Difluoroketamide derivatives as HTRA1 inhibitors

This application is a continuation of International Application No. PCT/EP2017/070985, filed on Aug. 21, 2017, the entire contents of which are incorporated herein by reference, which claims priority to European Patent Application No. 16185372.6, filed on Aug. 23, 2016.

The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to serine protease HtrA1 inhibitors for the treatment or prophylaxis of HtrA1-mediated ocular diseases, such as wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.

The present invention provides novel compounds of formula (I)

wherein

R 1 is selected from

i) C 1-6 -alkyl, ii) C 3-8 -cycloalkyl substituted with R 24 , R 25 and R 26 , iii) halo-C 1-6 -alkyl, iv) heterocycloalkyl-C 1-6 -alkyl substituted with R 24 , R 25 and R 26 , v) aryl-C 1-6 -alkyl substituted with R 24 , R 25 and R 26 , and vi) heteroaryl-C 1-6 -alkyl substituted with R 24 , R 25 and R 26 ;

R 2 , R 3 , R 4 , R 5 , R 7 , R 10 and R 23 are independently selected from

i) H, ii) C 1-6 -alkyl, and iii) C 3-8 -cycloalkyl;

X is selected from

i) —O—, ii) —S—, and iii) —S(O) 2 —;

R 6 is selected from

i) aryl substituted with R 12 , R 13 and R 14 , i) aryl-C 1-6 -alkyl substituted with R 12 , R 13 and R 14 , ii) heteroaryl substituted with R 12 , R 13 and R 14 , and iii) heteroaryl-C 1-6 -alkyl substituted with R 12 , R 13 and R 14 ;

A is selected from

i) —O—, ii) —CH 2 —, iii) —S(O) 2 NR 10 — and iv) —C(O)NR 10 —;

R 8 is selected from

i) H, and ii) —CH 2 R 9 ;

R 9 is selected from

i) H, and ii) hydroxy, iii) amino-C 1-6 -alkyl substituted on the nitrogen atom by one or two substituents selected from H, C 1-6 -alkylcarbonyl, C 1-6 -alkoxycarbonyl, C 1-6 -alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R 15 , R 16 and R 17 , iv) aminocarbonyl substituted on the nitrogen atom by one or two substituents selected from H, C 1-6 -alkylcarbonyl, C 1-6 -alkoxycarbonyl, C 1-6 -alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R 15 , R 16 and R 17 , v) aminocarbonyl-C 1-6 -alkyl substituted on the nitrogen atom by one or two substituents selected from H, C 1-6 -alkylcarbonyl, C 1-6 -alkoxycarbonyl, C 1-6 -alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R 15 , R 16 and R 17 , vi) carboxy, vii) carboxy-C 1-6 -alkyl, viii) C 1-6 -alkoxy, ix) C 1-6 -haloalkoxy, x) C 1-6 -alkoxycarbonyl, xi) C 1-6 -alkoxycarbonyl-C 1-6 -alkyl, xii) C 3-8 -cycloalkyl, xiii) aryl substituted with R 15 , R 16 and R 17 , xiv) aryl-C 1-6 -alkyl substituted with R 15 , R 16 and R 17 , xv) aryl-C 1-6 -alkoxy substituted with R 15 , R 16 and R 17 , xvi) heteroaryl substituted with R 15 , R 16 and R 17 , xvii) heteroaryl-C 1-6 -alkyl substituted with R 15 , R 16 and R 17 , and xviii) heteroaryl-C 1-6 -alkoxy substituted with R 15 , R 16 and R 17 xix) heterocycloalkyl substituted with R 15 , R 16 and R 17 , xx) heterocycloalkyl —C 1-6 -alkyl substituted with R 15 , R 16 and R 17 , and xxi) heterocycloalkyl —C 1-6 -alkoxy substituted with R 15 , R 16 and R 17 ;

R 11 is selected from

i) amino-C 1-6 -alkyl substituted on the nitrogen atom by R 21 and R 22 , ii) C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , iii) C 3-8 -cycloalkyl-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , iv) C 3-8 -cycloalkyl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , v) aryl substituted with R 18 , R 19 and R 20 , vi) aryl-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , vii) aryl-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , viii) aryl-heterocycloalkyl substituted with R 18 , R 19 and R 20 ix) aryl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , x) aryl(halo)-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , xi) aryl(halo)-heterocycloalkyl substituted with R 18 , R 19 and R 20 , xii) aryloxy-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , xiii) aryloxy-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , xiv) aryloxy-heterocycloalkyl substituted with R 18 , R 19 and R 20 , xv) aryloxy(halo)-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , xvi) aryloxy(halo)-heterocycloalkyl substituted with R 18 , R 19 and R 20 xvii) aryloxy(halo)-C 1-6 -alkyl, xviii) heterocycloalkyl substituted with R 18 , R 19 and R 20 , xix) heterocycloalkyl-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , xx) heterocycloalkyl-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , xxi) heterocycloalkyl(halo)-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , xxii) heterocycloalkyl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , xxiii) heteroaryl substituted with R 18 , R 19 and R 20 , xxiv) heteroaryl-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , xxv) heteroaryl-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , xxvi) heteroaryl(halo)-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , xxvii) heteroaryl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , xxviii) heteroaryloxy-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , xxix) heteroaryloxy-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , xxx) heteroaryloxy(halo)-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , and xxxi) heteroaryloxy(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 ;

R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 24 , R 25 and R 26 are independently selected from

i) H, ii) cyano, iii) halogen, iv) oxo, v) C 1-6 -alkyl, vi) amino substituted on the nitrogen atom by two substituents independently selected from H, C 1-6 -alkyl, C 1-6 -alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl, vii) amino-C 1-6 -alkyl substituted on the nitrogen atom by two substituents independently selected from H, C 1-6 -alkyl, C 1-6 -alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl, viii) C 1-6 -alkyl, ix) halo-C 1-6 -alkyl, x) C 3-8 -cycloalkyl, xi) C 1-6 -alkoxycarbonyl-C 1-6 -alkyl, xii) carboxy-C 1-6 -alkyl, xiii) C 1-6 -alkoxycarbonyl-C 1-6 alkylaminocarbonyl-C 1-6 alkyl, xiv) carboxy-C 1-6 -alkylaminocarbonyl-C 1-6 alkyl, xv) C 1-6 -alkoxy, xvi) halo-C 1-6 -alkoxy, xvii) C 1-6 -alkoxycarbonyl-C 1-6 -alkoxy, xviii) carboxy-C 1-6 -alkoxy, xix) C 1-6 -alkoxycarbonyl-C 1-6 -alkylaminocarbonyl-C 1-6 -alkoxy, xx) carboxy-C 1-6 -alkylaminocarbonyl-C 1-6 -alkoxy, and xxi) heterocycloalkyl;

R 21 and R 22 are independently selected from

i) H, ii) C 1-6 -alkoxycarbonyl, iii) carboxy-C 1-6 -alkyl, iv) arylcarbonyl, and v) heteroarylcarbonyl;

or pharmaceutically acceptable salts.

