HK40003361A - New difluoroketamide derivatives as htra1 inhibitors - Google Patents

Description

Novel difluoroketoamide derivatives as HTRA1 inhibitors

The present invention relates to organic compounds useful for treatment or prevention in mammals, and in particular to serine protease HtrA1 inhibitors for the treatment or prevention 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),

R¹is selected from

i)C_1-6-an alkyl group,

ii) by R²⁴、R²⁵And R²⁶Substituted C_3-8-a cycloalkyl group,

iii) halo-C_1-6-an alkyl group,

iv) by R²⁴、R²⁵And R²⁶Substituted heterocycloalkyl-C_1-6-an alkyl group,

v) by R²⁴、R²⁵And R²⁶Substituted aryl-C_1-6-alkyl, and

vi) by R²⁴、R²⁵And R²⁶Substituted heteroaryl-C_1-6-an alkyl group;

R²、R³、R⁴、R⁶、R⁷、R⁹、R¹⁰and R²³Is independently selected from

i)H，

ii)C_1-6-alkyl, and

iii)C_3-8-a cycloalkyl group;

R⁵is selected from

i) By R¹²、R¹³And R¹⁴A substituted aryl group,

ii) by R¹²、R¹³And R¹⁴Substituted aryl-C_1-6-an alkyl group,

iii) by R¹²、R¹³And R¹⁴Substituted heteroaryl, and

iv) by R¹²、R¹³And R¹⁴Substituted heteroaryl-C_1-6-an alkyl group;

R⁸is selected from

i)H，

ii) a hydroxyl group, and (iii) a hydroxyl group,

iii) amino-C substituted on the nitrogen atom by one or two substituents selected from_1-6-an alkyl group: H. c_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted by R¹⁵、R¹⁶And R¹⁷The substitution is carried out by the following steps,

iv) aminocarbonyl substituted on the nitrogen atom by one or two substituents selected from: H. c_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted by R¹⁵、R¹⁶And R¹⁷The substitution is carried out by the following steps,

v) aminocarbonyl-C substituted on the nitrogen atom by one or two substituents selected from_1-6-an alkyl group: H. c_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted by R¹⁵、R¹⁶And R¹⁷The substitution is carried out by the following steps,

vi) a carboxyl group,

vii) carboxy-C_1-6-an alkyl group,

viii)C_1-6-an alkoxy group,

ix)C_1-6-a halogenated alkoxy group,

x)C_1-6-an alkoxycarbonyl group, a carbonyl group,

xi)C_1-6-alkoxycarbonyl-C_1-6-an alkyl group,

xii)C_3-8-a cycloalkyl group,

xiii) by R¹⁵、R¹⁶And R¹⁷A substituted aryl group,

xiv) by R¹⁵、R¹⁶And R¹⁷Substituted aryl-C_1-6-an alkyl group,

xv) by R¹⁵、R¹⁶And R¹⁷Substituted aryl-C_1-6-an alkoxy group,

xvi) by R¹⁵、R¹⁶And R¹⁷(ii) a substituted heteroaryl group, wherein,

xvii) is substituted by R¹⁵、R¹⁶And R¹⁷Substituted heteroaryl-C_1-6-alkyl, and 2

xviii) by R¹⁵、R¹⁶And R¹⁷Substituted heteroaryl-C_1-6-an alkoxy group,

xix) by R¹⁵、R¹⁶And R¹⁷A substituted heterocycloalkyl group,

xx) by R¹⁵、R¹⁶And R¹⁷Substituted heterocycloalkyl-C_1-6-alkyl, and

xxi) by R¹⁵、R¹⁶And R¹⁷Substituted heterocycloalkyl-C_1-6-an alkoxy group;

R¹¹is selected from

i) At the nitrogen atom by R²¹And R²²Substituted amino-C_1-6-an alkyl group,

ii) by R¹⁸、R¹⁹And R²⁰Substituted C_3-8-a cycloalkyl group,

iii) by R¹⁸、R¹⁹And R²⁰Substituted C_3-8-cycloalkyl-C_1-6-an alkyl group,

iv) by R¹⁸、R¹⁹And R²⁰Substituted C_3-8-cycloalkyl (halo) -C_1-6-an alkyl group,

v) by R¹⁸、R¹⁹And R²⁰A substituted aryl group,

vi) by R¹⁸、R¹⁹And R²⁰Substituted aryl-C_1-6-an alkyl group,

vii) is substituted by R¹⁸、R¹⁹And R²⁰Substituted aryl-C_3-8-a cycloalkyl group,

viii) is substituted by R¹⁸、R¹⁹And R²⁰A substituted aryl-heterocycloalkyl group,

ix) by R¹⁸、R¹⁹And R²⁰Substituted aryl (halo) -C_1-6-an alkyl group,

x) by R¹⁸、R¹⁹And R²⁰Substituted aryl (halo) -C_3-8-a cycloalkyl group,

xi) is R¹⁸、R¹⁹And R²⁰Substituted aryl (halo) -heterocycloalkyl,

xii) by R¹⁸、R¹⁹And R²⁰Substituted aryloxy-C_1-6-an alkyl group,

xiii) by R¹⁸、R¹⁹And R²⁰Substituted aryloxy-C_3-8-a cycloalkyl group,

xiv) by R¹⁸、R¹⁹And R²⁰A substituted aryloxy-heterocycloalkyl group having a substituted aryloxy group,

xv) by R¹⁸、R¹⁹And R²⁰Substituted aryloxy (halo) -C_3-8-a cycloalkyl group,

xvi) by R¹⁸、R¹⁹And R²⁰Substituted aryloxy (halo) -heterocycloalkyl,

xvii) aryloxy (halo) -C_1-6-an alkyl group,

xviii) by R¹⁸、R¹⁹And R²⁰A substituted heterocycloalkyl group,

xix) by R¹⁸、R¹⁹And R²⁰Substituted heterocycloalkyl-C_1-6-an alkyl group,

xx) by R¹⁸、R¹⁹And R²⁰Substituted heterocycloalkyl-C_3-8-a cycloalkyl group,

xxi) by R¹⁸、R¹⁹And R²⁰Substituted heterocycloalkyl (halo) -C_3-8-a cycloalkyl group,

xxii) by R¹⁸、R¹⁹And R²⁰Substituted heterocycloalkyl (halo) -C_1-6-an alkyl group,

xxiii) by R¹⁸、R¹⁹And R²⁰(ii) a substituted heteroaryl group, wherein,

xxiv) is substituted by R¹⁸、R¹⁹And R²⁰Substituted heteroaryl-C_1-6-an alkyl group,

xxv) is substituted by R¹⁸、R¹⁹And R²⁰Substituted heteroaryl-C_3-8-a cycloalkyl group,

xxvi) is substituted by R¹⁸、R¹⁹And R²⁰Substituted heteroaryl (halo) -C_3-8-a cycloalkyl group,

xxvii) is substituted by R¹⁸、R¹⁹And R²⁰Substituted heteroaryl (halo) -C_1-6-an alkyl group,

xxviii) by R¹⁸、R¹⁹And R²⁰Substituted heteroaryloxy-C_1-6-an alkyl group,

xxix) by R¹⁸、R¹⁹And R²⁰Substituted heteroaryloxy-C_3-8-a cycloalkyl group,

xxx) by R¹⁸、R¹⁹And R²⁰Substituted heteroaryloxy (halo) -C_3-8-a cycloalkyl group, and

xxxi) is substituted by R¹⁸、R¹⁹And R²⁰Substituted heteroaryloxy (halo) -C_1-6-an alkyl group;

R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²⁴、R²⁵and R²⁶Is independently selected from

i)H，

ii) a cyano group, in the presence of a hydrogen atom,

iii) a halogen, in the presence of a halogen,

iv) an oxo group, in a pharmaceutically acceptable carrier,

v)C_1-6-an alkyl group,

vi) amino substituted on the nitrogen atom with two substituents independently selected from: H. c_1-6Alkyl radical, C_1-6Alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl,

vii) amino-C substituted on the nitrogen atom by two substituents independently selected from_1-6-an alkyl group: H. c_1-6Alkyl radical, C_1-6Alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl,

viii)C_1-6-an alkyl group,

ix) halo-C_1-6-an alkyl group,

x)C_3-8-a cycloalkyl group,

xi)C_1-6-alkoxycarbonyl-C_1-6-an alkyl group,

xii) carboxy-C_1-6-an alkyl group,

xiii)C_1-6-alkoxycarbonyl-C_1-6alkylaminocarbonyl-C_1-6An alkyl group, a carboxyl group,

xiv) carboxy-C_1-6-alkylaminocarbonyl-C_1-6An alkyl group, a carboxyl group,

xv)C_1-6-an alkoxy group,

xvi) halo-C_1-6-an alkoxy group,

xvii)C_1-6-alkoxycarbonyl-C_1-6-an alkoxy group,

xviii) carboxy-C_1-6-an alkoxy group,

xix)C_1-6alkoxycarbonyl-C_1-6alkylaminocarbonyl-C_1-6Alkoxy, and

xx) carboxy-C_1-6alkylaminocarbonyl-C_1-6An alkoxy group;

xxi) heterocycloalkyl;

R²¹and R²²Is independently selected from

i)H，

ii)C_1-6-an alkoxycarbonyl group, a carbonyl group,

iii) carboxy-C_1-6-an alkyl group,

iv) arylcarbonyl, and

v) a heteroarylcarbonyl group;

or a pharmaceutically acceptable salt;

the inhibition of serine protease HtrA1, which belongs to the family of HtrA proteins that are conserved evolutionarily, has the potential for protecting and treating tissue damage caused by degeneration of retinal or photoreceptor cells in the human eye, the pathophysiological relevance of HtrA1 in the progression of age-related macular degeneration has been strongly confirmed by human genetic studies, in which SNPs in the HtrA1 promoter region lead to increased transcription of HtrA1 and protein levels, age-related macular degeneration is the major cause of severe irreversible central vision loss and blindness in individuals over 65 years in developed countries, there are two forms of AMD, dry AMD and wet AMD, also known as exudative AMD, associated with the formation of choroidal neovessels after division of defined Bruch's membrane (i.e. Bruch's membrane), due to leakage from abnormal blood vessels and damage and finally to blindness in AMD, eye, the eye has been found in the eye, and has been found to be involved in the progression of several retinal connective tissue loss of retinal connective tissue, as distinct extracellular rete proteins, as distinct extracellular rete protein, as a factor inhibiting factor in vitro, protein, as well as a factor inhibiting, protein, inhibiting, promoting, increasing, and inhibiting, or inhibiting, promoting the progression of, or inhibiting, e.g, of, the progression of, the dry retinal, of, the dry retinal, macular degeneration, especially, reticulum, especially, in advanced, in developed, age-induced by several types of age-induced by the progression, age-induced by the intensive, eye, age-induced by several types of age-induced by the proximate, eye, age-induced by the proximate, the proximate retinal, the proximate to age-induced by the proximate retinal, the proximate to the proximate retinal, the proximate retinal, the proximate to the proximate, the proximate to the proximate.

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

The term "amino" denotes-NH₂A group.

