(en)This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1

and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

1.ApplicationNumber: US-201514955379-A
1.PublishNumber: US-9713606-B2
2.Date Publish: 20170725
3.Inventor: ANDERSKEWITZ RALF
BINDER FLORIAN
GRAUERT MATTHIAS
GRUNDL MARC
HAEBEL PETER WILHELM
OOST THORSTEN
PAUTSCH ALEXANDER
PETERS STEFAN
VINTONYAK VIKTOR

4.Inventor Harmonized: ANDERSKEWITZ RALF(DE)
BINDER FLORIAN(DE)
GRAUERT MATTHIAS(DE)
GRUNDL MARC(DE)
HAEBEL PETER WILHELM(DE)
OOST THORSTEN(DE)
PAUTSCH ALEXANDER(DE)
PETERS STEFAN(DE)
VINTONYAK VIKTOR(DE)

5.Country: US
6.Claims:
(en)This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1

and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

7.Description:
(en)FIELD OF INVENTION
This invention relates to substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1

and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

BACKGROUND INFORMATION




WO2004110988 discloses peptidyl nitrile inhibitors as dipeptidyl-peptidase I (DPPI) inhibitors for the treatment of a series of diseases.
WO2009074829 and WO2010142985 also disclose peptidyl nitrile inhibitors as dipeptidyl-peptidase I (DPPI) inhibitors for the treatment asthma, COPD or allergic rhinitis.




BRIEF SUMMARY OF THE INVENTION
Dipeptidyl-aminopeptidase I (DPPI or Cathepsin C; EC3.4.141), is a lysosomal cysteine protease capable of removing dipeptides from the amino terminus of protein substrates. DPPI was first discovered by Gutman and Fruton in 1948 (J. Biol. Chem 174: 851-858, 1948). The cDNA of the human enzyme has been described in 1995 (Paris et al.; FEBS Lett 369: 326-330, 1995). The DPPI protein is processed into a mature proteolytically active enzyme consisting of a heavy chain, a light chain, and a propeptide that remains associated with the active enzyme (Wolters et al.; J. Biol. Chem. 273: 15514-15520, 1998). Whereas the other cysteine Cathepsins (e.g. B, H, K, L and S) are monomers, DPPI is a 200-kD tetramer with 4 identical subunits, each composed of the 3 different polypeptide chains. DPPI is constitutively expressed in many tissues with highest levels in lung, kidney, liver and spleen (Kominami et al.; Biol. Chem. Hoppe Seyler 373: 367-373, 1992). Consistent with its role in the activation of serine proteases from hematopoetic cells, DPPI is also relatively highly expressed in neutrophils, cytotoxic lymphocytes, natural killer cells, alveolar macrophages and mast cells. Recent data from DPPI deficient mice suggest that, besides being an important enzyme in lysosomal protein degradation, DPPI also functions as the key enzyme in the activation of granule serine proteases in cytotoxic T lymphocytes and natural killer cells (granzymes A and B; Pham et al.; Proc. Nat. Acad. Sci 96: 8627-8632, 1999), mast cells (chymase and tryptase; Wolter et al.; J Biol. Chem. 276: 18551-18556, 2001), and neutrophils (Cathepsin G, elastase and proteinase 3; Adkison et al.; J Clin. Invest. 109: 363.371, 2002). Once activated, these proteases are capable of degrading various extracellular matrix components, which can lead to tissue damage and chronic inflammation.
Thus, inhibitors of Cathepsin C could potentially be useful therapeutics for the treatment of neutrophil-dominated inflammatory diseases such as chronic obstructive pulmonary disease (COPD), pulmonary emphysema, asthma, multiple sclerosis, and cystic fibrosis (Guay et al.; Curr. Topics Med. Chem. 10: 708-716, 2010; Laine and Busch-Petersen; Expert Opin. Ther. Patents 20: 497-506, 2010). Rheumatoid arthritis is also another chronic inflammatory disease where DPPI appears to play a role. Neutrophils are recruited to the site of joint inflammation and release Cathepsin G, elastase and proteinase 3, proteases which are believed to be responsible for cartilage destruction associated with rheumatoid arthritis. Indeed, DPPI deficient mice were protected against acute arthritis induced by passive transfer of monoclonal antibodies against type II collagen (Adkison et al.; J Clin. Invest. 109: 363.371, 2002).
In light of the role DPPI plays in activating certain pro-inflammatory serine proteases, it seems desirable to prepare compounds that inhibit its activity, which thereby inhibit downstream serine protease activity. It has been surprisingly found that the bicyclic compounds of the present invention possess potent Cathepsin C activity, high selectivity against other Cathepsins, e.g. Cathepsin K, and in general desirable pharmacokinetic properties.


DETAILED DESCRIPTION OF THE INVENTION
A compound of formula 1

wherein
R 1 is independently selected from H, C 1-6 -alkyl-, halogen, HO—, C 1-6 -alkyl-O—, H 2 N—, C 1-6 -alkyl-HN— and (C 1-6 -alkyl) 2 N—, C 1-6 -alkyl-C(O)HN—; or two R 1 are together C 1-4 -alkylene; R 2 is selected from
R 2.1 ; aryl-; optionally substituted with one, two or three residues independently selected from R 2.1 ; optionally substituted with one R 2.3 ; C 5-10 -heteroaryl-; containing one, two, three or four heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 ; and C 5-10 -heterocyclyl-; containing one, two, three or four heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three or four R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 or one R 2.5 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 or R 2 and R 4 are together with two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.2 ; R 2.1 is independently selected from among H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-6 -alkylene-, C 1-6 -alkyl-A-, C 1-6 -haloalkyl-A-, R 2.1.1 —C 1-6 -alkylene-A-, C 1-6 -alkyl-A-C 1-6 -alkylene-, C 3-8 -cycloalkyl-A-C 1-6 -alkylene-, C 1-6 -haloalkyl-A-C 1-6 -alkylene-, R 2.1.1 —C 1-6 -alkylene-A-C 1-6 -alkylene-, R 2.1.1 -A-C 1-6 -alkylene-, HO—C 1-6 -alkylene-A-, HO—C 1-6 -alkylene-A-C 1-6 -alkylene-, C 1-6 -alkyl-O—C 1-6 -alkylene-A- and C 1-6 -alkyl-O—C 1-6 -alkylene-A-C 1-6 -alkylene-;
R 2.1.1 is independently selected from
aryl-; optionally substituted independently from each other with one, two or three R 2.1.1.1 ; C 5-10 -heteroaryl-; containing one, two, three or four heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; C 5-10 -heterocyclyl-; containing one, two, three or four heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three or four R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; R 2.1.1.1 is independently selected from among halogen, HO—, O═, C 1-6 -alkyl-, C 1-6 -alkyl-O—, C 1-6 -haloalkyl-, C 1-6 -haloalkyl-O— and C 3-8 -cycloalkyl-; R 2.1.1.2 is independently selected from among O═, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 cycloalkyl, C 1-6 -alkyl-O—C 1-6 -alkyl-, H(O)C—, C 1-6 -alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-;

R 2.2 is independently selected from among H-A-C 1-6 -alkylene-, C 1-6 -alkyl-A-C 1-6 -alkylene-, C 3-8 -cycloalkyl-A-C 1-6 -alkylene-, C 1-6 -haloalkyl-A-C 1-6 -alkylene-, R 2.1.1 -A-C 1-6 -alkylene-, C 1-6 -alkyl-S(O) 2 —, C 1-6 -alkyl-C(O)— and R 2.1.1 -A-; R 2.3 and R 4 are together selected from among —O—, —S—, —N(R 2.3.1 )—, —C(O)N(R 2.3.1 )—, —N(R 2.3.1 )C(O)—, —S(O) 2 N(R 2.3.1 )—, —N(R 2.3.1 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O) 2 —, R 2.3 , R 2.3 , —C(R 2.3.2 )═C(R 2.3.2 )—, —C═N—, —N═C—, —C(R 2.3.2 ) 2 —O—, —O—C(R 2.3.2 ) 2 —, —C(R 2.3.2 ) 2 N(R 2.3.1 )—, —N(R 2.3.1 )C(R 2.3.2 ) 2 — and —C 1-4 -alkylene-;
R 2.3.1 is independently selected from among H, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and, (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-; R 2.3.2 is independently selected from among H, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-;
R 2.4 and R 4 are together selected from among-N(R 2.4.1 )—, —C(O)N(R 2.4.1 )—, —N(R 2.4.1 )C(O)—, —S(O) 2 N(R 2.4.1 )—, —N(R 2.4.1 )S(O) 2 —, —C(O)—, —S(O)—, —S(O) 2 —, —C(R 2.4.2 )═C(R 2.4.2 )—, —C═N—, —N═C—, —C(R 2.4.2 ) 2 N(R 2.4.1 )—, —N(R 2.4.1 )C(R 2.4.2 ) 2 — and —C 1-4 -alkylene-; and
R 2.4.1 is independently selected from H, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene-, (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-; R 2.4.2 is independently selected from H, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-;
R 2.5 and R 4 are together selected from —C(R 2.5.1 )═, ═C(R 2.5.1 )— and —N═; and
R 2.5.1 is independently selected from H, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-;

R 3 is H or F; R 4 is independently selected from F, Cl, phenyl-H 2 C—O—, HO—, C 1-6 -alkyl-, C 1-6 -haloalkyl-, C 3-8 -cycloalkyl-, C 1-6 -alkyl-O—, C 1-6 -haloalkyl-O—, C 1-6 -alkyl-HN—, (C 1-6 -alkyl) 2 -HN—, C 1-6 -alkyl-HN—C 1-4 -alkylene- and (C 1-6 -alkyl) 2 -HN—C 1-4 -alkylene-; A is a bond or independently selected
from —O—, —S—, —N(R 5 )—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —S(O)(═NR 5 )—N(R 5 )—, —N(R 5 )(NR 5 ═) S(O)—, —S(═NR 5 ) 2 —N(R 5 )—, —N(R 5 )(NR 5 ═) 2 S—, —C(R 5 )═C(R 5 )—, —C≡C—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O) 2 —, —S(═NR 5 )—, —S(O)(═NR 5 )—, —S(═NR 5 ) 2 —, —(R 5 )(O)S═N—, —(R 5 N═)(O)S— and —N═(O)(R 5 )S—;
R 5 is independently selected from H, C 1-6 -alkyl- and NC—;

or a salt thereof.

Preferred Embodiments


Preferred are the above compounds of formula 1, wherein R 1 is R 1.a and R 1.a is independently selected from H, C 1-4 -alkyl-, F and HO—.
Preferred are the above compounds of formula 1, wherein R 1 is R 1.b and R 1.b is H.
Preferred are the above compounds of formula 1, wherein R 1 is R 1.c and two R 1.c are together —CH 2 —.
Preferred are the above compounds of formula 1, wherein R 2 is R 2.a and R 2.a is R 2.1 .
Preferred are the above compounds of formula 1, wherein R 2 is R 2.b and R 2.b is R 2.1.a .
Preferred are the above compounds of formula 1, wherein R 2 is R 2.c and R 2.c is aryl-; optionally substituted with one, two or three residues independently selected from R 2.1 ; optionally substituted with one R 2.3 .
Preferred are the above compounds of formula 1, wherein R 2 is R 2.d and R 2.d is phenyl; optionally substituted with one, two or three residues independently selected from R 2.1 ; optionally substituted with one R 2.3 .
Preferred are the above compounds of formula 1, wherein R 2 is R 2.d and R 2.d is phenyl; optionally substituted with one, two or three residues independently selected from R 2.1 and
R 2.1 is R 2.1.a and R 2.1.a is selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, C 1-4 -haloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 —C 1-4 -alkylene-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, HO—C 1-4 -alkylene-A-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-, C 1-4 -alkyl-O—C 1-4 -alkylene-A- and C 1-4 -alkyl-O—C 1-4 -alkylene-A-C 1-4 -alkylene-; and
R 2.1.1 is R 2.1.1.a and R 2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R 2.1.1.1 ; C 5-10 -heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; C 5-10 -heterocyclyl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N, and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and
R 2.1.1.1 is independently selected from halogen, HO—, O═, C 1-4 -alkyl-, C 1-4 -alkyl-O—, C 1-4 -haloalkyl-, C 1-4 -haloalkyl-O— and C 3-6 -cycloalkyl-; and R 2.1.1.2 is independently selected from O═, C 1-4 -alkyl-, C 1-4 -haloalkyl-; C 3-6 -cycloalkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl-, H(O)C—, C 1-4 -alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.


Preferred are the above compounds of formula 1, wherein R 2 is R 2.g and R 2.g is selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; and
R 2.1 is R 2.1.a and R 2.1.a is selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, C 1-4 -haloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 —C 1-4 -alkylene-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, HO—C 1-4 -alkylene-A-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-, C 1-4 -alkyl-O—C 1-4 -alkylene-A- and C 1-4 -alkyl-O—C 1-4 -alkylene-A-C 1-4 -alkylene-; and
R 2.1.1 is R 2.1.1.a and R 2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R 2.1.1.1 ; C 5-10 -heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and C 5-10 -heterocyclyl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and
R 2.1.1.1 is independently selected from halogen, HO—, O═, C 1-4 -alkyl-, C 1-4 -alkyl-O—, C 1-4 -haloalkyl-, C 1-4 -haloalkyl-O— and C 3-6 -cycloalkyl-; and R 2.1.1.2 is independently selected from O═, C 1-4 -alkyl-, C 1-4 -haloalkyl-; C 3-6 -cycloalkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl-, H(O)C—, C 1-4 -alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and


R 2.2 is R 2.2.a and R 2.2.a is independently selected from H-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-S(O) 2 — and C 1-4 -alkyl-C(O)—, R 2.1.1 -A-.
Preferred are the above compounds of formula 1, wherein R 2 is R 2.e and R 2.e is C 5 or 6 -heteroaryl-, containing one, two, three or four heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .
Preferred are the above compounds of formula 1, wherein R 2 is R 2.f and R 2.f is bicyclic C 7-10 -heteroaryl-, each containing one, two, three or four heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .
Preferred are the above compounds of formula 1, wherein R 2 is R 2.g and R 2.g is selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .

Preferred are the above compounds of formula 1, wherein R 2 is R 2.h and R 2.h is selected from pyrazole, thiophene and furane, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .
Preferred are the above compounds of formula 1, wherein R 2 is R 2.i and R 2.i is selected from C 6 -heterocyclyl- and C 7-10 -heterocyclyl-, each containing one, two, three or four heteroatoms independently selected from S, O and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 or one R 2.5 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .
Preferred are the above compounds of formula 1, wherein R 2 is R 2.j and R 2.j is selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 or one R 2.5 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .

Preferred are the above compounds of formula 1, wherein R 2 is R 2.j and R 2.j is selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; and
R 2.1 is R 2.1.a and R 2.1.a is selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, C 1-4 -haloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 —C 1-4 -alkylene-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, HO—C 1-4 -alkylene-A-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-, C 1-4 -alkyl-O—C 1-4 -alkylene-A- and C 1-4 -alkyl-O—C 1-4 -alkylene-A-C 1-4 -alkylene-; and
R 2.1.1 is R 2.1.1.a and R 2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R 2.1.1.1 ; C 5-10 -heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and C 5-10 -heterocyclyl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and
R 2.1.1.1 is independently selected from halogen, HO—, O═, C 1-4 -alkyl-, C 1-4 -alkyl-O—, C 1-4 -haloalkyl-, C 1-4 -haloalkyl-O— and C 3-6 -cycloalkyl-; and R 2.1.1.2 is independently selected from O═, C 1-4 -alkyl-, C 1-4 -haloalkyl-; C 3-6 -cycloalkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl-, H(O)C—, C 1-4 -alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and


R 2.2 is R 2.2.a and R 2.2.a is independently selected from H-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 alkylene-, C 1-4 -alkyl-S(O) 2 — and C 1-4 -alkyl-C(O)—, R 2.1.1 -A-.
Preferred are the above compounds of formula 1, wherein R 2 is R 2.k and R 2.k is selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 or one R 2.5 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .

Preferred are the above compounds of formula 1, wherein R 2 is R 2.1 and R 2.1 is selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 or one R 2.5 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .

Preferred are the above compounds of formula 1, wherein R 2 is R 2.m and R 2.m is together with R 4 and two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from S, S(O), S(O) 2 , O and N, preferably pyrazole, naphthene, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 , wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.2 .
Preferred are the above compounds of formula 1, wherein R 2 is R 2.n and R 2.n is selected from aryl-, pyrazole, thiophene and furane; wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 ; or R 2.n is selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 or one R 2.5 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .

Preferred are the above compounds of formula 1, wherein R 2.p is R 2.p and R 2.p is selected from aryl-, pyrazole, thiophene and furane; wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .
Preferred are the above compounds of formula 1, wherein R 2 is R 2.p and R 2.p is selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 or one R 2.5 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 .

Preferred are the above compounds of formula 1, wherein R 2 is R 2.q and R 2.q is selected from among the substituents (a1) to (q1)

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other are substituted with R 2.2 ;

Particularly preferred R 2.q is substituent (a1) or (c1), wherein
carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other are substituted with R 2.2 .
Particularly preferred R 2.q denotes a substituent selected from the group (a1) to (q1), wherein carbon atoms of the ring are optionally and independently from each other substituted with a group selected from among ═O, Me, MeSO 2 —, Me-piperazinyl-SO 2 —, morpholinyl, —CN and F, and possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with Me 2 N—CH 2 —CH 2 —, F 2 CH—CH 2 —, —CH 3 and tetrahydrofuranyl.
Preferred are the above compounds of formula 1, wherein R 2 is R 2.s and R 2.s is Phenyl-R 2.3 , wherein the phenyl ring is optionally substituted with one or two residues R 2.1 , wherein
R 2.1 is R 2.1.a and R 2.1.a is selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, C 1-4 -haloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 —C 1-4 -alkylene-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, HO—C 1-4 -alkylene-A-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-, C 1-4 -alkyl-O—C 1-4 -alkylene-A- and C 1-4 -alkyl-O—C 1-4 -alkylene-A-C 1-4 -alkylene-; and R 2.1.1 is R 2.1.1.a and R 2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R 2.1.1.1 ; C 5-10 -heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; C 5-10 -heterocyclyl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N, and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and
R 2.1.1.1 is independently selected from halogen, HO—, O═, C 1-4 -alkyl-, C 1-4 -alkyl-O—, C 1-4 -haloalkyl-, C 1-4 -haloalkyl-O— and C 3-6 -cycloalkyl-; and R 2.1.1.2 is independently selected from O═, C 1-4 -alkyl-, C 1-4 -haloalkyl-; C 3-6 -cycloalkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl-, H(O)C—, C 1-4 -alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl. and R 2.s and R 4 together denote a group (r1),


wherein the N-atom is optionally substituted with —R 2.2 , wherein
R 2.2 is independently selected from H-A-C 1-6 -alkylene-, C 3-8 -cycloalkyl-, C 1-6 -alkyl-A-C 1-6 -alkylene-, C 3-8 -cycloalkyl-A-C 1-6 -alkylene-, C 1-6 -haloalkyl-A-C 1-6 -alkylene-, R 2.1.1 -A-C 1-6 -alkylene-, C 1-6 -alkyl-S(O) 2 , C 1-6 -alkyl-C(O)— and R 2.1.1 -A-.

Particularly preferred are the above compounds of formula 1, wherein R 2 is R 2.s and R 2.s is Phenyl-R 2.3 ,
wherein the phenyl ring is optionally substituted with one or two residues independently selected from F and —CN,
and R 2.s and R 4 together denote a group (r1), wherein the N-atom is optionally substituted with —CH 3 ,









Particularly preferred are the above compounds of formula 1, wherein
R 1 is H, R 3 is H or F, preferably F,

and
R 2 is R 2.s and R 2.s is Phenyl-R 2.3 ,
wherein the phenyl ring is optionally substituted with one or two residues independently selected from F and —CN, and R 2.s and R 4 together denote a group (r1), wherein the N-atom is optionally substituted with —CH 3 ;


Particularly preferred are the above compounds of formula 1, wherein R 2.s and R 4 together denote a group (r1), optionally substituted as described above, in meta and para position of the phenyl ring.
Preferred are the above compounds of formula 1, wherein R 2 is R 2.r and R 2.r is selected from among the substituents (a2) to (w2) or
R 2 together with R 4 denotes a group selected from among (a3) to (e3).






























Particularly preferred R 2.r is substituent (a2) or (c2).
Particularly preferred R 2 is substituted Phenyl-R 2.3 wherein R 2 together with R 4 denotes a group selected from among (a3), (b3), (c3), (d3) and (e3).
Preferred are the above compounds of formula 1, wherein R 2.1 is R 2.1.a and R 2.1.a is selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, C 1-4 -haloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 —C 1-4 -alkylene-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, HO—C 1-4 -alkylene-A-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-, C 1-4 -alkyl-O—C 1-4 -alkylene-A- and C 1-4 -alkyl-O—C 1-4 -alkylene-A-C 1-4 -alkylene-.
Preferred are the above compounds of formula 1, wherein R 2.1.1 is R 2.1.1.a and R 2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R 2.1.1.1 ; C 5-10 -heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 and C 5-10 -heterocyclyl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other are substituted with one, two or three R 2.1.1.2 ; and R 2.1.1.1 is independently selected from halogen, HO—, O═, C 1-4 -alkyl-, C 1-4 -alkyl-O—, C 1-4 -haloalkyl-, C 1-4 -haloalkyl-O— and C 3-6 -cycloalkyl-; and R 2.1.1.2 is independently selected from O═, C 1-4 -alkyl-, C 1-4 -haloalkyl-; C 3-6 -cycloalkyl-, C 1-4 alkyl-O—C 1-4 -alkyl-, H(O)C—, C 1-4 -alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R 2.1.1 is R 2.1.1.b and R 2.1.1.b is phenyl or selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.1.1.2 ; and
R 2.1.1.1 is independently selected from halogen, HO—, O═, C 1-4 -alkyl-, C 1-4 -alkyl-O—, C 1-4 -haloalkyl-, C 1-4 -haloalkyl-O— and C 3-6 -cycloalkyl-; and R 2.1.1.2 is independently selected from O═, C 1-4 -alkyl-, C 1-4 -haloalkyl-; C 3-6 -cycloalkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl-, H(O)C—, C 1-4 -alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R 2.1.1 is R 2.1.1.c and R 2.1.1.c is phenyl or selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 , wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.1.1.2 ; and
R 2.1.1.1 is independently selected from F, Cl, Me, MeO— and cyclopropyl-; and R 2.1.1.2 is independently selected from Me, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R 2.1.2 is R 2.1.2.a and R 2.1.2.a is selected from H, NC—, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene- and (C 1-4 -alkyl)-O—C 1-4 -alkylene-.
Preferred are the above compounds of formula 1, wherein R 2.1.2 is R 2.1.2.b and R 2.1.2.b is selected from H, and C 1-4 -alkyl-, and C 3-6 -cycloalkyl-;
Preferred are the above compounds of formula 1, wherein R 2.2 is R 2.2.a and R 2.2.a is independently selected from H-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, C 1-4 -alkyl-S(O) 2 — and C 1-4 -alkyl-C(O)—, R 2.1.1 -A-;
Preferred are the above compounds of formula 1, wherein R 2.2 is R 2.2.b and R 2.2.b is together with R 4 selected from —C(O)—, —S(O)—, —S(O) 2 —, —C(R 2.1.1 )═C(R 2.1.2 ) and —C 1-4 -alkylene-;
Preferred are the above compounds of formula 1, wherein R 2.3 is together with R 4 a group R 2.3.a and
R 2.3.a is selected from —O—, —S—, —N(R 2.3.1 )—, —C(O)N(R 2.3.1 )—, —N(R 2.3.1 )C(O)—, —S(O) 2 N(R 2.3.1 )—, —N(R 2.3.1 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O) 2 —, —C(R 2.3.2 )═C(R 2.3.2 )—, —C(R 2.3.2 ) 2 —O—, —O—C(R 2.3.2 ) 2 —, —C(R 2.3.2 ) 2 N(R 2.3.1 )—, —N(R 2.3.1 )C(R 2.3.2 ) 2 — and —C 1-4 -alkylene-; and R 2.3.1 is independently selected from H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-; R 2.3.2 is independently selected from H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-.

Preferred are the above compounds of formula 1, wherein R 2.4 is together with R 4 a group R 2.4.a and
R 2.4.a is selected from —N(R 2.4.1 )—, —C(O)N(R 2.4.1 )—, —N(R 2.4.1 )C(O)—, —S(O) 2 N(R 2.4.1 )—, —N(R 2.4.1 )S(O) 2 —, —C(O)—, —S(O)—, —S(O) 2 —, —C(R 2.4.2 )═C(R 2.4.2 )—, —C═N—, —N═C—, —C(R 2.4.2 ) 2 N(R 2.4.1 )—, —N(R 2.4.1 )C(R 2.4.2 ) 2 — and C 1-4 - alkylene; and R 2.4.1 is independently selected from H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-; R 2.4.2 is independently selected from H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene-, (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-.

Preferred are the above compounds of formula 1, wherein R 2.5 is together with R 4 a group R 2.5.a and R 2.5.a is selected from —C(R 2.5.1 )═, ═C(R 2.5.1 )— and —N═; and
R 2.5.1 is independently selected from H, C 1-4 -alkyl, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-.

Preferred are the above compounds of formula 1, wherein R 2 is R 2.m and R 2.m is together with R 4 and two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 , wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.2 ; and
R 2.1 is R 2.1.a and R 2.1.a is selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, C 1-4 -haloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 —C 1-4 -alkylene-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, HO—C 1-4 -alkylene-A-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-, C 1-4 -alkyl-O—C 1-4 -alkylene-A- and C 1-4 -alkyl-O—C 1-4 -alkylene-A-C 1-4 -alkylene-; and
R 2.1.1 is R 2.1.1.a and R 2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R 2.1.1.1 ; C 5-10 -heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; C 5-10 -heterocyclyl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and
R 2.1.1.1 is independently selected from halogen, HO—, O═, C 1-4 -alkyl-O—, C 1-4 -haloalkyl-, C 1-4 -haloalkyl-O— and C 3-6 -cycloalkyl-; and R 2.1.1.2 is independently selected from O═, C 1-4 -alkyl-, C 1-4 -haloalkyl-; C 3-6 -cycloalkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl, H(O)C—, C 1-4 -alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and


R 2.2 is R 2.2.a and R 2.2.a is independently selected from H-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, C 1-4 -alkyl-S(O) 2 — and C 1-4 -alkyl-C(O)—, R 2.1.1 -A-.
Preferred are the above compounds of formula 1, wherein R 2 is R 2.n and R 2.n is selected from aryl-, pyrazole, thiophene and furane; wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 ; or R 2.n is selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; wherein a carbon atom of the ring is optionally substituted with one R 2.3 or one R 2.5 ; a nitrogen atom of the ring is optionally substituted with one R 2.4 ; and
R 2.1 is R 2.1.a and R 2.1.a is selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, C 1-4 -haloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 alkylene-, R 2.1.1 —C 1-4 -alkylene-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 alkylene-, HO—C 1-4 -alkylene-A-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-, C 1-4 -alkyl-O—C 1-4 -alkylene-A- and C 1-4 -alkyl-O—C 1-4 -alkylene-A-C 1-4 -alkylene-; and
R 2.1.1 is R 2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R 2.1.1.1 ; C 5-10 -heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and C 5-10 -heterocyclyl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and
R 2.1.1.1 is independently selected from halogen, HO—, O═, C 1-4 -alkyl-O—, C 1-4 -haloalkyl-, C 1-4 -haloalkyl-O— and C 3-6 -cycloalkyl-; and R 2.1.1.2 is independently selected from O═, C 1-4 -alkyl-, C 1-4 -haloalkyl-; C 3-6 -cycloalkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl-, H(O)C—, C 1-4 -alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and
R 2.2 is R 2.2.a and R 2.2.a is independently selected from H-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, C 1-4 -alkyl-S(O) 2 — and C 1-4 -alkyl-C(O)—, R 2.1.1 -A-; and R 2.3 is together with R 4 a group R 2.3.a and R 2.3.a is selected
from —O—, —S—, —N(R 2.3.1 )—, —C(O)N(R 2.3.1 )—, —N(R 2.3.1 )C(O)—, —S(O) 2 N(R 2.3.1 )—, —N(R 2.3.1 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O) 2 —, —C(R 2.3.2 )═C(R 2.3.2 )—, —C═N—, —N═C—, —C(R 2.3.2 ) 2 —O—, —O—C(R 2.3.2 ) 2 —, —C(R 2.3.2 ) 2 N(R 2.3.1 )—, —N(R 2.3.1 )C(R 2.3.2 ) 2 — and —C 1-4 -alkylene-; and R 2.3.1 is independently selected from H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-; R 2.3.2 is independently selected from H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-; and
R 2.4 is together with R 4 a group R 2.4.a and R 2.4.a is selected
from —N(R 2.4.1 )—, —C(O)N(R 2.4.1 )—, —N(R 2.4.1 )C(O)—, —S(O) 2 N(R 2.4.1 )—, —N(R 2.4.1 )S(O) 2 —, —C(O)—, —S(O)—, —S(O) 2 —, —C(R 2.4.2 )═C(R 2.4.2 )—, —C═N—, —N═C—, —C(R 2.4.2 ) 2 N(R 2.4.1 )—, —N(R 2.4.1 )C(R 2.4.2 ) 2 — and —C 1-4 -alkylene-; and R 2.4.1 is independently selected from H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-; R 2.4.2 is independently selected from H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-; and
R 2.5 is together with R 4 a group R 2.5.a and R 2.5.a is selected from —C(R 2.5.1 )═, ═C(R 2.5.1 )— and —N═; and
R 2.5.1 is independently selected from H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-.


Preferred are the above compounds of formula 1, wherein
R 1 is R 1.b and R 1.b is H; or two R 1 are together —CH 2 —; R 2 is selected from
R 2.1 ; phenyl-; optionally substituted with one or two residues independently selected from R 2.1 ; optionally substituted with one R 2.3 ; C 5 -heteroaryl-; containing two or three independently selected from S, O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R 2.2 ; monocyclic C 6 -heterocyclyl containing one or two nitrogen atoms, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R 2.2 ; and bicyclic C 9 or 10 -heterocyclyl-; containing one, two, three or four heteroatoms independently selected from S(O) 2 , O and N, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R 2.2; R 2.1 is independently selected from halogen, NC—, O═, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, and HO—C 1-4 -alkylene-A-C 1-4 -alkylene-;
R 2.1.1 is independently selected from
phenyl-; and C 5 or 6 -heterocyclyl-; containing one or two heteroatoms independently selected from O and N, wherein the ring is fully or partially saturated, wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one C 1-4 -alkyl-;

R 2.2 is independently selected from H-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene- and C 1-4 -alkyl-C(O)—; R 2.3 and R 4 are together a group selected from —N(R 2.3.1 )—, —C(O)N(R 2.3.2 )— and —N(R 2.3.1 )C(O)—;
R 2.3.1 is independently selected from H and H 3 C—;

R 3 is H or F; R 4 is R 4.b and R 4.b is F; A is a bond or independently selected
from —O—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, —S(O) 2 — and —N═(O)(R 5 )S—;
R 5 is independently selected from H and C 1-4 -alkyl-;

or a salt thereof.


Preferred are the above compounds of formula 1, wherein R 2 is selected from the
Table 1 R 2 —Embodiments of the invention for R 2 , R 2.1 , R 2.1.1 , R 2.2 , R 2.3 , R 2.4 and R 2.5 (if present):












E#
R 2
R 2.1
R 2.1.1
R 2.2
R 2.3-5












1
R 2.a
R 2.1
R 2.1.1.a

—

2
R 2.a
R 2.1
R 2.1.1.b

—

3
R 2.a
R 2.1
R 2.1.1.c

—

4
R 2.b
R 2.1.a
R 2.1.1.a

—

5
R 2.b
R 2.1.a
R 2.1.1.b

—

6
R 2.b
R 2.1.a
R 2.1.1.c

—

7
R 2.c
R 2.1.a
R 2.1.1.a
—
—

8
R 2.c
R 2.1.a
R 2.1.1.b
—
—

9
R 2.c
R 2.1.a
R 2.1.1.c
—
—

10
R 2.c
R 2.1.a
R 2.1.1.c
—
R 2.3.a

11
R 2.c
R 2.1.a
R 2.1.1.c
—
R 2.4.a

12
R 2.c
R 2.1.a
R 2.1.1.c
—
R 2.5.a

13
R 2.d
R 2.1.a
R 2.1.1.a
—
—

14
R 2.d
R 2.1.a
R 2.1.1.b
—
—

15
R 2.d
R 2.1.a
R 2.1.1.c
—
—

16
R 2.d
R 2.1.a
R 2.1.1.c
—
R 2.3.a

17
R 2.d
R 2.1.a
R 2.1.1.c
—
R 2.4.a

18
R 2.d
R 2.1.a
R 2.1.1.c
—
R 2.5.a

19
R 2.e
R 2.1.a
R 2.1.1.a
R 2.2.a
—

20
R 2.e
R 2.1.a
R 2.1.1.b
R 2.2.a
—

21
R 2.e
R 2.1.a
R 2.1.1.c
R 2.2.a
—

22
R 2.f
R 2.1.a
R 2.1.1.a
R 2.2.a
—

23
R 2.f
R 2.1.a
R 2.1.1.b
R 2.2.a
—

24
R 2.f
R 2.1.a
R 2.1.1.c
R 2.2.a
—

25
R 2.g
R 2.1.a
R 2.1.1.a
R 2.2.a
—

26
R 2.g
R 2.1.a
R 2.1.1.b
R 2.2.a
—

27
R 2.g
R 2.1.a
R 2.1.1.c
R 2.2.a
—

28
R 2.h
R 2.1.a
R 2.1.1.b
R 2.2.a
—

29
R 2.h
R 2.1.a
R 2.1.1.b
R 2.2.a
—

30
R 2.h
R 2.1.a
R 2.1.1.c
R 2.2.a
—

31
R 2.e
R 2.1.a
R 2.1.1.c
—
R 2.3.a

32
R 2.e
R 2.1.a
R 2.1.1.c
—
R 2.4.a

33
R 2.e
R 2.1.a
R 2.1.1.c
—
R 2.5.a

34
R 2.g
R 2.1.a
R 2.1.1.c
—
R 2.3.a

35
R 2.g
R 2.1.a
R 2.1.1.c
—
R 2.4.a

36
R 2.g
R 2.1.a
R 2.1.1.c
—
R 2.5.a

37
R 2.h
R 2.1.a
R 2.1.1.c
—
R 2.3.a

38
R 2.h
R 2.1.a
R 2.1.1.c
—
R 2.4.a

39
R 2.h
R 2.1.a
R 2.1.1.c
—
R 2.5.a

40
R 2.i
R 2.1.a
R 2.1.1.a
R 2.2.a
—

41
R 2.i
R 2.1.a
R 2.1.1.b
R 2.2.a
—

42
R 2.i
R 2.1.a
R 2.1.1.c
R 2.2.a
—

43
R 2.j
R 2.1.a
R 2.1.1.a
R 2.2.a
—

44
R 2.j
R 2.1.a
R 2.1.1.b
R 2.2.a
—

45
R 2.j
R 2.1.a
R 2.1.1.c
R 2.2.a
—

46
R 2.k
R 2.1.a
R 2.1.1.a
R 2.2.a
—

47
R 2.k
R 2.1.a
R 2.1.1.b
R 2.2.a
—

48
R 2.k
R 2.1.a
R 2.1.1.c
R 2.2.a
—

49
R 2.l
R 2.1.a
R 2.1.1.a
R 2.2.a
—

50
R 2.l
R 2.1.a
R 2.1.1.b
R 2.2.a
—

51
R 2.l
R 2.1.a
R 2.1.1.c
R 2.2.a
—






































































For a better understanding of the Table 1 R 2 —Embodiments of the invention example (E#) 21, can also be read as a group R 2 , wherein
R 2 is R 2.e and R 2.e is C 5 or 6 -heteroaryl-, containing one, two, three or four heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.2 ; and
R 2.1 is R 2.1.a and R 2.1.a is selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, C 1-4 -haloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 —C 1-4 -alkylene-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, HO—C 1-4 -alkylene-A-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-, C 1-4 -alkyl-O—C 1-4 -alkylene-A- and C 1-4 -alkyl-O—C 1-4 -alkylene-A-C 1-4 -alkylene-; and
R 2.1.1 is R 2.1.1.c and R 2.1.1.c is phenyl or selected from


















wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 , wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.1.1.2 ; and
R 2.1.1.1 is independently selected from F, Cl, Me, MeO— and cyclopropyl-; and
R 2.1.1.2 is independently selected from Me, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and


R 2.2 is R 2.2.a and R 2.2.a is independently selected from H-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, C 1-4 -alkyl-S(O) 2 —, C 1-4 -alkyl-C(O)—, R 2.1.1 -A-.