Inhibition of the serine protease HtrA1, which belongs to an evolutionarily conserved family of HtrA proteins, has the potential to protect and treat tissue damage caused by the degeneration of retinal or photoreceptor cells in the human eye. The pathophysiological relevance of HtrA1 in the progression of the age-related macular degeneration has been firmly established by human genetic studies where a SNP in the HtrA1 promoter region results in increased HtrA1 transcript and protein levels. Age-related macular degeneration is the leading cause of severe irreversible central vision loss and blindness in individuals over 65 years of age in developed countries. There are two forms of AMD: dry AMD and wet AMD. Wet AMD (also known as exudative AMD), is associated with pathologic posterior choroidal neovascularization subsequent to the disruption of the delimiting Bruch's membrane. Tissue edema due to the leakage from the abnormal blood vessels damages the macula and impairs vision, eventually leading to blindness. In dry AMD, drusen have been reported in the macula of the eye, the cells in the macula die for the progressive accumulation of the drusen, resulting in progressive vision loss. Dry AMD is clinically described to occur in three stages: 1) early, 2) intermediate, and 3) advanced dry AMD. Dry AMD can also progress into wet AMD during any stage of the disease. Treatment strategies for wet AMD exists and the current standard of care is Lucentis (Genentech/Roche) and Eylea (Regeneron), an anti-VEGF antibody and an anti-VEGF trap injected intravitreally respectively. There are no current treatments for preventing loss of vision for the dry form and for preventing progression of dry AMD to local atrophy of the retinal tissue. As discussed above, HtrA1 risk alleles have been associated, with high statistical significance, with the AMD onsets and the protein has been reported to be present in drusen. These studies and further evidences provide relevance that HtrA1 is a fundamental factor involved in the pathophysiology and progression in AMD. This concept is further confirmed in different AMD disease models, where increased HtrA1 protein levels in the retina tissue have been shown to be responsible for the degradation of extracellular matrix (ECM) proteins like fibronectin, fibulins and aggrecan. The physiological balance between production and disintegration of the ECM components allows for both creation and maintenance of proper retina tissue architecture. Such balance has been reported to be lost in the progression of the age-related macular degeneration. In particular, the fibulins (mainly-3, -5, -6) have been reported to be important components of the Bruch's membrane in maintaining the integrity of elastic lamina and organization of the retina tissue overall. Several variants in fibulin 5 and fibulin 3 were reported to be associated with AMD. Missense mutations of the fibulin 5 gene have been associated with reduced secretion of fibulin 5. Different studies have reported that HtrA1 protease activity is directed to the cleavage of the fibulins as substrates. A direct inhibition of HtrA1 protease activity is expected to provide a protection reducing degradation of extracellular matrix proteins, in particular fibulins and fibrionectin, therefore preserving the retina tissue structure. The relevance of HtrA1's role in maintenance of the physiological homeostasis of the ECM components is firmly provided by the identification of human loss-of-function mutations causing familial ischemic cerebral small-vessel disease. The molecular mechanism underlies in the deficient TGFbeta inhibition by HtrA1 resulting in increased signaling levels, which in conjunction with deficient HtrA1-mediated degradation of various extracellular matrix components determine thickening of the intima responsible for the ischemic small-vessels. Given its fundamental role in regulating intracellular signaling pathways (e.g. TGFbeta) and the regulation of ECM proteins turnover, HtrA1 has been involved in several pathologies, as ocular diseases, rheumatoid arthritis, osteoarthritis, Alzheimer's disease, and some types of cancer.

Objects of the present invention are the compounds of formula (I) and their aforementioned salts and esters and their use as therapeutically active substances, a process for the manufacture of the said compounds, intermediates, pharmaceutical compositions, medicaments containing the said compounds, their pharmaceutically acceptable salts or esters, the use of the said compounds, salts or esters for the treatment or prophylaxis of disorders or conditions that are associated with the activity of HtrA1, particularly in the treatment or prophylaxis of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.

The term “amino” denotes a —NH 2 group.

The term “amino-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by an amino group. Examples of amino-C 1-6 -alkyl groups are aminomethyl, aminoethyl or aminopropyl. Particular examples of amino-C 1-6 -alkyl is aminomethyl.

The term “aminocarbonyl” denotes a group of the formula —C(O)—R′, wherein R′ is an amino group.

The term “aminocarbonyl-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by an aminocarbonyl group. Examples of aminocarbonyl-C 1-6 -alkyl groups are aminocarbonylmethyl, aminocarbonylethyl or aminocarbonylpropyl

The term “C 1-6 -alkoxy” denotes a group of the formula —O—R′, wherein R′ is an C 1-6 -alkyl group. Examples of C 1-6 -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular example is methoxy. In the case of R 12 , particular example is methoxy.

The term “C 1-6 -alkoxycarbonyl” denotes a group of the formula —C(O)—R′, wherein R′ is a C 1-6 -alkoxy group. Particular example of C 1-6 -alkoxycarbonyl is a group wherein R′ is tert-butoxy.

The term “C 1-6 -alkoxycarbonyl-C 1-6 -alkoxy” denotes an C 1-6 -alkoxy group wherein one of the hydrogen atoms of the C 1-6 -alkoxy group has been replaced by a C 1-6 -alkoxycarbonyl group. Particular example of C 1-6 -alkoxycarbonyl-C 1-6 -alkoxy is a methoxy wherein one of the hydrogen atoms has been replaced by tert-butoxycarbonyl.

The term “C 1-6 -alkoxycarbonyl-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by a C 1-6 -alkoxycarbonyl group. Particular example of C 1-6 -alkoxycarbonyl-C 1-6 -alkyl is a methyl wherein one of the hydrogen atoms has been replaced by tert-butoxycarbonyl.

The term “C 1-6 -alkoxycarbonyl-C 1-6 -alkylaminocarbonyl-C 1-6 -alkoxy” denotes an C 1-6 -alkoxy group wherein one of the hydrogen atoms of the C 1-6 -alkoxy group has been replaced by a C 1-6 -alkoxycarbonyl-C 1-6 -alkylaminocarbonyl group. Particular example is methoxy wherein one of the hydrogen atoms has been replaced by tert-butoxycarbonylmethylamino.

The term “C 1-6 -alkoxycarbonyl-C 1-6 -alkylaminocarbonyl-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by a C 1-6 -alkoxycarbonyl-C 1-6 -alkylaminocarbonyl group. Particular example is methyl wherein one of the hydrogen atoms has been replaced by tert-butoxycarbonylmethylaminocarbonyl.

The term “C 1-6 -alkoxycarbonyl-C 1-6 -alkylaminocarbonyl” denotes a group of the formula —C(O)—R′, wherein R′ is a C 1-6 -alkoxycarbonyl-C 1-6 -alkylamino group. Particular example is a group wherein R′ is tert-butoxycarbonylmethylamino.

The term “C 1-6 -alkoxycarbonyl-C 1-6 -alkylamino” denotes a group of the formula —NH—R′, wherein R′ is an C 1-6 -alkoxycarbonyl-C 1-6 -alkyl group. Particular example is a group wherein R′ is tert-butoxycarbonylmethyl.

The term “C 1-6 -alkoxycarbonyl-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by an C 1-6 -alkoxycarbonyl group. Particular example is a methyl wherein one of the hydrogen atoms of has been replaced by a tert-butoxycarbonyl.

The term “C 1-6 -alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. Examples of C 1-6 -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Particular C 1-6 -alkyl groups are methyl and isopropyl. In the case of R 2 , particular example is isopropyl.

The term “aryl” denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl group include phenyl and naphthyl. Particular aryl group is phenyl.

The term “aryl(halo)-C 1-6 -alkyl” denotes a halo-C 1-6 -alkyl group wherein one of the hydrogen atoms of the halo-C 1-6 -alkyl group has been replaced by an aryl group. Particular examples are groups wherein the aryl group is phenyl. Further particular example is phenyl-difluoromethyl.

The term “aryl-C 1-6 -alkyl” denotes an —C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by an aryl group. Particular aryl-C 1-6 -alkyl group is phenyl-C 1-6 -alkyl. Further particular examples of aryl-C 1-6 -alkyl are phenylmethyl and phenylpropyl. Furthermore particular examples of aryl-C 1-6 -alkyl is phenylmethyl.

The term “aryl-C 1-6 -alkoxy” denotes an —C 1-6 -alkoxy group wherein one of the hydrogen atoms of the —C 1-6 -alkoxy group has been replaced by an aryl group. Particular examples are groups wherein the aryl group is phenyl. Particular aryl-C 1-6 -alkoxy group is phenylmethoxy.

The term “aryloxy” denotes a group of the formula —O—R′, wherein R′ is an aryl group. Particular examples of aryloxy group are groups wherein R′ is phenyl.

The term “aryloxy-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by an aryloxy group. Particular examples are groups wherein the aryloxy group is phenoxy. Further particular example of aryloxy-C 1-6 -alkyl is phenoxyalkyl. Further particular example is phenoxymethyl.

The term “aryloxy(halo)-C 1-6 -alkyl” denotes a halo-C 1-6 -alkyl group wherein one of the hydrogen atoms of the halo-C 1-6 -alkyl group has been replaced by an aryloxy group. Particular examples are groups wherein the aryloxy group is phenoxy.

The term “arylcarbonyl” denotes a group of the formula —C(O)—R′, wherein R′ is an aryl group. Particular example is a group wherein R′ is phenyl.

The term “aryl(halo)-C 3-8 -cycloalkyl” denotes a halo-C 3-8 -cycloalkyl group wherein one of the hydrogen atoms of the halo-C 3-8 -cycloalkyl group has been replaced by an aryl group. Particular examples are groups wherein the aryl group is phenyl. Further particular example is phenyl-difluorocyclopropyl.

The term “aryl-C 3-8 -cycloalkyl” denotes a halo-C 3-8 -cycloalkyl group wherein one of the hydrogen atoms of the C 3-8 -cycloalkyl group has been replaced by an aryl group. Particular examples are groups wherein the aryl group is phenyl. Further particular example is phenylcyclopropyl.

The term “aryloxy-C 3-8 -cycloalkyl” denotes a C 3-8 -cycloalkyl group wherein one of the hydrogen atoms of the C 3-8 -cycloalkyl group has been replaced by an aryloxy group. Particular examples are groups wherein the aryloxy group is phenoxy. Further particular example is phenyl-difluorocyclopropyl.

