoate (43j)

Allyl chloroacetate (3.25 g, 24.1 mmol) was added drop by drop to a soln of tert.-butyl 4-amino-2-methylbenzoate (40j; 1.0 g, 4.8 mmol) and TBAI (1 .78 g, 4.8 mmol) in DMF (13 mL) and THF (13 mL). The mixture was heated to 80°C for 16 h. Aq. workup (EtOAc, sat. aq. NaHCOs soln, H2O, sat. aq. NaCI soln; Na2S0₄) and purification by FC (hexane / EtOAc) yielded 43j (0.88 g, 59%).

Data of 43j: Ci₇H₂₃N0₄ (305.4). LC-MS (method 1f): R_t = 2.44 (99%), 306.3 ([M+H]⁺).

Tert.-butyl 2-((5-nitronaphthalen-2-yl)amino)acetate (41 k)

5-Nitronaphthalen-2-amine (40k) was prepared according to the method of H. Plieninger et al. Chem. Ber. 1967, 100, 2421 - 2426; C. Parkanyi et al. Monatshefte fur Chemie 1992, 123, 637 - 645.

Data of 40k: CioH₈N₂02 (188.2). LC-MS (method 3a): R_t = 0.93 (98%), 230.1 ([M+H+CH₃CN]⁺); 189.2 ([M+H]⁺). A soln of K2CO3 (2.2 g, 15.9 mmol) and 40k (1.0 g, 5.3 mmol) in DMF (40 mL) was heated to 50°C. Tert.-butyl bromoacetate (3.1 mL, 21.2 mmol) was added and the mixture was stirred at 50°C for 16 h. Aq. workup (EtOAc, sat. aq. NaHCC>3 soln / ice, H2O, sat. aq. NaCI soln; Na₂S0₄) and FC (hexane / EtOAc) afforded 41 k (1.1 g, 69%).

Data of 41 k: Ci₆Hi₈N₂0₄ (302.3). LC-MS (method 1 a): R_t = 2.43 (89%), 303.2 ([M+H]⁺).

2-(((Allyloxy)carbonyl)(4-(tert.-butoxycarbonyl)phenyl)amino)acetic acid (39I)

Allyl chloroacetate (0.43 mL, 3.7 mmol) was added to a suspension of tert.-butyl 4- aminobenzoate (40I; 1.4 g, 7.2 mmol) and TBAI (1 .34 g, 3.6 mmol) in DMF (20 mL). The mixture was stirred at 80°C for 20 h. More allyl chloroacetate (0.21 mL, 1.8 mmol) was added and stirring was continued at 90°C for 20 h followed by aq. workup (EtOAc, half-sat. aq. NaHCOs soln; Na₂S0₄). Purification by FC (hexane / EtOAc / MeOH) afforded 43I (0.76 g, 72%).

Data of 43I: Ci₆H₂i N0₄ (291 .3). LC-MS (method 1 d): R_t = 2.28 (98%), 292.1 ([M+H]⁺). At 0°C, allyl chloroformate (0.67 mL, 6.3 mmol) in CH2CI2 (2 mL) was added to a mixture of sat. aq. NaHCOs soln (16.8 mL) and a soln of 43I (1.75 g, 6.0 mmol) in CH2CI2 (40 mL). The mixture was stirred at rt for 16 h. More allyl chloroformate (0.67 mL, 6.3 mmol) in CH2CI2 (2 mL) was added at 0°C. The mixture was stirred at rt for 24 h. The mixture was cooled to 0°C and allyl chloroformate (0.67 mL, 6.3 mmol) in CH2CI2 (2 mL) was added followed by sat. aq. NaHCOs soln (1 1 .2 mL). The mixture was stirred for 60 h at rt. Allyl chloroformate (0.67 mL, 6.3 mmol) in CH₂CI₂ (2 mL) was added at 0°C. The mixture was stirred for 4 h at rt. Aq. workup (EtOAc, sat. aq. NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc) afforded 44I (1 .85 g, 81 %).

Data of 44I: C20H25NO6 (375.4). LC-MS (method 1 d): R_t = 2.51 (97%), 376.1 ([M+H]⁺). A soln of 44I (1 .8 g, 4.8 mmol) in DME (58 mL) was cooled to 0°C followed by slow addn of 2 M aq. LiOH soln (24 mL, 48 mmol). The mixture was stirred at rt for 2 h, acidified with 1 M aq HCI soln and extracted with CH2CI2. The organic phase was dried (Na₂S0₄), filtered and concentrated to give 39I (1.6 g, 100%).

Data of 39I: Ci₇H₂iN0₆ (335.4). LC-MS (method 1 a): R_t = 2.07 (92%), 336.1 ([M+H]⁺); 280.0.

2-(lsoquinolin-7-ylamino)acetic acid (38m)

A mixture of 7-aminoisoquinoline (40m; 3.1 g, 21.5 mmol) and ethylglyoxylate soln (50% w/w in toluene, 4.7 mL, 23.6 mmol) was dissolved in EtOH (100 mL). Aq. HCI soln (32% w/w; 15 mL) was added. The mixture was then hydrogenated for 4 h at rt and under normal pressure in the presence of 10% Pt on activated charcoal (1 .0 g). The suspension was filtered through a plug of celite. The filtrate was concentrated to obtain an oil which was slowly poured into 2 M aq. Na2CC>3 soln (20 mL). The mixture was extracted with CH2CI2. The aq. phase was acidified with aq. HCI soln (32% w/w) and concentrated. The residue obtained was suspended in EtOH (80 mL) and filtered. The filtrate was evaporated, suspended in MeOH (80 mL), filtered and concentrated to give 38m (3.1 g, 72%).

Data of 38m: C11 H10N2O2 (202.2). LC-MS (method 5a): R_t = 1 .47, 203.1 ([M+H]⁺). H- NMR (DMSO-de): 9.30 (s, 1 H); 8.24 (d, J = 6.1 , 1 H); 8.05 (d, J = 6.1 , 1 H); 7.95 (d, J = 9.0, 1 H); 7.62 (dd, J = 2.3, 8.9, 1 H); 7.15 (br. s, 1 H); 7.05 (d, J = 2.1 , 1 H); 3.99 (s, 2 H).

2-(((Allyloxy)carbonyl)(4-chloro-3-(trifluoromethyl)phenyl)amino)acetic acid (39n) A mixture of K2CO3 (2.1 g, 15.2 mmol), 4-chloro-3-(trifluoromethyl)aniline (40n; 1 .0 g,

5.1 mmol) and tert. -butyl bromoacetate (3.05 mL, 20.3 mmol) in DMF (20 mL) was heated to 50°C for 18 h. Aq. workup (EtOAc, half-sat. aq. NaHCOs soln / ice, H₂0;

Na₂S0₄) and FC (hexane / CH2CI2 / Et₂0) afforded 41 n (0.65 g, 41 %).

Data of 41 n: C13H15CIF3NO2 (309.7). LC-MS (method 6b): R_t = 9.36 (95%), 351.0 ([M+H+CH₃CN]⁺); 310.1 ([M+H]⁺).

Allyl chloroformate (0.24 mL, 2.2 mmol) was added to a mixture of sat. aq. NaHCOs soln (5 mL) and a soln of 41 n (0.55 g, 1 .78 mmol) in CH2CI2 (5 mL). The mixture was stirred at rt for 4 h. More allyl chloroformate (0.24 mL, 2.2 mmol) and dioxane (5 mL) were added and the mixture was stirred at rt for 18 h. Aq. workup (EtOAc, half-sat. aq. NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc) afforded 42n (0.54 g, 77%).

Data of 42n: Ci7Hi₉CIF₃N0₄ (393.8). LC-MS (method 1 d): R_t = 2.67 (80%), 338.0 ([M-

(t-Bu)+2H]⁺). H-NMR (DMSO-de): 7.79 - 7.75 (m, 2 H); 7.62 (dd, J = 2.6, 8.6, 1 H);

5.88 (m, 1 H); 5.27 - 5.17 (m, 2 H); 4.60 (m, 2 H); 4.35 (s, 2 H); 1.41 (s, 9 H).

TFA (1 mL) was slowly added to a soln of 42n (0.54 g, 1.3 mmol) in CH₂CI₂ (5 mL). The soln was stirred at rt for 3 h. More TFA (1 mL) was added and stirring was continued for 18 h. Toluene (5 mL) was added and the volatiles were evaporated.

The residue was taken up in Et.20 and concentrated to give 39n (0.5 g, used without further purification).

Data of 39n: Ci₃HnCIF₃N0₄ (337.7). LC-MS (method 2e): R_t = 1 .25 (81 %), 335.9 ([M- H]-). 2-(((Allyloxy)carbonyl)(5-nitronaphthalen-2-yl)amino)acetic acid (39k)

Allyl chloroformate (0.18 mL, 1.65 mmol) was added to a mixture of sat. aq. NaHCC>3 soln (5 mL) and a soln of 41 k (0.4 g, 1.32 mmol) in CH2CI2 (5 mL). The mixture was stirred at rt for 4 h. More allyl chloroformate (0.18 mL, 1.65 mmol) and dioxane (5 mL) were added and the mixture was stirred at rt for 18 h. Aq. workup (EtOAc, half-sat. aq. NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc) afforded 42k (0.47 g, 92%). Data of 42k: C20H22N2O6 (386.4). LC-MS (method 1 d): Rt = 2.50 (98%), 387.2 ([M+H]⁺); 331.2.

TFA (1 mL) was slowly added to a soln of 42k (0.46 g, 1 .2 mmol) in CH₂CI₂ (5 mL). The soln was stirred at rt for 3 h. More TFA (1 mL) was added and stirring continued for 18 h. Toluene (5 mL) was added and the volatiles were evaporated. The residue was taken up in Et.20 and concentrated to give 39k (0.45 g, contained residual solvent; used without further purification).

Data of 39k: Ci₆Hi₄N₂0₆ (330.3). LC-MS (method 2e):R_t =1.16 (94%), 329.0 ([M- H]-).

Allyl 2-(naphthalen-2-ylamino)acetate 43b

Allyl chloroacetate (0.36 mL, 3.1 mmol) was slowly added to a soln of 2- naphthylamine (40b; 0.87 g, 6.1 mmol) and TBAI (1.1 g, 3.1 mmol) in DMF/THF 1 :1 (16 mL). The mixture was stirred at 60°C for 16 h followed by an aq. workup (EtOAc, aq. NaHCOs soln; Na₂S0₄). Purification by FC (hexane / EtOAc) afforded 43b (0.54 g, 73%).

Data of 43b: Ci₅Hi₅N0₂ (241 .3). LC-MS (method 1 d): R_t = 2.26 (89%), 242.1 ([M+H]⁺). (S)-5-Allyl 1 -benzyl 2-(4-(((2S,4R)-4-((tert.-butoxycarbonyl)amino)pyrrolidin-2- yl)methoxy)-N-methylbenzamido)pentanedioate (47)

(S)-5-Allyl 1 -benzyl 2-(4-hydroxy-N-methylbenzamido)pentanedioate (45) was prepared as described in the preceding patent application WO201 1/014973 A2.

Synthesis of the arylether 46

At 0°C, ADDP (2.9 g, 1 1.5 mmol) was slowly added to soln of phenol 45 (3.13 g, 7.6 mmol), alcohol 13 (3.35 g, 9.3 mmol) and PPh₃ (3.0 g, 1 1.4 mmol) in degassed CHCI₃ (60 mL). The mixture was stirred at rt for 3 h. Evaporation of the volatiles and purification of the residue by FC (hexane / EtOAc) afforded 46 (4.86 g, 84%). Data of 46: C39H55N3O10S1 (754.0). LC-MS (method 4a): R_t = 2.05 (93%), 754.4 ([M+H]⁺).

Synthesis of the amine 47

At 0°C, TBAF (1 M in THF, 3.0 mL, 3 mmol) was added to a soln of 46 (0.9 g, 1.2 mmol) in THF (15 mL). The mixture was allowed to warm to rt and stirring was continued for 16 h. Aq. workup (EtOAc, sat. aq. NaHCC soln, H2O, sat. aq. NaCI soln; Na₂S0₄) and purification by FC (CH2CI2 / MeOH) yielded 47 (0.54 g, 74%). Data of 47: C33H43N3O8 (609.7). LC-MS (method 1 d): R_t = 1 .91 (92%), 610.0 ([M+H]⁺).

4-(((2S,4R)-1-((Allyloxy)carbonyl)-4-(3-chlorobenzamido)pyrrolidin-2- yl)methoxy)benzoic acid (51 )

Synthesis of the arylether 48

ADDP (14.9 g, 59.2 mmol) in CHCI₃ (75 mL) was added drop by drop to a soln of methyl 4-hydroxybenzoate (3; 7.2 g, 47.3 mmol), alcohol 14 (1 1.85 g, 39.5 mmol) and PPh₃ (15.5 g, 59.2 mmol) in CHCI₃ (200 mL). The mixture was stirred at rt for 3 h followed by an aq. workup (CH2CI2, sat. aq. NaHCC soln; Na2S0₄). The resulting crude product was suspended in CH2CI2 / hexane 2:8 and filtered. The filtrate was concentrated and purified by FC (hexane / EtOAc) to afford 48 (16.0 g, 93%).

Data of 48: C22H30N2C7 (434.5). LC-MS (method 1 a): R_t = 2.31 (92%), 435.2 ([M+H]⁺).

Synthesis of the amine 49

A soln of HCI (4 M in dioxane, 1 1 1 mL) was added at 0°C to a soln of 48 (12.07 g, 27.8 mmol) in dioxane (57 mL). The mixture was allowed to stir at rt for 4 h. The volatiles were evaporated to give 49 HCI (10.0 g, 97%).

Data of 49 HCI: C17H22N2O5 HCI (334.4+36.5). LC-MS (method 1 d): Rt = 1.42 (97%), 334.9 ([M+H]⁺). Synthesis of the amide 50

At 0°C, i-Pr₂NEt (19.4 mL, 1 14 mmol) was slowly added to a soln of amine 49 HCI (10.6 g, 28.6 mmol), 3-chlorobenzoic acid (5.37 g, 34.3 mmol), HATU (16.3 g, 42.9 mmol) and HOAt (5.84 g, 42.9 mmol) in DMF (100 mL). The soln was stirred at rt for 16 h followed by an aq. workup (EtOAc, H₂0, 1 M aq. HCI soln, H₂0, sat. aq. NaHCOs soln, sat. aq. NaCI soln; Na₂S0₄) and FC (hexane / EtOAc ) to afford 50 (13.0 g, 96%). Data of 50: C24H25CIN2O6 (472.9). LC-MS (method 1 a): R_t = 2.31 (97%), 473.0 ([M+H]⁺).

Synthesis of the acid 51

At 0°C, a 1 M aq. LiOH soln (55 mL, 55 mmol) was slowly added to a soln of 50 (12.95 g, 27 mmol) in MeOH / THF 1 :1 (170 mL). The mixture was allowed to warm to rt and was then heated for 2 h to 60°C. The mixture was concentrated, acidified with 1 M aq. HCI soln and extracted with CHCI3. The organic phase - a milky suspension - was separated, treated with MeOH to get a clear soln, dried (Na2S0₄), filtered and concentrated to yield 51 (13 g, 100%).

Data of 51 : C23H23CIN2O6 (458.9). LC-MS (method 1 d): Rt = 2.00 (95%), 458.8 ([M+H]⁺).

(S)-5-Allyl 1 -benzyl 2-(N-methyl-4-(((2S,4R)-4-(3- (trifluoromethyl)benzamido)pyrrolidin-2-yl)methoxy)benzamido)pentanedioate (56) and (S)-5-allyl 1 -benzyl 2-(4-(((2S,4R)-4-(3-chlorobenzamido)pyrrolidin-2- yl)methoxy)-N-methylbenzamido)pentanedioate (57)

Synthesis of arylether 52

At 0°C, ADDP (3.6 g, 14.2 mmol) was slowly added to soln of phenol 45 (3.9 g, 9.4 mmol), alcohol 15 (3.8 g, 9.5 mmol) and PPh₃ (3.7 g, 14.2 mmol) in degassed CHCI3 (75 mL). The mixture was stirred at rt for 3 h. Evaporation of the volatiles and purification of the residue by FC (hexane / EtOAc) afforded 52 (6.83 g, 91 %).

Data of 52: C₃9H₄₆N₄Oi2S (794.9). LC-MS (method 4e): R_t = 2.39 (85%), 795.2 ([M+H]⁺).

Synthesis of amide 54

To a suspension of 52 (4.4 g, 5,5 mmol) in dioxane (20 mL) was added 4 M HCI in dioxane (60 mL). The resulting solution was stirred at rt for 3 h. The volatiles were evaporated to give 53 HCI (4.18 g), which was dissolved in CH2CI2 (80 mL) and cooled to 0°C. i-Pr2NEt (3.0 mL, 17.5 mmol) and 3-(trifluoromethyl)benzoyl chloride (1.2 mL, 8.1 mmol) were added. The mixture was stirred at rt for 3 h followed by an aq. workup (CH2CI2, 1 M aq. NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc) to afford 54 (4.8 g, 98%).

Data of 54: C₄₂H₄i F₃N₄0nS (866.9). ¹H-NMR (DMSO-d₆): 8.14 - 7.95 (m, 7 H); 7.83 (d, J = 7.8, 1 H); 7.62 (t, J = 7.8, 1 H); 7.40 (s, 5 H); ca. 7.35 - 7.14 (br. m, 2 H); ca. 7.1 - 6.9 (br. m, 2 H); 5.90 (m, 1 H); 5.33 - 5.15 (m, 4 H); 4.90, 4.6 - 4.2 (several br. m, 7 H); 3.71 (dd, J = 4.9, 1 1.3, 1 H); 3.55 (dd, J = 2.7, 1 1.2, 1 H); ca 2.95 - 2.80 (br. s, 3 H); ca 2.4 - 2.0 (br. m, 6 H). Synthesis of amide 55

TFA (5.0 mL) was slowly added at 0°C to a soln of 52 (2.23 g, 2.8 mmol) in CH₂CI₂ (50 mL). The soln was stirred at 0°C to rt for 2 h. The volatiles were evaporated to give 53 CF3CO2H (2.9 g), which was dissolved in CH2CI2 (25 mL) and cooled to 0°C. Et₃N (1 .6 mL, 1 1 .5 mmol) and 3-chlorobenzoyl chloride (0.5 mL, 3.8 mmol) were added. The mixture was stirred at rt for 3 h followed by an aq. workup (CH2CI2, 1 M aq. NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc) to afford 55 (1.9 g, 81 %).

Data of 55: C₄i H₄iCIN₄0nS (833.3). LC-MS (method 3a): R_t = 2.16 (90%), 833.3 ([M+H]⁺). Synthesis of amine 56

Thiophenol (0.9 mL, 8.8 mmol) and K2CO3 (1.53 g, 1 1 .1 mmol) were added to a soln of 54 (4.8 g, 5.6 mmol) in CH₃CN (100 mL). The mixture was stirred for 3 h at rt, followed by an aq. workup (EtOAc, 1 M aq. NaHCOs soln; Na₂S0₄) and FC (CH2CI2 / MeOH) to afford 56 (3.1 g, 81 %).

Data of 56: CseHssFsNsO/ (681.7). LC-MS (method 1 d): R_t = 2.04 (87%), 682.3 ([M+H]⁺).

Synthesis of amine 57

Thiophenol (0.15 mL, 1.4 mmol) and K2CO3 (0.23 g, 1 .68 mmol) were added to a soln of 55 (0.7 g, 0.84 mmol) in CH₃CN (25 mL). The mixture was stirred for 18 h at rt, followed by an aq. workup (CH2CI2, sat. aq. NaHCOs soln; Na₂S0₄) and FC (CH2CI2 / MeOH) to afford 57 (0.47 g, 86%).

Data of 57: C35H38CIN3O7 (648.1 ). LC-MS (method 1 d): Rt = 1 .93 (89%), 648.3 ([M+H]⁺).

Synthesis of final products Ex.1 - Ex.3 (Scheme 3):

Synthesis of the amide 58a

HATU (0.31 g, 0.82 mmol) was added to a soln of the amine 47 (0.33 g, 0.54 mmol), the acid 39a (0.17 g, 0.71 mmol) and i-Pr₂NEt (0.28 mL, 1.63 mmol) in DMF (6 mL). The mixture was stirred at rt for 3 h followed by an aq. workup (EtOAc, 1 M aq.

NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc) to give 58a (0.43 g, 96%).

Data of 58a: C₄₅H₅₄N₄0n (826.9). LC-MS (method 1 d): R_t = 2.62 (86%), 827.1

([M+H]⁺).

Synthesis of the amino acid 59a

Pd(PPh₃)₄ (50 mg) was added to a degassed soln of 58a (0.36 g, 0.45 mmol) and DMBA (0.204 g, 1.3 mmol) in EtOAc / CH₂CI₂ 1 :1 (16 mL). The mixture was stirred at rt for 3 h. The volatiles were evaporated. FC (EtOAc, then CH₂CI₂ / MeOH) afforded 59a (0.22 g, 72%).

Data of 59a: C₃₈H₄₆N₄09 (702.8). LC-MS (method 1 d): Rt = 2.17 (87%), 703.1 ([M+H]⁺).

Synthesis of the macrocyclic lactam 60a

At 80°C, a soln of 59a (1 19 mg, 0.17 mmol) in DCE (10 mL) was added over 2 h to a soln of 2-chloro-1 -methylpyridinium iodide (173 mg, 0.68 mmol) and i-Pr₂NEt (0.12 mL, 0.68 mmol) in DCE (240 mL). Stirring was continued for 1 h followed by evaporation of the volatiles and purification of the residue by FC (hexane / EtOAc) to yield 60a (60 mg, 52%).

Data of 60a: C₃₈H₄₄N₄08 (684.8). LC-MS (method 1 c): R_t = 2.27 (97%), 685.2 ([M+H]⁺).

Synthesis of the macrocyclic acid 61a

A soln of 60a (1 10 mg, 0.16 mmol) in EtOH / THF 4:1 (2.5 mL) was hydrogenated at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (15 - 20% Pd, moistened with 50% H₂0; 30 mg) for 18 h. The mixture was filtered through a plug of celite. The filtrate was concentrated to give crude 61a (130 mg; used without further purification).

Data of crude 61a: C₃iH₃8N₄0₈ (594.7). LC-MS (method 1 d): R_t = 1.67 (76%), 595.0 ([M+H]⁺).

Synthesis of the macrocyclic amide 62a

At 0°C, i-Pr₂NEt (0.108 mL, 0.63 mmol) was added to a soln of crude 61a (125 mg), β-alanine methylester hydrochloride (28 HCI; 59 mg, 0.42 mmol), HATU (160 mg, 0.42 mmol) and HOAt (57 mg, 0.42 mmol) in DMF (4 mL). Stirring at 0°C was continued for 2 h. Aq workup (EtOAc, aq. NaHCOs soln; Na2S0₄) and FC (hexane /

EtOAc / MeOH) afforded 62a (104 mg, 95% over the two steps).

Data of 62a: C₃₅H₄₅N₅09 (679.8). LC-MS (method 1 a): R_t = 1 .78 (95%), 680.1

([M+H]⁺).

Synthesis of the macrocyclic amine 63a

At rt, the Boc amine 62a (105 mg, 0.15 mmol) was treated with 4 M HCI in dioxane (3 mL) for 2 h. Evaporation of the volatiles gave crude 63a HCI (103 mg).

Data of 63a HCI: C30H37N5O7 HCI (579.6 + 36.5). LC-MS (method 2c): R_t = 1.34 (94%), 579.9 ([M+H]⁺).

Synthesis of the macrocyclic amide 64a

At 0°C, i-Pr₂NEt (0.1 16 mL, 0.68 mmol) was added to a soln of crude 63a HCI (103 mg) and 3-chlorobenzoyl chloride (59 mg, 0.34 mmol) in CH2CI2 (4 mL). The mixture was stirred at rt for 3 h followed by an aq. workup (CH2CI2, 1 M aq. NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc / MeOH) to give 64a (64 mg, 58% over the two steps).

Data of 64a:

(718.2). LC-MS (method 1 d): R_t = 1 .87 (86%), 718.0 ([M+H]⁺).

Synthesis of the monocarboxylic acid Ex.1

LiOH H2O (15 mg, 0.36 mmol) was added at 0°C to a soln of 64a (62 mg, 0.086 mmol) in THF / MeOH 2:1 (4.5 mL) and H₂0 (0.087 mL). The mixture was stirred for 18 h at 0°C to rt, acidified with 2 M aq. HCI soln (10 mL) and extracted with EtOAc. The organic phase was dried (Na2S0₄), filtered and concentrated. Purification of the crude product by prep. HPLC (method 1 a) afforded Ex.1 (37 mg, 61 %).

Data of Ex.1 : cf. Table 01a.

Synthesis ot the amide 58b

i-Pr₂NEt (0.38 mL, 2.2 mmol) was slowly added to a soln of amine 47 (0.45 g, 0.74 mmol), acid 39b (0.34 g, 1 .18 mmol) and T3P (50% in EtOAc; 0.87 mL, 1 .5 mmol) in CH2CI2 (3 mL). The mixture was stirred at rt for 3 h followed by an aq. workup (CH2CI2, sat. aq. NaHCOs soln; Na2S0₄) and purification of the crude product by FC (hexane / EtOAc) to give 58b (0.47 g, 72%).

Data of 58b: C₄₉H₅₆N₄0ii (877.0). LC-MS (method 1 d): R_t = 2.74, 877.9 ([M+H]⁺). Synthesis of the macrocyclic lactam 60b

Pd(PPh₃)4 (31 mg) was added to a degassed soln of 58b (0.46 g, 0.53 mmol) and DMBA (0.25 g, 1 .6 mmol) in EtOAc / CH₂CI₂ 1 :1 (12 mL). The mixture was stirred at rt for 3 h. The volatiles were evaporated. FC (hexane / CH2CI2 / MeOH) afforded 59b (0.40 g, 100%).

At 80°C a soln of 59b (200 mg, 0.26 mmol) in DCE (20 mL) was added over 2 h to a soln of 2-chloro-1 -methylpyridinium iodide (136 mg, 0.53 mmol) and i-Pr2NEt (0.14 mL, 0.8 mmol) in DCE (500 mL). The volatiles were evaporated. Purification of the crude product by FC (hexane / EtOAc) yielded 60b (106 mg, 54%).

Data of 60b: C42H46N4O8 (734.8). LC-MS (method 1 c): R_t = 2.46 (85%), 735.3 ([M+H]⁺).

Synthesis of the macrocyclic acid 61 b

A soln of 60b (199 mg, 0.27 mmol) in i-PrOH (5 mL) was hydrogenated at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (15 - 20% Pd, moistened with 50% H₂0; 100 mg) for 2 h. The mixture was filtered through a plug of celite. The filtrate was concentrated to give crude 61 b (150 mg, 86%).

Data of 61 b: C35H40N4O8 (644.7). LC-MS (method 1 d): Rt = 1 .90 (91 %), 645.2 ([M+H]⁺).

Synthesis of the macrocyclic amide 62b

At 0°C, i-Pr₂NEt (0.084 mL, 0.49 mmol) was added to a soln of 61 b (79 mg, 0.123 mmol), β-alanine methylester hydrochloride (28 HCI; 22 mg, 0.16 mmol), HATU (70 mg, 0.18 mmol) and HOAt (25 mg, 0.18 mmol) in DMF (4 mL). Stirring at 0°C was continued for 2 h. Aq. workup (EtOAc, aq. NaHCOs soln; Na2S04) and FC (hexane / EtOAc / MeOH) afforded 62b (77 mg, 86%).