Preferred are the above compounds of formula 1, wherein R 3 is R 3.a and R 3.a is H.
Preferred are the above compounds of formula 1, wherein R 3 is R 3.b and R 3.b is F.
Preferred are the above compounds of formula 1, wherein R 4 is R 4.a and R 4.a is selected from F, Cl, phenyl-H 2 C—O—, HO—, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-O— and C 1-4 -haloalkyl-O—.
Preferred are the above compounds of formula 1, wherein R 4 is R 4.b and R 4.b is F; preferably in ortho position.
Preferred are the above compounds of formula 1, wherein A is A a and A a is a bond or independently selected
from —O—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, —S(O) 2 —, —(R 5 )(O)S═N—, —(R 5 N═)(O)S— and —N═(O)(R 5 )S— and R 5 is R 5.a and R 5.a is independently selected from H, C 1-4 -alkyl- and NC—.
Preferred is a compound of formula 1, wherein
R 1 is independently selected from H, C 1-4 -alkyl-, halogen, HO—, C 1-4 -alkyl-O—, H 2 N—, C 1-6 -alkyl-HN—, (C 1-6 -alkyl) 2 N- and C 1-6 -alkyl-C(O)HN—; or two R 1 are together C 1-4 -alkylene; R 2 is selected of the examples of the Table 1 R 2 —Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, 41, 42, 43, 44, 45, 45, 46, 47, 48, 49, 50, 51; R 3 is H or F; R 4 is independently selected from F, Cl, phenyl-H 2 C—O—, HO—, C 1-6 -alkyl-, C 1-6 -haloalkyl-, C 3-8 -cycloalkyl-, C 1-6 -alkyl-O—, C 1-6 -haloalkyl-O—, C 1-6 -alkyl-HN—, (C 1-6 -alkyl) 2 -HN—, C 1-6 -alkyl-HN—C 1-4 -alkylene- and (C 1-6 -alkyl) 2 -HN—C 1-4 -alkylene-; A is a bond or independently selected
from —O—, —S—, —N(R 5 )—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —S(O)(═NR 5 )—N(R 5 )—, —N(R 5 )(NR 5 ═), S(O)—, —S(═NR 5 ) 2 —N(R 5 )—, —N(R 5 )(NR 5 ═) 2 S—, —C(R 5 )═C(R 5 )—, —C≡C—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, S(O) 2 —, —S(═NR 5 )—, —S(O)(═NR 5 )—, —S(═NR 5 ) 2 —, —(R 5 )(O)S═N—, —(R 5 N═)(O)S— and —N═(O)(R 5 )S—;
R 5 is independently selected from H, C 1-6 -alkyl- and NC—;

or a salt thereof.


Preferred is a compound of formula 1, wherein
R 1 is R 1.a and R 1.a is independently selected from H, C 1-4 -alkyl-, F and HO—, or two R 1 are together C 1-4 -alkylene; R 2 is selected of the examples of the Table 1 R 2 —Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, 41, 42, 43, 44, 45, 45, 46, 47, 48, 49, 50, 51; R 3 is H or F; R 4 is R 4.a and R 4.a is F, Cl, phenyl-H 2 C—O—, HO—, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-O— and C 1-4 -haloalkyl-O—; A is a bond or independently selected
from —O—, —S—, —N(R 5 )—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —S(O)(═NR 5 )—N(R 5 )—, —N(R 5 )(NR 5 ═) S(O)—, —S(═NR 5 ) 2 —N(R 5 )—, —N(R 5 )(NR 5 ═) 2 S—, —C(R 5 )═C(R 5 )—, —C≡C—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, S(O) 2 —, —S(═NR 5 )—, —S(O)(═NR 5 )—, —S(═NR 5 ) 2 —, —(R 5 )(O)S═N—, —(R 5 N═)(O)S— and —N═(O)(R 5 )S—;
R 5 is independently selected from H, C 1-6 -alkyl- and NC—;

or a salt thereof.


Preferred is a compound of formula 1, wherein
R 1 is R 1.a and R 1.a is independently selected from H, C 1-4 -alkyl-, F and HO—, or two R 1 are together C 1-4 -alkylene; R 2 is selected of the examples of the Table 1 R 2 —Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29, 30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47 and 48; R 3 is H or F; R 4 is R 4.a and R 4.a is selected from F, Cl, phenyl-H 2 C—O—, HO—, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-O— and C 1-4 -haloalkyl-O—; A is A a and A a is a bond or independently selected
from —O—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, S(O) 2 —, —(R 5 )(O)S═N—, —(R 5 N═)(O)S— and —N═(O)(R 5 )S—;
R 5 is R 5.a and R 5.a is independently selected from H, C 1-4 -alkyl- and NC—;

or a salt thereof.


Preferred is a compound of formula 1, wherein
R 1 is R 1.b and R 1.b is H; or two R 1 are together —CH 2 —; R 2 is selected of the examples of the Table 1 R 2 —Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29, 30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47 and 48; R 3 is H or F; R 4 is R 4.b and R 4.b is F; A is A a and A a is a bond or independently selected
from —O—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, S(O) 2 —, —(R 5 )(O)S═N—, —(R 5 N═)(O)S— and —N═(O)(R 5 )S—;
R 5 is R 5.a and R 5.a is independently selected from H, C 1-4 -alkyl- and NC—;

or a salt thereof.


Preferred is a compound of formula 1, wherein
R 1 is R 1.b and R 1.b is H; or two R 1 are together —CH 2 —; R 2 is selected of the examples of the Table 1 R 2 —Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29, 30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47 and 48; R 3 is H or F; R 4 is R 4.b and R 4.b is F; A is A a and A a is a bond or independently selected
from —O—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, S(O) 2 —, —(R 5 )(O)S═N—, —(R 5 N═)(O)S— and —N═(O)(R 5 )S—;
R 5 is R 5.a and R 5.a is independently selected from H, C 1-4 -alkyl- and NC—;

or a salt thereof.


Preferred is a compound of formula 1, wherein
R 1 is R 1.b and R 1.b is H; or two R 1 are together —CH 2 —; R 2 is selected from
R 2.1 ; phenyl-; optionally substituted with one or two residues independently selected from R 2.1 ; optionally substituted with one R 2.3 ; C 5 -heteroaryl-; containing two or three independently selected from S, O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R 2.2 ; monocyclic C 6 -heterocyclyl containing one or two nitrogen atoms, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R 2.2 ; and bicyclic C 9 or 10 -heterocyclyl-; containing one, two, three or four heteroatoms independently selected from S(O) 2 , O and N, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R 2.2 ; R 2.1 is independently selected from halogen, NC—, O═, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-; preferably F, NC—, O═, H-A-, H-A-CH 2 —, R 2.1.1 -A-, H 3 C-A-, H 3 C—CH 2 -A-, Cyclopropyl-A-, R 2.1.1 —CH 2 —CH 2 -A-, R 2.1.1 —CH 2 -A-, H 3 C-A-CH 2 —CH 2 — and HO—C 4 -alkylene-A-CH 2 —;
R 2.1.1 is independently selected from
phenyl-; and C 5 or 6 -heterocyclyl-; containing one or two heteroatoms independently selected from 0 and N, wherein the ring is fully or partially saturated, wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one C 1-4 -alkyl-; preferably H 3 C—;

R 2.2 is independently selected from H-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-C(O)—; preferably H-A-CH 2 —, H-A-CH 2 —CH 2 —, cyclopropyl-, H 3 C-A-CH 2 —CH 2 —, R 2.1.1 -A-CH 2 — and H 3 C—C(O)—; R 2.3 and R 4 are together a group selected from —N(R 2.3.1 )—, —C(O)N(R 2.3.2 )— or —N(R 2.3.1 )C(O)—;
R 2.3.1 is independently selected from H and H 3 C—;

R 3 is H or F; R 4 is R 4.b and R 4.b is F; A is a bond or independently selected
from —O—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, —S(O) 2 — and —N═(O)(R 5 )S—;
R 5 is independently selected from H or C 1-4 -alkyl-;

or a salt thereof.


Preferred are the above compounds of formula 1, wherein
R 3 is R 3.a and R 3.a is H, and R 4 is R 4.b and R 4.b is F;

Particularly preferred are the above compounds of formula 1, wherein
R 3 is H, R 4 is F and R 2 is R 2.q and R 2.q is selected from among the substituents (a1) to (q1).

Particularly preferred are the above compounds of formula 1, wherein
R 3 is F and R 2 and R 4 together denote a group selected from among (r1) to (t1).

Preferably (a1) to (q1) or (r1) to (t1) are independently substituted by a substituent selected from among
═O, Me, MeSO 2 —, Me-piperazinyl-SO 2 —, morpholinyl, furanyl, Me 2 N—CH 2 —CH 2 —, F 2 CH—CH 2 —, —CN and F.
Preferred are the compounds of formula I, wherein the compounds are selected from the group consisting of examples 2, 3, 6, 16, 43, 155, 193, 249, 250, 254, 283, 284, 322, 323, 324, 325, 326, 328, 329, 330, 331, 333, 342, 343, 351, 352, 353, 354, 355, 356, 357, 358 and 359.
Particularly preferred are the compounds of formula I, wherein the compounds are selected from the group consisting of examples 322, 323, 324, 325 and 326.
Preferred are the above compounds of formula 1, in its enantiomerically pure form of formula 1′

wherein R 1 , R 2 , R 3 and R 4 have the above mentioned meaning.

Used Terms and Definitions

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C 1-6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
In general in single groups like HO, H 2 N, S(O), S(O) 2 , NC (cyano), HOOC, F 3 C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent “aryl-C 1-4 -alkyl-” means an aryl group which is bound to a C 1-4 -alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
Alternatively “*” indicates within a chemical entity the binding site, i.e. the point of attachment.
In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
Many of the followings terms may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
The term “substituted” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
The expressions “prevention”, “prophylaxis”, “prophylactic treatment” or “preventive treatment” used herein should be understood synonymous and in the sense that the risk to develop a condition mentioned hereinbefore is reduced, especially in a patient having elevated risk for said conditions or a corresponding anamnesis, e.g. elevated risk of developing metabolic disorder such as diabetes or obesity or another disorder mentioned herein. Thus the expression “prevention of a disease” as used herein means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders. Success of said preventive treatment is reflected statistically by reduced incidence of said condition within a patient population at risk for this condition in comparison to an equivalent patient population without preventive treatment.
The expression “treatment” or “therapy” means therapeutic treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve symptoms of the specific indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity thereof. Thus the expression “treatment of a disease” as used herein means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder. Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.
Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
As used herein the term “prodrug” refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (ii) a substance that gives rise to a pharmacologically active metabolite, although not itself active (i.e. an inactive precursor).
The terms “prodrug” or “prodrug derivative” mean a covalently-bonded derivative, carrier or precursor of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). Such prodrugs either have metabolically cleavable or otherwise convertible groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood or by activation via oxidation as in case of thioether groups. Most common prodrugs include esters and amide analogs of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: “Design and Applications of Prodrugs”; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their entireties.
The term “pharmaceutically acceptable prodrug” as used herein means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine(2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine(2, 2′,2″-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2, 5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts,) also comprise a part of the invention.
The term halogen generally denotes fluorine, chlorine, bromine and iodine.
The term “C 1-11 -alkyl”, wherein n is an integer selected from 2, 3, 4, 5 or 6, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C 1-5 -alkyl embraces the radicals H 3 C—, H 3 C—CH 2 —, H 3 C—CH 2 —CH 2 —, H 3 C—CH(CH 3 )—, H 3 C—CH 2 —CH 2 —CH 2 —, H 3 C—CH 2 —CH(CH 3 )—, H 3 C—CH(CH 3 )—CH 2 —, H 3 C—C(CH 3 ) 2 —, H 3 C—CH 2 —CH 2 —CH 2 —CH 2 —, H 3 C—CH 2 —CH 2 —CH(CH 3 )—, H 3 C—CH 2 —CH(CH 3 )—CH 2 —, H 3 C—CH(CH 3 )—CH 2 —CH 2 —, H 3 C—CH 2 —C(CH 3 ) 2 —, H 3 C—C(CH 3 ) 2 —CH 2 —, H 3 C—CH(CH 3 )—CH(CH 3 )— and H 3 C—CH 2 —CH(CH 2 CH 3 )—.
The term “C 1-n -alkylene” wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term C 1-4 -alkylene includes —CH 2 —, —CH 2 —CH 2 —, —CH(CH 3 )—, —CH 2 —CH 2 —CH 2 —, —C(CH 3 ) 2 —, —CH(CH 2 CH 3 )—, —CH(CH 3 )—CH 2 —, —CH 2 —CH(CH 3 )—, —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH(CH 3 )—, —CH(CH 3 )—CH 2 —CH 2 —, —CH 2 —CH(CH 3 )—CH 2 —, —CH 2 —C(CH 3 ) 2 —, —C(CH 3 ) 2 —CH 2 —, —CH(CH 3 )—CH(CH 3 )—, —CH 2 —CH(CH 2 CH 3 )—, —CH(CH 2 CH 3 )—CH 2 —, —CH(CH 2 CH 2 CH 3 )—, —CH(CH(CH 3 )) 2 — and —C(CH 3 )(CH 2 CH 3 )—.
The term “C 3-n -cycloalkyl”, wherein n is an integer selected from 4, 5, 6, 7 or 8, preferably 4, 5 or 6, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to 8 C atoms. For example the term C 3-8 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
By the term “halo” added to a “alkyl”, “alkylene” or “cycloalkyl” group (saturated or unsaturated) is such a alkyl or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H 2 FC—, HF 2 C—, F 3 C—.
The term “aryl” as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second five- or six-membered, carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
The term “C 5-10 -heterocyclyl” means a saturated or unsaturated mono- or polycyclic-ring systems including aromatic ring system containing one or more heteroatoms independently selected from N, O or S(O) r , wherein r=0, 1 or 2, consisting of 5 to 10 ring atoms wherein none of the heteroatoms is part of the aromatic ring. The term “heterocyclyl” is intended to include all the possible isomeric forms. Thus, the term “heterocyclyl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent (single or double) bond to any atom so long as appropriate valences are maintained:
















The term “C 5-10 -heteroaryl” means a mono- or polycyclic-ring systems containing one or more heteroatoms independently selected from N, O or S(O) r , wherein r=0, 1 or 2, consisting of 5 to 10 ring atoms wherein at least one of the heteroatoms is part of aromatic ring. The term “heteroaryl” is intended to include all the possible isomeric forms. Thus, the term “heteroaryl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
















Preparation
General Synthetic Methods
The invention also provides processes for making a compound of Formula I. In all methods, unless specified otherwise, R 1 , R 2 and n in the formulas below shall have the meaning of R 1 , R 2 and n in Formula I of the invention described herein above.
Optimal reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC) or LC-MS, if desired, and intermediates and products may be purified by chromatography on silica gel, HPLC and/or by recrystallization. The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds without undue experimentation. Starting materials and intermediates used, in the methods below, are either commercially available or easily prepared from commercially available materials by those skilled in the art.
A compound of Formula V, VII and IX may be made by the method outlined in Scheme 1:









As illustrated in Scheme 1, a compound of Formula II, wherein PG represents a protecting group (e.g. tert-butoxycarbonyl), may be reacted with an aqueous ammonia solution, using standard literature procedures for the formation of an amide. For example, in the presence of a base such as N-methyl-morpholine or N-ethyl-morpholine and an activating agent such as O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) or O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU). The reaction is conveniently carried out in a suitable solvent such as N, N-dimethylformamide. Standard peptide coupling reactions known in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) may be employed in these syntheses.
Dehydration of an amide such as in a compound of Formula III or Formula IX to the corresponding nitrile of Formula IV or VII may be carried out by use of a dehydration agent such as (methoxycarbonylsulfamoyl)triethyl ammonium hydroxide, in a suitable solvent such as dichloromethane (DCM).
Reacting an acid of Formula VI using standard literature procedures for the formation of an amide, for example in the presence of a base such as N, N-diisopropylethylamine (DIPEA) and an activating agent such as HATU or TBTU, with an amine of Formula V or VIII in a suitable solvent, provides a compound of Formula VII or IX. Standard peptide coupling reactions known in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) may be employed in these syntheses.
The protection and deprotection of functional groups is described in ‘Protective Groups in Organic Synthesis’, T. W. Greene and P. G. M. Wuts, Wiley-Interscience. For example, for the deprotection of tert-butoxycarbonyl, an acid such as formic acid, trifluoroacetic acid, p-toluenesulfonic acid or HCl may be used in a suitable solvent such as water, DCM or dioxane. Another method to deprotect tert-butoxycarbonyl is the reaction with trimethyliodosilane or trimethylchlorosilane in combination with sodium iodide in an appropriate solvent like acetonitrile, DMF or DCM.









During the reaction sequences depicted in Scheme 1 and Scheme 2 a hydroxy group (X=OH) can be converted to a trifluoromethanesulfonyl group (X=OTf) at any level. Especially, a compound IX with X=OH is transformed to the appropriate triflate (X=OTf) by reaction with N,N-bis-(trifluoromethanesulfonyl) aniline, or trifluoromethanesulfonyl chloride or anhydride, in the presence of an organic base e.g. triethylamine, morpholine, piperidine, DIPEA in an appropriate anhydrous solvent, e.g. DCM.
As illustrated in Scheme 2, (transition) metal catalyzed reaction of a compound of Formula VII or IX wherein X is I, Br, Cl or OTf, provides a compound of Formula X or XI. For example, reaction with a boronic acid or the corresponding boronic acid ester, in a suitable solvent such as acetonitrile, in the presence of a suitable catalyst such as 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and a suitable base such as K 2 CO 3 provides a compound of Formula X or XI. Alternatively, reaction of a compound of Formula VII or IX, wherein X is I, Br, Cl or OTf with a tributyl(vinyl)tin reagent in the presence of a suitable catalyst such as bis-(triphenylphosphin)-palladiumchloride, in a suitable solvent such as dimethylformamide (DMF) and if desirable in the presence of an additive such as tetraethylammonium chloride provides compounds of Formula X or XI. Further, reaction of a compound of Formula VII or IX, wherein X is I or Br, may be reacted with an amine in the presence of a suitable catalyst such as Cu(I)I and a suitable base such as caesium carbonate and a suitable promotor such as L-proline provides a compound of Formula X or XI.
In an inversed fashion compounds of formula VII or IX (X: I, Br, Cl, OTf) can be converted into the corresponding boronic acid derivatives VIIa or IXa, wherein R can be H or lower alkyl independently and the residues R can form a ring. For example, VII or IX can be reacted with bis-pinacolato-diboron in the presence of a suitable catalyst such as 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and a suitable base such as potassium acetate or sodium, potassium or cesium carbonate or phosphate, in a suitable solvent such as dioxan, dimethylformamide (DMF), or dichloromethane (DCM) to yield the boronic esters VIIa or IXa, respectively. These can be reacted with appropriate aromatic halides in analogy as above to yield the desired coupling products of formula X or XI.
Further, as illustrated in Scheme 2, reaction of a compound of Formula VII or IX, wherein X is N 3 with an alkyne in the presence of a suitable catalyst such as copper(II)sulfate pentahydrate and a suitable reducing agent such as L-ascorbic acid in a suitable solvent such as dimethyl sulfoxide (DMSO)/water provides a compound of Formula X or XI.
Further modifications of compounds of Formula X, XI and I by methods known in the art and illustrated in the Examples below, may be used to prepare additional compounds of the invention.
Dehydration of an amide of Formula XI to the corresponding nitrile of Formula X may be carried out by use of a dehydration agent such as (methoxycarbonylsulfamoyl)triethyl ammonium hydroxide, in a suitable solvent such as DCM.









As illustrated in Scheme 3, (transition) metal catalyzed reaction of a compound of Formula IV wherein X is I, Br, Cl or OTf, provides a compound of Formula XII. For example, reaction with a boronic acid or the corresponding boronic acid ester, in a suitable solvent such as acetonitrile, in the presence of a suitable catalyst such as 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and a suitable base such as K 2 CO 3 provides a compound of Formula XII.
An acid of Formula VI using standard literature procedures for the formation of an amide, for example in the presence of a base such as DIPEA and an activating agent such as HATU or TBTU, can be reacted with an amine of Formula XII in a suitable solvent. Standard peptide coupling reactions known in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) may be employed in these syntheses. Deprotection of functional groups is described in ‘Protective Groups in Organic Synthesis’, T. W. Greene and P. G. M. Wuts, Wiley-Interscience. For example, for the deprotection of tert-butoxycarbonyl, an acid such as formic acid, p-toluenesulfonic acid, trifluoroacetic acid or HCl may be used in a suitable solvent such as water, DCM or dioxane and can be performed on the crude amide coupling product to provide a compound of Formula I. Another method to deprotect tert-butoxycarbonyl is the reaction with trimethyliodosilane or trimethylchlorosilane in combination with sodium iodide in an appropriate solvent like acetonitrile, DMF or DCM.









As illustrated in Scheme 4, amino nitrile derivatives of Formula XIII can be converted to substituted amino nitriles of Formula V via alkylation to compounds of Formula XIV, followed by deprotection of the amino group. During the alkylation step a suitable base is used in an appropriate solvent, using a benzylation agent XV with an appropriate leaving group like Cl, Br, or sulfonates. Especially useful is the use of sodium hydroxide as base in water and DCM under phase transfer conditions using benzyltrimethylammonium chloride as described for example by Naidu et al, W02011/46873. The protective group is removed under acidic conditions, e.g. aq. HCl in dioxan. The amino nitrile V is further processed as depicted in Scheme 1.









As illustrated in Scheme 5, nitro compounds of formula XV can be reduced to anilines of formula XVI by catalytic hydrogenation under conditions, where the nitrile group is still stable. Better suited are reagents like sodium dithionite, SnCl 2 or iron in a suitable solvent like water, methanol, ethanol, acetonitrile or ethyl acetate.
Reacting of 2-halo-benzoic acid, especially 2-iodo-benzoic acid using standard literature procedures for the formation of an amide, for example in the presence of a base such as N, N-diisopropylethylamine (DIPEA) and an activating agent such as HATU or TBTU, with an amine of Formula XVI in a suitable solvent, provides a compound of Formula XVII. Standard peptide coupling reactions known in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) may be employed in these syntheses.
The benzoic amide group as in Formula XVII can be protected by an acid labile group, especially by alkoxymethyl or silylalkoxymethyl groups as mentioned for example in ‘Protective Groups in Organic Synthesis’, T. W. Greene and P. G. M. Wuts, Wiley-Interscience. Especially useful is the use of 2-trimethylsilylethoxymethylchloride as alkylating agent after having removed the amide proton by a strong base such as NaH in an inert solvent like DMF, THF or dioxan. The products are compounds of the formula XVIII.
Cyclisation of compounds like formula XVIII can be performed with the aid of a palladium catalyst like Pd(PPh 3 ) 4 (tetrakis(triphenylphosphine)palladium(0) and a base like potassium acetate or sodium, potassium or cesium carbonate or phosphate, especially sodium carbonate in a suitable solvent, e.g. DMF, preferrably under elevated temperature. This results in the formation of compound of the formula XIXa and XIXb, which can be separated or processed further as a mixture.
Compounds like XIXa or XIXb or a mixture thereof can be deprotected in acidic medium. Deprotection of functional groups is described in ‘Protective Groups in Organic Synthesis’, T. W. Greene and P. G. M. Wuts, Wiley-Interscience. For example, an acid such as formic acid, p-toluenesulfonic acid, trifluoroacetic acid or HCl may be used in a suitable solvent such as water, DCM or dioxane and can be performed on the crude amide coupling product to provide a compound of Formula XXa and XXb. Another method to deprotect first the tert-butoxycarbonyl is the reaction with trimethyliodosilane or trimethylchlorosilane in combination with sodium iodide in an appropriate solvent like acetonitrile, DMF or DCM. After that the trimethylsilylmethoxymethyl group can be removed in acidic medium as mentioned above, especially with formic acid again leading to compounds of the formula XXa and XXb.
SYNTHETIC EXAMPLES
The following are representative compounds of the invention which can be made by the general synthetic schemes, the examples, and known methods in the art. Starting materials and intermediates were either commercially available and purchased from catalogues of AATPHARM, ABCR, ACROS, ACTIVATE, ALDRICH, ALFA, ALLICHEM, ANICHEM, ANISYN, ANISYN Inc., APAC, APOLLO, APOLLO-INTER, ARKPHARM, ARKPHARMINC, ASIBA PHARMATECH, ATOMOLE, BACHEM, BEPHARM, BIOFOCUS, BIOGENE, BORON-MOL, BOROPHARM, CHEMBRIDGE, CHEMCOLLECT, CHEMFUTURE, CHEMGENX, CHEMIMPEX, CHESS, COMBI-BLOCKS, COMBI-PHOS, DLCHIRAL, EGA, E-MERCK, EMKA-CHEMIE, ENAMINE, EPSILON, FLROCHEM, FLUKA, FOCUS, FRONTIER, ISOCHEM, JW PHARMLAB, KINGSTONCHEM, LANCASTER, MANCHESTER, MANCHESTER ORGANICS, MAYBRIDGE, MAYBR-INT, MERCACHEM, MERCK, MILESTONE, MOLBRIDGE, NETCHEM, OAKWOOD, PHARMABRIDGE, PLATTE, RIEDEL DE HAEN, SMALL-MOL, SPECS, SPECTRA GROUP LIMITED, INC, SYNCHEM OHG, SYNCHEM-INC, SYNCOM, TCI, VIJAYA PHARMA, WAKO, WUXIAPPTEC or were synthesized according to literature or as described below in “Synthesis of starting materials/educts”
“Liquid chromatography-mass spectroscopy” (LCMS) retention time and observed m/z data for the compounds below are obtained by one of the following methods:
LC-MS Method 001_CA07
Device-Description Waters Acquity with DAD and MSD Column Waters Sunfire C18 Column Dimension 2.1 × 50 mm Particle Size 2.5 μm % Sol % Sol [Acetonitrile Gradient/Solvent [H 2 O 0.1% 0.08% Flow Temp Time [min] TFA] TFA] [ml/min] [° C.] 0.0 95.0 5.0 1.5 60.0 0.75 0.0 100.0 1.5 60.0 0.85 0.0 100.0 1.5 60.0
LC-MS Method 002_CA03

Device-Description Agilent 1100 with DAD and MSD Column Waters Sunfire C18 Column Dimension 3.0 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H 2 O 0.1% TFA] [Acetonitrile [ml/min] [° C.] 0.0 99.0 1.0 2.0 60.0 0.9 0.0 100.0 2.0 60.0 1.1 0.0 100.0 2.0 60.0
LC-MS Method 002_CA07

Device-Description Waters Acquity with 3100 MS Column Waters XBridge BEH C18 Column Dimension 3.0 × 30 mm Particle Size 1.7 μm Gradient/ Solvent % Sol % Sol Flow Temp Time [min] [H 2 O 0.1% NH4OH] [Acetonitrile [ml/min] [° C.] 0.0 95.0 5.0 1.5 60.0 0.7 0.1 99.9 1.5 60.0 0.8 0.1 99.9 1.5 60.0 0.81 95.0 5.0 1.5 60.0 1.1 95.0 5.0 1.5 60.0
LC-MS Method 003_CA04

Device-Description Agilent 1100 with DAD and MSD Column Waters XBridge C18 Column Dimension 3.0 × 30 mm Particle Size 2.5 μm Gradient/ Solvent % Sol % Sol Flow Temp Time [min] [H 2 O 0.1% NH4OH] [Acetonitrile [ml/min] [° C.] 0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0
LC-MS Method 004_CA01

Agilent 1100 with DAD, Waters Autosampler and Device-Description MSD Column Waters Sunfire C18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μm Gradient/Solvent % Sol [H 2 O 0.1% % Sol Flow Temp Time [min] TFA] [Acetonitrile] [ml/min] [° C.] 0.0 98.0 2.0 2.5 60.0 1.5 0.0 100.0 2.5 60.0 1.8 0.0 100.0 2.5 60.0
LC-MS Method 004_CA05

Waters Acquity with DAD and MSD, CTC Device-Description Autosampler Column Waters XBridge C18 Column Dimension 3.0 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol [H 2 O 0.1% % Sol Flow Temp Time [min] NH 4 OH] [Acetonitrile] [ml/min] [° C.] 0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0
LC-MS Method 004_CA07

Device-Description Waters Acquity with with 3100 MS Column YMC Triart C18 Column Dimension 2.0 × 30 mm Particle Size 1.9 μm Gradient/ Solvent % Sol % Sol Flow Temp Time [min] [H 2 O 0.1% NH4OH] [Acetonitrile [ml/min] [° C.] 0.0 95.0 5.0 1.5 60.0 0.75 0.1 99.9 1.5 60.0 0.8 0.1 99.9 1.5 60.0 0.81 95.0 5.0 1.5 60.0 1.1 95.0 5.0 1.5 60.0
LC-MS Method 005_CA01

Agilent 1100 with DAD, Waters Autosampler and MS- Device-Description Detector Column Waters Sunfire C18 Column Dimension 3.0 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol [H 2 O % Sol Flow Time [min] 0.1% TFA] [Acetonitrile [ml/min] Temp [° C.] 0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0
LC-MS Method V001_003

Device-Description Waters Alliance with DAD and MSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA] [Methanol] [ml/min] [° C.] 0.0 95 5 4 60 0.20 95 5 4 60 1.5 0 100 4 60 1.75 0 100 4 60
LC-MS Method V001_007

Device-Description Waters Alliance with DAD and MSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA] [Methanol] [ml/min] [° C.] 0.0 95 5 4 60 1.6 0 100 4 60 1.85 0 100 4 60 1.9 95 5 4 60
LC-MS Method V003_003

Device-Description Waters Alliance with DAD and MSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H 2 O, 0.1% NH 3 ] [Methanol] [ml/min] [° C.] 0.0 95 5 4 60 0.2 95 5 4 60 1.5 0 100 4 60 1.75 0 100 4 60
LC-MS Method V011_S01

Device-Description Waters Alliance with DAD and MSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H 2 O, 0.1% NH 3 ] [Acetonitril] [ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60
LC-MS Method V012_S01

Device-Description Waters Alliance with DAD and MSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H 2 O, 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60
LC-MS Method V018_S01

Device-Description Waters Alliance with DAD and MSD Column Waters Sunfire C18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H 2 O, 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60
LC-MS Method W018_S01

Device-Description Waters 1525 with DAD and MSD Column Waters Sunfire C18 Column Dimension 4.6 × 30 mm Particle Size 2.5 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H 2 O, 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0 97 3 4 60 0.15 97 3 3 60 2.15 0 100 3 60 2.20 0 100 4.5 60 2.40 0 100 4.5 60
LC-MS Method X001_002

Device-Description Waters Acquity with DAD and MSD Column Waters XBridge BEH C18 Column Dimension 2.1 × 30 mm Particle Size 1.7 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H 2 O, 0.10% TFA] [Methanol] [ml/min] [° C.] 0.0 99 1 1.3 60 0.05 99 1 1.3 60 1.05 0 100 1.3 60 1.2 0 100 1.3 60
LC-MS Method X001_004

Device-Description Waters Acquity with DAD and MSD Column Waters XBridge C18 Column Dimension 2.1 × 20 mm Particle Size 2.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H 2 O, 0.10% TFA] [Methanol] [ml/min] [° C.] 0.0 95 5 1.4 60 0.05 95 5 1.4 60 1.00 0 100 1.4 60 1.1 0 100 1.4 60
LC-MS Method X002_002

Device-Description Waters Acquity with DAD and MSD Column Waters Sunfire C18 Column Dimension 2.1 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.10% TFA] [Methanol] [ml/min] [° C.] 0.00 99 1 1.2 60 0.15 99 1 1.2 60 1.10 0 100 1.2 60 1.25 0 100 1.2 60
LC-MS Method X011_S02

Device-Description Waters Acquity with DAD and MSD Column Waters XBridge BEH C18 Column Dimension 2.1 × 30 mm Particle Size 1.7 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H2O, 0.1% NH3] [Acetonitril] [ml/min] [° C.] 0.00 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60
LC-MS Method X011_S03

Device-Description Waters Acquity with DAD and MSD Column Waters XBridge BEH C18 Column Dimension 2.1 × 30 mm Particle Size 1.7 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H2O, 0.1% NH3] [Acetonitril] [ml/min] [° C.] 0.00 95 5 1.3 60 0.02 95 5 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60
LC-MS Method X012_S01

Device-Description Waters Acquity with DAD and MSD Column Waters XBridge BEH C18 Column Dimension 2.1 × 30 mm Particle Size 1.7 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H 2 O, 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0 99 1 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60
LC-MS Method X012 S02

Device-Description Waters Acquity with DAD and MSD Column Waters XBridge BEH C18 Column Dimension 2.1 × 30 mm Particle Size 1.7 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H2O, 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60
LC-MS Method X016_S01

Device-Description Waters Acquity with DAD and MSD Column Waters XBridge BEH Phenyl Column Dimension 2.1 × 30 mm Particle Size 1.7 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H 2 O, 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0 99 1 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60
LC-MS Method X018_S01

Device-Description Waters Acquity with DAD and MSD Column Waters Sunfire C18 Column Dimension 2.1 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H 2 O, 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0 99 1 1.5 60 0.02 99 1 1.5 60 1.00 0 100 1.5 60 1.10 0 100 1.5 60
LC-MS Method X018 S02

Device-Description Waters Acquity with DAD and MSD Column Waters Sunfire C18 Column Dimension 2.1 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H 2 O, 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60
LC-MS Method Z001_002

Device-Description Agilent 1200 with DAD and MSD Column Waters XBridge C18 Column Dimension 3 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H 2 O, 0.1% TFA] [Methanol] [ml/min] [° C.] 0.0 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.80 0 100 2.2 60
LC-MS Method Z011_S03

Device-Description Agilent 1200 with DAD and MSD Column Waters XBridge C18 Column Demension 3 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H 2 O, 0.1% NH3] [Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
LC-MS Method Z011_U03

Device-Description Agilent 1200 with DAD and MSD Column Waters XBridge C18 Column Dimension 3 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H 2 O, 0.1% NH3] [Acetonitril] [ml/min] [° C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
LC-MS Method Z012 S04

Device-Description Agilent 1200 with DAD and MSD Column Waters XBridge C18 Column Dimension 3 × 30 mm Particle Size 2.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H 2 O, 0.1% NH3] [Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
LC-MS Method Z018 S04

Device-Description Agilent 1200 with DAD and MSD Column Waters Sunfire C18 Column Dimension 3 × 30 mm Particle Size 2.5 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H 2 O, 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
LC-MS Method Z020_S01

Device-Description Agilent 1200 with DAD and MSD Column Waters Sunfire C18 Column Dimension 3 × 30 mm Particle Size 2.5 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H 2 O, 0.1% FA] [Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
LC-MS Method V001_007

Device-Description Waters Alliance with DA- and MS-Detector Column XBridge C18 Column Dimension 4.6 × 30 mm Particle Size 3.5 μm Solvent Gradient % Sol % Sol Flow Temp time[min] [H 2 O, 0.1% FA] [Methanol] [ml/min] [° C.] 0.0 95 5 4.0 60 1.6 0 100 4.0 60 1.85 0 100 4.0 60 1.9 95 5 4.0 60
LC-MS Method I_ADH_15_MEOH_DEA.M

Device-Description Agilent 1260 SFC with DAD Column Daicel Chiralpak AD-H Column Dimension 4.6 × 250 mm Particle Size 5 μm Solvent % Sol Gradient [Methanol, time % Sol 0.2% Flow Temp Backpressure [min] [scCO 2 ] Diethylamine] [ml/min] [° C.] [bar] 0.00 85 15 4 40 150 10.00 85 15 4 40 150
LC-MS Method I_OJH_10_IPROP_DEA.M

Device-Description Agilent 1260 SFC with DAD Column Daicel Chiralcel OJ-H Column Dimension 4.6 × 250 mm Particle Size 5 μm Solvent % Sol Gradient [Isopropanal, time % Sol 0.2% Flow Temp Backpressure [min] [scCO 2 ] Diethylamine] [ml/min] [° C.] [bar] 0.00 90 10 4 40 150 10.00 90 10 4 40 150
LC-MS Method I_IC_20_MEOH_NH3.M