The term “aryloxy(halo)-C 3-8 -cycloalkyl” denotes a halo-C 3-8 -cycloalkyl group wherein one of the hydrogen atoms of the halo-C 3-8 -cycloalkyl group has been replaced by an aryloxy group. Particular examples are groups wherein the aryloxy group is phenoxy. Further particular example is phenoxy-difluorocyclopropyl.

The term “aryloxy-C 3-8 -cycloalkyl” denotes a C 3-8 -cycloalkyl group wherein one of the hydrogen atoms of the C 3-8 -cycloalkyl group has been replaced by an aryloxy group. Particular examples are groups wherein the aryloxy group is phenoxy. Further particular example is phenoxycyclopropyl.

The term “bicyclic ring system” denotes two rings which are fused to each other via a common single or double bond (annelated bicyclic ring system), via a sequence of three or more common atoms (bridged bicyclic ring system) or via a common single atom (spiro bicyclic ring system). Bicyclic ring systems can be saturated, partially unsaturated, unsaturated or aromatic. Bicyclic ring systems can comprise heteroatoms selected from N, O and S.

The term “carboxy” denotes a —COOH group.

The term “carboxy-C 1-6 -alkoxy” denotes an C 1-6 -alkoxy group wherein one of the hydrogen atoms of the C 1-6 -alkoxy group has been replaced by a carboxy group. Particular example is carboxymethoxy.

The term “carboxy-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by a carboxy group. Particular example is carboxymethyl.

The term “carboxy-C 1-6 -alkylaminocarbonyl-C 1-6 alkoxy” denotes an C 1-6 -alkoxy group wherein one of the hydrogen atoms of the C 1-6 -alkoxy group has been replaced by a carboxy-C 1-6 -alkylaminocarbonyl group. Particular example is carboxymethylaminocarbonylmethoxy.

The term “carboxy-C 1-6 alkylaminocarbonyl-C 1-6 alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by a carboxy-C 1-6 alkylaminocarbonyl group. Particular example is carboxymethylaminocarbonylmethyl.

The term “carboxy-C 1-6 alkylaminocarbonyl group” denotes a group of the formula —C(O)—R′, wherein R′ is a carboxy-C 1-6 alkylamino group. Particular example is carboxymethylamino.

The term “carboxy-C 1-6 alkylamino” denotes a group of the formula —NH—R′, wherein R′ is a carboxy-C 1-6 alkyl group. Particular example is a group wherein R′ is carboxymethyl.

The term “cyano” denotes a —C≡N group.

The term “C 3-8 -cycloalkyl” denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbocycles having two carbon atoms in common. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl group is cyclopropyl.

The term “C 3-8 -cycloalkyl(halo)-C 1-6 -alkyl” denotes a halo-C 1-6 -alkyl group wherein one of the hydrogen atoms of the halo-C 1-6 -alkyl group has been replaced by an C 3-8 -cycloalkyl group.

The term “C 3-8 -cycloalkyl-C 1-6 -alkyl” denotes an —C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by an C 3-8 -cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl and bicyclo[2.2.2]octanylethyl. Particular examples of cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl and bicyclo[2.2.2]octanylethyl. Further particular examples cycloalkylalkyl is cyclohexylethyl.

The term “halo-C 1-6 -alkoxy” denotes an C 1-6 -alkoxy group wherein at least one of the hydrogen atoms of the C 1-6 -alkoxy group has been replaced by same or different halogen atoms. The term “perhaloalkoxy” denotes an alkoxy group where all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy. Particular haloalkoxy groups is difluoromethoxy.

The term “halo-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein at least one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by the same or different halogen atoms. The term “perhaloalkyl” denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl group is trifluoroethyl.

The term “halo-C 3-8 -cycloalkyl” denotes an C 3-8 -cycloalkyl group wherein at least one of the hydrogen atoms of the C 3-8 -cycloalkyl group has been replaced by the same or different halogen atoms.

The term “halogen” and “halo” are used interchangeably herein and denote fluoro, chloro, bromo or iodo. Particular halogen is chloro.

The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl group include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and benzothiophenyl. Particular heteroaryl groups are pyrazinyl, pyridinyl, pyrimidinyl and thiophenyl. In the case of substituent R 11 , particular heteroaryl groups are pyrazinyl, pyridinyl, pyrimidinyl and thiophenyl, more particularly pyridinyl.

The term “heteroaryl(halo)-C 1-6 -alkyl” denotes a halo-C 1-6 -alkyl group wherein one of the hydrogen atoms of the halo-C 1-6 -alkyl group has been replaced by a heteroaryl group.

The term “heteroaryl-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by a heteroaryl group.

The term “heteroaryl-C 1-6 -alkoxy” denotes an C 1-6 -alkoxy group wherein one of the hydrogen atoms of the C 1-6 -alkoxy group has been replaced by a heteroaryl group.

The term “heteroaryloxy” denotes a group of the formula —O—R′, wherein R′ is a heteroaryl group.

The term “heteroaryloxy-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by an heteroaryloxy group.

The term “heteroaryloxy(halo)-C 1-6 -alkyl” denotes a halo-C 1-6 -alkyl group wherein one of the hydrogen atoms of the halo-C 1-6 -alkyl group has been replaced by a heteroaryloxy group.

The term “heteroarylcarbonyl” denotes a group of the formula —C(O)—R′, wherein R′ is a heteroaryl group. Particular heteroarylcarrbonyl is a group wherein R′ is pyridinyl.

The term “heteroaryl(halo)-C 3-8 -cycloalkyl” denotes a halo-C 3-8 -cycloalkyl group wherein one of the hydrogen atoms of the halo-C 3-8 -cycloalkyl group has been replaced by a heteroaryl group.

The term “heteroaryl-C 3-8 -cycloalkyl” denotes a halo-C 3-8 -cycloalkyl group wherein one of the hydrogen atoms of the C 3-8 -cycloalkyl group has been replaced by a heteroaryl group.

The term “heteroaryloxy-C 3-8 -cycloalkyl” denotes a C 3-8 -cycloalkyl group wherein one of the hydrogen atoms of the C 3-8 -cycloalkyl group has been replaced by a heteroaryloxy group.

The term “heteroaryloxy(halo)-C 3-8 -cycloalkyl” denotes a halo-C 3-8 -cycloalkyl group wherein one of the hydrogen atoms of the halo-C 3-8 -cycloalkyl group has been replaced by a heteroaryloxy group.

The term “heterocycloalkyl” denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two cycles having two ring atoms in common, i.e. the bridge separating the two rings is either a single bond or a chain of one or two ring atoms. Examples for monocyclic saturated heterocycloalkyl are 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples for bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl.

The term “heterocycloalkyl-C 1-6 -alkyl” denotes an C 1-6 -alkyl group wherein one of the hydrogen atoms of the C 1-6 -alkyl group has been replaced by a heterocycloalkyl group. In the case of R 1 , particular heterocycloalkyl-C 1-6 -alkyl is morpholinoethyl.

The term “heterocycloalkyl-C 1-6 -alkoxy” denotes an C 1-6 -alkoxy group wherein one of the hydrogen atoms of the C 1-6 -alkoxy group has been replaced by a heterocycloalkyl group.

The term “heterocycloalkyl(halo)-C 1-6 -alkyl” denotes a halo-C 1-6 -alkyl group wherein one of the hydrogen atoms of the halo-C 1-6 -alkyl group has been replaced by a heterocycloalkyl group.

The term “heterocycloalkyl(halo)-C 3-8 -cycloalkyl” denotes a halo-C 3-8 -cycloalkyl group wherein one of the hydrogen atoms of the halo-C 3-8 -cycloalkyl group has been replaced by a heterocycloalkyl group.

The term “hydroxy” denotes a —OH group.

The term “oxo” denotes a ═O group.

The term “phenoxy” denotes a group of the formula —O—R′, wherein R′ is a phenyl.

The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition, these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts, methanesulfonic acid salts and citric acid salts.

“Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes a group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. Particular protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Further particular protecting groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting group is the tert-butoxycarbonyl (Boc) group.

The abbreviation uM means microMolar and is equivalent to the symbol μM.

The abbreviation uL means microliter and is equivalent to the symbol μL.

The abbreviation ug means microgram and is equivalent to the symbol μg.

The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbon atom can be of the “R” or “S” configuration.

Depending on the individual compound and the conditions it has been exposed, the CF 2 -ketone moieties in compounds I exist in part, mainly or totally in form of its hydrate. Thus, any description of a CF 2 -ketone moiety always describes both ketone and hydrate form.