The term "amino-C_1-6-alkyl "denotes such C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl group has been replaced by an amino group. amino-C_1-6Examples of-alkyl are aminomethyl, aminoethyl or aminopropyl. amino-C_1-6A particular example of an-alkyl group is aminomethyl.

The term "aminocarbonyl" denotes a group of formula-C (O) -R ', wherein R' is amino.

The term "aminocarbonyl-C_1-6-alkyl "denotes such C_1-6-alkyl, whereinThe C is_1-6One of the hydrogen atoms of the alkyl group has been replaced by an aminocarbonyl group. aminocarbonyl-C_1-6Examples of-alkyl are aminocarbonylmethyl, aminocarbonylethyl or aminocarbonylpropyl.

The term "C_1-6-alkoxy "represents a group of formula-O-R ', wherein R' is C_1-6-an alkyl group. C_1-6Examples of the-alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particular example is methoxy. At R¹²In the case of (2), a particular example is methoxy.

The term "C_1-6-alkoxycarbonyl "represents a group of formula-C (O) -R ', wherein R' is C_1-6-alkoxy groups. C_1-6Particular examples of alkoxycarbonyl groups are those in which R' is tert-butoxy.

The term "C_1-6-alkoxycarbonyl-C_1-6Alkoxy represents such a group C_1-6-alkoxy, wherein the C_1-6One of the hydrogen atoms of the alkoxy radical has been replaced by C_1-6-alkoxycarbonyl substitution. C_1-6-alkoxycarbonyl-C_1-6A particular example of an alkoxy group is a methoxy group in which one of the hydrogen atoms has been replaced by a tert-butoxycarbonyl group.

The term "C_1-6-alkoxycarbonyl-C_1-6-alkyl "denotes such C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl radical having been replaced by C_1-6-alkoxycarbonyl substitution. C_1-6-alkoxycarbonyl-C_1-6Particular examples of-alkyl are methyl in which one of the hydrogen atoms has been replaced by a tert-butoxycarbonyl group.

The term "C_1-6alkoxycarbonyl-C_1-6alkylaminocarbonyl-C_1-6Alkoxy "denotes such a C_1-6-alkoxy, wherein the C_1-6One of the hydrogen atoms of the alkoxy radical has been replaced by C_1-6alkoxycarbonyl-C_1-6Alkyl amino carbonyl. Particular examples are those in which one of the hydrogen atoms has been replacedTert-butoxycarbonylmethylamino instead of methoxy.

The term "C_1-6alkoxycarbonyl-C_1-6alkylaminocarbonyl-C_1-6Alkyl "denotes such a C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl radical having been replaced by C_1-6alkoxycarbonyl-C_1-6Alkyl amino carbonyl. A particular example is a methyl group in which one of the hydrogen atoms has been replaced by a tert-butoxycarbonylmethylaminocarbonyl group.

The term "C_1-6alkoxycarbonyl-C_1-6Alkylaminocarbonyl "denotes a group of formula-C (O) -R ', wherein R' is C_1-6alkoxycarbonyl-C_1-6An alkylamino group. Particular examples are groups wherein R' is tert-butoxycarbonylmethylamino.

The term "C_1-6-alkoxycarbonyl-C_1-6-alkylamino "represents a radical of formula-NH-R ', wherein R' is C_1-6-alkoxycarbonyl-C_1-6-an alkyl group. Particular examples are groups wherein R' is tert-butoxycarbonylmethyl.

The term "C_1-6-alkoxycarbonyl-C_1-6-alkyl "denotes such C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl radical having been replaced by C_1-6-alkoxycarbonyl substitution. A particular example is a methyl group in which one of the hydrogen atoms has been replaced by a tert-butoxycarbonyl group.

The term "C_1-6-alkyl "denotes a monovalent straight or branched chain saturated hydrocarbon radical of 1 to 6 carbon atoms. C_1-6Examples of-alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl. In particular C_1-6Alkyl is methyl and isopropyl. At R²In the case of (2), a 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 groups include phenyl and naphthyl. A particular aryl group is phenyl.

The term "aryl (halo) -C_1-6Alkyl represents such a halo-C_1-6-alkyl, wherein the halo-C_1-6One of the hydrogen atoms of the alkyl group has been replaced by an aryl group. Particular examples are groups wherein aryl is phenyl. A further particular example is phenyl-difluoromethyl.

The term "aryl-C_1-6-alkyl "denotes such a radical-C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl group has been replaced by an aryl group. Particular aryl radicals-C_1-6Alkyl is phenyl-C_1-6-an alkyl group. aryl-C_1-6Further particular examples of alkyl groups are phenylmethyl and phenylpropyl. aryl-C_1-6A further particular example of an alkyl group is phenylmethyl.

The term "aryl-C_1-6Alkoxy represents such a radical-C_1-6-alkoxy, wherein the-C_1-6One of the hydrogen atoms of the alkoxy group has been replaced by an aryl group. Particular examples are groups wherein aryl is phenyl. Particular aryl radicals-C_1-6-alkoxy is phenylmethoxy.

The term "aryloxy" denotes a group of formula-O-R ', wherein R' is aryl. Particular examples of aryloxy groups are groups wherein R' is phenyl.

The term "aryloxy-C_1-6-alkyl "denotes such C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl group has been replaced by an aryloxy group. Particular examples are groups in which aryloxy is phenoxy. Aryloxy group-C_1-6Further particular examples of-alkyl are phenoxyalkyl. A further particular example is phenoxymethyl.

The term "aryloxy (halo) -C_1-6Alkyl represents such a halo-C_1-6-alkyl, wherein the halo-C_1-6One of the hydrogen atoms of the alkyl group has been replaced by an aryloxy group. Particular examples are groups in which aryloxy is phenoxy.

The term "arylcarbonyl" denotes a group of formula-C (O) -R ', wherein R' is aryl. Particular examples are groups wherein R' is phenyl.

The term "aryl (halo) -C_3-8Cycloalkyl represents such a halo-C_3-8-cycloalkyl, wherein the halo-C_3-8-one of the hydrogen atoms of the cycloalkyl group has been replaced by an aryl group. Particular examples are groups wherein aryl is phenyl. A further particular example is phenyl-difluorocyclopropyl.

The term "aryl-C_3-8Cycloalkyl represents such a halo-C_3-8-cycloalkyl, wherein C_3-8-one of the hydrogen atoms of the cycloalkyl group has been replaced by an aryl group. Particular examples are groups wherein aryl is phenyl. A further particular example is phenylcyclopropyl.

The term "aryloxy-C_3-8Cycloalkyl represents such a group C_3-8-cycloalkyl, wherein the C_3-8-one of the hydrogen atoms of the cycloalkyl group has been replaced by an aryloxy group. Particular examples are groups in which aryloxy is phenoxy. A further particular example is phenyl-difluorocyclopropyl.

The term "aryloxy (halo) -C_3-8Cycloalkyl represents such a halo-C_3-8-cycloalkyl, wherein the halo-C_3-8-one of the hydrogen atoms of the cycloalkyl group has been replaced by an aryloxy group. Particular examples are groups in which aryloxy is phenoxy. A further particular example is phenoxy-difluorocyclopropyl.

The term "aryloxy-C_3-8Cycloalkyl represents such a group C_3-8-cycloalkyl, wherein the C_3-8-one of the hydrogen atoms of the cycloalkyl group has been replaced by an aryloxy group. Particular examples are groups in which aryloxy is phenoxy. A further particular example is phenoxycyclopropyl.

The term "bicyclic ring system" denotes two rings fused to each other via a common single or double bond (fused bicyclic ring system), two rings fused to each other via a sequence of three or more common atoms (bridged bicyclic ring system) or two rings fused to each other via a single common atom (spirobicyclic ring system). Bicyclic ring systems may be saturated, partially unsaturated, unsaturated or aromatic. The bicyclic ring system may comprise a heteroatom selected from N, O and S.

The term "carboxyl" denotes the-COOH group.

The term "carboxy-C_1-6Alkoxy represents such a group C_1-6-alkoxy, wherein the C_1-6One of the hydrogen atoms of the alkoxy group has been replaced by a carboxyl group. A particular example is carboxymethoxy.

The term "carboxy-C_1-6-alkyl "denotes such C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl group has been replaced by a carboxyl group. A particular example is carboxymethyl.

The term "carboxy-C_1-6-alkylaminocarbonyl-C_1-6Alkoxy "denotes such a C_1-6-alkoxy, wherein the C_1-6One of the hydrogen atoms of the alkoxy radical having been substituted by a carboxyl group-C_1-6-alkylaminocarbonyl substitution. A particular example is carboxymethylaminocarbonylmethoxy.

The term "carboxy-C_1-6alkylaminocarbonyl-C_1-6Alkyl "denotes such a C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl radical having been substituted by a carboxyl group-C_1-6Alkyl amino carbonyl. A particular example is carboxymethylaminocarbonylmethyl.

The term "carboxy-C_1-6Alkylaminocarbonyl "denotes a group of formula-C (O) -R ', wherein R' is carboxy-C_1-6An alkylamino group. A particular example is carboxymethylamino.

The term "carboxy-C_1-6Alkylamino "denotes a group of formula-NH-R ', wherein R' is carboxy-C_1-6An alkyl group. Particular examples are groups wherein R' is carboxymethyl.

The term "cyano" denotes a-C ≡ N group.

The term "C_3-8-cycloalkyl "denotes a monovalent saturated monocyclic hydrocarbon radical of 3 to 8 ring carbon atoms. Bicyclic refers to a ring system consisting of two saturated carbocyclic rings sharing two carbon atoms. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. A more particular monocyclic cycloalkyl group is cyclopropyl.

The term "C_3-8-cycloalkyl (halo) -C_1-6Alkyl represents such a halo-C_1-6-alkyl, wherein the halo-C_1-6One of the hydrogen atoms of the alkyl radical having been replaced by C_3-8-cycloalkyl substitution.

The term "C_3-8-cycloalkyl-C_1-6-alkyl "denotes such a radical-C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl radical having been replaced by C_3-8-cycloalkyl substitution. Examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo [4.1.0]Heptylmethyl, bicyclo [4.1.0 ]]Heptyl ethyl, bicyclo [2.2.2]Octyl methyl and bicyclo [2.2.2]And (3) octyl ethyl. Particular examples of cycloalkylalkyl radicals are cyclohexylmethyl, cyclohexylethyl, bicyclo [4.1.0]Heptylmethyl, bicyclo [4.1.0 ]]Heptyl ethyl, bicyclo [2.2.2]Octyl methyl and bicyclo [2.2.2]And (3) octyl ethyl. A further particular example of a cycloalkylalkyl group is cyclohexylethyl.

The term "halo-C_1-6Alkoxy represents such a group C_1-6-alkoxy, wherein the C_1-6At least one of the hydrogen atoms of the alkoxy groups has been replaced by the same or a different halogen atom. The term "perhaloalkoxy" denotes an alkoxy group wherein all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, and the like,Trifluoromethyl ethoxy, trifluoromethyl ethoxy and pentafluoroethoxy. A particular haloalkoxy group is difluoromethoxy.