Device-Description Agilent 1260 SFC with DAD and MSD Column Daicel Chiralpak IC Column Dimension 4.6 × 250 mm Particle Size 5 μm Solvent Gradient % Sol time % Sol [20 mM NH3 in Flow Temp Backpressure [min] [scCO 2 ] Methanol] [ml/min] [° C.] [bar] 0.00 80 20 4 40 150 10.00 80 20 4 40 150
LC-MS Method I_ADH_40_MEOH_DEA.M

Device-Description Agilent 1260 SFC with DAD Column Daicel Chiralpak AD-H Column Dimension 4.6 × 250 mm Particle Size 5 μm Solvent % Sol Gradient [Methanol, time % Sol 0.2% Flow Temp Backpressure [min] [scCO 2 ] Diethylamine] [ml/min] [° C.] [bar] 0.00 60 40 4 40 150 10.00 60 40 4 40 150
LC-MS Method I_ASH_30_10 MIN_SS4P.M

Device-Description Berger SFC Analytix with DAD Column Daicel Chiralpak AS-H Column Dimension 4.6 × 250 mm Particle Size 5 μm Solvent Gradient % Sol time % Sol [Ethanol, 0.2% Flow Temp Backpressure [min] [scCO 2 ] Diethylamine] [ml/min] [° C.] [bar] 0.00 70 30 4 40 120 10.00 70 30 4 40 120
LC-MS Method I_OJH_10_MEOH_DEA.M








Device-Description Agilent 1260 SFC with DAD

Column Daicel Chiralcel OJ-H

Column Dimension 4.6 × 250 mm

Particle Size 5 μm








Solvent

% Sol




Gradient

[Methanol,

time
% Sol
0.2%
Flow
Temp
Backpressure

[min]
[scCO 2 ]
Diethylamine]
[ml/min]
[° C.]
[bar]










0.00
90
10
4
40
150

10.00
90
10
4
40
150




























Mixture of stereoisomers can be separated on preparative scale by one of the following chiral SFC methods. 2× describes two columns switched in a row.
Methode: Chiral SFC A


Column: 2× Daicel Chiralpak AD-H 5 μm 20×250 mm
Eluent: 85% scCO 2 , 15% Methanol 0.2% Diethylamine
Flow: 55 mL/min
Temperature: 40° C.
Backpressure: 120 bar
Wavelength: 254 nm
Concentration: 52 mg/ml in Methanol
Injection volume: 300 μl
Device-Description: Thar MultiGram II

Methode: Chiral SFC B

Column: 2× Chiralcel OJ-H 5 μm, 20×250 mm
Eluent: 90% scCO 2 , 10% Isopropanol 0.2% Diethylamine
Flow: 60 mL/min
Temperature: 40° C.
Backpressure: 150 bar
Wavelength: 254 nm
Concentration: 50 mg/ml in Methanol
Injection volume: 200 μl
Device-Description: Janco Rockclaw 150

Methode: Chiral SFC C

Column: 2× Daicel Chiralpak AD-H 5 nm, 10×250 mm
Eluent: 85% scCO 2 , 15% Methanol 0.2% Diethylamine
Flow: 10 mL/min
Temperature: 40° C.
Backpressure: 120 bar
Wavelength: 254 nm
Concentration: 15 mg/ml in Methanol
Injection volume: 100 μl
Device-Description: Thar MiniGram

Methode: Chiral SFC D

Column: 1× Daicel Chiralpak AD-H, 5 μm, 20×250 mm
Eluent: 60% scCO 2 , 40% Methanol 0.2% Diethylamine
Flow: 60 mL/min
Temperature: 40° C.
Backpressure: 120 bar
Wavelength: 254 nm
Concentration: 50 mg/ml in Methanol
Injection volume: 400 μl
Device-Description: Thar MultiGram II

Methode: Chiral SFC E

Column: 2× Daicel Chiralpak AS-H 5 μm, 20×250 mm
Eluent: 70% CO 2 , 30% Ethanol 0.2% Diethylamine
Flow: 55 mL/min
Temperature: 40° C.
Backpressure: 120 bar
Wavelength: 254 nm
Concentration: 100 mg/ml in Methanol
Injection volume: 200 μl
Device-Description: Thar MultiGram II

Methode: Chiral SFC F

Column: Daicel Chiralpak IC 5 nm, 20×250 mm
Eluent: 85% scCO 2 , 15% Ethanol
Flow: 60 mL/min
Temperature: 40° C.
Backpressure: 150 bar
Wavelength: 254 nm
Concentration: 35 mg/ml in Methanol
Injection volume: 500 μl
Device-Description: Sepiatec Prep SFC 100

Methode: Chiral SFC G

Column: Chiralpak AY-10 μm, 50×300 mm
Eluent: A for CO 2 , and B for ethanol: n-heptane=1:1
Gradient: B 10%
Flow: 170 mL/min
Temperature: 38° C.
Backpressure: 100 bar
Wavelength: 220 nm
Concentration: 300 mg/ml in ethanol
Injection volume: 4 mL per injection
Cycle time: 3.5 min
Device-Description: Thar 200 preparative SFC

Synthesis Methods

Method A



Synthesis of (1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(2-methylisoindolin-5-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 1)

Step 1: Synthesis of Intermediate I-1.1

R1 (20.0 g, 55 mmol) is suspended in DCM (400 mL) and a solution of R2 (26.4 g, 111 mmol) dissolved in DCM is added. The reaction mixture is stirred for 12 h under argon atmosphere. The reaction mixture is washed with water. The organic layer is dried over MgSO 4 , filtrated and concentrated. The residue is dissolved in DCM, filtrated by flash chromatography (using solvent mixture cyclohexane/ethyl acetate=70/30) and concentrated to give I-1.1. Yield 97% m/z 287/343 [M+H]+, rt 1.29 min, LC-MS Method X012_S01.
The following intermediate as shown in Table 2 is synthesized in a similar fashion from the appropriate intermediates:
TABLE 2 Intermediate Educt Structure m/z [M + H]+ rt (min) LC-MS method I-1.1.1 R1.1 391 1.29 V012_S01
Step 2: Synthesis of Intermediate I-1.2

To I-1.1 (5.80 g, 17 mmol) in anhydrous dioxane (60 mL) R3 (5.20 g, 20 mmol) and potassium acetate (4.98 g, 51 mmol) are added. The mixture is purged with argon, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl 2 (dppf)) (1.38 g, 1.7 mmol) is added to the mixture and heated to 80° C. for 2 h. DCM is added and the mixture is filtrated. The filtrate is diluted with water and extracted with DCM. The organic layer is dried over MgSO 4 , filtrated and concentrated. The residue is purified by flash chromatography (cyclohexane/ethyl acetate=8/2) and concentrated. Yield 97% m/z 291/335/391 [M+H]+, rt 1.36 min, LC-MS Method V012_S01.
Step 3: Synthesis of Intermediate I-1.3
I-1.2 (1.22 g, 5 mmol) and R4 (2.30 g, 5.9 mmol) are dissolved in acetonitrile (25 mL). Na 2 CO 3 -solution (2 mol/L, 4.9 mL) and 1,1′-Bis(di-tert-butylphosphino)ferrocene-palladium dichloride (319 mg, 0.49 mmol) are added. The reaction mixture is stirred at 80° C. for 1 h. The crude mixture is extracted with ethyl acetate, washed with half saturated brine. The organic layer is dried over MgSO 4 , filtrated and concentrated and the residue is purified by reversed phase HPLC. Yield 59%, m/z=396 [M+H]+, rt 0.96 min, LC-MS Method V012_S01.
The following intermediates as shown in Table 3 are synthesized in a similar fashion from the appropriate intermediates:
TABLE 3 m/z LC-MS Intermediate Educt Structure of Intermediate [M + H]+ rt (min) method I-1.3.1 I-1.1.1, direct coupling with boronic ester R7.3 444 1.21 V-018_S01 I-1.3.2 I-1.2 446 1.18 V012_S01 I-1.3.3 I-1.1, direct coupling with boronic ester R7.1 444 1.14 V011_S01
Step 4: Synthesis of Intermediate I-1.4

I-1.3 (1.15 g, 2.91 mmol) is dissolved in acetonitrile. 1.39 g p-toluenesulfonic acid monohydrate is added and stirred for 48 h. The precipitate is filtered off, dissolved in ethyl acetate and washed with saturated NaHCO 3 -solution. The organic layer is dried over MgSO 4 , filtrated and concentrated. Yield 78%. m/z 296 [M+H]+, rt 1.03 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 4 are synthesized in a similar fashion from the appropriate intermediates:
TABLE 4 m/z LC-MS Intermediate Educt Structure of Intermediate [M + H]+ rt (min) method I-1.4.1 I-1.3.1 344 0.76 V018_S01 I-1.4.2 I-1.3.2 346 0.96 V011_S01 I-1.4.3 I-1.3.3 344 0.77 V018_S01
Step 5: Synthesis of Intermediate I-1.5

To R5 (purchased from Aldrich or synthesized in analogy to Tararov et al, Tetrahedron Asymmetry 13 (2002), 25-28) (98 mg, 0.4 mmol) in DMF (1.5 mL) diisopropylethylamine (0.18 mL, 1.0 mmol) and HATU (154 mg, 0.4 mmol) are added and the reaction mixture is stirred for 15 min. Then intermediate I-1.4 (100 mg, 0.3 mmol) is added and the mixture is stirred for 12 h. DCM is added and the mixture is washed with saturated Na2CO3 solution. The organic layer is dried over MgSO 4 , filtrated, and the residue is concentrated. Then the residue is purified by reversed phase HPLC. Yield 68%, m/z 419/463/518 [M+H]+, rt 1.29 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 5 are synthesized in a similar fashion from the appropriate intermediates:
TABLE 5 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M + H]+ (min) method I-1.5.1 I-1.4.1 567 1.24 V018_S01 I-1.5.2 I-1.4.2 569 1.24 V011_S01 I-1.5.3 I-1.4.3 567 1.14 V011_S01
Step 6 : Synthesis of Example 1

To I-1.5 (120 mg, 0.23 mmol) in acetonitrile, p-toluenesulfonic acid monohydrate (110 mg, 0.58 mmol) is added and stirred for 3 d. The reaction solution is purified by reversed phase HPLC. Yield 47%, m/z 419 [M+H]+, rt 1.16 min, LC-MS Method V011_S01.
Method A1
Synthesis of (1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-methyl-2-oxo-indolin-6-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 2)

Step 1: Synthesis of Intermediate I-2.1

To R5 (7.59 g, 31 mmol) in DCM (300 mL) diisopropylethylamine (4.8 mL, 28 mmol) and HATU (11.5 g, 30 mmol) are added and stirred for 25 min. Then R6 (10.4 g, 28 mmol) and diisopropylethylamine (7.2 mL, 42 mmol) are added and stirred for 3 h. The solvent is evaporated, dissolved in ethyl acetate and washed with water, 0.5 M HCl and aq. NaHCO3 solution (10%). The organic layer is dried over MgSO 4 , filtrated and concentrated. The residue is purified by flash chromatography (using solvent mixture DCM/methanol=95/5). Yield >95%, m/z 484 [M+H]+, rt 1.18 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 6 are synthesized in a similar fashion from the appropriate intermediate:
TABLE 6 m/z rt LC-MS Intermediate Structure [M + H]+ (min) method I-2.1.1 496 0.95 Z018_S04 I-2.1.2 484/486 0.71 X018_S02 I-2.1.3 440 0.55 Z011_S03
Step 2: Synthesis of Intermediate I-2.2

To I-2.1 (12.7 g, 26 mmol) in DCM (130 mL) R2 (12.5 g, 52 mmol) is added. The reaction mixture is stirred for 12 h. The solvent is evaporated, dissolved in ethyl acetate and washed with water, 0.1 M HCl and aq. NaHCO3 solution (5%). The organic layer is dried over MgSO 4 and concentrated. The residue is recrystallized from DCM and acetonitrile. Yield 64% m/z 466 [M+H]+, rt 1.30 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 7 are synthesized in a similar fashion from the appropriate intermediate:
TABLE 7 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M + H]+ (min) method I-2.2.1 I-2.1.1 478 1.03 Z018_S04 I-2.2.3 I-2.1.2 466/468 1.27 V011_S01
Synthesis of Intermediate I-2.2.2

Synthesis of tert-butyl(1S,2S,4R)-2-[[(1S)-2-amino-1-[[2,3-difluoro-4-trifluoromethylsulfonyl oxy)phenyl]methyl]-2-oxo-ethyl]carbamoyl]-3-azabicyclo[2.2.1]heptane-3-carboxylate









The phenol I-2.1.3 is transformed into the corresponding trifluoromethanesulfonate I-2.2.2:I.2.1.3 (200 mg, 0.46 mmol) is dissolved in anhydrous DCM (1.5 mL). Triethylamine (95 μL, 0.69 mmol) is added and the reaction mixture is cooled to 0° C. R18 (179 mg, 0.50 mmol) is then added and the mixture was stirred at 0° C. for 90 minutes and additional 12 h at room temperature. The mixture is concentrated and the residue is purified by reversed phase HPLC. Yield 85%, m/z 472 [M+H-BOC]+, rt 0.97 min, LC-MS Method Z011_S03.
Step 3: Synthesis of Intermediate I-2.3
To I-2.2 (5.00 g, 10 mmol) in acetonitrile (100 mL) R7 (3.07 g, 11 mmol) is added. The mixture is purged with argon, 1,1-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.70 g, 1.1 mmol) and aq. sodium carbonate solution (2 mol/L, 1.07 mL) are added and the mixture is heated to 70° C. for 3.5 h. Ethyl acetate and water are added to the reaction mixture. The organic layer is washed with aq. NaHCO3 solution (5%) and water. The organic layer is dried over MgSO 4 and concentrated. The residue is purified by flash chromatography (cyclohexane/ethyl acetate=1/1). Yield 41% m/z 533 [M+H]+, rt 1.25 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 8 are synthesized in a similar fashion from the appropriate intermediates ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):










TABLE 8






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-2.3.1
I-2.2









560
0.76
X018_S01



I-2.3.2
I-2.2









528
0.88
004_CA01



I-2.3.3
I-2.2









470
0.90
004_CA05



I-2.3.4
I-2.2









510
0.87
004_CA05



I-2.3.5
I-2.2









482
0.77
004_CA05



I-2.3.6
I-2.2









468
0.92
004_CA05



I-2.3.7
I-2.2









454
0.82
Z011_S03



I-2.3.8
I-2.2









496
0.82
004_CA05



I-2.3.9
I-2.2









538
1.00
004_CA05



I-2.3.10
I-2.2









470
0.91
004_CA05



I-2.3.11
I-2.2









539
0.66
004_CA05



I-2.3.12
I-2.2









482
0.75
004_CA05



I-2.3.13
I-2.2.1









407
1.03
Z018_S04



I-2.3.14
I-2.2









499
0.86
004_CA05



I-2.3.15
I-2.2









438 [M + H − BOC]+
0.94
X018_S04



I-2.3.16
I-2.2









552
0.77
004_CA05



I-2.3.17
I-2.2









556
0.91
X018_S04



I-2.3.18
I-2.2









518
0.89
004_CA05



I-2.3.19
I-2.2









482
0.77
004_CA05



I-2.3.20
I-2.2









510
0.86
004_CA05



I-2.3.21
I-2.2









482
0.75
004_CA01



I-2.3.22
I-2.2









496
0.82
004_CA01



I-2.3.23
I-2.2









554
0.68
004_CA05



I-2.3.24
I-2.2.1









530
1.02
Z018_S04



I-2.3.25
I-2.2









512
0.83
004_CA01



I-2.3.26
I-2.2









354
1.02
Z018_S04



I-2.3.27
I-2.2









530
0.91
004_CA01



I-2.3.28
I-2.2









499
0.82
004_CA05



I-2.3.29
I-2.2









395 [M + H − BOC]+
1.02
Z018_S04



I-2.3.30
I-2.2









560
0.76
X018_S01



I-2.3.31
I-2.2









468
0.9
004_CA01



I-2.3.32
I-2.2.1









397
0.97
Z018_S04



I-2.3.33
I-2.2









431
1.07
Z018_S04



I-2.3.34
I-2.2









512
0.75
004_CA01



I-2.3.35
I-2.2









536
0.89
004_CA05



I-2.3.36
I-2.2









454
0.85
004_CA01



I-2.3.37
I-2.2









468
0.69
004_CA01



I-2.3.38
I-2.2









482
0.78
004_CA01



I-2.3.39
I-2.2.1









411
1.01
Z018_S04



I-2.3.40
I-2.2









354
0.87
Z018_S04



I-2.3.41
I-2.2









514
0.44
004_CA05



I-2.3.42
I-2.2









538
0.76
004_CA01



I-2.3.43
I-2.2









483
0.93
V012_S01



I-2.3.44
I-2.2









536
0.85
004_CA05



I-2.3.45
I-2.2









483
0.81
004_CA05



I-2.3.46
I-2.2









482
0.77
004_CA05



I-2.3.47
I-2.2.1









547
0.83
004_CA05



I-2.3.48
I-2.2.1









519
0.71
004_CA05



I-2.3.49
I-2.2.1









533
0.77
004_CA05



I-2.3.50
I-2.2.1









519
0.89
004_CA05



I-2.3.51
I-2.2.1









540
0.9
004_CA05



I-2.3.52
I-2.2.1









531
0.74
004_CA05



I-2.3.53
I-2.2.1









530
0.81
004_CA05



I-2.3.54
I-2.2.1









555
0.72
004_CA05



I-2.3.55
I-2.2.1









530
0.85
004_CA05



I-2.3.56
I-2.2.1









494
0.79
004_CA05



I-2.3.57
I-2.2.1









569
0.71
004_CA05



I-2.3.58
I-2.2.1









569
0.66
004_CA05



I-2.3.59
I-2.2.1









554
0.79
004_CA05



I-2.3.60
I-2.2.1









502
0.81
004_CA05



I-2.3.61
I-2.2.1









555
0.74
004_CA05



I-2.3.62
I-2.2.1









554
0.79
004_CA05



I-2.3.63
I-2.2.1









511
0.87
004_CA05



I-2.3.64
I-2.2.1









519
0.73
004_CA05



I-2.3.65
I-2.2.1









531
0.71
004_CA05



I-2.3.66
I-2.2.1









545
0.74
004_CA05



I-2.3.67
I-2.2.1









545
0.76
004_CA05



I-2.3.68
I-2.2.1









569
0.79
004_CA05



I-2.3.69
I-2.2.1









568
0.82
004_CA05



I-2.3.70
I-2.2









460 [M + H − BOC]+
0.97
X018_S04



I-2.3.71
I-2.2









468 [M + H − BOC]+
1.00
X018_S04



I-2.3.72
I-2.2









577
n.d.
n.d.



I-2.3.73
I-2.2









561
n.d.
n.d.



I-2.3.74
I-2.2.2









469
0.89
Z018_S04



I-2.3.75
I-2.2.2









578
0.88
Z018_S04



I-2.3.76
I-2.2.2









455 (M + H − BOC)+
0.85
Z018_S04



I-2.3.77
I-2.2.2









488 (M + H − BOC)
0.89
Z018_S04



I-2.3.78
I-2.2.2









503 (M + H − BOC)+
0.89
Z018_S04



I-2.3.79
I-2.2









626
0.54
X012_S01



I-2.3.80
I-2.2









398 (M + H − BOC)+
0.89
Z018_S04



I-2.3.81
I-2.2









398 [M + H − BOC]+
0.89
n.d.



I-2.3.82
I-2.2









508
0.94
Z018_S04



I-2.3.83
I-2.2









n.d.
n.d.
n.d.






















































































































































































During the synthesis of intermediates I-2.3.17 and I-2.3.29 the bromide (I-2.2) is transformed into the corresponding dioxaborolane compound. Coupling with aromatic bromides is performed in analogy to the synthesis of intermediate I-1.3 (method A).
Intermediate I-2.3.43 is further processed via hydrogenation before the BOC group is removed (step 4)









To I-2.3.43 (90 mg, 0.19 mmol) in methanol (10 mL) Pd/C (10%, 20 mg) is added. The reaction mixture is stirred under hydrogen (50 psi) for 3 h. Then the mixture is filtered and concentrated. The crude product is carried on with step 4. Yield >95%
In analogy the following intermediates as shown in Table 9 are prepared.










TABLE 9






m/z
rt
LC-MS

Intermediate
educt
Structure
[M + H]+
(min)
method



I-2.3.43.2
I-3.2.78









517
0.47.
X012_S02



I-2.3.43.3
I-2.3.83









561
n.d.
n.d.




















Intermediates I-2.3.74-78 and I-2.3.43.2 are converted to the corresponding nitriles in analogy to step 2 of method A1 to yield the compounds in the following Table 10.










TABLE 10






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-2.3.74.1
I-2.3.74









451 [M + H − BOC]+
0.98
Z018_S01



I-2.3.75.1
I-2.3.75









460 (M + H+) − BOC
0.96
Z018_S04



I-2.3.76.1
I-2.3.76









437 (M + H − BOC)+
0.93
Z018_S04



I-2.3.77.1
I-2.3.77









470 (M + H − BOC)+
0.96
Z018_S04



I-2.3.78.1
I-2.3.78









485 (M + H − BOC)+
0.96
Z018_S04



I-2.3.43.2.1
I-2.3.43.2









499
0.54
X012_S02




























The intermediate I-2.3.7 is combined with appropriate halogenides or acid chlorides before (in step 4) the BOC group is removed









To I-2.3.7 (45 mg, 0.10 mmol) and R17 (19 μL, 0.20 mmol) in DMF (1.5 mL) potassium carbonate (42 mg, 0.30 mmol) is added. The reaction mixture is heated to 80° C. for 12 h. The mixture is purified directly by reversed phase HPLC. Yield 65%, m/z 526 [M+H]+, rt 0.71 min, LC-MS Method X018_S01.
The following intermediates as shown in Table 11 are synthesized in a similar fashion from the appropriate intermediates:










TABLE 11






m/z
rt
LC-MS

Intermediate
educt
Structure of Intermediate
[M + H]+
(min)
method



I-2.3.7.3
I-2.3.7









496
0.77
X018_S01



I-2.3.7.4
I-2.3.7









538
0.72
X018_S01



I-2.3.7.5
I-2.3.7









552
0.79
X018_S01



I-2.3.7.6
I-2.3.7









512
0.72
X018_S01



I-2.3.7.7
I-2.3.7









438 [M + H − BOC]+
1.11
X018_S01



I-2.3.7.8
I-2.3.7









593
0.69
X018_S01



I-2.3.7.9
I-2.3.7









566
0.79
X018_S01



I-2.3.7.10
I-2.3.7









526
0.75
X018_S01



I-2.3.7.11
I-2.3.7









494(M + H − BOC)+
1.03
Z018_S04


































The reaction conditions for I-2.3.7.11 differ: Pyridine and dichlormethane instead of potassium carbonate and DMF is used.
Intermediate I-2.3.7.4 is separated according to method chiral SFC B to give the following intermediates as shown in Table 11.1
TABLE 11.1 m/z rt Intermediate Educt Structure of Intermediate [M + H]+ (min) LC-MS method I-2.3.7.4.1 I-2.3.7.4 n.d. 3.90 I_OJH_10_IPROP_DEA.M I-2.3.7.4.2 I-2.3.7.4 n.d. 3.4 I_OJH_10_IPROP_DEA.M
Step 4: Synthesis of Example 2

To I-2.3 (2.35 g, 4.4 mmol) in acetonitrile (50 mL) sodium iodide (1.98 g, 13 mmol) and chlorotrimethylsilane (1.44 g, 13 mmol) are added. The mixture is stirred for 1 h, then methanol is added, stirred for additional 30 min and then concentrated. The residue is purified by reversed phase HPLC. Yield 47%, m/z 433 [M+H]+, rt 0.59 min, LC-MS Method X011_S01.
Method A2.1
Synthesis of (1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxo-3H-isobenzofuran-5-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 3)

Step 1: Synthesis of Intermediate I-3.1

To I-2.1 (1.00 g, 2.1 mmol) in dioxane (5 mL) R3 (0.58 g, 2.3 mmol) is added. The mixture is purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a complex with dichloromethane (34 mg, 0.04 mmol) and potassium acetate (0.39 g, 3.9 mmol) are added. The mixture is heated to 100° C. for 12 h. Water is added to the reaction mixture, which is extracted with diethyl ether. The organic layer is washed with brine, dried over MgSO 4 , filtrated and concentrated. Yield 74% m/z 532 [M+H]+
The following intermediates as shown in Table 12a are synthesized in a similar fashion from the appropriate intermediate:










TABLE 12a






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-3.1.1
(1RS)- I-2.2









514
0.90
V011_S01



I-3.1.2
I-2.2









432
1.05
V018_S01



I-3.1.3
I-2.2









514
0.95
Z011_S03



I-3.1.5
I.2.1









450 (Boron acid)
0.67
V011_S01
























During the synthesis of intermediate I-3.1.2, I-3.1.4 and I-3.1.5 instead of R3 5,5,5′,5′-Tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] is used.
During the synthesis of intermediate I-3.1 I-3.1.2 and I-3.1.4 also the corresponding boronic acid is isolated as shown in Table 12b. Either the boronic ester or boronic acid is used for the next steps.
TABLE 12b m/z rt LC-MS Intermediate Educt Structure of Intermediate [M + H]+ (min) method I-3.1.4 I-2.2.3 432 0.88 V011_S01 I-3.1.6 I-2.1 449 0.42 X016_S01 I-3.1.7 I.2.2 432 0.56 X018_S01
Step 2: Synthesis of Intermediate I-3.2

To I-3.1 (295 mg, 0.66 mmol, as boronic acid (I-3.1.6)) in acetonitrile (4 mL) aq. Na 2 CO 3 -solution (2 M, 663 μL) is added. The mixture is purged with argon, R8 (154 mg, 0.72 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a complex with dichloromethane (80 mg, 0.10 mmol) are added. The reaction is stirred at 70° C. for 4 h. Ethyl acetate is added and the mixture is filtrated. The filtrate is washed with water and aq. Na 2 CO 3 solution (10%). The organic layer is dried over MgSO 4 and concentrated. The residue is purified by flash chromatography (DCM/methanol=97/3). Yield 53%.
The following intermediates as shown in Table 13 are synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):










TABLE 13



Inter-


m/z
rt
LC-MS

mediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-3.2.1
I-3.1









551
1.08
V011_S01



I-3.2.2
I-3.1.1









520
1.21
V011_S01



I-3.2.5
I-3.1









n.d.
n.d.
n.d.



I-3.2.6
(1S)-I-3.1.1









447/491/547
1.18
V011_S01



I-3.2.8
I-3.1









n.d.
n.d.
n.d.



I-3.2.10
(1S)-I-3.1.1









519
1.11
V011_S01



I-3.2.11
I-3.1.1









n.d.
n.d.
n.d.



I-3.2.12
I-3.1.1









n.d.
n.d.
n.d.



I-3.2.13
I-3.1.1









n.d.
n.d.
n.d.



I-3.2.15
I-3.1









n.d.
n.d.
n.d.



I-3.2.16
I-3.1









n.d.
n.d.
n.d.



I-3.2.17
I-3.1









n.d.
n.d.
n.d.



I-3.2.36
I-3.1.3









368 (M + H − BOC)+
0.73
004_CA05



I-3.2.37
I-3.1.3









382 (M + H − BOC)+
0.75
004_CA05



I-3.2.38
I-3.1.3









415 (M+ H − BOC)+
0.95
004_CA05



I-3.2.39
I-3.1.3









430 (M + H − BOC)+
0.91
004_CA05



I-3.2.40
I-3.1.3









405 (M + H − BOC)+
0.74
004_CA05



I-3.2.41
I-3.1.3









405 (M + H − BOC)+
0.67
004_CA05



I-3.2.42
I-3.1.3









405 (M + H − BOC)+
0.77
004_CA05



I-3.2.43
I-3.1.3









382 (M + H − BOC)+
0.72
004_CA05



I-3.2.44
I-3.1.3









394 (M + H − BOC)+
0.70
004_CA05



I-3.2.45
I-3.1.3









411 (M + H − BOC)+
0.88
004_CA05



I-3.2.46
I-3.1.3









397 (M + H − BOC)+
0.68
004_CA05



I-3.2.47
I-3.1.3









379 (M + H − BOC)+
0.85
004_CA05



I-3.2.48
I-3.1.3









442 (M + H − BOC)+
0.92
004_CA05



I-3.2.49
I-3.1.3









442 (M + H − BOC)+
0.94
004_CA05



I-3.2.50
I-3.1.3









412 (M + H − BOC)+
0.84
004_CA05



I-3.2.51
I-3.1.3









611
n.d.
n.d.



I-3.2.52
I-3.1.3









613
1.24
V012_S01



I-3.2.53
I-3.1.3









466 (M + H − BOC)+
0.91
Z018_S04



I-3.2.54
I-3.1.3









647
n.d.
n.d.



I-3.2.55
I-3.1.2









568
1.23
V-11_S01



I-3.2.56
I-3.1.2









622
1.24
V011_S01



I-3.2.57
I-3.1.2









547
0.76
X011_S03



I-3.2.58
I-3.1.2









494
0.57
X011_S03



I-3.2.59
I-3.1.2









494
0.56
X011_S03



I-3.2.60
I-3.1.2









552
0.58
X011_S03



I-3.2.61
I-3.1.2









380 (M + H − BOC)+
0.52
X011_S03



I-3.2.62
I-3.1.2









380 (M + H − BOC)+
0.52
X011_S03



I-3.2.63
I-3.1.3









455 (M + H − BOC)+
0.93
Z018_S04



I-3.2.64
I-3.1.3









538
0.94
Z018_S04



I-3.2.65
I-3.1.3









466 (M + H − BOC)+
0.91
Z018_S04



I-3.2.66
I-3.1.3









525 (M + H − BOC)+
0.93
Z011_S03



I-3.2.67
I-3.1.7









538
0.83
X018_S01



I-3.2.68
I-3.1.7









526
1.11
V011_S01



I-3.2.69
I-3.1.7









586
1.29
V011_S01



I-3.2.70
I-3.1.7









640
1.31
V011_S01



I-3.2.71
I-3.1.7









604
n.d.
n.d.



I-3.2.72
I-3.1.7









n.d.
n.d.
n.d.



I-3.2.73
I-3.1.7









590
1.03
Z011_S03



I-3.2.74
I-3.1









529
0.48
X012_S02



I-3.2.75
I-3.1









543
1.04
V011_S01



I-3.2.76
I-3.1









543
1.02
V011_S01



I-3.2.77
I-3.1.4









n.d.
n.d.
n.d.



I-3.2.78
I-3.1









n.d.
n.d.
n.d.



I-3.2.79
I-3.1.7









539
1.18
V011_S01



I-3.2.80
I-3.1.7









546 (M + H − Boc-t-Bu)
1.106
Z020_S01



I-3.2.81
I-3.1.6









557
1.05
V011_S01



I-3.2.82
I-3.1.6









577
0.50
X018_S02



I-3.2.83
I-3.1.1









644
0.53
X012_S01



I-3.2.84
I-3.1.7









640
0.53
X12_S01



I-3.2.85
I-3.1.7









551
0.59
X011_S03



I-3.2.86
I-3.1.7









544
0.60
X012_S02



I-3.2.87
I-3.1.7









n.d.
n.d.
n.d.



I-3.2.88
I-3.1.2









533
1.08
V011_S01



I-3.2.90
I-3.1.6









563
1.29
V011_S01



I-3.2.91
I-3.1.7









n.d.
n.d.
n.d.






















































































































































Intermediate I-3.2.64 is separated according to method chiral SFC A to give the following intermediates as shown in Table 13.1










TABLE 13.1






m/z
rt


Intermediate
Educt
Structure
[M + H]+
(min)
LC-MS method



I-3.2.64.1
I-3.2.64









n.d.
3.828
I_ADH_15_MEOH_DEA.M



I-3.2.64.2
I-3.2.64









n.d.
4.631
I_ADH_15_MEOH_DEA.M




















Intermediate I-3.2.74, I-3.2.75, I-3.2.81, I-3.2.82, I-3.2.89, I-3.2.90, I-3.2.113, is further processed via hydrogenation before the BOC group is removed (step 4)









To I-3.2.74 (210 mg, 0.33 mmol) in methanol (10 mL) Pd/C (10%, 90 mg) is added. The reaction mixture is stirred at 50° C. under hydrogen (50 psi) for 6 h. Then the mixture is filtered and concentrated. The crude product is carried on with step 4. Yield 85%, m/z 531 [M+H]+, rt 0.48 min, LC-MS Method X012_S02.
In analogy the following intermediates as shown in Table 17 are prepared.










TABLE 17






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-3.2.122
I-3.2.75









545
0.98
V011_S01



I-3.2.123
I-3.2.75









545
1.03
V011_S01



I-3.2.124
I-3.2.81









559
0.62
X011_S03



I-3.2.125
I-3.2.82









489
0.44
X018_S02



I-3.2.126
I-3.2.89









516
1.02
V011_S01



I-3.2.127
I-3.2.90









475
0.41
X018_S02



I-3.2.128
I-3.2.113









530
1.12
V011_S01



I-3.2.129
I-3.2.113









530
1.00
V011_S01
































Intermediate I-3.2.91 is further processed in the following way:









To I-3.2.91 (200 mg, 0.28 mmol) in ACN (3 mL) is added p-toluene sulfonic acid monohydrate (79.67 mg, 0.42 mmol) and stirred at r.t. for 2.5 h. The reaction mixture is diluted with TEA, filtered and purified by reversed phase HPLC.
Yield 68%
Intermediate I-3.2.125, I-3.2.126, I-3.2.129 and I-3.2.131 is further processed via reductive amination before the BOC group is removed (step 4)









To I-3.2.125 (130 mg, 0.266 mmol) in dichlormethane is added 3-oxotetrahydrofuran (27.49 mg, 0.319 mmol) and glacial acetic acid (15.22 μL, 0.266 mmol) and stirred for 45 min at r.t. Sodium triacetoxyborohydride (83.1 mg, 0.372 mmol) is added and the reaction mixture is stirred at r.t. overnight.
The reaction mixture is diluted with dichlormethane and sat. NaHCO 3 . The organic layer is separated, dried and concentrated. The crude product is used for the next step without further purification.
Yield 99%, m/z 559 [M+H]+, rt 0.44 min, LC-MS Method X018_502.
In analogy the following intermediates as shown in Table 18 are prepared.










TABLE 18






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-3.2.133,
I-3.2.126,









586
0.50
X012_S02



I-3.2.134
I-3.2.126









530
1.14
V011_S01



I-3.2.135
I-3.2.129









586
1.09
V011_S01



I-3.2.136
I-3.2.131









n.d.
n.d.
n.d.
























