TRIFLUOROMETHYLPROPANAMIDE DERIVATIVES AS HTRA1 INHIBITORS
20180371016 ยท 2018-12-27
Assignee
Inventors
- Benoit Hornsperger (Basel, CH)
- Roberto Iacone (Basel, CH)
- Hans P. Maerki (Basel, CH)
- Peter Mohr (Basel, CH)
- Michael Reutlinger (Basel, CH)
Cpc classification
A61P9/10
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
C07K5/0827
CHEMISTRY; METALLURGY
C07K5/06191
CHEMISTRY; METALLURGY
C07K5/0821
CHEMISTRY; METALLURGY
C07K5/0806
CHEMISTRY; METALLURGY
C07K5/06121
CHEMISTRY; METALLURGY
C07K5/06139
CHEMISTRY; METALLURGY
C07K5/081
CHEMISTRY; METALLURGY
C07K5/06026
CHEMISTRY; METALLURGY
International classification
Abstract
The invention provides novel compounds having the general formula (I)
##STR00001##
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.3, R.sup.8, R.sup.10, R.sup.11 and R.sup.23 are as described herein, compositions including the compounds and methods of using the compounds.
Claims
1. Compounds of formula (I) ##STR00317## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.10 and R.sup.23 are independently selected from i) H, ii) C.sub.1-6-alkyl, and iii) C.sub.3-8-cycloalkyl; R.sup.5 is selected from i) aryl substituted with R.sup.12, R.sup.13 and R.sup.14, ii) aryl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14, iii) heteroaryl substituted with R.sup.12, R.sup.13 and R.sup.14, and iv) heteroaryl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14; R.sup.8 is selected from i) H, ii) hydroxy, iii) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17, iv) aminocarbonyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17, v) aminocarbonyl-C.sub.1-6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17, vi) carboxy, vii) carboxy-C.sub.1-6-alkyl, viii) C.sub.1-6-alkoxy, ix) C.sub.1-6-haloalkoxy, x) C.sub.1-6-alkoxycarbonyl, xi) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, xii) C.sub.3-8-cycloalkyl, xiii) aryl substituted with R.sup.15, R.sup.16 and R.sup.17, xiv) aryl-C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, xv) aryl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17, xvi) heteroaryl substituted with R.sup.15, R.sup.16 and R.sup.17, xvii) heteroaryl-C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, and xviii) heteroaryl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17 xix) heterocycloalkyl substituted with R.sup.15, R.sup.16 and R.sup.17, xx) heterocycloalkyl C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, xxi) heterocycloalkyl C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17, xxii) cyano-C.sub.1-6-alkyl, and xxiii) halo-C.sub.1-6-alkoxy; R.sup.11 is selected from i) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by R.sup.21 and R.sup.22, ii) C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) C.sub.3-8-cycloalkyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, v) aryl substituted with R.sup.18, R.sup.19 and R.sup.20, vi) aryl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vii) aryl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, viii) aryl-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20 ix) aryl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, x) aryl(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xi) aryl(halo)-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xii) aryloxy-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xiii) aryloxy-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xiv) aryloxy-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xv) aryloxy(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xvi) aryloxy(halo)-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20 xvii) aryloxy(halo)-C.sub.1-6-alkyl, xviii) heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xix) heterocycloalkyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xx) heterocycloalkyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxi) heterocycloalkyl(halo)-C.sub.38-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxii) heterocycloalkyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxiii) heteroaryl substituted with R.sup.18, R.sup.19 and R.sup.20, xxiv) heteroaryl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxv) heteroaryl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxvi) heteroaryl(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxvii) heteroaryl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxviii) heteroaryloxy-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxix) heteroaryloxy-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxx) heteroaryloxy(halo)-C.sub.38-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and xxxi) heteroaryloxy(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxxii) aryl(cycloalkyl)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxxiii) aryl(heterocycloalkyl)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and xxxiv) aryl(hydroxy, halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20; R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19 and R.sup.20 are independently selected from i) H, ii) cyano, iii) halogen, iv) oxo, v) C.sub.1-6-alkyl, vi) amino substituted on the nitrogen atom by two substituents independently selected from H, C.sub.1-6-alkyl, C.sub.1-6-alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl, vii) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by two substituents independently selected from H, C.sub.1-6-alkyl, C.sub.1-6-alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl, viii) halo-C.sub.1-6-alkyl, ix) C.sub.3-8-cycloalkyl, x) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, xi) carboxy-C.sub.1-6-alkyl, xii) C.sub.1-6-alkoxycarbonyl-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkyl, xiii) carboxy-C.sub.1-6-alkylaminocarbonyl-C.sub.1-6alkyl, xiv) C.sub.1-6-alkoxy, xv) halo-C.sub.1-6-alkoxy, xvi) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, xvii) hydroxycarbonyl-C.sub.1-6-alkoxy, xviii) carboxy-C.sub.1-6-alkoxy, xix) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkylaminocarbonyl-C.sub.1-6-alkoxy, xx) carboxy-C.sub.1-6-alkylaminocarbonyl-C.sub.1-6-alkoxy,heterocycloalkyl, and xxi) cyano; R.sup.21 and R.sup.22 are independently selected from i) H, ii) C.sub.1-6-alkoxycarbonyl, iii) carboxy-C.sub.1-6-alkyl, iv) arylcarbonyl, and v) heteroarylcarbonyl; or pharmaceutically acceptable salts; with the proviso that CAS 1349796-81-1 is excluded.
2. A compound according to claim 1, wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.10 and R.sup.23 are independently selected from i) H, ii) C.sub.1-6-alkyl, and iii) C.sub.3-8-cycloalkyl; R.sup.5 is selected from i) aryl substituted with R.sup.12, R.sup.13 and R.sup.14, ii) aryl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14, iii) heteroaryl substituted with R.sup.12, R.sup.13 and R.sup.14, and iv) heteroaryl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14; R.sup.8 is selected from i) H, ii) hydroxy, iii) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17, iv) aminocarbonyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17, v) aminocarbonyl-C.sub.1-6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17, vi) carboxy, vii) carboxy-C.sub.1-6-alkyl, viii) C.sub.1-6-alkoxy, ix) C.sub.1-6-haloalkoxy, x) C.sub.1-6-alkoxycarbonyl, xi) C.sub.1-s-alkoxycarbonyl-C.sub.1-6-alkyl, xii) C.sub.3-8-cycloalkyl, xiii) aryl substituted with R.sup.15, R.sup.16 and R.sup.17, xiv) aryl-C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, xv) aryl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17, xvi) heteroaryl substituted with R.sup.15, R.sup.16 and R.sup.17, xvii) heteroaryl-C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, and xviii) heteroaryl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17 xix) heterocycloalkyl substituted with R.sup.15, R.sup.16 and R.sup.17, xx) heterocycloalkyl C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, and xxi) heterocycloalkyl C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17; R.sup.11 is selected from i) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by R.sup.21 and R.sup.22 ii) C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) C.sub.3-8-cycloalkyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, v) aryl substituted with R.sup.18, R.sup.19 and R.sup.20, vi) aryl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vii) aryl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, viii) aryl-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20 ix) aryl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, x) aryl(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xi) aryl(halo)-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xii) aryloxy-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xiii) aryloxy-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xiv) aryloxy-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xv) aryloxy(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xvi) aryloxy(halo)-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20 xvii) aryloxy(halo)-C.sub.1-6-alkyl, xviii) heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20 xix) heterocycloalkyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xx) heterocycloalkyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxi) heterocycloalkyl(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxii) heterocycloalkyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxiii) heteroaryl substituted with R.sup.18, R.sup.19 and R.sup.20, xxiv) heteroaryl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxv) heteroaryl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxvi) heteroaryl(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxvii) heteroaryl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxviii) heteroaryloxy-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxix) heteroaryloxy-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxx) heteroaryloxy(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and xxxi) heteroaryloxy(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20; R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19 and R.sup.20 are independently selected from i) H, ii) cyano, iii) halogen, iv) oxo, v) C.sub.1-6-alkyl, vi) amino substituted on the nitrogen atom by two substituents independently selected from H, C.sub.1-6-alkyl, C.sub.1-6-alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl, vii) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by two substituents independently selected from H, C.sub.1-6-alkyl, C.sub.1-6-alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl, viii) C.sub.1-6-alkyl, ix) halo-C.sub.1-6-alkyl, x) C.sub.3-8-cycloalkyl, xi) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, xii) carboxy-C.sub.1-6-alkyl, xiii) C.sub.1-6-alkoxycarbonyl-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkyl, xiv) carboxy-C.sub.1-6-alkylaminocarbonyl-C.sub.1-6alkyl, xv) C.sub.1-6-alkoxy, xvi) halo-C.sub.1-6-alkoxy, xvii) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, xviii) carboxy-C.sub.1-6-alkoxy, xix) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkylaminocarbonyl-C.sub.1-6-alkoxy, xx) carboxy-C.sub.1-6-alkylaminocarbonyl-C.sub.1-6-alkoxy, and xxi) heterocycloalkyl; R.sup.21 and R.sup.22 are independently selected from i) H, ii) C.sub.1-6-alkoxycarbonyl, iii) carboxy-C.sub.1-6-alkyl, iv) arylcarbonyl, and v) heteroarylcarbonyl; or pharmaceutically acceptable salts; with the proviso that CAS 1349796-81-1 is excluded.
3. A compound according to claim 1, wherein R.sup.2 is C.sub.1-6-alkyl; R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.10 and R.sup.23 are H; R.sup.5 is selected from i) phenyl substituted with R.sup.12, R.sup.13 and R.sup.14, and ii) phenyl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14, R.sup.8 is selected from i) H, ii) hydroxy, iii) carboxy-C.sub.1-6-alkyl, iv) C.sub.1-6-alkoxy, v) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, vi) C.sub.3-8-cycloalkyl, vii) phenyl substituted with R.sup.15, R.sup.16 and R.sup.17, viii) phenyl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17, ix) pyridinyl substituted with R.sup.15, R.sup.16 and R.sup.17, x) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkoxycarbonyl, pyridinylcarbonyl, pyridazinylcarbonyl and pyrazinylcarbonyl, wherein pyridinylcarbonyl, pyridazinylcarbonyl and pyrazinylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17 xi) aminocarbonyl substituted on the nitrogen atom by H, xii) cyano-C.sub.1-6-alkyl, and xiii) halo-C.sub.1-6-alkoxy; R.sup.11 is selected from i) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by R.sup.21 and R.sup.22, ii) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) naphtyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) phenyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, v) phenyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vi) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vii) phenoxy-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, viii) heteroaryl substituted with R.sup.18, R.sup.19 and R.sup.20, wherein heteroaryl is selected from pyrazinyl, pyridinyl, pyrimidinyl and thiophenyl, ix) pyridinyl-C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, and x) heterocycloalkyl substituted with R.sup.15, R.sup.16 and R.sup.17, wherein heterocycloalkyl is selected from pyrrolidinyl and piperidinyl, xi) C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xii) phenyl(cycloalkyl)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xiii) phenyl(heterocycloalkyl)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and xiv) phenyl(hydroxy, halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20; R.sup.12 is selected from i) H, and ii) C.sub.1-6-alkoxy, iii) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, and iv) hydroxycarbonyl-C.sub.1-6-alkoxy; R.sup.13, R.sup.14, R.sup.17 and R.sup.20 are H; R.sup.15 is selected from i) H, ii) cyano, iii) halogen, iv) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, and v) carboxy-C.sub.1-6-alkoxy, vi) amino substituted on the nitrogen atom by one H and one substituent selected from H, C.sub.1-6-alkoxycarbonyl and pyridinylcarbonyl; R.sup.16 is selected from i) H, and ii) halogen; R.sup.18 is selected from i) H, ii) halogen, iii) oxo, iv) C.sub.1-6-alkyl, v) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by one H and one substituents selected from H and C.sub.1-6-alkoxycarbonyl, vi) C.sub.1-s-alkoxycarbonyl-C.sub.1-6-alkoxy, vii) carboxy-C.sub.1-6-alkoxy, viii) C.sub.1-6alkoxycarbonyl-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkoxy, and ix) carboxy-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkoxy, x) halo-C.sub.1-6-alkyl, xi) halo-C.sub.1-6-alkoxy, xii) C.sub.1-6-alkoxy, and xiii) cyano; R.sup.19 is selected from i) H, ii) halogen, iii) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, and iv) carboxy-C.sub.1-6-alkoxy; R.sup.21 is selected from i) H, ii) C.sub.1-6-alkoxycarbonyl, and iii) pyridinylcarbonyl; R.sup.22 is H; or pharmaceutically acceptable salts.