Data of 62b: C39H47N5O9 (729.8). LC-MS (method 1 d): Rt = 2.01 (96%), 730.3 ([M+H]⁺). Synthesis of the macrocyclic amine 63b

The Boc amine 62b (84 mg, 0.1 15 mmol) was treated with 4 M HCI in dioxane (3 mL) for 3 h at rt. Evaporation of the volatiles gave crude 63b HCI (100 mg, contained residual dioxane).

Data of 63b HCI: C34H39N5O7 HCI (629.7 + 36.5). LC-MS (method 1 d): Rt = 1 .46 (86%), 630.2 ([M+H]⁺). Synthesis of the macrocyclic amide 64b

At 0°C, i-Pr₂NEt (0.10 mL, 0.46 mmol) was added to a soln of crude 63b HCI (100 mg) and 3-chlorobenzoyl chloride (55 mg, 0.31 mmol) in CH2CI2 (3 mL). The mixture was stirred at rt for 3 h followed by an aq. workup (CH2CI2, 1 M aq. NaHCC>3 soln; Na₂S0₄) and FC (hexane / EtOAc / MeOH) to give 64b (64 mg, 72% over the two steps).

Data of 64b: C4i H₄₂CIN₅08 (768.3). LC-MS (method 1 d): Rt = 2.07 (89%), 768.2 ([M+H]⁺).

For an alternative synthesis: Vide infra, Scheme 4

Synthesis of the monocarboxylic acid Ex.2

LiOH H2O (6.9 mg, 0.16 mmol) was added at 0°C to a soln of 64b (63 mg, 0.082 mmol) in THF / MeOH 2:1 (4.5 mL) and H₂0 (0.08 mL). The mixture was stirred for 18 h at 0°C to rt, acidified with 1 M aq. HCI soln (20 mL) and extracted with EtOAc. The organic phase was dried (Na2S0₄), filtered and concentrated to give Ex.2 (51 mg, 82%).

Data of Ex.2: cf. Table 01a. ¹H-NMR (DMSO-d₆): 12.21 (br. s, 1 H); 8.64 (d, J = 7.1 , 1 H); 8.22 (t, J = 5.1 , 1 H); 8.05 - 7.95 (m, 2 H); 7.90 - 7.81 (m, 4 H); 7.62 - 7.10 (m, br. s, 8 H); 7.1 - 6.8 (very br. s, 1 H); 5.29 (d, J = 1 1.8, 1 H); 4.99 (d, J = 9.2, 1 H); 4.90 - 4.82 (m, 2 H); 4.15 - 3.98 (m, 3 H); 3.53 (dd, J = 7.5, 10.0, 1 H); ca 3.5 - 3.0 (several m, partially superimposed by H2O signal, 3 H); 2.59 (s, 3 H); 2.38 (br. m, 1 H); 2.18 - 2.08 (m, 2 H); 1 .87 (br. dd, J ca. 4.0, 17.1 , 1 H); 1.59 (br. dd, J = 12.8, 17.0, 1 H); 1.37 - 1.15 (m, 3 H).

For an alternative synthesis: Vide infra, Scheme 4

Synthesis ot the amide 58c

At 0°C, HATU (0.56 g, 1 .48 mmol) was added to a soln of the amine 47 (0.60 g, 0.98 mmol), the acid 39c (0.36 g, 1.28 mmol) and i-Pr₂NEt (0.51 mL, 2.95 mmol) in DMF (10 mL). The mixture was stirred at 0°C to rt for 1 .5 h followed by an aq. workup (EtOAc, half-sat. aq. Na₂C0₃ soln; Na₂S0₄) and FC (hexane / EtOAc) to give 58c (0.95 g, 98%; contained ca 10% of DMF).

Data of 58c: C49H56N4O11 (877.0). LC-MS (method 1 d): R_t = 2.68 (97%), 877.6 ([M+H]⁺). Synthesis of the amino acid 59c

Pd(PPh₃)₄ (220 mg) in CH₂CI₂ (3 mL) was added to a degassed soln of 58c (0.835 g, 0.95 mmol) and DMBA (0.595 g, 3.81 mmol) in EtOAc / CH₂CI₂ 8:5 (13 mL). The mixture was stirred at rt for 2 h. The mixture was filtered. The residue was washed (CH₂CI₂). The combined filtrate and washings were concentrated and purified by FC (CH₂CI₂ / MeOH) to give 59c (645 mg, 90%).

Data of 59c: C₄₂H48N₄09 (752.9). LC-MS (method 1 d): Rt = 2.43 (95%), 753.4 ([M+H]⁺). Synthesis of the macrocyclic lactam 60c

At 80°C, a soln of 59c (150 mg, 0.20 mmol) and i-Pr₂NEt (0.07 mL, 0.4 mmol) in DCE (5 mL) was added over 1.5 h to a soln of 2-chloro-1-methylpyridinium iodide (205 mg, 0.8 mmol) and i-Pr₂NEt (0.07 mL, 0.4 mmol) in DCE (250 mL). Stirring was continued for 1 h. The volatiles were evaporated. Purification of the crude product by FC (hexane / EtOAc) yielded 60c (contained ca 30% of a diastereomer; 58 mg, 40%).

Data of 60c: C₄₂H46N₄08 (734.8). LC-MS (method 1 d): Rt = 2.45 (85%), 735.2 ([M+H]⁺).

Synthesis of the macrocyclic acid 61c

A soln of 60c (73 mg, 0.10 mmol) in EtOH / THF 4:1 (2.5 mL) was hydrogenated at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (15 - 20% Pd, moistened with 50% H₂0; 19 mg) for 18 h. The mixture was filtered through a plug of celite. The filtrate was concentrated to give crude 61c (contained ca 15% of a diastereomer; 54 mg; used without further purification).

Data of 61c: C₃₅H₄oN₄08 (644.7). LC-MS (method 2a): R_t = 1 .27 (80%), 645.1 ([M+H]⁺).

Synthesis of the macrocyclic amide 62c

At 0°C, i-Pr₂NEt (0.057 mL, 0.34 mmol) was added to a soln of crude 61c (54 mg), β- alanine methylester hydrochloride (28 HCI; 18 mg, 0.13 mmol), HATU (64 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol) in DMF (2 mL). Stirring at 0°C was continued for 2 h. Aq workup (EtOAc, aq. NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc / MeOH) afforded 62c (contained ca 10% of a diastereomer; 39 mg, 54% over the two steps). Data of 62c: C39H47N5O9 (729.8). LC-MS (method 1 d): Rt = 1 .98 (85%), 730.2 ([M+H]⁺).

Synthesis of the macrocyclic amine 63c

The Boc amine 62c (34 mg, 0.047 mmol) was treated with 4 M HCI in dioxane (3 mL) for 3 h at rt. Evaporation of the volatiles gave crude 63c HCI (contained ca 10% of a diastereomer and residual dioxane; 38 mg).

Data of crude 63c HCI: C34H39N5O7 HCI (629.7 + 36.5). LC-MS (method 4b): R_t = 1 .54 (83%), 630.1 ([M+H]⁺). Synthesis of the macrocyclic amide 64c

At 0°C, i-Pr₂NEt (0.04 mL, 0.23 mmol) was added to a soln of crude 63c HCI (38 mg) and 3-chlorobenzoyl chloride (15 mg, 0.086 mmol) in CH2CI2 (2 mL). The mixture was stirred at rt for 3 h followed by an aq. workup (CH2CI2, 1 M aq. NaHCC soln; Na2S0₄) and FC (CH2CI2 / MeOH) to give 64c (contained ca 10% of a diastereomer; 21 mg, 58% over the two steps).

Data of 64c: C₄i H₄₂CIN₅0₈ (768.3). LC-MS (method 2b): R_t = 2.04 (87%), 768.2 ([M+H]⁺).

Synthesis of the monocarboxylic acid Ex.3

L1OH H2O (4.6 mg, 0.1 1 mmol) was added at 0°C to a soln of 64c (19 mg, 0.025 mmol) in THF / MeOH 2:1 (1.5 mL) and H₂0 (0.025 mL). The mixture was stirred for 18 h at 0°C to rt, acidified with 2 M aq. HCI soln (10 mL) and extracted with EtOAc. The organic phase was dried (Na2S0₄), filtered and concentrated. Purification of the crude product by prep. HPLC (method 1 a) gave Ex.3 (10 mg, 54%).

Data of Ex.3: cf. Table 01a.

Synthesis of final products Ex.2, Ex.4 - Ex.13 (Scheme 4):

Synthesis of the acids 66b and 66d - 66k

Synthesis of amide 65b and acid 66b

A soln of 27 (1 .45 g, 3.1 mmol) in DCE (56 mL) was treated with i-Pr₂NEt (2.63 mL, 15.5 mmol) for 5 min, then 41 b (1.75 g, 6.8 mmol) was added, followed by 2-chloro-1- methylpyridinium iodide (2.37 g, 9.3 mmol). The mixture was stirred at 50°C for 15 h. Aq. workup (EtOAc, sat. aq. NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc) afforded 65b (1 .1 g, 50%). Data of 65b: C41 H45N3O8 (707.8). LC-MS (method 4e): R_t = 2.35 (88%), 708.4 ([M+H]⁺).

At 0°C, TFA (20 mL) was slowly added to a soln of 65b (2.1 g, 3.0 mmol) in CH₂CI₂ (20 mL). The mixture was stirred at 0°C to rt for 3 h. The volatiles were evaporated. The residue was twice taken up in toluene and concentrated. The residue was taken up in CH2CI2 and concentrated to give 66b (2.35 g, contained residual solvent; used without further purification).

Data of 66b: C37H37N3O8 (651 .7). LC-MS (method 4e): R_t = 2.04 (88%), 652.1 ([M+H]⁺).

Synthesis of amide 65d and acid 66d

A soln of 27 (0.9 g, 1.92 mmol) and 41d (1.058 g, 3.84 mmol) in CH2CI2 (21 mL) was cooled to 0°C. A soln of 1 -chloro-N,N,2-trimethylpropenylamine (0.25 mL, 1 .93 mmol) in CH2CI2 (2 mL) was added drop by drop. The mixture was stirred at 0°C for 1 h. More 1 -chloro-N,N,2-trimethylpropenylamine (0.25 mL, 1.93 mmol) in CH₂CI₂ (2 mL) was added slowly and stirring was continued for 4 h at 0°C. An aq. workup (EtOAc, sat. aq. NaHCOs soln; Na₂S0₄) and FC (hexane / EtOAc) gave 65d (1.12 g, contained ca 15% of Ν,Ν-dimethylisobutyramide; used without further purification). At 0°C, TFA (5.3 mL) was slowly added to a soln of 65d (1 .0 g) in CH2CI2 (21 mL). The mixture was stirred at 0°C to rt for 15 h. The volatiles were evaporated. The residue was purified by FC (hexane / EtOAc then CH2CI2 / MeOH) to give 66d (0.87 g, 75% over the two steps).

Data of 66d: C34H34F3N3O8 (669.6). LC-MS (method 1 d): R_t = 2.22 (96%), 670.3 ([M+H]⁺).

Synthesis of amide 65e and acid 66e

The amide 65e (purified by FC (hexane / EtOAc); 0.84 g, 59%) was obtained from 27 (0.9 g, 1 .92 mmol) and 41e (1 .1 1 g, 3.84 mmol) applying the procedure described for the synthesis of 65d.

Data of 65e:

(739.8). LC-MS (method 1 d): Rt = 2.71 (82%), 740.4 ([M+H]⁺).

At 0°C, TFA (4.2 mL) was slowly added to a soln of 65e (0.82 g, 1.1 1 mmol) in CH2CI2 (17 mL). The mixture was stirred at 0°C to rt for 15 h. The volatiles were evaporated. The residue was purified by FC (hexane / EtOAc then CH2CI2 / MeOH) to give 66e (0.77 g, quant, yield). Data of 66e: CssHseFsNsOs (683.7). LC-MS (method 1 d): Rt = 2.26 (92%), 684.1 ([M+H]⁺).

Synthesis of amide 65f and acid 66f

A soln of 27 (1 .0 g, 2.13 mmol) and 41f (1 .23 g, 4.27 mmol) in CH₂CI₂ (24 mL) was cooled to 0°C. A soln of 1 -chloro-N,N,2-trimethylpropenylamine (0.28 mL, 2.13 mmol) in CH2CI2 (2 mL) was added drop by drop. The mixture was stirred at 0°C for 1 h. More 1 -chloro-N,N,2-trimethylpropenylamine (0.28 mL, 2.13 mmol) in CH2CI2 (2 mL) was added slowly and stirring was continued for 3 h at 0°C and for 15 h at rt. The mixture was then cooled to 0°C, followed by the addn of more 1 -chloro-N,N,2- trimethylpropenylamine(0.28 mL, 2.13 mmol) in CH2CI2 (2 mL). Stirring at 0°C was continued for 3 h. Aq. workup (EtOAc, sat. aq. NaHCC>3 soln; Na2S0₄) and FC (hexane / EtOAc) gave 65f (1 .45 g, contained Ν,Ν-dimethylisobutyramide and an unknown side product; used without further purification).

At 0°C, TFA (7.3 mL) was slowly added to a soln of 65f (1 .42 g) in CH₂CI₂ (30 mL). The mixture was stirred at 0°C to rt for 15 h. The volatiles were evaporated. The residue was purified by FC (hexane / EtOAc then CH2CI2 / MeOH) to give 66f (0.94 g, 64% over the two steps).

Data of 66f: CssHseFsNsOs (683.7). LC-MS (method 1 d): Rt = 2.33 (87%), 684.1 ([M+H]⁺).

Synthesis of amide 65g and acid 66g

A mixture of 27 (0.8 g, 1 .7 mmol), 41 g (0.58 g, 2.6 mmol), K₂C0₃ (0.472 g, 3.4 mmol) and CH2CI2 (20 mL) was cooled to 0°C. A soln of 1 -chloro-N,N,2- trimethylpropenylamine (0.68 mL, 5.12 mmol) in CH2CI2 (3 mL) was added drop by drop. The mixture was stirred at 0°C for 2 h and concentrated. Aq. workup (EtOAc, sat. aq. NaHCOs soln, sat. aq. NaCI soln; Na2S0₄) and FC (hexane / EtOAc) yielded 65g (0.95 g, 83%).

Data of 65g:

(675.7). LC-MS (method 1 d): R_t = 2.60 (92%), 676.3 ([M+H]⁺).

At 0°C, TFA (5.3 mL) was slowly added to a soln of 65g (0.94 g, 1 .4 mmol) in CH2CI2 (15 mL). The mixture was stirred at 0°C to rt for 5 h. The volatiles were evaporated. The residue was dissolved in CHCI3 and concentrated to give 66g (1 .1 g; ca 70% w/w, contained residual solvents; used without any further purification).

Data of 66g: C33H34FN3O8 (619.6). LC-MS (method 1 d): R_t = 2.13 (94%), 620.0 ([M+H]⁺). Synthesis of amide 65h and acid 66h

Amide 65h (1 .9 g, contained ca 20% of Ν,Ν-dimethylisobutyramide; used without further purification) was obtained from 27 (1.33 g, 2.84 mmol) and 41 h (1 .01 g, 4.26 mmol) applying the procedure described for the synthesis of 65g.

Data of 65h: C38H45N3O9 (687.8). LC-MS (method 1 d): Rt = 2.58 (85%), 688.3 ([M+H]⁺).

At 0°C, TFA (1 1 ml.) was slowly added to a soln of 65h (1.9 g, ca 80% w/w) in CH₂CI₂ (30 ml_). The mixture was stirred at 0°C to rt for 15 h. The volatiles were evaporated. FC (hexane / EtOAc then CH₂CI₂ / MeOH) gave 66h (1 .53 g, 85% over the two steps).

Data of 66h: C34H37N3O9 (631 .7). LC-MS (method 1 d): Rt = 2.1 1 (98%), 632.2 ([M+H]⁺).

Synthesis of amide 65i and acid 66i

Amide 65i (0.84 g, contained ca 15% of Ν,Ν-dimethylisobutyramide; used without further purification) was obtained from 27 (0.73 g, 1.56 mmol) and 41 i (0.6 g, 2.34 mmol) applying the procedure described for the synthesis of 65g.

Data of 65i: C38H44CIN3O8 (706.2). LC-MS (method 1 d): Rt = 2.76 (86%), 706.2 ([M+H]⁺).

At 0°C, TFA (4.4 mL) was slowly added to a soln of 65i (0.82 g, ca 85% w/w, ca 1 mmol) in CH₂CI₂ (12 mL). The mixture was stirred at 0°C to rt for 5 h. The volatiles were evaporated to give 66i (0.92 g; contained ca 15% of N,N-dimethylisobutyramide and residual solvent).

Data of 66i: C34H36CIN3O8 (650.1 ). LC-MS (method 1 d): Rt = 2.24 (88%), 650.1 ([M+H]⁺).

Synthesis of amide 65j and acid 66j

A mixture of 27 (0.877 g, 1 .87 mmol), 43j (0.86 g, 2.81 mmol), K₂C0₃ (0.517 g, 3.7 mmol) and CH₂CI₂ (20 mL) was cooled to 0°C. A soln of 1 -chloro-N,N,2- trimethylpropenylamine (0.74 mL, 5.62 mmol) in CH₂CI₂ (5 mL) was added drop by drop. The mixture was stirred at 0°C for 1 h. Aq. workup (EtOAc, sat. aq. NaHCC>3 soln, sat. aq. NaCI soln; Na₂SC>4) and FC (hexane / EtOAc) gave 65j (1.3 g, contained ca 20% of Ν,Ν-dimethylisobutyramide; yield ca 75%).

Data of 65j: C₄₂H49N₃Oio (755.9). LC-MS (method 1 d): Rt = 2.75 (85%), 756.5 ([M+H]⁺). A soln of 65j (1 .3 g, ca 80% w/w, ca 1 .35 mmol) in THF (16 mL) was treated with Pd(PPh₃)4 (98 mg) and phenylsilane (0.64 mL, 5.1 mmol) at rt for 1 h. The volatiles were evaporated. FC (EtOAc, then CH₂CI₂ / MeOH) afforded 66j (0.91 g, 94%).

Data of 66j: C39H45N3O10 (715.8). LC-MS (method 1 d): Rt = 2.42 (97%), 716.1 ([M+H]⁺).

Synthesis of amide 65k and acid 66k

A soln of 1 -chloro-N,N,2-trimethylpropenylamine (0.43 mL, 3.28 mmol) in CH2CI2 (2 mL) was added drop by drop to a soln of 27 (1 .02 g, 2.18 mmol) and 41 k (0.99 g, 3.28 mmol) in CH2CI2 (27 mL). The mixture was stirred at rt for 1 h. More 1 -chloro-

N,N,2-trimethylpropenylamine (0.13 mL, 1 mmol) in CH2CI2 (1 mL) was added slowly and stirring was continued for 1 h, followed by evaporation of the volatiles. Aq. workup (EtOAc, sat. aq. NaHCC>3 soln, sat. aq. NaCI soln; IS^SCU) and FC (hexane /

EtOAc) gave 65k (0.89 g, used without further purification).

Data of 65k: C41 H44N4O10 (752.8). LC-MS (method 2c): R_t = 2.65 (78%), 753.4

([M+H]⁺).

At 0°C, TFA (4.4 mL) was slowly added to a soln of 65k (0.87 g) in CH2CI2 (18 mL). The mixture was stirred at 0°C to rt for 5 h. The volatiles were evaporated. FC (hexane / EtOAc then CH2CI2 / MeOH) afforded 66k (0.74 g, 49% over the two steps). Data of 66k: C37H36N4O10 (696.7). LC-MS (method 1 d): Rt = 2.19 (85%), 697.4 ([M+H]⁺).

Synthesis of the resins 67b and 67d - 67k Synthesis of resins; general procedure:

Preswelling of the resin: Under argon, 2-chlorotrityl chloride resin (matrix: copoly(styrene - 1 % DVB), 100 - 200 mesh) was suspended in CH2CI2, shaken for 1 h and filtered.

Immobilisation of acids: The resin was suspended in CH2CI2. A soln of the respective amide and i-Pr2NEt in DMF (or CH2CI2) was added. The mixture was shaken at rt for 2.5 h under argon. The resin was filtered and washed (CH2CI2, DMF and CH2CI2). Capping: Jhe resin was shaken in CH2CI2 / MeOH / i-Pr2NEt 15:2:3 for 30 min and filtered. The capping step was repeated twice. The resin was washed (CH2CI2, DMF, CH₂CI₂ and Et₂0).

Yield: The resin was dried i.v. to afford the respective resin (loading determined by mass increase and / or by release of the respective amide). The following acids were used: 66b, 66d - 66k. Synthesis of 67b

Preswelling of the resin: 2-Chlorotrityl chloride resin (loading 1 .22 mmol/g; 500 mg, 0.61 mmol) in CH₂CI₂ (5 mL);

Immobilisation: CH₂CI₂ (4 mL), 66b (398 mg, 0.61 mmol) and i-Pr₂NEt (0.418 mL,

2.44 mmol) in DMF (1 mL);

Capping: CH₂CI₂ / MeOH / i-Pr₂NEt 15:2:3 (5 mL);

Yield: 67b (791 mg, loading determined by mass increase: 0.6 mmol/g; loading determined by release of 66b: 0.61 mmol/g).

Synthesis of the resin 67d

Preswelling of the resin: 2-Chlorotrityl chloride resin (loading 1 .22 mmol/g; 1 .1 12 g, 1 .36 mmol) in CH₂CI₂ (1 1 mL);

Immobilisation: CH₂CI₂ (9 mL), 66d (0.765 g, 1.14 mmol) and i-Pr₂NEt (0.929 mL, 5.43 mmol) in DMF (2 mL);

Capping: CH₂CI₂ / MeOH / i-Pr₂NEt 15:2:3 (1 1 mL);

Yield: 67d (1.35 g, loading determined by mass increase: 0.27 mmol/g; loading determined by release of 66d: 0.24 mmol/g).

Synthesis of the resin 67e

Preswelling of the resin: 2-Chlorotrityl chloride resin (loading 1 .42 mmol/g; 372 mg, 0.53 mmol) in CH₂CI₂ (4 mL);

Immobilisation: CH₂CI₂ (3 mL), 66e (476 mg, 0.69 mmol) and i-Pr₂NEt (0.181 mL, 1 .05 mmol) in DMF (1 mL);

Capping: CH₂CI₂ / MeOH / i-Pr₂NEt 15:2:3 (4 mL);

Yield: 67e (582 mg, loading determined by mass increase: 0.56 mmol/g).

Synthesis of the resin 67f

Preswelling of the resin: 2-Chlorotrityl chloride resin (loading 1 .42 mmol/g; 0.7 g, 1.0 mmol) in CH₂CI₂ (8 mL);

Immobilisation: CH₂CI₂ (8 mL), 66f (0.94 g, 1.37 mmol) and i-Pr₂NEt (0.341 mL, 2.0 mmol) in DMF (2 mL);

Capping: CH₂CI₂ / MeOH / i-Pr₂NEt 15:2:3 (8 mL);

Yie/d:67i (697 mg, loading determined by release of 66f: 0.12 mmol/g). Synthesis of the resin 67g

Preswelling of the resin: 2-Chlorotrityl chloride resin (loading 1.22 mmol/g; 1 .19 g, 1 .46 mmol) in CH₂CI₂ (1 1 mL);

Immobilisation: CH₂CI₂ (8 mL), 66g (1.03 g, ca 70% w/w, ca 1.16 mmol) and i-Pr₂NEt (1.0 mL, 5.8 mmol) in DMF (2 mL);

Capping: CH₂CI₂ / MeOH / i-Pr₂NEt 15:2:3 (1 1 mL);

Yield: 67g (1.8 g, loading determined by mass increase: 0.58 mmol/g; loading determined by release of 66g: 0.57 mmol/g). Synthesis of the resin 67h

Preswelling of the resin: 2-Chlorotrityl chloride resin (1.42 mmol/g; 1.04 g, 1 .48 mmol) in CH₂CI₂ (12 mL);

Immobilisation: CH₂CI₂ (10 mL), 66h (1 .25 g, 1.98 mmol) and i-Pr₂NEt (1.015 mL, 5.93 mmol) in DMF (2 mL);

Capping: CH₂CI₂ / MeOH / i-Pr₂NEt 15:2:3 (12 mL);

Yield: 67h (1.3 g, loading determined by mass increase: 0.35 mmol/g; loading determined by release of 66h: 0.44 mmol/g).

Synthesis of the resin 67i

Preswelling of the resin: 2-Chlorotrityl chloride resin (1.22 mmol/g; 1.06 g, 1 .29 mmol) in CH₂CI₂ (1 1 mL);

Immobilisation: CH₂CI₂ (8 mL), 66i (0.84 g, ca 80% w/w, ca. 1 mmol) and i-Pr₂NEt (0.89 mL, 5.18 mmol) in DMF (2 mL);

Capping: CH₂CI₂ / MeOH / i-Pr₂NEt 15:2:3 (1 1 mL);

Yield: 67i (1.5 g, loading determined by mass increase: 0.48 mmol/g; loading determined by release of 66i: 0.51 mmol/g).

Synthesis of the resin 67j

Preswelling of the resin: 2-Chlorotrityl chloride resin (1.42 mmol/g; 470 mg, 0.67 mmol) in CH₂CI₂ (5 mL);

Immobilisation: CH₂CI₂ (4 mL), 66j (0.6 g, 0.83 mmol) and i-Pr₂NEt (0.23 mL, 1.3 mmol) in CH₂CI₂ (1 mL);

Capping: CH₂CI₂ / MeOH / i-Pr₂NEt 15:2:3 (5 mL);

Yield: 67j (0.62 g, loading determined by mass increase: 0.35 mmol/g; loading determined by release of 66j: 0.32 mmol/g). Synthesis of the resin 67k

Preswelling of the resin: 2-Chlorotrityl chloride resin (1.42 mmol/g; 405 mg, 0.58 mmol) in CH₂CI₂ (4 ml_);

Immobilisation: CH₂CI₂ (4 ml_), 66k (0.57 g, 0.81 mmol) and i-Pr₂NEt (0.2 ml_, 1 .15 mmol) in DMF (0.5 ml_);

Capping: CH₂CI₂ / MeOH / i-Pr₂NEt 15:2:3 (5 ml_);

Yield: 67k (0.67 g, loading determined by mass increase: 0.6 mmol/g; loading determined by release of 66k: 0.6 mmol/g). Synthesis of the amino acids 68b and 68d - 68k

Synthesis of amino acids; general procedure:

Preswelling of ^'the resin: The respective resin was suspended in DMF, shaken for 1 h and filtered.

Cleavage of the Fmoc group: The resin was resuspended in a soln of 2% v/v DBU in DMF, shaken for 10 min, filtered off and washed with DMF. This deprotection step was repeated once. The resin was washed (DMF and CH₂CI₂).

Coupling of the acid 51: The resin was suspended in DMF, then acid 51 , HOAt and DIC (or i-Pr₂NEt, HATU, HOAt and acid 51) were added. The mixture was shaken at rt for 16 h. The resin was filtered off and washed (DMF and CH₂CI₂).

Cleavage of the Alloc group: The resin was resuspended in CH₂CI₂. Phenylsilane and Pd(PPh₃)₄ were added. The mixture was shaken for 15 min. The resin was filtered off and washed (CH₂CI₂). This deprotection step was repeated once. The resin was washed (CH₂CI₂, DMF, MeOH, CH₂CI₂).

Release of the respective amino acid from solid support: The resin was resuspended in HFIP / CH₂CI₂ 2:3 and shaken for 30 min. The mixture was filtered and the resin was washed (CH₂CI₂). The cleavage step was repeated once. The combined filtrates and washings were concentrated. The crude product was dissolved in CH3CN and concentrated to afford the respective amino acid, which was used in the next step without further purification.