The reaction time for I-3.2.133 and I-3.2.135 is 30 min at r.t. and for I-3.2.134 2 h at r.t. and for I-3.2.136 1 h at r.t.
Intermediate I-3.2.136 is deprotected (see example 359) and further processes via hydrogenation to give example 358:









To example 359 (20 mg, 0.047 mmol) in methanol (3 mL) Pd/C (10%, 5 mg) is added. The reaction mixture is stirred at r.t. under hydrogen (50 psi) for 10 min. Then the mixture is filtered and concentrated. The crude product is purified by reversed phase HPLC to give example 358. Yield 35%, m/z 425 rt 0.715 min, LC-MS Method Z012_S04.
Intermediate I-3.2.127 is further processed via alkylation before the BOC group is removed (step 4)









To I-3.2.127 (71 mg, 0.15 mmol) in DMF (2 mL) is added 2-bromoethyl methyl ether (29.53 μL, 0.31 mmol) and potassium carbonate (41.36, 0.266 mmol) and stirred overnight at r.t. The reaction mixture is diluted with dichlormethane and water. The organic layer is separated, dried and concentrated. The crude product is purified by reversed phase HPLC. Yield 40%, m/z 533 [M+H]+, rt 1.05 min, LC-MS Method V011_S01.
Step 3: Synthesis of Intermediate I-3.3
To I-3.2 (187 mg, 0.35 mmol) in DCM (12 mL) R2 (182 mg, 0.77 mmol) is added. The reaction mixture is stirred for 12 h, concentrated, dissolved in ethyl acetate and extracted with 0.1M HCl and water. The organic layer is dried over MgSO 4 and concentrated. Yield 86%.
The following intermediates as shown in Table 19 are synthesized in a similar fashion from the appropriate intermediate:
TABLE 19 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M + H]+ (min) method I-3.3.1 I-3.2.1 533 1.21 V011_S01 I-3.3.3 I-3.2.5 n.d. n.d. n.d. I-3.3.4 I-3.2.8 n.d. n.d. n.d. I-3.3.5 I-3.2.15 626 n.d. n.d. I-3.3.6 I-3.2.16 n.d. n.d. n.d. I-3.3.7 I-3.2.17 n.d. n.d. n.d. I-3.3.8 I-3.2.130 513 0.55 X012_S02 I-3.3.9 I-3.2.75 525 1.17 V011_S01 I-3.3.10 I-3.2.76 525 1.15 V011_S01 I-3.3.11 I-3.2.122 527 1.15 V011_S01 I-3.3.12 I-3.2.123 527 1.12 V011_S01 I-3.3.13 I-3.2.78 496 0.54 X012_S02 I-3.3.14 I-3.2.124 541 0.71 X011_S03 I-3.3.15; I-3.2.132 541 0.49 X018_S02 I-3.3.16 I-3.2.133 568 1.22 V011_S01 I-3.3.17 I-3.2.134 512 1.26 V011_S01 I-3.3.18 I-3.2.137 515 1.17 V011_S01 I-3.3.19 I-3.2.128 512 1.25 V011_S01 I-3.3.20 I-3.2.135 568 1.23 V011_S01
Step 4: Synthesis of Example 3

To I-3.3 (155 mg, 0.30 mmol) in acetonitrile, sodium iodide (134 mg, 0.89 mmol) and chlorotrimethylsilane (114 μl, 0.89 mmol) are added. The mixture is stirred for 2 h, then methanol is added, stirred for additional 30 min and then concentrated. The residue is purified by reversed phase HPLC. Yield 62%, m/z 420 [M+H]+, rt 0.41 min, LC-MS Method X016_S01.
Method A2.2
Synthesis of (1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(4-phenylpiperazin-1-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 32)









Example 32
Step 1: Synthesis of Intermediate I-3.2.4
To I-3.1.2 (150 mg, 0.30 mmol) in DCM (6 mL), triethylamine (85 μL, 0.61 mmol), R112 (55.22 mg, 0.34 mmol) and copper(II)acetate (85 mg, 0.47 mmol) are added. The mixture is stirred for 72 h at r.t. 7M ammonium solution in methanol is added, the mixture is concentrated. The residue dissolved in acetonitrile and filtrated. The product is purified by reversed phase HPLC. Yield 54%, m/z 548 [M+H]+, rt 1.37 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 14 are synthesized in a similar fashion from the appropriate intermediate










TABLE 14








LC-MS

Intermediate
Educt
Structure of Intermediates
m/z [M + H]+
rt (min)
method



I-3.2.7
I-3.1.2









528
1.10
V011_S01



I-3.2.9
I-3.1.2









550
1.11
V011_S01



I-3.2.14
I-3.1.2









556
1.20
V011_S01



I-3.2.19
I-3.1.2









544
1.22
V011_S01



I-3.2.20
I-3.1.2









354 (M + H − BOC)+
1.20
V011_S01



I-3.2.22
I-3.1.2









530
1.13
V011_S01



I-3.2.24
I-3.1.2









512
1.28
V011_S01



I-3.2.25
I-3.1.2









500
1.21
V011_S01



I-3.2.26 (forms together with I-3.2.27)
I-3.1.2









516
1.02
V011_S01



I-3.2.27 (forms together with I-3.2.26)
I-3.1.2









516
1.02
V011_S01



I-3.2.28;
I-3.1.2









558
1.25
V011_S01



I-3.2.29
I-3.1.2









500
1.21
V011_S01



I-3.2.30
I-3.1.2









556
1.13
V011_S01



I-3.2.31
I-3.1.2









499
1.49
V011_S01



I-3.2.32;
I-3.1.2









514
1.21
V011_S01



I-3.2.33
I-3.1.2









471
1.39
V011_S01



I-3.2.34
I-3.1.2









472
1.36
V011_S01



I-3.2.35
I-3.1.2









473
1.17
V011_S011



I-3.2.92
I-3.1.2









n.d.
0.67
X011_S03



I-3.2.93;
I-3.1.2









540
1.09
V011_S01



I-3.2.94
I-3.1.2









561
1.07
V011_S01



I-3.2.95
I-3.1.2









559
1.08
V011_S01



I-3.2.96
I-3.1.2









528
0.78
X011_S03



I-3.2.97
I-3.1.2









528
0.77
X011_S03



I-3.2.98
I-3.1.7









542
1.26
V011_S01



I-3.2.99
I-3.1.7









512
1.26
V011_S01



I-3.2.100
I-3.1.7









526
0.72
X011_S03



I-3.2.101
I-3.1.7









500
1.24
V011_S01



I-3.2.102
I-3.1.4









486
1.13
V011_S01



I-3.2.103
I-3.1.2









584
1.36
V011_S01



I-3.2.104
I-3.1.7









512
1.31
V011_S01



I-3.2.105
I-3.1.7









568
0.75
X011_S03



I-3.2.106
I-3.1.7









498
1.20
V011_S01



I-3.2.107
I-3.1.7









542
1.13
V011_S01



I-3.2.108
I-3.1.7









512
1.29
V011_S01



I-3.2.109
I-3.1.2









572
1.36
V011_S01



I-3.2.110
I-3.1.2









556
0.65
X011_S03



I-3.2.111
I-3.1.1









528
0.79
X011_S03



I-3.2.112
I-3.1.7









513
0.69
X011_S03



I-3.2.114
I-3.1.7









n.d.
n.d.
n.d.



I-3.2.115
I-3.1.7









542
0.99
Z011_S03



I-3.2.116
I-3.1.7









542
1.017
Z011_S03




































































































For the synthesis of the intermediates I-3.2.117 and I-3.2.118 to the educt I-3.1.2 with the appropriate amine in MeOH 0.14 eq copper(I)oxide is added (as shown in Table 15).










TABLE 15







rt


Intermediate
Educt
Structure of Intermediate
m/z [M + H]+
(min)
LC-MS method



I-3.2.117
I-3.1.2









422 (M + H − BOC)+
1.32
V011_S01



I-3.2.118
I-3.1.2









526
1.28
V011_S01



I-3.2.119
I-3.2.118









498
1.84
I_OJH_10_MEOH_DEA.M



I-3.2.120
I-3.2.119









525
1.10.
V011_S01
























The synthesis of I-3.2.119 proceeds in the following way: I-3.2.118 (785 mg, 1.49 mmol) is dissolved in THF. LiOH (1.5 eq.) as aq. solution is added and stirred at r.t. for 9 h. The product mixture is acidified with 1 M HCl to pH 5 and purified by HPLC-MS. Yield: 61%.
The amide coupling for synthesis of intermediate I-3.2.120 proceeds in the following way: I-3.2.119 (40 mg, 0.08 mmol) HATU (33.6 mg, 0.088 mmol) and DIPEA (55.3 μL, 0.322 mmol) are dissolved in DMF. The mixture is stirred at r.t. for 15 min. Dimethylamine (120.6 μL, 0.241 mmol) is added, and the reaction mixture is stirred at r.t. for 1.5 h. The product mixture is separated by HPLC-MS.
The fractions are combined and freeze-dried. Yield: 85%.
The following intermediate as shown in Table 16 is synthesized in a similar fashion from the appropriate intermediate










TABLE 16






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-3.2.121
I-3.2.119









567
1.10
V011_S01


















The reaction conditions for I-3.2.94 and I-3.2.95 differ: Pyridine instead of TEA is used. The reaction conditions are 80° C. overnight.
The reaction conditions for I-3.2.111 differ: 2 eq of N-Methylmorpholine N-Oxide is added to the reaction.
Step 2: Synthesis of Example 32
To I-3.2.4 (82 mg, 0.15 mmol) in acetonitrile, p-toluenesulfonic acid monohydrate (95 mg, 0.50 mmol) is added and stirred overnight at r.t. The reaction mixture is basified with ammonium solution. 0.5 mL water and 1 mL ACN are added. The precipitate is filtered off, washed with ACN and dried. The crude product is triturated with aq. sodium hydrogencarbonate solution, filtered by suction and dried. Yield 31%, m/z 448 [M+H]+, rt 1.28 min, LC-MS Method V011_S01.
Method A3
Synthesis of (1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methylsulfonylphenyl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 4)

Step 1: Synthesis of Intermediate I-4.1

To I-1.1 (5.00 g, 14 mmol) in acetonitrile (250 mL) p-toluenesulfonic acid monohydrate (3.05 g, 16 mmol) is added and the mixture is stirred for 3 d. The precipitate is filtered off and the solution is washed with acetonitrile. The residue is stirred with aq. NaHCO3 solution (2%), and extracted with ethyl acetate. The organic layer is dried over MgSO 4 and concentrated. Yield 78%, m/z 243/245 [M+H]+, rt 0.76 min, LC-MS Method V018_S01.
The further intermediates belong to the following description
Synthesis of 2-amino-3-(4-bromo-2-fluoro-phenyl)propanenitrile

Step 1.1: Synthesis of Intermediate I-4.0 (Compare with Synthesis of Intermediate I-7.1)

To R19 (28.1 g, 104 mmol) and R20 (21.0 g, 95 mmol) in DCM (130 mL) benzyltrimethylammonium chloride (1.77 g, 9.5 mmol) is added. Under strong stirring water (8 mL) and aq. NaOH solution (19 mol/L, 9 mL) are added (exothermic reaction). The reaction mixture is stirred for 12 h. Water is added and the product is extracted with DCM. The organic layer is dried over MgSO 4 and concentrated. The crude product is used in step 2. Yield >95%, rt 1.56 min, LC-MS Method V003_003.
The following intermediates as shown in Table 20 are synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
TABLE 20 m/z LC-MS Intermediate Structure [M + H]+ rt (min) method I-4.0.1 n.d. n.d. n.d. I-4.0.2 425/427 1.51 V011_S01 I-4.0.3 n.d. n.d. n.d. I-4.0.4 495/497 0.96 X018_S01
Step 1.2: Synthesis of Intermediate I-4.1.1 (Compare with Synthesis of Intermediate I-7.2)

To I-4.0 (40.8 g, 100 mmol) in dioxane (400 mL) hydrogen chloride solution in dioxane (4 mol/L, 27.5 mL, 9.5 mmol) is added. The reaction mixture is stirred for 12 h. Aq. hydrochloric acid (1 mol/L, 100 mL) is added and the mixture is stirred for additional 2 h. The reaction is concentrated, the residue is stirred with acetonitrile and the precipitate is filtered off. Yield 49%, m/z 243 rt 0.42 min, LC-MS Method X001_004.
The following intermediates as shown in Table 21 are synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
TABLE 21 m/z rt LC-MS Intermediate educt Structure [M + H]+ (min) method I-4.1.1.1 I-4.0.1 261 0.35 Z001_002 I-4.1.1.2 I-4.0.2 261/263 0.34 V012_S01 I-4.1.1.3 I-4.0.3 259 0.39 X001_004 I-4.1.1.4 I-4.0.4 331/333 0.48 V018_S01
Step 2: Synthesis of Intermediate I-2.2

To R5 (2.82 g, 11 mmol) in dry DCM (150 mL) diisopropylethylamine (5.8 mL, 33 mmol) and HATU (5.1 g, 13 mmol) are added and the mixture is stirred for 30 min. Then a solution of I-4.1 (2.75 g, 11 mmol) in DCM (50 mL) is added and stirred for 12 h. The mixture is washed with water, aq. K2CO3 solution (5%) and 1 M HCl. The organic layer is dried over MgSO 4 and concentrated. Yield 68%, m/z 466/468 [M+H]+, rt 1.25 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 22 are synthesized in a similar fashion from the appropriate intermediate: ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group)
TABLE 22 Intermediate educt Structure m/z [M + H]+ rt (min) LC-MS method I-4.2.1 I-4.1.1 466 0.78 X001_004 I-4.2.2 I-4.1.1.1 484 1.29 V011_S01 I-4.2.3 I-4.1.1.2 484/486 1.29 V011_S01 I-4.2.4 I-4.1.1.3 n.d. n.d. n.d. I-4.2.5 I-4.1.1.4 554 1.42 V011_S01
Step 3: Synthesis of Intermediate I-4.3

To I-2.2 (300 mg, 0.64 mmol) in acetonitrile (7.5 mL) R9 (142 mg, 0.71 mmol) is added. The mixture is purged with argon 1,1-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (42 mg, 0.10 mmol) and aq. sodium carbonate solution (2 mol/L, 0.64 mL) are added and heated to 70° C. for 2.5 h. Ethyl acetate and water are added to the reaction mixture. The organic layer is washed with aq. NaHCO3 solution (5%) and water. The organic layer is dried over MgSO 4 and concentrated. Yield raw product >95% m/z 442 [M+H]+, rt 0.93 min, LC-MS Method Z018_S04.
The following intermediates as shown in Table 23 are synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):










TABLE 23






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-4.3.1
I-4.2.1









567
1.19
V011_S01



I-4.3.2
I-4.2.1









533
0.75
X001_004



I-4.3.3
I-2.2









442
0.92
Z018_S04



I-4.3.4
I-4.2.3









585
1.20
V011_S01



I-4.3.5
I-4.2.1









519
0.62
Z001_002



I-4.3.6
I-2.2









429
0.95
Z018_S04



I-4.3.8
I-4.2.2









551
1.22
V011_S01



I-4.3.9
I-4.2.1









n.d.
1.39
V003_003



I-4.3.10
I-4.2.1









543
0.57
001_CA07



I-4.3.11
I-4.2.1









518
0.55
001_CA07



I-4.3.12
I-4.2.1









n.d.
n.d.
n.d.



I-4.3.13
I-4.2.1









532
0.57
001_CA07



I-4.3.14
I-4.2.1









556
0.60
001_CA07



I-4.3.15
I-4.2.3









551
1.21
V011_S01



I-4.3.16
I-4.2.1









506
0.56
001_CA07



I-4.3.17
I-4.2.1









541
0.60
001_CA07



I-4.3.18
I-4.2.1









542
0.56
001_CA07



I-4.3.19
I-4.2.5









621
1.33
V011_S01



I-4.3.20
I-4.2.1









556
0.60
001_CA07



I-4.3.21
I-4.2.1









556
0.62
001_CA07



I-4.3.22
I-4.2.1









532
0.58
001_CA07



I-4.3.23
I-4.2.1









n.d.
1.22
Z018_S04



I-4.3.24
I-4.2.4









n.d.
n.d.
n.d.



I-4.3.25
I-4.2.1









506
0.55
001_CA07



I-4.3.26
I-4.2.1









n.d.
n.d.
n.d.



I-4.3.27
I-4.2.1









534
0.63
001_CA07



I-4.3.28
I-2.2









500
0.98
V011_S01



I-4.3.29
I-2.2









442 (M + H − BOC)+
1.09
Z018_S04



I-4.3.30
I-4.3.29









414 (M + H − BOC)+
0.60
Z011_S03



I-4.3.31
I-2.2









408 (M + H − BOC)+
0.93
Z018_S04












































































The reaction conditions for I-4.3.28 differ: Under argon atmosphere I-2.2 (250 mg, 0.54 mmol), potassium carbonate (150 mg, 1.07 mmol), copper (I) iodide (10 mg, 0.05 mmol), N,N′-dimethylethylenediamine (25 μL, 0.23 mmol) and 4-methyl-piperazin-2-one (75 mg, 0.66 mmol) in dioxane (10 mL) are heated to 80° C. for 8 d. The reaction mixture is filtered and the solution is concentrated. The residue is purified by reversed phase HPLC. Yield 30%, m/z 500 [M+H]+, rt 0.98 min, LC-MS Method V011_S01.
The synthesis of I-4.3.30 proceeds in the following way: I-4.3.29 (509 mg, 0.94 mmol) is dissolved in dioxane. LiOH (1.5 eq.) as aq. solution is added dropwise to the solution and stirred at r.t. for 8 h. The product mixture is extracted 2× with DCM. The organic layer is extracted twice with water. The water phase is acidified with 1 M HCl to pH 4, the solvent removed in vacuo to yield the crude product, which is purified by HPLC-MS (Gilson, mass flow 120 mL/min, 10 μM, 200 g Xbridge RP18, ACN/water/NH 3 ). Yield: 44%.
Intermediate I-4.3.19 is additionally treated with BBr 3 to give example 120:









I-4.3.19 (600 mg, 0.97 mmol) in DCM (50 mL) is stirred at −5° C. Then boron tribromide solution (1 mol/L in DCM, 2.90 mL) is added dropwise. The reaction mixture is stirred at 0° C. for 90 min and then stirred at room temperature for additional 12 h. The mixture is cooled down again to −5° C. and is quenched with conc ammonia solution. The mixture is concentrated and purified by reversed phase HPLC. Yield 5%, m/z 429 [M+H]+, rt 0.81 min, LC-MS Method V018_S04.
Additional Step: Amide Coupling to Afford I-4.3.32
The amide coupling for synthesis of intermediate I-4.3.32 proceeds in the following way: I-4.3.30 (35 mg, 0.068 mmol) TBTU (45 mg, 0.14 mmol) and N-methylmorpholine (75 μL, 0.68 mmol) are dissolved in DMF. The mixture is stirred at r.t. for 5 min 0.5 M ammonia in dioxane (2 mL, 1 mmol) is added, and the reaction mixture is stirred at r.t. for 12 h. The product mixture is separated by HPLC-MS (Waters, 30×100 mm, 10 μM, sunfire RP18, ACN/water/TFA). The fractions are combined and freeze-dried. Yield: 59%.
The following amide intermediates as shown in Table 24.1 are synthesized in a similar fashion from the appropriate intermediates:










TABLE 24.1






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-4.3.32
I-4.3.30









413 (M + H − BOC)+
0.89
Z018_S04



I-4.3.33
I-4.3.30









427 (M + H − BOC)+
0.92
Z018_S04



I-4.3.34
I-4.3.30









455 (M + H − BOC)+
1.00
Z018_S04



I-4.3.35
I-4.3.30









467 (M + H − BOC)+
0.99
Z018_S04



I-4.3.36
I-4.3.30









441 (M + H − BOC)+
0.95
Z018_S04



I-4.3.37
I-4.3.31









435 (M + H − BOC)+
0.95
Z018_S04



I-4.3.38
I-4.3.31









490 (M + H − BOC)+
0.75
Z018_S04



I-4.3.39
I-4.3.31









421 (M + H − BOC)+
0.91
Z018_S04



I-4.3.40
I-4.3.31









491 (M + H − BOC)+
0.94
Z018_S04



I-4.3.41
I-4.3.31









477 (M + H − BOC)+
0.93
Z018_S04



I-4.3.42
I-4.3.31









475 (M + H − BOC)+
1.02
Z018_S04



I-4.3.43
I-4.3.31









435 (M + H − BOC)+
0.94
Z018_S04



I-4.3.44
I-4.3.31









461 (M + H − BOC)+
0.97
Z018_S04



I-4.3.45
I-4.3.30









496 (M + H − BOC)+
0.89
Z011_S03



I-4.3.46
I-4.3.30









519 (M + H − BOC)+
0.90
Z018_S04



I-4.3.47
I-4.3.30









524 (M + H − BOC)+
0.97
Z011_S03



I-4.3.48
I-4.3.30









540 (M + H − BOC)+
0.91
Z011_S03



I-4.3.49
I-4.3.30









422 (M + H − BOC)+
0.98
Z011_S03



I-4.3.50
I-4.3.30









483 (M + H − BOC)+
0.90
Z011_S03



I-4.3.51
I-4.3.30









424 (M + H − BOC)+
0.86
Z011_S03



I-4.3.52
I-4.3.30









564 (M + H − BOC)+
0.98
Z018_S04



I-4.3.53
I-4.3.30









510 (M + H − BOC)+
0.85
Z011_S03



I-4.3.54
I-4.3.30









583 (M + H − BOC)+
0.89
Z011_S03



I-4.3.55
I-4.3.30









497 (M + H − BOC)+
0.91
Z011_S03



I-4.3.56
I-2.3.41









413 (M + H − BOC)+
0.84
Z011_S03



I-4.3.57
I-2.3.41









519 (M + H − BOC)+
0.94
Z018_S04



I-4.3.58
I-2.3.80









522 (M + H − BOC)+
0.87
Z018_S04



I-4.3.59
I-2.3.81









397 (M + H − BOC)+
0.86
Z018_S04



I-4.3.60
I-2.3.81









503 (M + H − BOC)+
0.88
Z011_S03



I-4.3.61
I-2.3.81









480 (M + H − BOC)+
0.74
Z018_S04



I-4.3.62
I-2.3.81









425 (M + H − BOC)+
0.91
Z018_S04



I-4.3.63
I-2.3.82









407 (M + H − BOC)+
1.02
Z018_S04



I-4.3.64
I-2.3.82









490 (M + H − BOC)+
0.76
Z018_S04



I-4.3.65
I-2.3.80









467 (M + H − BOC)+
0.91
Z018_S04



I-4.3.66
I-2.3.80









480 (M + H − BOC)+
0.73
Z018_S04






















































































The reaction conditions for I-4.3.63 differ: I-2.3.82 (100 mg, 0.197 mmol), HATU (82.4 mg, 0.217 mmol) and DIPEA (68 μL, 2 eq) are dissolved in DMF. The mixture is stirred at r.t. for 30 min Ammonium chloride (63.2 mg, 1.182 mmol) and DIPEA (204 μL, 6 eq) are added, and the reaction mixture is stirred at r.t. for 3 h. The product mixture is separated by HPLC-MS (Waters, 30×100 mm, 10 μM, xBridge RP18, ACN/water/TFA). The fractions are combined and freeze-dried. Yield: 27%.
The reaction conditions for I-4.3.65 and I-4.3.66 differ: DCM is used as solvent instead of DMF.
Step 4: Synthesis of Example 4
I-4.3 (348 mg, 0.64 mmol) in formic acid is stirred for 10 min at 40° C. The reaction solution is diluted with DMF and directly purified by reversed phase HPLC. Yield 86%, m/z 442 [M+H]+, rt 0.65 min, LC-MS Method Z018_S04.
Method A4
Synthesis of (1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-[4-(1H-indol-5-yl)triazol-1-yl]phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 5)

Step 1: Synthesis of Intermediate I-5.1

I-2.1 (2.26 g, 4.7 mmol), sodium azide (0.61 g, 9.3 mmol), trans-(1R,2R)-N,N′-bismethyl-1,2-cylcohexane diamine (147 μl, 0.93 mmol), copper(I)iodide (89 mg, 0.47 mmol) and L-ascorbic acid sodium salt (92 mg, 0.47 mmol) are dissolved in ethanol/water=7/3 (60 mL). The mixture is heated to 100° C. for 1.5 h. Water and DCM are added to the reaction mixture. The organic layer is washed with water and brine, dried over MgSO 4 and concentrated. The residue is purified by reversed phase HPLC. Yield 85% m/z 447 [M+H]+, rt 0.91 min, LC-MS Method Z018_S04.
Step 2: Synthesis of Intermediate I-5.2
To I-5.1 (1.76 g, 3.9 mmol) in anhydrous DCM (30 mL) R2 (2.35 g, 9.9 mmol) is added. The reaction mixture is stirred for 11 h. The reaction mixture is extracted with 0.5M HCl and water. The organic layer is extracted with half saturated Na2CO3 solution, water and brine. The residue is purified by reversed phase HPLC. Yield 54% m/z 329 [M+H]+, rt 0.96 min, LC-MS Method Z018_S04.
Step 3: Synthesis of Example 5
To R10 (28 mg, 0.20 mmol) in DMSO (1.3 mL) I-5.2 (43 mg, 0.10 mmol) is added. Then copper(II) sulfate pentahydrate (2.2 mg, 0.01 mmol), L-ascorbic acid sodium salt (11 mg, 0.05 mmol) and 100 μL water are added. The reaction mixture is stirred for 12 h. The reaction mixture is diluted with DMF and directly purified by reversed phase HPLC. The achieved substance is dissolved in formic acid, stirred at 40° C. for 10 min and the reaction mixture is purified again by reversed phase HPLC. Yield 34% m/z 470 [M+H]+, rt 0.70 min, LC-MS Method Z018_S04.
Method A5
Synthesis of (1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 6)

Step 1: Synthesis of Intermediate I-6.1

To I-3.1 (90 mg, 0.20 mmol) in DCM (4 mL), triethylamine (60 μL, 0.43 mmol), R11 (23 μL, 0.21 mmol) and copper(II)acetate (55 mg, 0.30 mmol) are added. The mixture is stirred for 12 h. 7M ammonium solution in methanol is added, the mixture is concentrated. The residue dissolved in acetonitrile and filtrated. The product is purified by reversed phase HPLC. Yield 32%, m/z 504 [M+H]+, rt 1.00 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 24.2 are synthesized in a similar fashion from the appropriate intermediates:
TABLE 24.2 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M + H]+ (min) method I-3.2.89 I-3.1.5 606 1.40 V011_S01 I-3.2.113 I-3.1.5 606 1.37 V011_S01
Step 2: Synthesis of Intermediate I-6.2

To I-6.1 (40 mg, 0.08 mmol) in DCM (1 mL) R2 (35 mg, 0.15 mmol) is added. The reaction mixture is stirred for 12 h. The reaction mixture is concentrated and the residue is purified by reversed phase HPLC. Yield 67%, m/z 486 [M+H]+, rt 1.12 min, LC-MS Method V011_S01.
Step 3: Synthesis of Example 6
To I-6.2 (25 mg, 0.05 mmol) in acetonitrile, p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) is added and stirred for 12 h. The product is purified by reversed phase HPLC. Yield 86%, m/z 386 [M+H]+, rt 0.98 min, LC-MS Method V011_S01.
Method B
Synthesis of (1S,2S,4R)-N-[2-[4-(1-acetyl-5-methyl-pyrazol-3-yl)-2-fluoro-phenyl]-1-cyano-ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 7)

Step 1: Synthesis of Intermediate I-7.1

R12 (340 mg, 1.54 mmol), R13 (480 mg, 1.54 mmol), benzyltrimethylammonium chloride (29 mg, 0.15 mmol) and DCM (10 mL) are put together. Under stirring water (250 μL) and sodium hydroxide solution (19 mol/L, 146 μL) are added. The reaction mixture is stirred for 1 h. Half saturated brine and DCM are added. The organic layer is concentrated and purified by reversed phase HPLC. Yield 22%. m/z 451 [M+H]+, rt 1.48 min, LC-MS Method V011_S01.
The following intermediate as shown in Table 25 are synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
TABLE 25 m/z rt LC-MS Intermediate Structure [M + H]+ (min) method I-7.1.1 447/449 0.78 X012_S01 I-7.1.2 356 0.75 X012_S01 I-7.1.3 500 0.95 X012_S01 I-7.1.4 413 0.90 X012_S01 I-7.1.5 401 0.86 X012_S01 I-7.1.6 500 0.95 X012_S01 I-7.1.7 466 0.82 X011_S02
Step 2: Synthesis of Intermediate I-7.2

To I-7.1 (155 mg, 0.34 mmol) in dioxane (6 mL) aq. HCl (1 mol/L, 361 μL) is added. The reaction mixture is stirred for 1 h. 135 μL aq. HCl (1 M) is added and stirred for additional 30 min. The product is purified by reversed phase HPLC. Yield >95%. m/z 287 [M+H]+, rt 1.01 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 26 are synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
TABLE 26 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M + H]+ (min) method I-7.2.1 I-7.1.1 284/286 0.48 X012_S01 I-7.2.2 I-7.1.2 n.d. n.d. n.d. I-7.2.3 I-7.1.3 336 0.56 X012_S01 I-7.2.4 I-7.1.4 249 0.47 X012_S01 I-7.2.5 I-7.1.5 227 0.43 X012_S01 I-7.2.6 I-7.1.6 336 0.55 X012_S01 I-7.2.7 I-7.1.7 318/320 (M + H2O) 0.48 X011_S02
Step 3: Synthesis of Intermediate I-7.3

To R5 (50 mg, 0.21 mmol) in DMF (1.5 mL) HATU (87 mg, 0.23 mmol) and diisopropylethylamine (143 μL, 0.83 mmol) are added and the reaction mixture is stirred for 15 min. Then intermediate I-7.2 (87 mg, 0.22 mmol) is added and the mixture stirred for 12 h. The reaction solution is purified by reversed phase HPLC. Yield 81%, m/z 510/454/410 rt 1.28 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 27 are synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):










TABLE 27






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-7.3.1
I-7.2.1









506/508
0.66
X012_S01



I-7.3.2
I-7.2.2









415
0.61
X012_S01



I-7.3.3
I-7.2.3









559
0.84
X012_S01



I-7.3.4
I-7.2.4









472
0.78
X012_S01



I-7.3.5
I-7.2.5









460
0.74
X012_S01



I-7.3.6
I-7.2.6









559
0.84
X012_S01



I-7.3.7
I-7.2.7









524/526
0.71
X011_S02






























Intermediate I-7.3.7 is separated according to method “Chiral SFC F” to give the following compounds of Table 28
TABLE 28 m/z rt Intermediate Educt Structure [M + H]+ (min) SFC method I-7.3.8 I-7.3.7 n.d. 2.432 I_IC-20_MEOH_NH3.M I-7.3.9 I-7.3.7 n.d. 1.946 I_IC_20_MEOH_NH3.M
Step 4: Synthesis of Example 7

To I-7.3 (40 mg, 0.08 mmol) in acetonitrile (1 mL) sodium iodide (14 mg, 0.09 mmol) and chlorotrimethylsilane (12 μL, 0.09 mmol) are added. The mixture is stirred for 20 min. The product is purified by reversed phase HPLC. Yield 39%, m/z 410 [M+H]+, rt 0.96 min, LC-MS Method V018_S01
For example 58 I-7.3 is stirred in formic acid at 50° C. for 10 min in a pressure vessel.
Method C
Synthesis of (1S,2S,4R)-N-[1-cyano-2-(1H-indazol-5-yl)ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 8)

Step 1: Synthesis of Intermediate I-8.1

To R5 (102 mg, 0.42 mmol) in DMF (3 mL) diisopropylethylamine (296 μL, 1.70 mmol) and TBTU (136 mg, 0.23 mmol) are added and the reaction mixture is stirred for 15 min. Then R14 (135 mg, 0.42 mmol) is added and the mixture is stirred for additional 1 h. Water is added to the reaction mixture and extracted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4 and concentrated. Yield 70%.
The following intermediate as shown in Table 29 is synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the amide group):










TABLE 29






m/z
rt
LC-MS

Intermediate
educt
Structure
[M + H]+
(min)
method



I-8.1.1
R14.1









428
0.91
V011_S01



I-8.1.2
R14.2









437
0.64
X012_S01



I-8.1.3
R47









512
1.26
V011_S01



I-8.1.4
R49









517
1.09
V011_S01
























The reaction conditions for I-8.1.3 and I-8.1.4 differ: HATU is used instead of TBTU.
Step 2: Synthesis of Intermediate I-8.2
To I-8.1 (126 mg, 0.29 mmol) in DCM (1 mL) R2 (155 mg, 0.65 mmol) is added. The reaction mixture is stirred for 12 h and then concentrated. Yield 100% m/z 310/354/410 [M+H]+, rt 1.02 min, LC-MS Method V012_S01.
The following intermediates as shown in Table 30 are synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
TABLE 30 m/z rt LC-MS Intermediate educt Structure [M + H]+ (min) method I-8.2.1 I-8.1.1 n.d. n.d. n.d. I-8.2.2 I-8.1.2 420 0.70 X012_S01 I-8.2.3 I-8.1.3 494 1.37 V011_S01 I-8.2.4 I-8.1.4 499 1.22 V011_S01 I-8.2.5 I-24.3.2 527 0.66 X011_S03
Step 3: Synthesis of Example 8

To I-8.1 (120 mg, 0.29 mmol) in acetonitrile (7 mL) sodium iodide (132 mg, 0.88 mmol) and chlorotrimethylsilane (106 μl, 0.88 mmol) are added. The mixture is stirred for 12 h, then methanol (7 mL) is added, stirred for 1 h and then concentrated. The residue is dissolved in ethyl acetate, washed with water and brine, dried over Na 2 SO 4 and concentrated. The product is purified by reversed phase HPLC. Yield 19%, m/z 310 [M+H]+, rt 0.86 min, LC-MS Method V011_S01.
Method D
Synthesis of (1S,2S,4R)-N-[1-cyano-2-(6-oxo-5H-phenanthridin-8-yl)ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 9)

Step 1: Synthesis of Intermediate I-9.1

I-7.3.1 (200 mg, 0.39 mmol) and R16 (65 mg, 0.47 mmol) in acetonitrile (5 mL) is purged with argon. 1,1-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (26 mg, 0.04 mmol) and aq. sodium carbonate solution (2 mol/L, 395 μL) are added and heated to 70° C. for 3 h. DCM and water are added to the reaction mixture. The organic layer is dried over MgSO 4 and concentrated. The product is purified by reversed phase HPLC. Yield 50% m/z 487 [M+H]+, rt 0.60 min, LC-MS Method X012_S01.
Step 2: Synthesis of Example 9
To I-9.4 (115 mg, 0.24 mmol) in acetonitrile (5 mL) sodium iodide (106 mg, 0.71 mmol) and chlorotrimethylsilane (90 μL, 0.71 mmol) are added. The mixture is stirred for 90 min. The product is purified by reversed phase HPLC. Yield 32%, m/z 387 [M+H]+, rt 0.39 min, LC-MS Method X012_S01.
Synthesis of Intermediate I-9.1.1
I-9.1 (100 mg, 0.2 mmol) and MeI (14.2 μL, 0.23 mmol) are dissolved in 2 mL DMF, and NaH (9.04 mg, 0.23 mmol, as 60% suspension in paraffin oil) is added. After stirring for 12 h at r.t., the mixture is diluted with methanol, filtered and purified by HPLC. The product fractions are freeze-dried to yield 42 mg (41%) I-9.1.1. m/z 501 [M+H]+, rt 0.65 min, LC-MS Method X012_S01.
Boc deprotection to Example 206 is performed in analogy to the synthesis of Example 9.
Method D1
Synthesis of (1S,2S,4R)-N-[2-(3-chloro-5-methyl-6-oxo-phenanthridin-8-yl)-1-cyano-ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 305)

Step 1: Synthesis of Intermediate I-18.1

To I-7.3.1 (4.0 g, 7.9 mmol) in anhydrous dioxane (50 mL) R3 (2.93 g, 11.5 mmol) and potassium acetate (2.27 g, 23.2 mmol) are added. The mixture is purged with argon, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichlormethan complex (PdCl 2 (dppf)) (0.66 g, 0.81 mmol) is added to the mixture and heated to 70° C. overnight. The reaction mixture is diluted with DCM and water. The organic layer is separated, dried and concentrated. The residue is purified by reversed phase HPLC. Yield 71% m/z 554 [M+H]+, rt 0.74 min, LC-MS Method X011_S03.
The following intermediates as shown in Table 31 are synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
TABLE 31 m/z rt LC-MS Intermediate educt Structure [M + H]+ (min) method I-18.1.1 I-7.3.7 572 0.72 X011_S02 I-18.1.2 I-7.3.8 572 0.74 X012_S01
Step 2: Synthesis of Intermediate I-18.2