4. A compound according to claim 1, wherein R.sup.2 is C.sub.1-6-alkyl; R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.10 and R.sup.23 are H; R.sup.5 is selected from i) phenyl substituted with R.sup.12, R.sup.13 and R.sup.14, and ii) phenyl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14 R.sup.8 is selected from i) H, ii) hydroxy, iii) carboxy-C.sub.1-6-alkyl, iv) C.sub.1-6-alkoxy, v) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, vi) C.sub.3-8-cycloalkyl, vii) phenyl substituted with R.sup.15, R.sup.16 and R.sup.17, viii) phenyl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17, ix) pyridinyl substituted with R.sup.15, R.sup.16 and R.sup.17; R.sup.11 is selected from i) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by R.sup.21 and R.sup.22, ii) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) naphtyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) phenyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, v) phenyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vi) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vii) phenoxy-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, viii) heteroaryl substituted with R.sup.18, R.sup.19 and R.sup.20, wherein heteroaryl is selected from pyrazinyl, pyridinyl, pyrimidinyl and thiophenyl, ix) pyridinyl-C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, and x) heterocycloalkyl substituted with R.sup.15, R.sup.16 and R.sup.17, wherein heterocycloalkyl is selected from pyrrolidinyl and piperidinyl; R.sup.12 is selected from i) H, and ii) C.sub.1-6-alkoxy; R.sup.13, R.sup.14, R.sup.17 and R.sup.20 are H; R.sup.15 is selected from i) H, ii) cyano, iii) halogen, iv) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, and v) carboxy-C.sub.1-6-alkoxy; R.sup.16 is selected from i) H, and ii) halogen; R.sup.18 is selected from i) H, ii) halogen, iii) oxo, iv) C.sub.1-6-alkyl, v) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by one H and one substituents selected from H and C.sub.1-6-alkoxycarbonyl, vi) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, vii) carboxy-C.sub.1-6-alkoxy, viii) C.sub.1-6alkoxycarbonyl-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkoxy, and ix) carboxy-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkoxy; R.sup.19 is selected from i) H, ii) halogen, iii) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, and iv) carboxy-C.sub.1-6-alkoxy; R.sup.21 is selected from i) H, ii) C.sub.1-6-alkoxycarbonyl, and iii) pyridinylcarbonyl; R.sup.22 is H; or pharmaceutically acceptable salts.
5. A compound according to any one of claims 1 to 4, wherein R.sup.2 is C.sub.1-6-alkyl.
6. A compound according to any one of claims 1 to 5, wherein R.sup.2 is isopropyl.
7. A compound according to any one of claims 1 to 6, wherein R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.10 and R.sup.23 are H.
8. A compound according to any one of claims 1 to 7, wherein R.sup.5 is selected from i) phenyl substituted with R.sup.12, R.sup.13 and R.sup.14, and ii) phenyl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14.
9. A compound according to any one of claims 1 to 8, wherein R.sup.5 is phenyl substituted with one C.sub.1-6-alkoxy.
10. A compound according to any one of claims 1 to 9, wherein R.sup.8 is selected from i) H, ii) hydroxy, iii) carboxy-C.sub.1-6-alkyl, iv) C.sub.1-6-alkoxy, v) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, vi) C.sub.3-8-cycloalkyl, vii) phenyl substituted with R.sup.15, R.sup.16 and R.sup.17, viii) phenyl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17, ix) pyridinyl substituted with R.sup.15, R.sup.16 and R.sup.17, x) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkoxycarbonyl, pyridinylcarbonyl, pyridazinylcarbonyl and pyrazinylcarbonyl, wherein pyridinylcarbonyl, pyridazinylcarbonyl and pyrazinylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17, xi) aminocarbonyl substituted on the nitrogen atom by H, xii) cyano-C.sub.1-6-alkyl, and xiii) halo-C.sub.1-6-alkoxy.
11. A compound according to any one of claims 1 to 10, wherein R.sup.8 is selected from i) H, ii) hydroxy, iii) carboxy-C.sub.1-6-alkyl, iv) C.sub.1-6-alkoxy, v) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, vi) C.sub.3-8-cycloalkyl, vii) phenyl substituted with R.sup.15, R.sup.16 and R.sup.17, viii) phenyl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17, ix) pyridinyl substituted with R.sup.15, R.sup.16 and R.sup.17.
12. A compound according to any one of claims 1 to 11, wherein R.sup.8 is selected from i) H, ii) hydroxy, iii) phenyl substituted with R.sup.15, R.sup.16 and R.sup.17, iv) phenyl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17, and v) C.sub.1-6-alkoxy.
13. A compound according to any one of claims 1 to 12, wherein R.sup.8 is selected from i) H, ii) hydroxy, iii) phenyl substituted with R.sup.15, R.sup.16 and R.sup.17, iv) phenyl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17.
14. A compound according to any one of claims 1 to 13, wherein R.sup.8 is phenyl substituted with R.sup.15, R.sup.16 and R.sup.17.
15. A compound according to any one of claims 1 to 14, wherein R.sup.11 is selected from i) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by R.sup.21 and R.sup.22, ii) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) naphtyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) phenyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, v) phenyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vi) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vii) phenoxy-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, viii) heteroaryl substituted with R.sup.18, R.sup.19 and R.sup.20, wherein heteroaryl is selected from pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl and thiophenyl, ix) pyridinyl-C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, and x) piperazinyl substituted with R.sup.15, R.sup.16 and R.sup.17, xi) C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xii) phenyl(cycloalkyl)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xiii) phenyl(haloalkyl)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xiv) phenyl(heterocycloalkyl)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and xv) phenyl(hydroxy,haloalkyl)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20.
16. A compound according to any one of claims 1 to 15, wherein R.sup.11 is selected from i) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by R.sup.21 and R.sup.22, ii) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) naphtyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) phenyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, v) phenyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vi) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vii) phenoxy-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, viii) heteroaryl substituted with R.sup.18, R.sup.19 and R.sup.20, wherein heteroaryl is selected from pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl and thiophenyl, ix) pyridinyl-C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, and x) piperazinyl substituted with R.sup.15, R.sup.16 and R.sup.17.
17. A compound according to any one of claims 1 to 16, wherein R.sup.11 is selected from i) C.sub.3-8-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, ii) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) phenyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and v) thiophenyl substituted with R.sup.18, R.sup.19 and R.sup.20.
18. A compound according to any one of claims 1 to 17, wherein R.sup.11 is selected from i) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, ii) phenyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and iv) thiophenyl substituted with R.sup.18, R.sup.19 and R.sup.20.
19. A compound according to any one of claims 1 to 18, wherein R.sup.11 is selected from i) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, and ii) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20.
20. A compound according to any one of claims 1 to 19, wherein R.sup.12 is selected from i) H, ii) C.sub.1-6-alkoxy, iii) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, and iv) hydroxycarbonyl-C.sub.1-6-alkoxy.
21. A compound according to any one of claims 1 to 20, wherein R.sup.12 is selected from i) hydroxycarbonyl-C.sub.1-6-alkoxy, and ii) C.sub.1-6-alkoxy.
22. A compound according to any one of claims 1 to 21, wherein R.sup.12 is selected from i) H, and ii) C.sub.1-6-alkoxy.
23. A compound according to any one of claims 1 to 22, wherein R.sup.12 is C.sub.1-6-alkoxy.
24. A compound according to any one of claims 1 to 23, wherein R.sup.13, R.sup.14, R.sup.17 and R.sup.20 are H.
25. A compound according to any one of claims 1 to 24, wherein R.sup.15 is selected from i) H, ii) cyano, iii) halogen, iv) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, and v) carboxy-C.sub.1-6-alkoxy, vi) amino substituted on the nitrogen atom by one H and one substituent selected from H, C.sub.1-6-alkoxycarbonyl and pyridinylcarbonyl.
26. A compound according to any one of claims 1 to 25, wherein R.sup.15 is selected from i) H, ii) cyano, iii) halogen, iv) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, and v) carboxy-C.sub.1-6-alkoxy.
27. A compound according to any one of claims 1 to 26, wherein R.sup.15 is selected from i) H, ii) cyano, iii) halogen, and iv) carboxy-C.sub.1-6-alkoxy, v) amino substituted on the nitrogen atom by one H and one substituent selected from H, C.sub.1-6-alkoxycarbonyl and pyridinylcarbonyl.
28. A compound according to any one of claims 1 to 27, wherein R.sup.15 is selected from i) H, ii) cyano, iii) halogen, and iv) carboxy-C.sub.1-6-alkoxy.
29. A compound according to any one of claims 1 to 28, wherein R.sup.16 is H.
30. A compound according to any one of claims 1 to 29, wherein R.sup.18 is selected from i) H, ii) halogen, iii) oxo, iv) C.sub.1-6-alkyl, v) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by one H and one substituents selected from H and C.sub.1-6-alkoxycarbonyl, vi) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, vii) carboxy-C.sub.1-6-alkoxy, viii) C.sub.1-6alkoxycarbonyl-C.sub.1-6alkylaminocarbonyl-C.sub.1-6-alkoxy, and ix) carboxy-C.sub.1-6alkylaminocarbonyl-C.sub.1-6-alkoxy x) halo-C.sub.1-6-alkyl, xi) halo-C.sub.1-6-alkoxy, xii) C.sub.1-6-alkoxy, and xiii) cyano.
31. A compound according to any one of claims 1 to 30, wherein R.sup.18 is selected from i) H, ii) halogen, iii) oxo, iv) C.sub.1-6-alkyl, v) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by one H and one substituents selected from H and C.sub.1-6-alkoxycarbonyl, vi) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, vii) carboxy-C.sub.1-6-alkoxy, viii) C.sub.1-6alkoxycarbonyl-C.sub.1-6alkylaminocarbonyl-C.sub.1-6-alkoxy, and ix) carboxy-C.sub.1-6alkylaminocarbonyl-C.sub.1-6-alkoxy.
32. A compound according to any one of claims 1 to 31, wherein R.sup.18 is selected from i) H, ii) halogen, iii) amino-C.sub.1-alkyl substituted on the nitrogen atom by two H, and iv) carboxy-C.sub.1-6-alkoxy, v) C.sub.1-6-alkyl, vi) halo-C.sub.1-6-alkyl.
33. A compound according to any one of claims 1 to 32, wherein R.sup.18 is selected from i) H, ii) halogen, iii) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by two H, and iv) carboxy-C.sub.1-6-alkoxy.
34. A compound according to any one of claims 1 to 33, wherein R.sup.18 is halogen.
35. A compound according to any one of claims 1 to 34, wherein R.sup.19 is selected from i) H, ii) halogen, iii) C.sub.1 i-alkoxycarbonyl-C.sub.1-6-alkyl, and iv) carboxy-C.sub.1-6-alkoxy.
36. A compound according to any one of claims 1 to 35, wherein R.sup.19 is selected from i) H, and ii) halogen.
37. A compound according to any one of claims 1 to 36, wherein R.sup.19 is halogen.
38. A compound according to any one of claims 1 to 37, wherein R.sup.21 is selected from i) H, ii) C.sub.1-6-alkoxycarbonyl, and iii) pyridinylcarbonyl.
39. A compound according to any one of claims 1 to 38, wherein R.sup.22 is H.
40. A compound according to any one of claims 1 to 39, wherein R.sup.2 is C.sub.1-6-alkyl; R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.10 and R.sup.23 are H; R.sup.5 is phenyl substituted with one C.sub.1-6-alkoxy; R.sup.8 is phenyl substituted with R.sup.15, R.sup.16 and R.sup.17. R.sup.1 is selected from i) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, ii) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20; R.sup.15 is selected from i) H, ii) cyano, iii) halogen, and iv) carboxy-C.sub.1-6-alkoxy; R.sup.16 is H; R.sup.17 and R.sup.20 are H; R.sup.18 and R.sup.19 are is halogen; or pharmaceutically acceptable salts.