The following resins were used: 67b, 67d - 67k.

Synthesis of the amino acid 68b

Preswelling of the resin: Resin 67b (200 mg, loading 0.61 mmol/g; 0.12 mmol), DMF (2 ml_); Cleavage of the Fmoc group: ' 2% v/v DBU in DMF (2 mL) for each deprotection cycle; Coupling of the acid 51: DMF (2 mL), then i-Pr₂NEt (0.251 mL, 1.46 mmol), HATU (162 mg, 0.43 mmol), HOAt (58 mg, 0.42 mmol) and acid 51 (1 12 mg, 0.24 mmol); Cleavage of the Alloc group: Per deprotection cycle CH2CI2 (2 mL), phenylsilane (0.30 mL, 2.44 mmol) and Pd(PPh₃)₄ (28 mg);

Release of the amino acid 68b from solid support: HFIP / CH2CI2 2:3 (2 mL) per cleavage cycle;

Yield: Crude 68b (103 mg).

Data of crude 68b: C₄i H₄₄CIN₅0₉ (786.3). LC-MS (method 3a): R_t = 1.28 (70%), 786.3 ([M+H]⁺).

Synthesis of the amino acid 68d

Pres welling of the resin: Resin 67d (650 mg, loading 0.24 mmol/g; 0.16 mmol), DMF (6.5 mL);

Cleavage of the Fmoc group: 2% v/v DBU in DMF (6.5 mL) for each deprotection cycle;

Coupling of the acid 51: DMF (6 mL), then acid 51 (143 mg, 0.31 mmol), HOAt soln (0.5 M in DMF, 0.624 mL, 0.312 mmol) and DIC (0.049 mL, 0.312 mmol);

Cleavage of the Alloc group: Per deprotection cycle CH2CI2 (6.5 mL), phenylsilane (0.38 mL, 3.12 mmol) and Pd(PPh₃)₄ (36 mg);

Release of the amino acid 68d from solid support: HFIP / CH2CI2 2:3 (6.5 mL) per cleavage cycle;

Yield: Crude 68d (153 mg).

Data of crude 68d: CssH^ CIFsNsOg (804.2). LC-MS (method 3a): R_t = 1 .28 (78%), 804.4 ([M+H]⁺).

Synthesis of the amino acid 68e

Pres welling of the resin: Resin 67e (340 mg, loading 0.56 mmol/g; 0.19 mmol), DMF (3.4 mL);

Cleavage of the Fmoc group: 2% v/v DBU in DMF (3.4 mL) for each deprotection cycle;

Coupling of the acid 51: DMF (2.6 mL), then acid 51 (175 mg, 0.38 mmol), HOAt soln (0.5 M in DMF, 0.76 mL, 0.312 mmol) and DIC (0.059 mL, 0.38 mmol);

Cleavage of the Alloc group: Per deprotection cycle CH2CI2 (1 .9 mL), phenylsilane (0.47 mL, 3.8 mmol) and Pd(PPh₃)₄ (0.025 M in CH₂CI₂; 1.5 ml); Release of the amino acid 68e from solid support: HFIP / CH2CI2 2:3 (3.4 mL) per cleavage cycle;

Yield: Crude 68e (101 mg).

Data of crude 68e: C39H43CIF3N5O9 (818.2). LC-MS (method 3a): R_t = 1 .32 (91 %), 818.4 ([M+H]⁺).

Synthesis of the amino acid 68f

Preswelling of the resin: Resin 67f (650 mg, loading 0.12 mmol/g; 0.078 mmol), DMF (6.5 mL);

Coupling of the acid 51: DMF (6 mL), then acid 51 (72 mg, 0.156 mmol), HOAt soln (0.5 M in DMF, 0.31 mL, 0.156 mmol) and DIC (0.024 mL, 0.156 mmol);

Cleavage of the Alloc group: Per deprotection cycle CH2CI2 (6.5 mL), phenylsilane (0.194 mL, 1.56 mmol) and Pd(PPh₃)₄ (18 mg);

Release of the amino acid 68f from solid support: HFIP / CH2CI2 2:3 (6.5 mL) per cleavage cycle;

Yield: Crude 68f (31 mg).

Data of crude 68f:

(818.2). LC-MS (method 3a): R_t = 1.34 (80%), 818.4 ([M+H]⁺).

Synthesis of the amino acid 68g

Preswelling of the resin: Resin 67g (172 mg, loading 0.58 mmol/g; 0.10 mmol), DMF (2 mL);

Cleavage of the Fmoc group: 2% v/v DBU in DMF (2 mL) for each deprotection cycle;

Coupling of the acid 51: DMF (1 .6 mL), then acid 51 (92 mg, 0.2 mmol), HOAt soln

(0.5 M in DMF, 0.4 mL, 0.2 mmol) and DIC (0.031 mL, 0.2 mmol);

Cleavage of the Alloc group: Per deprotection cycle CH2CI2 (2 mL), phenylsilane

(0.25 mL, 2 mmol) and Pd(PPh₃)₄ (23 mg);

Release of the amino acid 68g from solid support: HFIP / CH2CI2 2:3 (2 mL) per cleavage cycle;

Yield: Crude 68g (99 mg).

Data of crude 68g: C37H41 CIFN5O9 (754.2). LC-MS (method 3a): R_t = 1 .19 (83%), 754.3 ([M+H]⁺). Synthesis of the amino acid 68h

Preswelling of the resin: Resin 67h (286 mg, loading 0.35 mmol/g; 0.10 mmol), DMF (3 mL);

Cleavage of the Fmoc group: ' 2% v/v DBU in DMF (3 mL) for each deprotection cycle; Coupling of the acid 51: DMF (2.6 mL), then acid 51 (92 mg, 0.2 mmol), HOAt soln (0.5 M in DMF, 0.4 mL, 0.2 mmol) and DIC (0.031 mL, 0.2 mmol);

Cleavage of the Alloc group: Per deprotection cycle CH2CI2 (2 mL), phenylsilane (0.25 mL, 2 mmol) and Pd(PPh₃)₄ (23 mg);

Release of the amino acid 68h from solid support: HFIP / CH2CI2 2:3 (3 mL) per cleavage cycle;

Yield: Crude 68h (103 mg).

Data of crude 68h: C₃8H₄₄CIN₅Oio (766.2). LC-MS (method 3a): R_t = 1.19 (81 %), 766.3 ([M+H]⁺). Synthesis of the amino acid 68i

Preswelling of the resin: Resin 67i (208 mg, loading 0.48 mmol/g; 0.10 mmol), DMF (2 mL);

Cleavage of the Fmoc group: 2% v/v DBU in DMF (2 mL) for each deprotection cycle; Coupling of the acid 51: DMF (1 .6 mL), then acid 51 (92 mg, 0.2 mmol), HOAt soln (0.5 M in DMF, 0.4 mL, 0.2 mmol) and DIC (0.031 mL, 0.2 mmol);

Release of the amino acid 68/ from solid support: HFIP / CH2CI2 2:3 (2 mL) per cleavage cycle;

Yield: Crude 68i (98 mg).

Data of crude 68i:

(784.7). LC-MS (method 3a): R_t = 1 .28 (83%), 784.3 ([M+H]⁺).

Synthesis of the amino acid 68j

Preswelling of the resin: Resin 67j (286 mg, loading 0.35 mmol/g; 0.10 mmol), DMF (3 mL);

Cleavage of the Fmoc group: 2% v/v DBU in DMF (3 mL) for each deprotection cycle; Coupling of the acid 51: DMF (2.6 mL), then acid 51 (92 mg, 0.2 mmol), HOAt soln (0.5 M in DMF, 0.4 mL, 0.2 mmol) and DIC (0.031 mL, 0.2 mmol);

Cleavage of the Alloc group: Per deprotection cycle CH2CI2 (3 mL), phenylsilane (0.25 mL, 2 mmol) and Pd(PPh₃)₄ (23 mg); Release of the amino acid 68/ from solid support: HFIP / CH2CI2 2:3 (3 mL) per cleavage cycle;

Yield: Crude 68j (88 mg).

Data of crude 68j: C43H52CIN5O11 (850.4). LC-MS (method 3a): R_t = 1 .44 (89%), 850.4 ([M+H]⁺).

Synthesis of the amino acid 68k

Preswelling of the resin: Resin 67k (230 mg, loading 0.6 mmol/g; 0.14 mmol), DMF (2.5 mL);

Cleavage of the Fmoc group: 2% v/v DBU in DMF (2.5 mL) for each deprotection cycle;

Coupling of the acid 51: DMF (2.5 mL), then acid 51 (127 mg, 0.28 mmol), HOAt soln (0.5 M in DMF, 0.55 mL, 0.28 mmol) and DIC (0.043 mL, 0.28 mmol);

Cleavage of the Alloc group: Per deprotection cycle CH2CI2 (2.5 mL), phenylsilane (0.34 mL, 2.8 mmol) and Pd(PPh₃)₄ (32 mg);

Release of the amino acid 68k from solid support: HFIP / CH2CI2 2:3 (2.5 mL) per cleavage cycle;

Yield: Crude 68k (124 mg).

Data of crude 68k: C41 H43CIN6O11 (831 .3). LC-MS (method 3a): R_t = 1 .28 (75%), 831 .4 ([M+H]⁺).

Synthesis of the macrocyclic esters 64b and 69d - 69k

Synthesis of macrocyclic esters; general procedure:

A soln of the respective linear amino acid and i-Pr2NEt in DMF was slowly added over 2 h by syringe pump to a soln of FDPP in DMF. Stirring was continued for 15 h. The volatiles were evaporated. Aq. workup (CH2CI2, sat. aq. Na2CC>3 soln; Na2S0₄) and purification by prep. HPLC (method 2a) afforded the respective macrocyclic ester. The following linear amino acids were used: 68b, 68d - 68k.

Synthesis of the macrocyclic ester 64b

The macrocyclic ester 64b (1 1 mg, 20% based on 67b) was obtained according to the general procedure by adding crude 68b (60 mg) and i-Pr2NEt (0.106 mL, 0.62 mmol) in DMF (10 mL) to a soln of FDPP (59 mg, 0.154 mmol) in DMF (120 mL).

Data of 64b: C₄i H₄₂CIN₅0₈ (768.3). LC-MS (method 3b): R_t = 1 .61 (94%), 768.7 ([M+H]⁺). For an alternative synthesis: Vide supra, Scheme 3 Synthesis of the macrocyclic ester 69d

The macrocyclic ester 69d (43 mg, 35% based on 67d) was obtained according to the general procedure by adding crude 68d (148 mg) and i-Pr2NEt (0.246 ml_, 1.44 mmol) in DMF (20 mL) to a soln of FDPP (138 mg, 0.359 mmol) in DMF (270 ml_).

Data of 69d: CssHsgCIFsNsOs (786.2). LC-MS (method 3a): R_t = 1.61 (92%), 786.3 ([M+H]⁺). Synthesis of the macrocyclic ester 69e

The macrocyclic ester 69e (37 mg, 28% based on 67e) was obtained according to the general procedure by adding crude 68e (82 mg) and i-Pr2NEt (0.17 mL, 1 .0 mmol) in DMF (20 mL) to a soln of FDPP (96 mg, 0.25 mmol) in DMF (180 mL).

Data of 69e: C39H41CIF3N5O8 (800.2). LC-MS (method 3b): R_t = 1.65 (96%), 800.4 ([M+H]⁺).

Synthesis of the macrocyclic ester 69f

The macrocyclic ester 69f (9 mg, 14% based on 67f) was obtained according to the general procedure by adding crude 68f (31 mg) and i-Pr2NEt (0.052 mL, 0.3 mmol) in DMF (5 mL) to a soln of FDPP (29 mg, 0.076 mmol) in DMF (55 mL).

Data of 69f: C39H41CIF3N5O8 (800.2). LC-MS (method 1 c): R_t = 2.13 (94%), 800.2 ([M+H]⁺).

Synthesis of the macrocyclic ester 69g

The macrocyclic ester 69g (30 mg, 41 % based on 67g) was obtained according to the general procedure by adding crude 68g (99 mg) and i-Pr2NEt (0.187 mL, 1 .09 mmol) in DMF (20 mL) to a soln of FDPP (105 mg, 0.272 mmol) in DMF (200 mL).

Data of 69g: C37H39CIFN5O8 (736.2). LC-MS (method 3a): R_t = 1.46 (95%), 736.2 ([M+H]⁺).

Synthesis of the macrocyclic ester 69h

The macrocyclic ester 69h (34 mg, 45% based on 67h) was obtained according to the general procedure by adding crude 68h (103 mg) and i-Pr2NEt (0.186 mL, 1.09 mmol) in DMF (20 mL) to a soln of FDPP (105 mg, 0.272 mmol) in DMF (200 mL).

Data of 69h:

(748.2). LC-MS (method 3a): R_t = 1 .46 (95%), 748.1 ([M+H]⁺). Synthesis of the macrocyclic ester 69i

The macrocyclic ester 69i (22 mg, 29% based on 67i) was obtained according to the general procedure by adding crude 68i (98 mg) and i-Pr₂NEt (0.177 ml_, 1.04 mmol) in DMF (20 mL) to a soln of FDPP (100 mg, 0.259 mmol) in DMF (190 ml_).

Data of 69i: CssFUiC NsOs (766.7). LC-MS (method 3a): R_t = 1.59 (97%), 766.3 ([M+H]⁺).

Synthesis of the macrocyclic ester 69j

The macrocyclic ester 69j (31 mg, 37% based on 67j) was obtained according to the general procedure by adding crude 68j (88 mg) and i-Pr2NEt (0.156 mL, 0.91 mmol) in DMF (20 mL) to a soln of FDPP (87 mg, 0.228 mmol) in DMF (160 mL).

Data of 69j: C43H50CIN5O10 (832.3). LC-MS (method 3a): R_t = 1.78 (96%), 832.4 ([M+H]⁺). Synthesis of the macrocyclic ester 69k

The macrocyclic ester 69k (34 mg, 30% based on 67k) was obtained according to the general procedure by adding crude 68k (124 mg) and i-Pr2NEt (0.189 mL, 1.1 mmol) in DMF (20 mL) to a soln of FDPP (106 mg, 0.276 mmol) in DMF (200 mL).

Data of 69k: C₄iH₄iCIN₆Oio (813.3). LC-MS (method 1 c): R_t = 2.03 (93%), 813.2 ([M+H]⁺).

Synthesis of final products Ex.2, Ex.4 - Ex.9

Saponification of the respective ester; general procedure:

At 0°C, an aq. soln of LiOH was added to a soln of the respective ester in THF / MeOH / H2O. The mixture was stirred at rt. The volatiles were evaporated. Aq. workup (EtOAc, 1 M aq. HCI soln; Na2S0₄) afforded the respective acid.The following esters were used: 64b, 69d - 69i. Synthesis of Ex.2

The acid Ex.2 (10 mg, 100%) was obtained according to the general procedure by treating a soln of 64b (10 mg, 0.013 mmol) in THF / MeOH 2:1 (0.9 mL) with 1 M aq.

LiOH soln (0.029 mL, 0.029 mmol) for 15 h.

Data of Ex.2: cf. Table 01a.

For an alternative synthesis and ¹H-NMR data: Vide supra, Scheme 3

Synthesis of Ex.4 The acid Ex.4 (18 mg, 92%) was obtained according to the general procedure by treating a soln of 69d (20 mg, 0.025 mmol) in THF / MeOH / H₂0 6:2:1 (0.9 ml.) with 0.5 M aq. LiOH soln (0.1 ml_, 0.050 mmol) for 1 .5 h.

Data of Ex.4: cf. Table 01a.

Synthesis of Ex.5

The acid Ex.5 (28 mg, 95%) was obtained according to the general procedure by treating a soln of 69e (30 mg, 0.037 mmol) in THF / MeOH / H₂0 3:1 :1 (2.0 ml.) with 1 M aq. LiOH soln (0.082 ml_, 0.082 mmol) for 1.5 h.

Data of Ex.5: cf. Table 01a.

Synthesis of Ex.6

The acid Ex.6 (8 mg, 90%) was obtained according to the general procedure by treating a soln of 69f (9 mg, 0.01 1 mmol) in THF / MeOH / H₂0 6:2:1.5 (0.95 mL) with 0.5 M aq. LiOH soln (0.045 mL, 0.022 mmol) for 2.5 h.

Data of Ex.6: cf. Table 01a.

Synthesis of Ex.7

The acid Ex.7 (29 mg, 99%) was obtained according to the general procedure by treating a soln of 69g (30 mg, 0.041 mmol) in THF / MeOH / H₂0 12:4:2.5 (1 .85 mL) with 0.5 M aq. LiOH soln (0.163 mL, 0.082 mmol) for 4 h.

Data of Ex.7: cf. Table 01a.

Synthesis of Ex.8

The acid Ex.8 (32 mg, 96%) was obtained according to the general procedure by treating a soln of 69h (34 mg, 0.045 mmol) in THF / MeOH / H₂0 12:4:2 (1.8 mL) with 0.5 M aq. LiOH soln (0.182 mL, 0.091 mmol) for 4 h.

Data of Ex.8: cf. Table 01a. Synthesis of Ex.9

The acid Ex.9 (9 mg, 42%) was obtained according to the general procedure by treating a soln of 69i (22 mg, 0.029 mmol) in THF / MeOH / H₂0 9:3:2 (1 .4 mL) with 0.5 M aq. LiOH soln (0.1 15 mL, 0.057 mmol) for 4 h.

Data of Ex.9: cf. Table 01a. Synthesis of the final product Ex.10 Synthesis of acid 70j

At 0°C, TFA (0.4 mL) was added to a soln of 69j (31 mg, 0.037 mmol) in CH₂CI₂ (1.6 mL). The soln was stirred at rt for 3 h. The volatiles were evaporated. The residue was treated with CH3CN and concentrated. The residue was treated with CH2CI2 and concentrated to give crude 70j (29 mg).

Data of crude 70j: C39H42CIN5O10 (776.2). LC-MS (method 1 c): R_t = 1.76 (83%), 776.0 ([M+H]⁺).

Synthesis of acid Ex.10

HATU (0.5 M in DMF; 0.129 mL, 0.064 mmol), HOAt (0.5 M in DMF; 0.129 mL, 0.064 mmol), NH4CI (7 mg, 0.129 mmol) and then i-Pr₂NEt (0.033 mL, 0.193 mmol) were added to a soln of crude 70j (29 mg) in DMF (1 mL). The mixture was stirred at rt for 4 h. Aq. workup (EtOAc, sat. aq. NaHC0₃ soln; Na₂S0₄) afforded crude amide 71j (32 mg) which was dissolved in THF / MeOH / H₂0 9:3:1 .8 (1.38 mL) and cooled to 0°C. Aq. 0.5 M LiOH soln (0.129 mL, 0.064 mmol) was added. The mixture was stirred at rt for 4 h. The volatiles were evaporated. Aq. workup (EtOAc, 1 M aq. HCI soln; Na2S0₄) and purification by prep. HPLC (method 1 a) afforded Ex.10 (10 mg, 35% over the three steps, based on 69j).

Data of Ex.10: cf. Table 01a.

Synthesis of the final product Ex.11 Synthesis of the aniline 72k

Thiophene (4% in i-Pr₂0; 0.015 mL, 0.0075 mmol), V2O5 (1.7 mg, 0.0093 mmol) and then 5% platinum on activated charcoal (15 mg) were added to a soln of 69k (15 mg, 0.018 mmol) and Et₃N (0.00026 mL, 0.0018 mmol) in dry THF (2 mL). The mixture was hydrogenated at rt under normal pressure for 7 h. The mixture was diluted with CH2CI2 and filtered through a plug of celite. The residue was washed (CH2CI2). The combined filtrates and washings were concentrated. Purification by prep. TLC (EtOAc / EtOH 93:7) afforded 72k (8 mg, 55%).

Data of 72k: C4i H₄₃CIN₆08 (783.3). LC-MS (method 1 a): R_t = 1 .66 (95%), 783.2 ([M+H]⁺). Synthesis of acid Ex.1 1

At 0°C, LiOH soln (0.5 M in H₂0; 0.039 mL, 0.019 mmol) was added to a soln of 72k (7.7 mg, 0.01 mmol) in THF / MeOH / H₂0 3:1 :1 (2 mL). The mixture was stirred at 0°C for 15 min then at rt for 4 h followed by an aq. workup (EtOAc, sat. NH4CI soln; Na2S0₄). The resulting solid product was washed with hexane to give Ex.1 1 (7.2 mg, 95%).

Data of Ex.11 : cf. Table 01a.

Synthesis of the final products Ex.12 and Ex.13

Synthesis of amide 73I

T3P (50% in EtOAc; 0.678 mL, 1 .15 mmol) and then i-Pr₂NEt (0.295 mL, 1 .73 mmol) were added to a soln of 56 (392 mg, 0.575 mmol) and 39I (235 mg, 0.70 mmol) in CH2CI2 (5 mL). The mixture was stirred for 3 h at rt and concentrated. FC (hexane / EtOAc) of the residue afforded 73I (492 mg, 86%).

Data of 73I: C₅3H₅7F₃N₄Oi2 (999.0). LC-MS (method 4d): R_t = 2.51 (85%), 999.6 ([M+H]⁺).

Synthesis of amide 73m

After 15 min stirring at rt, T3P (50% in EtOAc; 2.9 mL, 4.9 mmol) was added to a mixture of of 56 (1.1 g, 1.6 mmol), 38m (723 mg, 3.6 mmol) and i-Pr₂NEt (1.12 mL, 6.6 mmol) in CH2CI2 (25 mL). The mixture was stirred for 3 h at rt. Aq. workup (CH2CI2, 1 M aq. NaHCOs soln; Na₂S0₄) and filtration through silica gel (CH2CI2 / MeOH) afforded crude 73m (1 .2 g, 86%; used without further purification).

Data of crude 73m: C47H46F3N5O8 (865.9). LC-MS (method 3a): R_t = 1.72 (81 %), 866.4 ([M+H]⁺).

Synthesis of the macrocyclic lactam 75I

A soln of 73I (480 mg, 0.48 mmol) and DMBA (188 mg, 1.2 mmol) in EtOAc / CH2CI2 1 :1 (8 mL) was treated with Pd(PPh₃)₄ (56 mg) for 3 h at rt. The volatiles were evaporated and the residue was purified by FC (CH2CI2 / MeOH) to give 74I (362 mg, 86%; used without further purification).

At 90°C, a soln of 74I (170 mg, 0.194 mmol) in DCE (5 mL) was slowly added over 1 .5 h to a soln of 2-chloro-1-methylpyridinium iodide (496 mg, 1.94 mmol) in DCE (1000 mL). Stirring at 90°C was continued for 2 h. The volatiles were evaporated. Purifcation of the residue by FC (hexane / EtOAc) afforded 75I (101 mg, 61 %).

Data of 75I: C46H47F3N4O9 (856.9). LC-MS (method 3a): R_t = 2.16 (91 %), 857.4 ([M+H]⁺).

Synthesis of the macrocyclic lactam 75m

A soln of 73m (600 mg, 0.69 mmol) and DMBA (325 mg, 2.1 mmol) in EtOAc / CH₂CI₂ 1 :1 (20 mL) was treated with Pd(PPh₃)₄ (40 mg) for 18 h at rt. The volatiles were evaporated and the residue was filtered through silica gel (CH2CI2 / MeOH) to give crude 74m (446 mg, 78%; used without further purification).

At 90°C, a soln of 74m (100 mg, ca 0.12 mmol) in DCE (40 mL) was slowly added over 1 h to a soln of 2-chloro-1-methylpyridinium iodide (300 mg, 1 .17 mmol) in DCE (1000 mL). Stirring at 90°C was continued for 3 h. The volatiles were evaporated. Filtration through silica gel (hexane / EtOAc) gave crude 75m (22 mg, 61 %). The material was used without further purification.

Data of crude 75m: C44H40F3N5O7 (807.8). LC-MS (method 1 c): R_t = 1.94 (61 %), 808.3 ([M+H]⁺). Synthesis of the macrocyclic amide 77I

A soln of 75I (163 mg, 0.19 mmol) in EtOH (10 mL) was hydrogenated at rt and under normal pressure in the presence of palladium hydroxide on activated charcoal (15 - 20% Pd, moistened with 50% H2O; 40 mg) for 4 h. The mixture was filtered through a plug of celite. The residue was washed with EtOH. The combined filtrate and washings were concentrated to give the acid 76I (150 mg).

At 0°C, i-Pr₂NEt (0.15 mL, 0.88 mmol) was added to a soln of 76I (150 mg), HATU (120 mg, 0.32 mmol), HOAt (50 mg, 0.37 mmol) and β-alanine methylester hydrochloride (28 HCI; 39 mg, 0.28 mmol) in DMF (4 mL). The mixture was stirred at 0°C to rt for 18 h followed by an aq. workup (EtOAc, 1 M aq. NaHCOs soln). The crude product was purified by FC (hexane / EtOAc / MeOH) to yield 77I (135 mg, 83% over the two steps).

Data of 77I: C₄₃H₄8F₃N₅Oio (851 .9). ¹H-NMR (DMSO-d₆): 8.76 (d, J = 7.1 , 1 H); 8.27 (br. t, 1 H); 8.18 - 8.15 (m, 2 H); 8.00 - 7.91 (m, 3 H); 7.74 (t, J = 7.7, 1 H); 7.43 - 7.3 (m, 4 H); ca 7.3 - 6.8 (very br. m, 2 H); 5.23 (br. d, J ca 10.9, 1 H); 5.05 - 4.70 (m, 3 H); 4.14 - 3.97 (m, 3 H); 3.61 (s, 3 H); 3.56 - 3.2 (m, partially superimposed by H₂0 signal, 4 H); 2.69 (s, 3 H); 2.55 (t, J = 6.9, 2 H); ca 2.5 - 2.0 (several m, 4 H); 1 .75 (m, 1 H); 1 .56 (s, 9 H); 1.35 (m, 1 H).

Synthesis of the macrocyclic amide 77m

A soln of crude 75m (75 mg, ca 0.09 mmol) in EtOH (5 mL) was hydrogenated at rt and under normal pressure in the presence of palladium hydroxide on activated charcoal (15 - 20% Pd, moistened with 50% H2O; 174 mg) for 48 h. The mixture was filtered through a plug of celite. The residue was washed with EtOH. The combined filtrate and washings were concentrated to give the acid 76m (52 mg).

At 0°C, i-Pr₂NEt (0.013 mL, 0.08 mmol) was added to a soln of 76m (50 mg), HATU (15 mg, 0.04 mmol), HOAt (5.3 mg, 0.04 mmol) and β-alanine methylester hydrochloride (28 HCI; 5.4 mg, 0.04 mmol) in DMF (2 mL). The mixture was stirred at

0°C to rt for 3 h followed by an aq. workup (EtOAc, 2 M aq. Na₂C0₃ soln; Na₂S0₄).

The crude product was purified by FC (CH2CI2 / MeOH) to yield 77m (13 mg, ca

1 %). The material was used without further purification.

Data of 77m: C₄i H₄iF₃N₆0₈ (802.8). LC-MS (method 1 c): R_t = 1 .61 (71 %), 803.3

([M+H]⁺).