Also an embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein

R 1 is selected from

i) halo-C 1-6 -alkyl, and ii) morpholinyl-C 1-6 -alkyl substituted with R 24 , R 25 and R 26 ;

R 2 is C 1-6 -alkyl;

R 3 , R 4 , R 5 , R 7 , R 10 and R 23 are H;

X is selected from

i) —O—, ii) —S—, and iii) —S(O) 2 —;

R 6 is phenyl-C 1-6 -alkyl substituted with R 12 , R 13 and R 14 ;

A is selected from

i) —O—, and ii) —C(O)NR 10 —;

R 8 is —CH 2 R 9 ;

R 9 is selected from

i) H, ii) hydroxy, iii) C 1-6 -alkoxy, and iv) phenyl substituted with R 15 , R 16 and R 17 ;

R 11 is selected from

i) phenyl substituted with R 18 , R 19 and R 20 , ii) phenyl-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , iii) phenyl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , iv) pyridinyl substituted with R 18 , R 19 and R 20 ;

R 12 is selected from

i) H, and ii) C 1-6 -alkoxy;

R 13 , R 14 , R 17 and R 20 are H

R 15 is selected from

i) cyano, ii) halogen, and iii) C 1-6 -alkyl;

R 16 , R 18 and R 19 are independently selected from

i) H, and ii) halogen;

or pharmaceutically acceptable salts.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 1 is selected from

i) C 1-6 -alkyl, and ii) morpholinyl-C 1-6 -alkyl substituted with R 24 , R 25 and R 26 .

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 1 is halo-C 1-6 -alkyl.

A furthermore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 1 is trifluoroethyl.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 2 is C 1-6 -alkyl.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 2 is isopropyl.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 3 , R 4 , R 5 , R 7 , R 10 and R 23 are H.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein X is —S(O) 2 —.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 6 is phenyl-C 1-6 -alkyl substituted with R 12 , R 13 and R 14 .

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein A is selected from

i) —O—, and ii) —C(O)NR 10 —.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein A is —C(O)NR 10 —.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 is —CH 2 R 9 .

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 9 is selected from

i) H, ii) hydroxy, iii) C 1-6 -alkoxy, and iv) phenyl substituted with R 15 , R 16 and R 17 .

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 9 is phenyl substituted with R 15 , R 16 and R 17 .

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 11 is selected rom

i) phenyl substituted with R 18 , R 19 and R 20 , ii) phenyl-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , iii) phenyl(halo)-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 , iv) pyridinyl substituted with R 18 , R 19 and R 20 .

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 11 is selected rom

v) phenyl substituted with R 18 , R 19 and R 20 , and vi) pyridinyl substituted with R 18 , R 19 and R 20 .

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 12 is selected from

i) H, and ii) C 1-6 -alkoxy.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 12 is C 1-6 -alkoxy.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 13 , R 14 , R 17 and R 20 are H.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 15 is selected from

i) cyano, ii) halogen, and iii) C 1-6 -alkyl.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 15 is halogen.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 16 , R 18 and R 19 are independently selected from

i) H, and ii) halogen.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 16 is H.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 18 is halogen.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 19 is H.

Particular examples of compounds of formula (I) as described herein are selected from

(2S,4R)-1-[(2S)-2-[(3-chlorobenzoyl)amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2-(2,5-dichlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2,2-difluoro-2-(3-fluorophenyl)acetyl]amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[(2-methylpropan-2-yl)oxy]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[(3-chlorobenzoyl)amino]-3-methoxypropanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxypropanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide; N—((S)-3-(3-cyanophenyl)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; N—((S)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidin-1-yl)-1-oxo-3-(m-tolyl)propan-2-yl)picolinamide; 5-chloro-N-((2S)-3-(3-cyanophenyl)-1-((4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; (2S,4R)-1-((R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoyl)-N—((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((R)-3-(3-chlorophenyl)-2-((5-chloropyridin-3-yl)oxy)propanoyl)-N—((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-chlorobenzamido)-3-(3-fluorophenyl)propanoyl)-N—((S)-5,5-difluoro-2-methyl-6-((2-morpholinoethyl)amino)-4,6-dioxohexan-3-yl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidine-2-carboxamide; (2S,4R)—N—((S)-5,5-difluoro-2-methyl-6-((2-morpholinoethyl)amino)-4,6-dioxohexan-3-yl)-1-((S)-3-(3-fluorophenyl)-2-(1-(2-fluorophenyl)cyclopentanecarboxamido)propanoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidine-2-carboxamide; N—((S)-3-(3,4-dichlorophenyl)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)thio)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; N—((S)-3-(3-chiorophenyl)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; N—((S)-1-((2S,4R)-4-(benzylsulfonyl)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)pyrrolidin-1-yl)-3-(3-chlorophenyl)-1-oxopropan-2-yl)picolinamide; (2S,4R)-1-((R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoyl)-N—((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)-4-((4-methoxybenzyl)thio)pyrrolidine-2-carboxamide; (2S,4R)-4-(benzylsulfonyl)-1-((R)-3-(3-chlorophenyl)-2-((5-chloropyridin-3-yl)oxy)propanoyl)-N—((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxypropanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide; N—((S)-3-(3,4-dichlorophenyl)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; N—((S)-3-(3-chlorophenyl)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)oxy)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide;

and pharmaceutically acceptable salts thereof.

Processes for the manufacture of compounds of formula (I) as described herein are an object of the invention.

Synthesis

Processes for the manufacture of compounds of formula (I) as described herein are an object of the invention.

The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. In case a mixture of enantiomers or diastereomers is produced during a reaction, these enantiomers or diastereomers can be separated by methods described herein or known to the man skilled in the art such as, e.g., chromatography on a chiral column or crystallization. The substituents and indices used in the following description of the processes have the significance given herein.

The following abbreviations are used in the present text:

Boc=t-butyloxycarbonyl, DBU=2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepine, DCE=1,2-dichloroethane, DCM=dichloromethane, DIAD=diisopropyl-azodicarboxylate, DCC=N,N′-dicyclohexylcarbodiimide, DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide, EDCI=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, eq.=equivalents, Fmoc=fluorenylmethoxycarbonyl, HATU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, HPLC=high performance liquid chromatography, HOBT=1-hydroxybenzo-triazole, Huenig's base=iPr 2 NEt=N-ethyl diisopropylamine, LAH=lithium aluminum hydride, PG=protecting group, rt=room temperature, TBME=t-butyl methyl ether, TBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate, TEA=Et 3 N=triethylamine, TFA=trifluoroacetic acid, THF=tetrahydrofuran, quant.=quantitative.

The synthesis of compounds of the general formula I can be accomplished according to scheme 1. Appropriately protected (e. g., with a Boc-group) α-amino-aldehyde 1 is reacted with the Reformatsky reagent derived from ethyl 2-bromo-2,2-difluoroacetate 2 to provide, under chelation control, amino-hydroxy-ester 3 (step a). The latter is transformed into amide 5 by treatment with the necessary amine 4 at elevated temperature, typically in boiling methanol (step b). Conventional deprotection, in the case of a Boc group with, e.g., TFA in DCM or anhydrous HCl in dioxane or a mixture of dioxane and MeOH, delivers free amine 6 (step c) which can then be coupled with N-protected-4-substituted-pyrrolidine-2-carboxylic acid 7 under standard peptide coupling conditions, e. g., with HATU or TBTU, and an appropriate base, e. g., Huenig's base or TEA, in an inert solvent like DMF, to furnish intermediate 8 (step d). Subsequent deprotection under appropriate conditions, depending on the nature of the protecting group PG′ (step e), gives compounds 9 (e.g. acidic conditions such as treatment with 4M HCl in dioxane in a solvent like MeOH or treatment with TFA in DCM around room temperature can be used for removal of a Boc protecting group, catalytic hydrogenation conditions using suitable catalysts such as Pd/C, Pd(OH) 2 in a solvent like MeOH, EtOH or AcOEt around room temperature can be used for removal of a Cbz protecting group, etc.). Reaction of compounds 9 with a N-protected-α-amino acid compounds 10, such as (2S)-2-(tert-butoxycarbonylamino)propanoic acid, can be performed by using one of various coupling reagents such as TBTU, HATU, EDC/HOBt, etc., and a base like Huenig's base or triethyl amine in a solvent like N,N-dimethylformamide preferably between 0° C. and room temperature to give compounds 11 (step f). Subsequent deprotection under appropriate conditions, depending on the nature of the protecting group PG (step g), gives compounds 12 (e.g. acidic conditions such as treatment with 4M HCl in dioxane in a solvent like MeOH or treatment with TFA in DCM around room temperature can be used for removal of a Boc protecting group, catalytic hydrogenation conditions using suitable catalysts such as Pd/C, Pd(OH) 2 in a solvent like MeOH, EtOH or AcOEt around room temperature can be used for removal of a Cbz protecting group, treatment with a mild base such as piperidine in a solvent like DCM around room temperature can be used for removal of a Fmoc protecting group, etc.). Reaction of compounds 12 with the appropriate carboxylic acid compounds 13, activated by one of the various coupling reagents such as TBTU, HATU, EDCI/HOBt, etc., and a base like Huenig's base or triethyl amine in a solvent like N,N-dimethylformamide preferably between 0° C. and room temperature gives compounds 14 (step h). Alternatively, compounds 12 can be reacted with suitable sulfonyl chloride 13′ in presence of a base such as Huenig's base or triethyl amine in a solvent like DCM or DMF preferably between 0° C. and room temperature to generate compounds 14 (step h). Compounds 14 containing a protected amino function as e.g. a tert-butoxycarbonylamino group can be converted into the corresponding primary or secondary amine compounds 14 using conditions as described for the removal of tert-butoxycarbonylamino groups in step c. Eventually, oxidation of compounds 9 can e.g. be performed using Swern's conditions (oxalyl chloride, dimethyl sulfoxide, triethyl amine in dichloromethane between −78° C. and RT) or with the help of an appropriate specific oxidizing agent as Dess-Martin Periodinane in a solvent like DCM or a mixture of DCM and THF as solubilizing agent between 0° C. and room temperature, generates the final target molecule I (step i).