41. A compound according to any one of claims 1 to 40, selected from N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; (2S)-3-(3-chlorophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-2-(3-pyridin-3-ylpropanoylamino)propanamide; N-[(2S)-3-(3-fluorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; 3-chloro-N-[(2S)-3-(3-fluorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; 5-chloro-N-[(2S)-3-(3-fluorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-fluorophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-fluorophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-cyanophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 5-chloro-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxo-3-pyridin-3-ylpropan-2-yl]benzamide; 3-chloro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxo-3-pyridin-3-ylpropan-2-yl]benzamide; (2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-pyridin-3-ylpropanamide; N-[(2S)-3-(2-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(2-cyanophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; tert-butyl 2-[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetate; tert-butyl 2-[4-[(2S)-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxo-2-(pyridine-2-carbonylamino)propyl]phenoxy]acetate; tert-butyl 2-[4-[(2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetate; tert-butyl 2-[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetate; tert-butyl 2-[3-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetate; tert-butyl 2-[3-[(2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetate; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; (2S)-2-[(2,2-difluoro-2-phenylacetyl)amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 2,5-dichloro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; 3-chloro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; 1-(3-chlorophenyl)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]cyclopropane-1-carboxamide; (2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(3-chlorophenyl)acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3 S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 2-chloro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2-chlorophenyl)acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3 S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[(2-fluoro-2-phenylacetyl)amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3 S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 5-chloro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; 5-bromo-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; (2S)-2-[[2-(4-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 2-(3-chlorophenyl)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-2-methylpropanamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 3-chloro-N-[(2S)-3-methoxy-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-[(2-methylpropan-2-yl)oxy]propanamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]pyridine-2-carboxamide; 3-chloro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]benzamide; 5-chloro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]thiophene-2-carboxamide; (2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-[(2-methylpropan-2-yl)oxy]propanamide; 3-chloro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxo-3-phenylmethoxypropan-2-yl]benzamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxo-3-phenylmethoxypropan-2-yl]pyridine-2-carboxamide; tert-butyl (4S)-4-[(3-chlorobenzoyl)amino]-5-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3 S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-5-oxopentanoate; tert-butyl (4S)-4-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-5-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-5-oxopentanoate; N-[(2S)-3-(3-chlorophenyl)-1-oxo-1-[[(1S and 1R)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]propan-2-yl]pyrazine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-oxo-1-[[(1S and 1R)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]propan-2-yl]-1-methylpyrrolidine-3-carboxamide; N-[(2S)-3-(3,4-dichlorophenyl)-1-oxo-1-[[(1S and 1R)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]propan-2-yl]pyrazine-2-carboxamide; N-[(2S)-3-(3,4-dichlorophenyl)-1-oxo-1-[[(1S and 1R)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]propan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3,4-dichlorophenyl)-1-oxo-1-[[(1S and 1R)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]propan-2-yl]pyrimidine-5-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S and 1R)-1-(3-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]pyrazine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-oxo-1-[[(2S)-1-oxo-3-phenyl-1-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]propan-2-yl]amino]propan-2-yl]pyrazine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-oxo-1-[[(2S)-1-oxo-3-phenyl-1-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]propan-2-yl]amino]propan-2-yl]pyrimidine-5-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-oxo-1-[[(2S)-1-oxo-3-phenyl-1-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]propan-2-yl]amino]propan-2-yl]-1-methylpiperidine-4-carboxamide; N-[(2R)-3-(3-chlorophenyl)-1-oxo-1-[[(2S)-1-oxo-3-phenyl-1-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]propan-2-yl]amino]propan-2-yl]pyrimidine-5-carboxamide; N-[(2R)-3-(3-chlorophenyl)-1-oxo-1-[[(2S)-1-oxo-3-phenyl-1-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]propan-2-yl]amino]propan-2-yl]pyrazine-2-carboxamide; N-[(2S)-3-(3,4-dichlorophenyl)-1-oxo-1-[[(2S)-1-oxo-3-phenyl-1-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]propan-2-yl]amino]propan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3,4-dichlorophenyl)-1-oxo-1-[[(2S)-1-oxo-3-phenyl-1-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]propan-2-yl]amino]propan-2-yl]pyrazine-2-carboxamide; N-[(2S)-3-cyclohexyl-1-oxo-1-[[(2S)-1-oxo-3-phenyl-1-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]propan-2-yl]amino]propan-2-yl]naphthalene-2-carboxamide; tert-butyl N-[2-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]carbamate; tert-butyl N-[[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenyl]methyl]carbamate; tert-butyl N-[[2-chloro-4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[2-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]phenyl]methyl]carbamate; tert-butyl 2-[6-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]pyridin-2-yl]oxyacetate; tert-butyl 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3 S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetate; tert-butyl 2-[6-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]pyridin-3-yl]oxyacetate; tert-butyl 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3 S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]-2-oxopyridin-1-yl]acetate; tert-butyl 2-[3-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetate; tert-butyl 2-[5-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]-2-oxopyridin-1-yl]acetate; tert-butyl 2-[4-[2-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3 S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethoxy]phenoxy]acetate; tert-butyl 2-[3-[[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetate; tert-butyl 2-[4-[[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetate; N-[3-(3-chlorophenyl)-1-[[(1S and 1R)-1-(3-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S and 1R)-1-(3-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3-methylpyridine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S and 1R)-1-(3-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-4-methylpyridine-3-carboxamide; N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2R)-3-(3-chlorophenyl)-1-oxo-1-[[(1S and 1R)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]propan-2-yl]pyridine-2-carboxamide; N-[(2R)-3-(3-chlorophenyl)-1-oxo-1-[[(1S and 1R)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]propan-2-yl]pyrazine-2-carboxamide; N-[(2R)-3-(3-chlorophenyl)-1-oxo-1-[[(1S and 1R)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]propan-2-yl]pyrimidine-5-carboxamide; tert-butyl N-[[4-[[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[2-[[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]phenyl]methyl]carbamate; tert-butyl 2-[[2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetate; tert-butyl 2-[[2-[3-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetate; tert-butyl 2-[[2-[4-[[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetate; tert-butyl 2-[[2-[3-[[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetate; 2-[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3 S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetic acid; 2-[4-[(2S)-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxo-2-(pyridine-2-carbonylamino)propyl]phenoxy]acetic acid; 2-[4-[(2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetic acid; 2-[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetic acid; 2-[3-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3 S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetic acid; 2-[3-[(2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetic acid; (4S)-4-[(3-chlorobenzoyl)amino]-5-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-5-oxopentanoic acid; (4S)-4-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-5-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-5-oxopentanoic acid; (2S)-2-[(2-aminoacetyl)amino]-3-(3-chlorophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide, trifluoroacetic acid salt; 4-(aminomethyl)-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide, trifluoroacetic acid salt; 4-(aminomethyl)-3-chloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide, trifluoroacetic acid salt; (2S)-2-[[2-[4-(aminomethyl)phenyl]acetyl]amino]-3-(3-chlorophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide, trifluoroacetic acid salt; 2-[6-[[3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]pyridin-2-yl]oxyacetic acid; 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic acid; 2-[6-[[3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]pyridin-3-yl]oxyacetic acid; 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]-2-oxopyridin-1-yl]acetic acid; 2-[3-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic acid; 2-[5-[[3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]-2-oxopyridin-1-yl]acetic acid; 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic acid; 2-[3-[[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic acid; 2-[4-[[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic acid; 4-(aminomethyl)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide, trifluoroacetic acid salt; (2S)-2-[[2-[4-(aminomethyl)phenyl]acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide, trifluoroacetic acid salt; 2-[[2-[4-[[3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetic acid; 2-[[2-[3-[[3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetic acid; 2-[[2-[4-[[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetic acid; 2-[[2-[3-[[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetic acid; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; N-[(2S)-3-hydroxy-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; 3-chloro-N-[(2S)-3-hydroxy-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; 5-chloro-N-[(2S)-3-hydroxy-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; (2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; N-[2-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]pyridine-2-carboxamide; and pharmaceutically acceptable salts thereof.
42. A compound according to any one of claims 1 to 40, selected from (2S)-3-(3-Chlorophenyl)-2-[[2-(3-chlorophenyl)acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 1-(3-chlorophenyl)-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]cyclopropane-1-carboxamide; 5-bromo-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; (2S)-2-[[2,2-difluoro-2-(3-fluorophenyl)acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 1-(3-chlorophenyl)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]cyclobutane-1-carboxamide; (2S)-2-[[2-(2,5-dichlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2,3-dichlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 2-(3-chlorophenyl)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[(1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl)amino]ethyl]amino]-1-oxopropan-2-yl]-1,3-dioxolane-2-carboxamide; 1-(4-chlorophenyl)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]cyclopentane-1-carboxamide; (2S)-2-[[2,2-difluoro-2-[2-(trifluoromethoxy)phenyl]acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2-ethoxyphenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2,2-difluoro-2-[2-(trifluoromethyl)phenyl]acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 1-(2-chloro-6-fluorophenyl)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]cyclopentane-1-carboxamide; 1-(2-fluorophenyl)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[(1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl)amino]ethyl]amino]-1-oxopropan-2-yl]cyclopentane-1-carboxamide; 2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]propanamide; 3,3,3-trifluoro-2-hydroxy-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-2-[3-(trifluoromethyl)phenyl]propanamide; 2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]propanamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-2-(trifluoromethoxy)benzamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3-(trifluoromethyl)benzamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-2-(trifluoromethyl)benzamide; 2-(4-chlorophenyl)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3-methylbutanamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-2-phenylbutanamide; (2S)-2-[[2-(4-chlorophenyl)-2-cyclopropylacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-(4-chlorophenyl)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3-methylbutanamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-1-phenylcyclopentane-1-carboxamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3-methylbenzamide; 3-methoxy-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; 3-cyano-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3-(trifluoromethoxy)benzamide; 3-ethoxy-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; (2S)-2-[[2,2-difluoro-2-(2-methoxyphenyl)acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 4-chloro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; 3,3,3-trifluoro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-2-[3-(trifluoromethyl)phenyl]propanamide; 2-(difluoromethoxy)-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclobutane-1-carboxamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclohexane-1-carboxamide; N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclopentane-1-carboxamide; (2S)-2-[[(2S)-2-(4-chlorophenyl)-2-cyclobutylacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[(2R)-2-(4-chlorophenyl)-2-cyclobutylacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; N-[(2S)-3-methoxy-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclopentane-1-carboxamide; 1-fluoro-N-[(2S)-3-methoxy-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]cyclopentane-1-carboxamide; tert-butyl N-[(4S)-4-[(3-chlorobenzoyl)amino]-5-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-5-oxopentyl]carbamate; tert-butyl N-[(5S)-5-[(3-chlorobenzoyl)amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-6-oxohexyl]carbamate; tert-butyl N-[(5S)-5-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-6-oxohexyl]carbamate; tert-butyl N-[[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-2-[[2,2-difluoro-2-[2-(trifluoromethyl)phenyl]acetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-2-[[1-(4-chlorophenyl)cyclopentanecarbonyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-2-[(5-chlorothiophene-2-carbonyl)amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-2-[[(2S)-2-(4-chlorophenyl)-3-methylbutanoyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-2-[[(2R)-2-(4-chlorophenyl)-3-methylbutanoyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-2-[[2-(4-chlorophenyl)-2-cyclobutylacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxo-2-[[3-(trifluoromethyl)benzoyl]amino]propyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxo-2-[[1-(trifluoromethyl)cyclopentanecarbonyl]amino]propyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxo-2-[[3,3,3-trifluoro-2-[3-(trifluoromethyl)phenyl]propanoyl]amino]propyl]phenyl]methyl]carbamate; 3-chloro-N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxo-3-(trifluoromethoxy)propan-2-yl]benzamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-(trifluoromethoxy)propanamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-cyano-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 3-chloro-N-[(2S)-3-cyano-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; tert-butyl 2-[4-[(1S)-1-[[(2S)-2-[(5-chlorothiophene-2-carbonyl)amino]-3-(3-fluorophenyl)propanoyl]amino]-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]phenoxy]acetate; tert-butyl 2-[4-[(1S)-1-[[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-fluorophenyl)propanoyl]amino]-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]phenoxy]acetate; N-[(2S)-5-Amino-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopentan-2-yl]-3-chlorobenzamide; N-[(2S)-6-amino-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxohexan-2-yl]-3-chlorobenzamide;2,2,2-trifluoroacetic acid; (2S)-6-amino-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]hexanamide;2,2,2-trifluoroacetic acid; N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3-chlorobenzamide;2,2,2-trifluoroacetic acid; (2S)-3-[4-(aminomethyl)phenyl]-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide;2,2,2-trifluoroacetic acid; (2S)-3-[4-(aminomethyl)phenyl]-2-[[2,2-difluoro-2-[2-(trifluoromethyl)phenyl]acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide;2,2,2-trifluoroacetic acid; N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-1-(4-chlorophenyl)cyclopentane-1-carboxamide;2,2,2-trifluoroacetic acid; N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-5-chlorothiophene-2-carboxamide;2,2,2-trifluoroacetic acid; (2S)N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-2-(4-chlorophenyl)-3-methylbutanamide;2,2,2-trifluoroacetic acid; (2R)N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-2-(4-chlorophenyl)-3-methylbutanamide;2,2,2-trifluoroacetic acid; (2S)-3-[4-(aminomethyl)phenyl]-2-[[2-(4-chlorophenyl)-2-cyclobutylacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide;2,2,2-trifluoroacetic acid; N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3-(trifluoromethyl)benzamide;2,2,2-trifluoroacetic acid; N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclopentane-1-carboxamide;2,2,2-trifluoroacetic acid; N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3,3,3-trifluoro-2-[3-(trifluoromethyl)phenyl]propanamide;2,2,2-trifluoroacetic acid; (2S)-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2,5-dichlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2,2-difluoro-2-(3-fluorophenyl)acetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2,2-difluoro-2-[2-(trifluoromethoxy)phenyl]acetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2-ethoxyphenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2-ethylphenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 1-(4-chlorophenyl)-N-[(2S)-3-hydroxy-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]cyclopentane-1-carboxamide; (2S)-2-[[2,2-difluoro-2-(2-methoxyphenyl)acetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2-cyanophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[(3-chlorobenzoyl)amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]butanediamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]butanediamide; (2S)-2-[(3-chlorobenzoyl)amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]pentanediamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]pentanediamide; 2-[4-[(1S)-1-[[(2S)-2-[(5-chlorothiophene-2-carbonyl)amino]-3-(3-fluorophenyl)propanoyl]amino]-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]phenoxy]acetic acid; 2-[4-[(1S)-1-[[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-fluorophenyl)propanoyl]amino]-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]phenoxy]acetic acid; N-[(5S)-5-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-6-oxohexyl]pyridine-2-carboxamide; N-[(5S)-5-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-6-oxohexyl]pyrazine-2-carboxamide; N-[(5S)-5-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-6-oxohexyl]pyrimidine-5-carboxamide; N-[(5S)-5-[(3-chlorobenzoyl)amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-6-oxohexyl]pyridine-2-carboxamide; N-[(4S)-4-[(3-chlorobenzoyl)amino]-5-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-5-oxopentyl]pyridine-2-carboxamide; N-[[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]pyridine-2-carboxamide; and pharmaceutically acceptable salts thereof.