Synthesis of the macrocyclic amide 79I

At 0°C, TFA (0.48 mL) was slowly added to a soln of 77I (1 10 mg, 0.129 mmol) in CH2CI2 (5 mL). Stirring at 0°C was continued for 4 h followed by evaporation of the volatiles to give crude 78I (128 mg), which was dissolved in DMF (4 mL) and cooled to 0°C. NH4CI (35 mg, 0.64 mmol), HATU (98 mg, 0.26 mmol) and then i-Pr₂NEt (0.177 mL, 1 .03 mmol) were added. The mixture was stirred at 0°C for 3 h, followed by an aq. workup (CH2CI2, H2O; Na2S0₄). Purification of the crude product by FC (hexane / EtOAc / MeOH) gave 79I (74 mg, 72%).

Data of 79I: C39H41 F3N6O9 (794.8). LC-MS (method 1 d): Rt = 1.72 (80%), 795.3 ([M+H]⁺).

Synthesis of the final product Ex.12

At 0°C, LiOH H2O (17.3 mg, 0.412 mmol) was added to a soln of 79I (72 mg, 0.91 mmol) in MeOH (3 mL) / THF (1 mL) / H₂0 (0.35 mL). The mixture was stirred for 4 h at 0°C. The volatiles were evaporated after addn of 2 M aq. HCI soln (0.2 mL). The residue was purified by prep. HPLC (method 1 a) to afford Ex.12 (48 mg, 68%).

Data of Ex.12: cf. Table 01a. Synthesis of the final product Ex.13

At 0°C, aq. LiOH soln (2 M, 0.022 mL, 0.045 mmol) was added to a soln of 77m (12 mg, ca 0.015 mmol) in THF / MeOH 3:1 (0.8 mL). The mixture was stirred for 4 h at 0°C. The volatiles were evaporated after addn of 2 M aq. HCI soln (0.03 mL). The residue was purified by prep. HPLC (method 1 a) to afford Ex.13 CF3CO2H (6.2 mg, 46%).

Data of Ex.13 CF3CO2H: cf. Table 01a. Synthesis of Ex.14 - Ex.19 (Scheme 5):

Synthesis of amide 80

To a soln of amine 56 (1.32 g, 1 .94 mmol) and acid 39b (0.685 g, 2.40 mmol) in CH2CI2 (20 mL) at rt was slowly added T3P (3.4 mL, 5.81 mmol) followed by i-Pr₂NEt (1.3 mL, 7.75 mmol). The mixture was stirred at rt for 0.5 h followed by an aq. workup (EtOAc, 1 M aq. NaHCOs soln; Na₂S0₄) and purification by FC (hexane / EtOAc / MeOH) to give 80 (1.49 g, 81 %).

Data of 80: C52H51 F3N4O10 (949.0). ¹H-NMR (DMSO-d₆): 2 rotamers ca 70:30; 8.86, 8.82 (2 d, J = 6.8, 6.9, 1 H); 8.18 - 8.13 (m, 2 H); 7.93 - 7.68 (m, 6 H); 7.56 - 7.46 (m, 3 H); 7.43 - 7.34 (br. m, 2 H); 7.38 (s, 5 H); 7.18 (very br. s, 1 H); 7.05 - 6.90 (very br. m, 1.3 H); 6.79 (d, J = 0.7 H); 6.00 - 5.75 (br. m, 2 H); 5.32 - 5.04 (several m, 6 H); ca 5.0 - 4.7 (br. m, 2 H); ca 4.7 - 4.4 (br. m, 7 H); 4.17 - 4.04 (br. m, 1 .3 H); 3.92 (br. dd, J ca 7.5, 10.2, 0.7 H); 3.67 (d, J = 7.2, 0.4 H); 3.50 (dd, J = 6.4, 10.1 , 0.6 H); 2.85, 2.82 (2 br. s, 3 H); 2.40 - 2.05 (several br. m, 6 H). Synthesis of macrocyclic lactam 82

To a soln of 80 (1 .45 g, 1.53 mmol) and DMBA (0.731 g, 4.68 mmol) in a mixture of degassed CH2CI2 (15 mL) and EtOAc (15 mL) at rt was added Pd(PPh₃)₄ (0.31 g). The mixture was stirred at rt for 3 h and was then concentrated. Filtration through silica gel (CH2CI2 / MeOH) afforded 81 (1.33 g, contained unidentified impurities; used without further purification).

To a soln of 2-chloro-1 -methylpyridinium iodide (1257 mg, 4.92 mmol) in DCE (1000 mL) at 90°C was slowly added over 1.5 h a soln of 81 (310 mg, ca 75% w/w, ca. 0.28 mmol) in DCE (50 mL). The mixture was stirred at 90°C for 3 h and then at rt overnight. The solvent was evaporated, and the crude product was purified by FC (hexane / EtOAc / MeOH) to give 82 (137 mg, 47% over the two steps). Data of 82: C45H41 F3N4O7 (806.8). LC-MS (method 1 c): R_t = 2.51 (96%), 807.2 ([M+H]⁺).

Synthesis of macrocyclic acid 83

A solution of 82 (470 mg, 0.583 mmol) in THF (20 mL) was hydrogenated for 18 h at normal pressure and at rt in the presence of palladium hydroxide on activated charcoal (15 - 20% Pd, wet, ca. 50% H2O; 170 mg). The mixture was filtered through celite, and the filtrate was concentrated to afford 83 (374 mg, 89%).

Data of 83: C38H35F3N4O7 (716.7). LC-MS (method 2b): R_t = 1 .40 (94%), 717.3 ([M+H]⁺).

Synthesis of macrocyclic diester 84

To a soln of 83 (51 .7 mg, 0.072 mmol), amine 31 CF3CO2H (34 mg, 0.108 mmol), HATU (41 mg, 0.108 mmol) and HOAt (15 mg, 0.108 mmol) in DMF (3 mL) at 0°C was added i-Pr₂NEt (0.049 mL, 0.289 mmol), and the mixture was stirred at 0°C for 2 h. An aq. workup (EtOAc, 1 M aq. NaHCOs soln; Na₂S0₄) followed by FC (CH₂CI₂ / EtOH) afforded 84 (67 mg, quant, yield; contained residual amounts of DMF).

Data of 84: C47H48F3N5O10 (899.9). LC-MS (method 1 c): R_t = 2.36 (83%), 900.3 ([M+H]⁺).

Synthesis of macrocyclic diacid Ex.14

To a soln of 84 (65 mg, 0.072 mmol) in a mixture of THF (2 mL) and EtOH (0.5 mL) at 0°C was added 2 M aq. LiOH soln (0.15 mL, 0.30 mmol). The mixture was stirred at rt for 3 h. 1 M Aq. H3PO4 soln was added, the mixture was extracted with EtOAc, and the combined organic layer was dried (Na₂S04), filtered and concentrated. Purification of the crude product by prep. HPLC (method 1 a) afforded Ex.14 (47 mg, 77%).

Data of Ex.14: cf. Table 01a. Synthesis of macrocyclic diester 85

To a soln of 83 (21.0 mg, 0.029 mmol), 33 HCI (12 mg, 0.059 mmol), HATU (17 mg, 0.044 mmol) and HOAt (6.0 mg, 0.044 mmol) in DMF (3 mL) at 0°C was added i- Pr₂NEt (0.020 mL, 0.1 17 mmol), and the mixture was stirred at 0°C for 2 h. An aq. workup (EtOAc, 1 M aq. NaHCOs soln; Na₂S0₄) followed by FC (hexane / EtOAc / MeOH) afforded 85 (28 mg, quant, yield; contained residual amounts of solvents). Data of 85: C45H46F3N5O10 (873.9). LC-MS (method 1 a): R_t = 2.18 (94%), 874.3 ([M+H]⁺).

Synthesis of macrocyclic diacid Ex.15

To a soln of 85 (27 mg, 0.031 mmol) in a mixture of THF (2 mL) and MeOH (0.5 mL) at 0°C was added 2 M aq. LiOH soln (0.046 mL, 0.093 mmol). The mixture was stirred at 0°C for 2 h. 1 M Aq. H3PO4 soln was added, the mixture was extracted with EtOAc, and the combined organic layer was dried (Na2SC>4), filtered and concentrated. Purification of the crude product by prep. HPLC (method 1 a) afforded Ex.15 (12.5 mg, 48%).

Data of Ex.15: cf. Table 01a. ¹ H-NMR (DMSO-d₆): 12.30 (br. s, exchanged upon addn of D₂0, 2 H); 8.78 (d, J = 7.1 , exchanged upon addn of D₂0, 1 H); 8.19 - 8.13 (m, partially (1 H) exchanged upon addn of D₂0, 3 H); 8.05 - 7.90 (m, 4 H); 7.86 (s, 1 H); 7.74 (t, J = 7.8, 1 H); 7.60 - 7.55 (m, 2 H); 7.45 (dd, J = 1.7, 8.7, 1 H); ca 7.5 - 7.15 (br. m, partially unresolved, 3 H); ca 7.0 - 6.8 (br. m, unresolved, 1 H); 5.29 (d, J = 1 1.5, 1 H); 5.00 - 4.83 (m, 3 H); 4.47 (m, 1 H); 4.16 - 4.07 (m, 2 H); 4.00 (d, J = 12.4, 1 H); 3.55 (m, 1 H); 3.31 (d, J = 14.2, 1 H); ca 2.7 - 2.35 (m, partially superimposed by DMSO-d signal, 5 H); 2.57 (s, 3 H); 2.21 - 2.06 (m, 2 H); 1.86 (br. dd, 1 H); 1.52 (dd, J = 13.0, 17.1 , 1 H); 1 .29 (m, 1 H).

Synthesis of macrocyclic diester 86

To a soln of 83 (22.0 mg, 0.031 mmol), 34 HCI (17 mg, 0.061 mmol), HATU (20 mg, 0.053 mmol) and HOAt (12 mg, 0.088 mmol) in DMF (3 mL) at 0°C was added i- Pr₂NEt (0.021 mL, 0.123 mmol), and the mixture was stirred at 0°C for 2 h. An aq. workup (EtOAc, 1 M aq. NaHCOs soln; Na₂S0₄) followed by FC (CH₂CI₂ / EtOH) afforded 86 (21 mg, 72%).

Data of 86: C50H56F3N5O10 (944.0). LC-MS (method 3a): R_t = 2.20 (99%), 944.3 ([M+H]⁺). Synthesis of macrocyclic diacid Ex.16

To a soln of diester 86 (21 mg, 0.022 mmol) in CH₂CI₂ (2 mL) at 0°C was added slowly TFA (0.20 mL). The mixture was stirred at 0°C for 2 h and at rt for 24 h. The mixture was concentrated to dryness, and the residue was coevaporated twice with CH₂CI₂ to give Ex.16 (19.8 mg, quant, yield; contained residual amounts of solvents). Data of Ex.16: cf. Table 01a. Synthesis of tetrazole Ex.17

To a soln of 83 (19.0 mg, 0.027 mmol), (1 H-tetrazole-5-yl)methanamine (37; 4 mg, 0.040 mmol), HATU (20 mg, 0.053 mmol) and HOAt (12 mg, 0.088 mmol) in DMF (3 mL) at 0°C was added i-Pr2NEt (0.020 mL, 0.1 17 mmol), and the mixture was stirred at 0°C for 2 h. An aq. workup (EtOAc, H₂0; Na₂S0₄) and purification by prep. HPLC (method 1 a) afforded Ex.17 (1 1 mg, 52%).

Data of Ex.17: cf. Table 01a.

Synthesis of phosphonic acid Ex.18

To a suspension of (aminomethyl)phosphonic acid (35; 19 mg, 0.174 mmol) in CH2CI2 (3 mL) at rt were added i-Pr₂NEt (0.080 mL, 0.467 mmol) and trimethylchlorosilane (0.027 mL, 0.349 mmol). The mixture was stirred at rt for 2 h and was then cooled to 0°C. HOAt (9.5 mg, 0.070 mmol), 83 (25 mg, 0.035 mmol) and DIC (0.027 mL, 0.174 mmol) were added, and the mixture was stirred at rt for 18 h. An aq. workup (EtOAc, 1 M aq. HCI soln; Na2S0₄) and purification by prep. HPLC (method 1 a) afforded Ex.18 (10 mg, 35%).

Data of Ex.18: cf. Table 01a.

Synthesis of phosphonic acid Ex.19

To a suspension of (2-aminoethyl)phosphonic acid (36; 22 mg, 0.174 mmol) in CH2CI2 (3 mL) at rt were added i-Pr₂NEt (0.080 mL, 0.467 mmol) and trimethylchlorosilane (0.030 mL, 0.383 mmol). The mixture was stirred at rt for 2 h and was then cooled to 0°C. HOAt (10 mg, 0.073 mmol), 83 (25 mg, 0.035 mmol) and DIC (0.027 mL, 0.174 mmol) were added, and the mixture was stirred at rt for 18 h. An aq. workup (EtOAc, 1 M aq. HCI soln; Na2S0₄) and purification by prep. HPLC (method 1 a) afforded Ex.19 (9 mg, 31 %).

Data of Ex.19: cf. Table 01a. ¹H-NMR (DMSO-d₆): Ca 1 1 .4 - 9.9 (very br. s, exchanged upon addn of D2O, 2 H); 8.78 (d, J = 7.2, exchanged upon addn of D2O, 1 H); 8.19 - 8.13 (m, partially (1 H) exchanged upon addn of D₂0, 3 H); 8.06 - 7.91 (m, 4 H); 7.86 (s, 1 H); 7.74 (t, J = 7.8, 1 H); 7.60 - 7.57 (m, 2 H); 7.46 - 7.41 (m, 3 H); 7.32 (br. m, unresolved, 1 H); 6.95 (br. m, unresolved, 1 H); 5.29 (d, J = 1 1 .5, 1 H); 5.01 - 4.87 (m, 2 H); 4.85 (d, J = 14.2, 1 H); 4.17 - 4.02 (m, 2 H); 4.00 (d, J = 12.5, 1 H); 3.55 (t-like dd, 1 H); 3.40 - 3.27 (m, partially superimposed by H₂0 signal, 3 H); 2.60 (s, 3 H); ca. 2.4 (m, 1 H); 2.20 (dd-like m, 1 H); 2.06 (dd-like m, 1 H); 1.91 - 1 .78 (m, 3 H); 1 .60 (br. dd; J ca 13.1 , 16.7, 1 H); 1 .35 (br. t-like m, 1 H). Synthesis of Ex.20 (Scheme 6):

The macrocyclic acid 87 was prepared as described in the preceding patent application WO201 1/014973 A2.

Synthesis of amide 88

At 0°C, i-Pr₂NEt (0.13 mL, 0.759 mmol) was slowly added to a soln of acid 87 (100 mg, 0.188 mmol), amine 31 CF3CO2H (71.0 mg, 0.225 mmol), HATU (214 mg, 0.563 mmol) and HOAt (66 mg, 0.485 mmol) in DMF (3 mL). The soln was stirred at 0°C for 2 h followed by an aq. workup (EtOAc, H₂0; Na₂S0₄) and FC (CH2CI2 / MeOH; repurification with EtOAc / EtOH) to afford 88 (59 mg, 44%).

Data of 88: CssFUgNsOn (715.8). LC-MS (method 1 c): R_t = 1 .92 (96%), 716.3 «M+H]⁺). Synthesis of amide 90

TFA (1 mL) was slowly added at 0°C to a soln of 88 (58 mg, 0.081 mmol) in CH₂CI₂ (3 mL). The soln was stirred at 0°C to rt for 2 h. An aq. workup (CH2CI2, sat. aq. NaHCOs soln; Na₂S0₄) afforded 89 (43.0 mg).

To a soln of amine 89 (42 mg, 0.068 mmol) in CH2CI2 (2 mL) was added i-Pr₂NEt (0.030 mL, 0.175 mmol). The mixture was cooled to 0°C, and 3-chlorobenzoyl chloride (0.018 mL, 0.140 mmol) was added. The mixture was stirred at 0°C for 2 h. Evaporation of the solvent and purification of the crude product by FC (CH2CI2 / MeOH) afforded 90 (43 mg, 71 % over the two steps).

Data of 90: C₃7H₄₄CIN₅Oio (754.2). LC-MS (method 1 c): R_t = 1.91 (98%), 754.2 ([M+H]⁺).

Synthesis of diacid Ex.20

At 0°C, 2 M aq. LiOH soln (0.080 mL, 0.159 mmol) was added to a soln of 90 (30 mg, 0.040 mmol) in THF (1 mL) and EtOH (0.3 mL). The mixture was stirred at 0°C for 15 min and at rt for 3 h. 1 M Aq. ΗβΡ0₄ soln was added until acidic reaction, the mixture was extracted with EtOAc, and the combined organic layer was dried (Na2S0₄), filtered and concentrated to afford Ex.20 (23 mg, 83%).

Data of Ex.20: cf. Table 01a. Synthesis of final products Ex.21 - Ex.44 (Scheme 7):

Synthesis of the resins 95 and 99 Synthesis of ester 91

At 0°C, i-Pr₂NEt (22.8 mL, 134 mmol) was added within 5 min to a mixture of 24 (15.9 g, 33.6 mmol), β-alanine-tert.-butyl ester hydrochloride (29 HCI; 7.32 g, 40.3 mmol), HATU (19.2 g, 50.4 mmol) and HOAt (6.86 g, 50.4 mmol) in DMF (260 mL). Stirring was continued for 3 h followed by aq. workup (EtOAc, 1 M aq. HCI soln, H₂0, sat. aq. NaHCOs soln; sat. aq. NaCI soln; Na₂S0₄). FC (hexane / EtOAc) gave 91 (19.1 g, 94%).

Data of 91 : CssFUolS Oz (600.7). LC-MS (method 1 d): Rt = 2.76 (99%), 601 .3 ([M+H]⁺).

Synthesis of the acid 92

A soln of 91 (5.0 g, 8.0 mmol) in EtOAc (300 mL) was hydrogenated for 20 h at rt and under normal pressure in the presence of 5% palladium on activated charcoal (moistened with 50% H2O; 0.5 g). The mixture was filtered through a pad of celite. The residue was washed with EtOAc. The combined filtrate and washings were concentrated and purified by FC (0.1 % AcOH in EtOAc) to yield 92 (3.4 g, 79%). Data of 92: C28H₃₄N₂07 (510.6). LC-MS (method 1 d): F¾ = 2.23 (98%), 51 1 .3 ([M+H]⁺).

Synthesis of the ester 93

1 -Chloro-N,N,2-trimethyl-1-propenylamine (0.73 mL, 5.5 mmol) in CH2CI2 (2 mL) was added drop by drop to a mixture of 92 (2.34 g, 4.6 mmol) and 43b (1.66 g, 6.9 mmol) in CH2CI2 (66 mL). Stirring was continued for 1 h followed by an aq. workup (EtOAc, sat. aq. NaHCOs soln, sat. aq. NaCI soln; Na2S0₄) and FC (hexane / EtOAc) to afford

93 (3.36 g, 99%).

Data of 93: C43H47N3O8 (733.8). LC-MS (method 1 d): Rt = 2.84 (96%), 734.4 ([M+H]⁺). Synthesis of the acid 94

Pd(PPh3)₄ (0.53 g) and phenylsilane (3.4 mL, 27 mmol) were added to a soln of 93 (6.7 g, 9.1 mmol) in THF (90 mL). The mixture was stirred for 2 h at rt. The volatiles were evaporated and the residue purified by FC (EtOAc, then CH2CI2 / MeOH) to give

94 (6.17 g, 97%).

Data of 94: C₄oH₄₃N₃08 (693.8). LC-MS (method 1 d): R_t = 2.5 (92%), 694.4 ([M+H]⁺). Synthesis of resin 95

Preswelling of the resin: Under N₂, 2-chlorotrityl chloride resin (matrix: copoly(styrene - 1 % DVB), 100 - 200 mesh; loading: 1 .42 mmol/g; 2.5 g, 3.55 mmol) was suspended in dry CH2CI2 (25 ml_). The suspension was mixed by bubbling N2 through for 1 h and filtered.

Immobilisation of 94: T e resin was suspended in CH2CI2 (20 ml_). A soln of 94 (3.28 g, 4.26 mmol) in DMF (5 ml.) and i-Pr₂NEt (0.912 ml_, 5.3 mmol) were added. N₂ was bubbled through the suspension for 2.5 h. The resin was filtered and washed (CH2CI2, DMF and CH₂CI₂).

Capping: he resin was suspended in CH2CI2 / MeOH / i-Pr₂NEt 15:2:3 (25 ml_); N₂ was bubbled through for 30 min and the resin was filtered. The capping step was repeated twice. The resin was washed (CH2CI2, DMF, ChbC and Et.20).

Yield: The resin was dried i.v. to afford 95 (3.87 g; loading determined by mass increase: 0.54 mmol/g; loading determined by release of 94: 0.54 mmol/g).

Synthesis of the resin 99

Resin 99 (3.3 g, loading determined by mass increase: 0.59 mmol/g; loading determined by release of 66b: 0.58 mmol/g) was obtained by immobilizing 66b (1.67 g, 2.05 mmol) in the presence of i-Pr2NEt (1 .75 ml_, 10.32 mmol) on 2-chlorotrityl chloride resin (matrix: copoly(styrene - 1 % DVB), 100 - 200 mesh; loading: 1.22 mmol/g; 2.1 g, 2.6 mmol), applying the procedure described for the synthesis of resin 95.

Synthesis of the amino acids 97aa2, 97aa3, 97aa4, 97aa5, 97aa6, 97aa8, 97aa9, 97aa10, 97aa12, 97aa13, 97bb1 , 97cc8, 97dd1 , 97dd7, 97ee1 , 97gg9, 97hh9, and of the amino acids 101ee8 and 101ff12

Synthesis of the resins 96aa, 96bb, 96cc, 96dd, 96ee, 96gg, and 96hh, and synthesis of resins 100ee and 10O f

General procedure:

Preswelling of the resin: Resin 95 (loading 0.54 mmol/g; 80 mg, 0.043 mmol) or resin 99 (loading 0.58 mmol/g; 80 mg, 0.046 mmol), respectively, was suspended in DMF (3 ml_), shaken for 30 min and filtered.

Cleavage of the Fmoc group: The resin was resuspended in a soln of 2% v/v DBU in DMF (3 ml_), shaken for 30 min and filtered off. This deprotection step was repeated once. The resin was washed (DMF). Coupling of the 4-hydroxy benzoic acids 1, 4 - 10: Under argon, the resin was suspended in DMF (3 mL), then the corresponding 4-hydroxybenzoic acid (5 equiv.), HOAt (5 equiv.) and DIC (5 equiv.) were added. The mixture was shaken at rt for 18 h. The resin was filtered off and washed (DMF, CH₂CI₂, MeOH, CH₂CI₂, Et₂0).

[Intermediates of resins 96bb, 96cc, 96dd, 96ee, and 96gg and intermediates of resins 100ee and 100ff were treated after the coupling step with 10% v/v n- butylamine in THF (3 mL) at rt for 18 h. The resin was filtered off and washed (THF, DMF, MeOH, CH₂CI₂, MeOH, CH₂CI₂, Et₂0).]

Mitsunobu arylether synthesis: Under argon, the resin was suspended in dry THF (2.5 mL) and shaken for 30 min. The resin was filtered off. A soln of alcohol 18 (10 equiv.) in THF (1.25 mL) and a soln of PPh₃ (10 equiv.) in THF (1.25 mL) were added. While stirring, a soln of DIAD (10 equiv.) in THF (0.25 mL) was added slowly over 10 min. Shaking at rt was continued for 16 h. The resin was filtered off and washed (MeOH, CH₂CI₂, MeOH, CH₂CI₂, Et₂0).

Cleavage of the Alloc group: The resin was resuspended in dry CH₂CI₂ (2.5 mL), shaken for 30 min and filtered off. The resin was suspended in dry CH₂CI₂ (1 .7 mL) and morpholine (50 equiv.) was added. A soln of Pd(PPh₃)4 (0.01 M in CH₂CI₂; 0.2 equiv.) was added. The mixture was shaken for 2 h at rt. The resulting resins were filtered off, washed (CH₂CI₂, DMF, MeOH, CH₂CI₂, Et₂0) and used in the subsequent step.

The following 4-hydroxybenzoic acid derivatives were used:

Resin 96aa: 4-hydroxybenzoic acid (1 ); resin 96bb: 2,3-difluoro-4-hydroxybenzoic acid (4); resin 96cc: 2,6-difluoro-4-hydroxybenzoic acid (5); resin 96dd: 3-chloro-4- hydroxybenzoic acid (6); resins 96ee, 100ee: 2-chloro-4-hydroxybenzoic acid (7); resin 100ff: 3,5-dichloro-4-hydroxybenzoic acid (8); resin 96gg: 4-hydroxy-2- methoxybenzoic acid (9); resin 96hh: 4-hydroxy-3-methoxybenzoic acid (10).

General procedure

Coupling of carboxylic acids R^XC02H: The respective resin was suspended in dry DMF (3 mL) and shaken for 30 min. The resin was filtered off. Carboxylic acid (5 equiv.) in DMF (2 mL), PyBOP (0.5 M in DMF; 5 equiv.) and i-Pr₂NEt (10 equiv.) were added and the mixture was shaken at rt for 16 h. The resin was filtered off and washed (DMF, MeOH, CH₂CI₂, MeOH, CH₂CI₂, Et₂0). Coupling of sulfonyl chlorides R^XS02CI: The respective resin was suspended in dry pyridine (2.5 ml.) and shaken for 30 min. The resin was filtered off. Pyridine (2.5 ml.) was added followed by the sulfonyl chloride (5 equiv.). The mixture was shaken at rt for 16 h. The resin was filtered off and washed (DMF, MeOH, CH₂CI₂, MeOH, CH₂CI₂, Et₂0).

Coupling of isocyanates R^xNCO: The respective resin was suspended in dry THF (2.5 ml.) and shaken for 30 min. The resin was filtered off. THF (3.5 ml.) was added followed by i-Pr₂NEt (10 equiv.) and the isocyanate (4 equiv.). The mixture was shaken at rt for 16 h. The resin was filtered off and washed (THF, MeOH, CH₂CI₂, MeOH, CH₂CI₂, Et₂0).

Cleavage of the Nosy/ group: The resin was suspended in DMF (2 ml.) and shaken for 30 min. The resin was filtered off. DMF (2 ml.) was added, followed by 2- mercaptoethanol (10 equiv.) and DBU (5 equiv.). The mixture was shaken at rt for 16 h. The resin was filtered off and washed (DMF, MeOH, CH₂CI₂, Et₂0).

Release of the amino acid from solid support: he resin was resuspended in HFIP / CH₂CI₂ 2:3 (2.5 ml.) and shaken for 30 min. The mixture was filtered. The cleavage step was repeated once. The resin was washed with CH₂CI₂. The combined filtrates and washings were concentrated and dried i.v. to afford the crude amino acids, which were used without any further purification.

The following R^xC0₂H, R^xS0₂CI and R^xNCO were used:

97aa2: 3-(Trifluoromethyl)benzoic acid; 97aa3: 3-methoxybenzoic acid; 97aa4: 3- (methylthio)benzoic acid; 97aa5: 3-cyanobenzoic acid; 97aa6: 3-methylbenzoic acid; 97aa8, 97cc8, 101ee8: 4-chlorobenzoic acid; 97aa9, 97gg9, 97hh9: 3,5- dichlorobenzoic acid; 97aa10: 4-(tert.-butoxycarbonyl)benzoic acid; 97aa12; 101ff12: 3-chlorobenzenesulfonyl chloride; 97aa13: 3-chlorophenyl isocyanate; 97bb1 , 97dd1 , 97ee1 : 3-chlorobenzoic acid and 97dd7: 2-chlorobenzoic acid.