The term "halo-C_1-6-alkyl "denotes such C_1-6-alkyl, wherein the C_1-6At least one of the hydrogen atoms of the alkyl group has been replaced by the same or a different halogen atom. The term "perhaloalkyl" denotes an alkyl group wherein all of the hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of the haloalkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a trifluoromethylethyl group and a pentafluoroethyl group. A particular haloalkyl group is trifluoroethyl.

The term "halo-C_3-8Cycloalkyl represents such a group C_3-8-cycloalkyl, wherein the C_3-8-at least one of the hydrogen atoms of the cycloalkyl group has been replaced by the same or different halogen atom.

The terms "halogen" and "halo" are used interchangeably herein and denote fluorine, chlorine, bromine or iodine. A particular halogen is chlorine.

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 groups include pyrrolyl, furyl, thienyl, imidazolyl, and the like,Oxazolyl, thiazolyl, triazolyl,Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azaRadical diazaBasic group, heteroAzolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolylAzolyl, benzisoylAzolyl, benzothiazolyl, benzisothiazolyl, benzoOxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and benzothienyl. Particular heteroaryl groups are pyrazinyl, pyridinyl, pyrimidinyl and thienyl. At the substituent R¹¹In the case of (a), particular heteroaryl groups are pyrazinyl, pyridyl, pyrimidinyl and thienyl, more particularly pyridyl.

The term "heteroaryl (halo) -C_1-6Alkyl represents such a halo-C_1-6-alkyl, wherein the halo-C_1-6One of the hydrogen atoms of the alkyl group has been replaced by a heteroaryl group.

The term "heteroaryl-C_1-6-alkyl "denotes such C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl group has been replaced by a heteroaryl group.

The term "heteroaryl-C_1-6Alkoxy represents such a group C_1-6-alkoxy, wherein the C_1-6-one of the hydrogen atoms of the alkoxy group has been replaced by a heteroaryl group.

The term "heteroaryloxy" denotes a group of formula-O-R ', wherein R' is heteroaryl.

The term "heteroaryloxy-C_1-6-alkyl "denotes such C_1-6-an alkyl group,wherein the C is_1-6One of the hydrogen atoms of the alkyl radical has been replaced by a heteroaryloxy radical.

The term "heteroaryloxy (halo) -C_1-6Alkyl represents such a halo-C_1-6-alkyl, wherein the halo-C_1-6One of the hydrogen atoms of the alkyl radical has been replaced by a heteroaryloxy radical.

The term "heteroarylcarbonyl" denotes a group of formula-C (O) -R ', wherein R' is heteroaryl. Particular heteroarylcarbonyl groups are those wherein R' is pyridyl.

The term "heteroaryl (halo) -C_3-8Cycloalkyl represents such a halo-C_3-8-cycloalkyl, wherein the halo-C_3-8-one of the hydrogen atoms of the cycloalkyl group has been replaced by a heteroaryl group.

The term "heteroaryl-C_3-8Cycloalkyl represents such a halo-C_3-8-cycloalkyl, wherein the C_3-8-one of the hydrogen atoms of the cycloalkyl group has been replaced by a heteroaryl group.

The term "heteroaryloxy-C_3-8Cycloalkyl represents such a group C_3-8-cycloalkyl, wherein the C_3-8-one of the hydrogen atoms of the cycloalkyl group has been replaced by a heteroaryloxy group.

The term "heteroaryloxy (halo) -C_3-8Cycloalkyl represents such a halo-C_3-8-cycloalkyl, wherein the halo-C_3-8-one of the hydrogen atoms of the cycloalkyl group has been replaced by a heteroaryloxy group.

The term "heterocycloalkyl" denotes a monovalent saturated or partially unsaturated monocyclic 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 rings sharing two ring atoms, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. An example of a monocyclic saturated heterocycloalkyl is 4, 5-dihydro-Azolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, and the like,Oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepinyl, diazepanyl, homopiperazinyl, or oxazepinyl. An example of a bicyclic saturated heterocycloalkyl is 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 radical. Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, dihydro-Oxazolyl, tetrahydro-pyridyl or dihydropyranyl.

The term "heterocycloalkyl-C_1-6-alkyl "denotes such C_1-6-alkyl, wherein the C_1-6One of the hydrogen atoms of the alkyl group has been replaced by a heterocycloalkyl group. At R¹In the case of (A), particular heterocycloalkyl-C_1-6-alkyl is morpholinoethyl.

The term "heterocycloalkyl-C_1-6Alkoxy represents such a group C_1-6-alkoxy, wherein the C_1-6One of the hydrogen atoms of the alkoxy group has been replaced by a heterocycloalkyl group.

The term "heterocycloalkyl (halo) -C_1-6Alkyl represents such a halo-C_1-6-alkyl, wherein the halo-C_1-6One of the hydrogen atoms of the alkyl group has been replaced by a heterocycloalkyl group.

The term "heterocycloalkyl (halo) -C_3-8Cycloalkyl represents such a halo-C_3-8-cycloalkyl, wherein the halo-C_3-8-one of the hydrogen atoms of the cycloalkyl group has been replaced by a heterocycloalkyl group.

The term "hydroxy" denotes an-OH group.

The term "oxo" denotes an ═ O group.

The term "phenoxy" denotes a group of formula-O-R ', wherein R' is phenyl.

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological utility and properties of the free base or free acid, which are not biologically or otherwise undesirable. The salts were formed with the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, particularly 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-acetylcysteine and the like. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, the following: 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 the compounds of formula (I) are the hydrochloride, mesylate and citrate salts.

By "pharmaceutically acceptable ester" is meant that the compound of formula (I) may be derivatised at functional groups to provide a derivative which is capable of conversion back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl, methylthiomethyl and pivaloyloxymethyl esters. In addition, any physiologically acceptable equivalent of a compound of formula (I) that is capable of producing the parent compound of formula (I) in vivo, like a metabolically labile ester, is within the scope of the invention.

The term "protecting group" (PG) denotes a group: a group that selectively blocks a reactive site in a polyfunctional compound in the conventional meaning associated with it in synthetic chemistry so that a chemical reaction can proceed selectively at another unprotected reactive site. The protecting group may be removed at a suitable 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 fluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting groups are tert-butoxycarbonyl (Boc) groups.

The abbreviation uM denotes micromolar concentration and is equivalent to the symbol μ M.

The abbreviation uL stands for microliter and is equivalent to the symbol μ L.

The abbreviation ug denotes microgram and is equivalent to the symbol ug.

The compounds of formula (I) may contain several asymmetric centers and can exist in the following forms: optically pure enantiomers, mixtures of enantiomers (such as, for example, racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

According to the Cahn-Ingold-Prelog rule, the asymmetric carbon atom may be in either the "R" or "S" configuration.

CF in Compound I depending on the Individual Compound and the conditions to which it is exposed₂The ketone moiety being partly, predominantly or completely in the form of its hydrateAre present. Therefore, any pair of CF₂The description of the ketone moiety always describes both the ketone and the hydrate forms.

Furthermore, an embodiment of the present invention is a compound according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular a compound according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more in particular a compound according to formula (I) as described herein.

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

R¹Is selected from

i)C_1-6-alkyl, and

ii) by R²⁴、R²⁵And R²⁶Substituted heterocycloalkyl-C_1-6-an alkyl group;

R²is C_1-6-an alkyl group;

R³、R⁴、R⁶、R⁷、R⁹and R¹⁰Is H;

R⁵is selected from;

i) by R¹²、R¹³And R¹⁴Substituted phenyl, and

ii) by R¹²、R¹³And R¹⁴Substituted phenyl-C_1-6-an alkyl group,

R⁸is by R¹⁵、R¹⁶And R¹⁷Substituted phenyl;

R¹¹is selected from

i) By R¹⁸、R¹⁹And R²⁰Substituted phenyl, and

ii) by R¹⁸、R¹⁹And R²⁰A substituted pyridyl group;

R¹²is selected from

i) H, and

iii)C_1-6-an alkoxy group;

R¹³、R¹⁴、R¹⁷and R²⁰Is H;

R¹⁵is selected from

i)H，

ii) cyano, and

iii) halogen;

R¹⁶is selected from

i) H, and

ii) a halogen;

R¹⁸is selected from

i) Halogen, and

ii) a cyano group, in the presence of a hydrogen atom,

R¹⁹is selected from

i)H，

ii) a cyano group, in the presence of a hydrogen atom,

iii)C_1-6-alkyl, and

iv) a halogen;

or a pharmaceutically acceptable salt thereof.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹Is selected from

i)C_1-6-alkyl, and

ii) by R²⁴、R²⁵And R²⁶Substituted heterocycloalkyl-C_1-6-an alkyl group.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is¹Is halo-C_1-6-an alkyl group.

A further more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹Is trifluoroethyl.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²Is C_1-6-an alkyl group.

Furthermore, a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is²Is isopropyl.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³Is H.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁴Is H.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁶Is H.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁷Is H.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁹Is H.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁰Is H.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is³、R⁴、R⁶、R⁷、R⁹And R¹⁰Is H.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁵Is selected from

i) By R¹²、R¹³And R¹⁴Substituted phenyl, and

ii) by R¹²、R¹³And R¹⁴Substituted phenyl-C_1-6-an alkyl group.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is⁵Is by R¹²、R¹³And R¹⁴Substituted phenyl-C_1-6-an alkyl group.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁵Is covered by a C_1-6-alkoxy-substituted phenyl.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁸Is by R¹⁵、R¹⁶And R¹⁷A substituted phenyl group.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is⁸Is selected from

i) A hydroxyl group, and

ii) by R¹⁵、R¹⁶And R¹⁷A substituted phenyl group.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁸Is by R¹⁵、R¹⁶And R¹⁷A substituted phenyl group.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹¹Is selected from

i) By R¹⁸、R¹⁹And R²⁰Substituted phenyl, and

ii) by R¹⁸、R¹⁹And R²⁰A substituted pyridyl group.

Hair brushA more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹¹Is by R¹⁸、R¹⁹And R²⁰A substituted phenyl group.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹²Is selected from

i) H, and

ii)C_1-6-alkoxy groups.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹²Is C_1-6-alkoxy groups.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹³、R¹⁴、R¹⁷And R²⁰Is H.

Furthermore, an embodiment of the present invention is a compound according to formula (I) as described herein, wherein R is¹⁵Is selected from

i)H，

ii) cyano, and

iii) a halogen.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is¹⁵Is a halogen.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁶Is selected from

i) H, and

ii) a halogen.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁶Is H.

Another embodiment of the invention is a root as described hereinA compound according to formula (I) wherein R¹⁸Is selected from

i) Halogen, and

ii) a cyano group.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁹Is selected from

i) Cyano radicals, and

ii) a halogen.