43. A compound according to any one of claims 1 to 40 and 42, selected from N-[(2S)-3-methoxy-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclopentane-1-carboxamide; N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3-chlorobenzamide;2,2,2-trifluoroacetic acid; (2S)-3-[4-(aminomethyl)phenyl]-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide;2,2,2-trifluoroacetic acid; (2S)-3-[4-(aminomethyl)phenyl]-2-[[2,2-difluoro-2-[2-(trifluoromethyl)phenyl]acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide;2,2,2-trifluoroacetic acid; (2S)N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-2-(4-chlorophenyl)-3-methylbutanamide;2,2,2-trifluoroacetic acid; N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]-3-(trifluoromethyl)benzamide;2,2,2-trifluoroacetic acid; (2S)-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2,5-dichlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2,2-difluoro-2-(3-fluorophenyl)acetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2-ethylphenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 2-[4-[(1S)-1-[[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-fluorophenyl)propanoyl]amino]-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]phenoxy]acetic acid; N-[[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]pyridine-2-carboxamide; and pharmaceutically acceptable salts thereof.
44. A compound according to any one of claims 1 to 41, selected from N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; 3-chloro-N-[(2S)-3-(3-fluorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-fluorophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-fluorophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-cyanophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 5-chloro-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; (2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-pyridin-3-ylpropanamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(2-cyanophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; 2-[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetic acid; 2-[3-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetic acid; 4-(aminomethyl)-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide, trifluoroacetic acid salt; 4-(aminomethyl)-3-chloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide, trifluoroacetic acid salt; (2S)-2-[[2-[4-(aminomethyl)phenyl]acetyl]amino]-3-(3-chlorophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide, trifluoroacetic acide salt; 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic acid; 2-[3-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic acid; (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; (2S)-2-[[2-(2-chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; and pharmaceutically acceptable salts thereof.
45. A process to prepare a compound according to any one of claims 1 to 44 comprising the reaction of a compound of formula (II) in oxidative conditions. ##STR00318## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.3, R.sup.8, R.sup.10, R.sup.11 and R.sup.23 are as defined in any of claim 1 to 40.
46. A compound according to any one of claims 1 to 44 for use as therapeutically active substance.
47. A pharmaceutical composition comprising a compound according to any one of claims 1 to 44 and a therapeutically inert carrier.
48. The use of a compound according to any one of claims 1 to 44 for the treatment or prophylaxis of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.
49. A compound according to any one of claims 1 to 44 for the treatment or prophylaxis of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.
50. The use of a compound according to any one of claims 1 to 44 for the preparation of a medicament for the treatment or prophylaxis of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.
51. A method for the treatment or prophylaxis a renal condition selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, conditions of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy, which method comprises administering an effective amount of a compound according to any one of claims 1 to 44.
52. A compound according to any one of claims 1 to 44, when manufactured according to a process of claim 45.
53. The invention as hereinbefore described
Description
EXAMPLES
[0803] All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.
[0804] Abbreviations: aq.=aqueous; CAS-RN=Chemical Abstracts Service Registry Number; HPLC=high performance liquid chromatography; MS=mass spectrum; sat.=saturated
Intermediate A-1
(S)-2-Amino-3-(3-chlorophenyl)-N((S)-1-(4-methoxypheyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)propanamide
[0805] ##STR00014##
[A] tert-Butyl ((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)carbamate
[0806] ##STR00015##
[0807] In a round-bottomed flask, (S)-2-((tert-butoxycarbonyl)amino)-2-(4-methoxyphenyl)acetic acid (1 g, 3.55 mmol) (2S,3S)-3-amino-1,1,1-trifluoro-4-methylpentan-2-olHCl (0.738 g, 3.55 mmol) and HATU (1.49 g, 3.91 mmol) were dissolved in DMF (20 mL) and the mixture cooled to 0 C. Hunig's base (1.86 mL, 10.7 mmol) was added to the reaction mixture which was stirred at this temperature for 15 min, then allowed to warm up to room temperature and stirring was continued for 5 hours. The mixture was diluted with EtOAc, poured into 1N HCl (15 mL) and the aqueous layer was extracted with EtOAc (240 mL). Combined organics were washed with a sat. NaHCO.sub.3 solution (15 mL), then brine before being dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 70% EtOAc-heptane gradient to give the title compound (1.37 g, 86%) as a an off-white solid. MS: 435.3 (M+H.sup.+).
[B] (S)-2-Amino-2-(4-methoxyphenyl)-N-((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)acetamide
[0808] ##STR00016##
[0809] 4M HCl in dioxane (3.94 mL, 15.8 mmol) was added at 0 C. to a solution of tert-butyl ((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)carbamate (1.37 g, 3.15 mmol) in MeOH (18 mL). The reaction mixture was stirred at this temperature for 10 min and then allowed to warm to room temperature and stirring was continued for 6 hours. The mixture was evaporated to dryness and the residue was triturated with diisopropylether. The solid precipitate was filtered off and further dried under the high vacuum to give the title compound (1.19 g, 97%, HCl salt) as colorless solid. MS: 335.2 (M+H.sup.+).
[C] tert-Butyl ((S)-3-(3-chlorophenyl)-1-(((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)amino)-1-oxopropan-2-yl)carbamate
[0810] ##STR00017##
[0811] In a round-bottomed flask, (S)-2-amino-2-(4-methoxyphenyl)-N-((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)acetamide hydrochloride (0.418 g, 1.13 mmol), (2S)-2-(tert-butoxycarbonylamino)-3-(3-chlorophenyl)propanoic acid (0.338 g, 1.13 mmol) and HATU (0.471 g, 1.24 mmol) were dissolved in DMF (4 mL) and the mixture cooled to 0 C. Hnig's base (0.591 mL, 3.38 mmol) was added to the reaction mixture which was stirred at this temperature for 10 min, then allowed to warm up to room temperature and stirring was continued for 2.5 hours. The mixture was diluted with EtOAc, poured into a 1N aqueous HCl solution (5 mL) and the aqueous layer was extracted with EtOAc (220 mL). Combined organics were washed with a sat. NaHCO.sub.3 solution (5 mL), then brine before being dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 70% EtOAc-heptane gradient to give the title compound (0.598 g, 84%) as an off-white solid. MS: 616.4 (M+H.sup.+).
[D] (S)-2-Amino-3-(3-chlorophenyl)-N((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)propanamide
[0812] ##STR00018##
[0813] 4M HCl in dioxane (1.46 mL, 5.82 mmol) was added at 0 C. to a solution of tert-butyl ((S)-3-(3-chlorophenyl)-1-(((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)amino)-1-oxopropan-2-yl)carbamate (0.598 g, 0.971 mmol) in MeOH (6 mL). The reaction mixture was stirred at this temperature for 10 min and then allowed to warm up to room temperature and stirring was continued for 5 hours. The mixture was evaporated to dryness and the residue was triturated with diisopropylether. The solid precipitate was filtered off and further dried under the high vacuum to give the title compound (0.476 g, 86%, HCl salt) as an off-white solid. MS: 516.3 (M+H.sup.+).
Intermediate A-2
(S)-2-Amino-3-(3-fluorophenyl)-N((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)propanamide
[0814] ##STR00019##
was prepared in analogy to intermediate A-1, but using in step C] (2S)-2-(tert-butoxycarbonylamino)-3-(3-fluorophenyl)propanoic acid, to give the title compound as light green solid as hydrochloride; MS: 500.4 (M+H.sup.+).
Intermediate A-3
(S)-2-Amino-3-(3-cyanophenyl)-N((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)propanamide
[0815] ##STR00020##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-2-(tert-butoxycarbonylamino)-3-(3-cyanophenyl)propanoic acid, to give the title compound as light brown solid as hydrochloride; MS: 507.3 (M+H.sup.+).
Intermediate A-4
(2S)-2-Amino-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]-3-pyridin-3-ylpropanamide
[0816] ##STR00021##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-2-(tert-butoxycarbonylamino)-3-(3-pyridyl)propanoic acid, to give the title compound as off-white solid as hydrochloride; MS: 483.4 (M+H.sup.+).
Intermediate A-5
(2S)-2-Amino-3-(2-cyanophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpenta-3-yl]amino]ethyl]propanamide
[0817] ##STR00022##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-2-(tert-butoxycarbonylamino)-3-(2-cyanophenyl)propanoic acid, to give the title compound as off-white solid as hydrochloride; MS: 483.4 (M+H.sup.+).
Intermediate A-6
tert-Butyl 2-[4-[(2S)-2-amino-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetate
[0818] ##STR00023##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoic acid (Intermediate K-1) and replacing in step D methanol by dioxane as solvent, to give the title compound as colorless solid as hydrochloride; MS: 612.3 (M+H.sup.+).
Intermediate A-7
tert-Butyl 2-[3-[(2S)-2-amino-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetate
[0819] ##STR00024##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoic acid (Intermediate K-2) and replacing in step D methanol by dioxane as solvent, to give the title compound as colorless solid as hydrochloride; MS: 612.3 (M+H.sup.+).
Intermediate A-8
(2S)-2-Amino-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide
[0820] ##STR00025##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-2-(tert-butoxycarbonylamino)propanoic acid, to give the title compound as colorless solid as hydrochloride; MS: 406.5 (M+H.sup.+).