Synthesis of the macrocyclic esters 98aa2, 98aa3, 98aa4, 98aa5, 98aa6, 98aa8, 98aa9, 98aa10, 98aa12, 98aa13, 98bb1 , 98cc8, 98dd1 , 98dd7, 98ee1 , 98gg9, and 98hh9, and of the macrocyclic esters 102ee8 and 102ff12

General procedure

At rt, a soln of the respective amino acid (ca. 0.04 mmol) and i-Pr₂NEt (10 equiv.) in DMF (5 ml.) was slowly added by syringe pump over 2 h to a soln of FDPP (2.5 equiv.) in DMF (75 ml). Stirring at rt was continued for 16 h. The volatiles were evaporated. Aq. workup (CH₂CI₂, sat. aq. NaHCOs soln; Na₂S0₄) and purification by prep. HPLC (method 2a) afforded the respective macrocyclic ester, which was used without any further purification for subsequent ester cleavage.

The following amino acids were used: 97aa2, 97aa3, 97aa4, 97aa5, 97aa6, 97aa8, 97aa9, 97aa10, 97aa12, 97aa13, 97bb1 , 97cc8, 97dd1 , 97dd7, 97ee1 , 97gg9, 97hh9, and of the amino acids 101ee8 and 101ff12.

An analytical sample of the respective macrocyclic ester was analyzed by LC-MS: Data of 98aa2:

C45H48F3N5O8 (843.9). LC-MS (method 1 c): R_t = 2.36 (98%), 844.3 ([M+H]⁺).

Data of 98aa3:

C45H51 N5O9 (805.9). LC-MS (method 1 c): R_t = 2.19 (98%), 806.4 ([M+H]⁺).

Data of 98aa4:

C45H51 N5O8S (822.0). LC-MS (method 1 c): R_t = 2.28 (97%), 822.3 ([M+H]⁺).

Data of 98aa5:

C45H48N6O8 (800.9). LC-MS (method 3a): R_t = 1 .70 (95%), 801 .4 ([M+H]⁺).

Data of 98aa6:

C45H51 N5O8 (789.9). LC-MS (method 3a): R_t = 1 .80 (97%), 790.4 ([M+H]⁺).

Data of 98aa8:

C44H48CIN5O8 (810.3). LC-MS (method 3a): R_t = 1 .85 (91 %), 810.3 ([M+H]⁺).

Data of 98aa9:

C₄4H47CI₂N₅08 (844.8). LC-MS (method 3a): R_t = 2.01 (94%), 844.3 ([M+H]⁺).

Data of 98aa10:

C49H57N5O10 (876.0). LC-MS (method 3a): R_t = 2.00 (97%), 876.4 ([M+H]⁺).

Data of 98aa12:

C43H48CIN5O9S (846.4). LC-MS (method 3a): R_t = 1.83 (92%), 846.3 ([M+H]⁺).

Data of 98aa13:

C44H49CIN6O8 (825.3). LC-MS (method 3a): R_t = 1 .85 (88%), 825.4 ([M+H]⁺).

Data of 98bb1 :

C44H46CIF2N5O8 (846.3). LC-MS (method 3b): R_t = 1.97 (94%), 846.3 ([M+H]⁺).

Data of 98cc8:

C44H46CIF2N5O8 (846.3). LC-MS (method 1 c): R_t = 2.44 (96%), 846.1 ([M+H]⁺).

Data of 98dd1 :

C44H47CI2N5O8 (844.8). LC-MS (method 3b): R_t = 1.95 (95%), 844.3 ([M+H]⁺).

Data of 98dd7:

C₄4H47CI₂N₅08 (844.8). LC-MS (method 3b): R_t = 1.83 (95%), 844.2 ([M+H]⁺). Data of 98ee1 :

C₄4H47CI₂N₅08 (844.8). LC-MS (method 3b): R_t = 1.97 (94%), 844.2 ([M+H]⁺).

Data of 98gg9:

C₄5H₄9Cl2N₅09 (874.8). LC-MS (method 3b): R_t = 2.05 (95%), 874.3 ([M+H]⁺).

Data of 98hh9:

C₄5H₄9Cl2N₅09 (874.8). LC-MS (method 3b): R_t = 2.02 (97%), 874.2 ([M+H]⁺).

Data of 102ee8:

C4i H₄iCI₂N₅08 (802.7). LC-MS (method 3b): R_t = 1.71 (90%), 802.3 ([M+H]⁺).

Data of 102ff12:

C₄oH₄oCl3N₅09S (873.2). LC-MS (method 3b): R_t = 1 .85 (91 %), 874.1 ([M+H]⁺).

Synthesis of Ex.21 - Ex.37

General procedure:

The respective tert. -butyl ester was treated with TFA / CH2CI2 1 :4 (1 mL) for 2.5 h at rt. The volatiles were evaporated. The residue was dissolved in CH₃CN and concentrated then twice dissolved in CH2CI2 and concentrated.

The indicated overall yields are based on the engaged quantity of the resin 95.

Ex 21 (5 2 mg, 16%) was obtained from 98aa2. Data of Ex.21 : cf. Table 01a.

Ex 22 (5 2 mg, 16%) was obtained from 98aa3. Data of Ex.22: cf. Table 01a.

Ex 23 (4 2 mg, 14%) was obtained from 98aa4. Data of Ex.23: cf. Table 01a.

Ex 24 (5 2 mg, 17%) was obtained from 98aa5. Data of Ex.24: cf. Table 01a.

Ex 25 (4 8 mg, 16%) was obtained from 98aa6. Data of Ex.25: cf. Table 01a.

Ex 26 (3 1 mg, 10%) was obtained from 98aa8. Data of Ex.26: cf. Table 01a.

Ex 27 (5 5 mg, 17%) was obtained from 98aa9. Data of Ex.27: cf. Table 01a

Ex 28 (3 0 mg, 10%) was obtained from 98aa10. Data of Ex.28: cf. Table 01a

Ex 29 (3 5 mg, 1 1 %) was obtained from 98aa12. Data of Ex.29: cf. Table 01a

Ex 30 (2 5 mg, 8%) was obtained from 98aa13. Data of Ex.30: cf. Table 01a.

Ex 31 (2 4 mg, 7%) was obtained from 98bb1. Data of Ex.31 : cf. Table 01a.

Ex 32 (3 1 mg, 10%) was obtained from 98cc8. Data of Ex.32: cf. Table 01a.

Ex 33 (5 1 mg, 15%) was obtained from 98dd1. Data of Ex.33: cf. Table 01a.

Ex 34 (2 5 mg, 7%) was obtained from 98dd7. Data of Ex.34: cf. Table 01a.

Ex 35 (5 5 mg, 16%) was obtained from 98ee1. Data of Ex.35: cf. Table 01a.

Ex 36 (7 1 mg, 20%) was obtained from 98gg9. Data of Ex.36: cf. Table 01a.

Ex 37 (7 8 mg, 22%) was obtained from 98hh9. Data of Ex.37: cf. Table 01a. Synthesis of Ex.38

Aq. 0.5 M LiOH soln (0.020 mL, 0.010 mmol) was added at 0°C to a soln of the methylester 102ee8 (3.6 mg, 0.0045 mmol) in THF / MeOH / H₂0 3:1 :1 (1.0 mL). The mixture was stirred at rt for 5 h. The volatiles were evaporated. Aq. workup (EtOAc, 1 M aq. HCI soln; Na₂S0₄) and purification by prep. TLC (CH₂CI₂ / MeOH 85:15) afforded Ex.38 (3.2 mg, 90%; overall yield based on engaged quantity of resin 99: 9%).

Data of Ex.38: cf. Table 01a. Synthesis of Ex.39

Aq. 0.5 M LiOH soln (0.021 mL, 0.01 1 mmol) was added at 0°C to a soln of the methylester 102ff12 (2.8 mg, 0.003 mmol) in THF / MeOH 2:1 (0.9 mL). The mixture was stirred at rt for 2 h. H₂0 (0.3 mL) was added and stirring continued for 16 h. More 0.5 M aq. LiOH soln (0.007 mL, 0.0035 mmol) was added at 0°C and stirring at rt continued for 24 h. The volatiles were evaporated. Aq. workup (EtOAc, 1 M aq. HCI soln; Na₂S0₄) and purification by prep. TLC (CH₂CI₂ / MeOH 85:15) afforded Ex.39 (1.8 mg, 65%; overall yield based on engaged quantity of resin 99: 5%).

Data of Ex.39: cf. Table 01a. Synthesis of Ex.40 - Ex.43

Synthesis of macrocyclic acid Ex.40

To a soln of 63b CF₃C0₂H (15 mg, 0.020 mmol), 3-(4-methoxyphenoxy)benzoic acid (5.9 mg, 0.024 mmol), HATU (12 mg, 0.030 mmol) and HOAt (4.1 mg, 0.030 mmol) in DMF (1 .2 mL) at 0°C was added i-Pr₂NEt (0.014 mL, 0.081 mmol), and the mixture was stirred at 0°C for 1 h. An aq. workup (EtOAc, 1 M aq. HCI soln, sat. aq. NaHC0₃ soln, sat. aq. NaCI soln; Na₂S0₄) followed by FC (hexane / EtOAc) afforded 102aa14 (1 1 mg, used without further purification).

Data of 102aa14: C₄8H₄₉N₅Oio (855.9). LC-MS (method 1 d): R_t = 2.21 (75%), 856.5 ([M+H]⁺).

To a soln of 102aa14 (10 mg, 0.012 mmol) in a mixture of THF (0.5 mL) and MeOH (0.05 mL) at 0°C was added 1 M aq. LiOH soln (0.026 mL, 0.026 mmol), and the mixture was stirred at 0°C to rt for 3 h. The solvents were evaporated, followed by an aq. workup (EtOAc, 1 M aq. HCI soln; Na₂S0₄) to give acid Ex.40 (8.9 mg, 52% over the two steps).

Data of Ex.40: cf. Table 01a. Synthesis of macrocyclic acid Ex.41

To a soln of 5-chlorothiophene-2-carboxylic acid (14 mg, 0.087 mmol) in CH2CI2 (1.3 mL) at rt was added oxalyl chloride (0.026 mL, 0.303 mmol) followed by one drop of DMF. The mixture was stirred at rt for 1 h and was then concentrated. The residue was coevaporated twice with CH2CI2 and was then dissolved in THF (2.5 mL). Amine 63b CF3CO2H (50 mg, 0.067 mmol) was added at rt, the mixture was cooled to 0°C, and a soln of i-Pr₂NEt (0.035 mL, 0.202 mmol) in THF (0.7 mL) was slowly added. The mixture was stirred at 0°C for 1 h and at rt overnight and was then concentrated. An aq. workup (EtOAc, 1 M aq. HCI soln) followed by FC (CH₂CI₂ / MeOH) afforded 102aa15 (21 mg, 40%).

Data of 102aa15: C39H40CIN5O8S (774.3). LC-MS (method 7b): R_t = 1 .64 (93%), 774.3 ([M+H]⁺).

To a soln of 102aa15 (18 mg, 0.023 mmol) in a mixture of THF (1.4 mL) and MeOH (0.7 mL) at 0°C was slowly added 1 M aq. LiOH soln (0.051 mL, 0.051 mmol), and the mixture was stirred at 0°C to rt overnight. The mixture was acidified with 1 M aq. HCI soln, the solvents were evaporated, and the crude product was purified by FC (CH2CI2 / MeOH) to give acid Ex.41 (20 mg, quant, yield; contained residual amounts of solvents).

Data of Ex.41 : cf. Table 01a.

Synthesis of macrocyclic diacid Ex.42

To a soln of 63b CF₃C0₂H (25 mg, 0.034 mmol) and i-Pr₂NEt (0.017 mL, 0.101 mmol) in CH2CI2 (0.5 mL) at 0°C was slowly added a soln of ethyl oxalyl chloride (0.0045 mL, 0.040 mmol) in CH2CI2 (0.5 mL), and the mixture was stirred at rt for 2 h. An aq. workup (CH2CI2, 1 M aq. Na₂C0₃ soln; Na₂S0₄) followed by FC (EtOAc / MeOH) afforded 102aa16 (15 mg, 60%).

Data of 102aa16: C38H43N5O10 (729.8). LC-MS (method 1 d): Rt = 1.78 (85%), 730.2 ([M+H]⁺).

To a soln of 102aa16 (15 mg, 0.021 mmol) in a mixture of THF (0.5 mL), MeOH (0.25 mL) and H₂0 (0.25 mL) at 0°C was slowly added 1 M aq. LiOH soln (0.062 mL, 0.062 mmol), and the mixture was stirred at 0°C for 6 h. The mixture was acidified with 1 M aq. HCI soln and extracted with EtOAc. The combined organic layer was dried (Na2S0₄), filtered and concentrated. The residue was dissolved in CH3CN / H2O 1 :3 and lyophilized to give diacid Ex.42 (9.7 mg, 70%).

Data of Ex.42: cf. Table 01a. Synthesis of macrocyclic acid Ex.43

4-Acetoxybenzoic acid (13 mg, 0.070 mmol) was transformed into the acid chloride with oxalyl chloride (0.020 mL, 0.242 mmol) and one drop of DMF in CH₂CI₂ (1 .0 mL) at rt for 1 h. The volatiles were evaporated, the residue was dissolved in THF (2 mL) and reacted with 63b CF₃C0₂H (40 mg, 0.054 mmol) and with a solution of i-Pr₂NEt (0.028 mL, 0.161 mmol) in THF (0.5 mL) at 0°C. Stirring was continued at 0°C for 1 h and at rt overnight. An aq. workup (EtOAc, 1 M aq. HCI soln) followed by FC (CH₂CI₂, then CH₂CI₂ / MeOH) afforded 102aa17 (31 mg, used without further purification). Data of 102aa17: C₄3H₄5N₅Oio (791 .8). LC-MS (method 3a): R_t = 1.48 (82%), 792.3 ([M+H]⁺).

To a soln of 102aa17 (28 mg, 0.035 mmol) in a mixture of THF (2 mL) and MeOH (1 mL) at 0°C was slowly added 1 M aq. LiOH soln (0.156 mL, 0.156 mmol), and the mixture was stirred at 0°C to rt overnight. The mixture was acidified with 1 M aq. HCI soln, the solvents were evaporated, and the crude product was purified by FC (CH₂CI₂ / MeOH) to give the acid Ex.43 (28 mg, 71 % over the two steps).

Data of Ex.43: cf. Table 01a.

Synthesis of Ex.44 Synthesis of ether 103

CMBP (0.39 mL, 1 .50 mmol) was added at rt to a soln of 14 (300 mg, 1 .0 mmol) and methyl 4-hydroxy-3-nitrobenzoate (11 ; 236 mg, 1 .20 mmol) in toluene (7 mL). The mixture was heated at reflux for 2 h and was then concentrated to dryness. Purification of the residue by FC (CH₂CI₂ / EtOAc) afforded 103 (421 mg, 88%).

Data of 103: C₂₂H₂₉N₃09 (479.5). LC-MS (method 1 a): R_t = 2.29 (94%), 480.1 ([M+H]⁺).

Synthesis of acid 104

To a soln of 103 (413 mg, 0.861 mmol) in a mixture of THF (14 mL) and MeOH (7 mL) at 0°C was slowly added 2 M aq. LiOH soln (0.9 mL, 1.80 mmol). The mixture was stirred at rt for 18 h. 1 M aq. HCI soln (50 mL) was added, the mixture was extracted with CH₂CI₂, and the combined organic layer was dried (Na₂S0₄), filtered and concentrated to afford the acid 104 (374 mg, 93%).

Data of 104: C₂iH₂₇N₃09 (465.5). LC-MS (method 1 a): R_t = 2.00 (88%), 466.1 ([M+H]⁺). Synthesis of amide 105

A soln of 1 -chloro-N,N,2-trimethylpropenylamine (0.57 mL, 4.27 mmol) in CH2CI2 (2 mL) was slowly added at 0°C to a suspension of 27 (1.00 g, 2.13 mmol), 43b (0.773 g, 3.20 mmol) and K2CO3 (0.354 g, 2.56 mmol) in CH2CI2 (9 mL). The mixture was stirred at 0°C to rt for 3 h. The solvent was evaporated, followed by an aq. workup (EtOAc, sat. aq. NaHCC>3 soln; Na2S0₄). The crude product was purified by FC (hexane / EtOAc) to give 105 (1 .02 g, 69%).

Data of 105: C₄oH₄iN₃0₈ (691 .8). LC-MS (method 1 d): Rt = 2.59 (88%), 692.2 ([M+H]⁺).

Synthesis of amine 106

Piperidine (0.29 mL, 2.89 mmol) was added at rt to a soln of 105 (1 .00 g, 1.45 mmol) in DMF (4 mL), and the mixture was stirred at rt for 1 h. An aq. workup (EtOAc, sat. aq. NaHCOs soln; Na₂S0₄) followed by FC (hexane / EtOAc, then EtOAc, CH2CI2, CH2CI2 / MeOH) afforded 106 (645 mg, 95%).

Data of 106: C25H31 N3O6 (469.5). LC-MS (method 1 d): R_t = 1 .64 (96%), 470.2 ([M+H]⁺).

Synthesis of amide 107

To a soln of 104 (370 mg, 0.795 mmol), 106 (448 mg, 0.954 mmol), HATU (453 mg, 1 .19 mmol) and HOAt (162 mg, 1.19 mmol) in DMF (5 mL) at 0°C was added i-Pr₂NEt (0.41 mL, 2.39 mmol). The mixture was stirred at 0°C to rt for 3 h. An aq. workup (EtOAc, 1 M aq. HCI soln, sat. aq. NaCI soln; Na₂S0₄) followed by FC (hexane / EtOAc) afforded 107 (675 mg, 93%).

Data of 107: C46H₅6N₆Oi4 (917.0). LC-MS (method 1 d): Rt = 2.44 (83%), 917.4 ([M+H]⁺).

Synthesis of amino acid 108

To a degassed soln of 107 (625 mg, 0.682 mmol) and DMBA (255 mg, 1 .64 mmol) in a mixture of CH2CI2 (5 mL) and EtOAc (5 mL) at rt was added Pd(PPh₃)₄ (79 mg). The mixture was stirred at rt for 3 h and was then concentrated. Purification of the crude product by FC (CH2CI2 / MeOH) afforded 108 (430 mg, 80%).

Data of 108: C39H₄₈N₆Oi2 (792.8). LC-MS (method 1 d): Rt = 1 .66 (85%), 793.3 ([M+H]⁺). Synthesis of macrocyclic lactam 109

A soln of amino acid 108 (400 mg, 0.505 mmol) and i-Pr₂NEt (0.17 ml_, 1 .02 mmol) in DMF (5 ml.) was added at rt to a soln of FDPP (485 mg, 1.26 mmol) and i-Pr₂NEt (0.26 ml_, 1.51 mmol) in DMF (1000 ml.) over 2 h. The mixture was stirred at rt overnight. The solvent was evaporated, followed by an aq. workup (EtOAc, sat. aq. NaHCOs soln; Na₂S0₄) and purification by FC (CH₂CI₂ / MeOH) to give 109 (276 mg, 71 %).

Data of 109:

(774.8). LC-MS (method 1 c): R_t = 2.1 1 (97%), 775.3 ([M+H]⁺).

Synthesis of aniline 110

To a soln of 109 (190 mg, 0.245 mmol) in MeOH (7 ml.) at rt was added platinum(IV) oxide hydrate (28 mg, 0.123 mmol), and the mixture was hydrogenated at normal pressure overnight. Additional platinum(IV) oxide hydrate (28 mg, 0.123 mmol) was added, and the mixture was again hydrogenated overnight. The mixture was then filtered through celite, and the filtrate was concentrated to dryness to give 1 10 (177 mg, 97%).

Data of 1 10:

(744.8). LC-MS (method 1 c): R_t = 1 .79 (92%), 745.3 ([M+H]⁺).

Synthesis of amide 112

To a soln of 110 (170 mg, 0.228 mmol) in dioxane (1 .5 ml.) at rt was added 4 M HCI soln in dioxane (1.5 ml_), and the suspension was stirred at rt for 3 h. The volatiles were removed under reduced pressure, and the product was dried i.v. to give crude 11 1 HCI (140 mg).

To a soln of 11 1 HCI (55 mg, 0.065 mmol), 3-chlorobenzoic acid (9.1 mg, 0.058 mmol), HATU (37 mg, 0.097 mmol) and HOAt (13 mg, 0.097 mmol) in DMF (2 ml.) at 0°C was added i-Pr₂NEt (0.044 ml_, 0.258 mmol), and the mixture was stirred at 0°C for 2 h. An aq. workup (EtOAc, sat. aq. NaHCOs soln; Na₂S0₄) and purification by FC (CH₂CI₂, then CH₂CI₂ / MeOH) afforded 112 (30 mg, 42% over the two steps).

Data of 112: C₄i H₄3CIN₆08 (783.3). LC-MS (method 1 d): R_t = 1 .84 (90%), 783.2 ([M+H]⁺).

Synthesis of macrocyclic acid Ex.44

To a soln of 112 (28 mg, 0.036 mmol) in a mixture of THF (0.8 mL) and MeOH (0.35 mL) at 0°C was slowly added 2 M aq. LiOH soln (0.039 mL, 0.079 mmol), and the mixture was stirred at 0°C to rt for 3 h. An aq. workup (EtOAc, 0.5 M aq. HCI soln; Na₂S0₄) afforded a crude product which was coevaporated twice with toluene and purified by FC (CH₂CI₂ / MeOH) to afford the acid Ex.44 (16 mg, 58%).

Data of Ex.44: cf. Table 01a.

Synthesis of Ex.45 (Scheme 8):

Synthesis of diester 113

At 0°C, i-Pr₂NEt (2.0 mL, 1 1 .86 mmol) was slowly added to a soln of amine 28 HCI (0.496 g, 3.56 mmol), acid 25 (1.00 g, 2.96 mmol), HATU (1.69 g, 4.45 mmol) and

HOAt (0.605 g, 4.45 mmol) in DMF (13 mL). The mixture was stirred at rt for 1 h followed by an aq. workup (EtOAc, 1 M aq. HCI soln, H₂0, sat. aq. NaHCC soln;

Na₂S0₄) and purification by FC (hexane / EtOAc) to afford 113 (1.25 g, quant, yield).

Data of 113: C₂iH₃₀N₂O₇ (422.5). FI-MS: (423.1 ) ([M+H]⁺). ¹H-NMR (DMSO-d₆): 7.99 (t, J = 5.6, 1 H); 7.47 - 7.23 (m, 6 H); 5.04 (d, J = 12.7, 1 H); 4.99 (d, J = 12.6, 1 H);

3.93 (m, 1 H); 3.59 (s, 3 H); 3.28 (m, 2 H); 2.46 (t, J = 6.8, 2 H); 2.19 (t, J = 7.7, 2 H);

1 .81 (m, 1 H); 1 .68 (m, 1 H); 1.38 (s, 9 H).

Synthesis of acid 114

TFA (1 1 mL) was slowly added at 0°C to a soln of 1 13 (1.24 g, 2.935 mmol) in CH₂CI₂ (10 mL). The soln was stirred at 0°C for 15 min and at rt for 2 h. Evaporation of the volatiles and coevaporation of the residue with toluene, CHCI3 and CH₂CI₂ afforded 114 (1 .20 g, quant, yield; contained residual TFA, used without further purification). Data of 114: Ci₇H₂₂N₂0₇ (366.4). FI-MS: (367.1 ) ([M+H]⁺). ¹H-NMR (DMSO-de): 8.00 (t, J = 5.6, 1 H); 7.47 - 7.24 (m, 6 H); 5.04 (d, J = 12.7, 1 H); 4.99 (d, J = 12.7, 1 H); 3.93 (m, 1 H); 3.59 (s, 3 H); 3.28 (m, 2 H); 2.46 (t, J = 6.8, 2 H); 2.22 (t, J = 7.7, 2 H); 1 .83 (m, 1 H); 1 .70 (m, 1 H).

Synthesis of amide 115

A soln of 1-chloro-N,N,2-trimethylpropenylamine (1.0 mL, 7.78 mmol) in CH₂CI₂ (5 mL) was slowly added at 0°C to a suspension of 114 (0.95 g, 2.59 mmol), 41 b (1.00 g, 3.89 mmol) and K₂C0₃ (0.72 g, 5.19 mmol) in CH₂CI₂ (30 mL). The mixture was stirred at 0°C for 1 h and was then concentrated to dryness. An aq. workup (EtOAc, sat. aq. NaHC03 soln, sat. aq. NaCI soln; Na₂S0₄) followed by FC (hexane / EtOAc) afforded 1 15 (1 .38 g, 87%; contained 20% of dimethyl isobutyramide, used without further purification). Data of 115: C33H39N3O8 (605.7). LC-MS (method 1 d): Rt = 2.40 (84%), 606.2 ([M+H]⁺).

Synthesis of amine 116

A solution of 115 (ca 80% w/w; 1 .265 g, ca 1 .6 mmol) in MeOH (70 mL) was hydrogenated for 2 h at normal pressure and at rt in the presence of palladium hydroxide on activated charcoal (15 - 20% Pd, wet, ca. 50% H₂0; 1 .265 g). The mixture was filtered through celite, the residue was rinsed with MeOH, and the filtrate was concentrated. Purification of the crude product by FC (EtOAc, then CH2CI2 / MeOH) afforded 116 (0.677 g, 86%).

Data of 116: C25H33N3O6 (471 .5). LC-MS (method 1 a): R_t = 1 .75 (97%), 472.2 ([M+H]⁺).

Synthesis of nosylate 117

2-Nitrobenzenesulfonyl chloride (333 mg, 1 .50 mmol) was added at 0°C to a soln of

116 (590 mg, 1.25 mmol) and pyridine (0.4 mL, 4.38 mmol) in CH₂CI₂ (6 mL). The mixture was stirred at 0°C to rt overnight, followed by an aq. workup (CH2CI2, 1 M aq. HCI soln; Na₂S0₄). The crude product was purified by FC (CH2CI2 / MeOH) to afford

117 (656 mg, 80%).

Data of 1 17: C3i H₃₆N₄OioS (656.7). LC-MS (method 1 d): Rt = 2.33 (95%), 657.1 ([M+H]⁺).

Synthesis of N-ethyl sulfonamide 118

lodoethane (0.15 mL, 1.90 mmol) was added at 0°C to a suspension of 117 (250 mg, 0.38 mmol) and K2CO3 (263 mg, 1 .90 mmol) in DMF (1.5 mL). The mixture was stirred at 0°C to rt overnight, followed by an aq. workup (EtOAc, 1 M aq. HCI soln, H₂0, sat. aq. NaHCOs soln; Na₂S0₄) to afford 1 18 (243 mg, 93%).

Data of 1 18: C₃3H₄₀N₄OioS (684.8). LC-MS (method 1 d): Rt = 2.50 (94%), 685.1 ([M+H]⁺).

Synthesis of ethylamine 119

Thiophenol (0.062 mL, 0.607 mmol) was added at rt to a suspension of 1 18 (231 mg, 0.337 mmol) and Cs₂C0₃ (363 mg, 1 .1 1 mmol) in degassed CH₃CN (2.5 mL). The mixture was stirred at rt overnight and was then filtered. The filter cake was washed with Et₂0, the combined filtrate was concentrated at 30°C (bath temperature), and the crude product was purified by FC (CH₂CI₂ / MeOH) to afford 119 (149 mg, 88%). Data of 119: C27H37N3O6 (499.6). LC-MS (method 2a): R_t = 2.18 (99%), 500.2 ([M+H]⁺).