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

(S) -4- ((S) -2- ((R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionylamino) -2-phenylacetylamino) -2, 2-difluoro-5-methyl-N- (2-morpholinoethyl) -3-oxohexanamide;

(S) -4- ((S) -2- ((R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -3- (3-chlorophenyl) -2- (3, 5-dichlorophenoxy) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chloro-5-methylphenoxy) -3- (3-chlorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chlorophenoxy) -3- (3, 4-dichlorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -3- (3-chlorophenyl) -2- (3, 5-dicyanophenoxy) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -3- (3-chlorophenyl) -2- ((5-chloropyridin-3-yl) oxy) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chlorophenoxy) -3- (3, 5-dichlorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((S) -3- (3-chlorophenyl) -2- (3, 5-dichlorophenoxy) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((S) -3- (3-chlorophenyl) -2- (3, 5-dichlorophenoxy) propionylamino) -2-phenylacetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chloro-5-cyanophenoxy) -3- (3-chlorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chloro-5-cyanophenoxy) -3- (3-chlorophenyl) propionylamino) -2-phenylacetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(4S) -4- ((2S) -2- (2- (3-chloro-5-cyanophenoxy) -3- (3-cyanophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3, 5-dicyanophenoxy) -3- (3-fluorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-cyanophenoxy) -3- (3-fluorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chlorophenoxy) -3- (3-fluorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

and pharmaceutically acceptable salts thereof.

A process for the preparation of a compound of formula (I) as described herein is an object of the present invention.

Synthesis of

A process for the preparation of a compound of formula (I) as described herein is an object of the present invention.

The preparation of the compounds of formula (I) according to the invention can be carried out in a sequential or convergent synthetic route. The synthesis of the present invention is shown in the following general scheme. The techniques required to carry out the reaction and the purification of the resulting product are known to those skilled in the art. Where a mixture of enantiomers or diastereomers is produced during the course of the reaction, these enantiomers or diastereomers may be separated by methods described herein or known to those skilled in the art, such as, for example, chromatography on a chiral column or crystallization. The substituents and symbols used in the following description of the process have the meanings given herein.

The following abbreviations are used in the description of the present invention:

BOC ═ tert-butoxycarbonyl, DBU ═ 2,3,4,6,7,8,9, 10-octahydro-pyrimido [1,2-a ]]Aza, DCE ═ 1, 2-dichloroethane, DCM ═ dichloromethane, DEAD ═ diethyl azodicarboxylate, DIAD ═ diisopropyl azodicarboxylate, DCC ═ N, N ' -dicyclohexylcarbodiimide, DMAP ═ 4-dimethylaminopyridine, DMF ═ N, N-dimethylformamide, EDCI ═ N- (3-dimethylaminopropyl) -N ' -ethylcarbodiimide hydrochloride, eq. ═ eq., (HATU ═ O- (7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate, HPLC ═ high performance liquid chromatography, HOBT 1-hydroxybenzo-triazole, Huenig's base ═ iPr₂NEt ═ N-ethyldiisopropylamine, LAH ═ hydrogenLithium aluminide, PG ═ protecting group, rt ═ room temperature, TBAF ═ tetrabutylammonium fluoride, TBDMS ═ tert-butyldimethylsilyl, TBME ═ tert-butylmethyl ether, TBTU ═ O-benzotriazol-1-yl-N, N' -tetramethyl-uronium tetrafluoroborate, TEA ═ Et₃N-triethylamine, TFA-trifluoroacetic acid, THF-tetrahydrofuran, quant.

The synthesis of compounds of general formula I can be achieved according to scheme 1.α -amino-aldehyde 1, suitably protected (e.g. using BOC-groups), is reacted with Reformatsky reagent derived from ethyl 2-bromo-2, 2-difluoroacetate 2 to provide amino-hydroxy-ester 3 under chelation control (scheme 1, step a). the latter is converted to amide 5 by treatment with the requisite amine 4 at elevated temperature (typically in boiling methanol) (scheme 1, step b). TFA or bis-TFA in DCM, for example, is used in the case of BOC groupsAlkane or diConventional deprotection of anhydrous HCl in a mixture of alkanes and MeOH affords the free amine 6 (scheme 1, step c), which can then be extended with the appropriate appropriately protected (e.g., using a BOC-group) amino acid 7 in an inert solvent such as DMF under standard peptide coupling conditions, e.g., using HATU or TBTU and a suitable base such as Huenig's base or TEA, to provide intermediate 8 (scheme 1, step d). The above deprotection affords amino alcohol 9 (scheme 1, step e), which is ready for coupling again with acid 10 (see below for its synthesis) under standard peptide coupling conditions to afford the penultimate intermediate 11 (scheme 1, step f). Finally, oxidation, for example using Dess martin oxidizer (Dess martinperiodine) in an inert solvent such as DCM or a mixture of DCM and THF as solubilizer yields the final target molecule I. Starting aldehydes 1-in R with racemization tendencies²Or R³One of them is hydrogen-prepared from the corresponding Weinreb amide by reduction with LAH as described in the literature and used immediately in the next step (j.med. chem.1992,35, 4795-.

The building block 10 used in scheme 1 can be synthesized as summarized in scheme 2. an appropriate commercially available grignard reagent 1 is reacted with the epoxy ester 2 in a regioselective and stereoselective manner, typically under copper catalysis (e.g., copper dimethyl sulfide bromide), in an inert solvent such as THF, in a temperature range of-78 ℃ to-20 ℃, to give α -hydroxy ester 3. the latter is treated with phenolic compound 4 to complete the subsequent etherification by treatment in an inert solvent such as THF, in a temperature range of-20 ℃ to room temperature, under typical Mitsunobu conditions (e.g., DIAD or DEAD and triphenylphosphine), the reaction occurs at a complete transition in the case of 10 being used as a pure chiral alcohol, the careful hydrolysis under standard conditions (e.g., LiOH in a mixture of water, MeOH or EtOH and THF) in a temperature range of-20 ℃ to room temperature gives building block 10 without chemical integrity.

At R¹¹Is an optionally substituted alkyl group, it is introduced by classical alkylation with the appropriate halide (preferably iodide) and a base (e.g. NaH and KOtBu) in a polar aprotic solvent such as DMF, acetone or acetonitrile, as shown in scheme 3.

In another embodiment, or if residue R is⁸Containing functional groups incompatible with metal organic reagents, compound 10 in preparation scheme 1 can be as outlined in scheme 4.

An aldehyde or ketone 1 is reacted with a suitable protected Witting-Horner reagent 2 (e.g., as TBDMS-ether) in an inert solvent such as THF or DMF in the presence of a base such as KOtBu or NaH at a temperature in the range of-20 ℃ to room temperature to provide an enol ether 3 as an E/Z-mixture (scheme 4, step a). Hydrogenation at room temperature and atmospheric pressure in a solvent such as EtOH, MeOH or AcOEt under standard conditions (e.g., using 10% Pd on activated carbon) affords intermediate 4 (scheme 4, step b), followed by deprotection to afford the free alcohol 5 (scheme 4, step c). In the case of silyl ethers, TBAF treatment in THF is very suitable. The subsequent etherification is accomplished by treatment with phenolic compound 6 under typical Mitsunobu conditions (e.g., DIAD or DEAD and triphenylphosphine) in an inert solvent such as THF at a temperature range of-20 ℃ to room temperature (scheme 4, step d). The standard hydrolysis described above, e.g. using LiOH in water, MeOH or a mixture of EtOH and THF, at a temperature range of-20 ℃ to room temperature, ultimately yields building block 10 (scheme 4, step e). By using a chiral catalyst in step b, it is in principle also possible to prepare 4,5, 6 and 7 as pure enantiomers by this route.

Furthermore, an embodiment of the present invention is a process for the preparation of a compound of formula (I) as defined above, said process comprising

i) Reacting a compound of formula (III) with a compound of formula (IV)

In particular, in the presence of a base such as diisopropylamine, and in the presence of a coupling agent such as HATU, in a solvent such as DMF, at 0 ℃ to room temperature.

Then the

II) reaction of a compound of the formula (II) under oxidizing conditions

In particular, in the presence of 1,1, 1-triacetoxy-1, 1-dihydro-1, 2-benziodo-3 (1H) -one (dess-martin oxidizer) in a solvent such as DCM at between 0 ℃ and room temperature.

Wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R³、R⁸、R⁹、R¹⁰And R¹¹As defined above.

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

Furthermore, 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 present invention is the use of a compound according to formula (I) as described herein for the treatment or prevention of an eye disease, in particular an HtrA1 mediated eye disease, more particularly wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity or polypoidal choroidal vasculopathy.

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

Furthermore, an object of the present invention is a method for the treatment or prevention of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

Furthermore, an embodiment of the present invention is a compound of formula (I) as described herein, prepared according to any of the methods described herein.

Measurement procedure

Protein purification for enzyme assays

The human HtrA1 protein comprising the catalytic and PDZ domains from amino acids Asp161 to Pro480 was expressed in BL21(DE3) cells as an N-terminal fusion protein with a 6xHis-SUMO tag. The transformed cells were cultured in LB medium at 37 ℃ until the optical density at 600nm was 0.6 to 0.8. Then, the temperature was lowered to 18 ℃ and recombinant protein production was induced by adding IPTG to a final concentration of 250 mM. The fermentation was carried out overnight at 18 ℃.

The following four-step procedure was followed to purify the protein to homogeneity. 40g of cells were suspended in 50mM HEPES pH 7.8, 250mM NaCl, 10mM MgCl2, 0.35% CHAPS, 10% glycerol (containing 20 tablets/l of EDTA-free complete protease inhibitor (Roche) and 30mg/l of DNase and RNase). The cells were disrupted by a single pass through the homogenizer at 750 bar and then centrifuged at 20' 000Xg for 30 minutes. The clear supernatant was applied to a triple 5ml HisTrap column (GE Healthcare) equilibrated in 50mM HEPES pH 7.8, 500mM NaCl, 0.35% CHAPS, 10% glycerol. After washing with increasing concentrations of imidazole (20mM, 40mM, 50mM), the HtrA1 fusion protein was eluted in a linear gradient of 10 to 100% of the same buffer containing 500mM imidazole. The HtrA1 containing fractions were pooled, concentrated, and applied to a Superdex S200 preparative (XK 26/100-GE Healthcare) column equilibrated in 50mM ethanolamine pH9.6, 500mM NaCl, 0.35% CHAPS, 10% glycerol, 0.02% sodium azide. To fragment the SUMO fusion protein and release active HtrA1, pooled fractions from size exclusion chromatography were mixed with SUMO protease (Life Technologies) and incubated at room temperature for about 20 hours. HtrA1 was isolated from the reaction solution by chromatography on a Superdex S200 preparative (XK 26/100-GE Healthcare) column equilibrated with 50mM ethanolamine pH9.6, 500mM NaCl, 0.35% CHAPS, 10% glycerol, 0.02% sodium azide. Fractions containing active HtrA1 were pooled and concentrated. Following the above strategy, 150mg of HtrA1 (catalytic domain/PDZ construct) can be purified. As shown by RP-HPLC and SDS-PAGE, > 98% pure protein was obtained.

HtrA1 enzyme inhibition assay

The enzyme activity was measured by observing the increase in fluorescence intensity caused by cleavage of the fluorophore-containing peptide substrate, the emission of which was quenched in the intact peptide.