Intermediate A-9
(2S)-2-Amino-3-methoxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide
[0821] ##STR00026##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid, to give the title compound as a light yellow solid as hydrochloride; MS: 436.3 (M+H.sup.+).
Intermediate A-10
(S)-2-Amino-3-(tert-butoxy)-N((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)propanamide
[0822] ##STR00027##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)propanoic acid and replacing in step D methanol by dioxane as solvent, to give the title compound as colorless solid as hydrochloride; MS: 478.3 (M+H.sup.+).
Intermediate A-11
(2S)-2-Amino-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]-3-phenylmethoxypropanamide
[0823] ##STR00028##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-3-benzyloxy-2-(tert-butoxycarbonylamino)propanoic acid, to give the title compound as off-white solid as hydrochloride; MS: 512.3 (M+H.sup.+).
Intermediate A-12
tert-Butyl (4S)-4-amino-5-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-5-oxopentanoate
[0824] ##STR00029##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-5-tert-butoxy-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid and replacing in step D methanol by dioxane as solvent, to give the title compound as colorless solid; MS: 520.3 (M+H.sup.+).
Intermediate A-13
2-[4-[[(2S)-3-(3-(Chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic Acid
[0825] ##STR00030##
[A] tert-Butyl 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetate
[0826] ##STR00031##
[0827] (S)-2-Amino-3-(3-chlorophenyl)-N((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)propanamide hydrochloride (Intermediate A-1, 0.06 g, 0.109 mmol), 4-(2-tert-butoxy-2-oxo-ethoxy)benzoic acid (0.027 g, 0.109 mmol) and HATU (0.045 g, 0.119 mmol) were dissolved in DMF (1 mL) in a round-bottomed flask, and the mixture cooled to 0 C. Hnig's base (0.057 mL, 0.326 mmol) was added to the reaction mixture which was stirred at this temperature for 10 min, then allowed to warm up to room temperature and stirring was continued for 2 hours. The mixture was diluted with EtOAc, poured into a 1N aqueous HCl solution (5 mL) and the aqueous layer was extracted with EtOAc (210 mL). Combined organics were washed with a sat. NaHCO.sub.3 solution (5 mL), then brine before being dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.079 g, 95%) as colorless solid. MS: 750.6 (M+H.sup.+).
[B] 2-[4-[[(2S)-3-(3-Chlorophenyl)-1-[[(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic Acid
[0828] ##STR00032##
[0829] To a solution of tert-butyl 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetate (0.079 g, 0.105 mmol) in DCM (0.5 mL) was added TFA (0.405 mL, 5.26 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was triturated in diisopropylether, filtered and further dried under high vacuum to give the title compound (0.057 g, 62%) as an off-white solid. MS: 694.3 (M+H.sup.+).
Intermediate A-14
2-[3-[[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic Acid
[0830] ##STR00033##
was prepared in analogy to intermediate A-13, but using in step [A] 3-(2-tert-butoxy-2-oxo-ethoxy)benzoic acid, to give the title compound as colorless solid; MS: 694.5 (M+H.sup.+).
Intermediate A-15
2-[4-[[(2S)-3-(3-Cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic Acid
[0831] ##STR00034##
was prepared in analogy to intermediate A-13, but using in step [A] (S)-2-amino-3-(3-cyanophenyl)-N((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)propanamide hydrochloride (Intermediate A-3), to give the title compound as colorless solid; MS: 685.3 (M+H.sup.+).
Intermediate A-16
2-[3-[[(2S)-3-(3-Cyanophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic Acid
[0832] ##STR00035##
was prepared in analogy to intermediate A-13, but using in step [A] (S)-2-amino-3-(3-cyanophenyl)-N((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)propanamide hydrochloride (Intermediate A-3) and 3-(2-tert-butoxy-2-oxo-ethoxy)benzoic acid, to give the title compound as colorless solid; MS: 685.3 (M+H.sup.+).
Intermediate A-17
tert-Butyl N-[(5S)-5-amino-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-6-oxohexyl]carbamate
[0833] ##STR00036##
[A]tert-butyl N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-6-oxohexyl]carbamate
[0834] ##STR00037##
[0835] To a solution of (S)-2-amino-2-(4-methoxyphenyl)-N-((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)acetamide hydrochloride (Intermediate A-1 [B], 0.200 g, 0.539 mmol), (2S)-6-(tert-butoxycarbonylamino)-2-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid (0.253 g, 0.539 mmol) and HATU (0.246 g, 0.647 mmol) in DMF (2 mL) cooled to 0 C. was added Huenig's base (0.283 mL, 1.62 mmol). The reaction mixture was stirred for 15 minutes, then allowed to warm up and stirred at room temperature for 2.5 hours. The mixture was diluted with EtOAc, poured into water and the aqueous phase was extracted with EtOAc. Combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 10 to 80% EtOAc-heptane gradient to give the title compound (0.350 g, 78%) as a white solid. MS: 785.4 (M+H.sup.+).
[B] tert-Butyl N-[(5S)-5-amino-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-6-oxohexyl]carbamate
[0836] ##STR00038##
[0837] To a solution of tert-butyl N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-6-oxohexyl]carbamate (0.350 g, 0.446 mmol) in DMF (3 mL) was added diethylamine (0.230 mL, 2.6 mmol) and the reaction mixture stirred at room temperature for 2 hours. The solvent was evaporated to dryness and the residue was purified by silica gel flash chromatography eluting with a 0 to 15% MeOH-DCM gradient to give the title compound (0.192 g, 69%) as a light yellow solid. MS: 563.3 (M+H.sup.+).
Intermediate A-18
tert-Butyl N-[(4S)-4-amino-5-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-5-oxopentyl]carbamate
[0838] ##STR00039##
[0839] was prepared in analogy to intermediate A-17, but using in step [A] (2S)-5-(tert-butoxycarbonylamino)-2-(9H-fluoren-9-ylmethoxycarbonylamino)pentanoic acid, to give the title compound as a light yellow waxy solid. MS: 549.3 (M+H.sup.+).
Intermediate A-19
tert-Butyl N-[[4-[(2S)-2-amino-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate
[0840] ##STR00040##
was prepared in analogy to intermediate A-17, but using in step [A] (2S)-3-[4-[(tert-butoxycarbonylamino)methyl]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, to give the title compound as a white solid. MS: 611.3 (M+H.sup.+).
Intermediate A-20
(2S)-2-Amino-3-[tert-butyl(dimethyl)silyl]oxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide
[0841] ##STR00041##
[A] 9H-Fluoren-9-ylmethyl N-[(2S)-3-[tert-butyl(dimethyl)silyl]oxy-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamate
[0842] ##STR00042##
[0843] To a solution of (S)-2-amino-2-(4-methoxyphenyl)-N-((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)acetamide hydrochloride (Intermediate A-1 [B], 0.240 g, 0.647 mmol) in DMF (10 mL) cooled to 0 C. with an ice bath was added Huenig's base (0.565 mL, 3.24 mmol). Then, (2S)-3-[tert-butyl (dimethyl)silyl]oxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (0.286 g, 0.647 mol) followed by HATU (0.295 g, 0.777 mmol) were added and the reaction mixture was stirred at this temperature for 1 hour. The mixture was diluted with EtOAc, poured into a sat. NaHCO.sub.3 aqueous solution and the aqueous layer extracted with EtOAc. Combined organics were washed with NH.sub.4Cl and brine, then dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0 to 60% EtOAc/heptane gradient to give the title compound (0.321 g, 65%) as a colorless solid. MS: 758.4 (M+H.sup.+).
[B] (2S)-2-Amino-3-[tert-butyl(dimethyl)silyl]oxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide
[0844] ##STR00043##
[0845] To a solution of 9H-fluoren-9-ylmethyl N-[(2S)-3-[tert-butyl(dimethyl)silyl]oxy-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamate (0.315 g, 0.416 mmol) in DCM (3 mL) was added diethylamine (0.434 mL, 4.16 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by silica gel flash chromatography, eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.161 g, 72%) as a colorless solid. MS: 536.3 (M+H.sup.+).
Intermediate A-21
(2S)-2-Amino-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]-3-(trifluoromethoxy)propanamide
[0846] ##STR00044##
[A] Benzyl (2S)-[(2-(2-methylpropan-2-yl)oxycarbonylamino]-3-(trifluoromethoxy)propanoate
[0847] ##STR00045##
[0848] In a sealed tube, potassium fluoride (0.123 g, 2.12 mmol, dried on the high vacuum overnight), silver trifluoromethanesulfonate (0.385 g, 1.5 mmol), selectfluor (0.266 g, 0.750 mmol) and benzyl (2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-propanoate (0.148 g, 0.5 mmol) were added successively under Argon. Then, dry EtOAc (2.5 mL), 2-fluoropyridine (0.129 mL, 1.5 mmol) and (trifluoromethyl)trimethylsilane (0.240 mL, 1.5 mmol) were added successively under argon and the reaction mixture was stirred at room temperature overnight. The mixture was filtered through a plug of Decalite and washed with EtOAc. The filtrate was evaporated and the residue purified by silica gel flash chromatography, eluting with 0-100% EtOAc/heptane gradient to give the title compound (0.064 g, 72%) as a colorless oil. MS: 308.0 (M-tBu+H.sup.+).
[B] (2S)-2-[(2-Methylpropan-2-yl)oxycarbonylamino]-3-(trifluoromethoxy)propanoic Acid
[0849] ##STR00046##
[0850] A solution of benzyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(trifluoromethoxy)propanoate (0.121 g, 0.333 mmol) in methanol (7 mL) was purged several times with Ar, then Pd on C (0.018 g, 0.017 mmol) was added and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration and the filtrate concentrated in vacuo to give the title compound (0.085 g, 93%) as a colorless solid. MS: 272.2 (MH.sup.).
[C] tert-Butyl N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxo-3-(trifluoromethoxy)propan-2-yl]carbamate
[0851] ##STR00047##
[0852] To a solution of (S)-2-amino-2-(4-methoxyphenyl)-N-((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)acetamide hydrochloride (Intermediate A-1 [B], 0.115 g, 0.311 mmol), (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(trifluoromethoxy)propanoic acid (0.085 g, 0.311 mmol) and HATU (0.130 g, 0.342 mmol) in DMF (1 mL) cooled to 0 C. was added Huenig's base (0.163 mL, 0.933 mmol). The reaction mixture was stirred for 15 minutes, then allowed to warm up to room temperature and stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, poured into water and the aqueous layer was extracted with EtOAc. Combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.041 g, 22%) as a colorless solid. MS: 590.3 (M+H.sup.+).
[D] (2S)-2-Amino-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]-3-(trifluoromethoxy)propanamide
[0853] ##STR00048##
[0854] To a solution of tert-butyl N-[(2S)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxo-3-(trifluoromethoxy)propan-2-yl]carbamate (0.41 g, 0.069 mmol) in methanol (1 mL) was added 4M HCl in dioxane (0.174 mL, 0.695 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was triturated with diisopropylether. The solid precipitate was filtered off and further dried under the high vacuum to give the title compound (0.034 g, 94%, HCl salt) as an orange solid. MS: 490.2 (M+H.sup.+).
Intermediate A-22
(2S)-2-amino-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]-N-[(4-methylphenyl)-diphenylmethyl]butanediamide
[0855] ##STR00049##
was prepared in analogy to intermediate A-17, but using in step [A] (2S)-4-[[diphenyl(p-tolyl)methyl]amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-butanoic acid, to give the title compound as a yellow waxy solid. MS: 705.3 (M+H.sup.+).
Intermediate A-23
(2S)-2-Amino-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]-N-[(4-methylphenyl)-diphenylmethyl]butanediamide
[0856] ##STR00050##
was prepared in analogy to intermediate A-17, but using in step [A] (2S)-5-[[diphenyl(p-tolyl)methyl]amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-pentanoic acid, to give the title compound as a yellow foam. MS: 719.4 (M+H.sup.+).
Intermediate A-24
(2S)-2-Amino-3-cyano-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide
[0857] ##STR00051##
was prepared in analogy to intermediate A-1, but using in step [C] (2S)-2-(tert-butoxycarbonylamino)-3-cyano-propanoic acid and replacing in step [D] methanol by dioxane as solvent, to give the title compound as a colorless solid as hydrochloride. MS: 431.2 (M+H.sup.+).