Synthesis of amide 120

At 0°C, i-Pr₂NEt (0.23 mL, 1.35 mmol) was slowly added to a soln of amine 119 (135 mg, 0.270 mmol), acid 51 (149 mg, 0.324 mmol), HATU (154 mg, 0.405 mmol) and HOAt (55 mg, 0.405 mmol) in DMF (3.5 mL). The mixture was warmed to rt and stirred at rt for 5 d. An aq. workup (EtOAc, 1 M aq. HCI soln, H₂0, sat. aq. NaHC0₃ soln; Na₂S0₄) and purification by FC (hexane / EtOAc) afforded 120 (177 mg, 69%). Data of 120: CsoHseCINsOn (940.5). LC-MS (method 1 d): Rt = 2.58 (95%), 940.1 ([M+H]⁺).]

Synthesis of the amino acid 121

Silica gel (390 mg) was added to a soln of ester 120 (131 mg, 0.140 mmol) in toluene (5 mL), and the mixture was stirred at 1 10°C for 6 h and at rt for 18 h. The suspension was filtered, the filtrate was concentrated, and the residue was dissolved in a mixture of CH2CI2 (4 mL) and EtOAc (4 mL). DMBA (65 mg, 0.419 mmol) and Pd(PP i3)₄ (81 mg) were added, and the mixture was stirred at rt for 5 h. The solvents were evaporated, and the crude product was purified by FC (CH2CI2 / MeOH) to afford 121 (86 mg, 77%).

Data of 121 :

(800.3). LC-MS (method 2b): R_t = 1 .47 (92%), 800.3 ([M+H]⁺).

Synthesis of the macrocyclic lactam 122

A soln of amino acid 121 (86 mg, 0.107 mmol) in DMF (20 mL) was slowly added (over 1 h) at rt to a soln of FDPP (83 mg, 0.215 mmol) and i-Pr₂NEt (0.04 mL, 0.215 mmol) in DMF (530 mL). The mixture was stirred at rt for 2 h. The solvent was evaporated, followed by an aq. workup (EtOAc, 1 M aq. NaHC03 soln; Na2S0₄) and purification by FC (CH₂CI₂ / MeOH) to give 122 (45 mg, 53%).

Data of 122: C₄₂H₄₄CIN₅08 (782.3). LC-MS (method 1 c): R_t = 2.12 (94%), 782.2 ([M+H]⁺).

Synthesis of the macrocyclic acid Ex.45

To a soln of 122 (43 mg, 0.055 mmol) in a mixture of THF (1 mL) and MeOH (0.5 mL) at 0°C was added 2 M aq. LiOH soln (0.027 mL, 0.055 mmol). The mixture was stirred at 0°C to rt for 18 h. 1 M aq. H₃P0₄ soln (0.5 mL) was added, followed by purification by prep. HPLC (method 1 a) to give Ex.45 (33 mg, 78%).

Data of Ex.45: cf. Table 01a. Synthesis of Ex.46 - Ex.50 (Scheme 9):

Synthesis of amide 123a

To a soln of amine 57 (289 mg, 0.446 mmol), acid 39n (301 mg, 0.892 mmol) and i- Pr₂NEt (0.25 mL, 1 .46 mmol) in CH₂CI₂ (5 mL) at rt was slowly added T3P (50% w/w in EtOAc; 0.80 mL, 1.36 mmol). The mixture was stirred at rt for 4 h, followed by an aq. workup (CH2CI2, sat. aq. NaHCC>3 soln; Na2S0₄) and purification by FC (hexane / EtOAc / MeOH) to give 123a (290 mg, 67%).

Data of 123a: C48H₄₇Cl2F₃N₄Oio (967.8). LC-MS (method 6c): R_t = 10.37 (88%), 967.3 ([M+H]⁺).

Synthesis of amide 123b

In analogy to the synthesis of 123a, amine 57 (450 mg, 0.694 mmol) was coupled with acid 39k (344 mg, 1.04 mmol) in the presence of T3P (50% w/w in EtOAc; 1.2 mL, 2.04 mmol) and i-Pr₂NEt (0.40 mL, 2.34 mmol) in CH2CI2 (8 mL) at rt for 4 h to give 123b (657 mg, 99%) after aq. workup and FC (hexane / EtOAc).

Data of 123b: C51 H50CIN5O12 (960.4). LC-MS (method 6a): R_t = 9.80 (89%), 960.3 ([M+H]⁺).

Synthesis of amide 123c

In analogy to the synthesis of 123a, amine 57 (417 mg, 0.643 mmol) was coupled with acid 39I (324 mg, 0.965 mmol) in the presence of T3P (50% w/w in EtOAc; 1.2 mL, 2.04 mmol) and i-Pr₂NEt (0.35 mL, 2.05 mmol) in CH2CI2 (8 mL) at rt for 4 h to give 123c (520 mg, 84%) after aq. workup and FC (hexane / EtOAc).

Data of 123c: C₅2H₅₇CIN₄Oi₂ (965.5). LC-MS (method 3a): R_t = 2.41 (89%), 965.6 ([M+H]⁺). ¹ H-NMR (DMSO-d₆): 2 rotamers ca 7:3; 8.73 (d, J = 6.7, 0.7 H); 8.68 (d, J = 6.6, 0.3 H); 7.89 - 7.79 (m, 4 H); 7.62 (dd-like m, 1 H); 7.51 (t, J = 7.8, 1 H); 7.46 - 6.85 (several br. m, 12 H); 5.87 - 5.77 (m, 2 H); 5.32 - 5.06 (m, 6 H); 4.95 - 4.67 (m, 2 H); 4.60 - 4.40 (m, 7 H); ca 4.2 - 4.05 (2 br. m, 1 H); 3.87 (dd-like m, 1 H); 3.64, 3.49 (2 m, 1 H); 2.86 (br. s, 3 H); 2.35 - 2.00 (br. m, 6 H); 1 .53, 1 .52 (2 s, 9 H). Synthesis of amino acid 124a

To a soln of 123a (284 mg, 0.293 mmol) and DMBA (185 mg, 1.17 mmol) in a mixture of CH₂CI₂ (3 ml.) and EtOAc (3 ml.) at rt was added Pd(PPh₃)₄ (34 mg). The mixture was stirred at rt for 3 h and was then concentrated. Purification of the crude product by FC (CH2CI2 / MeOH) afforded 124a (235 mg, 95%).

Data of 124a: C4i H₃9Cl2F₃N₄08 (843.7). LC-MS (method 1 d): Rt = 2.45 (95%), 843.2 ([M+H]⁺).

Synthesis of amino acid 124b

In analogy to the synthesis of 124a, compound 123b (640 mg, 0.666 mmol) was deprotected with DMBA (420 mg, 2.67 mmol) and Pd(PPh₃)₄ (77 mg) in a mixture of CH2CI2 (6 mL) and EtOAc (6 mL) at rt for 3 h to give after FC (CH2CI2 / MeOH) the amino acid 124b (552 mg, 99%).

Data of 124b: C₄4H₄2CIN₅Oio (836.3). LC-MS (method 1 d): Rt = 2.35, 836.2 ([M+H]⁺). ¹ H-NMR (DMSO-de): 2 rotamers, ca 8:2; 8.80 (d, J = 6.8, 0.8 H); 8.72 (d, J = 6.6, 0.2 H); 8.05 (d, J = 9.4, 1 H); 7.93 (m, 1 H); 7.86 - 7.75 (m, 3 H); 7.64 (dd-like m, 1 H); 7.53 (t, J = 7.8, 1 H); 7.44 - 7.16 (m, 9 H); ca 7.1 - 6.95 (m, 2 H); 6.90 (s, 0.8 H); 6.86 (s, 0.2 H); 6.48 (t, J = 7.6, 0.2 H); 6.47 (t, J = 5.1 , 0.8 H); 5.19 (d, J = 12.4, 1 H); 5.14 (d, J = 12.4, 1 H); 4.90 (br. m, 1 H); 4.81 (m, 1 H); ca 4.6 - 4.4 (2 br. m, 1 H); 4.29 - 4.14 (br. m, 2 H); 4.06 - 3.94 (br. m, 2 H); 3.60 (dd-like m, 1 H); ca 3.3 (1 H, superimposed by H2O signal); 2.88 (br. s, 3 H); ca 2.4 - 1 .95 (several br. m, 6 H).

Synthesis of amino acid 124c

In analogy to the synthesis of 124a, compound 123c (515 mg, 0.533 mmol) was deprotected with DMBA (252 mg, 1.60 mmol) and Pd(PPh₃)₄ (65 mg) in a mixture of CH2CI2 (5 mL) and EtOAc (5 mL) at rt for 4 h to give after FC (CH2CI2 / MeOH) the amino acid 124c (440 mg, 98%).

Data of 124c: C₄₅H₄₉CIN₄Oio (841 .3). LC-MS (method 1 d): Rt = 2.44 (94%), 841 .4 ([M+H]⁺).

Synthesis of macrocyclic lactam 125a

To a soln of 2-chloro-1-methylpyridinium iodide (500 mg, 1.95 mmol) in DCE (500 mL) at 90°C was slowly added over 1 h a soln of 124a (160 mg, 0.190 mmol) in DCE (10 mL). When the addition was finished, additional 2-chloro-1-methylpyridinium iodide (500 mg, 1.95 mmol) was added. The mixture was stirred at 90°C for 1 h followed by evaporation of the solvent. Purification of the crude product by FC (hexane / EtOAc / MeOH) afforded 125a (94 mg, 60%).

Data of 125a: C41 H37CI2F3N4O7 (825.7). LC-MS (method 1 d): R_t = 2.50 (98%), 825.2 ([M+H]⁺).

Synthesis of macrocyclic lactam 125b

To a soln of 2-chloro-1 -methylpyridinium iodide (750 mg, 2.94 mmol) in DCE (1000 mL) at 90°C was slowly added over 1 h a soln of 124b (250 mg, 0.3 mmol) in DCE (40 mL). When the addition was finished, additional 2-chloro-1-methylpyridinium iodide (750 mg, 2.94 mmol) was added. The mixture was stirred at 90°C for 1 h followed by evaporation of the solvent. Purification of the crude product by FC (hexane / EtOAc / MeOH) afforded 125b (96 mg, 39%).

Data of 125b: C44H40CIN5O9 (818.3). LC-MS (method 1 c): R_t = 2.40 (94%), 818.2 ([M+H]⁺).

Synthesis of macrocyclic lactam 125c

To a soln of 2-chloro-1 -methylpyridinium iodide (585 mg, 2.29 mmol) in DCE (1000 mL) at 90°C was slowly added over 1 h a soln of 124c (187 mg, 0.222 mmol) in DCE (50 mL). The mixture was stirred at 90°C for 1 h followed by evaporation of the solvent. An aq. workup (CH2CI2, sat. aq. NaHCC>3 soln; Na2SC>4) and purification by FC (hexane / EtOAc) afforded 125c (104 mg, 57%).

Data of 125c: C45H47CIN4O9 (823.3). LC-MS (method 1 c): R_t = 2.53 (86%), 823.3 ([M+H]⁺). Synthesis of macrocyclic acid 126a

To a soln of 125a (130 mg, 0.157 mmol) in a mixture of THF (2.5 mL) and MeOH (0.5 mL) at 0°C was added 2 M aq. LiOH soln (0.15 mL, 0.3 mmol), and the mixture was stirred at 0°C for 3 h. 1 M aq. HCI soln (30 mL) was added at 0°C, followed by extraction with EtOAc. The combined organic layer was dried (Na2S04), filtered and concentrated to give 126a (1 16 mg, quant, yield).

Data of 126a: C34H31CI2F3N4O7 (735.5). LC-MS (method 1 d): R_t = 2.04 (93%), 735.1 ([M+H]⁺).

Synthesis of macrocyclic acid 126b

To a soln of 125b (188 mg, 0.230 mmol) in a mixture of THF (4 mL) and MeOH (1 mL) at 0°C was added 2 M aq. LiOH soln (0.23 mL, 0.460 mmol), and the mixture was stirred at 0°C for 3 h. 1 M aq. HCI soln (20 mL) was added at 0°C, followed by extraction with EtOAc. The combined organic layer was dried (Na2S0₄), filtered and concentrated, and the obtained product was washed with EtOAc/Et₂0 (4:1 ) to give 126b (151 mg, 90%).

Data of 126b: C37H34CIN5O9 (728.1 ). LC-MS (method 7b): R_t = 1 .04 (85%), 745.1 ([M+NH₄]⁺), 728.1 ([M+H]⁺).

Synthesis of macrocyclic acid 126c

In analogy to the synthesis of 126a, 125c (200 mg, 0.243 mmol) was saponified with 2 M aq. LiOH soln (0.27 mL, 0.534 mmol) in a mixture of THF (4 mL) and MeOH (2 mL) at 0°C for 4 h to give after aq. workup 126c (184 mg, quant, yield; contained residual amounts of solvents).

Data of 126c: C₃₈H₄i CIN₄09 (733.2). LC-MS (method 1 d): Rt = 2.06 (81 %), 733.2 ([M+H]⁺).

Synthesis of macrocyclic diester 127a

To a soln of 126a (1 14 mg, 0.155 mmol) in DMF (4 mL) at 0°C were added a soln of HATU (90 mg, 0.237 mmol) in DMF (0.5 mL) and a soln of HOAt (32 mg, 0.235 mmol) in DMF (0.5 mL). A soln of 31 CF3CO2H (80 mg, 0.254 mmol) and i-Pr₂NEt (0.2 mL, 1 .168 mmol) in DMF (0.5 mL) was slowly added to this mixture at 0°C, and stirring at 0°C was continued for 2 h. An aq. workup (EtOAc, 1 M aq. NaHCC>3 soln) followed by FC (hexane / EtOAc / MeOH) afforded 127a (122 mg, 86%; contained residual DMF). An analytical product sample was obtained after repurification by prep. HPLC (method 1 a).

Data of 127a: C43H₄₄Cl2F₃N₅Oio (918.7). LC-MS (method 1 c): R_t = 2.40 (98%), 918.1 ([M+H]⁺). H-NMR (DMSO-de): 8.62 (d, J = 6.5, exchanged upon addn of D₂0; NH); 7.87 - 7.78 (m, 4 H); 7.69 (br. d, J ca 8.3, 1 H); 7.61 (d, J = 7.5, 1 H); 7.51 (t, J = 7.8, 1 H); 7.35 - 7.25 (br. m, 2 H); ca 7.2 - 7.0 (br. m, unresolved, 2 H); 5.23 (d, J = 1 1.2, 1 H); 4.90 - 4.73 (m, 3 H); 4.65 (d, J = 8.4, 1 H); 4.41 (d, J = 8.7, 1 H); 4.24 - 4.13 (m, 7 H); 4.03 - 3.95 (m, 2 H); 3.47 (m, 1 H); 3.34 (d, J = 14.1 , 1 H); 2.81 (s, 3 H); ca 2.5 (m, 1 H, partially superimposed by DMSO-d signal); 2.17 (m, 1 H); 1.95 - 1.80 (br. m, 3 H); 1.61 (m, 1 H); 1 .21 (t, J = 7.0, 3 H); 1 .12 (t, J = 7.1 , 3 H).

Synthesis of macrocyclic diester 127b

To a soln of 126b (150 mg, 0.206 mmol) in DMF (4 mL) at 0°C were added a soln of HATU (120 mg, 0.316 mmol) in DMF (0.5 mL) and a soln of HOAt (50 mg, 0.367 mmol) in DMF (0.5 mL). A soln of 31 CF3CO2H (120 mg, 0.381 mmol) and i-Pr₂NEt (0.2 mL, 1 .168 mmol) in DMF (0.5 mL) was slowly added to this mixture at 0°C, and stirring at 0°C was continued for 2 h. An aq. workup (EtOAc, 1 M aq. NaHCC>3 soln) followed by FC (hexane / EtOAc / MeOH) afforded 127b (180 mg, 96%). The material was used without further purification.

Data of 127b: C46H47CIN6O12 (91 1.4). LC-MS (method 1 d): Rt = 2.24 (74%), 91 1 .3 ([M+H]⁺).

Synthesis of macrocyclic diester 127c

To a soln of 126c (180 mg, 0.245 mmol) in DMF (4 mL) at 0°C were added a soln of HATU (200 mg, 0.526 mmol) in DMF (0.5 mL) and a soln of HOAt (70 mg, 0.514 mmol) in DMF (0.5 mL). A soln of 31 CF3CO2H (120 mg, 0.381 mmol) and i-Pr₂NEt (0.2 mL, 1 .168 mmol) in DMF (0.5 mL) was slowly added to this mixture at 0°C, and stirring at 0°C was continued for 2 h. An aq. workup (EtOAc, 1 M aq. NaHC03 soln) followed by FC (hexane / EtOAc / MeOH) afforded 127c (229 mg, quant, yield; contained residual amounts of DMF).

Data of 127c: C47H54CIN5O12 (916.4). LC-MS (method 6a): R_t = 8.67 (93%), 916.3 ([M+H]⁺). Synthesis of macrocyclic diacid Ex.46 and monoacid Ex.47

To a soln of 127a (92 mg, 0.100 mmol) in a mixture of THF (4 mL) and EtOH (1 mL) at 0°C was slowly added 2 M aq. LiOH soln (0.15 mL, 0.30 mmol), and the mixture was stirred at 0°C for 3.5 h. 1 M aq. HCI soln was added at 0°C, followed by extraction with EtOAc. The combined organic layer was dried (Na2S04), filtered and concentrated, and the crude product was purified by prep. HPLC (method 2a) to give diacid Ex.46 NH₃ (40 mg, 45%) together with monoacid Ex.47 NH₃ (8 mg, 9%).

Data of Ex.46 NH₃: cf. Table 01a.

Data of Ex.47 NH₃: cf. Table 01a. Synthesis of naphthylamine 128

To a suspension of 127b (46 mg, 0.05 mmol) and zinc powder (25 mg, 0.379 mmol) in MeOH (3 mL) at rt was added acetic acid (0.014 mL, 0.252 mmol), and the mixture was stirred at 60°C for 2 h. After cooling to rt, an aq. workup (EtOAc, sat. aq. NaHCOs soln; Na₂S0₄) and purification by prep. HPLC (method 2a) afforded 128 (10 mg, 22%). Data of 128: C46H₄9CIN₆Oio (881.4). LC-MS (method 2b): R_t = 2.13 (87%), 881.3 ([M+H]⁺). ¹H-NMR (DMSO-de): 8.62 (d, J = 7.0, 1 H); 8.13 (d, J = 9.0, 1 H); 7.89 (s, 1 H); 7.80 (d, J = 7.7, 1 H); 7.68 (d, J = 1.6, 1 H); 7.60 (d, J = 8.8, 1 H); 7.50 (t, J = 7.8, 1 H); 7.35 - 7.20 (br. m, 4 H); ca 7.2 - 7.0 (d and br. s, 3 H); 6.71 (d, J = 7.4, 1 H); 5.81 (s, 2 H); 5.29 (d, J = 12.1 , 1 H); 4.91 - 4.82 (m, 3 H); 4.66 (d, J = 9.2, 1 H); 4.41 (d, J = 9.3, 1 H); 4.27 - 4.10 (m, 7 H); 4.04 - 4.01 (m, 2 H); 3.53 (dd, J = 7.3, 10.0, 1 H); ca. 3.4 (1 H, partially superimposed by H₂0 signal); 2.80 (s, 3 H); 2.40 (m, 1 H); 2.15 (m, 1 H); 1.95 - 1 .75 (m, 3 H); 1 .59 (m, 1 H); 1.21 (t, J = 7.1 , 3 H); 1.12 (t, J = 7.1 , 3 H).

Synthesis of diacid Ex.48

To a soln of 128 (73 mg, 0.083 mmol) in a mixture of THF (4 mL) and MeOH (1 mL) at 0°C was slowly added 2 M aq. LiOH soln (0.060 mL, 0.120 mmol), and the mixture was stirred at 0°C for 3 h. 1 M aq. HCI soln was added at 0°C, followed by extraction with EtOAc. The combined organic layer was dried (Na2S0₄), filtered and concentrated, and the crude product was purified by prep. HPLC (method 2a) to give diacid Ex.482 NH₃ (28 mg, 39%).

Data of Ex.482 NH₃: cf. Table 01a. ¹H-NMR (DMSO-d₆): 8.62 (d, J = 6.6, exchanged upon addn. of D₂0, 1 H); 8.12 (d, J = 9.0, 1 H); 7.90 (s, 1 H); 7.82 (d, J = 7.6, 1 H); 7.69 (s, 1 H); 7.59 (d, J = 8.0, 1 H); 7.48 (t, J = 7.8, 1 H); 7.35 - 7.20 (m, 4 H); 7.20 - 7.05 (m, 3 H); 6.69 (d, J = 7.4, 1 H); ca 7.4 - 6.5 (very br. s, 8 H, exchanged upon addn of D₂0); 5.80 (s, 2 H, exchanged upon addn of D₂0); 5.26 (d, J = 12.3, 1 H); 5.00 (t-like m, 1 H); 4.81 - 4.75 (m, 2 H); 4.48 (d, J = 7.8, 1 H); 4.31 (d, J = 7.9, 1 H); 4.15 (br. m, 1 H); 4.03 - 3.93 (m, 4 H); ca 3.3 (m, 2 H, partially superimposed by H₂0 signal); 2.81 (s, 3 H); 2.40 (m, 1 H); 2.18 (m, 1 H); 2.00 - 1.75 (m, 3 H); 1.56 (m, 1 H).

Synthesis of primary amide 129

To a soln of ester 127c (220 mg, 0.240 mmol) in CH₂CI₂ (5 mL) at 0°C was added slowly TFA (1 mL). The mixture was stirred at 0°C for 2 h and was then concentrated to dryness. The residue was dissolved in DMF (5 mL), cooled to 0°C, and NH₄CI (65 mg, 1.21 mmol), HATU (183 mg, 0.480 mmol), HOAt (65 mg, 0.48 mmol) and i- Pr₂NEt (0.2 mL, 1.168 mmol) were consecutively added. Stirring at 0°C was continued for 3 h, followed by an aq. workup (EtOAc, 1 M aq. NaHCC soln; Na₂S0₄) and purification by FC (hexane / EtOAc / MeOH) to give 129 (135 mg, 65%).

Data of 129: C₄₃H₄₇CIN₆0n (859.3). LC-MS (method 1 d): R_t = 1 .87 (91 %), 859.5 ([M+H]⁺). Synthesis of diacid Ex.49

To a soln of 129 (56 mg, 0.065 mmol) in a mixture of THF (4 mL) and MeOH (1 mL) at 0°C was slowly added 2 M aq. LiOH soln (0.10 mL, 0.200 mmol), and the mixture was stirred at 0°C for 3 h. 1 M aq. HCI soln was added at 0°C, followed by extraction with EtOAc. The combined organic layer was dried (Na₂S0₄), filtered and concentrated, and the crude product was purified by prep. HPLC (method 2a) to give the diacid Ex.492 NH₃ (20 mg, 37%).

Data of Ex.492 NH₃: cf. Table 01a. ¹H-NMR (DMSO-d₆): 8.60 (d, J = 6.2, exchanged upon addn. of D₂0, NH); 8.01 (br. s, 1 H, exchanged upon addn of D₂0); 7.88 (br. s- like m, 4 H, 1 H exchanged upon addn of D₂0); 7.81 (d, J = 7.5, 1 H); 7.59 (d, J = 8.0, 1 H); 7.49 (t, J = 7.9, 1 H); 7.42 - 7.40 (br. m, 4 H; 2 H exchanged upon addn of D₂0); 7.26 - 7.24 (m, 3 H, 1 H exchanged upon addn of D₂0); 7.04 (br. s, 2 H); ca 6.5 - 5.4 (very br. s, ca 2 H; exchanged upon addn of D₂0); 5.23 (d, J = 1 1.2, 1 H); 5.00 (br. m, unresolved, 1 H); 4.78 - 4.69 (m, 2 H); 4.44 (d, J = 7.5, 1 H); 4.29 (d, J = 7.0, 1 H); 4.13 (t-like m, 1 H); ca 4.1 - 3.9 (m, 4 H); ca. 3.3 (2 H, superimposed by H₂0 signal); 2.82 (s, 3 H); 2.37 (m, 1 H); 2.17 (m, 1 H); ca 1.9 - 1.75 (br. m, unresolved, 3 H); 1.51 (br. m, 1 H).

Synthesis of monoacid Ex.50

To a soln of 129 (30 mg, 0.035 mmol) in a mixture of THF (2 mL) and EtOH (0.5 mL) at 0°C was slowly added 2 M aq. LiOH soln (0.017 mL, 0.034 mmol), and the mixture was stirred at 0°C for 2 h. Additional 2 M aq. LiOH soln (0.017 mL, 0.034 mmol) was added, and stirring at 0°C was continued for 2 h. 1 M aq. HCI soln was added at 0°C, followed by extraction with EtOAc. The combined organic layer was dried (Na₂S0₄), filtered and concentrated, and the crude product was purified by prep. HPLC (method 2a) to give the monoacid Ex.50 NH₃ (13 mg, 44%).

Data of Ex.50 NH₃: cf. Table 01a. Table 01a: Analytical data of Examples (Ex.), continued on the following page

Monoisotopic [M+H]⁺ LC-MS

Ex. Formula Rt (purity)

Mass found Method

Ex.1 CseHssCINsOs 703.2 1.21 (97%) 704.0 Method 2b

Ex.2 C40H40CIN5O8 753.3 1.92 (89%) 754.3 Method 1 e

Ex.3 C40H40CIN5O8 753.3 1.91 (99%) 754.0 Method 1 c

Ex.4 C37H37CIF3N5O8 771 .2 1.92 (89%) 772.3 Method 1 c

Ex.5 C38H39CIF3N5O8 785.2 1.96 (98%) 786.1 Method 1 c

Ex.6 CssHsssCIFsNsOs 785.2 1.99 (99%) 786.2 Method 1 c

Ex.7 CseHs/CIFNsOs 721 .2 1.76 (99%) 722.2 Method 1 c

Ex.8 C37H₄oCIN₅0₉ 733.3 1.75 (97%) 734.2 Method 1 c

Ex.9 C37H39CI2N5O8 751 .2 1.89 (98%) 752.0 Method 1 c

Ex.10 CssFUi CINeOg 760.3 1.53 (98%) 761 .2 Method 1 c

Ex.11 C40H41 CIN6O8 768.3 1.28 (92%) 767.0 ⁴> Method 2d

Ex.12 C38H39F3N6O9 780.3 1.16 (96%) 781 .3 Method 2b

Ex.13 ³⁾ C40H39F3N6O8 788.3 1.31 (93%) 789.2 Method 2b

Ex.14 C43H40F3N5O10 843.3 1.96 (86%) 844.3 Method 1 c

Ex.15 C43H42F3N5O10 845.3 1.93 (98%) 846.2 Method 1 g

Ex.16 C42H40F3N5O10 831 .3 1.94 (87%) 832.2 Method 1 g

Ex.17 C40H38F3N9O6 797.3 1.99 (99%) 798.1 Method 1 c

Ex.18 C39H39F3N5O9P 809.2 1.18 (99%) 810.2 ¹> Method 2b

Ex.19 C40H41 F3N5O9P 823.3 1.35 (99%) 824.2 Method 2b

Ex.20 C33H36CIN5O10 697.2 1.40 (93%) 698.2 Method 1 d

Ex.21 C41 H40F3N5O8 787.3 1.57 (97%) 788.4 Method 3b

Ex.22 C41 H43N5O9 749.3 1.40 (91 %) 750.4 Method 3b

Ex.23 C41 H43N5O8S 765.3 1.50 (95%) 766.4 Method 3b

Ex.24 C41 H40N6O8 744.3 1.35 (94%) 745.4 Method 3b

Ex.25 C41 H43N5O8 733.3 1.46 (96%) 734.4 Method 3b

Ex.26 C40H40CIN5O8 753.3 1.07 (88%) 754.4 Method 7a

Ex.27 C40H39CI2N5O8 787.2 1.64 (96%) 788.4 Method 3b

Ex.28 C41 H41 N5O10 763.3 1.22 (97%) 764.4 Method 3b

Ex.29 C39H40CIN5O9S 789.2 1.42 (96%) 790.4 Method 3b

Ex.30 C40H41 CIN6O8 768.3 1.07 (88%) 769.4 Method 7a

Ex.31 C40H38CIF2N5O8 789.2 2.02 (90%) 789.8 Method 1 c Monoisotopic [M+H]⁺ LC-MS

Ex. Formula Rt (purity)

Mass found Method

Ex.32 C40H38CIF2N5O8 789.2 2.04 (97%) 789.8 Method 1c

Ex.33 C40H39CI2N5O8 787.2 1.99 (87%) 788.1 Method 1c

Ex.34 C40H39CI2N5O8 787.2 1.86 (96%) 788.2 Method 1c

Ex.35 C40H39CI2N5O8 787.2 2.02 (98%) 788.2 Method 1c

Ex.36 C41H41CI2N5O9 817.2 2.08 (98%) 818.1 Method 1c

Ex.37 C41H41CI2N5O9 817.2 2.05 (90%) 818.1 Method 1c

Ex.38 C40H39CI2N5O8 787.2 2.02 (92%) 788.3 Method 1c

Ex.39 CsgHasClsNsOgS 857.1 2.10 (94%) 858.3 Method 1c

Ex.40 C47H47N5O10 841.3 1.61 (93%) 842.5 Method 2c

Ex.41 CssHssCINsOsS 759.2 1.92 (94%) 760.2 Method 1d

Ex.42 C35H37N5O10 687.3 1.46 (88%) 688.0 Method 1c

Ex.43 C40H41 N5O9 735.3 1.62 (89%) 736.2 Method 1d

Ex.44 C40H41CIN6O8 768.3 1.75 (91%) 769.2 Method 1c

Ex.45 C41H42CIN5O8 767.3 1.99 (99%) 768.3 Method 1c

Ex.46²) C39H36CI2F3N5O10 861.2 1.99 (93%) 862.2 Method 1c

Ex.472) C41 H40CI2F3N5O10 889.2 2.16 (92%) 890.3 Method 1c

Ex.482) C42H41CIN6O10 824.3 1.11 (89%) 825.3 Method 2b

Ex.492) C39H39CIN6O11 802.2 1.40 (94%) 803.2 Method 1c

Ex.502) C41H43CIN6O11 830.3 1.62 (98%) 831.3 Method 1c

1) Ex.18: Base peak in MS: 827.2 ([M+NH₄]⁺).