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

Enzyme: human HtrA1Cat-PDZ at a final concentration of 1nM

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

Mca ═ 7-methoxycoumarin-4-yl) acetyl

Dnp ═ 2, 4-dinitrophenyl

Final volume: 51 μ l

Excitation at 320nm and emission at 390nm

After 30min preincubation of HtrA1 protease with compound, substrate was added to the wells and initial RFU was measured. After 2 hours incubation at room temperature, the substrate is cleaved by the enzyme activity, releasing the fluorescent Mca-peptide conjugate, and the final RFU value is measured. The presence of inhibitors leads to a reduction in the final RFU.

For analysis, Δ RFU was calculated as RFU_{Final (a Chinese character of 'gan')}-RFU_{Starting point}Percent inhibition was then calculated using the formula:

PCT _ inhibition 100-_{Compound (I)}-ΔRFU_{Blank space})/(ΔRFU_{Negative control}-ΔRFU_{Blank space})

Wherein

Negative controls were protease with substrate and DMSO

Blank is a negative control without protease

The compound is a negative control plus a desired concentration of test compound

Determination of IC Using a 4-Point Hill-fitting equation₅₀Wherein

x ═ concentration of test compound

A-extrapolated value of the curve at an effector concentration equal to 0

B-extrapolated value of the curve where the effector concentration equals infinity

Concentration of C ═ S curve at bending point (IC)₅₀)

D is the Hill coefficient of the slope at the bend point of the fitted curve

As a counter screen, compounds were added to the protease-substrate reaction mixture only after 2h incubation when all substrates were turned over to determine the autofluorescent or absorbing compounds that gave false positive hits.

Compounds of formula (I) and pharmaceutically acceptable salts or esters thereof as described herein have an IC of from 0.00001 μ M to 1000 μ M₅₀Values, particular compounds have an IC of 0.0001. mu.M to 500. mu.M₅₀Values, additional particular compounds have an IC of 0.0001. mu.M to 50. mu.M₅₀Values, more particular compounds have an IC of 0.0001. mu.M to 5. mu.M₅₀The value is obtained. These results have passedObtained using the enzyme 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 (for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (for example in the form of nasal sprays), rectally (for example in the form of suppositories) or topically ocularly (for example in the form of solutions, ointments, gels or water-soluble polymer inserts). However, administration can also be effected parenterally, such as intramuscularly, intravenously or intraocularly (e.g., in the form of sterile injectable solutions).

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

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

Suitable auxiliaries for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

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 and the like.

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

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

The dosage can vary within wide limits and will of course be adapted to the individual requirements in each particular case. In general, in the case of oral administration, the following should be appropriate: a daily dose of about 0.1mg to 20mg/kg body weight, preferably about 0.5mg to 4mg/kg body weight (e.g. about 300 mg/person), is divided into preferably 1-3 individual doses, which may for example consist of the same amount. In the case of topical administration, the formulation may contain from 0.001% to 15% by weight of the drug, and the required dose (which may be from 0.1 to 25mg) may be administered in a single dose per day or week, or in multiple doses per day (2 to 4), or in multiple doses per week. In the case of parenteral administration (e.g., intramuscular, intravenous or intraocular), the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be 0.01 to 25mg, may be administered in a single dose daily, weekly or monthly, or in multiple doses daily (2 to 4), or in multiple doses weekly or monthly. It is clear, however, that the upper or lower limits given herein may be exceeded when this appears to be necessary.

The present invention is illustrated below by examples, which are not intended to be limiting.

In the case of the preparation examples obtained as mixtures of enantiomers, the pure enantiomers can be obtained by the methods described herein or known to the person skilled in the art, such as, for example, chiral chromatography or crystallization.

Examples

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

Abbreviations: aq. is aqueous; CAS-RN ═ Chemical abstracts service registry Number (Chemical abstracts service registry Number); HPLC ═ high performance liquid chromatography; MS ═ mass spectrum; sat.

Examples

Intermediate Ia

(3R,4S) -4-amino-2, 2-difluoro-3-hydroxy-5-methyl-N- (2,2, 2-trifluoroethyl) hexanamide

A ] (S) - (3-methyl-1-oxobutan-2-yl) carbamic acid tert-butyl ester

To a solution of commercially available tert-butyl (S) - (1- (methoxy (methyl) amino) -3-methyl-1-oxobutan-2-yl) carbamate (3g, 11.5mmol, eq: 1) in THF (100ml) was added LiAlH in THF dropwise at 0 ℃ under argon over 3min₄1M (11.5ml, 11.5mmol, eq: 1) (0->At 4 ℃ C. After stirring for 20min while cooling, the reaction mixture was taken up in 1N KHSO₄The solution was quenched and extracted with EtOAc; the layers were separated and the aqueous layer was re-extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Dried and concentrated in vacuo to give the title compound as a colourless liquid, 2.38g, which was used directly in the next step.

B ] (3R,4S) -4-amino-2, 2-difluoro-3-hydroxy-5-methylhexanoic acid ethyl ester

A solution of tert-butyl (S) - (3-methyl-1-oxobutan-2-yl) carbamate (2.01g, 9.99mmol, eq: 1) and ethyl 2-bromo-2, 2-difluoroacetate (6.08g, 3.84ml, 30mmol, eq: 3) in THF (15ml) prepared above was added dropwise to a suspension of active zinc (1.96g, 30mmol, eq: 3) in THF (65 ml). ThereafterThe reaction was refluxed for 2 hours. The heat source was removed and the reaction was allowed to cool to ambient temperature. The reaction mixture was poured into 15mL of 1N KHSO₄Medium and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine and Na₂SO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120g, 20% EtOAc in heptane) to give 1.41g of the title compound as a colorless oil.

C ] N- [ (3S,4R) -5, 5-difluoro-4-hydroxy-2-methyl-6-oxo-6- (2,2, 2-trifluoroethylamino) hex-3-yl ] carbamic acid tert-butyl ester

A mixture of ethyl (3R,4S) -4-amino-2, 2-difluoro-3-hydroxy-5-methylhexanoate (191.4mg, 588. mu. mol, eq: 1), 3,3, 3-trifluoropropan-1-amine (333mg, 2.94mmol, eq: 5) and N, N-diisopropylethylamine (380mg, 514. mu.l, 2.94mmol, eq: 5) prepared above was refluxed in 5mL of MeOH overnight. TLC after 17 hours showed the reaction was complete. The reaction volume was reduced in vacuo and EtOAc was added to the residue. The organic layer was washed with brine (3 ×), washed with Na₂SO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20g, 15% to 50% EtOAc in heptane) to yield 180mg of the title compound as a 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 25mL round-bottom flask, N- [ (3S,4R) -5, 5-difluoro-4-hydroxy-2-methyl-6-oxo-6- (2,2, 2-trifluoroethylamino) hex-3-yl prepared above was placed]Tert-butyl carbamate (177mg, 451. mu. mol, eq: 1) and 1, 4-bisAlkanes (6ml) were combined to give a colorless solution.

Adding at 0 deg.CHCl 4M in alkane (2.25ml, 9mmol, eq: 20) and the reaction mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo and carefully dried under high vacuum (hv) and then used directly in the next step (calculated as dihydrochloride).

Intermediate Ib

(3R,4S) -4-amino-2, 2-difluoro-3-hydroxy-5-methyl-N- (2-morpholin-4-ylethyl) hexanamide

Preparation was carried out analogously to intermediate Ia, but using 2-morpholin-4-ylethylamine instead of 3,3, 3-trifluoropropan-1-amine in step C ], as a pale yellow foam.

Intermediate IIa

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

A ] tert-butyl N- [ (1S) -2- [ [ (3S,4R) -5, 5-difluoro-4-hydroxy-2-methyl-6-oxo-6- (2,2, 2-trifluoroethylamino) hex-3-yl ] amino ] -2-oxo-1-phenylethyl ] carbamate

In a 25ml flask, (3R,4S) -4-amino-2, 2-difluoro-3-hydroxy-5-methyl-N- (2,2, 2-trifluoroethyl) hexanamide dihydrochloride [0.3M in DMF](intermediate Ia, 1.33ml, 398. mu. mol, eq: 1), (S) -2- ((tert-butoxycarbonyl) amino) -2-phenylacetic acid (0.100g, 398. mu. mol, eq: 1) and HATU (166mg, 438. mu. mol, eq: 1.1) were combined in DMF (4 ml). Hunig's base (257mg, 348. mu.l, 1.99mmol, eq: 5) was then added and the reaction mixture was stirred at room temperature for 2 h. It was diluted with EtOAc and poured into 1M KHSO₄And the aqueous layer was extracted with EtOAc (2 × 20 ml). The combined organic layers were washed with NaHCO₃Washed with brine and Na₂SO₄Dried and evaporated. Purification by flash chromatography (silica gel, 20g, 20% to 100% EtOAc in heptane) yielded 124mg of the title compound as a yellow foam; MS: 512.2(M + H)⁺。

B ] (3R,4S) -4- [ [ (2S) -2-amino-2-phenylacetyl ] amino ] -2, 2-difluoro-3-hydroxy-5-methyl-N- (2,2, 2-trifluoroethyl) hexanamide

To the N- [ (1S) -2- [ [ (3S,4R) -5, 5-difluoro-4-hydroxy-2-methyl-6-oxo-6- (2,2, 2-trifluoroethylamino) hex-3-yl group prepared above]Amino group]-2-oxo-1-phenylethyl]To a solution of tert-butyl carbamate (0.120g, 235. mu. mol, eq: 1) in MeOH (3ml) was added di-tert-butyl carbamateHCl 4M in alkane (293. mu.l, 1.17mmol, eq: 5); the reaction mixture was stirred at room temperature for 2 hours and at 40 ℃ for 2 hours. LC-MS indicated the reaction was complete. The solvent was carefully evaporated to dryness, leaving 119mg of the title compound as the hydrochloride salt, a light purple foam, which was used directly in the next step; MS: 412.2(M + H)⁺. The reaction may also be carried out only on the second stage instead of using MeOHIn an alkane.