Intermediate B-1
(2S)-2-Amino-3-(3-chlorophenyl)-N-[(1S and 1R)-2-oxo-1-phenyl-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide
[0858] ##STR00052##
was prepared in analogy to intermediate A-1, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-2-phenyl-acetic, to give the title compound as colorless solid as hydrochloride; MS: 486.2 (M+H.sup.+).
Intermediate B-2
(2S)-2-Amino-3-(3,4-dichlorophenyl)-N-[(1S and 1R)-)-2-oxo-1-phenyl-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide
[0859] ##STR00053##
was prepared in analogy to intermediate A-1, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-2-phenyl-acetic and in step [C] (2S)-2-(tert-butoxycarbonylamino)-3-(3,4-chlorophenyl)propanoic acid, to give the title compound as off-white solid as hydrochloride; MS: 520.2 (M+H.sup.+).
Intermediate B-3
(2R)-2-Amino-3-(3-chlorophenyl)-N-[(1S and 1R)-)-2-oxo-1-phenyl-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide
[0860] ##STR00054##
was prepared in analogy to intermediate A-1, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-2-phenyl-acetic and in step [C] (2R)-2-(tert-butoxycarbonylamino)-3-(3-chlorophenyl)propanoic acid, to give the title compound as light brown foam as hydrochloride; MS: 486.2 (M+H.sup.+).
Intermediate C-1
(2S)-2-Amino-3-(3-chlorophenyl)-N-[(1S and 1R)-1-(3-methoxyphenyl)-2-oxo-2-[[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropyl-propyl]amino]ethyl]propanamide
[0861] ##STR00055##
was prepared in analogy to intermediate A-1, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-2-(3-methoxyphenyl)acetic acid, to give the title compound as light brown gum as hydrochloride; MS: 516.2 (M+H.sup.+).
Intermediate D-1
(2S)-2-[[(2S)-2-Amino-3-(3-chlorophenyl)propanoyl]amino]-3-phenyl-N-[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]propanamide
[0862] ##STR00056##
was prepared in analogy to intermediate A-1, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid, to give the title compound as colorless solid as hydrochloride; MS: 500.2 (M+H.sup.+).
Intermediate D-2
(2S)-2-[[(2R)-2-Amino-3-(3-chlorophenyl)propanoyl]amino]-3-phenyl-N-[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]propanamide
[0863] ##STR00057##
was prepared in analogy to intermediate A-1, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid and in step [C] (2R)-2-(tert-butoxycarbonylamino)-3-(3-chlorophenyl)propanoic acid, to give the title compound as off-white solid as hydrochloride; MS: 500.2 (M+H.sup.+).
Intermediate D-3
(S)-2-Amino-3-(3,4-dichlorophenyl)-N((S)-1-oxo-3-phenyl-1-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)propan-2-yl)propanamide
[0864] ##STR00058##
was prepared in analogy to intermediate A-1, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid and in step [C] (2S)-2-(tert-butoxycarbonylamino)-3-(3,4-chlorophenyl)propanoic acid, to give the title compound as off-white solid as hydrochloride; MS: 534.4 (M+H.sup.+).
Intermediate D-4
(S)-2-Amino-3-cyclohexyl-N((S)-1-oxo-3-phenyl-1-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)propan-2-yl)propanamide
[0865] ##STR00059##
was prepared in analogy to intermediate A-1, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid and in step [C] (2S)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-propanoic acid, to give the title compound as off-white solid as hydrochloride; MS: 472.3 (M+H.sup.+).
Intermediate E-1
tert-Butyl 2-[4-[(1S)-1-[[(2S)-2-amino-3-(3-fluorophenyl)propanoyl]amino]-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]phenoxy]acetate
[0866] ##STR00060##
was prepared in analogy to intermediate A-2, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-2-[4-(2-tert-butoxy-2-oxo-ethoxy)phenyl]acetic acid and replacing in the deprotection steps [B] and [D] methanol by dioxane as solvent, to give the title compound as light brown solid as hydrochloride; MS: 600.4 (M+H.sup.+).
Intermediate J-1
3,3,3-Trifluoro-2-[3-(trifluoromethyl)phenyl]propanoic Acid
[0867] ##STR00061##
[A] Ethyl 3,3,3-trifluoro-2-methylsulfonyloxy-2-[3-(trifluoromethyl)phenyl]propanoate
[0868] ##STR00062##
[0869] To a solution of ethyl 3,3,3-trifluoro-2-hydroxy-2-[3-(trifluoromethyl)phenyl]propanoate (0.5 g, 1.58 mmol) in acetonitrile (5 mL) cooled to 5 C. was added TEA (0.882 mL, 6.33 mmol). Then, methanesulfonyl chloride (0.493 L, 6.33 mmol) was added dropwise and the solution was stirred at this temperature for 20 minutes. The mixture was poured into ice/water and extracted with DCM. Combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to dryness. The residue was purified by silica gel flash chromatography, eluting with a 0 to 40% EtOAc-heptane gradient to give the title compound (0.470 g, 75%) as a colorless liquid. MS: 299.1 (M-OS(O).sub.2CH.sub.3.sup.+).
[B] Ethyl 3,3,3-trifluoro-2-[3-(trifluoromethyl)phenyl]propanoate
[0870] ##STR00063##
[0871] In a sealed vessel, a solution of ethyl 3,3,3-trifluoro-2-methylsulfonyloxy-2-[3-(trifluoromethyl)phenyl]propanoate (0.470 g, 1.19 mmol) in methanol (5 mL) was purged several times with Ar, then Pd on C (0.254 mg, 0.238 mmol) was added and the reaction mixture was stirred at room temperature under 3 bar hydrogen for 10 hours. The catalyst was removed by filtration and the filtrate concentrated in vacuo to give the title compound (0.358 g, 100%) as a colorless liquid. MS: 394.3 (MH.sup.).
[C] 3,3,3-Trifluoro-2-[3-(trifluoromethyl)phenyl]propanoic Acid
[0872] ##STR00064##
[0873] To a solution of ethyl 3,3,3-trifluoro-2-[3-(trifluoromethyl)phenyl]propanoate (0.205 g, 0.683 mmol) in dioxane (1.5 mL) was added conc. HCl (0.75 mL, 9.13 mmol) and the reaction mixture was heated at reflux for 40 hours. The mixture was allowed to cool to room temperature, then DCM was added and the phases separated. The aqueous phase was extracted with DCM. Combined organics were extracted with a sat. Na.sub.2CO.sub.3 aqueous solution. Combined aqueous layers were acidified to pH 1 with a 2M HCl aqueous solution and extracted with DCM. The organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and evaporated to dryness to to give the title compound (0.070 g, 37%) as a light yellow solid. MS: 543.3 (2MH.sup.).
Intermediate J-2
[0874] ##STR00065##
[A] Ethyl 2-(3-chlorophenyl)-1,3-dioxolane-2-carboxylate
[0875] ##STR00066##
[0876] To a solution of 2-chloroethanol (0.503 L, 7.5 mmol) in a 2/1 mixture of DMF/THF (6 mL) was added ethyl 2-(3-chlorophenyl)-2-oxoacetate (1.06 g, 5 mmol) and the solution was cooled to 60 C. Potassium tert-butoxide (0.842 g, 7.5 mmol) in DMF (15 mL) was added dropwise over 30 minutes at this temperature. The reaction mixture was stirred for 1.5 hours, then allowed to warm to room temperature and stirred overnight. The mixture was diluted with EtOAc, poured into a 1M NH.sub.4Cl aqueous solution and the aqueous layer was extracted with EtOAc. Combined organics were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give the title compound (1.2 g, 94%) as a colourless oil. The crude product was used in the next step with no further purification.
[B] 2-(3-Chlorophenyl)-1,3-dioxolane-2-carboxylic Acid
[0877] ##STR00067##
[0878] To a solution of ethyl 2-(3-chlorophenyl)-1,3-dioxolane-2-carboxylate (0.196 g, 0.764 mmol) in THF (6 mL) cooled to 0 C. was added a 1M aqueous solution of LiOH (1.53 mL, 1.53 mmol) and the reaction was stirred for 2 hours. The mixture was diluted with EtOAc, poured in a 1M KHSO.sub.4 aqueous solution and the aqueous layer was extracted with EtOAc. Combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give the title compound (0.175 g, 100%) as a colourless oil. The crude product was used in the next step with no further purification. MS: 227.1 (MH.sup.).
Intermediate K-1
(2S)-2-[(2-Methylpropan-2-yl)oxycarbonylamino]-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoic Acid
[0879] ##STR00068##
[A] Benzyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoate
[0880] ##STR00069##
[0881] To a solution of benzyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (0.5 g, 1.35 mmol) in DMF (20 ml) were successively added potassium carbonate (0.372 g, 2.69 mmol) and tert-butyl 2-bromoacetate (0.199 ml, 1.35 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc, poured into H.sub.2O (25 ml) and the aqueous layer was extracted with EtOAc (220 ml). Combined organics were dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by flash chromatography eluting with a 0 to 60% EtOAc in heptane gradient to yield the title compound (0.588 g, 88%) as a colorless solid; MS: 484.3 (MH.sup.).
[B] (2S)-2-[(2-Methylpropan-2-yl)oxycarbonylamino]-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoic Acid
[0882] ##STR00070##
[0883] A solution of benzyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoate (0.588 g, 1.21 mmol) in methanol (20 ml) was purged several times with Ar, then Pd on C (0.064 g, 0.061 mmol) was added and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The catalyst was removed by filtration and the filtrate concentrated in vacuo to give the title compound (0.468 g, 98%) as a colorless solid; MS: 394.3 (MH.sup.).
Intermediate K-2
(2S)-2-[(2-Methylpropan-2-yl)oxycarbonylamino]-3-[3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoic Acid
[0884] ##STR00071##
[A] Benzyl (2S)-3-(3-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate
[0885] ##STR00072##
[0886] A solution of (2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoic acid (0.5 g, 1.78 mmol) and cesium carbonate (0.290 g, 0.889 mmol) in DMF (20 mL) was stirred at room temperature for 1.5 hours. Then, benzyl bromide (0.304 g, 1.78 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, poured into water and acetic acid was added to adjust the pH to 4. The aqueous phase was extracted with EtOAc (210 mL) and the combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by flash chromatography eluting with a 0 to 40% EtOAc in heptane gradient to yield the title compound (0.539 g, 82%) as a colorless and viscous oil; MS: 370.3 (MH.sup.).
[B] Benzyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoate
[0887] ##STR00073##
was prepared in analogy to intermediate K-1[A], but using benzyl (2S)-3-(3-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate (Intermediate K-2 [A]), to give the title compound as colorless solid.
[C](2S)-2-[(2-Methylpropan-2-yl)oxycarbonylamino]-3-[3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoic Acid
[0888] ##STR00074##
was prepared in analogy to intermediate K-1 [B], but using benzyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoate (Intermediate K-2 [B]), to give the title compound as colorless foam; MS: 394.3 (MH.sup.).
Intermediate K-3
2-[4-[2-[(2-Methylpropan-2-yl)oxy]-2-oxoethoxy]phenoxy]acetic Acid
[0889] ##STR00075##
was prepared in analogy to intermediate K-1, but using in step [A] tert-butyl 2-(4-hydroxyphenoxy)acetate instead of benzyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate and benzyl 2-bromoacetate instead of tert-butyl 2-bromoacetate, to give the title compound as colorless solid; MS: 281.3 (MH.sup.).
Intermediate L-1
6-(2-(tert-Butoxy)-2-oxoethoxy)picolinic Acid
[0890] ##STR00076##
[A] Benzyl 6-hydroxypicolinate
[0891] ##STR00077##
[0892] To a solution of 6-hydroxypyridine-2-carboxylic acid (1 g, 7.19 mmol) in DMF (15 mL) was added TEA (1.5 ml, 10.8 mmol) and the mixture was heated to 40 C. for 1 hour. Then, benzyl bromide (0.897 mL, 7.55 mmol) was added and the reaction mixture was heated to 77 C. for 3 hours. The mixture was cooled down to room temperature, diluted with EtOAc and poured into a sat. NaHCO.sub.3 solution (50 mL) and the aqueous layer was extracted with EtOAc (250 mL). Combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered, evaporated and further dried in high vacuum to yield the crude title compound (1.33 g, 81%) as light brown solid; MS: 230.1 (M+H.sup.+).