To I-18.1 (150 m g, 0.27 mmol) in anhydrous ACN (5 mL) (5-chloro-2-iodophenyl)methanamine (72.498 m g, 0.27 mmol) is added and purged with argon. 1,1 bis(di-tert.butylphosphino)ferrocene palladium dichloride (17.66 mg, 0.027 mmol) and a solution of sodium carbonate in water 2 mol/L (0.271 mL, 0.54 mmol) are added, purged again with argon and heated to 70° C. for 6 h. The reaction mixture is diluted with DCM and water. The organic layer is separated, dried and concentrated. The crude residue is used for the next step without further purification. Yield 93% m/z 536[M+H]+, rt 0.71 min, LC-MS Method X012_S01.
The following intermediates as shown in Table 32 are synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
TABLE 32 m/z rt LC-MS Intermediate Educt Structure [M + H]+ (min) method I-18.2.1 I-18.1.1 530 0.62 X011_S03 I-18.2.2 I-18.1.1 523 0.66 X011_S02 I-18.2.3 I-18.1 548 0.48 X011_S03 I-18.2.4 I-18.1.1 505 0.65 X011_S02 I-18.2.5 I-18.1.1 523 0.66 X011_S02 I-18.2.6 I-18.1 541 0.69 X012_S02 I-18.2.7 I-18.1 522 0.65 X012_S01 I-18.2.8 I-18.1 512 0.57 X012_S01 I-18.2.9 I-18.1 545 0.61 X011_S03 I-18.2.10 I-18.1 523 0.68 X012_S02 I-18.2.11 I-18.1 555 0.69 X011_S03 I-18.2.12 I-18.1 580 0.60 X011_S03 I-18.2.13 I-18.1 526 0.64 X012_S01 I-18.2.14 I-18.1 521 0.67 X011_S03 I-18.2.15 I-18.1 558 0.50 X012_S01 I-18.2.16 I-18.1 530 0.54 X011_S03 I-18.2.17 I-18.1 505 0.61 X012_S01 I-18.2.18 I-18.1 512 0.45 X012_S01 I-18.2.19 I-18.1 523 0.62 X012_S01 I-18.2.20 I-18.1 545 0.61 X011_S03 I-18.2.21 I-18.1 517 0.61 X011_S03 I-18.2.22 I-18.1 565 0.53 X012_S01 I-18.2.23 I-18.1 602 0.66 X012_S01 I-18.2.24 I-18.1.2 505 0.61 X012_S01 I-18.2.25 I-18.1.2 523 0.63 X012_S01 I-18.2.26 I-18.1.2 541 0.64 X012_S01 I-18.2.27 I-18.1.2 548 0.60 X012_S01 I-18.2.28 I-18.1.2 519 0.67 X012_S01 I-18.2.29 I-18.1 570 0.59 X012_S01
Step 3: Synthesis of Example 305

To I-18.2 (270 mg, 0.25 mmol) in THF (3 mL) methanesulfonic acid (81.87 μL, 1.26 mmol) is added and the reaction mixture is stirred at r.t. overnight. The reaction mixture is concentrated and the residue is purified by reversed phase HPLC. Yield 14% m/z 435 [M+H]+, rt 0.48 min, LC-MS Method X012_S01.
Method E
Synthesis of (1S,2S,4R)-N-[1-cyano-2-(6-oxo-5H-phenanthridin-3-yl)ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide and (1S,2S,4R)-N-[1-cyano-2-(6-oxo-5H-phenanthridin-1-yl)ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 123 and 128)

Step 1: Synthesis of Intermediate I-10.1

To I-7.3.2 (6.0 g, 14.5 mmol) in ethyl acetate (100 mL) tin(II)chloride dihydrate (16.3 g, 72.4 mmol) is added. The reaction mixture is stirred for 12 h. The mixture is set basic with potassium carbonate and aq. sodium hydroxide solution. The organic layer is separated, is dried over MgSO 4 and is concentrated. The residue is purified by reversed phase HPLC. Yield 32% m/z 385 [M+H]+, rt 0.42 min, LC-MS Method X012_S01.
Step 2: Synthesis of Intermediate I-10.2
To R23 (0.70 g, 2.81 mmol) in DCM (20 mL) diisopropylethylamine (1.20 mL, 7.02 mmol) and HATU (1.09 g, 2.81 mmol) are added and the reaction mixture is stirred for 7 min. Then intermediate I-10.1 (0.90 g, 2.34 mmol) is added and the mixture is stirred for additional 12 h. The mixture is concentrated and the residue is purified by flash chromatography (cyclohexane/ethyl acetate=70/30). Yield 90% m/z 615 [M+H]+, rt 0.66 min, LC-MS Method X012_S01.
The following intermediate as shown in Table 33 is synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
TABLE 33 m/z rt LC-MS Intermediate educt Structure [M + H]+ (min) method I-10.2.1 I-10.1 585/587 0.67 X012_S01
Step 3: Synthesis of Intermediate I-10.3

To I-10.2 (800 mg, 1.30 mmol) in DMF (20 mL) sodium hydride (58 mg, 1.43 mmol) is added and the reaction mixture is stirred for 10 min. Then 2-(trimethylsilyl)ethoxymethylchloride (0.25 mL, 1.43 mmol) is added and the mixture is stirred for additional 2 h. Water and DCM is added to the mixture and the organic layer is concentrated. The residue is purified by reversed phase HPLC. Yield 26% m/z 745 [M+H]+, rt 0.85 min, LC-MS Method X012_S01.
The following intermediate as shown in Table 34 is synthesized in a similar fashion from the appropriate intermediate:
TABLE 34 m/z rt LC-MS Intermediate Educt Structure [M + H]+ (min) method I-10.3.1 I-10.2.1 715/717 0.84 X012_S01
Step 4: Synthesis of Intermediate I-10.4

To I-10.3 (200 mg, 0.27 mmol) in anhydrous DMF (10 mL) tetrakis(triphenylphosphine)palladium (16 mg, 0.01 mmol) and sodium carbonate (58 mg, 0.55 mmol) is added. The reaction mixture is heated to 150° C. for 5 h. Water and ethyl acetate is added to the mixture. The organic layer is dried over MgSO 4 and is concentrated. The residue is purified by reversed phase HPLC. Yield 34% m/z 617 [M+H]+, rt 0.84 min, LC-MS Method X012_S01.
During this ring cyclization both isomeres are obtained; but it is first possible to separated them by reversed phase HPLC on the last step (see step 6).
The following intermediate as shown in Table 35 is synthesized in a similar fashion from the appropriate intermediate:
TABLE 35 m/z rt LC-MS Intermediate Educt Structure [M + H]+ (min) method I-10.4.1 I-10.3.1 635 0.86 X012_S01
Step 5: Synthesis of Intermediate I-10.5

To I-10.4 (57 mg, 0.09 mmol) in acetonitrile (5 mL) sodium iodide (42 mg, 0.28 mmol) and chlorotrimethylsilane (35 μL, 0.28 mmol) are added. The mixture is stirred for 90 min. Then methanol (5 mL) is added and the mixture is stirred for additional 15 min. The mixture is concentrated and DCM and water is added to the residue. The organic layer is separated, is dried over MgSO 4 and concentrated again. The crude product is carried on with step 6. Yield >95%, m/z 517 [M+H]+, rt 0.62 min, LC-MS Method X012_S01.
Step 6: Synthesis of Example 123 and 128
I-10.5 (48 mg, 0.09 mmol) is stirred in formic acid for 48 h. The mixture is purified by reversed phase HPLC. It is possible to separate the both isomers:
Isomer 1=example 123: yield 3%, m/z 387 [M+H]+, rt 0.38 min, LC-MS Method X012_S01,
Isomer 2=example 128: yield 6%, m/z 387 [M+H]+, rt 0.35 min, LC-MS Method X012_S01.
Method W
Synthesis of (1S,2S,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-[(1-methyl-4-piperidyl)oxy]phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 319)

Step 1: Synthesis of Intermediate I-19.1

I-2.2 (300 m g, 0.64 mmol) in anhydrous toluene is purged with argon. 4-hydroxy-1-methylpiperidine (148.18 mg, 1.29 mmol), allylpalladium chloride dimer (5.88 mg, 0.016 mmol), 2-(di-t-butylphosphino)-3-methoxy-6-methyl-2′-4′-6′-tri-i-propyl-1,1′-biphenyl (18.09 mg, 0.039 mmol), cesium carbonate (314.4 mg, 0.965 mmol) and molecular sieve (4 A) are added and purged with argon again. The reaction mixture is stirred at 90° C. for 21 h. Afterwards filtered through a pad of celite, washed with ethyl acetate and concentrated. The crude residue is purified by reversed phase HPLC and freeze dried. Yield 16%.
Step 2: Synthesis of Example 319
see method A2, Step 4
To I-19.1 (50 m g, 0.1 mmol) in acetonitrile (6 mL) sodium iodide (45 mg, 0.3 mmol) and chlorotrimethylsilane (38.1 μL, 0.3 mmol) are added. The mixture is stirred for 2 h, then methanol is added, stirred for additional 30 min and then concentrated. The residue is purified by reversed phase HPLC. Yield 34%, m/z 401 [M+H]+, rt 0.31 min, LC-MS Method X012_S02.
Method W1
Synthesis of (1S,2S,4R)-N-[(1S)-1-cyano-2-[4-[3-(dimethylamino)-1-piperidyl]-2-fluoro-phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 344)

Step 1: Synthesis of Intermediate I-20.1

To I-2.2 (300 mg, 0.64 mmol) in anhydrous dioxane (8 mL) are added 3-dimethylamino-piperidine (164.96 mg, 1.29 mmol) and cesium carbonate (846.87 mg, 2.57 mmol). The mixture is purged with argon and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (95.05 mg, 0.13 mmol) is added and stirred at 90° C. for 2 h. The reaction mixture is filtered and concentrated. The residue is diluted with dichlormethane and water. The organic layer is separated, dried and concentrated. The crude product is purified by reversed phase HPLC. Yield 12%.
Step 2: Synthesis of Example 344
See Method A5, Step 3
To I-20.1 (53 mg, 0.1 mmol) in acetonitrile (8 mL) p-toluenesulfonic acid monohydrate (68.70 mg, 0.36 mmol) is added and stirred at r.t. for 6 h. The mixture is concentrated, diluted with methanol and purified by reversed phase HPLC. Yield 28%, m/z 414 [M+H]+, rt 0.74 min, LC-MS Method 004_CA05.
Method Z
Synthesis of (1S,2S,4R)-N-[1-cyano-2-(3-fluorophenanthridin-8-yl)ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 315)

Step 1: Synthesis of Intermediate I-21.1

To I_18.1 (1.5 g, 2.7 mmol) in anhydrous THF (1 mL) under argon atmosphere lithium borhydride (59 m g, 2.7 mmol) is added. The mixture is heated to 50° C. overnight. The reaction mixture is carefully diluted with water and extracted with ethyl acetate. The organic layer is separated, dried and concentrated. The crude residue is filtered through a pad of silica gel (cyclohexane/ethyl acetate 1:2). Yield 37%.
Step 2: Synthesis of Intermediate I-21.2
To I-21.1 (260 m g, 0.495 mmol) in anhydrous ACN (5 mL) 5-fluoro-2-iodo-aniline (117.28 m g, 0.495 mmol), 1,1 bis(diphenylphosphino)ferrocene palladium dichloride (36.21 mg, 0.049 mmol) and a solution of sodium carbonate in water 2 mol/L (0.742 mL, 1.48 mmol) are added and purged with argon and heated to 80° C. for 1 h. The reaction mixture is diluted with DCM and water. The organic layer is separated, dried and concentrated. The crude residue is purified by reversed phase HPLC. Yield 41%, m/z 509[M+H]+, rt 0.66 min, LC-MS Method X011_S03.
The following intermediate as shown in Table 36 is synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
TABLE 36 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M + H]+ (min) method I-21.2.1 I-21.1 491 0.63 X011_S03
Step 3: Synthesis of Intermediate I-21.3

To I-21.2 (103 mg, 0.2 mmol) in DCM manganese(IV)oxide (153.65 mg, 8.73 mmol) is added under cooling. The reaction mixture is stirred at r.t. overnight and 1 h at 50° C. Another manganese(IV)oxide (50 mg, 2.84 mmol) is added and stirred for further 2 h at 50° C. The reaction mixture is filtered through a pad of cellulose and concentrated in vacuo. The residue is purified by reversed phase HPLC.
Yield 27%.
The following intermediate as shown in Table 37 is synthesized in a similar fashion from the appropriate intermediate ((R,S)=1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
TABLE 37 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M + H]+ (min) method I-21.3.1 I-21.2.1 n.d. n.d. n.d.
Step 4: Synthesis of Example 315

To I-21.3 (26.4 mg, 0.054 mmol) in acetonitrile, p-toluenesulfonic acid monohydrate (35.98 mg, 0.189 mmol) is added and stirred for 5 h. The reaction solution is purified by reversed phase HPLC. Yield 60%, m/z 389 [M+H]+, rt 0.37 min, LC-MS Method X12_S01.
Synthesis of Starting Materials/Educts
Synthesis of tert-butyl N-[(1S)-2-amino-1-[(4-bromo-2-fluoro-phenyl)methyl]-2-oxo-ethyl]carbamate (R1)

Step 1: Synthesis of Intermediate I-11.1

R2.4 (212 g, 1151 mmol) in tetrahydrofuran (dry) (600 mL) is cooled to −78° C. Then n-butyllithium (2.5 M in hexanes, 552 mL, 1381 mmol) is added dropwise, keeping the temperature below −78° C. After 30 min R25 (324 g, 1209 mmol) in tertahydrofuran (dry) (120 mL) is added dropwise. The reaction mixture is stirred at −78° C. for 1 h. The mixture is quenched with saturated NH 4 Cl solution and extracted three times with ethyl acetate. The organic layer is washed with brine, dried over Na 2 SO 4 and evaporated in vacuo. The residue is purified by flash chromatography (heptane/ethyl acetate=80/20). Yield 60%.
Step 2: Synthesis of Intermediate I-11.2
To I-11.1 (104 g, 265 mmol) in acetonitrile (600 mL) aq. 0.2 M HCl (2788 mL, 558 mmol) is added.
The mixture is stirred at RT for 12 h. The mixture is extracted with diethylether and the pH of the aq. layer is adjusted to −8 with sat. NaHCO 3 -solution. Then it is extracted three times with ethyl acetate. The organic layer is washed with brine, dried over Na 2 SO 4 and concentrated. Yield 80%.
Step 3: Synthesis of Intermediate I-11.3
I-11.2 (62.4 g, 211 mmol) is stirred in aq. 3 M HCl (3 mol/L, 1000 mL) at 60° C. for 16 h. The mixture is cooled down and the pH is adjusted to −7 with aq. 6 M NaOH. Then the reaction mixture is filtered, washed three times with water and dried in a vacuum oven at 40° C. for 12 h. Yield 74%.
Step 4: Synthesis of Intermediate I-11.4
To I-11.3 (151 g, 546 mmol) in 1,4-dioxane (2.2 L) is added aq. 2 M sodium carbonate (301 mL) and di-tertbutyl dicarbonate (138 g, 147 mL). The mixture is stirred for 4 h. Then water is added and the pH is adjusted to −4-5 with citric acid. The mixture is extracted three times with ethyl acetate. The organic layer is washed with brine, dried over Na 2 SO 4 and concentrated. The residue is stirred in heptane for 15 min and the product is filtered off. Yield 87%.
Step 5: Synthesis of R1
To I-11.4 (181 g, 476 mmol) in dry DMF (1200 mL) N-methylmorpholine (72 g, 713 mmol) and TBTU (153 g, 476 mmol) are added and the reaction mixture is stirred for 30 min. Then the reaction mixture is cooled to 0° C. and aq. 35% ammonium chloride solution (47 mL, 856 mmol) is added and the mixture is stirred at room temperature for 12 h. Water is added and the formed product is filtered off and washed three times with water. The product is dried in a vacuum oven at 40° C. for 72 h. Yield 64%.
The following intermediate as shown in Table 38 is synthesized in a similar fashion from the appropriate intermediates:









TABLE 38



Intermediate
Structure
m/z [M + H]+
rt (min)
LC-MS method



R1.1









409
1.05
V011_S01



R1.2









217 [M + H − BOC]+
0.69
Z018_S04



















Synthesis of (1S,2S,4R)-3-[(tert.-butoxy)carbonyl]-3-azabicyclo[2.2.1]heptane-2-carboxylate (R5)
The compound is commercially available or can be synthesized in analogy to Tararov et al, Tetrahedron Asymmetry 13 (2002), 25-28.

Step 1: Synthesis of R5C

A solution of R5A (44.9 g, 0.44 mol), freshly distilled from a commercially available solution in toluene (at 50 mbar, 55° C.) in diethylether (300 ml) is cooled at −10° C., followed by dropwise addition of R5B (53 g, 440 mmol), keeping the temperature below 0° C. After complete addition, MgSO4*H2O(91 g, 660 mmol) is added, and the resulting mixture stirred at room temperature overnight. The mixture is filtrated, the solution phase concentrated in vacuo and the residue distilled under reduced pressure to yield R5C (47 g, m/z 206 [M+H]+, rt 1.29 min, LC-MS Method V003_003). The product is used without further purification.
Step 2: A solution of R5C (47 g; 229 mmol) and R5D (30 g; 458 mmol) (freshly distilled from dicyclopentadiene) in DMF (150 ml) and 120 μl water is cooled to 0° C., before TFA (18 ml; 234 mmol) is added dropwise. The mixture is stirred overnight at room temperature, then added to a solution of 40 g NaHCO3 in 1200 ml water and extracted with diethylether. The organic layer is separated, washed subsequently with aqueous NaHCO3 and water, dried over MgSO4, and concentrated in vacuo. The residue is worked up by column chromatography on silica (cyclohexane/ethyl acetate=9:1) to yield R5E (Yield 52% m/z 272 [M+H]+, rt 0.42 min, LC-MS Method X001_004)
Step 3: To a solution of R5E (24.8 g, 91 mmol) in ethanol (250 ml), Raney-nickel is added (2.5 g) and reacted at 50 psi under a hydrogen atmosphere at room temperature. The catalyst is filtered of, the solution concentrated in vacuo and the residue worked up by chromatography on silica (cyclohexane/ethyl acetate 9:1). After evaporation of the organic solvent, the obtained product is redissolved in diethylether and triturated with solution of HCl in dioxane, concentrated in vacuo, redissolved in 200 ml ethanol and concentrated in vacuo to yield R5F: (Yield 78% m/z 274 [M+H]+, rt 0.42 min, LC-MS Method X001_004).
Step 4: To a solution of R5F (22 g, 71 mmol) in ethanol (250 ml), 10% Pd/C is added (2.5 g) and reacted at 15 bar under a hydrogen atmosphere at room temperature. The catalyst is filtered of, the solution concentrated in vacuo. The residue is washed with diisopropylether to yield R5G. (Yield 98% m/z 170 [M+H]+, rt 0.48 min, LC-MS Method V001_007).
Step 5: To R5G in a solution of triethylamine (24.6 ml), THF (150 ml) and water (2 ml), R5I (15.9 g; 73 mmol) is added and the resulting mixture stirred for 40 hours at room temperature, then concentrated in vacuo. Ethyl acetate is added to the residue, subsequently extracted with water, 1 N acidic acid and water, before the organic layer is dried over MgSO4 and concentrated in vacuo to yield R5I. (Yield 95% m/z 270 [M+H]+, rt 1.33 min, LC-MS Method V003_003).
Step 6: A mixture of R5I (16.9 g; 63 mmol) in acetone (152 ml), water (50 ml) and lithium hydroxide (3 g, 126 mmol) is stirred overnight at room temperature. Water (100 ml) was added, the volume reduced in vacuo before cooling to 0° C. followed by the addition of 1N aqueous HCl to acidify to a pH of 2-3, immediately followed by extraction with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and concentrated. To the residue, dichloromethane (100 ml) and cyclohexane (100 ml) was added, the volume reduced in vacuo by half and the mixture temperated at 15° C. The precipitate was filtered of, washed with cyclohexane to yield R5 (Yield 66%, m/z 242 [M+H]+).
Synthesis of (2S)-2-amino-3-(4-bromo-2-fluoro-phenyl)propanamide (R6)









To R1 (10.0 g, 27.7 mmol) in DCM (70 mL) TFA (25 mL, 162.0 mmol) is added and the reaction mixture is stirred for 12 h. Then the reaction mixture is concentrated, the residue is dissolved in DCM and diisopropylether is added. The product precipitates and is filtered by suction and washed with diisopropylether. Yield >95% m/z 261 [M+H]+, rt 0.67 min, LC-MS Method V018_S01.
The following intermediate as shown in Table 38.1 is synthesized in a similar fashion from the appropriate intermediates:









TABLE 38.1



Intermediate
Structure
m/z [M + H]+
rt (min)
LC-MS method



R6.1









217
0.08
Z011_S03

















For R6.1 the reaction time is 2 h. After the reaction mixture is concentrated, the crude residue is freeze-dried and used without further purification for the next step.
Synthesis of 2-Amino-3-(1H-indazol-5-yl)propanamide (R14)

Step 1: Synthesis of Intermediate I-8.3

1,1,3,3,-Tetramethylguanidin (0.44 mL, 3.51 mmol) in THF (5 mL) is cooled down to −70° C. Educt R22 (1.00 g, 3.36 mmol) is dissolved in 5 mL THF and is added. The mixture is stirred for 5 min before R15 (0.49 g, 3.36 mmol)—also dissolved in 5 mL THF—is added dropwise. The cooling is removed and the mixture warms up to room temperature. The reaction mixture is heated to 80° C. for 12 h. Because of remaining educt Tetramethylguanidin and R22 are added twice and the mixture is stirred at 80° C. for additional 4 h. The reaction mixture is concentrated. Ethyl acetate and water are added to the residue. 1 M sulfuric acid is added and the organic layer is separated, is dried over MgSO 4 and concentrated. Yield 87%, m/z 318 [M+H]+, rt 0.97 min, LC-MS Method V011_S01.
The following intermediate as shown in Table 39 is synthesized in a similar fashion from the appropriate intermediate:
TABLE 39 LC-MS Intermediate Structure m/z [M + H]+ rt (min) method I-8.3.1 318 1.00 V012_S01
Step 2: Synthesis of Intermediate I-8.4

To I-8.3 (925 mg, 2.91 mmol) in methanol (30 mL) Pd/C (10%, 130 mg) is added. The reaction mixture is stirred under hydrogen (3 bar) for 16 h. Then the mixture is filtered and the filtrate is concentrated. The residue is triturated with diethyl ether and the product is filtered by suction. Yield 88%, m/z 320 [M+H]+, rt 0.99 min, LC-MS Method V011_S01.
The following intermediate as shown in Table 40 is synthesized in a similar fashion from the appropriate intermediate:
TABLE 40 m/z LC-MS Intermediate Educt Structure of Intermediate [M + H]+ rt (min) method I-8.4.1 I-8.3.1 320 0.96 V011_S01
Step 3: Synthesis of Intermediate I-8.5

To I-8.4 (820 mg, 2.57 mmol) in methanol (15 mL) sodium hydroxide solution (2.5 mL, 1 mol/L) is added. The reaction mixture is heated to 40° C. for 2 h. The mixture is concentrated partially and 1 M HCl is added to neutralization. The precipitation is filtered with suction, is dissolved in methanol and concentrated quickly. Yield 65%, m/z 306 [M+H]+, rt 0.57 min, LC-MS Method V011_S01.
The following intermediate as shown in Table 41 is synthesized in a similar fashion from the appropriate intermediate:
TABLE 41 m/z LC-MS Intermediate educt Structure [M + H]+ rt (min) method I-8.5.1 I-8.4.1 306 0.55 V011_S01
Step 4: Synthesis of Intermediate I-8.6

To I-8.5 (400 mg, 1.31 mmol) in DMF (5 mL) diisopropylethylamine (502 μL, 2.88 mmol) and TBTU (421 mg, 1.31 mmol) are added and the reaction mixture is stirred for 15 min. Then aq. 30% ammonia solution (545 μL, 9.61 mmol) is added and the mixture is stirred for additional 12 h. Water is added to the reaction mixture and extracted with ethyl acetate. The organic layer is washed with brine and saturated NaHCO 3 solution, is dried over MgSO 4 and concentrated. Yield 55%, m/z 305 [M+H]+, rt 0.75 min, LC-MS Method V011_S01.
The following intermediate as shown in Table 42 is synthesized in a similar fashion from the appropriate intermediate:










TABLE 42






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



I-8.6.1
I-8.5.1









327 [M + Na]+
0.77
V011_S01



I-8.6.2
commercially available









315
n.d.
n.d.




















For I-8.6.2 N-methylmorpholine is used instead of diisopropylethylamine (in analogy to synthesis of R1)
Step 5: Synthesis of R14
To I-8.6 (130 mg, 0.43 mmol) in DCM (3 mL) TFA (358 μL, 0.47 mmol) is added and the reaction mixture is heated to 30° C. for 12 h. Then the reaction mixture is concentrated. Yield >95%.
The following intermediate as shown in Table 43 is synthesized in a similar fashion from the appropriate intermediate:










TABLE 43






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



R14.1
I-8.6.1









227 [M + Na]+
0.53
V011_S01



R14.2
I-8.6.2









214
0.31
X012_S01




















Synthesis of 5-bromo-2-methyl-isoindoline (R4)









The pH of a mixture of R26 (1.85 g, 7.9 mmol) in methanol (100 mL) and water (10 mL) is adjusted to ˜5 with acetic acid. Then a 37% formalin solution (1.28 mL, 15.8 mmol) is added and the mixture is stirred for 15 min. Sodium cyanoborohydride (0.74 g, 11.8 mmol) is added and the reaction mixture is stirred for additional 12 h. The mixture is concentrated and ethyl acetate and aq. 1 M NaOH solution are added to the residue. The organic layer is washed with NaCl solution, dried over MgSO 4 and concentrated. The residue is dissolved in diethyl ether and ethereal HCl is added dropwise. The resulting precipitate is filtered off. Yield 62% m/z 212/214 [M+H]+, rt 0.65 min, LC-MS Method V012_S01.
Synthesis of 1-(4-bromo-benzenesulfonyl)-4-methyl-piperazine (R34)









R33 (800 mg, 3.1 mmol) is dissolved in DCM, N-methyl-piperazine (313 mg, 3.1 mmol) is added and stirred for 12 h. After addition of 2 mL 1N HCl under stirring the phases are separated. The organic phase is dried over MgSO 4 and after filtration evaporated in vacuo. Yield: 84% m/z 319 (M+H)+.
The following intermediates as shown in Table 44 are synthesized in a similar fashion from the appropriate intermediate:










TABLE 44






m/z
rt
LC-MS

Intermediate
Educt
Structure of Intermediate
[M + H]+
(min)
method



R34.1
R33









304
n.d.
n.d.



R34.2
R33









306
n.d.
n.d.



R34.3
R33









340
0.64
X012_S01



R34.4










337/339
0.36
X012_S01



R34.5
R33









333/335
0.36
X012_S01


























For R34.4 and R34.5 additional 2 eq. of DIPEA are added to the reaction mixture.
Synthesis of Reagent R37

Step 1: Synthesis of R36

R35 (200 μL, 1.448 mmol) is dissolved in 10 mL methanol. Cyanamide (79.112 mg, 1.882 mmol), potassium tert-butoxide (194.9 mg, 1.737 mmol) and N-bromosuccinimide (386.282 mg, 2.171 mmol) are added and stirred for 1 h at room temperature. The product is purified by preparative HPLC (Waters 30×100 mm, 10 μm, sunfire RP18, acetonitrile/water/TFA). The fractions containing the product are combined and lyophilized. Yield 87%, m/z 244 [M+H]+, rt 0.62 min, LC-MS Method Z018_S04.
In analogy the following reagent as shown in Table 45 is prepared:
TABLE 45 m/z rt LC-MS Intermediate Educt Structure [M + H]+ (min) method R36.1 commercially available 243 0.64 Z018_S04
Step 2: Synthesis of R37

R36 (335 mg, 1.378 mmol) is dissolved in 3 mL ethanol. Potassium carbonate (571.315 mg, 4.134 mmol) and 3-chloroperbenzoic acid (356.696 mg, 2.067 mmol) are added at 0° C., and the mixture is stirred for 2 h at room temperature. The solvent is evaporated in vacuo and the residue is dissolved in DMF. The product is purified by preparative HPLC (Waters 30×100 mm, 10 μm, sunfire RP18, acetonitrile/water/TFA). The fractions containing the product are combined and lyophilized Yield 71%, m/z 260 [M+H]+, rt 0.68 min, LC-MS Method Z018_S04.
In analogy the following reagent as shown in Table 46 is prepared:










TABLE 46






m/z



Inter-


[M +
rt
LC-MS

mediate
Educt
Structure of Intermediate
H]+
(min)
method



R37.1
R36.1









259
0.67
Z011_S03



















Synthesis of 1-[13-[4-(bromomethyl)-3-fluoro-phenyl]-5-methyl-pyrazol-1-yl]ethanone (R13)

Step 1: Synthesis of Intermediate I-13.1

To potassium tert.-butylate (7.4 g, 65.6 mmol) in anhydrous THF (300 mL) is added crown ether 18-6 (12.2 g, 46.0 mmol). The mixture is cooled down to 0° C. and R28 (5.0 g, 32.9 mmol) is added and stirred for 15 min at room temperature. Then acetic acid methyl ester (5.2 mL 65.7 mmol) is added and the reaction mixture is stirred for additional 1 h. The mixture is concentrated and the residue is purified via flash chromatography (cyclohexane/ethyl acetate=95:5). Yield 79%, m/z 195 [M+H]+, rt 0.66 min, LC-MS Method V011_S01.
Step 2: Synthesis of Intermediate I-13.2
To I-13.1 (5.1 g, 26.1 mmol) 1 M hydrazine solution in THF (78.2 mL, 78.2 mmol) is added and the reaction mixture is heated to 80° C. for 12 h. The reaction mixture is concentrated and the residue is purified via flash chromatography (cyclohexane/ethyl acetate=70:30). Yield 90%, m/z 191 [M+H]+, rt 1.01 min, LC-MS Method V011_S01.
Step 3: Synthesis of Intermediate I-13.3
I-13.2 (1.00 g, 5.3 mmol) and acetic acid anhydride (5.00 mL, 53.0 mmol) are stirred for 12 h. Water and methanol are added to the reaction mixture, the precipitate is filtered by suction and dried in vacuo. Yield 87%, m/z 233 [M+H]+, rt 1.31 min, LC-MS Method V011_S01.
Step 4: Synthesis of R13
To I-13.3 (0.95 g, 4.1 mmol) in DCM (25 mL) is added N-bromo succinimide (0.80 g, 4.5 mmol) and 2,2′-azobis(isobutyronitrile) (50 mg). The reaction mixture is refluxed for 12 h under radiation with an Hg lamp. The mixture is concentrated and the residue is purified via flash chromatography (cyclohexane/DCM=75:25). Yield 39%, m/z 311 [M+H]+, rt 1.43 min, LC-MS Method V018_S01.
Synthesis of 6-bromo-2-methyl-3,4-dihydroisoquinolin-1-one (R32)









R31 (500 mg, 2.2 mmol) in DMF (3 mL) is cooled down to 0° C. Under argon atmosphere NaH (60%, 121 mg, 3.0 mmol) is added and stirred for 20 min. Then methyl iodide (0.275 mL, 4.4 mmol) is added and the mixture is stirred for additional 1 h at 0° C. Ice water is added to the reaction mixture and the precipitate is filtered by suction and dried at 50° C. in the vacuum oven for 12 h. Yield 73%, m/z 240/242 [M+H]+, rt 0.89 min, LC-MS Method V012_S01.
Synthesis of tert-butyl 2-(bromomethyl)-9H-carbazole-9-carboxylate (R13.1 for Synthesis of I-7.1.3)

Step 1: Synthesis of Intermediate I-15.1

3-Methyl-diphenylamine R38 (1.0 g, 5.5 mmol), K 2 CO 3 (75 mg, 0.55 mmol) and palladium acetate (37 mg, 0.16 mmol) in 2,2-dimethyl-1-propanol (5 mL) is stirred at 110° C. for 14 h. Water is added to the reaction mixture and extracted with dichloromethane. The combined organic layer is concentrated in vacuo, residue triturated with methanol/dichloromethane and dried in vacuo and directly taken to the next step. Yield 29%, m/z 182 [M+H]+, rt 0.67 min, LC-MS Method X012_S01.
Step 2: Synthesis of Intermediate I-15.2
I-15.1 (285 mg, 1.6 mmol), di-tert.-butyl dicarbonate (412 mg, 1.9 mmol) and DMAP (50 mg, 0.41 mmol) in dichloromethane (10 ml) are stirred at room temperature for 16 hours. The reaction mixture extracted with water, the organic layer is separated and concentrated in vacuo and directly taken to the next step. Yield 86%, m/z 282 [M+H]+, rt 0.89 min, LC-MS Method X012_S01.
Step 3: Synthesis of Intermediate R13.1
I-15.2 (380 mg, 1.4 mmol), N-bromosuccinimide (289 mg, 1.6 mmol), AIBN (20 mg, 0.12 mmol) in tetrachloromethane (5 mL) is heated to reflux over 16 h. Water and dichloromethane are added to the reaction mixture, the organic layer separated and concentrated. The residue is triturated with methanol and used directly in the next step. Yield 41%, m/z 360 [M+H]+, rt 0.67 min, LC-MS Method V011_S01.
Synthesis of tert-butyl 3-(chloromethyl)-9H-carbazole-9-carboxylate (R13.2 for Synthesis of I-7.1.6)

Step 1: Synthesis of Intermediate I-16.1

9H-Carbazole-3-carboxylic acid R39 (500 mg, 2.4 mmol), in methanol (20 mL) is cooled to 0° C. Thionylchloride (206 ml, 2.8 mmol) is added dropwise to the stirred mixture at this temperature. The mixture is then stirred at room temperature for 16 hours. The formed precipitate is filtered and dried in vacuo and directly taken to the next step. Yield 53%, m/z 226 [M+H]+, rt 0.59 min, LC-MS Method X012_S01.
Step 2: Synthesis of Intermediate I-16.2
I-16.1 (280 mg, 1.2 mmol), di-tert.-butyl dicarbonate (326 mg, 1.5 mmol) and DMAP (50 mg, 0.41 mmol) in dichloromethane (10 ml) are stirred at room temperature for 16 hours. The reaction mixture extracted with water, the organic layer is separated and concentrated in vacuo and directly taken to the next step. Yield 99%, m/z 326 [M+H]+, rt 0.84 min, LC-MS Method X012_S01.
Step 3: Synthesis of Intermediate I-16.3
I-16.2 (400 mg, 1.2 mmol) and boronhydride-tetrahydrofuran adduct (1,2 ml 1M in THF, 1.2 mmol) are dissolved in THF (5 ml). LiBH4 is repeatedly added in small portions at 50° C., until HPLC shows completion of reaction. Water and dichloromethane are added to the reaction mixture, the organic layer separated, concentrated and purified via HPLC. Yield 40%, m/z 280 [M−H2O+H]+, rt 0.70 min, LC-MS Method X012_S01.
Step 4: Synthesis of Intermediate R13.2
I-16.3 (145 mg, 0.5 mmol) and DIPEA (171 μl, 1.0 mmol) are dissolved in dichloromethane (10 ml) and cooled to −10° C. Methanesulfonylchloride (46 μl, 0.6 mmol) in dichloromethane (1 ml) is added dropwise. After complete addition, the mixture is stirred for 16 h at room temperature. Water is added to the reaction mixture, the organic layer separated, concentrated in vacuo to yield R13.2, which is directly taken to the next step. Yield 73%, rt 0.87 min, LC-MS Method X012_S01.
Synthesis of 2-(chloromethyl)-9,10-dihydrophenanthrene (R13.3 for Synthesis of I-7.1.4)

Step 1: Synthesis of Intermediate I-17.1

2-Acetyl-9,10-dihydro-phenanthrene R40 (1.0 g, 4.5 mmol) is added to solution of bromine (924.7 μl, 18 mmol) and KOH (3.3 g, 58.5 mmol) in water (20 ml) at 0° C. After addition is completed, the reaction mixture is heated to 55° C. for 16 hours. The mixture is cooled to r.t., extracted with dichloromethane. The aqueous phase is separated, acidified with 1 M HCl aq and the precipitating product is filtered off and dried in vacuo at 50° C. Yield 92%, m/z 225 [M+H]+, rt 0.62 min, LC-MS Method X012_S01.
Step 2: Synthesis of Intermediate I-17.2
I-17.1 (930 mg, 4.2 mmol) is dissolved in THF (10 ml), CDI (874 mg, 5.4 mmol) is added in small portions and the mixture is stirred for 1 h at 50° C. The mixture is added slowly to sodium borohydride (470 mg, 12.4 mmol) in ice water, so that the temperature remains below 10° C. The mixture is stirred for 16 hours at r.t. and extracted with dichloromethane/water. The organic layer is separated and concentrated in vacuo, the remaining crude product purified via HPLC. Yield 53%, m/z 210 [M]+, 193 [M−H 2 O]+, rt 0.61 min, LC-MS Method X012_S01.
Step 3: Synthesis of Intermediate R13.3
I-17.2 (460 mg, 2.2 mmol), DIPEA (766 μl, 4.4 mmol) are dissolved in dichloromethane (10 ml) and cooled to −10° C. Methanesulfonylchloride (207 μl, 2.6 mmol) in dichloromethane (1 ml) is added dropwise. After complete addition, the mixture is stirred for 16 h at room temperature. Water is added to the reaction mixture, the organic layer separated, concentrated in vacuo and the remaining crude product purified via HPLC. Yield 67%, m/z 228 [M]+, rt 0.79 min, LC-MS Method X012_S01.
Synthesis of 6-Aza-tricyclo[3.2.1.0*2,4*]octane-6,7-dicarboxylic acid 6-tert-butylester (R6.2)

Step 1: Synthesis of Intermediate R29.2

Dicyclopenta-1,3-diene is cracked and distilled at 42° C. and 1013 mbar to give cyclopenta-1,3-diene.
Ethyl 2-oxoacetate is also freshly distilled from a commercially available solution in toluene.
Assumed concentration is 50%.
To N-boc-imino-(triphenyl)phosphorane (11.32 g, 30.00 mmol) in toluene (100 mL) is added ethyl 2-oxoacetate (15 mL, 60.00 mmol) and cyclopenta-1,3-diene (5 mL, 60.00 mmol) and stirred overnight at r.t. The reaction mixture is concentrated and the crude residue is purified over silica gel (cyclohexane/ethyl acetate 7:3). Yield 16%
R29.2 can be obtained through preparative chiral chromatography from this mixture of R29.1 and R29.2 (table 46.1) using method Chiral SFC G.
TABLE 46.1 Intermediate Structure of Intermediate R29.1 R29.2
Step 2: Synthesis of Intermediate I-14.1

To R29.2 (5.00 g, 18.7 mmol) in diethylether (100 mL) is added palladium(II) acetate (0.42 g, 1.87 mmol). Under stirring diazomethane solution in diethylether (62 mmol) is added. The reaction mixture is stirred for 12 h. To destroy remaining diazomethane, silica gel and 3 mL acetic acid are added. Then the mixture is stirred for additional 1 h and filtrated. The solution is concentrated and extracted with DCM, water and brine. Yield 98%, m/z 226 [M+H-tButyl]+, rt 0.64 min, LC-MS Method X012_S01.
Step 3: Synthesis of R6.2
To I-14.1 (5.40 g, 19.2 mmol) in dioxane (60 mL) is added aq. 4 M NaOH (20 mL, 80 mmol). The reaction mixture is heated to 50° C. for 3 h. The mixture is extracted two times with DCM, then the water layer neutralized with 2 M HCl and extracted three times with DCM. The combined organic layers are dried over MgSO 4 and concentrated. The residue is dissolved in diethylether and evaporated, the product crystallizes. Yield 88%, m/z 198 [M+H-tButyl]+, rt 0.48 min, LC-MS Method X012_S01.
Synthesis of 1-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (R7)

Step 1: Synthesis of Intermediate I-12.1

To R27 (25.0 g, 111 mmol) in acetonitrile (750 mL) is added Met (15 mL, 241 mmol) and K 2 CO 3 (60.0 g, 434 mmol) and the reaction mixture is stirred at 60° C. for 2 h. The reaction mixture is filtered and concentrated. Water and ethyl acetate are added to the residue. The organic layer is extracted twice with water, dried over MgSO 4 and concentrated. Yield 56%, m/z 240/242 [M+H]+, rt 0.48 min, LC-MS Method X001_004.
The following intermediates as shown in Table 47 are synthesized in a similar fashion from the appropriate intermediates:









TABLE 47







LC-MS

Intermediate
Structure
m/z [M + H]+
rt (min)
method



I-12.1.1









311/313
0.362
Z020_S01



I-12.1.2









n.d.
n.d.
n.d.