Very analogously, the preparation was carried out in step a ] using (2S) -2- (4-methoxyphenyl) -2- [ (2-methylprop-2-yl) oxycarbonylamino ] acetic acid:

intermediate IIb

(3R,4S) -4- [ [ (2S) -2-amino-2- (4-methoxyphenyl) acetyl ] amino ] -2, 2-difluoro-3-hydroxy-5-methyl-N- (2,2, 2-trifluoroethyl) hexanamide

It is the hydrochloride salt, a yellow oil; MS: 442.2(M + H)⁺。

Very analogously, the preparation was carried out in step A ] using (2S) -2- [ (2-methylprop-2-yl) oxycarbonylamino ] -3-phenylpropionic acid:

intermediate IIc

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

It is the hydrochloride salt, a light yellow foam; MS: 426.2(M + H)⁺。

Very analogously, preparation was carried out in step a ] using (3R,4S) -4-amino-2, 2-difluoro-3-hydroxy-5-methyl-N- (2-morpholin-4-ylethyl) hexanamide:

intermediate IId

(3R,4S) -4- [ [ (2S) -2-amino-2-phenylacetyl ] amino ] -2, 2-difluoro-3-hydroxy-5-methyl-N- (2-morpholin-4-ylethyl) hexanamide

It is the hydrochloride salt, a light yellow foam; MS: 443.3(M + H)⁺。

Intermediate IIIa

(2R) -2- (3, 5-Dichlorophenoxy) -3-phenylpropionic acid

A ] (2R) -2- (3, 5-Dichlorophenoxy) -3-phenylpropionic acid methyl ester

Commercially available methyl (S) -2-hydroxy-3-phenylpropionate (500mg, 2.77mmol, eq: 1) and 3, 5-dichlorophenol (475mg, 2.91mmol, eq: 1.05) were combined with THF (11.1mL) in a 50mL pear-shaped flask at-10 ℃ to give a light brown solution; subsequently triphenylphosphine (946mg, 3.61mmol, eq: 1.3) and DIAD (729mg, 3.61mmol, eq: 1.3) were added and stirring was continued for 1h, TLC indicated that the starting alcohol had disappeared; the reaction mixture was quenched with 0.5N HCl, diluted with AcOEt, the organic layer was separated, washed with cold water, and Na₂SO₄Dried and evaporated to dryness; the crude product was purified by column chromatography SiO2(50g, heptane/AcOEt ═ 7/1) to give 610mg of the title compound as a light yellow solid; MS: 323.027(M-H)^-。

B ] (2R) -2- (3, 5-Dichlorophenoxy) -3-phenylpropionic acid

In a 50mL pear-shaped flask, the mixture is stirredMethyl (R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionate prepared above (609mg, 1.87mmol, eq: 1) was combined with THF (2.08mL) and MeOH (2.08mL) to give an off-white suspension; after cooling to-10 ℃, lithium hydroxide (89.7mg, 3.75mmol, eq: 2) and 1.04mL of water were added and the heterogeneous mixture was stirred at the same temperature; after 3h, TLC still indicated that some starting material was added an additional 3mL of THF for dissolution, and the reaction mixture was warmed to 0 ℃; after a further 30 minutes, the mixture was quenched with dilute HCl, extracted with AcOEt, and the organic layer was washed with water, washed with Na₂SO₄Dried and evaporated to dryness; after careful high vacuum drying (HV-drying), 595mg of the title compound are thus obtained as white crystals; MS: 309.1(M-H)^-。

Intermediate IIIb

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

A ] (2S) -3- (3-chlorophenyl) -2-hydroxypropionic acid methyl ester

In a 100mL four-necked flask, commercially available methyl (S) -oxirane-2-carboxylate (400mg, 343. mu.L, 3.92mmol, eq: 1) and copper dimethyl sulfide bromide (201mg, 980. mu. mol, eq: 0.25) were combined with anhydrous THF (25mL) to give a light brown suspension; after cooling to-35 deg.C, (3-chlorophenyl) magnesium bromide (1M in THF, 7.84ml, 7.84mmol, eq: 2) was added slowly via syringe over 15 minutes (slightly exothermic, keeping the temperature below-33 deg.C) and then allowed to warm to-25 deg.C; the reaction was carried out at-20 ℃ with saturated NH₄Quench with Cl solution, extract with AcOEt, wash with water, Na₂SO₄Dried and evaporated to dryness; by means of a rapid columnPurification of the chromatography (50g SiO2, heptane/AcOEt ═ 2/1) gave 615mg of the title compound as a colourless oil.

B ] (2R) -3- (3-chlorophenyl) -2- (3, 5-dichlorophenoxy) propionic acid methyl ester

In a 50mL pear-shaped flask, methyl (S) -3- (3-chlorophenyl) -2-hydroxypropionate (611mg, 2.85mmol, equivalent: 1) prepared above and 3, 5-dichlorophenol (487mg, 2.99mmol, equivalent: 1.05) were combined with THF (11.4mL) at-10 ℃ to give an off-white solution; triphenylphosphine (971mg, 3.7mmol, eq: 1.3) and DIAD (748mg, 726. mu.l, 3.7mmol, eq: 1.3) were then added and stirring was continued for 3/4h, TLC indicated that the starting alcohol had disappeared almost quantitatively; after 1.25h, the reaction mixture was quenched with 0.5N HCl, diluted with AcOEt, the organic layer was separated, washed with dilute brine, washed with Na₂SO₄Dried and evaporated to dryness; purification by column chromatography of SiO2(50g, heptane/AcOEt ═ 7/1) gave 767mg of the title compound finally as a light yellow oil.

C ] (2R) -3- (3-chlorophenyl) -2- (3, 5-dichlorophenoxy) propionic acid

In a 75mL pear-shaped flask, methyl (R) -3- (3-chlorophenyl) -2- (3, 5-dichlorophenoxy) propionate prepared above (763mg, 2.12mmol, eq: 1) was combined with THF (5mL) and MeOH (2mL) to give an off-white solution; after cooling to 0 ℃, lithium hydroxide (127mg, 5.3mmol, equiv: 2.5) and 1mL of water were added and the mixture was stirred for 1.5h, TLC indicated only trace amounts of starting material (if any) remained; after a further 30 minutes, the hydrolysis was quenched with dilute HCl, extracted with AcOEt, and the combined organic layers were washed with water, washed with Na₂SO₄Dried and evaporated to dryness; is based on heptane/5AcOEt crystallization gave 668mg of the title acid as white crystals; MS: 343.2(M-H)^-。

Preparation very similar to intermediate IIIb

Intermediate IIIc

(2R) -2- (3-chloro-5-methylphenoxy) -3- (3-chlorophenyl) propionic acid

But in step B]3-chloro-5-methylphenol is used to replace 3, 5-dichlorophenol, and the obtained product is white crystal; MS: 323.2(M-H)^-。

Intermediate IIId

(2R) -2- (3-chlorophenoxy) -3- (3, 4-dichlorophenyl) propionic acid

But in step A]In which (3, 4-dichlorophenyl) magnesium bromide is used instead of (3-chlorophenyl) -magnesium bromide, and in step B]3-chlorophenol is used for replacing 3, 5-dichlorophenol, and the dichlorophenol is white crystals; MS: 343.1(M-H)^-。

Intermediate IIIe

(2R) -3- (3-chlorophenyl) -2- (3, 5-dicyano-phenoxy) propionic acid

But in step B]In the method, 5-hydroxybenzene-1, 3-dicyan is used for replacing 3, 5-dichlorophenol, and the white solid is obtained; MS: 325.2(M-H)^-。

Intermediate IIIf

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

But in step B]In the method, 5-chloropyridine-3-alcohol is used for replacing 3, 5-dichlorophenol, and the mixture is white foam; MS: 310.2(M-H)^-。

Intermediate IIIg

(2R) -2- (3-chlorophenoxy) -3- (3, 5-dichlorophenyl) propionic acid

But in step A]In which (3, 5-dichlorophenyl) magnesium bromide is used instead of (3-chlorophenyl) -magnesium bromide, and in step B]3-chlorophenol is used to replace 3, 5-dichlorophenol, which is yellow semisolid; MS: 343.2(M-H)^-。

Intermediate IIIh

(2S) -2- (3-chlorophenoxy) -3- (3, 5-dichlorophenyl) propionic acid

But using in step a ] methyl (R) -oxirane-2-carboxylate instead of methyl (S) -oxirane-2-carboxylate and (3, 5-dichlorophenyl) magnesium bromide instead of (3-chlorophenyl) -magnesium bromide, respectively, and in step B ] 3-chlorophenol instead of 3, 5-dichlorophenol, which is a white solid; MS: 343.2(M-H) -.

Intermediate IIIi

(2R) -2- (3-chloro-5-cyanophenoxy) -3- (3-chlorophenyl) propanoic acid

But using 3-chloro-5-hydroxybenzonitrile instead of 3, 5-dichlorophenol in step B ], as a colorless oil; MS: 334.1(M-H) -.

Intermediate IIIj

(rac) -2- (3-chloro-5-cyanophenoxy) -3- (3-cyanophenyl) propionic acid

A ] (E, Z) -2- [ tert-butyl (dimethyl) silyl ] oxy-3- (3-cyanophenyl) prop-2-enoic acid methyl ester

In a 25mL three-necked flask, (rac) -2- ((tert-butyldimethylsilyl) oxy) -2- (dimethoxyphosphoryl) -acetic acid methyl ester (CAS registry number 78186-95-5, 498mg, 1.59mmol, equivalent: 1.1) was combined with THF (10mL) to give a colorless solution; potassium tert-butoxide (171mg, 1.52mmol, eq: 1.05) was added at-10 ℃ and the reaction mixture was stirred at this temperature for 1 hour, then at 0 ℃ for 1 hour to complete deprotonation. The resulting solution was cooled again to-10 ℃ and a solution of 3-formylbenzonitrile (190mg, 1.45mmol, eq: 1) in THF (5ml) was added. The reaction was allowed to proceed at-5 ℃ for 30 minutes, with 10ml of saturated NH₄The Cl solution was quenched and extracted with AcOEt (2 ×). The organic layers were washed with brine, combined and washed with Na₂SO₄Dried and concentrated in vacuo. Purification by flash chromatography (silica gel, 50g, 5% to 40% EtOAc in heptane) afforded finally 381mg of the title compound as a colorless liquid (approx. 1: 1E/Z-mixture); MS: 202.1(M-tBDMS) -.

B ] (rac) -methyl 2- [ tert-butyl (dimethyl) silyl ] oxy-3- (3-cyanophenyl) propanoate

To a solution of (rac) -2- ((tert-butyldimethylsilyl) oxy) -3- (3-cyanophenyl) -acrylic acid methyl ester prepared above (378mg, 1.19mmol, eq: 1) in EtOAc (30ml) was added Pd-C10% (100mg, 94 μmol, eq: 0.079) under argon and the mixture was stirred at ambient temperature under a hydrogen atmosphere. TLC after 4h showed the reaction was complete. The mixture was filtered through a pad of celite, carefully washed with AcOEt, and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50g, 5% to 20% EtOAc in heptane) to give 192mg of the title compound as a colorless liquid; in addition, 54mg of methyl 2- [ tert-butyl (dimethyl) silyl ] oxy-3- (3-methylphenyl) propionate was isolated as a by-product.

C ] (rac) -3- (3-cyanophenyl) -2-hydroxypropanoic acid methyl ester

In a 10mL round-bottom flask, methyl (rac) -2- ((tert-butyldimethylsilyl) -oxy) -3- (3-cyanophenyl) propanoate prepared above (186mg, 582. mu. mol, eq: 1) was combined with THF (6mL) to give a colorless solution. TBAF 1M (1.16ml, 1.16mmol, eq: 2) in THF was added at 0 deg.C and the yellow solution was stirred at 0 deg.C for 45 min, TLC showed the reaction was complete. The reaction mixture was washed with saturated NH₄The Cl solution was quenched and extracted with EtOAc (2 × 25 mL). The organic layers were combined and washed with Na₂SO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20g, 50% EtOAc in heptane) to give 121mg of the title alcohol as a colorless liquid.