2) Isolated as ammonium salt.

3) Isolated as TFA salt.

4) [M-H]-.

Table 01 b: lUPAC names of Examples (Ex.), continued on the following pages

Ex. lUPAC name

3-({[(45,6/?, 15 S)-6-[(3-chlorobenzoyl)amino]-16-methyl-9, 12, 17-trioxo-

Ex.1

1 1 -phenyl-2-oxa-8,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21- trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1-(2-naphthyl)-

Ex.2

9,12,17-trioxo-2-oxa-8, 1 1 , 16-triazatricyclo[16.2.2.0^{4 8}]docosa- 1 (20),18,21-trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1-(1-naphthyl)-

Ex.3

3-({[(45,6/?, 15 S)-6-[(3-chlorobenzoyl)amino]-16-methyl-9, 12, 17-trioxo-

Ex.4 1 1 -[3-(trifluoromethyl)phenyl]-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6/?,15S)-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1-[2-methyl-5-

Ex.5 (trifluoromethyl)phenyl]-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6/?,15S)-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1-[4-methyl-3-

Ex.6 (trifluoromethyl)phenyl]-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6/?,15S)-6-[(3-chlorobenzoyl)amino]-1 1 -(4-fluorophenyl)-16-

Ex.7

methyl-9, 12,17-trioxo-2-oxa-8, 1 1 ,16-triazatricyclo[16.2.2.0^{4 8}]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6/?,15S)-6-[(3-chlorobenzoyl)amino]-1 1 -(3-methoxyphenyl)-16-

Ex.8

3-({[(45,6/?,15S)-6-[(3-chlorobenzoyl)amino]-1 1 -(5-chloro-2-

Ex.9 methylphenyl)-16-methyl-9, 12,17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid Ex. lUPAC name

3-({[(45,6 ?,15S)-1 1-(4-carbamoyl-3-methylphenyl)-6-[(3-

Ex.10 chlorobenzoyl)amino]-16-methyl-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴<⁸]docosa-1 (20),18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-1 1-(5-amino-2-naphthyl)-6-[(3-chlorobenzoyl)amino]-

Ex.1 1

16-methyl-9,12,17-trioxo-2-oxa-8,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?, 15≤)-1 1 -(4-carbamoylphenyl)-16-methyl-9,12, 17-trioxo-6-

Ex.12 {[3-(trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴<⁸]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?, 15≤)-1 1 -(7-isoquinolinyl)-16-methyl-9, 12,17-trioxo-6-{[3-

Ex.13 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴<⁸]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

1 -{[(45,6/?, 155)-16-methyl-1 1 -(2-naphthyl)-9, 12, 17-trioxo-6-{[3-

Ex.14 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15-yl]carbonyl}-3,3- azetidinedicarboxylic acid

3-({[(45,6 ?,15S)-16-methyl-1 1-(2-naphthyl)-9,12,17-trioxo-6-{[3-

Ex.15 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)pentanedioic acid

(2 ^-2-({[(45,6 ?,15S)-16-methyl-1 1-(2-naphthyl)-9,12,17-trioxo-6-{[3-

Ex.16 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)succinic acid

(45,6 ?,155)-16-methyl-1 1 -(2-naphthyl)-9,12,17-trioxo-/V-(1 tetrazol-5-

Ex.17

ylmethyl)-6-{[3-(trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -triene-15-carboxamide

[({[(45,6 ?,15S)-16-methyl-1 1-(2-naphthyl)-9,12,17-trioxo-6-{[3-

Ex.18 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)methyl]phosphonic acid Ex. lUPAC name

[2-({[(45,6/?, 15S)-16-methyl-1 1 -(2-naphthyl)-9, 12, 17-trioxo-6-{[3-

Ex.19 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)ethyl]phosphonic acid

1-{[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-1 1 ,16-dimethyl-9,12,17-

Ex.20

trioxo-2-oxa-8,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21 -trien- 15-yl]carbonyl}-3,3-azetidinedicarboxylic acid

3-({[(45,6 ?,15S)-16-methyl-1 1-(2-naphthyl)-9,12,17-trioxo-6-{[3-

Ex.21 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-6-[(3-methoxybenzoyl)amino]-16-methyl-1 1-(2-

Ex.22

naphthyl)-9,12,17-trioxo-2-oxa-8,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-16-methyl-6-{[3-(methylsulfanyl)benzoyl]amino}-1 1-(2-

Ex.23

3-({[(45,6 ?,15S)-6-[(3-cyanobenzoyl)amino]-16-methyl-1 1 -(2-naphthyl)-

Ex.24

9,12,17-trioxo-2-oxa-8, 1 1 , 16-triazatricyclo[16.2.2.0^{4 8}]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-16-methyl-6-[(3-methylbenzoyl)amino]-1 1-(2-

Ex.25

3-({[(45,6 ?,15S)-6-[(4-chlorobenzoyl)amino]-16-methyl-1 1-(2-naphthyl)-

Ex.26

3-({[(45,6 ?,15S)-6-[(3,5-dichlorobenzoyl)amino]-16-methyl-1 1 -(2-

Ex.27

4-{[(45,6 ?,155)-15-[(2-carboxyethyl)carbamoyl]-16-methyl-1 1 -(2-

Ex.28

naphthyl)-9,12,17-trioxo-2-oxa-8,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa- 1 (20),18,21-trien-6-yl]carbamoyl}benzoic acid Ex. lUPAC name

3-({[(45,6 ?,15S)-6-{[(3-chlorophenyl)sulfonyl]amino}-16-methyl-1 1-(2-

Ex.29

naphthyl)-9,12,17-trioxo-2-oxa-8,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa- 1 (20),18,21-trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-6-{[(3-chlorophenyl)carbamoyl]amino}-16-methyl-1 1-

Ex.30 (2-naphthyl)-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20),18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-6-[(3-chlorobenzoyl)amino]-19,20-difluoro-16-methyl-

Ex.31 1 1 -(2-naphthyl)-9, 12,17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-6-[(4-chlorobenzoyl)amino]-19,22-difluoro-16-methyl-

Ex.32 1 1 -(2-naphthyl)-9, 12,17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-20-chloro-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1-(2-

Ex.33

3-({[(45,6 ?,15S)-20-chloro-6-[(2-chlorobenzoyl)amino]-16-methyl-1 1-(2-

Ex.34

3-({[(45,6 ?,15S)-19-chloro-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1-(2-

Ex.35

3-({[(45,6 ?,15S)-6-[(3,5-dichlorobenzoyl)amino]-19-methoxy-16-methyl-

Ex.36 1 1 -(2-naphthyl)-9, 12,17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-6-[(3,5-dichlorobenzoyl)amino]-20-methoxy-16-methyl-

Ex.37 1 1 -(2-naphthyl)-9, 12,17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid Ex. lUPAC name

3-({[(45,6 ?,15S)-19-chloro-6-[(4-chlorobenzoyl)amino]-16-methyl-1 1-(2-

Ex.38

3-({[(45,6 ?,15S)-20,21-dichloro-6-{[(3-chlorophenyl)sulfonyl]amino}-16-

Ex.39 methyl-1 1 -(2-naphthyl)-9, 12,17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-6-{[3-(4-methoxyphenoxy)benzoyl]amino}-16-methyl-

Ex.40 1 1 -(2-naphthyl)-9,12,17-trioxo-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-6-{[(5-chloro-2-thienyl)carbonyl]amino}-16-methyl-1 1-

Ex.41 (2-naphthyl)-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21 -trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,15S)-6-[(carboxycarbonyl)amino]-16-methyl-1 1-(2-

Ex.42

3-({[(45,6 ?,15S)-6-[(4-hydroxybenzoyl)amino]-16-methyl-1 1 -(2-

Ex.43

3-({[(45,6 ?,15S)-20-amino-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1-(2-

Ex.44

3-({[(45,6 ?,15S)-6-[(3-chlorobenzoyl)amino]-16-ethyl-1 1-(2-naphthyl)-

Ex.45

1-{[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-1 1-[4-chloro-3-

Ex.46 (trifluoromethyl)phenyl]-16-methyl-9, 12,17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20), 18,21 -trien-15-yl]carbonyl}-3,3- azetidinedicarboxylic acid Ex. lUPAC name

1-{[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-1 1-[4-chloro-3-

Ex.47 (trifluoromethyl)phenyl]-16-methyl-9, 12,17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴<⁸]docosa-1 (20), 18,21 -trien-15-yl]carbonyl}-3- (ethoxycarbonyl)-3-azetidinecarboxylic acid

1-{[(45,6 ?,155)-1 1-(5-amino-2-naphthyl)-6-[(3-chlorobenzoyl)amino]-

Ex.48

16-methyl-9,12,17-trioxo-2-oxa-8,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}-3,3-azetidinedicarboxylic acid

1-{[(45,6 ?,155)-1 1-(4-carbamoylphenyl)-6-[(3-chlorobenzoyl)amino]-

Ex.49

1-{[(45,6 ?,155)-1 1-(4-carbamoylphenyl)-6-[(3-chlorobenzoyl)amino]-

Ex.50 16-methyl-9,12,17-trioxo-2-oxa-8,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa- 1 (20),18,21-trien-15-yl]carbonyl}-3-(ethoxycarbonyl)-3- azetidinecarboxylic acid

Scheme 2

14 R^VIM = Alloc

15 RVIM = 4_NS 16 R^lx = Boc

HCI-dioxane

a) 13: Teoc-ONp, Et₃N, CH₂CI₂ 17 HCI R^IX = H b) 14: Allyl chloroformate, aq. NaHC0₃ soln, CH₂CI₂ Allyl chloroformate,

c) 15: ₄-Nitrobenzenesulfonyl chloride, NaHC0₃, H₂0, aq. Na₂C0₃ soln, dioxane

18 R^IX = Alloc dioxane

F

25

Scheme 2, continued

C0₂H SOCI₂, MeOH ^∞₂CH ,₃j ^ .C0O₂₂tt--BBuu

CO CH t-Bu0₂C^ H₂N¾(0)(OH)₂ ¾ -_H2N^C0₂CH₃ ^_H2 HC, "²" "™"^{2 N} T NH

^∞₂H N

32 33 HCI 34 HCI 35 n = 1 37

36 n = 2

38a 39a

40b 41b Ar = 2-Naphthyl, R' 39b Ar = 2-Naphthyl

Ar = 2-Naphthyl

42b Ar = 2-Naphthyl, R¹

40c 41c Ar = 1-Naphthyl, R¹ 39c Ar = 1-Naphthyl

Ar = 1-Naphthyl

42c Ar = 1-Naphthyl, R¹

a) Allyl chloroformate, CH₂CI₂, aq. NaHC0₃ soln

tert.-Butyl bromoacetate

.N .C0₂R

Ar

(Allyl chloroacetate)

40d - 40k 41d - 41i, 41k R

43 R = Allyl

40d, 41 d 40e, 41 e 40f, 41 f 40g, 41 g

40h, 41 h 40i, 41 i 40j, 43j 40k, 41k Scheme 2, continued

40m 38m a) Allyl chloroacetate, n-Bu₄NI, THF, DMF

b) Allyl chloroformate, CH₂CI₂, aq. NaHC0₃ soln

c) LiOH, H₂0, DME

d) Ethyl glyoxylate, H₂, 10% Pt-C, EtOH, aq. HCI soln

40n 41n R" = H 39n

Allyl chloroformate,

CH₂CI₂, aq. NaHC0₃ soln

42n R" = Alloc

40b 43b Scheme 2, continued

- 48 R^IX = Boc ^■ 50 R = CH₃

LiOH, H₂0,

HCI-dioxane

MeOH, THF

*. 49 Ri = H 51 R^VM = H

H

Scheme 3

47

58a Ar = Ph, R' = Alloc, R = Allyl 60a Ar = Ph, R^lv = Bn 59a Ar = Ph, R¹ : R"ⁱ = H b) 61a Ar = Ph, R^lv = H

58b Ar = 2-naphthyl, R" = Alloc, R 60b Ar = 2-naphthyl, R¹

b)

59b Ar = 2-naphthyl, R" = R^m = H 61b Ar = 2-naphthyl, R¹

58c Ar = 1-naphthyl, R" = Alloc, R' 60c Ar = 1-naphthyl, R' 59c Ar = 1-naphthyl, R" = R^m = H 61c Ar = 1-naphthyl, R' a) Pd(PPh₃)₄, 1 ,3-dimethylbarbituric acid, CH₂CI₂, EtOAc b) H₂, Pd(OH)₂-C, EtOH/THF (or i-PrOH for 61b)

Ex.2 Ar = 2-naphthyl

Ex.3 Ar = 1 -naphthyl a) HCI-dioxane

b) 3-Chlorobenzoyl chloride, i-Pr₂NEt, CH₂CI_: Scheme 4

67b, 67d - 67k

41 b 41 d 41e 41f 41 g

64b - 68b 65d - 69d 65e - 69e 65f - 69f 65g - 69g Ex.2 Ex.4 Ex.5 Ex.6 Ex.7

41 h 41 i 43j 41 k

65h - 69h 65i - 69i 65j - 69j 65k - 69k

Ex.8 Ex.9

39I 38m

73I - 77I 73m - 77m

Ex.13 Scheme 4, continued

1. 2% DBU in DMF

Scheme 4, continued

731 R" = Alloc, R¹¹¹ = Allyl 73m R" = H, R'" = Allyl

a) Pd(PPh₃)₄, DMBA, CH₂CI₂, EtOAc

Scheme 5, continued

Scheme 6

b) 3-Chlorobenzoyl chloride, i-Pr₂NEt, CH₂CI₂ Scheme 7

91 R'" = Bn 93 R' = Allyl

H₂, Pd-C, Pd(PPh₃)₄,

EtOAc PhSiH₃, THF

= H

95 R^v = t-Bu

R^v = t-Bu 96aa, 96bb, 96cc, 96dd, 96ee, 96gg, and 96hh R^v = t-Bu R^v = CH₃ 100ee and lOOff R^V = CH₃

97aa2, 97aa3, 97aa4, 97aa5, 97aa6, 97aa8, 97aa9, 97aa10, 97aa12, 97aa13, 97bb1 , 97cc8, 97dd1 , 97dd7, 97ee1 , 97gg9, and 97hh9 R^v = t-Bu

101ee8 and 101ff12 R^v = CH₃ Scheme 7, continued

97aa2, 97aa3, 97aa4, 97aa5, 97aa6, 97aa8, 97aa9, 98aa2, 98aa3, 98aa4, 98aa5, 98aa6, 98aa8, 98aa9, 97aa10, 97aa12, 97aa13, 97bb1 , 97cc8, 97dd1 , 98aa10, 98aa12, 98aa13, 98bb1 , 98cc8, 98dd1 , 97dd7,97ee1 , 97gg9, and 97hh9 R^v = t-Bu 98dd7,98ee1 , 98gg9, and 98hh9 R^v = t-Bu

101 ee8 and 101ff12 R^v = CH₃ 102ee8 and 102ff12 R^v = CH₃ i) or j) h) FDPP, i-Pr₂NEt, DMF; i) TFA, CH₂CI₂; j) LiOH, H₂0, MeOH,

R^v

t-Bu

1 X = CI t-Bu

H

t-Bu

2 X = CF₃ t-Bu

H

t-Bu

3 X = OCH₃ t-Bu

H

t-Bu

4 X = SCH₃ t-Bu

H

t-Bu

5 X = CN t-Bu

H

t-Bu

6 X = CH₃ t-Bu

H

CI O t-Bu

t-Bu

⁷ -"" H

Scheme 7, continued

Scheme 7, continued

63b CF₃C0₂H 102aa14, 102aa15, 102aa16 and 102aa17 Ex.40 - Ex.43

a) R^xC0₂H, HATU, HOAt, i-Pr₂NEt, DMF; or R^xCOCI, i-Pr₂NEt, THF;

or R^xCOCI, i-Pr₂NEt, CH₂CI₂

b) LiOH, H₂0, MeOH, THF

102aa14, Ex.40 102aa15, Ex.41 102aa16 Ex.42 102aa17 Ex.43

— 105 R^VI = Fmoc 107 R^vm = Alloc, R¹ = Allyl

Piperidine, Pd(PPh₃)₄, DMBA, DMF CH₂CI₂, EtOAc

■* 106 R^VI = H 108 R^vm = R' = H Scheme 7, continued

Scheme 8

CbzHN

1-c loro-N,N,2-trimet yl- 1-propenylamine,

K₂CO₃, CH₂CI₂

119 117 R^VI" 115 R^VI = Cbz

Etl, K₂C0₃, H₂, Pd(OH)₂-C,

DMF MeOH

118 R^vm 116 R^VI = H

120 R' = t-Bu, R^vm = Alloc

a) 1 . Si0₂, toluene; 2. Pd(PPh₃)₄, DMBA, CH₂CI₂, EtOAc Scheme 9

57 123a- 123c R" = Alloc, R¹" = Allyl 125a -125c R^lv = Bn b)

= H

Scheme 9, continued

Biological methods Preparation of the compounds

Compounds were weighed on a microbalance (Mettler MX5) and dissolved in 100% DMSO to a final concentration of 10 mM unless otherwise stated. Stock solutions were kept at +4°C, and protected from light.

Expression and purification of human R14A mutant Pin1

E.coli BL21 pLysE(DE3) cells (New England BioLabs, Ipswich, USA) were transformed with pET14b vector (Merck Millipore, Darmstadt, Germany) encoding for full length Pin1 (amino acids 1-163) with a stabilizing mutation in position 14 (arginine to alanine replacement; Y. Zhang et a/., ACS Chem Biol. 2007, 2(5), 320-328), a N- terminal 6xHis tag and a thrombin cleavage site, and were inoculated into 50 mL of lysogeny broth medium (LB medium; per liter: 10 g tryptone, 5 g yeast extract, 10 g NaCI), containing 100 μg/mL ampicillin and 34 μg/mL choramphenicol. The overnight culture was diluted 100-fold in LB medium containing 100 ng/mL ampicillin and 34 μg/mL choramphenicol. The diluted culture was shaken at 150 rpm and 37°C to an optical density at 595 nm (OD595) of 0.8. Subsequently, 0.25 mM isopropyl-3-D- thiogalactopyranosid (IPTG) was added and the culture was shaken for 4 hours at 150 rpm and 37°C. The cell culture was centrifuged at 5000 rcf for 20 minutes. The pellets were resuspended in 10x buffer A (25 mM Tris-HCI (pH 8.0), 0.5 M NaCI, 10 mM imidazole, 10 mM 2-mercaptoethanol and 1 % Tween 20 ( ν/\ή). The suspension was passed through a high-pressure microfluidizer. The homogenate was centrifuged down in a Sorvall centrifuge using an SS-34 rotor at 9000 rcf and 4°C for 30 minutes. The clear supernatant was kept for further purification.

The clarified supernatant was loaded onto a 5 mL Ni-NTA column at 2.5 mL/minute. The column was washed with 50 mL buffer A. A step gradient was applied at 2.5 mL/minute from 100% buffer A to 100 % buffer B (25 mM Tris-HCI (pH 8.0), 0.5 M NaCI, 10 mM 2-mercaptoethanol and 1 % Tween 20 { ν/\ή, 500 mM imidazole). Fractions of 5 mL were collected and analyzed by SDS-PAGE (4-12%). The fractions containing 6xHis Pin1 were collected and pooled. Pooled His-tagged Pin1 was digested with thrombin (1 U thrombin/mg protein; Sigma-Aldrich) during dialysis for 16 hours at 4°C (molecular weight cut-off: 3 kDa; dialysis buffer: 50 mM Tris-HCI (pH 8.0), 0.15 M NaCI, 5 mM MgCI₂, 2.5 mM CaCI₂, 1 mM DTT, 10% glycerol { ν/ή).

The overnight solution was passed through a Ni-NTA column (5 mL). The flow through was collected and concentrated to a volume of 2 mL for final size exclusion chromatography. The concentrate was loaded on a Superdex 75 column (90 ml.) with 2 mL/minute and eluted with buffer S (10 mM Hepes (pH 7.5), 0.1 M NaCI, 1 mM DTT). The fractions containing monomeric Pin1 were collected and pooled. Pooled Pin1 was concentrated to about 20 mg/mL for further studies (see below).

Pin1 Fluorescence polarization binding assay

Compounds were tested for competitive binding, using fluorescein-labeled Pintide (fluorescein-5(6)-carboxamidocaproyl-Trp-Phe-Tyr-Ser(P(0)(OH)2)-Pro-Phe-Leu-Glu; P.-J. Lu et a/., Science 1999, 283, 1325; WO 2004/005315 A2) and human mutant R14A Pin1 protein (see above). Serial dilutions of compounds were prepared in 100% DMSO and further diluted in assay buffer (25 mM MOPS, pH 7.5) to reach 0.5% final DMSO concentration ( ι/Λ). Compound dilutions were transfered to black polystyrene non-binding surface NBS 384-well microtiterplate (Corning, Cat. No. 3575). 300 nM of Pin1 was pre-incubated with compounds for 15 minutes, at room temperature, with gentle shaking. Finally, 25 nM of fluorescein-labeled Pintide was added and reaction incubated 15 minutes at room temperature with gentle shaking at 300 rpm, in the dark. Fluorescence polarization was subsequently measured on a Victor2 reader (Perkin Elmer) at room temperature, with an excitation wavelength at 485 nm and emission at 535 nm. The dose-response data were fitted to the 4- parameter Hill equation providing the I C50 value using Graphpad (Prism 5). Results are depicted in Table 02 below. I C50 values are given as mean (where applicable), further indicating the standard deviation (SD) and number of experiments (n).

Pin1 Peptidyl-prolyl isomerase assay

Compounds were tested for their ability to inhibit full length human Pin1 PPIase activity using the protease-free method described by Jankowski B. et al. {Anal. Biochem. 1997, 252, 299-307). In this assay, cis/trans isomerisation of synthetic tetrapeptide substrate Suc-Ala-Glu-Pro-Phe-pNA (commercially available at Bachem, L-1635) catalysed by full length Pin1 was measured. Human full length Pin1 was expressed and purified in analogy to R14A mutant Pin1 as described above.

Essentially, the following steps were performed:

Assay buffer (35 mM Hepes, pH 7.8) was cooled to 10°C (with stirring) in a precision glass cuvette, and inhibitor was added from a DMSO stock solution (final DMSO 1 % ( ν/ή). A blank spectrum was then obtained at a wavelength of 330 nm, using an Agilent 8453 spectrophotometer. Subsequently, recombinant human Pin1 and substrate Suc-Ala-Glu-Pro-Phe-pNA were added and the change in absorbance was measured over 5 minutes. Substrate stock solutions were prepared in 0.47 M LiCI/TFE. Typical final concentrations of substrate and Pin1 were as described in WO 2004/087720 A1 and by Zhang Y. et al. {Chem. Biol. 2007, 2(5), 320-328), respectively. The D-Peptide (D. Wildemann et al, J. Med. Chem. 2006, 49, 2147- 2150; compound 17) was used as a reference inhibitor.

A first order rate was fitted to the absorbance data to obtain a rate constant (first 10 to 15 seconds were eliminated due to mixing). The catalytic rate was calculated from the enzymatic rate minus the background rate. The K, for an inhibitor was obtained from the rate constant plotted against the inhibitor concentration (at least 6 points in duplicate).

Results are shown in Table 02 below.