[B] Benzyl 6-(2-(tert-butoxy)-2-oxoethoxy)picolinate
[0893] ##STR00078##
[0894] To a solution of benzyl 6-(2-(tert-butoxy)-2-oxoethoxy)picolinate (0.302 g, 1.32 mmol) in acetone (30 ml) were successively added potassium carbonate (0.868 g, 6.28 mmol) and tert-butyl 2-bromoacetate (0.186 mL, 1.26 mmol). The reaction mixture was heated to 65 C. for 3 h. The mixture was cooled to room temperature, the solid precipitate was filtered off and the filtrate concentrated in vacuo. The residue was purified by flash chromatography eluting with a 0 to 20% EtOAc in heptane gradient to yield the title compound (0.3 g, 70%) as a colorless solid; MS: 344.2 (M+H.sup.+).
[C] 6-(2-(tert-Butoxy)-2-oxoethoxy)picolinic Acid
[0895] ##STR00079##
was prepared in analogy to intermediate K-1 [B], but using benzyl 6-(2-(tert-butoxy)-2-oxoethoxy)picolinate (Intermediate L-1 [B]), to give the title compound as colorless solid; MS: 252.3 (MH.sup.).
Intermediate L-2
5-(2-(tert-Butoxy)-2-oxoethoxy)picolinic Acid
[0896] ##STR00080##
was prepared in analogy to intermediate L-1, but using in step [A] 5-hydroxypyridine-2-carboxylic acid, to give the title compound as yellow solid; MS: 254.2 (M+H.sup.+).
Intermediate L-3
1-(2-(tert-Butoxy)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic Acid
[0897] ##STR00081##
was prepared in analogy to intermediate L-1, but using in step [A] 2-hydroxypyridine-4-carboxylic acid, to give the title compound as colorless solid; MS: 252.2 (MH.sup.).
Intermediate L-4
1-[2-[(2-Methylpropan-2-yl)oxy]-2-oxoethyl]-6-oxopyridine-3-carboxylic Acid
[0898] ##STR00082##
was prepared in analogy to intermediate L-1, but using in step [A] 6-hydroxypyridine-3-carboxylic acid, to give the title compound as colorless solid; MS: 252.3 (MH.sup.).
Example 1
N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide
[0899] ##STR00083##
[A] N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide
[0900] ##STR00084##
[0901] In a round-bottomed flask, (S)-2-amino-3-(3-chlorophenyl)-N((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)propanamide hydrochloride (Intermediate A-1, 0.021 g, 0.038 mmol), benzoic acid (0.005 g, 0.038 mmol) and HATU (0.016 g, 0.041 mmol) were dissolved in DMF (1 mL) and the mixture cooled to 0 C. Hunig's base (0.020 mL, 0.114 mmol) was added to the reaction mixture which was stirred at this temperature for 10 min, then allowed to warm up to room temperature and stirring was continued for 2 hours. The mixture was diluted with EtOAc, poured into 1M HCl (5 mL) and the aqueous layer was extracted with EtOAc (210 mL). Combined organics were washed with a sat. NaHCO.sub.3 solution (5 mL), then brine before being dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.012 g, 51%) as a colorless solid. MS: 620.3 (M+H.sup.+).
[B] N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide
[0902] ##STR00085##
[0903] To a suspension of N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]benzamide (0.012 g, 0.019 mmol) in DCM (1 mL) was added 15% Dess-Martin periodinane in DCM solution (0.121 mL, 0.058 mmol) and the reaction mixture was stirred at room temperature overnight. A spatula of solid Na.sub.2S.sub.2O.sub.3 was added and stirring was continued for 5 min. The resulting white suspension was diluted with DCM/water, poured into a sat. NaHCO.sub.3 solution (5 mL) and then extracted with DCM (10 mL). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0-70% EtOAc-heptane gradient to give the title compound (0.007 g, 58%) as a colorless solid. MS: 618.3 (M+H.sup.+).
[0904] The following examples listed in Table 1 were prepared in analogy to the procedures described for the preparation of example 1 by using the indicated intermediate and carboxylic acid in step [A]
TABLE-US-00002 TABLE 1 Name Structure Reactant to be used in step MS Ex Aspect [A] (M + H.sup.+) 2 (2S)-3-(3-chlorophenyl)-N-[(1S)-1-(4- Intermediate A-1 647.3 methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1- and trifluoro-4-methyl-2-oxopentan-3- 3-(3-pyridyl)propanoic acid yl]amino]ethyl]-2-(3-pyridin-3- ylpropanoylamino)propanamide
Example 84
tert-Butyl 2-[[2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetate
[0905] ##STR00168##
[A] tert-Butyl 2-[[2-4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetate
[0906] ##STR00169##
[0907] In a round-bottomed flask, 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic acid (Intermediate A-13, 0.057 g, 0.082 mmol), tert-butyl 2-aminoacetate hydrochloride (0.013 g, 0.098 mmol) and HATU (0.034 g, 0.090 mmol) were dissolved in DMF (1 mL) and the mixture cooled to 0 C. Hunig's base (0.043 mL, 0.246 mmol) was added to the reaction mixture which was stirred at this temperature for 10 min, then allowed to warm up to room temperature and stirring was continued overnight. The mixture was diluted with EtOAc, poured into 1M HCl (5 mL) and the aqueous layer was extracted with EtOAc (210 mL). Combined organics were washed with a sat. NaHCO.sub.3 solution (5 mL), then brine before being dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.049 g, 67%) as a colorless solid. MS: 807.4 (M+H.sup.+).
[B] tert-Butyl 2-[[2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetate
[0908] ##STR00170##
was prepared in analogy to example 1[B], but using tert-butyl 2-[[2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetyl]amino]acetate, to give the title compound as colorless solid; MS: 805.5 (M+H.sup.+).
[0909] The following examples listed in Table 2 were prepared in analogy to the procedures described for the preparation of example 84 by using the indicated intermediate in step [A].
TABLE-US-00003 TABLE 2 Name Structure Reactant to be used in step MS Ex Aspect [A] (M + H.sup.+) 85 tert-butyl 2-[[2-[3-[[(2S)-3-(3-chlorophenyl)- Intermediate A-14 805.5 1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2- and [[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan- tert-butyl 2-aminoacetate 3-yl]amino]ethyl]amino]-1-oxopropan-2- HCl yl]carbamoyl]phenoxy]acetyl]amino]acetate
Example 88
2-[4-[(2S)-2-[(3-Chlorobenzoyl)amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetic Acid
[0910] ##STR00174##
[0911] To a solution of tert-butyl 2-[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-3-oxopropyl]phenoxy]acetate (Example 15, 0.018 g, 0.024 mmol) in DCM (1 mL) was added TFA (0.092 mL, 1.2 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo, the residue was triturated in diisopropylether, filtered and further dried under high vacuum. The residue was purified by preparative TLC (silica gel, 7/3 EtOAc/heptane) to give the title compound (0.015 g, 92%) as a colorless solid. MS: 692.6 (M+H.sup.+).
[0912] The following examples listed in Table 3 were prepared in analogy to the procedure described for the preparation of example 88 by using the indicated starting materials. Carboxylic acids were purified by preparative TLC to remove the traces amounts of remaining tert-butyl intermediate; amine products were triturated in diisopropylether and obtained as TFA salts.
TABLE-US-00004 TABLE 3 Name Reactant: compound Structure obtained in example MS Ex Aspect number indicated (M + H.sup.+) 89 2-[4-[(2S)-3-[[(1S)-1-(4-methoxyphenyl)- Example 16 659.3 2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2- oxopentan-3-yl]amino]ethyl]amino]-3-oxo- 2-(pyridine-2- carbonylamino)propyl]phenoxy]acetic acid
Example 115
(2S)-2-[[2-(3-Chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide
[0913] ##STR00201##
[0914] To a solution of (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-[(2-methylpropan-2-yl)oxy]propanamide (Example 39, 0.044 g, 0.066 mmol) in DCM (1 mL) was added wet TFA (2.5% H.sub.2O) (0.355 mL, 4.64 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 10 to 100% EtOAc-heptane gradient and the resulting material was triturated in diisopropylether, filtered and further dried under high vacuum to give the title compound (0.024 g, 57%) as a colorless solid. MS: 608.2 (M+H.sup.+).
[0915] The following examples listed in Table 4 were prepared in analogy to the procedure described for the preparation of example 115 by using the indicated starting materials.
TABLE-US-00005 TABLE 4 Name Reactant: compound Structure obtained in example MS Ex Aspect number indicated (M + H.sup.+) 116 N-[(2S)-3-hydroxy-1-[[(1S)-1-(4- Example 40 525.4 methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1- trifluoro-4-methyl-2-oxopentan-3- yl]amino]ethyl]amino]-1-oxopropan-2- yl]pyridine-2-carboxamide
Example 120
N-[2-[[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]pyridine-2-carboxamide
[0916] ##STR00206##
[A] (2,5-Dioxopyrrolidin-1-yl) pyridine-2-carboxylate
[0917] ##STR00207##
[0918] To a solution of picolinic acid (0.110 g, 0.894 mmol) in DCM (4 mL) were added EDCI (0.206 g, 1.07 mmol) followed by 1-hydroxypyrrolidine-2,5-dione (0.123 mg, 1.07 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and extracted with DCM (220 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (0.180 g, 91%) as off-white solid. The crude material was used in the next step. MS: 221.1 (M+H.sup.+).
[B] N-[2-[[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]pyridine-2-carboxamide
[0919] ##STR00208##
[0920] To a solution of (2S)-2-[(2-aminoacetyl)amino]-3-(3-chlorophenyl)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide; TFA salt (Example 96, 0.020 g, 0.029 mmol) in DCM (1 mL) cooled to 20 C. were added (2,5-dioxopyrrolidin-1-yl) pyridine-2-carboxylate (0.006 g, 0.029 mmol) followed by triethylamine (0.012 mL, 0.088 mmol) and the reaction mixture was stirred at this temperature for 1 hour and then left to stand at 5 C. overnight. The residue was diluted with DCM, poured into water (2 mL) and the aqueous layer was extracted with DCM (25 mL). Combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was triturated in diisopropylether, filtered and further dried under high vacuum to give the title compound (0.015 g, 76%) as colorless solid; MS: 676.5 (M+H.sup.+).
Example 121
(2S)-3-(3-Chlorophenyl)-2-[[2-(3-chlorophenyl)acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide
[0921] ##STR00209##
[A] (2S)-3-(3-Chlorophenyl)-2-[[2-(3-chlorophenyl)acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide
[0922] ##STR00210##
[0923] In a flask, (S)-2-amino-3-(3-chlorophenyl)-N((S)-1-(4-methoxyphenyl)-2-oxo-2-(((2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino)ethyl)propanamide hydrochloride (Intermediate A-1, 0.033 g, 0.060 mmol), 2-(3-chlorophenyl)acetic acid (0.010 g, 0.060 mmol) and HATU (0.027 g, 0.072 mmol) were dissolved in DMF (1 mL) and the mixture cooled to 0 C. Huenig's base (0.031 mL, 0.179 mmol) was added to the reaction mixture which was stirred at this temperature for 10 min, then allowed to warm up to room temperature and stirring was continued for 2 hours. The mixture was diluted with EtOAc, poured into H.sub.2O (5 mL) and the aqueous layer was extracted with EtOAc (210 mL). Combined organics were washed brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 10 to 100% EtOAc-heptane gradient to give the title compound (0.039 g, 96%) as a colorless solid. MS: 668.2 (M+H.sup.+).
[B] (2S)-3-(3-Chlorophenyl)-2-[[2-(3-chlorophenyl)acetyl]amino]-N-[1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopenta-3-yl]amino]ethyl]propanamide
[0924] ##STR00211##
[0925] To a solution of (2S)-3-(3-chlorophenyl)-2-[[2-(3-chlorophenyl)acetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide (0.039 g, 0.059 mmol) in DCM (1 mL) was added 15% Dess-Martin periodinane in DCM solution (0.369 mL, 0.178 mmol) and the reaction mixture was stirred at room temperature for 2.5 hours. The resulting white suspension was diluted with DCM/water, poured into a sat. NH.sub.4Cl aqueous solution (5 mL) and then extracted with DCM (10 mL). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 10-100% EtOAc-heptane gradient to give the title compound (0.024 g, 58%) as a colorless solid. MS: 666.3 (M+H.sup.+).