D ] (rac) -2- (3-chloro-5-cyanophenoxy) -3- (3-cyanophenyl) propionic acid methyl ester

To a mixture of methyl (rac) -3- (3-cyanophenyl) -2-hydroxypropionate prepared above (115mg, 560. mu. mol, eq: 1) and 3-chloro-5-hydroxybenzonitrile (90.4mg, 588. mu. mol, eq: 1.05) in DCM (5ml) was added triphenylphosphine (191mg, 729. mu. mol, eq: 1.3) and DIAD (147mg, 142. mu.l, 729. mu. mol, eq: 1.3) at-10 ℃ and the reaction was allowed to proceed for 1 hour at 0 ℃. The mixture was washed with saturated NH₄Cl and ice were quenched and extracted with DCM (2 × 25 mL). The organic layers were washed with brine, combined and washed with Na₂SO₄Dried and concentrated in vacuo. Finally, the crude material was purified by flash chromatography (silica gel, 20g, 25% EtOAc in heptane) to give 111mg of the title compound as a colorless oil.

E ] (rac) -2- (3-chloro-5-cyanophenoxy) -3- (3-cyanophenyl) propionic acid

In a 10mL round bottom flask, methyl (rac) -2- (3-chloro-5-cyanophenoxy) -3- (3-cyanophenyl) propanoate (103mg, 302. mu. mol, eq: 1) prepared above was combined with THF (1mL) and MeOH (0.5mL) to give a colorless solution. LiOH 1M (363. mu.l, 363. mu. mol, equivalent: 1.2) was added at 0 ℃ and the reaction mixture was stirred at the same temperature. LC-MS after 1h showed completion of hydrolysis. The reaction mixture is diluted with KHSO₄The solution and ice were quenched, extracted with AcOEt (2 ×), the organic layer washed with brine and dried (Na)₂SO₄) And concentrated in vacuo to leave 98mg of the title compound as a white semi-solid after careful high vacuum drying; MS: 325.2(M-H)^-。

Preparation very similar to intermediate IIIb

Intermediate IIIk

(2R) -2- (3, 5-dicyano-phenoxy) -3- (3-fluorophenyl) propionic acid

But in step A]Using (3-fluorophenyl) magnesium bromide instead of (3-chlorophenyl) -magnesium bromide, and in step B]In the method, 5-hydroxy isophthalonitrile is used for replacing 3, 5-dichlorophenol, and the isophthalonitrile is white solid; MS: 309.1(M-H)^-。

Intermediate IIIl

(2R) -2- (3-cyanophenoxy) -3- (3-fluorophenyl) propionic acid

But in step A]Using (3-fluorophenyl) magnesium bromide instead of (3-chlorophenyl) -magnesium bromide, and in step B]In the method, 3-hydroxybenzonitrile is used for replacing 3, 5-dichlorophenol, and the white solid is obtained; MS: 284.1(M-H)^-。

Intermediate IIIm

(2R) -2- (3-chlorophenoxy) -3- (3-fluorophenyl) propionic acid

But in step A]Using (3-fluorophenyl) magnesium bromide instead of (3-chlorophenyl) -magnesium bromide, and in step B]3-chlorophenol is used to replace 3, 5-dichlorophenol, which is white solid; MS: 293.1(M-H)^-。

Example 1

(4S) -4- [ [ (2S) -2- [ [ (2R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionyl ] amino ] -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide

A ] (3R,4S) -4- [ [ (2S) -2- [ [ (2R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionyl ] amino ] -2, 2-difluoro-3-hydroxy-5-methyl-N- (2,2, 2-trifluoroethyl) hexanamide

(R) -2- (3, 5-Dichlorophenoxy) -3-phenylpropionic acid (intermediate IIIa, 50mg, 161. mu. mol, eq: 1) and Hunig's base (104mg, 140. mu.l, 803. mu. mol, eq: 5) were combined with DMF (4mL) in a 10mL round bottom flask to give a colorless solution; (4S) -4- ((S) -2-amino-3-phenylpropionylamino) -2, 2-difluoro-3-hydroxy-5-methyl-N- (2,2, 2-trifluoroethyl) hexanamide hydrochloride (intermediate IIc, 74.2mg, 161. mu. mol, eq: 1) and HATU (73.3mg, 193. mu. mol, eq: 1.2) (->Yellow solution) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then poured into saturated NaHCO₃In solution, and extracted with EtOAc (2 ×). Subjecting the organic layer to 1N KHSO₄Washing with brine, mixing, and adding Na₂SO₄Dried and evaporated in vacuo. The crude material was purified by flash chromatography (silica gel, 20g, 10% to 60% EtOAc in heptane) to give 67mg of the title compound as a white foam; 718.2(M + H)⁺。

B ] (4S) -4- [ [ (2S) -2- [ [ (2R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionyl ] amino ] -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide

In a 10mL round bottom flask, (4S) -4- ((S) -2- ((R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionylamino) -2, 2-difluoro-3-hydroxy-5-methyl-N- (2,2, 2-trifluoroethyl) hexanamide (63.4mg, 88.2 μmol, equivalent: 1) prepared above was combined with DCM (4mL) to give a colorless solution. 15% (374mg, 275. mu.l, 132. mu. mol, equiv: 1.5) of dessimutane oxidant (periodinane) in dichloromethane was added at 0 ℃ and the reaction mixture was stirred at room temperature for 2h, TLC indicated completion of the reaction. The reaction mixture was poured into saturated NaHCO₃In solution and extracted with DCM (2 ×). The organic layers were washed with brine, combined and washed with Na₂SO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10g, 33.3% EtOAc in heptane) to give 38.5mg of the title product as a white solid; MS:716.2(M + H)⁺。

The preparation is carried out very analogously to example 1, using the appropriate intermediates indicated in the table below:

example A

The compounds of formula (I) can be used in a manner known per se as active ingredients for the preparation of tablets of the following compositions:

each tablet

Example B

The compounds of formula (I) can be used in a manner known per se as active ingredients for the preparation of capsules of the following compositions:

per capsule

Claims (34)

1. A compound of the formula (I),

wherein

R¹Is selected from

i)C_1-6-an alkyl group,

ii) by R²⁴、R²⁵And R²⁶Substituted C_3-8-a cycloalkyl group,

iii) halo-C_1-6-an alkyl group,

iv) by R²⁴、R²⁵And R²⁶Substituted heterocycloalkyl-C_1-6-an alkyl group,

v) by R²⁴、R²⁵And R²⁶Substituted aryl-C_1-6-alkyl, and

vi) by R²⁴、R²⁵And R²⁶Substituted heteroaryl-C_1-6-an alkyl group;

R²、R³、R⁴、R⁶、R⁷、R⁹、R¹⁰and R²³Is independently selected from

i)H，

ii)C_1-6-alkyl, and

iii)C_3-8-a cycloalkyl group;

R⁵is selected from

i) By R¹²、R¹³And R¹⁴A substituted aryl group,

ii) by R¹²、R¹³And R¹⁴Substituted aryl-C_1-6-an alkyl group,

iii) by R¹²、R¹³And R¹⁴Substituted heteroaryl, and

iv) by R¹²、R¹³And R¹⁴Substituted heteroaryl-C_1-6-an alkyl group;

R⁸is selected from

i)H，

i) A hydroxyl group(s),

ii) amino-C substituted on the nitrogen atom by one or two substituents selected from_1-6-an alkyl group: H. c_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted by R¹⁵、R¹⁶And R¹⁷The substitution is carried out by the following steps,

iii) aminocarbonyl substituted on the nitrogen atom by one or two substituents selected from: H. c_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted by R¹⁵、R¹⁶And R¹⁷The substitution is carried out by the following steps,

iv) aminocarbonyl-C substituted on the nitrogen atom by one or two substituents selected from_1-6-an alkyl group: H. c_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted by R¹⁵、R¹⁶And R¹⁷The substitution is carried out by the following steps,

v) a carboxyl group, and (c) a carboxyl group,

vi) carboxy-C_1-6-an alkyl group,

vii)C_1-6-an alkoxy group,

viii)C_1-6-a halogenated alkoxy group,

ix)C_1-6-an alkoxycarbonyl group, a carbonyl group,

x)C_1-6-alkoxycarbonyl-C_1-6-an alkyl group,

xi)C_3-8-a cycloalkyl group,

xii) by R¹⁵、R¹⁶And R¹⁷A substituted aryl group,

xiii) by R¹⁵、R¹⁶And R¹⁷Substituted aryl-C_1-6-an alkyl group,

xiv) by R¹⁵、R¹⁶And R¹⁷Substituted aryl-C_1-6-an alkoxy group,

xv) by R¹⁵、R¹⁶And R¹⁷(ii) a substituted heteroaryl group, wherein,

xvi) by R¹⁵、R¹⁶And R¹⁷Substituted heteroaryl-C_1-6-alkyl, and

xvii) is substituted by R¹⁵、R¹⁶And R¹⁷Substituted heteroaryl-C_1-6-an alkoxy group,

xviii) by R¹⁵、R¹⁶And R¹⁷A substituted heterocycloalkyl group,

xix) by R¹⁵、R¹⁶And R¹⁷Substituted heterocycloalkyl-C_1-6-alkyl, and

xx) by R¹⁵、R¹⁶And R¹⁷Substituted heterocycloalkyl-C_1-6-an alkoxy group;

R¹¹is selected from

i) At the nitrogen atom by R²¹And R²²Substituted amino-C_1-6-an alkyl group,

i) by R¹⁸、R¹⁹And R²⁰Substituted C_3-8-a cycloalkyl group,

ii) by R¹⁸、R¹⁹And R²⁰Substituted C_3-8-cycloalkyl-C_1-6-an alkyl group,

iii) by R¹⁸、R¹⁹And R²⁰Substituted C_3-8-cycloalkyl (halo) -C_1-6-an alkyl group,

iv) by R¹⁸、R¹⁹And R²⁰A substituted aryl group,

v) by R¹⁸、R¹⁹And R²⁰Substituted aryl-C_1-6-an alkyl group,

vi) by R¹⁸、R¹⁹And R²⁰Substituted aryl-C_3-8-a cycloalkyl group,

vii) is substituted by R¹⁸、R¹⁹And R²⁰A substituted aryl-heterocycloalkyl group,

viii) is substituted by R¹⁸、R¹⁹And R²⁰Substituted aryl (halo) -C_1-6-an alkyl group,

ix) by R¹⁸、R¹⁹And R²⁰Substituted aryl (halo) -C_3-8-a cycloalkyl group,

x) by R¹⁸、R¹⁹And R²⁰Substituted aryl (halo) -heterocycloalkyl,

xi) is R¹⁸、R¹⁹And R²⁰Substituted aryloxy-C_1-6-an alkyl group,

xii) by R¹⁸、R¹⁹And R²⁰Substituted aryloxy-C_3-8-a cycloalkyl group,

xiii) by R¹⁸、R¹⁹And R²⁰A substituted aryloxy-heterocycloalkyl group having a substituted aryloxy group,