I-12.1.3









211/213
0.55
X012_S01



I-12.1.4









n.d.
n.d.
n.d.



I-12.1.5









245
0.21
X012_S01



I-12.1.6









n.d.
n.d.
n.d.



I-12.1.7









268
0.71
X012_S01



I-12.1.8









211/213
0.55
X012_S01
































For I-12.1.1, I-12.1.2, I-12.1.3, I-12.1.5, I-12.1.7 and I-12.1.8 sodium hydride and DMF is used instead of potassium carbonate and ACN.
For I-12.1.3, I-12.1.7 and I-12.1.8 the reaction temperature is r.t.
For I-12.1.4 DMF is used.
For I-12.1.6 the reaction conditions differ: 1,1-Difluoro-2-trifluoromethanesulfonyl-ethane is used as alkylation reagent in triethylamine as solvent at r.t.
Step 2: Synthesis of Intermediate I-12.2
I-12.1 (15.0 g, 63 mmol) and hydrazine hydrate (30 mL, 618 mmol) are heated to 125° C. for 72 h. To the cool reaction mixture DCM is added and extracted with water and 1 M HCl. The organic layer is dried over MgSO 4 and concentrated. The crystallized residue is dissolved in DCM, methanol is added and the DCM is removed in vacuo. The crystallized product is filtered by suction and washed with cold methanol. Yield 63%, m/z 226/228 [M+H]+, rt 1.16 min, LC-MS Method V001_003.
The following intermediates as shown in Table 48 are synthesized in a similar fashion from the appropriate intermediates:
TABLE 48 m/z rt Intermediate Structure [M + H]+ (min) LC-MS method I-12.2.1 n.d. n.d. n.d. I-12.2.2 283/285 0.832 n.d. I-12.2.3 n.d. n.d. n.d.
Step 3: Synthesis of Intermediate R7

To I-12.2 (32.0 g, 142 mmol) in anhydrous dioxane (400 mL) is added R3 (54.4 g, 241 mmol) and potassium acetate (41.6 g, 424 mmol). The mixture is purged with Argon, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a complex with dichloromethane (11.2 g, 14 mmol) is added and the mixture is heated to 90° C. for 2 h. The reaction mixture is diluted with ethyl acetate and water, the organic layer is washed with water, dried over MgSO 4 and concentrated. The residue is purified via flash chromatography (cyclohexane/EA=70:30). Yield 72%, m/z 274 [M+H]+, rt 0.67 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 49 are synthesized in a similar fashion from the appropriate intermediates:









TABLE 49






rt


Intermediate
Structure
m/z [M + H]+
(min)
LC-MS method



R7.1









325 [M + NH 4 ]+
0.30
X018_S01



R7.2









276 [M + H]+
0.94
X002_002



R7.3









n.d.
n.d.
n.d.



R7.4









318
0.92
Z018_S04



R7.5









302
n.d.
n.d.



R7.6









294
0.85
Z018_S04



R7.7









260
0.65
X001_004



R7.8









n.d.
n.d.
n.d.



R7.9









280
0.63
X001_002


































Synthesis of Boronic Ester R7.6
2 g (10.3 mmol) 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2.9 mL (20.6 mmol) 4-(iodomethyl)-tetrahydro-2H-pyran are dissolved in 200 mL DMF and 4.274 g (30.9 mmol) K 2 CO 3 are added. The mixture is shaken at 80° C. for 5 h. After cooling to r.t. the mixture is filtered, the filtrate is concentrated in vacuo to approximately 60 mL. The product is separated using HPLC-MS (Gilson, mass flow 120 mL/min, 10 μm, 200 g Sunfire RP18, ACN/water/TFA). The product fractions are combined and freeze-dried to yield 115 mg product (3.8%) R7.6.
Synthesis of Boronic Ester R7.8
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.56 mmol) and pyridine (10 mL) are cooled down with an ice bath. Methanesulfonyl chloride (0.933 mL, 12.01 mmol) is dissolved in dichlormethane (10 mL) and added slowly dropwise. The reaction mixture is allowed to come to room temperature and concentrated. The residue is diluted with dichlormethane and water. The organic layer is separated, dried and concentrated. The crude product is used without further purification. Yield: >95%
Synthesis of Boronic Ester R7.9
Under nitrogen atmosphere to sodium hydride (50%) (0.218 g, 4.54 mmol) and DMF (3 mL) is added 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.5 g, 2.5 mmol) and stirred for 30 min at r.t. N-(2-chloroethyl)acetamide (0.775 mL, 7.52 mmol) is added and stirred at 90° C. overnight. Due to no reaction N-(2-chloroethyl)acetamide (0.26 mL) and copper(I)iodide (25 mg, 0.13 mmol) are added and stirred at 90° C. for 24 h. The reaction mixture is diluted with methanol, filtered through a thiol cartridge and concentrated. The crude product is used without further purification. Yield: 100%
All other boronic acid derivatives R9 and R16 and alkynes R10 are purchased or prepared by literature known procedures.
Synthesis of tert-butyl(1S,2S,4R)-2-(1-methoxycarbonylvinylcarbamoyl)-3-azabicyclo[2.2.1]heptane-3-carboxylate R41

Step 1: Synthesis of Intermediate I-22.1

To R5 (500 mg, 2.07 mmol) in DMF (5 mL) are added HATU (866.72 mg, 2.28 mmol) and DIPEA (1.43 mL, 8.29 mmol) and stirred at r.t. for 15 min To the reaction mixture is added methyl 2-amino-3-hydroxy-propanoate hydrochloride (354.64 mg, 2.28 mmol) and stirred at r.t. for 4 h. The reaction mixture is diluted with ACN and water and purified by reversed phase HPLC. Yield 79%, m/z 343 [M+H]+, rt 0.44 min, LC-MS Method X011_S03.
Step 2: Synthesis of R41
I-22.1 (100 mg, 0.29 mmol) is dissolved in dichlormethane (2 mL) and cooled down to 0° C. 4-dimethylamino pyridine (1.78 mg, 0.015 mmol), TEA (65.13 μL, 0.47 mmol) and methansulfonyl chloride (29.59 μL, 0.38 mmol) are added and stirred at r.t. for 3 h. The reaction mixture is diluted with sodium carbonate solution. The organic layer is separated, dried and concentrated. The crude residue is purified by reversed phase HPLC.
Yield 27%, m/z 324 [M+H]+, rt 0.63 min, LC-MS Method X011_S03.
Synthesis of methyl(E)-2-(benzyloxycarbonylamino)-3-[4-(1,4-dimethyl-4-piperidyl)-2-fluoro-phenyl]prop-2-enoate (R42)

Step 1: Synthesis of Intermediate I-23.1

To 1-fluoro-2-methoxy-benzene (25 mL, 222.79 mmol) and 1,4-dimethylpiperidin-4-ol (7 g, 54.18 mmol) is added trifluoromethanesulfonic acid (50 mL, 565.04 mmol) under ice bath cooling. The reaction mixture is stirred at r.t. overnight, poured into iced water and extracted with PE. To the aqueous phase is added solid sodium carbonate and extracted with ethyl acetate. The organic layer is dried and concentrated. The crude product is triturated with diisopropylether and the precipitate is filtered off. Yield 82%, m/z 238 [M+H]+, rt 0.39 min, LC-MS Method X018_S02.
Step 2: Synthesis of Intermediate I-23.2
To I-23.1 (16.9 g, 43.63 mmol) in dichlormethane (150 mL) is added boron tribromide 1M in dichlormethane (44 mL, 44 mmol) and stirred at r.t. overnight. The reaction mixture is diluted with dichlormethane and 10% K 2 CO 3 -solution. The resulting precipitate is filtered off. The aq. layer is repeatedly extracted with dichlormethane, the precipitate formed upon standing at rt is filtered off and washed with dichlormethane. The dichloromethane phase is concentrated and purified by reversed HPLC and freeze dried. The isolated precipitates and the corresponding HPLC fractions are combined to yield the desired product.
Yield 18%, m/z 224 [M+H]+, rt 0.61 min, LC-MS Method V011_S01.
Step 3: Synthesis of Intermediate I-23.3
To I-23.2 (1.4 g, 6.27 mmol) in anhydrous dichlormethane (40 mL) triethylamine (1.8 mL, 12.985 mmol) is added and cooled down to −20° C. Trifluoromethanesulfonic acid anhydride (1.1 mL, 6.538 mmol) is added dropwise and stirred at −10° C. for 30 min. The reaction mixture is diluted with dichlormethane, washed with K 2 CO 3 -solution and brine. The organic layer is dried and concentrated. The crude product is used for the next step without further purification. Yield 98%, m/z 356 [M+H]+, rt 1.30 min, LC-MS Method V011_S01.
Step 4: Synthesis of R42
2-benzyloxycarbonylamino-acrylicacidmethylester (2.274 g, 9.67 mmol), bis(dibenzylideneacetone) palladium (0) (295 mg, 0.32 mmol), (2-biphenylyl)di-tert-butylphosphine (345 mg, 1.156 mmol) and lithium chloride (710 mg, 16.73 mmol) are purged with argon. I-23.3 (2.29 g, 6.44 mmol) is dissolved in DMF (15 mL) and triethylamine are added and stirred at 80° C. overnight.
The reaction mixture is concentrated, then diluted with dichlormethane and washed with 5% K 2 CO 3 -solution. The organic layer is dried and concentrated. The crude product is purified by reversed phase HPLC.
Yield 33%, m/z 441 [M+H]+, rt 1.23 min, LC-MS Method V011_S01.
The following intermediate as shown in Table 50 is synthesized in an analogous manner from the appropriate intermediate R41 and R91:









TABLE 50





m/z



Intermediate
Structure
[M + H]+
rt (min)
LC-MS method



R42.1









558
0.47
X018_S01


















Synthesis of (2S)-2-amino-3-(4-benzyloxy-2-fluoro-phenyl)propanamide hydrochloride (R47)

Step 1: Synthesis of Intermediate I-24.1

R22 (22.58 g, 75.97 mmol) in Me-THF (50 mL) is cooled down to −10° C., 1,1,3,3-tetramethylguanidine (9.55 mL, 75.97 mmol) is added and stirred for 30 min. 4-benzyloxy-2-fluoro-benzaldehyde (15.9 g, 69.06 mmol) dissolved in 100 mL Me-THF is added dropwise and stirred for 3 h at −10° C. to 0° C. The cooling is removed and the mixture warms up to room temperature.
The reaction mixture is diluted with 300 mL Me-THF and extracted with water. The organic layer is treated with activated carbon, dried over MgSO 4 and concentrated.
The crude product is recristallized with cyclohexane and filtered off.
Yield 97%, m/z 402 [M+H]+, rt 0.80 min, LC-MS Method X018_S01.
The following intermediate as shown in Table 50.1 is synthesized in an analogous manner from the appropriate intermediates:
TABLE 50.1 m/z rt Intermediate Structure [M + H]+ (min) LC-MS method I-24.1.1 374/376 0.77 X018_S02
Step 2: Synthesis of Intermediate I-24.2

I-24.1 (2.8 g, 6.98 mmol) and (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I) trifluoromethanesulfonate (250 mg, 0.346 mmol) in methanol (60 mL) are stirred under hydrogen (50 psi) at r.t. for 2 h. Then the mixture is filtered and the filtrate is concentrated. Yield 100%, m/z 404 [M+H]+, rt 1.40 min, LC-MS Method V001_S01.
The following intermediates as shown in Table 51 are synthesized in an analogous manner from the appropriate intermediates:
TABLE 51 m/z rt Intermediate Structure [M + H]+ (min) LC-MS method I-24.2.1 443 1.24 V011_S01 I-24.2.2 560 0.68 X011_S03 I-24.2.3 376 n.d. n.d.
Step 3: Synthesis of Intermediate I-24.3

I-24.2 (2.95 g, 6.95 mmol) is dissolved in anhydrous methanol (15 mL). Calcium chloride (812 mg, 7.32 mmol) and ammonia in methanol 7N (15 mL, 10.5 mmol) is added and stirred at r.t. overnight. The reaction mixture is diluted with water (45 mL) and the precipitate is filtered off and washed with water.
Yield 90%, m/z 389 [M+H]+, rt 0.65 min, LC-MS Method X011_S03.
The following intermediate as shown in Table 52 is synthesized an analogous manner from the appropriate intermediates:









TABLE 52





m/z
rt


Intermediate
Structure
[M + H]+
(min)
LC-MS method



I-24.3.1









428
1.05
V011_S01



I-24.3.2









545
0.57
X011_S03



I-24.3.3









361/363
0.64
X018_S02






















Intermediate I-24.3.1 is purified by reversed phase HPLC.
Step 4: Synthesis of R47
To I-24.3 (2.42 g, 6.23 mmol) in dichlormethane (20 mL) is added HCl in dioxane 4 mol/L (7.79 mL, 31.15 mmol) and stirred at r.t. for 3 h. The reaction mixture is diluted with TBME and the precipitate is filtered off and washed with TBME.
Yield 95%, m/z 289 [M+H]+, rt 0.50 min, LC-MS Method X011_S03.
The following intermediate as shown in Table 52.1 is synthesized in an analogous manner from the appropriate intermediates:









TABLE 52.1



Inter-

m/z
rt
LC-MS

mediate
Structure
[M + H]+
(min)
method



R47.1









261/263
0.31
X018_S02


















Synthesis of (25)-2-amino-3-[4-(1,4-dimethyl-4-piperidyl)-2-fluoro-phenyl]propanamide R49









I-24.3.1 (625 mg, 1.46 mmol) and Pd/C 10% (150 mg) in methanol (60 mL) is stirred under hydrogen (50 psi) at r.t. for 3.5 h. The reaction mixture is filtered and concentrated. Yield 99%, m/z 294 [M+H]+, rt 0.80 min, LC-MS Method V011_S01.
Synthesis of (1-ethyl-3,6-dihydro-2H-pyridin-4-yl) trifluoromethanesulfonate (R51)









The reaction is carried out under argon atmosphere.
Diisopropylamine (5.289 mL, 38 mmol) in anhydrous THF (25 mL) is cooled down to −50° C. N-butyllithium in hexane 2.5M (13.786 mL, 34.47 mmol) is added dropwise and stirred for 45 min, then the solution is allowed to warm up to 0° C. and cooled down to −50° C. again. 1-Ethyl-4-piperidone (4 g, 31.45 mmol) dissolved in 30 mL THF is added dropwise and stirred for 30 min R18 (11.797 g, 33.02 mmol) dissolved in 30 mL THF is added dropwise. The cooling is removed and the reaction mixture stirred for 2 h.
The reaction mixture is diluted with 50 mL toluene. The organic layer is washed with 1N sodium hydroxide, half saturated brine, dried and concentrated. The residue is purified over silica gel.
Yield 15%, m/z 260 [M+H]+, rt 0.30 min, LC-MS Method X012_S01.
The following intermediates as shown in Table 53 are synthesized in an analogous manner from the appropriate intermediates:









TABLE 53





m/z
rt


Intermediate
Structure
[M + H]+
(min)
LC-MS method



R51.1









274
n.d.
n.d.



R51.2









n.d.
n.d.
n.d.



R51.3









n.d.
n.d.
n.d.



R51.4









322
1.41
V011-S01



R51.5









316
1.23
Z012_S04



R51.6









308
1.38
V11_S01




























For Intermediate R51.2, R51.3, R51.4 and R51.6 the reaction conditions differ: lithium bis(trimethylsilyl)amide is used and the reaction is carried out at −78° C. The crude product is used for the next step without further purification.
Intermediate R51.4 is purified over silica gel.
For Intermediate R51.5 the reaction conditions differ: lithium bis(trimethylsilyl)amide is used and the reaction is carried out at −50° C. The crude product is purified over silica gel.
Synthesis of (5-ethyl-1-isobutyl-pyrazol-3-yl) trifluoromethanesulfonate (R54)

Step 1: Synthesis of Intermediate I-25.1

Ethyl pent-2-ynoate (300 μL, 2 mmol), isobutylhydrazine hydrate (240 μL, 2 mmol), methanol (1 mL) and water (1 mL) are stirred together in the microwave at 140° C. for 15 min.
The crude product is used for the next step without further purification.
Step 2: Synthesis R54
Intermediate I-25.1 (380 mg, 2 mmol) is dissolved in anhydrous dichlormethane (10 mL), DIPEA (1.2 mL, 6.94 mmol) is added and cooled down to 0° C. Trifluoromethylsulfonyl trifluoromethanesulfonate
(375 μL, 2.26 mmol) dissolved in dichlormethane is added dropwise and stirred for 45 min Another trifluoromethylsulfonyl trifluoromethanesulfonate (188 μL, 1.13 mmol) is added and stirred for 30 min. The reaction mixture is extracted with NaHCO 3 -solution (5%). The organic layer is separated, dried and concentrated. The residue is purified over silica gel.
Yield 21%, m/z 301 [M+H]+, rt 0.86 min, LC-MS Method X018_S02.
Synthesis of 1-bromo-3-methylsulfonyl-5-(2,2,2-trifluoroethoxy)benzene(R57)

Step 1: Synthesis of Intermediate I-26.1

3-bromo-5-methylsulfanyl-phenol (5 g, 22.82 mmol) is dissolved in dichlormethane (100 mL) and cooled down to 0° C. 3-chloroperbenzoic acid (10.23 g, 45.64 mmol) is added and stirred at r.t. overnight. The reaction mixture is diluted with dichlormethane and water. The organic layer is separated, dried and concentrated. The crude product is purified by reversed phase HPLC and freeze dried.
Yield 55%, m/z 251/253 [M+H]+, rt 0.47 min, LC-MS Method X018_S01.
Step 2: Synthesis R57
To I-26.1 (150 mg, 0.597 mmol) and potassium carbonate (206.41 mg, 1.49 mmol) in DMF is added 1,1,1-trifluoro-2-iodo-ethane (147.196 μL, 1.493 mmol) and stirred over 3 days at 85° C.
The reaction mixture is diluted with water, the precipitate is filtered off, washed with water and dried. Yield 52%, m/z 350/352 [M+H]+, rt 1.16 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 54 are synthesized in a similar fashion from the appropriate intermediates:










TABLE 54





m/z

LC-MS


Intermediate
Structure
[M + H]+
rt (min)
method
elab



R57.1









332/334 [M + NH 4 ]+
1.01
V011_S01
LG1SLA00459



R57.2









296/298 [M + NH 4 ]+
1.11
V011_S01
LG1SLA00495




















The two intermediates in the table above are purified by reversed phase HPLC.
Synthesis of 4-bromo-N1-methyl-benzene-1,2-diamine (R58)

Step 1: Synthesis of Intermediate I-36.1

To 4-bromo-2-nitro-aniline (10 g, 46.08 mmol) in DMF (200 mL) are added potassium carbonate (15 g, 108.53 mmol) and portionwise methylamine hydrochloride (3.11 g, 46.08 mmol) and stirred overnight at r.t. The reaction mixture is filtered and concentrated. The crude product is triturated with DIPE, filtered off and dried. Yield 86%
Step 2: Synthesis of R58
To I-36.1 (5.27 g, 22.81 mmol) in ethyl acetate is added platinum on carbon (550 mg) and stirred under hydrogen (5 bar) at r.t. for 4 h. The reaction mixture is filtered through a pad of celite and concentrated. The crude product is used without further purification for the next step Yield 96%
Synthesis of 5-bromo-N,1-dimethyl-benzimidazol-2-amine (R60)

Step 1: Synthesis of Intermediate I-27.1

4-bromo-1-n-methylbenzene-1,2-diamine (4.42 g, 21.98 mmol), N,N′-carbonyl-di-(1,2,3-triazole (4.178 g, 24.18 mmol), and TEA (9.184 mL, 65.95 mmol) in THF (70 mL) are stirred at r.t. for 30 min, then heated under reflux overnight. The reaction mixture is concentrated, triturated with water, filtered off and dried. The residue is triturated again with DIPE and filtered off.
Yield 88%
Step 2: Synthesis of Intermediate I-27.2
I-27.1 (4.41 g, 19.42 mmol) and phosphoroxybromide (27.84 g, 97.11 mmol) are stirred at 100° C. for 3 h. The reaction mixture is diluted with iced water. The precipitate is filtered off and triturated with DIPE.
Yield 89%
Step 3: Synthesis of R60
I-27.2 (200 mg, 0.69 mmol) and methylamine in methanol 2 mol/L (2 mL, 4 mmol) are stirred at 80° C. for 16 h. The reaction mixture is purified by reversed phase HPLC.
Yield 63%, m/z 240/242 [M+H]+, rt 0.48 min, LC-MS Method X011_S03.
Synthesis of (7R,8aR)-7-methoxy-1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine (R63)

Step 1: Synthesis of Intermediate I-28.1

To 2-(tert-butoxycarbonylamino)acetic acid (1.5 g, 8.56 mmol) and HATU (3.58 g, 9.42 mmol) in DMF (15 mL) is added DIPEA (5.89 mL, 34.25 mmol) and stirred for 15 min Methyl(2R,4R)-4-methoxypyrrolidine-2-carboxylate hydrochloride (1.675 g, 8.56 mmol) is added and stirred at r.t. overnight. The reaction mixture is diluted with dichlormethan and NaHCO 3 -solution. The organic layer is separated and washed with brine, dried and concentrated. The crude residue is purified by reversed phase HPLC.
Yield 74%, m/z 317 [M+H]+, rt 0.47 min, LC-MS Method X018_S01.
Step 2: Synthesis of Intermediate I-28.2
I-28.1 (2 g, 6.32 mmol), hydrochloric acid in dioxane 4 mol/L (10 mL, 40 mmol) and dioxane (30 mL) are stirred at r.t. overnight. The reaction mixture is directly used for the next step.
Step 3: Synthesis of Intermediate I-28.3
To the reaction mixture from the previous step is added TEA till a pH value of 8 is reached. The precipitate is filtered off and the mother liquor is concentrated to isolate the desired product. Yield 97%, m/z 185 rt 0.18 min, LC-MS Method V011_S01.
Step 4: Synthesis of R63
To lithiumaluminium hydride 1 mol/L in THF (12.215 mL, 12.215 mmol) in THF (8 mL) is added a solution of I-28.3 (900 mg, 4.886 mmol) in THF (4 mL) dropwise and stirred at r.t. for 1.5 h. Under cooling the reaction mixture is poured into aq. sodium hydroxide (1 mol/L) and diluted with THF (30 ml). The precipitate is filtered off and the mother liquor is concentrated. The residue is diluted with methanol and stirred a few minutes at 50° C. The precipitate is filtered off and the mother liquor is concentrated to give the crude product which is purified over amino phase silica gel. Yield 36%
Synthesis of 3,4,4a,5,6,7,8,8a-octahydro-2H-2,6-naphthyridin-1-one (R65)









5,6,7,8-tetrahydro-2H-2,6-naphthyridin-1-one hydrochloride (250 mg, 1.339 mmol), platinum oxide (100 mg) and glacial acetic acid (10 mL) are stirred under hydrogen (5 bar) at r.t. for 24 h.
The reaction mixture is filtered off and concentrated. The crude product is purified over amino phase silica gel.
Yield 71%.
Synthesis of 4-bromo-2-isopropyl-1-methylsulfinyl-benzene (R67)









1-isopropyl-2-methylsulfanyl-benzene (400 mg, 2.41 mmol) is dissolved in dichlormethane (4 mL) and cooled down to 0° C. Bromine (123.21 μL, 2.41 mmol) is added and stirred at r.t. for 3 days. The reaction mixture is concentrated and purified by reversed phase HPLC.
Yield 53%, m/z 261/263 [M+H]+, rt 1.06 min, LC-MS Method V011_S01.
Synthesis of (3-bromophenyl)imino-dimethyl-oxo-sulfane (R70)









1-Bromo-3-iodo-benzene (250 μL, 1.96 mmol), (methylsulfonimidoyl) methane (219.188 mg, 2.353 mmol), cesium carbonate (894.466 mg, 2.745 mmol) and dioxane (12 mL) are purged with argon. (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (85.098, 0.147 mmol) and tris(dibenzylideneacetone)dipalladium(0) (44.89 mg, 0.049 mmol) are added, purged again with argon and stirred at 105° C. for 3 h.
The reaction mixture is filtered through a pad of celite. The filtrate is concentrated and purified by reversed phase HPLC.
Yield 94%, m/z 249 [M+H]+, rt 0.74 min, LC-MS Method Z018_S04.
The following intermediate as shown in Table 55 is synthesized in a similar fashion from the appropriate intermediates:










TABLE 55





m/z

LC-MS


Intermediate
Structure
[M + H]+
rt (min)
method
elab



R70.1









318
0.83
Z018_S04
CCCYUJ00250


















Synthesis of 2-(4-amino-3-bromo-phenyl)-N-methyl-acetamide (R71)









To 2-(4-amino-3-bromo-phenyl)acetic acid (5 g, 21.73 mmol) in methanol (50 mL) and dichlormethane (100 mL) is added at −5° C. trimethylsilyldiazomethane in diethylether 2 mol/L (31.51 mL, 63.03 mmol) dropwise over a period of 30 min. The reaction mixture is allowed to warm up to r.t. and concentrated. The crude product is used without further purification. Yield 95%, m/z 244/246 [M+H]+, rt 0.48 min, LC-MS Method X011_S03.
Synthesis of 2-(4-amino-3-bromo-phenyl)-N-methyl-acetamide; 2,2,2-trifluoroacetic acid (R72)

Step 1: Synthesis of Intermediate I-29.1

4-amino-3-bromophenylacetic acid methyl ester (22 g, 81.12 mmol), di-t-butyl-dicarbonate (20.13 g, 92.22 mmol), 4-dimethylaminopyridine (991.02 mg, 8.11 mmol) and dichlormethane (300 mL) are stirred together at r.t. overnight. The reaction mixture is extracted with KHSO 4 -solution (10%), NaHCO 3 -solution and brine. The organic layer is separated, dried and concentrated. The residue is purified over silica gel.
Yield 8%, m/z 344/346 [M+H]+, rt 1.34 min, LC-MS Method V011_S01.
Step 2: Synthesis of Intermediate I-29.2
To I-29.1 (4 g, 11.62 mmol) in dioxane (50 mL) is added a solution of lithium hydroxide (400 mg, 13.95 mmol) in water (5 mL) and stirred at r.t. overnight. The precipitate is filtered by suction and dried.
Yield 91%, m/z 274/276 [M+H-isobutene]+, rt 0.29 min, LC-MS Method X011_S03.
Step 3: Synthesis of Intermediate I-29.3
To I-29.2 (150 mg, 0.45 mmol) in DMF (2 mL) is added TBTU (175.04 mg, 0.55 mmol) and after 7 min methylamine 2 mol/L in THF (0.9 ml, 1.82 mmol) is added. The reaction mixture is stirred at r.t. overnight and purified by reversed phase HPLC.
Yield 35%, m/z n.d. [M+H]+, rt 0.55 min, LC-MS Method X011_S03.
Step 4: Synthesis of R72
To I-29.3 (97 mg, 0.28 mmol) in dichlormethane (2 mL) is added trifluoracetic acid (0.5 mL) and stirred at r.t. for 1 h. The reaction mixture is concentrated.
Yield 99%, m/z 243/245 [M+H]+, rt 0.26 min, LC-MS Method X012_S01.
Synthesis of 4-amino-3-fluoro-5-iodo-benzamide (R74)

Step 1: Synthesis of Intermediate I-30.1

2-fluoro-6-iodo-4-(methoxycarbonyl)aniline (30 g, 0.1 mol), ethanol (300 mL) and NaOH 20% (30 mL) are stirred together under reflux for 2 h. The reaction mixture is diluted with water and acidified with KHSO 4 -solution (1 mol/L). The precipitate is filtered off and recristallized with ethanol.
Yield 86%
Step 2: Synthesis of R74
To I-30.1 (26 g, 0.092 mol) in DMF (200 mL) is added 1,1′-carbonyldiimidazole (17.8 g, 0.11 mol) and ammonium carbonate (48 g, 0.5 mol) and stirred at 50° C. for 30 min. The reaction mixture is concentrated and the residue is diluted with water. The precipitate is filtered off and recristallized with ethanol.
Yield 83%
Synthesis of 4-amino-3-fluoro-5-iodo-benzonitrile (R74.1)









To R74 (2 g, 7.14 mmol) in dichlormethane (50 mL) is added R2 (3.4 g, 14.28 mmol) and stirred at r.t. overnight. The reaction mixture is extracted with water. The organic layer is separated, dried and concentrated. The crude residue is filtered through a pad of silica gel (eluent (ethyl acetate/cyclohexane 3:7).
Yield 53%, m/z 263 [M+H]+, rt 0.47 min, LC-MS Method X012_S01.
Synthesis of 3-tetrahydrofuran-3-yl-3,8-diazabicyclo[3.2.1]octane (R77)

Step 1: Synthesis of Intermediate I-31.1

To tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate hydrochloride (300 mg, 1.21 mmol) in THF (5 mL) is added tetrahydrofuran-3-one (114.21 mg, 1.33 mmol) and sodium triacetoxyborhydride (349.78 mg, 1.57 mmol) and stirred at r.t. for 0.5 h.
Sodium acetate (148.40 mg, 1.81 mmol) is added and stirred at r.t. overnight.
The reaction mixture is diluted with aq. sodiumhydrogen carbonate solution and extracted with ethyl acetate. The organic layer is separated, dried and concentrated. The crude residue is purified by reversed phase HPLC.
Yield 61%, m/z 283 [M+H]+, rt 0.61 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 56 are synthesized in an analogous manner from the appropriate intermediates:









TABLE 56



Inter-

m/z
rt
LC-MS

mediate
Structure
[M + H]+
(min)
method



I-31.1.1









213
n.d.
n.d.



I-31.1.2









303
1.34
V11_S01




















For I-31.1.1 sodium cyanoborhydride and methanol is used instead of sodium triacetoxyborhydride and THF.
Step 2: Synthesis of R77
I-31.1 (206 mg, 0.73 mmol) and hydrochloric acid in ether 1 mol/L (5 mL) is stirred at r.t. for 3 h. The reaction mixture is concentrated, diluted in dichlormethan/methanol 7/3 and filtered over amino phase silica gel.
Yield 99%, m/z 183 [M+H]+, rt 0.28 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 56.1 are synthesized in an analogous manner from the appropriate intermediates:









TABLE 56.1





m/z

LC-MS

Intermediate
Structure
[M + H]+
rt (min)
method



R77.1









n.d.
n.d.
n.d.