[0926] The following examples listed in Table 5 were prepared in analogy to the procedures described for the preparation of example 121 by using the indicated intermediate and carboxylic acid in step [A]. Alanine synthons (intermediate A-8) can undergo isomerization at variable extent during Dess-Martin oxidation (step [B]), thus the stereochemistry of these final compounds can be described as S and R unless isomerization was not observed to a great extent >5%.
TABLE-US-00006 TABLE 5 Name Structure Reactant to be used in step MS Ex Aspect [A] (M + H.sup.+) 122 1-(3-chlorophenyl)-N-[(2S)-3-(3- Intermediate A-1 692.3 chlorophenyl)-1-[[(1S)-1-(4-methoxyphenyl)- and 2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2- 1-(3- oxopentan-3-yl]amino]ethyl]amino]-1- chlorophenyl)cyclopropane oxopropan-2-yl]cyclopropane-1-carboxamide carboxylic acid
Example 182
N-[(2S)-5-Amino-1-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-1-oxopentan-2-yl]-3-chlorobenzamide
[0927] ##STR00272##
[0928] To a solution of tert-butyl N-[(4S)-4-[(3-chlorobenzoyl)amino]-5-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-5-oxopentyl]carbamate (Example 162, 0.025 g, 0.036 mmol) in DCM (0.5 mL) was added TFA (0.056 mL, 0.727 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was triturated in diisopropylether, filtered and further dried under high vacuum to give the title compound (0.018 g, 67%, TFA salt) as a colorless solid. MS: 585.2 (M+H.sup.+).
[0929] The following examples listed in Table 6 were prepared in analogy to the procedures described for the preparation of example 182 by using the indicated starting materials.
[0930] Amine products were triturated in diisopropylether and obtained as TFA salts.
TABLE-US-00007 TABLE 6 Name Reactant: compound Structure obtained in example MS Ex Aspect number indicated (M + H.sup.+) 183
Example 196
(2S)-2-[[2-(2,5-Dichlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide
[0931] ##STR00286##
[A] (2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide
[0932] ##STR00287##
[0933] In a flask, 2-(3,4-dichlorophenyl)-2,2-difluoroacetic acid (0.020 g, 0.084 mmol) and HATU (0.032 g, 0.084 mmol) were mixed in DMF (2 mL) at 0 C., Huenig's base (0.044 L, 0.252 mmol) was added and the reaction mixture was stirred at this temperature for 10 min. Then, (2S)-2-amino-3-[tert-butyl(dimethyl)silyl]oxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide (Intermediate A-20, 0.045 g, 0.252 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. After this time, 2-(3,4-dichlorophenyl)-2,2-difluoroacetic acid (0.020 g, 0.084 mmol) and HATU (0.032 g, 0.084 mmol) were added again to the mixture which was stirred at room temperature for a further 2 hours. The mixture was diluted with EtOAc, poured into water (10 mL) and the aqueous layer was extracted with EtOAc (220 mL). Combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0 to 50% EtOAc/heptane gradient to give the title compound (0.030 g, 47%) as a white solid. MS: 758.3 (M+H.sup.+).
[B] (2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide
[0934] ##STR00288##
[0935] To a solution of (2S)-3-[tert-butyl(dimethyl)silyl]oxy-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]propanamide (0.028 g, 0.037 mmol) in DCM (1.5 mL) was added 15% Dess-Martin periodinane in DCM solution (0.192 mL, 0.092 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM/water, poured into a sat. NH.sub.4Cl aqueous solution (5 mL) and extracted with DCM (10 mL). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0 to 70% EtOAc/heptane gradient to give the title compound (0.020 g, 72%) as a white solid. MS: 756.3 (M+H.sup.+).
[C] (2S)-2-[[2-(3,4-Dichlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxy-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide
[0936] ##STR00289##
[0937] To a solution of (2S)-3-[tert-butyl(dimethyl)silyl]oxy-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide (0.020 g, 26.4 mmol) in THF (0.5 mL) and water (0.05 mL) cooled to 0 C. with an ice bath was added 4M HCl (0.099 mL, 0.396 mmol) in dioxane and the reaction mixture was stirred at this temperature for 3 hours. The mixture was poured into water (5 mL) and extracted with EtOAc (10 mL). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was triturated in diisopropylether, the solvent was decanted and the solid precipitate was further dried on the high vacuum to give the title compound (0.012 g, 71%) as a white solid. MS: 642.1 (M+H.sup.+).
[0938] The following examples listed in Table 7 were prepared in analogy to the procedures described for the preparation of example 196 by using the indicated carboxylic acid in step [A].
TABLE-US-00008 TABLE 7 Reactant to be used in MS Ex Name Structure Aspect step [A] (M + H.sup.+) 197
Example 205
(2S)-2-[(3-Chlorobenzoyl)amino]-N[(S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]butanediamide
[0939] ##STR00298##
[A] (2S)-2-[(3-Chlorobenzoyl)amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]-N-[(4-methylphenyl)-diphenylmethyl]butanediamide
[0940] ##STR00299##
[0941] In a flask, (2S)-2-amino-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]-N-[(4-methylphenyl)-diphenylmethyl]butanediamide (Intermediate A-22, 0.080 g, 0.114 mmol), 3-chlorobenzoic acid (0.018 g, 0.114 mmol) and HATU (0.047 g, 0.125 mmol) were dissolved in DMF (1 mL) and the mixture cooled to 0 C. Huenig's base (0.060 ml, 0.341 mmol) was added to the reaction mixture which was stirred at this temperature for 15 min, then allowed to warm up to room temperature and stirring was continued for 5 hours. The mixture was diluted with EtOAc, poured into water (5 mL) and the aqueous layer was extracted with EtOAc (210 mL). Combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 10 to 80% EtOAc-heptane gradient to give the title compound (0.072 g, 71%) as a light brown waxy solid. MS: 841.4 (MH.sup.).
[B] (2S)-2-[(3-Chlorobenzoyl)amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-N-[(4-methylphenyl)-diphenylmethyl]butanediamide
[0942] ##STR00300##
[0943] To a solution of (2S)-2-[(3-chlorobenzoyl)amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]-N-[(4-methylphenyl)-diphenylmethyl]butanediamide (0.072 g, 0.085 mmol) in DCM (1 mL) was added 15% Dess-Martin periodinane in DCM solution (0.532 mL, 0.256 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with DCM/water, poured into a sat. NH.sub.4Cl aqueous solution (10 mL) and extracted with DCM (20 mL). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 10 to 100% EtOAc/heptane gradient to give the title compound (0.050 g, 68%) as a colourless waxy solid. MS: 839.4 (MH.sup.).
[C] (2S)-2-[(3-Chlorobenzoyl)amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]butanediamide
[0944] ##STR00301##
[0945] To a solution of (2S)-2-[(3-chlorobenzoyl)amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-N-[(4-methylphenyl)-diphenylmethyl]butanediamide (0.050 g, 0.059 mmol) in DCM (1 mL) cooled to 0 C. was added wet TFA (2.5% water, 0.227 mL, 2.97 mmol) and the reaction mixture was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography, eluting with a 10 to 100% EtOAc/heptane gradient to give the title compound (0.027 g, 73%) as an off-white solid. MS: 585.2 (MH.sup.).
[0946] The following examples listed in Table 8 were prepared in analogy to the procedures described for the preparation of example 205 by using the indicated intermediate and carboxylic acid in step [A]. Except for examples 206, 208 and 210 which were prepared in analogy to the procedure described for the preparation of example 196 by using the indicated intermediate and 2-(3-chlorophenyl)-2,2-difluoro-acetic acid in step [A] then following the procedures described for the preparation of example 205 in step [B] and [C].
[0947] Amide products were purified by silica gel flash chromatography; carboxylic acid products were triturated in diisopropylether.
TABLE-US-00009 TABLE 8 Reactant to be used MS Ex Name Structure Aspect in step [A] (M + H.sup.+) 206
Example 211
N-[(5S)-5-[[2-(3,4-Dichlorophenyl)-2,2-difluoroacetyl]amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-6-oxohexyl]pyridine-2-carboxamide
[0948] ##STR00307##
[A] tert-Butyl N-[(5S)-5-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-6-oxohexyl]carbamate
[0949] ##STR00308##
[0950] In a flask, 2-(3,4-dichlorophenyl)-2,2-difluoroacetic acid (0.045 g, 0.187 mmol) and HATU (0.078 g, 0.205 mmol) were mixed in DMF (1 mL) at 0 C., Huenig's base (0.098 L, 0.560 mmol) was added and the reaction mixture was stirred at this temperature for 10 min. Then, tert-butyl N-[(5S)-5-amino-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-6-oxohexyl]carbamate (Intermediate A-17, 0.105 g, 0.187 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. After this time, 2-(3,4-dichlorophenyl)-2,2-difluoroacetic acid (0.045 g, 0.187 mmol) and HATU (0.078 g, 0.205 mmol) were added again to the mixture which was stirred at room temperature for a further 2 hours. The mixture was diluted with EtOAc, poured into water (10 mL) and the aqueous layer was extracted with EtOAc (220 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0 to 100% EtOAc/heptane gradient to give the title compound (0.030 g, 20%) as a light brown solid. MS: 783.4 (M+H.sup.+).
[B] (2S)-6-Amino-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]hexanamide
[0951] ##STR00309##
[0952] 4M HCl in dioxane (0.096 mL, 388 mmol) was added at 0 C. to a solution of tert-butyl N-[(5S)-5-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-6-oxohexyl]carbamate (0.030 g, 39 mmol) in MeOH (1 mL). The reaction mixture was stirred at this temperature for 10 min and then allowed to warm to room temperature and stirring was continued overnight. The mixture was evaporated to dryness and the residue was triturated with diisopropylether. The solid precipitate was filtered off and further dried under the high vacuum to give the title compound (0.027 g, 93%, HCl salt) as light yellow solid. MS: 683.3 (M+H.sup.+).
[C] N-[(5S)-5-[[2-(3,4-Dichlorophenyl)-2,2-difluoroacetyl]amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-6-oxohexyl]pyridine-2-carboxamide
[0953] ##STR00310##
[0954] In a flask, (2S)-6-amino-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]hexanamide hydrochloride (0.027 g, 0.038 mmol), pyridine-2-carboxylic acid (0.005 g, 0.038 mmol) and HATU (0.016 g, 0.042 mmol) were mixed in DMF (1 mL) and the mixture cooled to 0 C. Huenig's base (0.020 mL, 0.114 mmol) was added to the reaction mixture which was stirred at this temperature for 10 min, then allowed to warm up to room temperature and stirring was continued for 4 hours. The mixture was diluted with EtOAc, poured into H2O (5 mL) and the aqueous layer was extracted with EtOAc (210 mL). Combined organics were washed brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc/heptane gradient to give the title compound (0.021 g, 70%) as a colorless solid. MS: 790.3 (M+H.sup.+).
[D] N-[(5S)-5-[[2-(3,4-Dichlorophenyl)-22-difluoroacetyl]amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]amino]-6-oxohexyl]pyridine-2-carboxamide
[0955] ##STR00311##
[0956] To a solution of N-[(5S)-5-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-6-[[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]amino]ethyl]amino]-6-oxohexyl]pyridine-2-carboxamide (0.021 g, 0.027 mmol) in DCM (0.5 mL) was added 15% Dess-Martin periodinane in DCM solution (0.168 mL, 0.081 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The resulting white suspension was diluted with DCM/water, poured into a sat. NH.sub.4Cl aqueous solution (5 mL) and then extracted with DCM (10 mL). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 10-100% EtOAc-heptane gradient to give the title compound (0.016 g, 71%) as a colorless solid. MS: 788.2 (M+H.sup.+).
[0957] The following examples listed in Table 9 were prepared in analogy to the procedures described for the preparation of example 211 by using the indicated intermediate and carboxylic acids in step [A] and [C] respectively.
TABLE-US-00010 TABLE 9 Reactant to be used MS Ex Name Structure Aspect in step [A] and [C] (M + H.sup.+) 212
Example A
[0958] A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
TABLE-US-00011 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg Total amount 425 mg
Example B
[0959] A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:
TABLE-US-00012 Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg Total amount 220.0 mg