Compounds I containing a tert-butyl-dimethyl-silyloxy or a tert-butoxycarbonylamino moiety in R 8 , R 10 or R 11 can be converted into the corresponding alcohols or amines under appropriate conditions depending on the nature of the functional groups, resulting in modified final compounds I (step j), (e.g. acidic conditions such as treatment with 4M HCl in dioxane in a solvent like dioxane or THF can be used for removal of tert-butyl-dimethyl-silyloxy groups and treatment with TFA in DCM around room temperature can be used for removal tert-butoxycarbonylamino groups).

Starting aldehyde 1 which is prone to racemization—in case one of R 2 or R 3 is hydrogen—is prepared as described in literature from the corresponding Weinreb amide by reduction with LAH and used immediately for the next step (J. Med. Chem. 1992, 35, 4795-4808).

In another synthetic variant, as outlined in scheme 2, intermediate 9 of scheme 1 is reacted with a carboxylic acids 10′ (for its synthesis, see below in scheme 7, 8, 9 or 10), such as (2S)-3-(3,4-dichlorophenyl)-2-(pyridine-2-carbonylamino)propanoic acid under standard peptide coupling conditions by treatment with a coupling reagent such as TBTU, HATU, EDCI/HOBT, etc., and a base like Huenig's base or TEA in an inert solvent like N,N-dimethylformamide to yield 11′ (step a). Oxidation of the free alcohol, e. g., with Dess Martin periodinane, in an inert solvent like DCM, delivers finally the target molecule I (step b). Compounds I containing a benzylsufide moiety in X—R 6 can be converted into the corresponding benzylsulfone under appropriate oxidation conditions, resulting in modified final compounds I (step c), (e.g. using mCPBA in a solvent like DCM preferably between 0° C. and room temperature).

N-protected-4-substituted-pyrrolidines 7 bearing a benzylsulfonyl or a benzylsulfanyl substituent can be prepared by methods known in the art or as described in the general synthetic procedure below (scheme 4). Commercially available (2S,4S)—N-protected-4-substituted-pyrrolidine-1,2-dicarboxylate 41 are treated with e.g. phenylmethanethiol or (4-methoxyphenyl)methanethiol and potassium tert-butoxide in DMF (for Cl: preferably between −5° C. and room temperature; for Br: 0° C. to room temperature; for Mesylate or Tosylate: room temperature to 100° C.) to give compounds 42 with inversion of the configuration (step a). Subsequent sulfide oxidation using mCPBA in a solvent like DCM preferably between 0° C. and room temperature give compounds 43 (step b). Hydrolysis of esters 42 or 43 can be achieved preferably with aqueous lithium hydroxide in a solvent like THF, MeOH or a mixture of THF/MeOH at 0° C. or sodium hydroxide in a solvent like ethanol between 0° C. and room temperature to give acids 7a and 7b (step c).

N-protected-4-substituted-pyrrolidines 7 can be prepared by methods known in the art or as described in the general synthetic procedure below (scheme 5). Compounds 1 bearing a benzyloxy substituent can be reacted with commercially available (2S,4S)—N-protected-4-hydroxypyrrolidine-1,2-dicarboxylate 51 using benzylbromide in a solvent like DMF in the presence of a base such as NaH preferably between 0° C. and room temperature to give compounds 52 with inversion of the configuration (step a). Alternatively, compounds 1 bearing a 4-methoxybenzyloxy substituent can be reacted with commercially available (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate 53 with suitable carboxylic acids 10′ (for its synthesis, see below in scheme 7, 8, 9 or 10) under standard coupling conditions by using a coupling reagent such as HATU and a base like Huenig's base in a solvent like DMF preferably between 0° C. and room temperature to give compounds 54 with retention of the configuration (step a′). Subsequent reaction of (2S,4R)—N-protected-4-hydroxypyrrolidine-1,2-dicarboxylate 54 (PG′=R 11 ACR 7 R 8 CO) with 4-methoxybenzyl 2,2,2-trichloroacetimidate in a solvent like DCM or DCE in the presence of a catalytic amount of acid such as p-toluenesulfonic acid or trifluoromethanesulfonic acid preferably between 0° C. and room temperature to give compounds 52 (PG′=R 11 ACR 7 R 8 CO; step b). Hydrolysis of esters 52 can be achieved preferably with aqueous lithium hydroxide in a solvent like THF, MeOH or a mixture of THF/MeOH at 0° C. or sodium hydroxide in a solvent like MeOH or ethanol between 0° C. and room temperature to give acids 7c (step c).

Acid 10′ in scheme 2 and 5, can be, if not commercial available, prepared as follows:

Amino acid 1 is coupled with NHS-ester 2 under Schotten Baumann-conditions in a mixture of, e. g., THF, DME, and water, in the presence of a mild base like NaHCO 3 to provide the desired N-acylated amino acid 10′. Building block 2 can be obtained from readily available acids R 11 —COOH by treatment with 1-hydroxypyrrolidine-2,5-dione, EDC, and pyridine in DCM at ambient temperature. In case R 8 and/or R 10 contain sensitive functional groups, they have to be protected; an alcohol e. g. as tert-butyldimethylsilyl ether, an acid as tert-butyl ester, or an amine as Boc-derivative. The respective functional groups are later liberated at the final stage by treatment with mild acid, e. g. dilute HCl, or fluoride ions, e. g. TBAF in THF, for silyl ethers, or by treatment with moderatley acidic conditions like TFA in DCM or anhydrous HCl in dioxane or a mixture of dioxane and MeOH. Alternatively, amino acid 1 can also be reacted with acid chloride 2′ in presence of a base such as Huenig's base or triethyl amine in a solvent like DCM or DMF preferably between 0° C. and room temperature to give 10′ (scheme 7).

In another synthetic variant, as outlined in scheme 8, amino acid 1 is first converted to the corresponding methyl ester 2 upon treatment with acetyl chloride in MeOH in a temperature range between room temperature and the reflux temperature (step a). The amine function of 2 is coupled with the appropriate acid 3 by treatment with a coupling reagent such as TBTU, HATU, EDCI/HOBT, etc., and a base like Huenig's base or TEA in an inert solvent like DMF to yield 10′ (step b). Alternatively, compounds 12 can be reacted with suitable sulfonyl chloride 3′ in presence of a base such as Huenig's base or triethyl amine in a solvent like DCM or DMF preferably between 0° C. and room temperature to generate compounds 10′ (step b).

In another embodiment, carboxylic acids 10′ in scheme 2 and 5, can be, if not commercial available, prepared as follows (scheme 9). The appropriate, commercially available alpha-hydroxy substituted propanoate derivative 100 is reacted under typical Mitsunobu conditions using a suitable phenol derivative 101, such as 3,5-dichlorophenol, using e.g. DIAD, triphenylphosphine, in a solvent like THF and in a temperature range between 0° C. and room temperature gives ether derivatives 102 (step a). Alkaline hydrolysis of the ester functional group with an appropriate base, such as aqueous or non aqueous sodium, potassium or cesium carbonate, sodium or potassium hydroxide, preferably aqueous lithium hydroxide, in a solvent like MeOH, EtOH, THF, dioxane, preferably in a mixture of THF/MeOH and in a temperature range between room temperature and the reflux temperature of the solvents, gives the alpha-phenoxy substituted propanoic acid derivative 10′ (step b).