R77.2









203
0.91
V11_S01




















For R77.1 p-toluenesulfonic acid monohydrate is used for the deprotection.
Synthesis of tert-butyl 4-(5-bromo-2-oxo-indolin-1-yl)piperidine-1-carboxylate (R79)

Step 1: Synthesis of Intermediate I-38.1

To 1,3-dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one (200 mg, 0.93 mmol) in dichlormethane (5 mL) are added TEA (0.129 mL, 0.93 mmol) and di-t-butyl-dicarbonate (201.82 mg, 0.93 mmol). The reaction mixture is stirred for 10 min, diluted with water and sodium hydrogencarbonate solution and extracted with dichlormethane. The organic layer is dried and concentrated.
Yield>95%, m/z 261 [M+H-tert.butyl]+, rt 1.055 min, LC-MS Method Z020_S01.
Step 2: Synthesis of R79
Tert-butyl 4-(2-oxoindolin-1-yl)piperidine-1-carboxylate (100 mg, 0.32 mmol) in ACN is cooled down to −10° C., N-bromosuccinimide (56.47 mg, 0.32 mmol) is added and stirred at −10° C. for 2 h. The reaction mixture is diluted with dichlormethane and water. The organic layer is separated, dried and concentrated. The crude product is used for the next step without further purification. Yield 99%, m/z 395 [M+H]+, rt 1.126 min, LC-MS Method Z020_S01.
Synthesis of 2-amino-N-cyclopropyl-3-iodo-benzamide (R82)









Synthesis of R82
To 2-amino-3-iodo-benzoic acid (200 mg, 0.76 mmol) in DMF (1 mL) TBTU (244.15 mg, 0.76 mmol) and DIPEA (245.69 μL, 1.52 mmol) are added and stirred at r.t. for 7 min Cyclopropylamine (52.69 μL, 0.76 mmol) is added and stirred at r.t. overnight. The reaction mixture is diluted with water and the precipitate is filtered off and dried.
Yield 89%, m/z 303 [M+H]+, rt 0.49 min, LC-MS Method X012_S01.
Synthesis of 6-bromo-1-(1-methyl-4-piperidyl)indolin-2-one (R85)

Step 1: Synthesis of Intermediate I-32.1

To sodium hydride 60% (1.536 g, 38.4 mmol) in DMSO (30 mL) under nitrogen atmosphere is added di-tert.butylmalonate (8.61 mL, 38.4 mmol) dropwise. The reaction mixture is stirred at 100° C. for 1 h, cooled down to 10° C. and a solution of 2,5-dibromonitrobenzene (4.93 g, 17.55 mmol) in DMSO (25 mL) is added dropwise. After the addition the reaction mixture is stirred at 100° C. for 1 h again.
The reaction mixture is poured into ammoniumchloride solution and the pH is adjusted with sodium hydrogensulfate to pH 7. Water and a mixture of ethylycetate/cyclohexane 1/1 is added. The aq. layer is extracted with this mixture. The organic layer is separated, washed with brine, dried and concentrated. The crude product is used for the next step without further purification.
Yield 45%, m/z 414/416 [M+H]+, rt 1.215 min, LC-MS Method Z011_S03.
Step 2: Synthesis of Intermediate I-32.2
To I-32.1 (1 g, 2.4 mmol) in ethanol is added platinum on carbon (50 mg) and stirred under hydrogen (50 psi) at r.t. for 67 h. The reaction mixture is filtered and concentrated. The crude residue is purified by reversed phase HPLC.
Yield 34%, m/z 274/276 [M+H]+, rt 1.156 min, LC-MS Method Z011_S03.
Step 3: Synthesis of Intermediate I-32.3
To I-32.2 (316.66 mg, 0.81 mmol) in dichlormethane (2 mL) and glacial acetic acid (73.88 mL, 1.22 mmol) are added Boc-4-piperidone (210.41 mg, 1.06 mmol), titanium (IV)isopropoxide (346.17 mg, 1.22 mmol) and sodium triacetoxyborhydride (258.14 mg, 1.22 mmol) and stirred at 50° C. for 3 h and at r.t. over 3 days. The reaction mixture is diluted with dichlormethane and water. The organic layer is separated and concentrated. The crude product is purified by reversed phase HPLC.
Yield 27%, m/z 569/571 [M+H]+, rt 1.049 min, LC-MS Method Z011_U03.
Step 4: Synthesis of Intermediate I-32.4
To I-32.3 (125.3 mg, 0.2 mmol) in toluene (1 mL) is added 4-ethyl-benzenesulfonic acid (163.9 mg, 0.9 mmol) and stirred at 140° C. by microwave irridation. The reaction mixture is concentrated and diluted with sodium hydroxide 1 mol/L and dichlormethane and concentrated again. The crude product is used without further purification for the next step.
Yield 92%, m/z 295/7 [M+H]+, rt 0.867 min, LC-MS Method Z011_S03.
Step 5: Synthesis of R85
To I-32.4 (60 mg, 0.20 mmol) in methanol (1 mL) are added formaldehyde in water (37%) (75.67 μL, 1.02 mmol) and glacial acetic acid (17.44 μL, 0.31 mmol), stirred at r.t. for 75 min, afterwards sodium triacetoxyborhydride (107.70 mg, 0.51 mmol) is added. The reaction mixture is stirred at r.t. overnight.
The reaction mixture is diluted with sodium hydroxide 1 mol/L and dichlormethane. The organic layer is separated, washed with brine, dried and concentrated. The crude product is used for the next step without further purification.
Yield 52%, m/z 309/311 [M+H]+, rt 0.912 min, LC-MS Method Z011_S03.
Synthesis of 6-bromo-N-methyl-1H-benzimidazol-2-amine (R88)

Step 1: Synthesis of Intermediate I-33.1

To 4-bromobenzene-1,2-diamine (0.5 g, 3 mmol) in dichlormethane (10 mL) and DIPEA (0.55 mL, 3 mmol) is added methylimino(thioxo)methane (0.2 g, 3 mmol) and stirred at 50° C. for 4 h and at r.t. overnight. The reaction mixture is extracted with, aq. acetic acid (1%), aq. sodium carbonate (10%) and brine. The organic layer is separated, dried and concentrated. The residue is purified over silica gel.
Yield 69%, m/z 260/262 [M+H]+, rt 0.45 min, LC-MS Method X018_S02.
Step 2: Synthesis of R88
To I-33.1 (130 mg, 0.50 mmol) in ACN (2.5 mL) are added benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) (330 mg, 0.50 mmol) and DBU (150 μL, 1.00 mmol) and stirred at r.t. for 0.5 h. The reaction mixture is purified by reversed phase HPLC.
Yield 51%
Synthesis of 4-(6-bromo-5-fluoro-tetralin-2-yl)morpholine (R91)









To 6-bromo-5-fluoro-tetralin-2-one (1 g, 4.11 mmol) and morpholine (0.36 mL, 4.11 mmol) in dichlormethane is added glacial acetic acid (0.52 mL, 9.05 mmol). The reaction mixture is cooled with an ice bath and sodium triacetoxyborhydride (1.74 g, 8.23 mmol) is added. The reaction mixture is stirred at r.t. overnight. Morpholine (0.2 mL) is added and stirred again at r.t. overnight. The reaction mixture is basified with potassium carbonate solution (20%) and stirred for 15 min. The organic layer is separated and the aq. layer is washed two times with dichlormethane. The organic layers are dried and concentrated. The crude product is purified by reversed phase HPLC Yield 57%, m/z 314/316 [M+H]+, rt 0.68 min, LC-MS Method X011_S03.
The following intermediate as shown in Table 57 is synthesized in a similar fashion from the appropriate intermediates:











TABLE 57







m/z

LC-MS


Intermediate
Structure
[M + H]+
rt (min)
method





R91.1









172
n.d.
n.d.



















Synthesis of 1-tetrahydrofuran-3-ylpiperidin-4-one (R91.2)









To R91.1 1-tetrahydrofuran-3-ylpiperidin-4-ol (200 mg, 1.17 mmol) in dichlormethane (5 mL) is added Dess-Martin periodine (595 mg, 1.40 mmol) and stirred at r.t. for 5 h. The reaction mixture is filtered through ALOX/N and washed with cyclohexane/ethyl acetate 1:3. The filtrate is concentrated.
Yield 51%
Synthesis of (4aS,7aR)-2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazine (R93)

Step 1: Synthesis of Intermediate I-34.1

To tert-butyl(4aS,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxylate (200 mg, 0.88 mmol) in methanol (3 mL) are added formaldehyde in water (37%) (26.44 mg, 0.33 mmol) and glacial acetic acid (79.71 mg, 1.31 mmol), stirred at r.t. for 75 min, afterwards sodium triacetoxyborhydride (464.19 mg, 2.19 mmol) is added. The reaction mixture is stirred at r.t. for 2 h Additional formaldehyde in water (37%) (26.44 mg, 0.33 mmol) is added and stirred in a 50° C. warm water bath for 10 min, sodium triacetoxyborhydride (464.19 mg, 2.19 mmol) is added and stirred at r.t. for 1.5 h. The reaction mixture is diluted with aq. sodium hydrogencarbonate solution and water and extracted with ethyl acetate. The organic layer is washed with aq. sodium hydrogencarbonate solution and brine, dried and concentrated. Yield 79
The following intermediates as shown in Table 58 are synthesized in a similar fashion from the appropriate intermediates:
TABLE 58 Inter- m/z rt LC-MS mediate Structure [M + H]+ (min) method I-34.1.1 n.d. n.d. n.d. I-34.1.2 n.d. n.d. n.d.
Step 2: Synthesis of R93

To I-34.1 (167 mg, 0.69 mmol) in dichlormethan (3 mL) p-toluenesulfonic acid monohydrate (655.48 mg, 3.45 mmol) is added and stirred at r.t. overnight. The reaction mixture is extracted with sodium hydroxide 1 mol/L. The organic layer is separated dried and concentrated. Due to less yield the aq. layer is saturated with sodium chloride and extracted with dichlormethane.
The aq layer is concentrated and extracted again with dichlormethane. All organic layers are combine, dried and concentrated. Yield 76%
The following intermediates as shown in Table 59 are synthesized in a similar fashion from the appropriate intermediates:









TABLE 59





m/z

LC-MS

Intermediate
Structure
[M + H]+
rt (min)
method



R93.1









n.d.
n.d.
n.d.



R93.2









n.d.
n.d.
n.d.




















Synthesis of 1-bromo-4-(bromomethyl)-2,5-difluoro-benzene (R99)









R98 (31.4 g, 15.17 mmol), N-bromosuccinimide (32.4 g, 1.6 mmol), AIBN (4.98 g, 30.34 mmol) in tetrachloromethane is heated at 90° C. overnight. The reaction mixture is cooled down to r.t. and concentrated. The residue is dissolved in ethyl acetate and extracted with water. The organic layer is dried over MgSO 4 , filtered and concentrated. The crude product is purified by high vacuum distillation (boiling point 95° C.-98° C. by oil bath temperature of 140° C.)
Yield 67%
The following intermediate as shown in Table 60 is synthesized in an analogous manner from the appropriate intermediates:









TABLE 60



Inter-

m/z
rt
LC-MS

mediate
Structure
[M + H]+
(min)
method



R99.1









n.d.
0.65
X012_S01


















For R99.1 the reaction temperature is 80° C. For the work up the reaction mixture is cooled to r.t. and the precipitate filtered off. The mother liquor is extracted with aq. hydrochloric acid (1 mol/L) and aq. sodium hydroxide (1 mol/L), dried and concentrated. The crude product is used without further purification.
Synthesis of 2-benzyloxy-4-bromo-1-(chloromethyl)benzene (R100)

Step 1: Synthesis of Intermediate I-35.1

To methyl 4-bromo-2-hydroxy-benzoate (4.3 g, 18.61 mmol) in acetonitrile (50 mL) are added bromomethylbenzene (2.23 mL, 19.54 mmol) and potassium carbonate (3.86 g, 27.92 mmol) and stirred for 4 h at reflux. The reaction mixture is cooled down to r.t., diluted with water and extracted with ethyl acetate. The organic layer is separated, dried over MgSO 4 and concentrated. The crude residue is purified over silica gel (eluent: cyclohexane/ethyl acetate 95:5). Yield 75%
Step 2: Synthesis of Intermediate I-35.2
I-35.1 (4.5 g, 14.01 mmol) is dissolved in THF (50 mL) and a solution of lithium aluminium hydride in THF (8.41 mL, 8.41 mmol) is added dropwise between 5° C.-10° C. The reaction mixture is stirred 1 h under cooling and 1.5 h at r.t. Afterwards the mixture is cooled down and hydrolysed with 30 mL aq. hydrodchloric acid (1 mol/L), diluted with water and extracted with ethyl acetate. The organic layer is washed with water, dried over MgSO 4 and concentrated. The crude residue is used for the next step without further purification. Yield 94%
Step 3: Synthesis of R100
To I-35.2 (3.85 g, 13.13 mmol) in dichlormethane (40 mL) is added triethylamine (2.21 mL, 15.76 mmol) and cooled down to 0° C.-−2° C. Methanesulfonyl chloride (1.12 mL, 14.45 mmol) dissolved in dichlormethane (3 mL) is added dropwise. The reaction mixture is stirred for 1 h at 2° C.-5° C. and overnight at r.t. The reaction mixture is concentrated, diluted with dichlormethane and water. The organic layer is washed with 1 mol/L hydrochloric acid, water, dried over MgSO 4 and concentrated. The crude residue is used for the next step without further purification. Yield 74%
Synthesis of tert-butyl N-(4-amino-3-bromo-phenyl)carbamate (R104)









To tert-butyl N-(3-bromo-4-nitro-phenyl)carbamate (1 g, 3.15 mmol) in ethyl acetate (20 mL) is added tin (II) chloride dihydrate (3.56 g, 15.77 mmol) and stirred overnight at r.t. The reaction mixture is basified with potassium carbonate/sodium hydroxide. The organic layer is separated, dried and concentrated. The crude product is used without further purification for the next step. Yield 83%, m/z 287/289[M+H]+, rt 0.58 min, LC-MS Method X011_S03.
The following intermediate as shown in Table 61 is synthesized in an analogous manner from the appropriate intermediates:









TABLE 61



Inter-

m/z
rt
LC-MS

mediate
Structure
[M + H]+
(min)
method



R104.1









197/199
0.45
X012_S01


















Synthesis of 3,4,6,7,9,9a-hexahydro-1H-pyrido[2,1-c][1,4]oxazin-8-one (R106)

Step 1: Synthesis of Intermediate I-37.1

To methyl 2-morpholin-3-ylacetate hydrochloride (1 g, 5.11 mmol) in methanol (25 mL) are added TEA (0.785 mL, 5.63 mmol) and acrylic acid methyl ester (0.465 mL, 5.16 mmol) and stirred overnight at r.t. Again acrylic acid methyl ester (0.465 mL, 5.16 mmol) is added and stirred 3 days at r.t. The reaction mixture is concentrated and the crude product is purified over silica gel (eluent: ethyl acetate).
Yield 93%, m/z 246[M+H]+, rt 0.77 min, LC-MS Method V011_S01.
Step 2: Synthesis of Intermediate I-37.2
Under argon atmosphere I-37.1 (1.09 g, 4.44 mmol) is dissolved in THF (40 mL) and cooled down to −70° C. Lithium bis(trimethylsilyl)amide 1 mol/L (9 mL, 9 mmol) is added dropwise and stirred for 4 h at −70° C. The reaction mixture is quenched with hydrochloric acid 1 mol/L (15 mL). Afterwards solid sodium carbonate (1 g) is added. The aq. layer is extracted with ethyl acetate. The organic layers are combined, dried and concentrated. The crude product is purified over silica gel (eluent: ethyl acetate). Yield 68%
Step 3: Synthesis of R106
I-37.2 (0.63 g, 2.96 mmol) and hydrochloric acid 4 mol/L (15 mL) are stirred at 100° C. overnight. The reaction mixture is diluted with water and freeze-dried. The crude product is filtered over amino phase silica gel (eluent: dichlormethane/methanol). Yield 82%
Synthesis of 5-bromo-2-methylsulfonyl-phenol (R109)









To 4-bromo-2-fluoro-1-methylsulfonyl-benzene (2 g, 7.9 mmol) in DMF (15 mL) is added 2-methanesulfonyl-ethanol (1.47 g, 11.85 mmol). Sodium hydride (948.16 mg, 23.71 mmol) is added in portions at 0° C. The reaction mixture is allowed to come to r.t. and is added dropwise into cooled aq. hydrochloric acid. The aq. layer is extracted with ethyl acetate. The organic layer is dried over MgSO 4 , filtered and concentrated. The crude residue is purified by reversed phase HPLC. Yield 86%, m/z 251/253[M+H]+, rt 0.42 min, LC-MS Method X018_501.
EXAMPLES
(rt=retention time) Deprotection Methods: TSA (toluene sulfonic acid cf. Example 1), SI (trimethylsilyl iodide cf. example 2 or 3), FA (formic acid cf. example 4 or 7), TFA (trifluoroacetic acid). Stereochemistry at the carbon atom adjacent to the nitrile group is assigned: Stereo bond means S-isomer, non-stereo bond means 1:1 mixture of stereoisomers.









TABLE 62






Syn./





Deprot.
Yield

Example
Structure
Educt
Method
[%]











1









I-1.5
A/TSA
47



2









I-2.3
A1/SI
44



3









I-3.3
A2.1/SI
62



4









I-4.3
A3/FA
86



5









I-5.2
A4/FA
34



6









I-6.2
A5/TSA
86



7









I-7.3
B/FA
39



8









I-8.2
C/ SI
19



9









I-9.1
D/SI
32



10









I-3.3.1
A2.1/SI
25



11









I-3.2.2
A2.1/SI
17



12









I-2.3.1
A1/FA
36



13









I-2.3.7.1
A1/FA
56



14









I-4.3.1
A3/SI
43



15









I-4.3.2
A3/SI
21



16









I-4.3.3
A3/TSA
93



17









I-2.3.2
A1/TSA
16



18









I-2.3.3
A1/TSA
36



19









I-4.3.1
A3/SI
59



20









I-2.3.7.3
A1/TSA
22



21









I-2.3.7.4
A1/FA
49



22









I-4.3.5
A3/SI
70



23









I-2.3.4
A1/TSA
37



24









I-2.3.74.1
A1/TFA
45



25









I-4.3.6
A3/TSA
45



26









I-2.3.5
A1/TSA
49



27









I-2.3.6
A1/TSA
38



28









I-2.3.7.5
A1/FA
75



29









I-4.3.7
A3/SI
40



30









I-2.3.8
A1/TSA
46



31









I-4.3.8
A3/SI
39



32









I-3.2.4
A2.2/TSA
31



33









I-2.3.9
A1/TSA
16



34









I-3.3.3
A2.1/SI
32



35









I-4.3.9
A3/SI
77



36









I-2.3.10
A1/TSA
39



37









I-4.3.10
A3/FA
98



38









I-2.3.11
A1/TSA
6



39









I-2.3.12
A1/TSA
30



40









I-2.3.13
A1/TSA
49



41









I-4.3.11
A3/FA
>95



42









I-3.2.6
A2.1/TSA
75



43









I-3.2.7
A2.2/TSA
84



44









I-2.3.7.6
A1/FA
64



45









I-4.3.12
A3/SI
58



46









I-2.3.14
A1/TSA
12



47









I-5.2
A4/TSA
57



48









I-2.3.7.7
A1/FA
20



49









I-4.3.13
A3/FA
93



50









I-2.3.15
A1/TSA
31



51









I-4.3.14
A3/FA
76



52









I-4.3.4
A3/SI
33



53









I-4.3.16
A3/FA
85



54









I-4.3.17
A3/FA
96



55









I-2.3.7.8
A1/FA
71



56









I-4.3.18
A3/FA
67



57









I-2.3.16
A1/TSA
38



58









I-7.3
B/FA
90



59









I-2.3.17
A1/FA
37



60









I-2.3.18
A1/TSA
33



61









I-4.3.15
A3/SI
47



62









I-4.3.20
A3/FA
91



63









I-2.3.19
A1/TSA
19



64









I-2.3.20
A1/TSA
48



65









I-2.3.21
A1/TSA
6



66









I-5.2
A4/TSA
23



67









I-5.2
A4/TSA
53



68









I-2.3.22
A1/TSA
17



69









I-2.3.23
A1/TSA
19



70









I-2.3.24
A1/TSA
58



71









I-4.3.21
A3/FA
>95



72









I-2.3.25
A1/TSA
13



73









I-2.3.26
A1/TSA
53



74









I-2.3.7.9
A1/TSA
41



75









I-3.3.4
A2.1/SI
4



76









I-4.3.22
A3/FA
89



77









I-5.2
A4/TSA
40



78









I-2.3.27
A1/TSA
7



79









I-4.3.23
A3/FA
80



80









I-2.3.28
A1/TSA
24



81









I-4.3.24
A3/SI
31



82









I-5.2
A4/TSA
44



83









I-4.3.25
A3/FA
>95



84









I-5.2
A4/TSA
46



85









I-2.3.29
A1/FA
60



86









I-2.3.30
A1/FA
63



87









I-2.3.7.10
A1/TSA
8



88









I-4.3.26
A3/FA
52



89









I-5.2
A4/TSA
48



90









I-5.2
A4/TSA
77



91









I-3.2.9
A2.2/TSA
92



92









I-2.3.31
A1/TSA
14



93









I-2.3.32
A1/TSA
54



94









I-5.2
A4/TSA
80



95









I-3.2.10
A2.1/TSA
53



96









I-2.3.33
A1/FA
87



97









I-2.3.34
A1/TSA
22



98









I-3.2.11
A2.1/SI
83



99









I-5.2
A4/TSA
34



100









I-2.3.35
A1/TSA
16



101









I-5.2
A4/TSA
48



102









I-3.2.12
A2.1/SI
29



103









I-2.3.36
A1/TSA
17



104









I-2.3.37
A1/TSA
8



105









I-5.2
A4/TSA/TSA
26



106









I-5.2
A4/TSA
30



107









I-4.3.27
A3/FA
80



108









I-3.2.13
A2.1/SI
42



109









I-5.2
A4/TSA
41



110









I-2.3.38
A1/TSA
21



111









I-5.2
A4/TSA
84



112









I-5.2
A4/TSA
22



113









I-2.3.39
A1/TSA
45



114









I-2.3.40
A1/TSA
53



115









I-2.3.41
A1/TSA
30



116









I-2.3.42
A1/TSA
8



117









I-2.3.43.1
A1/SI
57



118









I-2.3.44
A1/TSA
40



119









I-5.2
A4/TSA
37



120









I-4.3.19
A3/SI
5



121









I-2.3.45
A1/TSA
41



122









I-4.3.19
A3/SI
27



123









I-10.5
E/FA
10



124









I-5.2
A4/TSA
36



125









I-4.3.28
A3/TSA
79



126









I-2.3.46
A1/TSA
7



127









I-8.2.1
C/SI
36



128









I-10.5
E/FA
5



129









I-2.3.47
A1/TSA
21



130









I-2.3.48
A1/TSA
33



131









I-2.3.49
A1/TSA
28



132









I-2.3.50
A1/TSA
36



133









I-2.3.51
A1/TSA
28



134









I-2.3.52
A1/TSA
8



135









I-2.3.53
A1/TSA
25



136









I-2.3.54
A1/TSA
33



137









I-2.3.55
A1/TSA
25



138









I-2.3.56
A1/TSA
41



139









I-2.3.57
A1/TSA
26



140









I-2.3.58
A1/TSA
16



141









I-2.3.59
A1/TSA
28



142









I-2.3.60
A1/TSA
24



143









I-2.3.61
A1/TSA
33



144









I-2.3.62
A1/TSA
34



145









I-2.3.63
A1/TSA
21



146









I-2.3.64
A1/TSA
32



147









I-2.3.65
A1/TSA
34



148









I-2.3.66
A1/TSA
10



149









I-2.3.67
A1/TSA
23



150









I-2.3.68
A1/TSA
33



151









I-2.3.69
A1/TSA
25



152









I-2.3.70
A1/FA
68



153









I-2.3.71
A1/FA
73



154









I-3.2.14
A2.2/TSA
59



155









I-3.3.5
A2.1/SI
62



156









I-3.3.6
A2.1/SI
25



157









I-4.3.32
A3/FA
36



158









I-2.3.72
A1/SI
57



159









I-1.5.1
A/TSA
65



160









I-3.2.37
A2.1/TSA
34



161









I-4.3.33
A3/FA
75



162









I-3.2.47
A2.1/TSA
52



163









I-3.2.36
A2.1/TSA
40



164









I-4.3.34
A3/FA
78



165









I-4.3.35
A3/FA
90



166









I-3.3.7
A2.1/SI
33



167









I-3.2.46
A2.1/TSA
49



168









I-3.2.42
A2.1/TSA
37



169









I-1.5.2
A/TSA
79



170









I-4.3.36
A3/FA
77



171









I-3.2.39
A2.1/TSA
37



172









I-3.2.38
A2.1/TSA
36



173









I-3.2.45
A2.1/TSA
34



174









I-3.2.40
A2.1/TSA
33



175









I-3.2.50
A2.1/TSA
44



176









I-2.3.75.1
A1/FA
53



177









I-3.2.51
A2.1/SI
59



178









I-3.2.19
A2.2/TSA
81



179









I-3.2.49
A2.1/TSA
35



180









I-3.2.20
A2.2/TSA
56



181









I-2.3.76.1
A1/FA
31



182









I-3.2.22
A2.2/TSA
31



183









I-2.3.78.1
A1/FA
36



184









I-4.3.37
A3/TFA
51



185









I-4.3.38
A3/TFA
28



186









I-4.3.39
A3/TFA
40



187









I-3.2.24
A2.2/SI
17



188









I-3.2.25
A2.2/TSA
85



189









I-3.2.26
A2.2/TSA
13



190









I-3.2.27
A2.2/TSA
19



191









I-3.2.28
A2.2/TSA
84



192









I-3.2.29
A2.2/TSA
75



193









I-3.2.30
A2.2/TSA
42



194









I-3.2.41
A2.1/TSA
33



195









I-3.2.31
A2.2/TSA
86



196









I-3.2.32
A2.2/TSA
18



197









I-3.2.33
A2.2/TSA
68



198









I-3.2.48
A2.1/TSA
32



199









I-2.3.73
A1/SI
56



200









I-4.3.40
A3/TFA
51



201









I-2.3.43.2.1
A2/SI
65



202









I-4.3.41
A3/TFA
52



203









I-7.3.3
B/SI
56



204









I-3.2.34
A2.2/TSA
90



205









I-3.2.35
A2.2/TSA
76



206









I-9.1.1
D/SI
39



207









I-10.4.1
E/TFA
28



208









I-3.2.43
A2.1/TSA
22



209









I-7.3.4
B/SI
55



210









I-4.3.42
A3/TFA
46



211









I-4.3.43
A3/TFA
48



212









I-7.3.5
B/SI
54



213









I-7.3.6
B/SI
65



214









I-1.5.3
A/TSA
72



215









I-10.4.1
E/TFA
23



216









I-4.3.44
A3/TFA
38



217









I-3.2.52
A2.1/SI
64



218









I-2.3.77.1
A1/FA
24



219









I-2.3.43.3
A1/FA
41



220









I-8.2.2
C/SI
69



221









I-3.2.44
A2.1/TSA
17



222









I-3.2.53
A2.1/FA
59



223









I-2.3.43
A1/SI
60



224









I-2.3.79
A1/SI
47



225









I-4.3.45
A3/FA
15



226









I-4.3.46
A3/FA
53



227









I-4.3.47
A3/FA
28



228









I-4.3.48
A3/FA
37



229









I-4.3.49
A3/FA
14



230









I-4.3.50
A3/FA
47



231









I-4.3.51
A3/FA
30



232









I-4.3.52
A3/FA
60



233









I-4.3.53
A3/FA
37



234









I-4.3.54
A3/FA
71



235









I-4.3.55
A3/FA
38



236









I-4.3.56
A1/FA
41



237









I-4.3.57
A1/TSA
67



238









I-4.3.58
A1/FA
42



239









I-4.3.59
A1/FA
53



240









I-4.3.60
A1/FA
33



241









I-4.3.61
A1/FA
41



242









I-4.3.62
A1/FA
52



243









I-2.3.7.11
A1/FA
62



244









I-4.3.63
A1/FA
43



245









I-4.3.64
A1/FA
42



246









I-3.2.54
A2.1/SI
63



247









I-3.2.92
A2.2/TSA
20



248









I-3.2.93
A2.2/TSA
78



249









I-3.2.7
A2.2/TSA
6



250









I-3.2.7
A2.2/TSA
7



251









I-3.2.55
A2.1/TSA
65



252









I-3.2.56
A2.1/TSA
82



253









I-3.2.57
A2.1/TSA
73



254









I-3.2.58
A2.1/TSA
53



255









I-3.2.59
A2.1/TSA
58



256









I-3.2.60
A2.1/TSA
52



257









I-3.2.61
A2.1/TSA
41



258









I-3.2.62
A2.1/TSA
19



259









I-3.2.63
A2.1/FA
19



260









I-3.2.64.1
A2.1/FA
91



261









I-3.2.64.2
A2.1/FA
79



262









I-2.3.7.4.1
A1/FA
53



263









I-3.2.65
A2.1/FA
52



264









I-3.2.66
A2.1/FA
23



265









I-3.2.94
A2.2/TSA
14



266









I-3.2.95
A2.2/TSA
8



267









I-3.2.96
A2.2/TSA
41



268









I-3.2.97
A2.2/TSA
80



269









I-3.2.98
A2.2/TSA
27



270









I-3.2.99
A2.2/TSA
81



271









I-3.2.100
A2.2/TSA
17



272









I-3.2.101
A2.2/TSA
27



273









I-3.2.67
A2.1/TSA
7



274









I-3.2.68
A2.1/TSA
73



275









I-3.2.69
A2.1/TSA
71



276









I-3.2.70
A2.1/TSA
72



277









I-3.2.71
A2.1/TSA
2



278









I-3.2.72
A2.1/TSA
13



279









I-3.2.73
A2.1/TSA
28



280









I-3.3.8
A2.1/SI
90



281









I-3.3.9
A2.1/TSA
83



282









I-3.3.10
A2.1/TSA
42



283









I-3.3.11
A2.1/TSA
91



284









I-3.3.12
A2.1/TSA
80



285









I-3.2.117
A2.2/TSA
81



286









I-3.2.120
A2.2/TSA
80



287









I-3.2.121
A2.2/TSA
77



288









I-4.3.65
A3/FA
68



289









I-4.3.66
A3/FA
66



290









I-8.2.3
C/TSA
93



291









I-18.2.3
D1/MSA
18



292









I-18.2.1
D1/SI
11



293









I-18.2.2
D1/SI
24



294









I-18.2.4
D1/SI
20



295









I-18.2.5
D1/SI
13



296









I-18.2.6
D1/TSA
7



297









I-18.2.7
D1/SI
43



298









I-18.2.8
D1/SI
71



299









I-18.2.9
D1/SI
55



300









I-18.2.10
D1/TSA
24



301









I-18.2.11
D1/SI
27



302









I-18.2.12
D1/SI
58



303









I-18.2.13
D1/TSA
29



304









I-18.2.14
D1/SI
32



305









I-18.2
D1/MSA
14



306









I-18.2.15
D1/MSA
29



307









I-18.2.16
D1/SI
36



308









I-18.2.17
D1/SI
37



309









I-18.2.18
D1/MSA
11



310









I-18.2.19
D1/SI
63



311









I-18.2.20
D1/SI
13



312









I-18.2.21
D1/SI
28



313









I-18.2.22
D1/SI
7



314









I-18.2.23
D1/MSA
25



315









I-21.3
Z/TSA
60



316









I-21.3.1
Z/TSA
51



317









I-3.2.77
A2.1/TSA
47



318









I-3.2.102
A2.2/TSA
83



319









I-19.1
W/SI
34



320









I-3.3.13
A2.1/SI
74



321









I-8.2.4
C/TSA
91



322









I-18.2.24
D1/TSA
30



323









I-18.2.25
D1/TSA
32



324









I-18.2.26
D1/TSA
36



325









I-18.2.27
D1/TSA
9



326









I-18.2.28
D1/TSA
30



327









I-3.2.103
A2.2/TSA
62



328









I-3.2.104
A2.2/TSA
86



329









I-3.2.105
A2.2/TSA
62



330









I-3.2.106
A2.2/TSA
59



331









I-3.2.107
A2.2/TSA
70



332









I-3.2.79
A2.1/TSA
64



333









I-3.2.108
A2.2/TSA
33



334









I-3.2.80
A2.1/TSA
11



335









I-3.2.109
A2.2/TSA
90



336









I-3.2.110
A2.2/TSA
72



337









I-3.3.14
A2.1/TSA
86



338









I-3.3.15
A2.1/TSA
48



339









I-3.2.83
A2.1/TSA
54



340









I-3.2.84
A2.1/TSA
42



341









I-18.2.29
D1/TSA
17



342









I-3.2.85
A2.1/TSA
68



343









I-3.2.86
A2.1/TSA
35



344









I-20.1
W1/TSA
28



345









I-3.2.111
A2.2/TSA
2



346









I-3.2.87
A2.1/TSA
14



347









I-3.2.88
A2.1/TSA
18



348









I-3.3.16
A2.1/TSA
76



349









I-3.3.17
A2.1/TSA
73



350









I-3.3.18
A2.1/TSA
65



351









I-8.2.5
C/TSA
44



352









I-3.2.112
A2.2/TSA
78



353









I-3.3.19
A2.1/TSA
78



354









I-3.3.20
A2.1/TSA
62



355









I-3.2.114
A2.2/TSA
88



356









I-3.2.115
A2.2/TSA
>95



357









I-3.2.116
A2.2/TSA
80



358









Ex 359
A2.1
35



359









I-3.2.136
A2.1/TSA
61



































































































































































































































































































































































































































































































































































































































































































































































Analytical Data of Examples








TABLE 63




m/z



Ex.
[M + H]+
rt [min]
LC-MS-Method










1
419
1.16
V011_S01

2
433
0.59
X011_S01

3
420
0.41
X016_S01

4
442
0.65
Z018_S04

5
470
0.70
Z018_S04

6
386
0.98
V011_S01

7
410
0.96
V018_S01

8
310
0.86
V011_S01

9
387
0.39
X012_S01

10
447
0.42
X012_S01

11
420
0.41
X012_S01

12
460
0.67
Z018_S04

13
426
0.63
Z018_S04

14
467
0.86
V018_S01

15
433
1.04
V001_007

16
442
0.65
Z018_S04

17
428
0.81
004_CA01

18
370
0.80
004_CA01

19
467
0.86
V018_S01

20
396
0.66
Z018_S04

21
438
0.64
Z018_S04

22
419
0.41
Z001_002

23
410
0.78
004_CA01

24
451
0.69
Z018_S04

25
385
0.64
Z018_S04

26
382
0.68
004_CA01

27
368
0.82
004_CA01

28
452
0.70
Z018_S04

29
419
0.41
Z001_002

30
396
0.73
004_CA01

31
451
1.12
V011_S01

32
448
1.28
V011_S01

33
438
0.93
004_CA01

34
420
1.06
V011_S01

35
407
1.10
V001_007

36
370
0.80
004_CA01

37
443
0.62
Z018_S04

38
439
0.60
004_CA01

39
382
0.64
004_CA01

40
407
0.72
Z018_S04

41
419
0.61
Z018_S04

42
447
1.09
V011_S01

43
428
0.95
V011_S01

44
412
0.63
Z018_S04

45
421
0.90
V012_S01

46
399
0.73
004_CA01

47
461
0.72
Z018_S04

48
438
0.60
X018_S01

49
433
1.13
W018_S01

50
438
0.66
Z018_S04

51
457
0.64
Z018_S04

52
n.d.
n.d.
n.d.