xiv) by R¹⁸、R¹⁹And R²⁰Substituted aryloxy (halo) -C_3-8-a cycloalkyl group,

xv) by R¹⁸、R¹⁹And R²⁰SubstitutionAryloxy (halo) -heterocycloalkyl of (a),

xvi) aryloxy (halo) -C_1-6-an alkyl group,

xvii) is substituted by R¹⁸、R¹⁹And R²⁰A substituted heterocycloalkyl group,

xviii) by R¹⁸、R¹⁹And R²⁰Substituted heterocycloalkyl-C_1-6-an alkyl group,

xix) by R¹⁸、R¹⁹And R²⁰Substituted heterocycloalkyl-C_3-8-a cycloalkyl group,

xx) by R¹⁸、R¹⁹And R²⁰Substituted heterocycloalkyl (halo) -C_3-8-a cycloalkyl group,

xxi) by R¹⁸、R¹⁹And R²⁰Substituted heterocycloalkyl (halo) -C_1-6-an alkyl group,

xxii) by R¹⁸、R¹⁹And R²⁰(ii) a substituted heteroaryl group, wherein,

xxiii) by R¹⁸、R¹⁹And R²⁰Substituted heteroaryl-C_1-6-an alkyl group,

xxiv) is substituted by R¹⁸、R¹⁹And R²⁰Substituted heteroaryl-C_3-8-a cycloalkyl group,

xxv) is substituted by R¹⁸、R¹⁹And R²⁰Substituted heteroaryl (halo) -C_3-8-a cycloalkyl group,

xxvi) is substituted by R¹⁸、R¹⁹And R²⁰Substituted heteroaryl (halo) -C_1-6-an alkyl group,

xxvii) is substituted by R¹⁸、R¹⁹And R²⁰Substituted heteroaryloxy-C_1-6-an alkyl group,

xxviii) by R¹⁸、R¹⁹And R²⁰Substituted heteroaryloxy-C_3-8-a cycloalkyl group,

xxix) by R¹⁸、R¹⁹And R²⁰Substituted heteroaryloxy (halo) -C_3-8-a cycloalkyl group, and

xxx) by R¹⁸、R¹⁹And R²⁰Substituted heteroaryloxy (halo) -C_1-6-an alkyl group;

R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²⁴、R²⁵and R²⁶Is independently selected from

i)H，

i) The cyano group(s),

ii) a halogen, in the presence of a halogen,

iii) an oxo group, in the presence of a nitrogen atom,

iv)C_1-6-an alkyl group,

v) amino substituted on the nitrogen atom with two substituents independently selected from: H. c_1-6Alkyl radical, C_1-6Alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl,

vi) amino-C substituted on the nitrogen atom with two substituents independently selected from_1-6-an alkyl group: H. c_1-6Alkyl radical, C_1-6Alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl,

vii)C_1-6-an alkyl group,

viii) halo-C_1-6-an alkyl group,

ix)C_3-8-a cycloalkyl group,

x)C_1-6-alkoxycarbonyl-C_1-6-an alkyl group,

xi) carboxy-C_1-6-an alkyl group,

xii)C_1-6-alkoxycarbonyl-C_1-6alkylaminocarbonyl-C_1-6An alkyl group, a carboxyl group,

xiii) carboxy-C_1-6-alkylaminocarbonyl-C_1-6An alkyl group, a carboxyl group,

xiv)C_1-6-an alkoxy group,

xv) halo-C_1-6-an alkoxy group,

xvi)C_1-6-alkoxycarbonyl-C_1-6-an alkoxy group,

xvii) carboxy-C_1-6-an alkoxy group,

xviii)C_1-6alkoxycarbonyl-C_1-6alkylaminocarbonyl-C_1-6Alkoxy, and

xix) carboxy-C_1-6alkylaminocarbonyl-C_1-6An alkoxy group;

xx) heterocycloalkyl;

R²¹and R²²Is independently selected from

i)H，

ii)C_1-6-an alkoxycarbonyl group, a carbonyl group,

iii) carboxy-C_1-6-an alkyl group,

iv) arylcarbonyl, and

v) a heteroarylcarbonyl group;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein

R¹Is selected from

i)C_1-6-alkyl, and

ii) by R²⁴、R²⁵And R²⁶Substituted heterocycloalkyl-C_1-6-an alkyl group;

R²is C_1-6-an alkyl group;

R³、R⁴、R⁶、R⁷、R⁹and R¹⁰Is H;

R⁵is selected from;

i) by R¹²、R¹³And R¹⁴Substituted phenyl, and

ii) by R¹²、R¹³And R¹⁴Substituted phenyl-C_1-6-an alkyl group,

R⁸is by R¹⁵、R¹⁶And R¹⁷Substituted phenyl;

R¹¹is selected from

iii) by R¹⁸、R¹⁹And R²⁰Substituted phenyl, and

iv) by R¹⁸、R¹⁹And R²⁰A substituted pyridyl group;

R¹²is selected from

i) H, and

ii)C_1-6-an alkoxy group;

R¹³、R¹⁴、R¹⁷and R²⁰Is H;

R¹⁵is selected from

i)H，

ii) cyano, and

iii) halogen;

R¹⁶is selected from

i) H, and

ii) a halogen;

R¹⁸is selected from

i) Halogen, and

ii) a cyano group, in the presence of a hydrogen atom,

R¹⁹is selected from

i)H，

ii) a cyano group, in the presence of a hydrogen atom,

iii)C_1-6-alkyl, and

iv) a halogen;

or a pharmaceutically acceptable salt thereof.

3. The compound according to any one of claims 1 to 2, wherein R¹Is selected from

i)C_1-6-alkyl, and

ii) by R²⁴、R²⁵And R²⁶Substituted heterocycloalkyl-C_1-6-an alkyl group.

4. A compound according to any one of claims 1 to 3, wherein R¹Is halo-C_1-6-an alkyl group.

5. A compound according to any one of claims 1 to 4, wherein R¹Is trifluoroethyl.

6. A compound according to any one of claims 1 to 5, wherein R²Is C_1-6-an alkyl group.

7. A compound according to any one of claims 1 to 6, wherein R²Is isopropyl.

8. A compound according to any one of claims 1 to 7, wherein R³、R⁴、R⁶、R⁷、R⁹And R¹⁰Is H.

9. A compound according to any one of claims 1 to 8, wherein R⁵Is selected from

i) By R¹²、R¹³And R¹⁴Substituted phenyl, and

ii) by R¹²、R¹³And R¹⁴Substituted phenyl-C_1-6-an alkyl group.

10. The compound according to any one of claims 1 to 9, wherein R⁵Is by R¹²、R¹³And R¹⁴A substituted phenyl group.

11. The compound according to any one of claims 1 to 10, wherein R⁵Is covered by a C_1-6-alkoxy-substituted phenyl.

12. The compound according to any one of claims 1 to 11, wherein R⁸Is by R¹⁵、R¹⁶And R¹⁷A substituted phenyl group.

13. The compound according to any one of claims 1 to 12, wherein R¹¹Is selected from

i) By R¹⁸、R¹⁹And R²⁰Substituted phenyl, and

ii) by R¹⁸、R¹⁹And R²⁰A substituted pyridyl group.

14. The compound according to any one of claims 1 to 13, wherein R¹¹Is by R¹⁸、R¹⁹And R²⁰A substituted phenyl group.

15. The compound according to any one of claims 1 to 14, wherein R¹²Is selected from

i) H, and

ii)C_1-6-alkoxy groups.

16. The compound according to any one of claims 1 to 15, wherein R¹²Is C_1-6-alkoxy groups.

17. The compound according to any one of claims 1 to 16, wherein R¹³、R¹⁴、R¹⁷And R²⁰Is H.

18. The compound according to any one of claims 1 to 17, wherein R¹⁵Is selected from

i)H，

ii) cyano, and

iii) a halogen.

19. The compound according to any one of claims 1 to 18, wherein R¹⁵Is a halogen.

20. The compound according to any one of claims 1 to 19, wherein R¹⁶Is selected from

i) H, and

ii) a halogen.

21. The compound according to any one of claims 1 to 20, wherein R¹⁶Is H.

22. The compound according to any one of claims 1 to 21, wherein R¹⁸Is selected from

i) Halogen, and

iii) a cyano group.

23. The compound according to any one of claims 1 to 22, wherein R¹⁹Is selected from

i)H，

ii) cyano group

iii)C_1-6-alkyl, and

iv) a halogen.

24. According to claims 1 to 23The compound of any one of, wherein R¹⁹Is selected from

i) Cyano radicals, and

ii) a halogen.

25. A compound according to any one of claims 1 to 24 selected from

(S) -4- ((S) -2- ((R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionylamino) -2-phenylacetylamino) -2, 2-difluoro-5-methyl-N- (2-morpholinoethyl) -3-oxohexanamide;

(S) -4- ((S) -2- ((R) -2- (3, 5-dichlorophenoxy) -3-phenylpropionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -3- (3-chlorophenyl) -2- (3, 5-dichlorophenoxy) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chloro-5-methylphenoxy) -3- (3-chlorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chlorophenoxy) -3- (3, 4-dichlorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -3- (3-chlorophenyl) -2- (3, 5-dicyanophenoxy) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -3- (3-chlorophenyl) -2- ((5-chloropyridin-3-yl) oxy) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chlorophenoxy) -3- (3, 5-dichlorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((S) -3- (3-chlorophenyl) -2- (3, 5-dichlorophenoxy) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((S) -3- (3-chlorophenyl) -2- (3, 5-dichlorophenoxy) propionylamino) -2-phenylacetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chloro-5-cyanophenoxy) -3- (3-chlorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chloro-5-cyanophenoxy) -3- (3-chlorophenyl) propionylamino) -2-phenylacetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(4S) -4- ((2S) -2- (2- (3-chloro-5-cyanophenoxy) -3- (3-cyanophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3, 5-dicyanophenoxy) -3- (3-fluorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-cyanophenoxy) -3- (3-fluorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

(S) -4- ((S) -2- ((R) -2- (3-chlorophenoxy) -3- (3-fluorophenyl) propionylamino) -2- (4-methoxyphenyl) acetylamino) -2, 2-difluoro-5-methyl-3-oxo-N- (2,2, 2-trifluoroethyl) hexanamide;

and pharmaceutically acceptable salts thereof.

26. A process for preparing a compound according to any one of claims 1 to 25, the process comprising

i) Reacting a compound of formula (III) with a compound of formula (IV),

then the

II) reacting the compound of formula (II) under oxidizing conditions,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R³、R⁸、R⁹、R¹⁰And R¹¹Is as defined in any one of claims 1 to 28.

27. A compound according to any one of claims 1 to 25 for use as therapeutically active substance.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 and a therapeutically inert carrier.

29. Use of a compound according to any one of claims 1 to 25 for the treatment or prophylaxis of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.

30. A compound according to any one of claims 1 to 25 for use in the treatment or prevention of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.

31. Use of a compound according to any one of claims 1 to 25 for the preparation of a medicament for the treatment or prevention of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.

32. A method for the treatment or prevention of a renal disorder selected from the group consisting of a renal disorder, a liver disorder, an inflammatory disorder, wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, and polypoidal choroidal vasculopathy, the method comprising administering an effective amount of a compound according to any one of claims 1 to 25.

33. A compound according to any one of claims 1 to 25, when manufactured according to a process of claim 26.

34. The invention as described above.