Alternatively, building block 10′ used in scheme 2 and 5 can be synthesized as summarized in scheme 10. The appropriate, commercially available Grignard-reagent 110 is reacted with epoxy-ester 111 in a regio- and stereoselective manner to deliver α-hydroxy ester 112, typically under copper catalysis, e.g., copper bromide dimethyl sulfide, in an inert solvent like THF, in a temperature range of −78° C. to −20° C. Ensuing etherification is accomplished by treating the latter with a phenolic compound 101 under typical Mitsunobu-conditions, e. g., DIAD or DEAD and triphenylphosphine, in an inert solvent like THF, in a temperature range of −20° C. to RT to give 113. In case 112 is used as homochiral alcohol, this reaction takes place under clean inversion. Careful hydrolysis under standard conditions, e. g., LiOH in a mixture of water, MeOH or EtOH, and THF, in a temperature range of −20° C. to RT, delivers building block 10′ without erosion of the stereochemical integrity.

Also an embodiment of the present invention is a process to prepare a compound of formula (I) as defined above comprising the reaction of a compound of formula (II) in oxidative conditions;

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, A and R 11 are as defined above.

In particular, in the presence of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane), in a solvent like DCM between 0° C. and room temperature.

Also an object of the present invention is a compound according to formula (I) as described herein for use as a therapeutically active substance.

Likewise an object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.

An object of the invention is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of ocular diseases, in particular HtrA1-mediated ocular diseases, more particularly wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity or polypoidal choroidal vasculopathy.

In a particular embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity or polypoidal choroidal vasculopathy.

The present invention also relates to the use of a compound according to formula (I) as described herein 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.

Also an object of the invention is a method for the treatment or prophylaxis 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 formula (I) as described herein.

Also an embodiment of the present invention are compounds of formula (I) as described herein, when manufactured according to any one of the described processes.

Assay Procedures

Protein Purification for Use in Enzymatic Assays

Human HtrA1 protein comprising the catalytic and the PDZ domain from amino acid Asp161 up to Pro480 was expressed in BL21(DE3) cells as an N-terminal fusion protein with a 6×His-SUMO tag. The transformed cells were grown in LB medium at 37° C. until the optical density at 600 nm was between 0.6 and 0.8. Then, the temperature was decreased to 18° C. and the recombinant protein production induced by adding IPTG to a final concentration of 250 mM. Fermentation was performed over night at 18° C.

The protein was purified to homogeneity following a four-step procedure. 40 g of cells were suspended in 50 mM HEPES pH 7.8, 250 mM NaCl, 10 mM MgCl 2 , 0.35% CHAPS, 10% glycerol containing 20 tabs per liter of EDTA-free cOmplete Protease Inhibitor (Roche) as well as 30 mg/l DNAse and Rnase. The cells were broken by a single passage through a homogenizer at 750 bar and then centrifuged at 20′000×g for 30 minutes. The clear supernatant was applied on a triple 5 ml HisTrap column (GE Healthcare) equilibrated in 50 mM HEPES pH 7.8, 500 mM NaCl, 0.35% CHAPS, 10% glycerol. After washing with stepwise increasing concentrations of imidazole (20 mM, 40 mM, 50 mM) HtrA1 fusion protein was eluted within a linear gradient from 10 to 100% of the same buffer containing 500 mM imidazole. HtrA1 containing fractions were pooled, concentrated and then applied to a Superdex S200 prep grade (XK26/100—GE Healthcare) column equilibrated in 50 mM ethanolamine pH 9.6, 500 mM NaCl, 0.35% CHAPS, 10% glycerol, 0.02% sodium azide. In order to cleave the SUMO fusion protein and to release active HtrA1, the pooled fractions from the size exclusion chromatography were blended with SUMO protease (Life Technologies) and incubated ca. 20 hours at RT. HtrA1 was isolated out of the reaction solution by chromatography on a Superdex S200 prep grade (XK26/100—GE Healthcare) column equilibrated 50 mM ethanolamine pH 9.6, 500 mM NaCl, 0.35% CHAPS, 10% glycerol, 0.02% sodium azide. Fractions containing active HtrA1 were pooled and concentrated. Following the above strategy 150 mg of the HtrA1 (catalytical domain/PDZ construct) could be purified. As shown by RP-HPLC and SDS-PAGE, >98% pure protein was obtained.

HtrA1 Enzyme Inhibition Assay

Enzyme activity is measured by observing the increase in fluorescence intensity caused by cleavage of a peptide substrate containing a fluorophore, whose emission is quenched in the intact peptide.

Assay buffer: 500 mM Tris pH 8.0, 200 mM NaCl, 0.025% CHAPS, 0.005% BSG

Enzyme: human HtrA1 Cat-PDZ, final concentration 1 nM

Substrate: Mca-Ile-Arg-Arg-Val-Ser-Tyr-Ser-Phe-Lys(Dnp)-Lys, final concentration 500 nM (from Innovagen Cat: SP-5076-1, Lot: 89584.02)

Mca=(7-Methoxycoumarin-4-yl)acetyl

Dnp=2,4-Dinitrophenyl

Final volume: 51 μl

Excitation 320 nm, emission 390 nm

After a pre-incubation of the HtrA1 protease for 30 min with compounds, substrate is added to the wells and initial RFU is measured. Upon incubation for 2 hours at RT, the enzymatic activity cleaved the substrate releasing fluorescent Mca-peptide conjugate and the final RFU value is measured. The presence of inhibitors leads to a decreased final RFU.

For the analysis ΔRFU is calculated as RFU end −RFU start and then percent inhibition is calculated with the following formula:

PCT _Inhibition=100−100*(Δ RFU compound −ΔRFU blank )/(Δ RFU negctrl −ΔRFU blank )

where

neg. ctrl is protease with substrate and DMSO

blank is as neg. ctrl without protease

compound is as neg. ctrl with test compounds at desired concentration

The IC 50 is determined using a 4-point Hill-fit equation where

x=concentration of test compound

A=extrapolated value of the curve at effector concentration equals 0

B=extrapolated value of the curve at effector concentration equals infinite

C=concentration at the inflection point of the sigmoidal curve (IC 50 )

D=Hill coefficient of slope at the inflection point of the fitted curve

As a counter screen the compounds are added to the protease-substrate reaction mix only after 2 h incubation, when all the substrate is turned over, to identify auto-fluorescent or absorbing compounds giving false positive hits.

Compounds of formula (I) and their pharmaceutically acceptable salts or esters thereof as described herein have IC 50 values between 0.00001 μM and 1000 μM, particular compounds have IC 50 values between 0.0001 μM and 500 μM, further particular compounds have IC 50 values between 0.0001 μM and 50 μM, more particular compounds have IC 50 values between 0.0001 μM and 5 μM. These results have been obtained by using the enzymatic assay described above.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays), rectally (e.g. in the form of suppositories) or topical ocularly (e.g. in the form of solutions, ointments, gels or water soluble polymeric inserts). However, the administration can also be effected parenterally, such as intramuscularly, intravenously, or intraocularly (e.g. in the form of sterile injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées, hard gelatin capsules, injection solutions or topical formulations; lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Suitable adjuvants for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should it be appropriate. In the case of topical administration, the formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.1 and 25 mg, can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week. In case of parenteral application, such as intramuscularly, intravenously, or intraocularly, the formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.01 and 25 mg, can be administered either by single dose per day, per week or per month, or by multiple doses (2 to 4) per day, or by multiple doses per week or per month. It will, however, be clear that the upper or lower limit given herein can be exceeded when this is shown to be indicated.

The invention is illustrated hereinafter by Examples, which have no limiting character.

In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be obtained by methods described herein or by methods known to those skilled in the art, such as e.g. chiral chromatography or crystallization.

All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.

Abbreviations: aq.=aqueous; CAS-RN=Chemical Abstracts Service Registry Number; HPLC=high performance liquid chromatography; MS=mass spectrum; sat.=saturated

Intermediate P-1

(2S,4R)-4-benzylsulfonyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid

[A] (2S,4R)-1-tert-Butyl 2-methyl 4-(benzylthio)pyrrolidine-1,2-dicarboxylate

In a flask, potassium tert-butoxide 1M in THF (1.9 mL, 1.9 mmol) was combined with THF (7 mL) and the resulting colorless solution was cooled to −5° C. Phenylmethanethiol (267 μL, 2.28 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes. The reaction was cooled to 0° C. and a solution of (2S,4S)-1-tert-butyl 2-methyl 4-chloropyrrolidine-1,2-dicarboxylate (CAS [169032-99-9], 0.5 g, 1.9 mmol) in DMF (7 mL) was added dropwise. The mixture was stirred at this temperature for 30 minutes at 0° C. then allowed to warm up and stirring was continued at room temperature for 3 hours. The mixture was poured into a sat. NH 4 Claqueous solution and extracted with EtOAc. The organic layers were washed with a sat. NaHCO 3 aqueous solution and brine. Combined organics were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with a 10% to 80% EtOAc-heptanegradient to give the title compound (0.489 g, 73%) as a colorless oil.