53
407
0.61
Z018_S04

54
442
0.63
Z018_S04

55
493
0.64
Z018_S04

56
443
0.60
Z018_S04

57
452
0.69
004_CA01

58
368
0.79
V018_S01

59
456
0.43
X018_S01

60
418
0.80
004_CA01

61
451
0.88
V018_S01

62
457
0.64
Z018_S04

63
382
0.64
004_CA01

64
410
0.78
004_CA01

65
382
0.64
004_CA05

66
463
0.79
Z011_S03

67
395
0.82
Z011_S03

68
396
0.73
004_CA01

69
354
0.54
004_CA01

70
430
0.72
Z018_S04

71
456
0.67
Z018_S04

72
412
0.76
004_CA01

73
354
0.70
Z018_S04

74
466
0.70
Z018_S04

75
364
0.50
X012_S01

76
433
0.65
Z018_S04

77
491
0.86
Z011_S03

78
430
0.85
004_CA01

79
419
0.62
Z018_S04

80
399
0.62
004_CA01

81
449
0.90
V012_S01

82
441
0.63
Z018_S04

83
407
1.09
W018_S01

84
471
0.92
Z011_S03

85
395
0.50
X018_S01

86
460
0.67
Z018_S04

87
426
0.66
Z018_S04

88
442
0.64
Z018_S04

89
427
0.75
Z011_S03

90
397
0.60
Z018_S04

91
450
0.98
V011_S01

92
368
0.81
004_CA01

93
397
0.65
Z018_S04

94
461
0.90
Z011_S03

95
419
0.82
V012_S01

96
431
0.78
Z018_S04

97
412
0.65
004_CA01

98
400
0.94
V012_S01

99
468
0.73
Z011_S03

100
436
0.82
004_CA01

101
413
0.70
Z011_S03

102
400
0.92
V012_S01

103
354
0.76
004_CA01

104
368
0.79
004_CA05

105
413
0.79
Z011_S03

106
482
0.81
Z011_S03

107
435
1.25
W018_S01

108
400
0.82
V012_S01

109
441
0.80
Z011_S03

110
382
0.67
004_CA01

111
399
0.58
Z018_S04

112
443
0.75
Z011_S03

113
411
0.70
Z018_S04

114
354
0.59
Z018_S04

115
414
0.68
004_CA01

116
438
0.68
004_CA01

117
385
0.65
V012_S01

118
436
0.77
004_CA01

119
461
0.93
Z011_S03

120
431
0.81
V018_S01

121
383
0.71
004_CA01

122
521
0.97
V018_S01

123
387
0.38
X012_S01

124
427
0.83
Z011_S03

125
400
0.83
V011_S01

126
382
0.66
004_CA01

127
310
0.92
V011_S01

128
387
0.35
X012_S01

129
447
0.76
004_CA01

130
419
0.64
004_CA01

131
433
0.71
004_CA01

132
419
0.84
004_CA01

133
440
0.83
004_CA01

134
431
0.67
004_CA01

135
430
0.74
004_CA01

136
455
0.67
004_CA01

137
430
0.78
004_CA01

138
394
0.70
004_CA01

139
469
0.74
004_CA01

140
469
0.73
004_CA01

141
454
0.72
004_CA01

142
402
0.73
004_CA01

143
455
0.68
004_CA01

144
454
0.73
004_CA01

145
411
0.78
004_CA01

146
419
0.66
004_CA01

147
431
0.64
004_CA01

148
445
0.68
004_CA01

149
445
0.69
004_CA01

150
469
0.73
004_CA01

151
468
0.76
004_CA01

152
460
0.67
Z018_S04

153
468
0.70
Z018_S04

154
456
1.08
V011_S01

155
526
0.80
V012_S01

156
448
0.47
X012_S01

157
413
0.61
Z018_S04

158
477
0.87
V012_S01

159
467
0.85
V018_S01

160
382
0.64
004_CA05

161
427
0.64
Z018_S04

162
379
0.76
004_CA05

163
368
0.61
004_CA05

164
455
0.71
Z018_S04

165
467
0.70
Z018_S04

166
448
0.48
X12_S01

167
397
0.56
004_CA05

168
405
0.66
004_CA05

169
469
1.02
V011_S01

170
441
0.67
Z018_S04

171
430
0.83
004_CA05

172
415
0.87
004_CA05

173
411
0.78
004_CA05

174
405
0.63
004_CA05

175
412
0.74
004_CA05

176
460
0.67
Z18_S04

177
511
1.05
V012_S01

178
444
1.10
V011_S01

179
442
0.86
004_CA05

180
354
0.36
X018_S01

181
437
0.65
Z018_S04

182
430
0.26
X018_S01

183
485
0.67
Z018_S04

184
435
0.67
Z018_S04

185
490
0.55
Z018_S04

186
421
0.63
Z018_S04

187
412
0.26
X018_S01

188
400
1.10
V011_S01

189
416
0.88
V011_S01

190
416
0.89
V011_S01

191
458
1.14
V011_S01

192
400
1.10
V011_S01

193
456
1.00
V011_S01

194
405
0.55
004_CA05

195
399
1.42
V011_S01

196
414
0.65
V018_S01

197
371
1.28
V011_S01

198
442
0.84
004_CA05

199
461
1.24
V012_S01

200
491
0.67
Z018_S04

201
399
0.32
X012_S02

202
477
0.66
Z018_S04

203
359
0.46
X12_S01

204
372
0.93
V011_S01

205
373
1.05
V011_S01

206
401
0.43
X12_S01

207
405
0.41
X12_S01

208
382
0.60
004_CA05

209
372
0.52
X12_S01

210
475
0.74
Z018_S04

211
435
0.67
Z018_S04

212
360
0.48
X12_S01

213
359
0.43
X12_S01

214
467
1.02
V011_S01

215
405
0.37
X12_S01

216
461
0.70
Z018_S04

217
513
0.92
V012_S01

218
470
0.69
Z018_S04

219
461
0.82
V012_S01

220
320
0.39
001_CA07

221
394
0.59
004_CA05

222
466
0.65
Z018_S04

223
383
0.31
X012_S02

224
526
0.36
X012_S01

225
496
0.54
Z018_S04

226
519
1.17
Z018_S04

227
524
0.56
Z018_S04

228
540
0.83
Z011_S03

229
522
0.9
Z011_S03

230
483
0.8
Z011_S03

231
524
0.77
Z011_S03

232
564
1.31
Z018_S04

233
510
0.76
Z011_S03

234
538
0.95
Z018_S04

235
497
0.82
Z011_S03

236
413
0.60
Z018_S04

237
519
0.68
Z018_S04

238
522
0.66
Z018_S04

239
397
0.37
Z018_S04

240
503
0.64
Z018_S04

241
480
0.53
Z018_S04

242
425
0.64
Z018_S04

243
494
0.74
Z018_S04

244
407
0.73
Z018_S04

245
490
0.56
Z018_S04

246
547
1.05
V012_S01

247
400
0.58
X011_S03

248
440
0.97
V011_S01

249
428
0.97
V011_S01

250
428
0.97
V011_S01

251
468
1.14
V011_S01

252
522
0.61
X011_S02

253
447
0.67
X011_S03

254
395
0.56
004_CA05

255
395
0.55
004_CA05

256
452
0.60
004_CA05

257
381
0.5
004_CA05

258
381
0.50
004_CA05

259
455
0.64
n.d.

260
438
0.66
Z018_S04

261
438
0.65
Z018_S04

262
438
0.65
Z018_S04

263
466
0.65
Z018_S04

264
525
1.19
Z018_S04

265
461
0.59
003_CA04

266
459
0.6
003_CA04

267
428
0.61
004_CA07

268
427
0.59
004_CA07

269
442
0.78
003_CA04

270
412
0.82
003_CA04

271
426
0.65
n.d.

272
400
1.13
V011_S01

273
438
0.73
X011_S03

274
426
0.47
002_CA07

275
486
0.56
002_CA07

276
540
0.58
002_CA07

277
504
0.57
Z020_S01

278
490
0.54
n.d.

279
490
0.53
Z020_S01

280
413
0.35
X012_S02

281
425
1.03
V011_S01

282
425
1.02
V011_S01

283
427
0.49
004_CA07

284
427
0.46
004_CA07

285
422
1.26
V011_S01

286
425
0.58
004_CA05

287
467
0.57
004_CA05

288
467
0.64
Z018_S04

289
480
0.53
Z018_S04

290
394
1.28
V011_S01

291
448
0.64
Z011_S03

292
430
0.51
005_CA01

293
423
0.37
001_CA07

294
405
0.36
001_CA07

295
423
0.37
001_CA07

296
441
0.49
X012_S02 —

297
421
0.39
001_CA07

298
412
0.37
X012_S01 —

299
445
0.48
002_CA03

300
423
0.41
X012_S01 —

301
455
0.47
X012_S01 —

302
480
0.53
002_CA03

303
426
0.47
X012_S02 —

304
421
0.51
002_CA03

305
435
0.48
X012_S01 —

306
458
0.48
004_CA05

307
430
0.56
004_CA05

308
405
0.35
001_CA07

309
412
0.60
004_CA05

310
423
0.73
003_CA04

311
445
0.52
002_CA03

312
417
0.62
004_CA05

313
465
0.33
X012_S01 —

314
402
0.26
X012_S01 —

315
389
0.37
X012_S01

316
371
0.31
X012_S01

317
381
0.61
003_CA04

318
386
0.99
V011_S01

319
401
0.31
X012_S02

320
397
0.34
X012_S02

321
399
1.10
V011_S01

322
405
0.75
003_CA04

323
423
0.55
005_CA01

324
441
0.56
005_CA01

325
448
0.53
005_CA01

326
419
0.83
003_CA04

327
384
0.46
002_CA07

328
412
0.74
004_CA05

329
468
0.66
X011_S03

330
398
0.8
003_CA04

331
442
0.72
003_CA04

332
439
0.62
X011_S03

333
412
1.15
V011_S01

334
502
0.54
Z020_S01

335
372
0.93
V011_S01

336
456
0.67
004_CA05

337
441
0.63
X011_S03

338
441
0.29
X018_S02

339
544
0.35
X012_S01

340
540
0.83
003_CA04

341
470
0.40
X012_S01 —

342
452
0.47
004_CA07

343
445
0.48
004_CA07

344
414
0.74
004_CA05

345
428
0.30
X012_S01

346
516
0.98
Z011_S03

347
433
0.96
V011_S01

348
468
1.09
V011_S01

349
412
1.14
V011_S01

350
415
0.79
003_CA04

351
427
0.57
X011_S03

352
413
1.11
V011_S01

353
412
0.78
004_CA05

354
468
0.81
003_CA04

355
428
0.90
Z011_S03

356
442
0.91
Z011_S03

357
442
0.93
Z011_S03

358
425
0.71
Z012_S04

359
423
1.06
Z011_S03




























































































































































































































































































































































































Examples representing mixtures of stereoisomers can be detected and resolved into single stereoisomers through analytical and preparative chiral chromatography. Representatives of examples for this process are given in Table 64





TABLE 64



The abbreviation “Dist. example” refers to the distomer of the given example.






Analytical SFC Data














Stereoisomer 2

Prep.



Stereoisomer 1
rt
(Example
rt
SFC

Example
Methode
(Exampl No.).
[min]
No.)
[min]
Method











15
I_ASH_30_10MIN_SS4P.M
2
3.94
Dist.-2
5.67
chiral







SFC E

22
I_ADH_40_MEOH_DEA.M
29
3.60
Dist.-29
5.76
chiral







SFC D

43
I_ADH_15_MEOH_DEA.M
249
7.43
250
8.72
chiral







SFC C








































TABLE 65



List of Abbreviations










ACN
acetonitrile


AIBN
2,2′-azobis(isobutyronitrile)


ALOX
aluminium oxide


aq.
aqueous


BOC
tert. butyloxycyrbonyle-


d
day


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


DCM
dichlormethane


DEA
diethylamine


DIPEA
n,n-diisopropylethylamine


DIPE
diisopropyl ether


DMAP
4-dimethylaminopyridine


DMF
n,n-dimethylformamide


DMSO
dimethyl sulfoxide


EA
ethyl acetate


FA
formic acid


h
hour


HATU
o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-



tetramethyluronium hexafluoro-phosphate


LiOH
lithium hydroxide


MeOH
methanol


MSA
methanesulfonic acid


MeTHF
methyl tetrahydrofuran


NaH
sodium hydride


PE
petrol ether


RT, r.t.
room temperature, e.g. 15-25° C.


rt
retention time


SI
trimethylsilyl iodide


TBME
tert-butyl methyl ether


TBTU
o-(1H-benzo-1,2,3-triazol-1-yl)-N,N,N′,N′-



tetramethyluronium tetrafluoroborate


TEA
triethylamine


TFA
trifluoroacetic acid


THF
tetrahydrofuran


TSA
toluene sulfonic acid
























































Pharmacological Data
Other features and advantages of the present invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the invention.
Inhibition of Human DPPI (Cathepsin C)
Materials: Microtiterplates (Optiplate-384 F) were purchased from PerkinElmer (Prod. No. 6007270). The substrate Gly-Arg-AMC was from Biotrend (Prod.-No. 808756 Custom peptide). Bovine serum albumin (BSA; Prod. No. A3059) and Dithiothreitol (DTT; Prod. No D0632) were from Sigma. TagZyme buffer was from Riedel-de-Haen (Prod.-No. 04269), NaCl was from Merck (Prod.-No. 1.06404.1000) and morpholinoethane sulfonic acid (MES), was from Serva (Prod.-No. 29834). The DPP1 inhibitor Gly-Phe-DMK was purchased from MP Biomedicals (Prod.-No. 03DK00625). The recombinant human DPPI was purchased from Prozymex. All other materials were of highest grade commercially available.
The following buffers were used: MES buffer: 25 mM MES, 50 mM NaCl, 5 mM DTT, adjusted to pH 6.0, containing 0.1% BSA; TAGZyme Buffer: 20 mM NaH 2 PO 4 , 150 mM NaCl adjusted to pH 6.0 with HCl
Assay conditions: The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1 μg/ml, respectively), and then activated by mixing in a 1:2 ratio with a Cysteamine aqueous solution (2 mM) and incubating for 5 min at room temperature.
Five uL test compound (final concentration 0.1 nM to 100 μM) in aqua bidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 μL of DPPI in MES buffer (final concentration 0.0125 ng/μL) and incubated for 10 min. Then, 5 μL of substrate in MES buffer (final concentration 50 μM) were added. The microtiter plates were then incubated at room temperature for 30 mM Then, the reaction was stopped by adding 10 μL of Gly-Phe-DMK in MES-buffer (final concentration 1 μM). The fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an Envision Fluorescence Reader (Ex 355 nm, Em 460 nm).
Each assay microtiter plate contained wells with vehicle controls (1% DMSO in bidest+0.075% BSA) as reference for non-inhibited enzyme activity (100% Ctl; high values) and wells with inhibitor (Gly-Phe-DMK, in bidest+1% DMSO+0.075% BSA, final concentration 1 μM) as controls for background fluorescence (0% Ctl; low values).
The analysis of the data was performed by calculating the percentage of fluorescence in the presence of test compound in comparison to the fluorescence of the vehicle control after subtracting the background fluorescence using the following formula:

(RFU(sample)−RFU(background))*100/(RFU(control)−RFU(background))

Data from these calculations were used to generate IC 50 values for inhibition of DPPI, respectively.
TABLE 66 Inhibition of DPPI IC50 Example [μM] 1 0.0086 2 0.0020 3 0.0007 4 0.0014 5 0.0040 6 0.0107 7 0.0019 8 0.6794 9 0.0096 10 0.0015 11 0.0017 12 0.0019 13 0.0019 14 0.0020 15 0.0020 16 0.0026 17 0.0026 18 0.0027 19 0.0028 20 0.0031 21 0.0031 22 0.0033 23 0.0037 24 0.0037 25 0.0039 26 0.0040 27 0.0040 28 0.0041 29 0.0042 30 0.0042 31 0.0043 32 0.0045 33 0.0045 34 0.0046 35 0.0046 36 0.0047 37 0.0047 38 0.0048 39 0.0051 40 0.0051 41 0.0053 42 0.0053 43 0.0056 44 0.0059 45 0.0063 46 0.0069 47 0.0072 48 0.0072 49 0.0073 50 0.0074 51 0.0075 52 0.0076 53 0.0079 54 0.0082 55 0.0082 56 0.0083 57 0.0083 58 0.0084 59 0.0085 60 0.0087 61 0.0087 62 0.0091 63 0.0093 64 0.0093 65 0.0094 66 0.0094 67 0.0096 68 0.0097 69 0.0099 70 0.0102 71 0.0108 72 0.0108 73 0.0112 74 0.0114 75 0.0114 76 0.0117 77 0.0119 78 0.0120 79 0.0120 80 0.0124 81 0.0131 82 0.0131 83 0.0133 84 0.0137 85 0.0140 86 0.0141 87 0.0142 88 0.0152 89 0.0156 90 0.0160 91 0.0170 92 0.0177 93 0.0183 94 0.0187 95 0.0192 96 0.0198 97 0.0199 98 0.0203 99 0.0211 100 0.0223 101 0.0239 102 0.0248 103 0.0249 104 0.0249 105 0.0250 106 0.0259 107 0.0259 108 0.0264 109 0.0269 110 0.0286 111 0.0318 112 0.0333 113 0.0364 114 0.0367 115 0.0378 116 0.0391 117 0.0396 118 0.0443 119 0.0512 120 0.0556 121 0.1565 122 0.1817 123 0.1866 124 0.1869 125 0.2060 126 0.2751 127 0.8597 128 2.3930 129 0.0827 130 0.0435 131 0.1387 132 0.0189 133 0.0161 134 0.0178 135 0.2857 136 0.0102 137 0.0597 138 0.0145 139 0.0117 140 0.0215 141 0.0366 142 0.0631 143 0.0067 144 0.0263 145 0.0538 146 0.0305 147 0.0062 148 0.0304 149 0.0387 150 0.0386 151 0.0369 152 0.0021 153 0.0038 154 0.0135 155 0.0008 156 0.0006 157 0.0009 158 0.0015 159 0.0016 160 0.0017 161 0.0019 162 0.002 163 0.0021 164 0.0023 165 0.0027 166 0.0033 167 0.0034 168 0.0037 169 0.0041 170 0.0042 171 0.005 172 0.0052 173 0.0055 174 0.0056 175 0.0063 176 0.0066 177 0.0074 178 0.0074 179 0.0075 180 0.0077 181 0.0086 182 0.0088 183 0.0088 184 0.0088 185 0.009 186 0.0096 187 0.0098 188 0.0098 189 0.0104 190 0.0109 191 0.0112 192 0.0113 193 0.0123 194 0.0133 195 0.0147 196 0.0151 197 0.0156 198 0.0158 199 0.016 200 0.0165 201 0.0201 202 0.0229 203 0.0233 204 0.0245 205 0.0259 206 0.0263 207 0.0291 208 0.0298 209 0.0458 210 0.0494 211 0.0611 212 0.2955 213 0.619 214 0.8148 215 0.8819 216 217 0.0037 218 0.0189 219 0.0374 220 0.253 221 0.0037 222 0.0022 223 0.0059 224 0.0012 225 0.0008 226 0.0009 227 0.0010 228 0.0016 229 0.0017 230 0.0018 231 0.0022 232 0.0022 233 0.0022 234 0.0038 235 0.0047 236 0.0016 237 0.0046 238 0.0143 239 0.0034 240 0.0061 241 0.0068 242 0.0109 243 0.0048 244 0.0037 245 0.0059 246 0.0059 247 0.0084 248 0.0180 249 0.0063 250 0.0042 251 0.0115 252 0.0038 253 0.0110 254 0.0020 255 0.0109 256 0.0263 257 0.0399 258 0.0079 259 0.0060 260 0.0035 261 0.0042 262 0.0064 263 0.0118 264 0.0170 265 0.0627 266 0.0437 267 0.0105 268 0.0111 269 0.0094 270 0.0063 271 0.0059 272 0.0068 273 0.0289 274 0.0065 275 0.0330 276 0.0141 277 0.0030 278 0.0010 279 0.0055 280 0.0212 281 0.0033 282 0.0037 283 0.0097 284 0.0138 285 0.0093 286 0.0389 287 0.0397 288 0.0023 289 0.0025 290 0.0206 291 0.0059 292 0.0009 293 0.0013 294 0.0016 295 0.0021 296 0.0029 297 0.0032 298 0.0032 299 0.0032 300 0.0038 301 0.0045 302 0.0047 303 0.0050 304 0.0060 305 0.0069 306 0.0070 307 0.0072 308 0.0083 309 0.0091 310 0.0094 311 0.0099 312 0.0110 313 0.0136 314 0.0140 315 0.0135 316 0.0424 317 0.0520 318 0.2120 319 0.0175 320 0.0096 321 0.0568 322 0.0008 323 0.0008 324 0.0010 325 0.0013 326 0.0019 327 0.0034 328 0.0042 329 0.0070 330 0.0078 331 0.0093 332 0.0129 333 0.0153 334 0.0220 335 0.0245 336 0.0245 337 0.0282 338 0.0443 339 0.0013 340 0.0018 341 0.0076 342 0.0013 343 0.0045 344 0.0100 345 0.0184 346 0.0010 347 0.0085 348 0.0176 349 0.0206 350 0.0386 351 0.0828 352 0.0173 353 0.0065 354 0.0068 355 0.0224 356 0.0200 357 0.0338 358 0.0220 359 0.0088 WO09074829; Example 56 0.0441
Determination of Neutrophil Elastase Activity in U937 Cytosolic Lysate Preparation after Incubation with Test Compound

Materials:

Optiplate 384F were purchased from PerkinElmer (Prod. No. #6007270). 24 well Nunclon cell culture plates (No. 142475) and 96 well plates (No. 267245) were from Nunc. Dimethylsulfoxid (DMSO) was from Sigma (Prod. No. D8418). Nonidet-P40 (NP40) was from USBiological (Prod. No. N3500)
Substrate, specific for Neutrophil elastase, was from Bachem (MeOSuc-Ala-Ala-Pro-Val-AMC; Prod. No. I-1270).
Human neutrophil elastase was from Calbiochem (Prod. No. 324681)
Buffers:
Tris-buffer (100 mM Tris; 1M NaCL; pH 7.5)
Tris-buffer+HSA 0.1%; Human Serum Albumin from Calbiochem (Cat#. 126658)
Serine-protease buffer (20 mM Tris; 100 mM NaCL; pH 7.5)+0.1% HSA
Serine protease lysis buffer: 20 mM Tris-HCL; 100 mM NaCl pH 7.5; +0.2% Nonidet-P40;
PBS: phosphate buffered saline, without Ca and Mg, from Gibco
Cell Culture:
U937 from ECACC (Cat. No. 85011440) cultured in suspension at 37° C. and 5% CO2.
Cell density: 0.2-1 Mio. Cells/ml.
Medium: RPMI1640 GlutaMAX (No. 61870) with 10% FCS from Gibco
Cell Seeding and Treatment:
Compounds in 100% DMSO were diluted in Medium (-FCS) with 10% DMSO and further diluted according to the experiment planned.
20 μl of the compound solution was transferred in the respective wells of the 24 well plate and diluted with 2 ml cell suspension/well containing 1'105 cells/ml (final concentration of DMSO=0.1%). Compound dilution factor=100
Compounds (up to 7 concentrations) were tested in triplicates with 3 wells for the DMSO 0.1% control, incubated for 48 hours without medium change at 37° C., 5% CO2 and 95% relative humidity.
Cell Harvesting and Cell Lysate:
Transfer the cell suspension in 2,2 ml Eppendorf cups. Separate cells from medium by centrifugation (400×g; 5 min; RT); discard the supernatant. Resuspend in 1 ml PBS; centrifugation (400×g; 5 min; RT); wash cells twice with PBS. Add 100 μl Serin lysis buffer (ice cold) to the cell pellet; resuspend the pellet and store on ice for 15 minutes. Remove debris by centrifugation at 15000×g for 10 min at 4° C. Transfer 80-100 μl lysate supernatant in 96 well plate and store immediately at −80° C.
Neutrophil Elastase Activity Assay:
Frozen lysates were thawn at 37° C. for 10 minutes and stored on ice. Protein content was determined with Bradford protein assay. Lysates were diluted to 0.2-0.5 mg/ml protein in serine protease buffer+HSA.
Standard: NE (100 μg/ml stocksolution in Tris-buffer; stored at −80° C.) was diluted in Tris-buffer+HSA to 750 ng/ml, and further serially diluted 1:2 for the standard curve.
Buffer, blank, standard and lysate samples were transferred into 384 well plate
Pipetting Plan


Blank: 5 μl Tris-buffer+10 μl Tris-buffer+HSA+5 μl Substrate
Standard: 5 μl Tris-buffer+10 μl NE (diff. conc.)+5 μl Substrate
Lysate: 5 μl Tris-buffer+10 μl Lysat+5 μl Substrate


The increase in fluorescence (Ex360 nm/Em 460 nm) is determined over 30 minutes with a Molecular Device Spectramax M5 Fluorescence Reader. Kinetic Reduction (Vmax units/sec); 4 vmax points. The amount of neutrophil elastase (ng/ml) is calculated using the standard curve and the Spectramax software. The result is interpolated to ng/mg lysate protein using excel formula functions. Percent inhibition in the compound-treated lysate samples is calculated relative to the DMSO-treated control-sample (100−(compound-sample*100)/control-sample)
A test compound will give values between 0% and 100% inhibition of neutrophil elastase. 1050 is calculated using Graphpad Prism; nonlinear fitting (log(inhibitor) vs. response—Variable slope). The IC50 value is interpolated as the concentration of test compound which leads to a neutrophil elastase activity reduction of 50% (relative to the DMSO-treated control).
TABLE 67 Reduction of NE- activity in U937 cells Example IC50 [μM] 1 0.0023 2 0.0062 3 0.0029 4 0.0064 6 0.0024 11 0.0087 16 0.0145 29 0.0088 42 0.0083 43 0.0092 154 0.0046 155 0.0005 156 0.0023 158 0.0088 169 0.0091 177 0.0092 178 0.0036 182 0.0081 185 0.0039 187 0.0073 188 0.0044 191 0.0033 192 0.0041 193 0.0065 196 0.0053 217 0.0075 223 0.0030 224 0.0010 225 0.0028 226 0.0018 227 0.0009 228 0.0046 229 0.0029 232 0.0052 234 0.0069 237 0.0096 241 0.0053 245 0.0038 247 0.0080 249 0.0165 250 0.0115 253 0.0055 254 0.0305 267 0.0027 268 0.0007 269 0.0055 270 0.0014 271 0.0017 272 0.0024 277 0.0036 278 0.0010 279 0.0019 281 0.0019 282 0.0034 283 0.0045 284 0.0053 289 0.0039 293 0.0046 294 0.0078 295 0.0086 300 0.0089 303 0.0083 319 0.0093 320 0.0037 322 0.0021 323 0.0014 324 0.0013 325 0.0047 326 0.0019 328 0.0012 329 0.0025 330 0.0377 331 0.0060 332 0.0058 333 0.0047 339 0.0006 340 0.0008 342 0.0247 343 0.0169 344 0.0041 345 0.0069 346 0.0068 348 0.0020 349 0.0028 358 0.0037 359 0.0029 WO09074829; Example 56 0.1067
Inhibition of Human Cathepsin K

Materials: Microtiterplates (Optiplate-384 F were purchased from PerkinElmer (Prod. No. 6007270). The substrate Z-Gly-Pro-Arg-AMC was from Biomol (Prod.-No. P-142). L-Cysteine (Prod. No. 168149) was from Sigma. Sodium acetate was from Merck (Prod.-No. 6268.0250), EDTA was from Fluka (Prod.-No. 03680). The inhibitor E-64 was purchased from Sigma (Prod.-No. E3132). The recombinant human Cathepsin K proenzyme was purchased from Biomol (Prod. No. SE-367). All other materials were of highest grade commercially available.
The following buffers were used: Activation buffer: 32.5 mM sodium acetate, adjusted to pH 3.5 with HCl; Assay buffer: 150 mM sodium acetate, 4 mM EDTA, 20 mM L-Cysteine, adjusted to pH 5.5 with HCl,
Assay conditions: To activate the proenzyme, 5 μl procathepsin K were mixed with 1 ul activation buffer, and incubated at room temperature for 30 min.
5 μL test compound (final concentration 0.1 nM to 100 μM) in aqua bidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uL of Cathepsin K in assay buffer (final concentration 2 ng/μL) and incubated for 10 min. Then 5 μL of substrate in assay buffer (final concentration 12.5 μM) were added. The plates were then incubated at room temperature for 60 min. Then, the reaction was stopped by adding 10 μL of E64 in assay buffer (final concentration 1 μM). The fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm).
Each assay microtiter plate contains wells with vehicle controls (1% DMSO in bidest) as reference for non-inhibited enzyme activity (100% Ctl; high values) and wells with inhibitor (E64 in bidest+1% DMSO, final concentration 1 μM) as controls for background fluorescence (0% Ctl; low values). The analysis of the data was performed by calculating the percentage of fluorescence in the presence of test compound in comparison to the fluorescence of the vehicle control after subtracting the background fluorescence:

(RFU(sample)−RFU(background))*100/(RFU(control)−RFU(background))

Data from these calculations were used to generate IC 50 values for inhibition of Cathepsin K, respectively.
TABLE 68 Inhibition of Cathepsin K Example IC50 [μM] 2 2.8 3 2.1 4 2.6 5 2.6 6 2.5 7 8.0 10 2.7 11 2.6 12 2.1 13 3.4 14 2.7 15 3.2 16 2.1 17 6.1 18 3.0 19 5.4 20 2.9 21 4.9 22 3.2 23 3.8 24 13.3 25 6.3 26 3.6 27 3.2 28 2.7 29 1.4 30 3.1 31 7.3 32 3.9 33 4.8 34 2.5 35 4.4 36 3.0 37 5.1 38 2.9 39 7.8 40 7.8 41 4.7 42 2.9 43 2.2 44 4.0 45 4.4 46 4.0 47 3.4 48 3.3 49 6.5 50 3.6 51 4.9 52 17.0 53 4.1 54 4.5 55 3.9 56 4.0 57 2.3 58 11.1 59 2.5 60 12.3 61 10.9 62 3.9 63 6.2 64 4.2 65 11.7 66 4.8 67 4.6 68 7.3 69 2.4 70 12.0 71 4.8 72 7.3 73 3.1 74 2.5 75 5.3 76 5.3 77 5.3 78 6.7 79 3.5 80 4.1 81 4.5 82 5.4 83 5.1 84 4.9 85 3.0 86 6.8 88 8.8 89 5.4 90 3.5 91 2.5 92 8.2 93 6.9 94 4.9 95 3.6 96 5.5 97 7.9 98 8.4 99 2.9 100 8.2 101 6.5 102 4.3 103 5.9 104 10.3 105 5.2 106 5.3 107 4.7 108 9.4 109 4.5 110 9.8 111 4.3 112 5.6 113 8.3 114 6.8 115 2.3 116 7.7 117 2.7 118 3.9 119 4.5 121 5.2 130 10.2 132 12.2 133 19.4 134 6.7 136 6.2 138 6.4 139 4.8 140 8.4 141 8.8 143 5.1 144 11.1 145 7.4 146 9.6 147 9.7 148 14.6 149 7.6 150 9.3 151 4.8 152 6.1 153 4.4 154 4.6 155 1.0 156 7.8 157 7.4 158 9.4 159 3.3 161 10.7 167 6.3 169 5.2 176 13.9 181 9.7 182 3.5 185 1.7 186 3.5 190 3.7 193 2.2 199 11.7 200 3.3 201 2.5 203 8.4 218 26.0 222 1.7 228 2.0 229 1.6 230 5.9 231 2.4 233 3.0 234 2.9 235 3.0 236 1.7 237 1.9 238 9.3 239 2.0 240 9.4 241 2.5 242 2.5 244 2.0 245 1.2 247 4.5 249 3.6 250 3.1 252 3.3 253 5.7 254 4.5 259 3.7 260 3.9 261 3.8 262 2.8 263 2.1 267 4.7 268 3.8 269 1.7 270 6.1 274 3.5 276 5.5 278 1.2 281 1.9 282 1.8 283 3.6 285 8.7 288 2.2 293 2.7 294 2.2 295 4.7 296 >30.0 297 12.4 298 17.6 300 23.1 301 19.5 303 22.2 315 >30.0 319 4.5 322 1.1 323 0.9 324 0.8 325 2.3 326 1.1 328 7.7 330 6.6 331 1.5 332 6.2 333 2.4 343 5.3 344 6.2 345 9.2 346 4.0 348 4.3 349 5.0 358 9.6 359 6.3 WO09074829; Example 56 0.4
Determination of Metabolic Stability with Human Liver Microsomes

The metabolic degradation of the test compound is assayed at 37° C. with pooled human liver microsomes. The final incubation volume of 100 μl per time point contains TRIS buffer pH 7.6 (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg/ml) and the test compound at a final concentration of 1 μM. Following a short preincubation period at 37° C., the reactions are initiated by addition of beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM) and terminated by transferring an aliquot into acetonitrile after different time points. Additionally, the NADPH-independent degradation is monitored in incubations without NADPH, terminated at the last time point. The [%] remaining test compound after NADPH independent incubation is reflected by the parameter c (control) (metabolic stability). The quenched incubations are pelleted by centrifugation (10,000 g, 5 min) An aliquot of the supernatant is assayed by LC-MS/MS for the amount of parent compound.
The half-life (t½ INVITRO) is determined by the slope of the semilogarithmic plot of the concentration-time profile. The intrinsic clearance (CL_INTRINSIC) is calculated by considering the amount of protein in the incubation:

CL_INTRINSIC [μl/min/mg protein]=(ln 2/(half-life [min]*protein content [mg/ml]))*1,000.

The half-life (t½ INVITRO) values of selected compounds in the metabolic stability assay described above are listed in the following table








TABLE 69






In vitro stability in human liver



microsome incubations


Example
t½ [min]











2
>125


3
57


4
>130


5
92


6
>130


9
>120


10
>130


12
>130


14
>130


15
130


16
>130


19
>130


21
>130


22
>130


24
110


28
>130


29
>130


31
90


33
>130


35
>130


40
>130


41
>130


42
>130


43
>130


44
>130


47
84


49
>130


50
>130


52
>130


53
>130


54
>130


55
>130


57
95


58
>130


62
>130


67
89


71
>120


76
84


77
>130


78
130


82
>130


83
>130


86
>130


88
>130


89
>130


90
>130


91
>130


95
>130


96
82


97
>130


98
>130


99
>130


100
>130


102
>130


105
>130


106
>130


108
>130


109
>130


110
>130


111
>130


112
>130


114
>130


116
>130


117
>130


125
>130


132
>130


136
>130


139
>130


143
>130


147
>130


152
>130


153
110


154
>130


155
62


156
95


157
>130


158
>130


159
>130


162
>130


166
94


167
>130


169
>130


171
83


176
>130


178
>130


180
>120


181
>130


182
>130


183
>130


184
>130


185
>130


188
97


189
>130


190
>130


191
91


192
>130


193
>130


194
85


196
>130


199
88


200
>130


201
>130


204
>130


205
>130


218
>130


221
>130


222
>130


223
>130


230
>130


231
>130


233
>130


235
>130


236
>130


238
110


239
>130


240
110


241
84


242
>130


244
92


245
>130


247
>130


248
>130


249
>130


250
>130


252
130


253
>130


254
>130


255
>130


258
>130


259
>130


260
>130


261
>130


262
>120


263
>130


266
>130


267
>130


268
>130


269
>130


270
>130


271
130


272
>130


274
>125


276
130


277
>130


278
>130


281
>130


282
>130


283
>130


284
58


285
>130


288
>130


289
110


291
>130


292
94


293
>130


294
>130


295
>130


296
>130


298
105


300
>130


301
100


303
>130


305
91


306
>130


307
>130


308
>130


310
>130


313
>130


314
>130


315
92


319
>130


320
>130


321
>130


322
>130


323
>130


324
>130


325
>130


327
>130


328
>130


330
>130


331
>120


332
100


333
>130


335
>130


341
>130


342
>130


343
>130


344
110


345
>130


346
>130


347
>130


348
130


349
>130


358
>130


359
>130


WO09074829; Example 56
120



























































































































































































































Combinations
The compounds of general formula I may be used on their own or combined with other active substances of formula I according to the invention. The compounds of general formula I may optionally also be combined with other pharmacologically active substances. These include, β2-adrenoceptor-agonists (short and long-acting), anti-cholinergics (short and long-acting), anti-inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4-inhibitors, PDE7-inhibitors, LTD4 antagonists, EGFR-inhibitors, Dopamine agonists, PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor (BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, Histamine H4 receptor antagonists, dual Histamine H1/H3-receptor antagonists, PI3-kinase inhibitors, inhibitors of non-receptor tyrosine kinases as for example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAP kinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, inhibitors of the NF-κB signalling pathway as for example IKK2 kinase inhibitors, iNOS inhibitors, MRP4 inhibitors, leukotriene biosynthese inhibitors as for example 5-Lipoxygenase (5-LO) inhibitors, cPLA2 inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors, Non-steroidal anti-inflammatory agents (NSAIDs), CRTH2 antagonists, DPI-receptor modulators, Thromboxane receptor antagonists, CCR3 antagonists, CCR4 antagonists, CCR1 antagonists, CCR5 antagonists, CCR6 antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR30 antagonists, CXCR 3 antagonists, CXCR 4 antagonists, CXCR 2 antagonists, CXCR 1 antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR 3 antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1-Phosphate receptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosine receptor modulators as for example A2a-agonists, modulators of purinergic receptors as for example P2X7 inhibitors, Histone Deacetylase (HDAC) activators, Bradykinin (BK1, BK2) antagonists, TACE inhibitors, PPAR gamma modulators, Rho-kinase inhibitors, interleukin 1-beta converting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators, HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GABAa receptor antagonist, ENaC-inhibitors, Prostasin-inhibitors, Matriptase-inhibitors, Melanocortin receptor (MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelin antagonists, TNFα antagonists, anti-TNF antibodies, anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies, mucoregulators, immunotherapeutic agents, compounds against swelling of the airways, compounds against cough, VEGF inhibitors, NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinations of two or three active substances.
Preferred are betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors, 5-LO-inhibitors, Histamine receptor antagonists and SYK-inhibitors, NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinations of two or three active substances, i.e.:
Betamimetics with corticosteroids, PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists, Anticholinergics with betamimetics, corticosteroids, PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists, Corticosteroids with PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists PDE4-inhibitors with CRTH2-inhibitors or LTD4-antagonists CRTH2-inhibitors with LTD4-antagonists.

Indications
The compounds of the invention and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as inhibitors of dipeptidyl peptidase I activity, and thus may be used in the treatment of:
1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; alpha1-antitrypsin deficiency, bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, polyangiitis (Wegener Granulomatosis) and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
2. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;
3. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial;
4. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female);
5. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
6. other auto-immune and allergic disorders including rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome and Sazary syndrome;
7. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
8. infectious diseases: virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium , leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus , cryptococcal meningitis, Pneumocystis carnii , cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
9. pain: Recent literature data from Cathepsin C-deficient mice point to a modulatory role of Cathepsin C in pain sensation. Accordingly, inhibitors of Cathepsin C may also be useful in the clinical setting of various form of chronic pain, e.g. inflammatory or neuropathic pain.
For treatment of the above-described diseases and conditions, a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about 0.1 mg to about 20 mg/kg of body weight per dosage. For Example, for administration to a 70 kg person, the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage. Some degree of routine dose optimization may be required to determine an optimal dosing level and pattern. The active ingredient may be administered from 1 to 6 times a day.
The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the active ingredient will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.