Table 02: IC50 values from the Pini fluorescence polarization binding assay and Ki values from the Pini peptidyl-prolyl isomerase assay

n.d. = not determined

n.a. = not applicable

Claims

A compound of formula (I)

L is -C(O)-; or -S(0)₂-;

X is O; S; -S(O)-; or -S(0)₂-; t is an integer of 0-1 ;

i and p are independently an integer of 0-3 with the proviso that 1≤ i+p≤ 3; R¹ is H; CH₃; or CH₂CH₃;

R2, R³, R⁴, R⁵, and R⁶ are independently H; F; or CH₃;

with the proviso that

at most three substituents of R², R³, R⁴, R⁵, and R⁶ are F; or CH₃;

R⁷ is H; or F;

R⁸ is H; F; CF₃; or Ci-₃-alkyl;

R⁹, R¹⁰, R¹¹ , R¹², and R¹³ are independently H; F; or C_1-3 alkyl;

with the proviso that

at most three substituents of R⁹, R¹⁰, R¹¹ , R¹², and R¹³ are F; or Ci-₃ alkyl;

R¹⁴ is H; or Ci-3 alkyl;

R¹⁵ is H; F; or CH₃; E is a group of one of the formulae

R¹⁷ is -C(0)OH; -S(0)₂OH; or -P(0)(OH)₂;

1⁸ is a group of one of the formulae

R¹⁹ is H; Ci-2-alkyl; -(CHR²²)₀C(0)OR²¹; -(CHR²²)₀S(0)₂OH;

-(CHR²²)₀P(0)(OR² )₂; -(CHR²²)₀OH; -(CHR²²)₀C(0)NH₂;

R²² is H; F; or CH₃;

R²³ and R²⁴ are independently H; or CH3;

if E is E1 , o is an integer of 1 -3; if E is E2, o is an integer of 0-2;

if E is E3, o is an integer of 1 -2;

if E is E4; E5; E6; E7; or E8; o is an integer of 0-1 ; with the proviso that

in E at most three substituents R²² are different from H;

G is H; Ci-6-alkyl; C2-6-alkenyl; C3-6-cycloalkyl; C3-6-heterocyclyl; C6- C5-io-heteroaryl; or a group of one of the formulae

R²⁵ is H; F; CH₃; CF₃; OCH₃; OCF₃; or OCHF₂;

Ci-₃-thioalkoxy; -C(0)NR³ R³²; or -S(0)₂NR³ R³²;

R²⁸ is H; F; CI; CF₃; CN; OCF₃; OCHF₂; Ci_-3-alkyl; Ci_-3-alkoxy; or

Ci_-3-thioalkoxy;

R²⁹ is H; F; CF₃; OCF₃; OCHF₂; Ci_-3-alkyl; Ci_-3-alkoxy; or Ci_-3-thioalkoxy; R³⁰ is H; F; CI; CF₃; OH; OCF₃; OCHF₂; N0₂; Ci_-3-alkyl; Ci_-3-alkoxy;

Ci-₃-thioalkoxy; or -NR³ R³²;

R³¹ and R³² are independently H; or CH₃;

R³³ is H; Ci-3-alkyl; or -C(0)-Ci_-3-alkyl;

T is N; or CR²⁵;

M is 0; S; or NR³³; with the proviso that

in each of G1 to G4 at least two of the substituents are H;

if Q is O; S; -S(O)-; or -S(0)₂-; or

if R³⁴ in Q1 is H; F; CF₃; OH; SH; Ci_-8-alkyl; C₂-₈-alkenyl; C_2-8-alkynyl; Ci-8-alkoxy; Ci-e-thioalkoxy; C_3-8-cycloalkyl; C_3-8-heterocyclyl; or

-NR⁴⁸C(0)C(0)OR⁴⁸;

Q is O; S; -S(O)-; -S(0)₂-; or a group of one of the formulae

Z³ is -(CHR⁴⁷)-; O; -C(O)-; -C(0)NR⁴⁸-; -NR ⁸C(0)-; -NR ⁸C(0)NR⁴⁸-;

-NR ⁸C(0)0-; -OC(0)NR⁴⁸-; -NR ⁸S(0)₂-; -S(0)₂NR⁴⁸-; or

-NR ⁸S(0)₂NR⁴⁸-;

Ci-e-thioalkoxy; C_3-8-cycloalkyl; C_3-8-heterocyclyl; C6-io-aryl;

Cs-io-heteroaryl; or -NR ⁸C(0)C(0)OR⁴⁸;

R³⁵ is H; or CH₃;

R³⁶ is a group of one of the formulae

H6 H7 H8 H9

H14 H15

R³⁷ is H; F; CI; CH₃; OCH₃; CF₃; OCF₃; or OCHF₂;

Ci_-4-thioalkoxy; or C_3-4-cycloalkyl;

R³⁹ is H; F; CI; Br; I; CF₃; OH; OCF₃; OCHF₂; N0₂; CN; Ci_-6-alkyl; Ci_-6-alkoxy;

Ci-6-thioalkoxy; C_3-6-cycloalkyl; C_3-6-heterocyclyl; -C(0)OH;

-C(O)NR⁴⁰R⁴¹ ; or -S(O)₂NR⁴⁰R⁴¹ ;

R⁴⁰ and R⁴¹ are independently H; or Ci_-3-alkyl;

H16

R⁴³ -aryl; C5-6-heteroaryl; or a group of one of the formulae

R⁴⁴ is H; F; CI; CF₃; OH; OCF₃; OCHF₂; N0₂; CN; d-4-alkyl; d-4-alkoxy;

Ci-4-thioalkoxy; or C3-4-cycloalkyl;

R⁴⁷ is H; F; CI; CH₃; or CF₃;

R ⁸ is H; or Ci_-3 alkyl;

I is O; S; or NR⁴⁶;

T' is N; or CR³⁷;

e is an integer of 0-1 ;

g is an integer of 0-2; with the proviso that,

if G is H; C1-6 alkyl; C2-6-alkenyl; C_3-6-cycloalkyl; or C_3-6-heterocyclyl;

if i is 1 ; or p is 0;

then Q is Q1 ; or Q2;

and with the further proviso that,

if G is H; C1-6 alkyl; C2-6-alkenyl; C_3-6-cycloalkyl; or C_3-6-heterocyclyl;

in Q at most 3 substituents R⁴⁷ are different from H; an aromatic 5-membered (t=0) or 6-membered (t=1 ) ring system is positioned between functional moieties L and X; if t=0,

Y¹ is CR⁴⁹; NR⁵⁵; N; O; or S

Y² is CR⁵⁰; NR⁵⁵; N; O; or S

Y³ is CR⁵¹ ; NR⁵⁵; N; O; or S with the proviso that

the aromatic 5-membered ring system is a group of one of the formulae

wherein Y' is NR⁵⁵; O; or S;

Y¹ is CR⁴⁹; or N

Y² is CR⁵⁰; or N

Y³ is CR⁵¹ ; or N

Y⁴ is CR⁵²; or N with the proviso that

-membered ring system is a group of one of the fo

and with the further proviso that

in H29 two of the substituents are H;

in each of H30 to H33 one of the substituents is H;

R⁴⁹ and R⁵⁰ are independently H; F; CI; CH₃; CH₂CH₃; CF₃; OCH₃;

OCF₃; or OCHF₂;

R⁵³ and R⁵⁴ are independently H; or Ci_-2-alkyl;

R⁵⁵ is H; or CH₃; and wherein

in such a compound at most 12 halogen substituents are present; or a stereoisomer; or a tautomer or rotamer thereof; or a salt; or a pharmaceutically acceptable salt; or a solvate thereof.

2. A compound according to claim 1

wherein

2 stereocenters are further defined as in formula (II)

(II)

if Q is Q1 ;

if Q is Q2;

then, in the moiety comprising Q2, one further stereocenter is defined as in formula IV)

or a tautomer or rotamer thereof; or a salt; or a pharmaceutically acceptable salt; or a solvate thereof.

3. A compound according to any of claims 1 or 2

wherein

L is -C(O)-;

Xis O; t is 0;

i is 1, and p is 1; or

i is 2, and p is 1;

4. A compound according to any one of claims 1 or 2

wherein

L is -C(O)-;

Xis O; tis 1;

i is 1, and p is 1; or

i is 2, and p is 1; R¹ is CH₃; or CH₂CH₃;

5. A compound according to any one of claims 1 or 4

wherein

Eis E1; E2; E3; E5; or E7;

R²², R²³, and R²⁴ are H; G is Ci-3-alkyl; C₆-io-aryl; C₅-io-heteroaryl; G1; G2; G3; G4; G5; G6; G7; G8;

G9;G10; orG13;

R³0is H; OH; or -NR³¹R³²;

R³¹ and R³² are H; with the proviso that,

if Q is O; or S; or

if R³⁴in Q1 is H; F; CF₃; OH; SH; Ci_-8-alkyl; C₂-8-alkenyl; C₂-₈-alkynyl;

Ci-8-alkoxy; Ci_-8-thioalkoxy; C₃-8-cycloalkyl; C3-8-heterocyclyl; or

-NR⁴⁸C(0)C(0)OR⁴⁸;

then G is C₆-io-aryl; C₅-io-heteroaryl; G1; G2; G3; G4; G5; G6; G7; G8; G9;

G10; orG13;

Qis 0; S;Q1;orQ2;

R³⁶is H6; H7; H8; or H9;

R⁴³is H18;

C_3-4-cycloalkyl;

R ⁵is H; F; CI; or CH₃;

R⁴⁷ and R⁴⁸ are H;

m and n are 0;

e is 0;or1;

g is 0;or1; with the proviso that,

if G is Ci-₃alkyl;

then Q is Q1 ; or Q2; R³⁴ in Q1 is Ce-io-aryl; or Cs-io-heteroaryl; and with the proviso that,

if i is 1; or p is 0;

then Q is Q1; orQ2;

and with the further proviso that,

if G is Ci_-3alkyl;

then R³⁴ in Q1 is Ce-io-aryl; or Cs-io-heteroaryl; or a tautomer or rotamer thereof; or a salt; or a pharmaceutically acceptable salt; or a solvate thereof.

6. A compound according to any one of claims 1 to 5

wherein

E is E1 ; E2; E3; or E5;

R¹⁹ is H; -(CHR22)oC(0)OR²¹ ; -(CHR²²)oS(0)₂OH;

-(CHR²²)oP(0)(OR²¹)₂; -(CHR²²)oOH; -(CHR²²)₀C(0)NH₂;

-(CHR²²)₀NHC(0)NH₂; -(CHR²²)₀S(0)₂NH₂; or -(CHR²²)₀OC(0)NH R² is H; CH₃; CH₂CH₃; or -CH(CH₃)₂;

Z is -C(O)-; or -S(0)₂-;

if E is E1 , o is an integer of 1 -2;

if E is E2, o is an integer of 0-1 ;

if E is E3, o is 1 ;

if E is E5, o is 0;

G is Ci-3-alkyl; G5; or G13;

R³⁰ is H; OH; or -NR³¹R³²;

R³¹ and R³² are H;

T is N; or CH; with the proviso that

G13 is a group of one of the formulae

G13¹ G13" and with the proviso that,

if Q is O; S; or

if R³⁴ in Q1 is H; F; CF₃; OH; Ci-4-alkyl; C_2-4-alkenyl; or Ci_-4-alkoxy; or-NR⁴⁸C(0)C(0)OR⁴⁸;

then GisG5;G13';orG13";

Qis 0;S;Q1;orQ2;

Z³ is -NR⁴⁸C(0)-; -NR⁴⁸C(0)NR⁴⁸-; or -NR⁴⁸S(0)₂-;

R³⁴is H; F; CF₃; OH; Ci_-4-alkyl; C₂-₄-alkenyl; or Ci_-4-alkoxy; or

-NR⁴⁸C(0)C(0)OR⁴⁸;

R³⁶is H6;H7;orH8;

R³⁷ is H; F; CI; CH₃; OCH₃; CF₃; OCF₃; or OCHF₂;

Ci_-4-thioalkoxy; or C_3-4-cycloalkyl;

Ci-6-thioalkoxy; C_3-6-cycloalkyl; or C_3-6-heterocyclyl;

R³is H18;

R⁴⁴is H; F; CI; CF₃; OCF₃; OCHF₂; Ci_-4-alkyl; Ci-4-alkoxy; Ci-4-thioalkoxy; or

C_3-4-cycloalkyl;

R⁵is H; F; CI; or CH₃;

R⁴⁷ and R⁴⁸ are H; m and n are 0;

e is 1 ;

g is 0;or1;

Uis 0;orCHR⁴⁷; with the proviso that,

if i is 1, and p is 1;

then Q is Q1; orQ2;

and with the further proviso that,

if G is Ci_-3alkyl;

then Q is Q2; and with the proviso that,

if i is 2, and p is 1 ;

then Q is O; S; or Q1 ; R³⁴ in Q1 is H; or a tautomer or rotamer thereof; or a salt; or a pharmaceutically acceptable salt; or a solvate thereof.

7. A compound according to any one of claims , 2, or 4 to 6

wherein

tis 1;

Eis E1;E2;E3;orE5;

R⁸is H1;

R¹⁹ is H; -(CHR²²)_oC(0)OR²¹; or -(CHR²²)₀P(0)(OR² )₂; the 6-membered (t=1) ring system positioned between functional moieties L and X is H29; or a tautomer or rotamer thereof; or a salt; or a pharmaceutically acceptable salt; or a solvate thereof.

8. A compound according to any one of claims 1 , 2, or 4 to 7

wherein

for substituent E

R¹⁹ is H; or -(CHR²²)₀C(0)OR²¹;

R²¹ is H; CH₃; or CH₂CH₃;

Z is -C(O)-;

Z² is -C(0)NH-;

G is Ci-3-alkyl; G5; G13¹; or G13";

R²⁵is H;

R²⁶, R²⁷, and R²⁸ are independently H; F; CI; CH₃; CF₃; OCH₃; OCF₃; or OCHF₂ R²⁹is H; F; CH₃; or CF₃; with the proviso that,

if Q is O; S; or

if R³⁴in Q1 is H; F; CF₃; OH; Ci-4-alkyl; C₂-*-alkenyl; or Ci-4-alkoxy;

then GisG5;G13' orG13";

Qis 0;S;Q1;orQ2;

R³⁴is H; F; CF₃; OH; Ci-₄-alkyl; C_2-4-alkenyl; or Ci_-4-alkoxy; R³⁶ is is a group of one of the formulae

H6¹ H7¹

R³⁷ and R³⁸ are independently H; F; CI; CH₃; OCH₃; CF₃; OCF₃; or OCHF₂; R³⁹ is H; F; CI; CF₃; OH; OCF₃; OCHF₂; Ci-4-alkyl; Ci-4-alkoxy;

or Ci-4-thioalkoxy;

M' is 0; or S; with the proviso that,

if i is 1 , and p is 1 ;

then Q is Q1 ; or Q2;

and with the further proviso that,

if G is Ci_-3 alkyl;

then Q is Q2; and with the proviso that,

if i is 2, and p is 1 ;

then Q is O; S; or Q1 ; R³⁴ in Q1 is H; for H29 positioned between functional moieties L and X

R⁴⁹, R⁵⁰ and R⁵² are independently H; F; CI; CH₃; CF₃; OCH₃; OCF₃; or OCHF₂; R⁵ is H; F; CI; CF₃; OCF₃; OCHF₂; NH₂; Ci_-3-alkyl; or Ci_₃-alkoxy; with the proviso that in H29 two of the substituents are H; or a tautomer or rotamer thereof; or a salt; or a pharmaceutically acceptable salt; or a solvate thereof.

9. A compound according to any one of claims 6 to 8

wherein

R is CH₃;

E is E1 ; E2; or E5;

R¹⁷ is -C(0)OH; R¹⁹ is H; -(CH₂)oC(0)OH;

for substituent Q

R³⁶ is H7'; or a tautomer or rotamer thereof; or a salt; or a pharmaceutically acceptable salt; or a solvate thereof.

10. A compound according to any one of claims 1 , 2, 4 or 5 which is selected from the group consisting of Ex.1 to Ex.50, the lUPAC names of which are shown in the following Table below:

Ex. lUPAC name

3-({[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-16-methyl-9,12,17-trioxo-

Ex.1

1 1-phenyl-2-oxa-8,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20), 18,21 - trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1 -(2-naphthyl)-

Ex.2

9,12,17-trioxo-2-oxa-8 ,1 1 ,16-triazatricyclo[16.2.2.0⁴<⁸]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?, 15S)-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1 -(1 -naphthyl)-

Ex.3

3-({[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-16-methyl-9,12,17-trioxo-

Ex.4 1 1-[3-(trifluoromethyl)phenyl]-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1 -[2-methyl-5-

Ex.5 (trifluoromethyl)phenyl]-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1 -[4-methyl-3-

Ex.6 (trifluoromethyl)phenyl]-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-1 1-(4-fluorophenyl)-16-

Ex.7

methyl-9, 12, 17-trioxo-2-oxa-8, 1 1 , 16-triazatricyclo[16.2.2.0^{4 8}]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid Ex. lUPAC name

3-({[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-1 1-(3-methoxyphenyl)-16-

Ex.8

methyl-9, 12, 17-trioxo-2-oxa-8, 1 1 , 16-triazatricyclo[16.2.2.0^{4 8}]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-1 1-(5-chloro-2-

Ex.9 methylphenyl)-16-methyl-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-1 1-(4-carbamoyl-3-methylphenyl)-6-[(3-

Ex.10 chlorobenzoyl)amino]-16-methyl-9, 12,17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-1 1-(5-amino-2-naphthyl)-6-[(3-chlorobenzoyl)amino]-

Ex.11

16-methyl-9,12, 17-trioxo-2-oxa-8, 1 1 ,16-triazatricyclo[16.2.2.0^{4 8}]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?, 155)-1 1 -(4-carbamoylphenyl)-16-methyl-9, 12, 17-trioxo-6-

Ex.12 {[3-(trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-1 1-(7-isoquinolinyl)-16-methyl-9,12,17-trioxo-6-{[3-

Ex.13 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

1 -{[(45,6/?, 15 S)-16-methyl-1 1 -(2-naphthyl)-9, 12, 17-trioxo-6-{[3-

Ex.14 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15-yl]carbonyl}-3,3- azetidinedicarboxylic acid

3-({[(45,6 ?,155)-16-methyl-1 1 -(2-naphthyl)-9,12,17-trioxo-6-{[3-

Ex.15 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)pentanedioic acid

(2 ^-2-({[(45,6 ?,155)-16-methyl-1 1 -(2-naphthyl)-9,12,17-trioxo-6-{[3-

Ex.16 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)succinic acid Ex. lUPAC name

(45,6 ?,15≤)-16-methyl-1 1-(2-naphthyl)-9,12,17-trioxo- V-(1 ^tetrazol-5-

Ex.17

ylmethyl)-6-{[3-(trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0^{4 8}]docosa-1 (20), 18,21-triene-15-carboxamide

[({[(45,6 ?,155)-16-methyl-1 1 -(2-naphthyl)-9,12,17-trioxo-6-{[3-

Ex.18 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)methyl]phosphonic acid

[2-({[(45,6/?, 15≤)-16-methyl-1 1 -(2-naphthyl)-9, 12, 17-trioxo-6-{[3-

Ex.19 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)ethyl]phosphonic acid

1 -{[(45,6/?, 15 S)-6-[(3-chlorobenzoyl)amino]-1 1 , 16-dimethyl-9, 12,17-

Ex.20

trioxo-2-oxa-8,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien- 15-yl]carbonyl}-3,3-azetidinedicarboxylic acid

3-({[(45,6/?,155)-16-methyl-1 1 -(2-naphthyl)-9,12,17-trioxo-6-{[3-

Ex.21 (trifluoromethyl)benzoyl]amino}-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6/?,155)-6-[(3-methoxybenzoyl)amino]-16-methyl-1 1 -(2-

Ex.22

naphthyl)-9, 12,17-trioxo-2-oxa-8, 1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6/?,155)-16-methyl-6-{[3-(methylsulfanyl)benzoyl]amino}-1 1 -(2-

Ex.23

3-({[(45,6/?,155)-6-[(3-cyanobenzoyl)amino]-16-methyl-1 1-(2-naphthyl)-

Ex.24

9,12,17-trioxo-2-oxa-8 ,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid

3-({[(45,6/?,155)-16-methyl-6-[(3-methylbenzoyl)amino]-1 1 -(2-

Ex.25

3-({[(45,6/?,155)-6-[(4-chlorobenzoyl)amino]-16-methyl-1 1 -(2-naphthyl)-

Ex.26

9,12,17-trioxo-2-oxa-8 ,1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}amino)propanoic acid Ex. lUPAC name

3-({[(45,6 ?,155)-6-[(3,5-dichlorobenzoyl)amino]-16-methyl-1 1-(2-

Ex.27

4-{[(45,6 ?,15S)-15-[(2-carboxyethyl)carbamoyl]-16-methyl-1 1-(2-

Ex.28

naphthyl)-9, 12,17-trioxo-2-oxa-8, 1 1 ,16-triazatricyclo[16.2.2.0⁴'⁸]docosa- 1 (20),18,21 -trien-6-yl]carbamoyl}benzoic acid

3-({[(45,6 ?,155)-6-{[(3-chlorophenyl)sulfonyl]amino}-16-methyl-1 1 -(2-

Ex.29

3-({[(45,6 ?,155)-6-{[(3-chlorophenyl)carbamoyl]amino}-16-methyl-1 1 -

Ex.30 (2-naphthyl)-9,12,17-trioxo-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-19,20-difluoro-16-methyl-

Ex.31 1 1 -(2-naphthyl)-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-6-[(4-chlorobenzoyl)amino]-19,22-difluoro-16-methyl-

Ex.32 1 1 -(2-naphthyl)-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-20-chloro-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1 -(2-

Ex.33

3-({[(45,6 ?,155)-20-chloro-6-[(2-chlorobenzoyl)amino]-16-methyl-1 1 -(2-

Ex.34

3-({[(45,6 ?, 155)-19-chloro-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1 -(2-

Ex.35

3-({[(45,6 ?, 155)-6-[(3,5-dichlorobenzoyl)amino]-19-methoxy-16-methyl-

Ex.36 1 1 -(2-naphthyl)-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid Ex. lUPAC name

3-({[(45,6 ?,155)-6-[(3,5-dichlorobenzoyl)amino]-20-methoxy-16-methyl-

Ex.37 1 1 -(2-naphthyl)-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-tnen-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?, 155)-19-chloro-6-[(4-chlorobenzoyl)amino]-16-methyl-1 1 -(2-

Ex.38

3-({[(45,6 ?, 155)-20,21 -dichloro-6-{[(3-chlorophenyl)sulfonyl]amino}-16-

Ex.39 methyl-1 1 -(2-naphthyl)-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?,155)-6-{[3-(4-methoxyphenoxy)benzoyl]amino}-16-methyl-

Ex.40 1 1 -(2-naphthyl)-9, 12, 17-trioxo-2-oxa-8, 1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?, 155)-6-{[(5-chloro-2-thienyl)carbonyl]amino}-16-methyl-1 1 -

Ex.41 (2-naphthyl)-9,12,17-trioxo-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15- yl]carbonyl}amino)propanoic acid

3-({[(45,6 ?, 155)-6-[(carboxycarbonyl)amino]-16-methyl-1 1 -(2-

Ex.42

3-({[(45,6 ?, 155)-6-[(4-hydroxybenzoyl)amino]-16-methyl-1 1 -(2-

Ex.43

3-({[(45,6 ?,155)-20-amino-6-[(3-chlorobenzoyl)amino]-16-methyl-1 1 -(2-

Ex.44

3-({[(45,6 ?,155)-6-[(3-chlorobenzoyl)amino]-16-ethyl-1 1 -(2-naphthyl)-

Ex.45

1-{[(45,6 ?,15S)-6-[(3-chlorobenzoyl)amino]-1 1-[4-chloro-3-

Ex.46 (trifluoromethyl)phenyl]-16-methyl-9,12,17-trioxo-2-oxa-8,1 1 ,16- triazatncyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-trien-15-yl]carbonyl}-3,3- azetidinedicarboxylic acid

1-{[(45,6 ?,15S)-6-[(3-chlorobenzoyl)amino]-1 1-[4-chloro-3-

Ex.47 (trifluoromethyl)phenyl]-16-methyl-9,12,17-trioxo-2-oxa-8,1 1 ,16- triazatricyclo[16.2.2.0⁴'⁸]docosa-1 (20),18,21-tnen-15-yl]carbonyl}-3- (ethoxycarbonyl)-3-azetidinecarboxylic acid

1-{[(45,6 ?,155)-1 1 -(5-amino-2-naphthyl)-6-[(3-chlorobenzoyl)amino]-

Ex.48

16-methyl-9,12, 17-trioxo-2-oxa-8, 1 1 ,16-triazatricyclo[16.2.2.0^{4 8}]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}-3,3-azetidinedicarboxylic acid

1-{[(45,6 ?,15S)-1 1 -(4-carbamoylphenyl)-6-[(3-chlorobenzoyl)amino]-

Ex.49

1-{[(45,6 ?,15S)-1 1 -(4-carbamoylphenyl)-6-[(3-chlorobenzoyl)amino]-

Ex.50 16-methyl-9,12, 17-trioxo-2-oxa-8, 1 1 ,16-triazatricyclo[16.2.2.0^{4 8}]docosa- 1 (20), 18,21 -trien-15-yl]carbonyl}-3-(ethoxycarbonyl)-3- azetidinecarboxylic acid or a tautomer or rotamer thereof; or a salt; or a pharmaceutically acceptable salt; or a solvate thereof.

1 1. A compound according to any one of claims 1 to 10 having a modulating activity on Pin1 .

12. A pharmaceutical composition containing a compound or a mixture of compounds according to any one of claims 1 to 1 1 and at least one pharmaceutically inert carrier.

13. A pharmaceutical composition according to claim 12 in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, rectal, pulmonary or inhalation administration, especially in the form of tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, spray, nebulizer or suppositories.

14. A compound of formula (I) according to any one of claims 1 to 1 1 , or a pharmaceutically acceptable salt thereof, for use as a medicament.

15. The use of a compound according to any one of claims 1 to 1 1 , or a composition according to claims 12 or 13, for the treatment or prevention of diseases, disorders or conditions related to abnormal cell growth, in particular various cancers; or inflammatory diseases, cardiovascular diseases or disorders, acute neurological disorders, neurodegenerative diseases, osteolytic diseases, immune diseases or disorders, viral infections, infections with intracellular and extracellular pathogens, parasitic diseases, or transplant rejection.

16. The use of a compound according to any one of claims 1 to 1 1 for the manufacture of a medicament to treat or prevent diseases, disorders, or condition associated with, mediated by or resulting from the activity of Pin1 , particularly diseases, disorders or conditions related abnormal cell growth, in particular various cancers, such as breast cancer, prostate cancer, cervical cancer, lung cancer, liver cancer, esophageal cancer, or gastric cancer; or lymphoma, such as non-Hodgkin lymphoma; or leukemia, such as promyelotic leukemia; inflammatory diseases, such as asthma, allergic pulmonary eosinophilia, acute respiratory distress syndrome, rheumatoid arthritis or inflammatory bowel diseases; or acute neurological disorders, such as stroke; or neurodegenerative diseases, such as Huntington's disease and frontotemporal dementia; or viral infections, such as HIV/AIDS; or infection with intracellular and extracellular pathogens, such as infections by Chlamydia trachomatis, or osteolytic bone diseases, such as periodontitis; or cardivascular diseases, such as diabetic vascular disease or diabetic restenosis; or nonalcoholic steatohepatitis; or cardiac hypertrophy; or immune diseases or disorders, such as diabetes, multiple sclerosis, lupus, macrophage mediated tissue damage, gastritis, or myeloproliferative syndromes; or transplant rejection; or parasitic diseases, such as Theileriosis, such as lymphoproliferative Theileriosis caused by Theiieria annulata or Theiieria parva.

17. A method of treating or preventing a disease, disorder, or condition associated with, mediated by or resulting from the activity of Pin1 , particularly diseases, disorders or conditions related abnormal cell growth, in particular various cancers, such as breast cancer, prostate cancer, cervical cancer, lung cancer, liver cancer, esophageal cancer, or gastric cancer; or lymphoma, such as non-Hodgkin lymphoma; or leukemia, such as promyelotic leukemia; inflammatory diseases, such as asthma, allergic pulmonary eosinophilia, acute respiratory distress syndrome, rheumatoid arthritis or inflammatory bowel diseases; or acute neurological disorders, such as stroke; or neurodegenerative diseases, such as Huntington's disease and frontotemporal dementia; or viral infections, such as HIV/AIDS; or infection with intracellular and extracellular pathogens, such as infections by Chlamydia trachomatis, or osteolytic bone diseases, such as periodontitis; or cardivascular diseases, such as diabetic vascular disease or diabetic restenosis; or nonalcoholic steatohepatitis; or cardiac hypertrophy; or immune diseases or disorders, such as diabetes, multiple sclerosis, lupus, macrophage mediated tissue damage, gastritis, or myeloproliferative syndromes; or transplant rejection; or parasitic diseases, such as Theileriosis, such as lymphoproliferative Theileriosis caused by Theiieria annulata or Theiieria parva, comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound according to any one of claims 1 to 1 1 , or a composition according to claims 12 or 13.