[B] (2S,4R)-1-tert-Butyl 2-methyl 4-(benzylsulfonyl)pyrrolidine-1,2-dicarboxylate

In a flask, (2S,4R)-1-tert-butyl 2-methyl 4-(benzylthio)pyrrolidine-1,2-dicarboxylate (0.483 g, 1.37 mmol) was combined with DCM (20 mL) and the resulting colorless solution was cooled to 0° C. mCPBA (0.711 g, 2.89 mmol) was added at 0° C. and the reaction mixture was stirred for 1 hour at this temperature. The mixture was poured into a sat. NaHCO 3 aqueous solution and extracted with DCM (2×25 mL). The organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with a 20% to 70% EtOAc-heptanegradient to give the title compound (0.454 g, 86%) as a colorless oil. MS: 284.1 (M−Boc+H + ).

[C] (2S,4R)-4-Benzylsulfonyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid

In a flask, (2S,4R)-1-tert-butyl 2-methyl 4-(benzylsulfonyl)pyrrolidine-1,2-dicarboxylate (0.447 g, 1.17 mmol) was combined with THF (6 mL) and methanol (3 mL) and the resulting colorless solution was cooled to 0° C. A 1M aqueous solution of LiOH (1.52 mL, 1.52 mmol) was added at 0° C. and the reaction mixture was stirred for 2 hours at this temperature. The mixture was quenched with a 1M KHSO 4 aqueous solution and extracted with EtOAc (2×25 mL). The organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the title compound (0.426 g, 99%) as a colorless foam. MS: 368.3 (M−H − ).

Intermediate P-2

(2S,4R)-4-[(4-methoxyphenyl)methylsulfonyl]-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid

was prepared in analogy to intermediate P-1, but using in step [A] (4-methoxyphenyl)methanethiol, to give the title compound as colorless solid; MS: 300.1 (M−Boc+H + ).

Intermediate P-3

(2S,4R)-4-[(4-methoxyphenyl)methylsulfanyl]-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid

was prepared by reaction of (2S,4S)-1-tert-butyl 2-methyl 4-chloropyrrolidine-1,2-dicarboxylate and (4-methoxyphenyl)methanethiol in analogy to intermediate P-1, step [A], followed by hydrolysis of the resultant (2S,4R)-1-tert-butyl 2-methyl 4-(benzylsulfanyl)pyrrolidine-1,2-dicarboxylate in analogy to intermediate P-1, step [C].

Colorless and viscous oil; MS: 268.2 (M−Boc+H + ).

Intermediate B-1

(2S,4R)—N-[(3S,4R)-5,5-Difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

[A] (S)-tert-Butyl (3-methyl-1-oxobutan-2-yl)carbamate

To a solution of commercially available (S)-tert-butyl (1-(methoxy(methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (3 g, 11.5 mmol) in THF (100 mL) under argon at 0° C. was added LiAlH 4 1M in THF (11.5 mL, 11.5 mmol) dropwise over 3 min (0→4° C.). After stirring for 20 min in the cold, the reaction mixture was quenched with 1N KHSO 4 solution and extracted with EtOAc; the layers were separated and the aqueous layer was back-extracted with EtOAc. The organic layers were combined, dried over Na 2 SO 4 and concentrated in vacuo to yield the title compound as a colorless liquid, 2.38 g, which was used immediately for the next step.

[B] Ethyl (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methylhexanoate

A solution of the above prepared (S)-tert-butyl (3-methyl-1-oxobutan-2-yl)carbamate (2.01 g, 9.99 mmol) and ethyl 2-bromo-2,2-difluoroacetate (3.84 mL, 30 mmol) in THF (15 mL) was added dropwise to a suspension of activated zinc (1.96 g, 30 mmol) in THF (65 mL). Afterwards, the reaction was brought to reflux for 2 hours. The heat source was removed and the reaction was allowed to cool to ambient temperature. The reaction mixture was poured into 15 mL 1N KHSO 4 and extracted with EtOAc (2×25 mL). The organic layers were combined, washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with a 0 to 20% EtOAc-heptane gradient to give 1.41 g of the title compound as colorless oil.

[C] tert-Butyl N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamate

A mixture of the above prepared ethyl (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methylhexanoate (0.191 g, 0.588 mmol), 3,3,3-trifluoropropan-1-amine (0.333 g, 2.94 mmol) and N,N-diisopropylethylamine (0.514 mL, 2.94 mmol) was refluxed in 5 mL of MeOH overnight. The reaction volume was reduced in vacuo and to the residue was added EtOAc. The organic layer was washed with brine (3×), dried over Na 2 SO 4 , and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with a 15 to 50% EtOAc-heptane gradient to give 0.180 g of the title compound as white foam. MS: 391.4 (M−H − ).

[D] (3R,4S)-4-Amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide

In a 25 mL round-bottomed flask, the above prepared tert-butyl N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamate (0.177 g, 0.451 mmol) was combined with 1,4-dioxane (6 mL) to give a colorless solution. HCl 4M in dioxane (2.25 mL, 9 mmol) was added at 0° C. and the reaction mixture was stirred overnight at room temperature. The crude reaction mixture was concentrated in vacuo and dried on hv and then used directly for the next step (calculated as dihydrochloride).

[E] tert-Butyl (2S,4R)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-1-carboxylate

To a solution of (2S,4R)-4-[(4-methoxyphenyl)methylsulfonyl]-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (Intermediate P-2, 0.390 g, 0.976 mmol) (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide×HCl (0.307 g, 0.976 mmol) and HATU (0.445 g, 1.17 mmol) in DMF (4 mL) cooled to 0° C. was added Huenig's base (0.512 mL, 2.93 mmol) and the reaction mixture stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na 2 SO 4 , filtered and evaporated. The crude material was purified by silica gel flash chromatography eluting with a 0 to 75% EtOAc-heptane gradient to give the title compound (0.408 g, 63%) as an off-white solid. MS: 658.5 (M−H) − .

[F] (2S,4R)—N-[(3S,4R)-5,5-Difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide

To a solution of tert-butyl (2S,4R)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-1-carboxylate (0.385 g, 0.584 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (0.730 mL, 2.92 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was evaporated to dryness and the resulting crude material triturated with diisopropylether. The solid precipitate was filtered off and further dried under the high vacuum to give the title compound (0.320 g, 92%, HCl salt) as a colorless solid. MS: 560.2 (M+H + ).

Intermediate B-2

(2S,4R)—N-[(3S,4R)-5,5-Difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-(benzylsulfonyl)pyrrolidine-2-carboxamide

was prepared in analogy to intermediate B-1, but using in step [E] (2S,4R)-4-benzylsulfonyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (Intermediate P-1), to give the title compound as a colorless solid as hydrochloride.

Intermediate B-3

(2S,4R)—N-((3S,4R)-5,5-Difluoro-4-hydroxy-2-methyl-6-oxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)-4-((4-methoxybenzyl)thio)pyrrolidine-2-carboxamide

was prepared in analogy to intermediate B-1, but using in step [E] (2S,4R)-4-[(4-methoxyphenyl)methylsulfanyl]-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (Intermediate P-3), to give the title compound as an off-white foam as hydrochloride.

Intermediate B-4

(2S,4R)-[(2S)-2-Aminopropanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

[A] tert-Butyl N-[(2S)-1-[(2S,4R)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]carbamate

To a solution of (2S,4R)—N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide hydrochloride (Intermediate B-1, 0.312 g, 0.523 mmol), (2S)-2-(tert-butoxycarbonylamino)propanoic acid (0.099 g, 0.523 mmol) and HATU (0.219 g, 0.576 mmol) was added Huenig's base (0.274 mL, 1.57 mmol) and the reaction mixture stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na 2 SO 4 , filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 85% EtOAc-heptane gradient to give the title compound (0.345 g, 90%) as a colorless solid. MS: 731.4 (M+H + ).

[B] (2S,4R)-1-[(2S)-2-Aminopropanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

To a solution of tert-butyl N-[(2S)-1-[(2S,4R)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]carbamate (0.340 g, 0.465 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (0.582 mL, 2.33 mmol) and the reaction mixture stirred at room temperature overnight. The mixture was evaporated to dryness and triturated with diisopropylether. The solid precipitate was filtered off and further dried under the high vacuum to give the title compound (0.304 g, 98%, HCl salt) as a light green solid. MS: 631.5 (M+H + ).

Intermediate B-5

(2S,4R)-1-[(2S)-2-Amino-3-[(2-methylpropan-2-yl)oxy]propanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

was prepared in analogy to intermediate B-4, but using in step [A] (2S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)propanoic acid and replacing in step [B] methanol by dioxane as solvent, to give the title compound as an off-white solid as hydrochloride. MS: 703.3 (M+H + ).

Intermediate B-6

(2S,4R)-1-[(2S)-2-Amino-3-methoxypropanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

was prepared in analogy to intermediate B-4, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid, to give the title compound as colorless solid as hydrochloride. MS: 761.4 (M+H + ).

Intermediate C-1

(2S,4R)—N-[(1S,2R)-3,3-Difluoro-2-hydroxy-1-isopropyl-4-(2-morpholinoethylamino)-4-oxo-butyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

was prepared in analogy to intermediate B-1, but using in step [C] 2-morpholinoethanamine, to give the title compound as light yellow foam as dihydrochloride.

Intermediate E-1

(2S)-3-(3,4-Dichlorophenyl)-2-(pyridine-2-carbonylamino)propanoic acid

[A] (2,5-Dioxopyrrolidin-1-yl) pyridine-2-carboxylate

In a flask, pyridine-2-carboxylic acid (0.5 g, 4.06 mmol) was combined with DCM (20 mL) to give a colorless solution. At 0° C., pyridine (0.985 mL, 12.2 mmol), EDC (1.09 g, 5.69 mmol), and 1-hydroxypyrrolidine-2,5-dione (0.608 g, 5.28 mmol) were subsequently added, the ice-bath was removed, and the reaction mixture was stirred at rt overnight. The reaction mixture was then quenched with sat. NH 4 Cl sol. and extracted with DCM (2×20 mL). The organic layers were washed with sat NaHCO 3 , then with brine. The organic layers were combined, dried over Na 2 SO 4 , and concentrated in vacuo. The crude material was triturated with CH 2 Cl 2 /heptane to give 0.686 g of the title compound as light brown solid. MS: 221.1 (M+H) + .

[B] (2S)-3-(3,4-Dichlorophenyl)-2-(pyridine-2-carbonylamino)propanoic acid

A solution of the above prepared 2,5-dioxopyrrolidin-1-yl picolinate (0.250 g, 1.14 mmol) in DME (4 mL) was added to a mixture of (S)-2-amino-3-(3,4-dichlorophenyl)propanoic acid (0.266 g, 1.14 mmol) in THF (2 mL) and sodium bicarbonate (0.095 g, 1.14 mmol) in water (4 mL) and the reaction mixture was stirred at room temperature for 3 h. The mixture was poured into sat. NH 4 Cl sol. and extracted with EtOAc. The organic layers were washed with brine and the solvent was evaporated under vacuum. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% DCM-MeOH gradient to give the title compound (0.309 g, 80%) as a colorless solid. MS: 339.1 (M+H) + .

In close analogy, using the appropriate acidic building blocks, were prepared Intermediates E-2 to E-6, respectively, as summarized in the following Table:

Intermediate E-7

(2S)-3-(3-fluorophenyl)-2-[[1-(2-fluorophenyl)cyclopentanecarbonyl]amino]propanoic acid

[A] Methyl (2S)-2-amino-3-(3-fluorophenyl)propanoate

In a flask, acetyl chloride (1.16 mL, 16.4 mmol) was combined with MeOH (15 mL) under ice-bath cooling to give a colorless solution. The solution was stirred 15 min at room temperature then cooled to 0° C. (2S)-2-amino-3-(3-fluorophenyl)propanoic acid (300 mg, 1.64 mmol) was added, then the reaction mixture was heated to 65° C. and stirred at this temperature for 30 min. The crude reaction mixture was concentrated in vacuo. The residue was suspended in CH 2 Cl 2 and concentrated in vacuo (3 times) to give the title compound (0.380 g, 99%) as a colorless solid as hydrochloride. The crude material was used in the next step. MS: 198.1 (M+H + ).

[B] Methyl (2S)-3-(3-fluorophenyl)-2-[[1-(2-fluorophenyl)cyclopentanecarbonyl]amino]propanoate

In a flask, methyl (2S)-2-amino-3-(3-fluorophenyl)propanoate×HCl (0.380 g, 1.63 mmol) was combined with DMF (15 mL) to give a colorless solution. N,N-diisopropylethylamine (1.42 mL, 8.13 mmol) and 1-(2-fluorophenyl)cyclopentanecarboxylic acid (0.339 g, 1.63 mmol) were added at −10° C. followed by HATU (0.680 g, 1.79 mmol) and the reaction mixture was stirred at −10° C. for 1 hour. The mixture was quenched with a sat. NaHCO 3 aqueous solution and extracted with EtOAc The organic layer was washed with a 1N KHSO 4 solution and brine. The organic layer was dried over Na 2 SO 4 , filtered and evaporated. The crude material was purified by silica gel flash chromatography eluting with a 10 to 50% EtOAc-heptane gradient to give the title compound (0.488 g, 78%) as a colorless amorphous solid. MS: 388.2 (M+H + ).

[C] (2S)-3-(3-fluorophenyl)-2-[[1-(2-fluorophenyl)cyclopentanecarbonyl]amino]propanoic acid

To a solution of methyl (2S)-3-(3-fluorophenyl)-2-[[1-(2-fluorophenyl)cyclopentanecarbonyl]amino]propanoate (0.291 g, 0.751 mmol) in THF (3 mL), methanol (1.5 mL) cooled to 0° C. was added a solution of LiOH (0.018 g, 0.751 mmol) in water (1.5 mL) and the reaction mixture was stirred at room temperature for 6 hours. The mixture was extracted with tBuOMe. The aqueous layer was acidified with a 1N KHSO 4 aqueous solution and back-extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered and evaporated. The crude material was triturated with CH 2 Cl 2 /heptane. The solid precipitate was filtered off and further dried under the high vacuum to give the title compound (0.280 g, 46%) as a colorless solid. MS: 374.2 (M+H + ).

Intermediate F-1

(2R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoic acid

[A] Methyl (2S)-3-(3-chlorophenyl)-2-hydroxy-propanoate

In a flask, (S)-methyl oxirane-2-carboxylate (0.4 g, 3.92 mmol) and copper bromide dimethyl sulfide (0.2 g, 0.980 mmol) were combined with THF (25 mL) and cooled to −35° C. Then, (3-chlorophenyl)magnesium bromide (7.84 mL, 7.84 mmol) was added dropwise over 15 minutes while keeping the temperature below −33° C. The reaction mixture was slowly warmed up to −25° C. The mixture was quenched with a sat. NH 4 Cl aqueous solution at −20° C. and extracted with EtOAc. The organic layer was washed with water, dried over Na 2 SO 4 , filtered and evaporated to dryness. The crude material was purified by silica gel flash chromatography eluting with a 0 to 35% EtOAc-heptane gradient to give the title compound (0.615 g, 73%) as a colorless oil.

[B] Methyl (2R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoate

In a flask, methyl (2S)-3-(3-chlorophenyl)-2-hydroxy-propanoate (0.611 g, 2.85 mmol) and 3,5-dichlorophenol (0.487 g, 2.99 mmol) were combined with THF (11 mL) and cooled at −10° C. Triphenylphosphine (0.971 g, 3.7 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (726 μL, 3.7 mmol) were subsequently added and the reaction mixture was stirred at 0° C. for 1.5 hours. The mixture was quenched with a 0.5 N aqueous HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and evaporated to dryness. The crude material was purified by silica gel flash chromatography eluting with a 0 to 15% EtOAc-heptane gradient to give the title compound (0.763 g, 70%) as a light yellow oil.

[C] (2R)-3-(3-Chlorophenyl)-2-(3,5-dichlorophenoxy)propanoic acid

In a flask, methyl (2R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoate (0.763 g, 2.12 mmol) was combined with THF (5 mL) and MeOH (2 mL) and cooled to 0° C. Lithium hydroxide (0.127 g, 5.3 mmol) in water (1 mL) was added and the reaction mixture stirred for 2 hours. The mixture was quenched with a 0.5 N aqueous HCl solution and extracted with EtOAc. The organic layer was washed with water until pH>2, over Na 2 SO 4 , filtered and evaporated to dryness. The residue was recrystallized from EtOAc/heptane to give the title compound (0.668 g, 91%) as a white crystalline solid. MS: 343.2 (M−H − ).

Intermediate F-2

(2R)-3-(3-chlorophenyl)-2-(5-chloropyridin-3-yl)oxypropanoic acid

was prepared in analogy to intermediate F-1, but using in step [B] 5-chloropyridin-3-ol and replacing THF by DCM as solvent, to give the title compound as a white foam. MS: 312.1 (M+H + ).

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:

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: