APOL1 inhibitors

Abstract

The invention relates to thiophenyl derivatives and their use in the treatment and prophylaxis of diseases alleviated by APOL1 inhibition, such as an APOL1 mediated kidney disease, and to compositions containing said derivatives and processes for their preparation.

Description

[0001] NOVEL COMPOUNDS

[0002] FIELD OF THE INVENTION

[0003] The invention relates to thiophenyl derivatives and their use in the treatment and prophylaxis of diseases alleviated by APOL1 inhibition, such as an APOL1 mediated kidney disease, and to compositions containing said derivatives and processes for their preparation.

[0004] BACKGROUND OF THE INVENTION

[0005] Apolipoprotein L1 (APOL1) is an innate immunity gene expressed in humans, gorillas, mangabeys, mandrills, and baboons. APOL1 encodes a cation channel that is expressed in various tissues such as the liver, kidney, and lungs. When synthesized in the liver, APOL1 is secreted and forms part of the Trypanosome Lytic Factor (TLF) complex, along with high- density lipoprotein 3 and haptoglobin-related protein. APOL1 plays an important role in the innate immunity as part of TLF by protecting against infection from Leishmania and African trypanosome parasites. The TLF complex is taken up by the parasites, whereupon APOL1 forms cation channels that lead to parasite swelling and lysis.

[0006] An evolutionary arms race has led to human-infective Trypanosoma brucei subspecies, rhodesiense and gambiense, that are resistant to APOL1 -mediated lysis. In turn, variants of the APOL1 gene, G1 (S342G, I384M) G2 (N388del:N389del), have evolved the ability to overcome these parasites. When present in two copies, the G1 and G2 variants lead to a significant risk of developing chronic kidney disease (CKD). Several million African Americans are estimated to carry this “high risk” genotype, which is a significant factor in their high rate of CKD incidence.

[0007] The APOL1 G1 and G2 variants are associated with chronic kidney diseases that primarily affect the glomerulus and podocyte, leading to proteinuria. These include focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy (HIVAN), COVID associated nephropathy (COVAN), lupus nephritis, hypertension-attributed end stage renal disease (H- ESRD), and non-diabetic CKD. G1 and G2 are also associated with faster progression from CKD to renal failure, and shorter transplant graft survival if present in the donor kidney.

[0008] The mechanism underlying APOL1 -mediated kidney disease is the ability of G1 and G2 to form cation channels within the cells of the kidney. Although APOL1 is continuously present in the bloodstream as part of TLF, circulating APOL1 is not thought to contribute to disease, as varying plasma concentrations have no effect on CKD incidence or progression. Rather, retrospective kidney transplant studies have shown that kidneys from donors with the high- risk genotype have significantly shorter survival rates, which is independent of recipient APOL1 genotype. Additionally, several patients with interferon treatment mediated collapsing FSGS were retrospectively genotyped to reveal that all affected patients carried the high-risk genotype. As APOL1 expression is induced by pro-inflammatory cytokines, it has been hypothesized that a pro-inflammatory environment would lead to sustained APOL1 upregulation, causing cytotoxicity and disease. This has been supported by various cell culture and animal models, where increases in APOL1 expression have caused detectable ion flux within the affected cells, leading to cell death and kidney damage.

[0009] Therefore, a need exists to provide effective inhibitors of APOL1 channel function for the treatment of APOL1 -mediated kidney disease.

[0010] SUMMARY OF THE INVENTION

[0011] According to a first aspect of the invention, there is provided a compound of formula (I): or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein:

[0012] R1represents: halogen; hydroxy; thiol; amino; cyano; -0C(0)Ci-6 linear, branched, or cyclic alkyl; -C(0)0Ci-6 linear, branched, or cyclic alkyl; -NHC(O)CI-6 linear, branched, or cyclic alkyl; -C(O)NHCI-6 linear, branched, or cyclic alkyl; -NHC(O)aryl; -C(O)NHaryl;

[0013] -NHC(O)heteroaryl; -C(O)NHheteroaryl; -NHS(O)2CI-6 linear, branched, or cyclic alkyl;

[0014] -S(O)2NHCI-6linear, branched, or cyclic alkyl; -NHS(O)2aryl; -S(O)2NHaryl;

[0015] -NHS(O)2heteroaryl; -S(O)2NHheteroaryl; -NHC(O)NHCI-6 linear, branched, or cyclic alkyl; - NHC(O)NHaryl; -NHC(O)NHheteroaryl; C1-6 linear, branched, or cyclic alkyl; C2-6 linear, branched, or cyclic alkenyl; Ci-e linear, branched, or cyclic hydroxyalkyl; C1-6 linear, branched, or cyclic alkoxy; C1-6 linear, branched, or cyclic thioalkyl; C1-6 linear, branched, or cyclic haloalkyl; C1-6 linear, branched, or cyclic haloaminoalkyl; C1-6 linear, branched, or cyclic halothioalkyl; C1-6 linear, branched, or cyclic haloalkoxy; benzyloxy; benzylamino; benzylthio; 3 to 6-membered heterocycloalkenyl; 3 to 6-membered heterocycloalkyl; or 5 and 6-membered heteroaryl; m represents an integer selected from 0 to 4, such that when m represents 2, two R1groups together with the carbon atom to which they are attached may join to form a C4-8 cycloalkyl, aryl, or heteroaryl ring;

[0016] R2represents halogen; hydroxy; thiol; amino; cyano; -NHC(0)CI-6 linear, branched, or cyclic alkyl; -C(0)NHCI-6 linear, branched, or cyclic alkyl; -NHC(O)aryl; -C(O)NHaryl;

[0017] -NHC(O)heteroaryl; -C(O)NHheteroaryl; -NHS(O)2CI-6 linear, branched, or cyclic alkyl; -S(O)2NHCI-6linear, branched, or cyclic alkyl; -NHS(O)2aryl; -S(O)2NHaryl;

[0018] -NHS(O)2heteroaryl; -S(O)2NHheteroaryl; -NHC(O)NHCI-6 linear, branched, or cyclic alkyl; - NHC(O)NHaryl; -NHC(O)NHheteroaryl; C1-4 linear, branched, or cyclic alkyl; C2-4 linear, branched, or cyclic alkenyl; C1-4 linear, branched, or cyclic hydroxyalkyl; C1-4 linear, branched, or cyclic alkoxy; C1-4 linear, branched, or cyclic thioalkyl; C1-4 linear, branched, or cyclic haloalkyl; C1-4 linear, branched, or cyclic haloaminoalkyl; C1-4 linear, branched, or cyclic halothioalkyl; or C1-4 linear, branched, or cyclic haloalkoxy; n represents an integer selected from 0 to 3;

[0019] Y is selected from: divalent C1-8 linear or branched cyclic alkyl; divalent C1-8 linear or branched alkoxy; divalent C1-8 linear or branched aminoalkyl; or divalent C1-8 linear or branched thioalkyl; wherein the divalent alkyl, divalent alkoxy, divalent aminoalkyl, and divalent thioalkyl are optionally substituted with one or more groups chosen from: C1-6 alkyl; aryl; heteroaryl; halogen; hydroxy; or amino;

[0020] R3and R4are independently selected from: hydrogen; hydroxy; thiol; amino; halogen; C1-6 linear, branched, or cyclic alkyl; C1-6 linear, branched, or cyclic hydroxyalkyl; C1-6 linear, branched, or cyclic alkoxy; C1-6 linear, branched, or cyclic thioalkyl; C1-6 linear, branched, or cyclic haloalkyl; C1-6 linear, branched, or cyclic haloaminoalkyl; C1-6 linear, branched, or cyclic halothioalkyl; or C1-6 linear, branched, or cyclic haloalkoxy; or R3and R4, together with the carbon atom to which they are attached, may form a C3-6 cycloalkyl or carbonyl group; R5and R6are independently selected from: hydrogen; thiol; amino; halogen; hydroxy, C1-6 linear, branched, or cyclic alkyl; C1-6 linear, branched, or cyclic hydroxyalkyl; C1-6 linear, branched, or cyclic alkoxy; C1-6 linear, branched, or cyclic thioalkyl; C1-6 linear, branched, or cyclic haloalkyl; C1-6 linear, branched, or cyclic haloaminoalkyl; C1-6 linear, branched, or cyclic halothioalkyl; C1-6 linear, branched, or cyclic haloalkoxy; -0C(0)Ci-6 linear, branched, or cyclic alkyl; -C(0)0Ci-6 linear, branched, or cyclic alkyl; -NHC(O)CI-6 linear, branched, or cyclic alkyl; -C(O)NHCI-6 linear, branched, or cyclic alkyl; -NHC(O)aryl; -C(O)NHaryl; - NHC(O)heteroaryl; -C(O)NHheteroaryl; -NHS(O)2CI-6 linear, branched, or cyclic alkyl; - S(O)2NHCI-6linear, branched, or cyclic alkyl; -NHS(O)2aryl; -S(O)2NHaryl;

[0021] -NHS(O)2heteroaryl; -S(O)2NHheteroaryl; -NHC(O)NHCI-6 linear, branched, or cyclic alkyl; - NHC(O)NH aryl; or -NHC(O)NH heteroaryl; and

[0022] R7, R8and R9are independently selected from: hydrogen; C1-6 linear, branched, or cyclic alkyl; C1-6 linear, branched, or cyclic hydroxyalkyl; C1-6 linear, branched, or cyclic alkoxy; C1-6 linear, branched, or cyclic thioalkyl; C1-6 linear, branched, or cyclic haloalkyl; C1-6 linear, branched, or cyclic haloaminoalkyl; C1-6 linear, branched, or cyclic haloth ioalkyl; or C1-6 linear, branched, or cyclic haloalkoxy.

[0023] DETAILED DESCRIPTION OF THE INVENTION

[0024] Definitions

[0025] The term ‘alkyl’ as used herein as a group or part of a group refers to a straight-chain (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic that has a single point of attachment to the rest of the molecule. Unless otherwise specified, alkyl groups contain 1 to 20 alkyl carbon atoms, such as 1 to 10 aliphatic carbon atoms, in particular 1 to 8 aliphatic carbon atoms, more particularly 1 to 6 alkyl carbon atoms, especially 1 to 4 alkyl carbon atoms, more especially 1 to 3 alkyl carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, linear or branched, and substituted or unsubstituted alkyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g. decalin), bridged bicycloalkyl such as norbornyl or [2.2.2]bicyclo-octyl, or bridged tricyclic such as adamantyl. Alkyl groups may be substituted or unsubstituted. Alkyl groups may be straight-chain or branched.

[0026] The term ‘alkenyl’ as used herein refers to a straight-chain (i.e. unbranched), branched, substituted or unsubstituted hydrocarbon chain that contains one or more units of saturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that contains one or more units of unsaturation, but which is not aromatic (referred to herein as ‘cyclic alkenyl’). Alkenyl groups may be substituted or unsubstituted. Alkenyl groups may be straight-chain or branched.

[0027] The terms ‘alkoxy’ or ‘thioalkyl’ as used herein refer to an alkyl group, as defined herein, wherein one carbon of the alkyl group is replaced by an oxygen (‘alkoxy’) or sulfur (‘thioalkyl’) atom, respectively, provided that the oxygen and sulfur atoms are linked between two carbon atoms. A ‘cyclic alkoxy’ refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group, but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8- oxabicyclo[3.2.1]octanyl, and oxepanyl. ‘Alkoxy’ and / or ‘thioalkyl’ groups may be substituted or unsubstituted.

[0028] The term ‘amino’ as used herein refers to the group -NH2.

[0029] The term ‘aryl’ as used herein as a group or part of a group refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl rings. Aryl groups may be substituted or unsubstituted.

[0030] The term ‘cyano’ as used herein refers to a group where a carbon atom is triple bonded to a nitrogen atom.

[0031] The term ‘halo’ or ‘halogen’ as used herein refers to fluorine, chlorine, bromine or iodine.

[0032] The terms ‘haloalkyl’ and ‘haloalkoxy’ as used herein refer to a linear or branched alkyl or alkoxy, as the case may be, which is substituted with one or more halogen atoms. Nonlimiting examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CF2-, and perhaloalkyls, such as -CF2CF3. Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH2F, -OCF3, and -OCF2-.

[0033] The term ‘heteroaryl’ as used herein as a group or part of a group refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Heteroaryl groups may be substituted or unsubstituted. Heteroaryl groups have one or more heteroatoms chosen from nitrogen, oxygen, and sulfur. Heteroaryl groups may have one heteroatom or two heteroatoms. Heteroaryl groups may be monocyclic ring systems having five or six ring members.

[0034] Examples of five membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.

[0035] A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms; l) a furan ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms.

[0036] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1- b]thiazole) and imidazoimidazole (e.g. imidazo[1 ,2-a]imidazole). Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g. pyrazolo[1 ,5-a]pyrimidine), triazolopyrimidine (e.g. [1 ,2,4]triazolo[1 ,5-a]pyrimidine), benzodioxole, imidazopyridine and pyrazolopyridine (e.g. pyrazolo[1 ,5-a]pyridine) groups.

[0037] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, isochroman, chromene, isochromene, benzodioxan, quinolizine, benzoxazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.

[0038] Examples of polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiophene, dihydrobenzofuran, 2,3-dihydro-benzo[1 ,4]dioxine, benzo[1 ,3]dioxole, 4, 5,6,7- tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g. 5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3- a]pyrazine), chroman, thiochroman, isochroman, chromene, isochromene, benzodioxan, benzoxazine, benzodiazepine, and indoline groups.

[0039] The term ‘hydroxy’ or ’hydroxyl’ as used herein refers to the group -OH.

[0040] The term ‘optionally substituted’ as used herein refers to a group which may be substituted or unsubstituted by a substituent as herein defined.

[0041] The term ‘thiol’ as used herein refers to the group -SH.

[0042] Embodiments

[0043] In one embodiment, m represents an integer selected from 0 to 2. In a further embodiment, m represents an integer selected from 1 or 2. In an alternative embodiment, m represents an integer which is 0. In a yet further embodiment, m represents an integer which is 2.

[0044] In one embodiment, R1represents halogen. In a further embodiment, R1represents fluorine.

[0045] In one embodiment, m represents 2 and both R1groups represent halogen. In a further embodiment, m represents 2 and both R1groups represent fluorine. In one embodiment, n represents an integer selected from 0 to 2. In a further embodiment, n represents an integer selected from 0 or 1. In an alternative embodiment, n represents an integer which is selected from 1 or 2. In a yet further embodiment, n represents an integer which is 1 .

[0046] In one embodiment, R2represents halogen; C1-4 linear, branched, or cyclic haloalkyl; C1-4 linear, branched, or cyclic alkyl; or cyano. In a further embodiment, R2represents halogen, C1-4 linear haloalkyl, C1-4 linear alkyl or cyano. In a yet further embodiment, R2represents halogen (such as fluorine, chlorine or bromine), C1-4 linear haloalkyl (such as trifluoromethyl), C1-4 linear alkyl (such as methyl) or cyano. In a yet further embodiment, R2represents halogen (such as fluorine, chlorine or bromine). In a still yet further embodiment, R2represents fluorine, chlorine, bromine, trifluoromethyl, methyl or cyano. In a still yet further embodiment, R2represents fluorine.

[0047] In a further embodiment, R2represents halogen or C1-4 linear, branched, or cyclic haloalkyl. In a further embodiment, R2represents halogen or C1-4 linear haloalkyl. In a yet further embodiment, R2represents halogen (such as fluorine or chlorine) or C1-4 linear haloalkyl (such as trifluoromethyl). In a still yet further embodiment, R2represents fluorine, chlorine or trifluoromethyl.

[0048] In one embodiment, Y represents a divalent C1-8 linear or branched cyclic alkyl. In a further embodiment, Y represents a divalent C1-8 linear cyclic alkyl. In a further embodiment, Y represents an unsubstituted divalent C1-8 linear cyclic alkyl. In a yet further embodiment, Y represents an unsubstituted divalent C2-4 linear cyclic alkyl. In a still yet further embodiment,

[0049] Y represents an unsubstituted divalent C2 linear cyclic alkyl. In a still yet further embodiment,

[0050] Y represents -(CH2)2-.

[0051] In one embodiment, R3represents hydrogen or a C1-6 linear, branched, or cyclic alkyl. In a further embodiment, R3represents hydrogen or a C1-6 linear alkyl. In a yet further embodiment, R3represents hydrogen or a C1-4 linear alkyl. In a still yet further embodiment, R3represents hydrogen or methyl. In a still yet further embodiment, R3represents hydrogen.

[0052] In one embodiment, R4represents hydrogen or a C1-6 linear, branched, or cyclic alkyl. In a further embodiment, R4represents hydrogen or a C1-6 linear alkyl. In a yet further embodiment, R4represents hydrogen or a C1-4 linear alkyl. In a still yet further embodiment, R4represents hydrogen or methyl. In a still yet further embodiment, R4represents hydrogen. In a still yet further embodiment, R3and R4both represent hydrogen.

[0053] In one embodiment, R5represents hydrogen, a C1-6 linear, branched, or cyclic alkyl or hydroxy. In a further embodiment, R5represents hydrogen, a C1-6 linear alkyl or hydroxy. In a yet further embodiment, R5represents hydrogen, a C1-4 linear alkyl or hydroxy. In a still yet further embodiment, R5represents hydrogen, methyl or hydroxy. In a still yet further embodiment, R5represents hydrogen or hydroxy. In particular embodiment, R5represents hydrogen. In an alternative embodiment, R5represents hydroxy.

[0054] In one embodiment, R6represents hydrogen or a C1-6 linear, branched, or cyclic alkyl. In a further embodiment, R6represents hydrogen or a C1-6 linear alkyl. In a yet further embodiment, R6represents hydrogen or a C1-4 linear alkyl. In a still yet further embodiment, R6represents hydrogen or methyl. In a still yet further embodiment, R6represents hydrogen.

[0055] In a still yet further embodiment, R5and R6both represent hydrogen. In an alternative embodiment, R5represents hydroxy and R6represents hydrogen.

[0056] In one embodiment, R7represents hydrogen or a C1-6 linear, branched, or cyclic alkyl. In a further embodiment, R7represents hydrogen or a C1-6 linear alkyl. In a yet further embodiment, R7represents hydrogen or a C1-4 linear alkyl. In a still yet further embodiment, R7represents hydrogen or methyl. In a still yet further embodiment, R7represents hydrogen.

[0057] In one embodiment, R8represents hydrogen or a C1-6 linear, branched, or cyclic alkyl. In a further embodiment, R8represents hydrogen or a C1-6 linear alkyl. In a yet further embodiment, R8represents hydrogen or a C1-4 linear alkyl. In a still yet further embodiment, R8represents hydrogen or methyl. In a still yet further embodiment, R8represents hydrogen.

[0058] In one embodiment, R9represents hydrogen or a C1-6 linear, branched, or cyclic alkyl. In a further embodiment, R9represents hydrogen or a C1-6 linear alkyl. In a yet further embodiment, R9represents hydrogen or a C1-4 linear alkyl. In a still yet further embodiment, R9represents hydrogen or methyl. In a still yet further embodiment, R9represents hydrogen.

[0059] Sub-Formulae

[0060] In one embodiment, there is provided a compound of formula (I) wherein:

[0061] R1represents halogen; m represents an integer selected from 0 to 2; R2represents halogen; cyano; C1-4 linear, branched, or cyclic alkyl; or C1-4 linear, branched, or cyclic haloalkyl; n represents an integer selected from 1 or 2;

[0062] Y is divalent C1-8 linear or branched cyclic alkyl; R3and R4are both hydrogen;

[0063] R5and R6are either both hydrogen or one of R5and R6represents hydrogen and the other represents hydroxy; and

[0064] R7, R8and R9each represent hydrogen. In one embodiment, the compound of formula (I) is a compound of formula (IA): wherein R1, R2, R3, R4, R5, R6, R7, R8and R9are as defined herein. In a further embodiment, the compound of formula (I) is a compound of formula (IB):

[0065] wherein R1, R2and R5are as defined herein. In a further embodiment, the compound of formula (I) is a compound of formula (IB)a: wherein R1, R2, n, and R5are as defined herein, such as: wherein R1represents hydrogen or halogen, in particular both R1groups represent hydrogen or both R1groups represent halogen (i.e. fluorine); n represents 1 or 2; R2represents halogen; cyano; C1-4 linear, branched, or cyclic alkyl; or C1-4 linear, branched, or cyclic haloalkyl, in particular Rzrepresents chlorine, fluorine, bromine, cyano, methyl or trifluoromethyl; and

[0066] R5represents hydrogen or hydroxy.

[0067] In a yet further embodiment, the compound of formula (I) is a compound of formula (IC): wherein R2and R5are as defined herein.

[0068] In a still yet further embodiment, the compound of formula (I) is a compound of formula (ID):

[0069] wherein R2and R5are as defined herein. In a still yet further embodiment, the compound of formula (I) is a compound of formula (IE): wherein R2and R5are as defined herein. In a still yet further embodiment, the compound of formula (I) is a compound of formula (IF):

[0070] wherein R1, R2, R3, R4, R5, R6, R7, R8and R9are as defined herein.

[0071] 5 In a still yet further embodiment, the compound of formula (I) is a compound of formula (IG): wherein R1, R2, R3, R4, R5, R6, R7, R8and R9are as defined herein. In a still yet further embodiment, the compound of formula (I) is a compound of formula (IH): wherein R1, R2, R3, R4, R5, R6, R7, R8and R9are as defined herein.

[0072] In one embodiment, the invention provides a compound of formula (I) which is the free base of Examples 1-16, or a pharmaceutically acceptable salt or solvate thereof.

[0073] In a further embodiment, the invention provides a compound of formula (I) which is the free base of Examples 1-6, or a pharmaceutically acceptable salt or solvate thereof.

[0074] A reference to a compound of the formula (I) and sub-groups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, A / -oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; preferably, the salts or tautomers or isomers or / V-oxides or solvates thereof; and more preferably, the salts or tautomers or A / -oxides or solvates thereof, even more preferably the salts or tautomers or solvates thereof. Hereinafter, compounds and their ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, A / -oxides, esters, prodrugs, isotopes and protected forms thereof as defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention". Salts

[0075] Certain compounds of the formula (I) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (I) include the salt forms of the compounds.

[0076] The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0077] Acid addition salts (mono- or d / '-salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or d / -salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L- lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1 ,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L- pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

[0078] One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is the hydrochloride salt. Where the compounds of the formula (I) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I).

[0079] The compounds of the invention may exist as mono- or / -salts depending upon the pKaof the acid from which the salt is formed.

[0080] It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates or formates may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0081] Certain compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0082] Solvates

[0083] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention. In one embodiment, the pharmaceutically acceptable solvates of the compounds of the invention include the hydrate thereof. It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention.

[0084] As used herein "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

[0085] N-Oxides

[0086] Compounds of the formula (I) containing an amine function may also form A / -oxides. A reference herein to a compound of the formula (I) that contains an amine function also includes the / V-oxide.

[0087] Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an A / -oxide. Particular examples of A / -oxides are the / V-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

[0088] A / -Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Adv. Org. Chem., by Jerry March, 4th Edition, Wiley Interscience. More particularly, / V-oxides can be made by the procedure of L. W. Deady, Syn. Commun. 1977, 7, 509-514, in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0089] Prodrugs

[0090] It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All such prodrugs of compounds of the invention are included within the scope of the invention. Examples of prodrug functionality suitable for the compounds of the present invention are described in Drugs of Today, 19, 9, 1983, 499-538 and in Topics in Chemistry, Chapter 31 , pp. 306-316 and in “Design of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in “Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.

[0091] Also included within the scope of the compound and various salts of the invention are polymorphs thereof.

[0092] Enantiomers

[0093] The compounds of formula (I) contain stereogenic centres and therefore, the present invention includes within its scope all possible enantiomers and diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. The invention also extends to any tautomeric forms or mixtures thereof.

[0094] Isotopes

[0095] The subject invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0096] Examples of isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as2H (D) and3H (T), carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l,125l and131l, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

[0097] Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors. The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase) etc. The radioactive isotopes tritium, i.e.3H (T), and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.2H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0098] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

[0099] Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

[0100] Purity

[0101] Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are given on a weight by weight basis). Impure preparations of the compounds may be used for preparing the purer forms used in the pharmaceutical compositions.

[0102] Processes

[0103] According to a further aspect of the present invention there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following schemes are examples of synthetic schemes that may be used to synthesise the compounds of the invention. In the following schemes reactive groups can be protected with protecting groups and deprotected according to well-established techniques.

[0104] According to a further aspect of the invention there is provided a process for preparing a compound of formula (I) as herein defined which comprises:

[0105] (a) reacting a compound of formula (II):

[0106] wherein R1, R2, m, n and Y are as defined herein, with a compound of formula (III): wherein R3, R4, R5, R6, R7, R8and R9are as defined herein;

[0107] (b) reacting a compound of formula (IV): wherein R1, R2, m, n and Y are as defined herein and L1represents a suitable leaving group, such as an -O-C1-6 alkyl group, in particular -O-ethyl, with a compound of formula (III): wherein R3, R4, R5, R6, R7, R8and R9are as defined herein;

[0108] (c) deprotection of a protected derivative of a compound of formula (I);

[0109] (d) interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof; and

[0110] (e) optional formation of a pharmaceutically acceptable salt of a compound of formula (I).

[0111] Process (a) typically comprises combining a compound of formula (II) with a compound of formula (III) in a suitable solvent, such as methanol, in the presence of an amide synthesis reagent, such as 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMTMM.CI).

[0112] Process (b) typically comprises combining a compound of formula (IV) with a compound of formula (III) in a suitable reagent, such as trimethylaluminium.

[0113] Compounds of formula (II) may be prepared in accordance with the experimental procedures provided in Intermediates 2 to 4 and 6 to 12 herein.

[0114] Compounds of formula (III) are either known intermediates or may be prepared in accordance with the experimental procedures provided in Intermediate 1 herein.

[0115] Compounds of formula (IV) may be prepared in accordance with the experimental procedures provided in Example 14, Step 2 herein.

[0116] A wide range of well-known functional group interconversions for process (c) are known by a person skilled in the art for converting a precursor compound to a compound of formula (I) and are described in Advanced Organic Chemistry by Jerry March, 4thEdition, John Wiley & Sons, 1992. For example, possible metal catalysed functionalisations such as using organotin reagents (the Stille reaction), Grignard reagents and reactions with nitrogen nucleophiles are described in Palladium Reagents and Catalysts’ [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1 , Edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0],

[0117] If appropriate, the reactions described herein are followed or preceded by one or more reactions known to the skilled of the art and are performed in an appropriate order to achieve the requisite substitutions on R1, R2, R3, R4, R5, R6, R7, R8and R9defined herein to afford other compounds of formula (I). Non-limiting examples of such reactions whose conditions can be found in the literature include: protection of reactive functions, deprotection of reactive functions, halogenation, dehalogenation, dealkylation, alkylation of amine, aniline, alcohol and phenol, Mitsunobu reaction on hydroxyl groups, cycloaddition reactions on appropriate groups, reduction of nitro, esters, cyano, aldehydes, transition metal-catalyzed coupling reactions, acylation, sulfonylation / introduction of sulfonyl groups, saponification / hydrolysis of esters groups, amidification or transesterification of ester groups, esterification or amidification of carboxylic groups, halogen exchange, nucleophilic substitution with amine, thiol or alcohol, reductive amination, oxime formation on carbonyl and hydroxylamine groups, S-oxidation, A / -oxidation, salification.

[0118] It is recognised that the sequence of reactions involving aryl coupling and reduction may be varied. It is also recognised that a wide range of palladium-based catalysts are suitable for conducting aryl coupling reactions. It may also be recognised that isomer separation may occur at any suitable stage in the synthetic sequence. It should be stressed that such chiral separation forms a key aspect of the invention and that such separation may be conducted in accordance with the methodology described herein or may be conducted in accordance with known methodology. It is also recognised that it may be beneficial to temporarily form a protected derivative of an intermediate in the synthesis, for example, a Boc-protected amine, or SEM-protected amide, in order to facilitate chromatographic separation, chiral resolution or to give improved solubility or yields in particular steps.

[0119] In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis by T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2007.

[0120] A hydroxy group may be protected, for example, as an ether (-OR) or an ester (-OC(=O)R), for example, as: a tert-butyl ether; a tetrahydropyranyl (THP) ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or tert-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3).

[0121] An amine group may be protected, for example, as an amide (-NRCO-R) or a carbamate (- NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyl carbamate (-NHCO- OCH2C6H5, -NH-Cbz or NH-Z); as a tert-butyl carbamate (-NHCOOC(CH3)3, NH-Boc); a 2- biphenyl-2-propyl carbamate (-NHCO-OC(CH3)2C6H4C6H5, NH-Boc), as a 9-fluorenylmethyl carbamate (-NH-Fmoc), as a 6-nitroveratryl carbamate (-NH-Nvoc), as a 2-trimethylsilylethyl carbamate (-NH-Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-Troc), as an allyl carbamate (-NH-Alloc), or as a 2(-phenylsulfonyl)ethyl carbamate (-NH-Psec).

[0122] Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.

[0123] A carboxylic acid group may be protected as an ester for example, as: an C1-7 alkyl ester (e.g. a methyl ester; a tert-butyl ester); a C1-7 haloalkyl ester (e.g. a C1-7 trihaloalkyl ester); a triCi-7 alkylsilyl-Ci-7 alkyl ester; or a C5-20 aryl-C alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester; para-methoxybenzyl ester. It will be understood by those skilled in the art that certain compounds of the invention can be converted into other compounds of the invention according to standard chemical methods.

[0124] Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

[0125] Therapeutic Utility

[0126] The compounds of the invention, subgroups and examples thereof, are APOL1 inhibitors, which may be useful in preventing or treating disease states or conditions described herein. In addition, the compounds of the invention, and subgroups thereof, will be useful in preventing or treating diseases or conditions which may be alleviated by APOL1 inhibition.

[0127] In one embodiment, the disease or condition alleviated by APOL1 inhibition includes an APOL1 mediated kidney disease, such as one which impairs kidney function and can be attributed to APOL1 .

[0128] In a further embodiment, the APOL1 mediated kidney disease is associated with patients having two APOL1 risk alleles, e.g. are homozygous, or are compound heterozygous for the G1 or G2 alleles.

[0129] Examples of suitable APOL1 mediated kidney diseases include: end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal and segmental glomerulosclerosis (FSGS), HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

[0130] References herein to the term ‘FSGS’ include focal segmental glomerulosclerosis, which is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function. In one embodiment, FSGS is associated with two APOL1 risk alleles.

[0131] References to the term ‘NDKD’ as used herein means non-diabetic kidney disease, which is characterized by severe hypertension and progressive decline in kidney function. In one embodiment, NDKD is associated with two APOL1 risk alleles.

[0132] References herein to the terms ‘ESKD’ and ‘ESRD’ are used interchangeably to refer to end stage kidney disease or end stage renal disease. ESKD / ESRD is the last stage of kidney disease, i.e. kidney failure, and means that the kidneys have stopped working well enough for the patient to survive without dialysis or a kidney transplant. In one embodiment, ESKD / ESRD is associated with two APOL1 risk alleles.

[0133] Thus, according to a further aspect of the invention there is provided a compound of formula (I) as defined herein for use in therapy.

[0134] According to a further aspect of the invention there is provided a compound of formula (I) as defined herein for use in preventing or treating diseases or condition alleviated by APOL1 inhibition, in particular APOL1 mediated kidney disease.

[0135] According to a further aspect of the invention there is provided the use of a compound of formula (I) as defined herein in the manufacture of a medicament for preventing or treating diseases or condition alleviated by APOL1 inhibition, in particular APOL1 mediated kidney disease.

[0136] According to a further aspect of the invention there is provided a compound of formula (I) as defined herein for use in preventing or treating end-stage kidney disease (ESKD), nondiabetic kidney disease (NDKD), focal and segmental glomerulosclerosis (FSGS), HIV- associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

[0137] According to a further aspect of the invention there is provided the use of a compound of formula (I) as defined herein in the manufacture of a medicament for preventing or treating end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal and segmental glomerulosclerosis (FSGS), HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

[0138] The compounds of the present invention may be useful for the treatment of the adult population. The compounds of the present invention may be useful for the treatment of the pediatric population.

[0139] Pharmaceutical Compositions

[0140] While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation). In one embodiment this is a sterile pharmaceutical composition. Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising (e.g. admixing) at least one compound of formula (I) (and sub-groups thereof as defined herein), together with one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents, as described herein.

[0141] The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents, fillers or bulking agents, granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below.

[0142] The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0143] Pharmaceutical compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0144] The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery. The delivery can be by bolus injection, short term infusion or longer-term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump or syringe driver.

[0145] Pharmaceutical formulations adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, surface active agents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21 (2) 2004, p 201-230).

[0146] The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules, vials and prefilled syringes, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. In one embodiment, the formulation is provided as an active pharmaceutical ingredient in a bottle for subsequent reconstitution using an appropriate diluent.

[0147] The pharmaceutical formulation can be prepared by lyophilising a compound of formula (I), or sub-groups thereof. Lyophilisation refers to the procedure of freeze-drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms.

[0148] Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0149] Pharmaceutical compositions of the present invention for parenteral injection can also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.

[0150] Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil or olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of thickening or coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include agents to adjust tonicity, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminium monostearate and gelatin.

[0151] In one particular embodiment of the invention, the pharmaceutical composition is in a form suitable for intravenous (i.v.) administration, for example by injection or infusion. For i.v. administration, the solution can be dosed as is, or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose), before administration.

[0152] In another particular embodiment, the pharmaceutical composition is in a form suitable for sub-cutaneous (s.c.) administration.

[0153] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0154] Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g.; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here. Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the Gl tract.

[0155] Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.

[0156] The solid dosage forms (e.g. tablets, capsules etc.) can be coated or un-coated. Coatings may act either as a protective film (e.g. a polymer, wax or varnish) or as a mechanism for controlling drug release or for aesthetic or identification purposes. The coating (e.g. a Eudragit™ type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum, duodenum, jejenum or colon.

[0157] Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to release the compound in a controlled manner in the gastrointestinal tract. Alternatively, the drug can be presented in a polymer coating, e.g. a polymethacrylate polymer coating, which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. In another alternative, the coating can be designed to disintegrate under microbial action in the gut. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations (for example formulations based on ion exchange resins) may be prepared in accordance with methods well known to those skilled in the art.

[0158] The compound of formula (I) may be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of the nanoparticles assisting their absorption. In addition, nanoparticles offer the possibility of direct penetration into the cell. Nanoparticle drug delivery systems are described in “Nanoparticle Technology for Drug Delivery”, edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published 13thMarch 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172, and in Sinha et al., Mol. Cancer Ther., 2006, 5, 1909. The pharmaceutical compositions typically comprise from approximately 1% (w / w) to approximately 95% (w / w) active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients. Particularly, the compositions comprise from approximately 20% (w / w) to approximately 90% (w / w) active ingredient and from 80% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, particularly from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, tablets or capsules.

[0159] The pharmaceutically acceptable excipient(s) can be selected according to the desired physical form of the formulation and can, for example, be selected from diluents (e.g. solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and cosolvents), disintegrants, buffering agents, lubricants, flow aids, release controlling (e.g. release retarding or delaying polymers or waxes) agents, binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavouring agents, taste masking agents, tonicity adjusting agents and coating agents.

[0160] The skilled person will have the expertise to select the appropriate amounts of ingredients for use in the formulations. For example, tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers / or bulking agents (depending on drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Slow-release tablets would in addition contain 0-99% (w / w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0161] Parenteral formulations typically contain 0-20% (w / w) buffers, 0-50% (w / w) cosolvents, and / or 0-99% (w / w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w / w) oils.

[0162] Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into a polymer or waxy matrix that allow the active ingredients to diffuse or be released in measured amounts.

[0163] The compounds of the invention can also be formulated as solid dispersions. Solid dispersions are homogeneous extremely fine disperse phases of two or more solids. Solid solutions (molecularly disperse systems), one type of solid dispersion, are well known for use in pharmaceutical technology (see Chiou and Riegelman, J. Pharm. Sci., 1971 , 60, 1281-1300) and are useful in increasing dissolution rates and increasing the bioavailability of poorly water-soluble drugs.

[0164] This invention also provides solid dosage forms comprising the solid solution described above. Solid dosage forms include tablets, capsules, chewable tablets and dispersible or effervescent tablets. Known excipients can be blended with the solid solution to provide the desired dosage form. For example, a capsule can contain the solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. In addition, a capsule can contain a bulking agent, such as lactose or microcrystalline cellulose. A tablet can contain the solid solution blended with at least one disintegrant, a lubricant, a surfactant, a bulking agent and a glidant. A chewable tablet can contain the solid solution blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavours. Solid solutions may also be formed by spraying solutions of drug and a suitable polymer onto the surface of inert carriers such as sugar beads (‘nonpareils’). These beads can subsequently be filled into capsules or compressed into tablets.

[0165] The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient’s supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician’s instructions.

[0166] Compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods. Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound. Solutions of the active compound may also be used for rectal administration.

[0167] Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.

[0168] The compounds of the formula (I) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).

[0169] For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

[0170] The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

[0171] Methods of Treatment

[0172] The compounds of the formula (I) and sub-groups as defined herein may be useful in the prophylaxis or treatment of a range of disease states or conditions alleviated by APOL1 inhibition, in particular APOL1 mediated kidney disease. Thus, according to a further aspect of the invention there is provided a method of treating a disease state or condition alleviated by APOLI inhibition, in particular APOL1 mediated kidney disease, which comprises administering to a subject in need thereof a compound of formula (I) as described herein. Examples of such disease states and conditions are set out above, and in particular include end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal and segmental glomerulosclerosis (FSGS), HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

[0173] The compounds are generally administered to a subject in need of such administration, for example a human or animal patient, particularly a human.

[0174] The compounds will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic. However, in certain situations (for example in the case of life-threatening diseases), the benefits of administering a compound of the formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.

[0175] The compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively, they may be administered in a continuous manner or in a manner that provides intermittent dosing (e.g. a pulsatile manner).

[0176] A typical daily dose of the compound of formula (I) can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of bodyweight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) of bodyweight although higher or lower doses may be administered where required. The compound of the formula (I) can be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21 , or 28 days for example.

[0177] The compounds of the invention may be administered orally in a range of doses, for example 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g. 2 to 200 mg or 10 to 1000 mg, particular examples of doses including 10, 20, 50 and 80 mg. The compound may be administered once or more than once each day. The compound can be administered continuously (i.e. taken every day without a break for the duration of the treatment regimen). Alternatively, the compound can be administered intermittently (i.e. taken continuously for a given period such as a week, then discontinued for a period such as a week and then taken continuously for another period such as a week and so on throughout the duration of the treatment regimen). Examples of treatment regimens involving intermittent administration include regimens wherein administration is in cycles of one week on, one week off; or two weeks on, one week off; or three weeks on, one week off; or two weeks on, two weeks off; or four weeks on two weeks off; or one week on three weeks off - for one or more cycles, e.g. 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles.

[0178] In one particular dosing schedule, a patient will be given an infusion of a compound of the formula (I) for periods of one hour daily for up to ten days in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.

[0179] More particularly, a patient may be given an infusion of a compound of the formula (I) for periods of one hour daily for 5 days and the treatment repeated every three weeks.

[0180] In another particular dosing schedule, a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g. 3 hours.

[0181] In a further particular dosing schedule, a patient is given a continuous infusion for a period of 12 hours to 5 days, and in particular a continuous infusion of 24 hours to 72 hours.

[0182] In another particular dosing schedule, a patient is given the compound orally once a week.

[0183] In another particular dosing schedule, a patient is given the compound orally once-daily for between 7 and 28 days, such as 7, 14 or 28 days.

[0184] In another particular dosing schedule, a patient is given the compound orally once-daily for 1 day, 2 days, 3 days, 5 days or 1 week followed by the required number of days off to complete a one- or two-week cycle.

[0185] In another particular dosing schedule, a patient is given the compound orally once-daily for 2 weeks followed by 2 weeks off.

[0186] In another particular dosing schedule, a patient is given the compound orally once-daily for 2 weeks followed by 1 week off.

[0187] In another particular dosing schedule, a patient is given the compound orally once-daily for 1 week followed by 1 week off. Ultimately, however, the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

[0188] It will be appreciated that APOL1 inhibitors can be used as a single agent or in combination with other therapeutically active agents. Combination experiments can be performed, for example, as described in Chou T.C. and Talalay P., Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors., Adv. Enzyme Regulat., 1984, 22, 27-55.

[0189] The compounds as defined herein can be administered as the sole therapeutic agent or they can be administered in combination therapy with one of more other compounds (or therapies) for treatment of a particular disease state, for example end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal and segmental glomerulosclerosis (FSGS), HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with one or more other therapeutically agents which support the therapy of the disease being treated.

[0190] Each of the compounds present in the combinations of the invention may be given in individually varying dose schedules and via different routes. As such, the posology of each of the two or more agents may differ; each may be administered at the same time or at different times. A person skilled in the art would know through his or her common general knowledge the dosing regimens and combination therapies to use. For example, the compound of the invention may be used in combination with one or more other agents which are administered according to their existing combination regimen.

[0191] Where the compound of the formula (I) is administered in combination therapy with one, two, three, four or more other therapeutic agents (particularly one or two, more particularly one), the compounds can be administered simultaneously or sequentially. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. When administered sequentially, they can be administered at closely spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s). These dosages may be administered for example once, twice, or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.

[0192] In one embodiment is provided a compound of formula (I) for the manufacture of a medicament for use in therapy wherein said compound is used in combination with one, two, three, or four other therapeutic agents. In another embodiment is provided a medicament for treating end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal and segmental glomerulosclerosis (FSGS), HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease which comprises a compound of formula (I) wherein said medicament is used in combination with one, two, three, or four other therapeutic agents.

[0193] It will be appreciated that the particular method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated, and the particular host being treated. The optimum method, order of administration, as well as the dosage amounts and regimen can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.

[0194] The weight ratio of the compound according to the present invention and the one or more other therapeutic agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other therapeutic agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of formula (I) and another therapeutic agent may range from 1 / 10 to 10 / 1 , more in particular from 1 / 5 to 5 / 1 , even more in particular from 1 / 3 to 3 / 1.

[0195] In one embodiment the pharmaceutical composition comprises a compound of formula (I) together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agent(s). In another embodiment the invention relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition for preventing or treating endstage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal and segmental glomerulosclerosis (FSGS), HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

[0196] In a further embodiment the invention relates to a product containing a compound of formula (I) and one or more additional therapeutic agents, as a combined preparation for simultaneous, separate, or sequential use in the treatment of patients suffering from endstage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal and segmental glomerulosclerosis (FSGS), HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

[0197] Examples of suitable additional therapeutic agents include: methotrexate, corticosteroids like prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, cortisone and the like; mycophenolate mofetil, tacrolimus, leflunomide or teriflunomide, cyclosporine A, cyclophosphamide, mitoxanthrone, fingolimod, azathioprine, glatiramer acetate, dimethyl fumarate, an IK-1 inhibitor like TRAM-34, a JAK-inhibitor like Tofacitinib or braticinip, a SYK- inhibitor like Fostamatinib, interferon-beta (IFN- ).

[0198] EXAMPLES

[0199] The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

[0200] Preparation of Intermediates:

[0201] Intermediate 1

[0202] Step 1 : Methyl (2S)-2-(((benzyloxy)carbonyl)amino)-4-(methylsulfinyl)butanoate

[0203] To a solution of methyl ((benzyloxy)carbonyl)-Z_-methioninate (50.0 g, 168.1 mmol) in MeOH (400 mL) and H2O (200 mL) was added sodium periodate (37.8 g, 176.9 mmol) at 0°C, and the mixture stirred at this temperature for 3 hours. The mixture was filtered and diluted with H2O, extracted with 3 x EtOAc and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as yellow solid (45 g, 85%).1H NMR (400 MHz, DMSO-d6) 6 7.85 (dd, J = 8.0, 2.5 Hz, 1 H), 7.42 - 7.27 (m, 5H), 5.05 (s, 2H), 4.24 - 4.14 (m, 1 H), 3.66 (s, 3H), 2.89 - 2.59 (m, 2H), 2.52 (d, J = 6.5 Hz, 3H), 2.16 - 1.89 (m, 2H); LCMS m / z = 314 [M+H]+.

[0204] Step 2: Methyl (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate

[0205] Methyl (2S)-2-(((benzyloxy)carbonyl)amino)-4-(methylsulfinyl)butanoate (35.0 g, 112 mmol) was stirred in 2,4-dichlorotoluene (350 mL) 191 °C for 3 hours. The solvent was cooled to room temperature and purified by gradient column chromatography on silica gel (petroleum ether : EtOAc (100:1 to 10:1)) to afford the title compound as a white solid (13.5 g, 48.6%). This material was used directly in the next step without further manipulation due to its instability.1H NMR (400 MHz, CDCI3) 6 7.42 - 7.28 (m, 5H), 6.01 - 5.84 (m, 1 H), 5.58 - 5.45 (m, 1 H), 5.41 - 5.25 (m, 2H), 5.13 (s, 2H), 5.00 - 4.88 (m, 1 H), 3.76 (s, 3H); LCMS m / z = 250 [M+H]+.

[0206] Step 3: Methyl (2S)-2-(((benzyloxy)carbonyl)amino)-2-(oxiran-2-yl)acetate

[0207] To a solution of methyl (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate (7.00 g, 2.81 mmol) in CH2CI2 (50 mL) was added 3-chloroperoxybenzoic acid (17.1 g, 8.42 mmol) at 0°C, and the mixture was stirred overnight at 45°C. The mixture was diluted with CH2CI2, washed with saturated NaHCOa (aq.) and brine, then dried (NaaSC ), filtered and concentrated in vacuo to give crude methyl (2S)-2-(((benzyloxy)carbonyl)amino)-2-(oxiran-2-yl)acetate as a yellow oil (7.00 g). This material was used directly in the next step without further purification.1H NMR (400 MHz, DMSO-d6) 6 7.99 (d, J = 8.0 Hz, 1 H), 7.41 - 7.28 (m, 5H), 5.05 (s, 2H), 4.04 (dd, J = 8.0, 6.0 Hz, 1 H), 3.67 (s, 3H), 3.29 - 3.25 (m, 1 H), 2.82 (t, J = 4.5 Hz, 1 H), 2.72 - 2.68 (m, 1 H); LCMS m / z 266 [M+H]+.

[0208] Step 4: Methyl (2S)-4-azido-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutanoate

[0209] To a solution of methyl (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate (7.00 g, 26.4 mmol) in DMF (70 mL) was added NH4CI (1 .51 g, 27.7 mmol) and NaNa (17.2 g, 264 mmol) at 0°C, and the mixture was stirred overnight at 60°C. The mixture was diluted with H2O and extracted with 3 x EtOAc, then the organic layers were combined and washed with brine, filtered and concentrated to get the crude title compound (7.0 g) as a yellow oil, which was used directly in the next step without further purification. LCMS m / z 331 [M+Na]+.

[0210] Step 5: Benzyl ((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)carbamate

[0211] To a solution of methyl (2S)-4-azido-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutanoate (7.00 g, 22.7 mmol) in a mixture of MeOH, H2O and MeCN (5:1 :4, 100 mL) was added PPha (23.8 g, 90.8 mmol), and the resulting mixture was stirred overnight at 100°C. Volatiles were removed under vacuum, CH2CI2 (200 mL) was added and resulting mixture stirred at 50°C for 1 hour. After cooling to room temperature, the mixture was filtered to give crude material, which was then purified by gradient column chromatography on silica gel (petroleum ether : EtOAc (2:1) to CH2CI2 : MeOH (100:1 to 30:1) to afford the title compound as a white solid (3.50 g, 33%).1H NMR (400 MHz, MeOH-d4) 6 7.46 - 7.24 (m, 5H), 5.13 (s, 2H), 4.42 (q, J = 8.0 Hz, 1 H), 4.06 (d, J = 8.0 Hz, 1 H), 3.64 - 3.52 (m, 1 H), 3.11 (dd, J = 10.0, 7.5 Hz, 1 H); LCMS m / z 251 [M+H]+.

[0212] Step 6: (3S,4R)-3-Amino-4-hydroxypyrrolidin-2-one

[0213] To a solution of benzyl ((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)carbamate (500 mg, 2.0 mmol) in a mixture of CH2CI2 and MeOH (1 :1 , 20 mL) was added Pd / C (100 mg), and the resulting mixture was stirred overnight at 40°C under a H2 atmosphere. The mixture was filtered and concentrated in vacuo to afford (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one as a brown solid (200 mg, 86%).1H NMR (400 MHz, MeOH-d4) 64.29 (q, J = 7.5 Hz, 1 H), 3.58 (dd, J = 10.0, 8.0 Hz, 2H), 3.11 (dd, J = 10.0, 7.0 Hz, 1 H); LCMS m / z 117 [M+H]+.

[0214] Intermediate 2

[0215] Step 1 : 5-(5-Chlorothiophen-2-yl)-5-oxopentanoic acid

[0216] To a stirred solution of 2-bromo-5-chlorothiophene (1.00 g, 5.06 mmol) and dihydro-2 / 7- pyran-2,6(3 / - / )-dione (1 .15 g, 10.0 mmol) in THF (20 mL) was added isopropyl magnesium chloride lithium chloride complex (1.3 M in THF) (3.89 mL, 5.06 mmol) at -78°C. The reaction mixture was stirred at room temperature for 1 hour then diluted with ice cold H2O. The aqueous layer was then acidified to pH ~1 using 0.1 M HCI (aq.), then organics extracted with 3 x CH2CI2, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc : hexane (2:3) to afford the title compound as an off-white solid (0.45 g, 38%).1H NMR (400 MHz, DMSO-d6) 6 12.09 (s, 2H), 7.86 (d, J = 4.0 Hz, 1 H), 7.30 (d, J = 4.0 Hz, 1 H), 2.96 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.0 Hz, 1 H), 1.81 (t, J = 7.0 Hz, 2H); LCMS m / z 233 [M+H]+.

[0217] Step 2: 3-(2-(5-Chlorothiophen-2-yl)-5,7-difluoro-1 / - / -indol-3-yl)propanoic acid To a stirred solution of 5-(5-chlorothiophen-2-yl)-5-oxopentanoic acid (0.45 g, 1.93 mmol) in acetic acid (9.0 mL) was added (2,4-difluorophenyl) hydrazine hydrochloride (0.35 g, 1.93 mmol). The reaction mixture was stirred at 100°C for 16 hours, then diluted with H2O.

[0218] Organics were then extracted with 3 x CH2CI2, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was first subjected to flash column chromatography on silica gel (EtOAc : hexane (1 :9)), then triturated using Et20 (10 mL) and pentane (10 mL) followed by reversed-phase HPLC purification (CI8 column; MeCN gradient with 0.05% formic acid in H2O) to afford the title compound as white solid (74 mg, 11 %).1H NMR (400 MHz, DMSO- d6) 6 12.21 (s, 1 H), 11.84 (s, 1 H), 7.46 (d, J = 4.0 Hz, 1 H), 7.27 (m, 2H), 7.02 (m, 1 H), 3.07 (t, J = 7.0 Hz, 2H), 2.52 - 2.49 (m, 2H); LCMS m / z 342 [M+H]+.

[0219] Intermediate 3

[0220] Step 1 : Ethyl 5-(5-fluorothiophen-2-yl)pent-4-ynoate

[0221] To a stirred solution of 2-bromo-5-fluorothiophene (0.60 g, 3.31 mmol) in NEt3(6.0 mL) was added ethyl pent-4-ynoate (1.25 g, 9.94 mmol). The reaction mixture was purged with N2 for ca. 10 minutes, then copper(l) iodide (0.13 g, 0.66 mmol) was added followed by Pd(PPh3)2CI2(0.23 g, 0.33 mmol) at room temperature. The resulting mixture was stirred at 100°C for 3 hours, then diluted with H2O. Organics were then extracted with 3 x EtOAc, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc : hexane (1 :99)) to give the title compound as a yellow liquid (0.55 g, 73%).1H NMR (400 MHz, DMSO-d6) 5 6.95 (t, J = 4.0 Hz, 1 H), 6.70 - 6.69 (m, 1 H), 4.09 (q, J = 7.0 Hz, 2H), 2.69 - 2.65 (m, 2H), 2.59 - 2.58 (m, 2H), 1.19 (t, J = 7.0 Hz, 3H); LCMS m / z 245 [M+NH4]+.

[0222] Step 2: Ethyl 3-(5,7-difluoro-2-(5-fluorothiophen-2-yl)-1H-indol-3-yl)propanoate

[0223] To a stirred solution of ethyl 5-(5-fluorothiophen-2-yl) pent-4-ynoate (0.50 g, 2.21 mmol) and 2,4-difluoro-6-iodoaniline (0.67 g, 2.65 mmol) in 1 ,4-dioxane (10.0 mL) was added CS2CO3 (1 .07 g, 3.31 mmol). The reaction mixture was purged with N2 for ca. 30 minutes then Pd(dppf)Ch (0.16 g, 0.22 mmol) was added at room temperature and stirred at 100°C for 16 hours. The mixture was diluted with water, then organics extracted with 3 x EtOAc, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (EtOAc : hexane (1 :24)) to give the title compound as a yellow solid (0.40 g, 51 %).1H NMR (400 MHz, DMSO-d6) 5 11.81 (s, 1 H), 7.26 - 7.23 (m, 2H), 7.03 - 6.98 (m, 1 H), 6.90 - 6.89 (m, 1 H), 4.00 (q, J = 7.0 Hz, 2H), 3.10 (t, J = 7.0 Hz, 2H), 2.58 (t, J = 8.0 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H); LCMS m / z 352 [M-H]-.

[0224] Step 3: 3-(5,7-Difluoro-2-(5-fluorothiophen-2-yl)-1H-indol-3-yl)propanoic acid

[0225] To a stirred solution of ethyl 3-(5,7-difluoro-2-(5-fluorothiophen-2-yl)-1 H-indol-3-yl) propanoate (0.35 g, 0.99 mmol) in MeOH (11 .0 mL) was added a solution of NaOH (0.19 g, 4.95 mmol) in H2O (3.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 3 hours, then diluted with H2O and washed with n-hexane (2 x 30 mL) to remove impurities. The aqueous layer was acidified to pH ~1 using 0.1 M HCI (aq.), then organics were extracted with 3 x EtOAc, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (EtOAc : hexane (3:1 )) to afford 3-(5,7-difluoro-2-(5-fluorothiophen-2-yl)-1 / 7-indol-3-yl) propanoic acid as white solid (50.0 mg, 16%).1H NMR (400 MHz, DMSO-d6) 5 12.21 (s, 1 H), 11.80 (s, 1 H), 7.27 - 7.24 (m, 2H), 7.03 - 6.97 (m, 1 H), 6.90 - 6.89 (m, 1 H), 3.06 (t, J = 7.5 Hz, 2H), 2.52 - 2.48 (m, 2H); LCMS m / z 324 [M-H]-.

[0226] Intermediate 4

[0227] Step 1 : Ethyl 5-(5-(trifluoromethyl)thiophen-2-yl)pent-4-ynoate

[0228] To a stirred solution of 2-bromo-5-(trifluoromethyl) thiophene (0.40 g, 1.73 mmol) in NEta (0.35 g) was added ethyl pent-4-ynoate (0.65 g, 5.19 mmol). The reaction mixture was purged with N2 for ca. 10 minutes, then copper(l) iodide (65.0 mg, 0.35 mmol) was added followed by Pd(PPh3)2Cl2 (0.12 g, 0.17 mmol) at room temperature. The reaction mixture was stirred at 100°C for 2 hours then diluted with H2O. Organics were extracted with 3 x EtOAc, then dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc : hexane (1 :9)) to afford the title compound as a colourless liquid (0.35 g, 73%).1H NMR (400 MHz, DMSO-de): 5 7.67 - 7.66 (m, 1 H), 7.33 - 7.32 (m, 1 H), 4.10 (q, J = 7.0 Hz, 2H), 2.74 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H), 1.22 (t, J = 5.0 Hz, 3H); LCMS m / z 277 [M+H]+. Step 2: Ethyl 3-(5,7-Difluoro-2-(5-(trifluoromethyl)thiophen-2-yl)-1 / - / -indol-3- yl)propanoate

[0229] To a stirred solution of ethyl 5-(5-(trifluoromethyl) thiophen-2-yl) pent-4-ynoate (0.35 g, 1.3 mmol) and 2,4-difluoro-6-iodoaniline (0.38 g, 1.52 mmol) in 1 ,4-dioxane (7.0 mL) was added CS2CO3 (0.62 g, 1.90 mmol). The reaction mixture was purged with N2 ca. 10 minutes then Pd(dppf)Ch (92.0 mg, 0.13 mmol) was added at room temperature. The reaction mixture was stirred at 100°C for 16 hours, then diluted with H2O. Organics were extracted 3 x EtOAc, then dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc : hexane (1 :24)) to give the title compound as a white solid (0.18 g, 35%).1H NMR (400 MHz, DMSO-d6) 6 12.02 (s, 1 H),

[0230] 7.85 - 7.84 (m, 1 H), 7.68 - 7.67 (m, 1 H), 7.32 (dd, J = 9.0, 2.0 Hz, 1 H), 7.11 - 7.05 (m, 1 H), 3.99 (q, J = 7.0 Hz, 2H), 3.18 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 1.10 (t, J = 7.0 Hz, 3H); LCMS m / z 402 [M-H]-.

[0231] Step 3: 3-(5,7-Difluoro-2-(5-(trifluoromethyl)thiophen-2-yl)-1 H-indol-3-yl)propanoic acid To a stirred solution of ethyl 3-(5,7-difluoro-2-(5-(trifluoromethyl) thiophen-2-yl)-1 / - / -indol-3-yl) propanoate (0.15 g, 0.37 mmol) in MeOH (6.0 mL) was added a solution of NaOH (0.07 g,

[0232] 1.86 mmol) in H2O (1.50 mL) at 0°C. The reaction mixture was stirred at room temperature for 16 hours, then diluted with H2O and washed with n-hexane (2 x 30 mL) to remove impurities. The aqueous layer was acidified to pH ~1 using 0.1 M HCI (aq.) and organics were extracted using 3 x EtOAc, then dried (Na2SO4), filtered and concentrated in vacuo. The crude material was triturated using Et20 and n-pentane, dried in vacuo to get 3-(5,7- difluoro-2-(5-(trifluoromethyl) thiophen-2-yl)-1 / - / -indol-3-yl) propanoic acid as a yellow solid (0.09 g, 64%).1H NMR (400 MHz, DMSO-d6) 6 12.37 (s, 1 H), 12.01 (s, 1 H), 7.85 - 7.84 (m, 1 H), 7.69 - 7.68 (m, 1 H), 7.36 - 7.31 (m, 1 H), 7.10 - 7.04 (m, 1 H), 3.14 (t, J = 7.0 Hz, 2H), 2.55 - 2.53 (m, 2H); LCMS m / z 374 [M-H]-.

[0233] Intermediate 5

[0234] 5-Bromo-2-fluoro-3-methylthiophene

[0235] To a stirred solution 5-bromo-3-methylthiophene-2-carboxylic acid (0.600 g, 2.71 mmol, 1.00 eq.) in cyclohexane (6 mL) and water (3 mL) was added potassium fluoride (0.630 g, 10.9 mmol, 4.00 eq.) and selectfluor (1.90 g, 5.43 mmol, 2.00 eq.). The reaction was stirred at 70 °C for 15 hours and monitored by TLC (100% hexane) analysis. After completion of the reaction, the obtained mixture was poured into water (50 mL). The aqueous layer was extracted with diethyl ether (2 X 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated at room temperature under reduced pressure to give crude 5-bromo-2-fluoro-3-methylthiophene as a yellow liquid (426 mg, 80%). This material was used without further purification.

[0236] Intermediate 6

[0237] 3-(5,7-Difluoro-2-(5-fluoro-4-methylthiophen-2-yl)-1 H-indol-3-yl)propanoic acid

[0238] This compound was synthesised as for Intermediate 3, using 5-bromo-2-fluoro-3- methylthiophene (Intermediate 5).1H NMR (400 MHz, DMSO-d6) 5 12.18 (bs, 1 H), 11.75 (s, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.19 (d, J = 4.4 Hz, 1 H), 6.99 (t, J = 19.2 Hz, 1 H), 3.05 (t, J = 15.6 Hz, 2H), 2.47 (m, 2H), 2.15 (s, 3H); LCMS m / z 338.1 [M+1 ]+.

[0239] Intermediate 7

[0240] 3-(5,7-Difluoro-2-(5-methylthiophen-2-yl)-1 H-indol-3-yl)propanoic acid

[0241] This compound was synthesised as for Intermediate 3, using 2-bromo-5-methylthiophene.1H NMR (400 MHz, DMSO-d6) 5 12.19 (s, 1 H), 11.67 (s, 1 H), 7.41-7.40 (d, J = 3.2 Hz, 1 H), 7.22-7.20 (m, 1 H), 6.99-6.90 (m, 2H), 3.11-3.07 (t, J = 12.4 Hz, 2H), 2.51-2.45 (m, 5H);

[0242] LCMS m / z 322.2 [M+1]+.

[0243] Intermediate 8

[0244] 3-(5,7-Difluoro-2-(4-methylthiophen-2-yl)-1 H-indol-3-yl)propanoic acid

[0245] This compound was synthesised as for Intermediate 3, using 2-bromo-4-methylthiophene.1H NMR (400 MHz, DMSO-d6) 6 12.13 (s, 1 H), 11.71 (s, 1 H), 7.44 (s, 1 H), 7.27 (s, 1 H), 7.24- 7.21 (d, J = 9.6 Hz, 1 H), 6.99-6.94 (t, J = 21.2 Hz, 1 H), 3.13-3.09 (t, J = 15.6 Hz, 2H), 2.5(m, 2H), 2.28 (s, 3H); LCMS m / z 322.2 [M+ 1 ]+.

[0246] Intermediate 9

[0247] 3-(2-(5-Cyanothiophen-2-yl)-5,7-difluoro-1 H-indol-3-yl)propanoic acid

[0248] This compound was synthesised as for Intermediate 3, using 5-bromothiophene-2- carbonitrile.1H NMR (400 MHz, DMSO-d6) 6 12.20 (s, 1 H), 12.06 (s, 1 H), 8.08-8.07 (d, J = 4.0 Hz, 1 H), 7.74-7.73 (d, J = 3.6 Hz, 1 H), 7.35-7.32 (d, J = 9.2 Hz, 1 H), 7.12-7.07 (t, J = 20 Hz, 1 H), 3.17-3.13 (t, J =15.2 Hz, 2H), 2.55-2.53 (m, 2H); LCMS m / z 330.9 [M+1]+.

[0249] Intermediate 10

[0250] 3-(2-(5-Bromothiophen-2-yl)-5,7-difluoro-1H-indol-3-yl)propanoic acid

[0251] This compound was synthesised as for Intermediate 3, using 2,5-dibromothiophene.1H NMR (400 MHz, DMSO-d6) 5 12.20 (s, 1 H), 11.83 (s, 1 H), 7.43 (d, J = 4.0 Hz, 1 H), 7.36 (d, J = 3.6 Hz, 1 H), 7.28-7.25 (m, 1 H), 7.05-6.99 (m, 1 H), 3.08 (t, J = 7.2 Hz, 2H), 2.52(s, 2H);

[0252] LCMS m / z 383.9 [M+1]+. Intermediate 11

[0253] 3-(2-(5-Chloro-4-methylthiophen-2-yl)-5,7-difluoro-1 H-indol-3-yl)propanoic acid

[0254] This compound was synthesised as for Intermediate 3, using 5-bromo-2,3- dimethylthiophene.1H NMR (400 MHz, DMSO-d6) 6 12.20 (Bs, 1 H), 11.78 (s, 1 H), 7.41 (s, 1 H), 7.26-7.23 (m, 1 H), 7.03-6.97 (m, 1 H), 3.07 (t, J=7.2 Hz, 2H), 2.22 (s, 3H); LCMS m / z 354.1 [M+1]+.

[0255] Intermediate 12 3-(2-(5-Chlorothiophen-2-yl)-1 H-indol-3-yl)propanoic acid

[0256] Step 1 :

[0257] To a stirred solution of 2-bromo-5-chlorothiophene (1.00 g, 5.06 mmol, 1.00 eq.) in tetrahydrofuran (20 mL) was added isopropyl magnesium chloride lithium chloride complex (i-PrMgCL LiCI) (1.3 M in tetrahydrofuran) (4.70 mL, 6.07 mmol, 1.20 eq.) at -78°C. After 30 minutes, dihydro-2H-pyran-2,6(3H)-dione (1.15 g, 10.1 mmol, 2.00 eq.) was added and the reaction mixture was stirred at -78 °C for 30 minutes. The conversion was monitored by TLC (50% ethyl acetate in hexane). After completion, the reaction was quenched with saturated ammonium chloride solution (50 mL). The aqueous layer was extracted with dichloromethane (3 X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(5- chlorothiophen-2-yl)-5-oxopentanoic acid as an off white solid (0.30 g, 26%).1H NMR (400 MHz, DMSO-d6) 5 12.11 (s, 2H), 7.86 (d, J = 4 Hz, 1 H), 7.30 (d, J = 4 Hz, 1 H), 2.96 (t, J = 7.6 Hz, 2H), 2.71 (t, J = 7.2 Hz, 2H), 1 .81 (t, J = 7.6 Hz, 2H); LCMS m / z 233.0 [M+ 1 ]+.

[0258] Step 2:

[0259] To a stirred solution of 5-(5-chlorothiophen-2-yl)-5-oxopentanoic acid (0.10 g, 0.43 mmol, 1.00 eq.) in acetic acid (2 mL) was added phenyl hydrazine (0.09 g, 0.86 mmol, 2.0 eq.). The reaction mixture was stirred at 100 °C for two hours, and conversion was monitored by TLC (50% ethyl acetate in hexane). After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash column chromatography using 40% acetonitrile in water as the eluent. The pure fractions were lyophilized to give the title compound as a white solid (0.045 g, 34%).1H NMR (400 MHz, DMSO-d6) 6 612.20 (s, 1 H), 11.35 (s, 1 H), 7.56 (d, J = 8 Hz, 1 H), 7.32 (m, 2H), 7.24 (d, J = 4 Hz, 1 H), 7.13 (m, 1 H), 7.01 (m, 1 H), 3.12 (t, J = 8 Hz, 1 H); LCMS m / z 306.1 [M+1]+.

[0260] Preparation of Examples:

[0261] Example 1

[0262] 3-(2-(5-Chlorothiophen-2-yl)-5,7-difluoro-1H-indol-3-yl)-A / -((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propenamide (E1)

[0263] To a stirred solution of Intermediate 2 (59.8 mg, 0.175 mmol) and Intermediate 1 (34.7 mg, 0.26 mmol) in MeOH (875 pL), was added 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4- methylmorpholin-4-ium chloride (DMTMM.CI) (71.9 mg, 0.26 mmol), and the mixture was stirred overnight at room temperature. Additional 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4- methylmorpholin-4-ium chloride (DMTMM.CI) (24.2 mg, 0.088 mmol) and intermediate 1 (11 .6 mg, 0.088 mmol) was added, and the mixture stirred for a further 5 hours. A pH 2 buffer solution was added, then organics extracted with 3 x EtOAc, dried (MgSO4), filtered and concentrated in vacuo. The crude product was first subjected to flash chromatography on silica gel (100% EtOAc), then slurried in a 4:1 mixture of heptane : acetone (10 mL), and filtered under suction to give the title compound as an off-white solid (43.0 mg, 56%);1H NMR (500 MHz, DMSO-d6) 6 11 .80 (s, 1 H), 8.22 (d, J = 7.5 Hz, 1 H), 7.76 (s, 1 H), 7.48 - 7.45 (m, 1 H), 7.29 - 7.25 (m, 1 H), 7.27 - 7.25 (m, 1 H), 7.05 - 6.98 (m, 1 H), 5.46 (d, J = 5.0 Hz, 1 H), 4.15 - 4.05 (m, 2H), 3.40 - 3.35 (m, 1 H), 3.11 - 3.04 (m, 2H), 2.92 (dd, J = 9.5, 6.5 Hz, 1 H), 2.46 - 2.39 (m, 2H); LCMS m / z = 438 [M+H]+. Example 2 3-(5,7-Difluoro-2-(5-fluorothiophen-2-yl)-1H-indol-3-yl)-A / -((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propenamide (E2)

[0264] To a stirred solution of Intermediate 3 (65.0 mg, 0.20 mmol) and Intermediate 1 (39.6 mg, 0.30 mmol) in MeOH (1.00 ml_) was added 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4- methylmorpholin-4-ium chloride (DMTMM.CI) (83.0 mg, 0.30 mmol), and the mixture was stirred overnight at room temperature. Additional 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4- methylmorpholin-4-ium chloride (DMTMM.CI) (27.7 mg, 0.10 mmol) and Intermediate 1 (13.2 mg, 0.10 mmol) was added, and the mixture stirred for a further 5 hours. A pH 2 buffer solution was added, then organics extracted with 3 x EtOAc, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (100% EtOAc) to give the title compound as a white solid (64.0 mg, 76%);1H NMR (500 MHz, DMSO-d6) 6 11.78 (s, 1 H), 8.22 (d, J = 7.5 Hz, 1 H), 7.77 (s, 1 H), 7.29 - 7.24 (m, 2H), 7.04 - 6.97 (m, 1 H), 6.89 (dd, J = 4.0, 2.0 Hz, 1 H), 5.47 (d, J = 5.0 Hz, 1 H), 4.16 - 4.08 (m, 2H), 3.41 - 3.36 (m, 1 H), 3.09 - 3.02 (m, 2H), 2.92 (dd, J = 9.5, 6.5 Hz, 1 H), 2.46 - 2.39 (m, 2H); LCMS m / z = 446 [M+Na]+.

[0265] Example 3 3-(5,7-Difluoro-2-(5-(trifluoromethyl)thiophen-2-yl)-1 / - / -indol-3-yl)-N-((3S,4 / ?)-4-hydroxy- 2-oxopyrrolidin-3-yl)propenamide (E3) To a stirred solution of Intermediate 4 (75.0 mg, 0.20 mmol) and Intermediate 1 in MeOH (1.00 mL) was added 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMTMM.CI) (83.0 mg, 0.30 mmol), and the mixture was stirred overnight at room temperature. Additional 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMTMM.CI) (27.7 mg, 0.10 mmol) and Intermediate 1 (13.2 mg, 0.10 mmol) was added, and the mixture stirred for a further 5 hours. A pH 2 buffer solution was added, then organics extracted with 3 x EtOAc, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (100% EtOAc) to give the title compound as a yellow solid (74.0 mg, 78%);1H NMR (500 MHz, DMSO-de) 6 12.0 (s, 1 H), 8.22 (d, J = 7.5 Hz, 1 H), 7.85 - 7.82 (m, 1 H), 7.76 (s, 1 H), 7.70 - 7.67 (m, 1 H), 7.32 (dd, J = 9.5, 2.0 Hz, 1 H), 7.10 - 7.04 (m, 1 H), 5.46 - 5.44 (m, 1 H), 4.14 - 4.05 (m, 2H), 3.38 - 3.35 (m, 1 H), 3.13 (dd, J = 9.5, 6.5 Hz, 2H), 2.94 - 2.88 (m, 1 H), 2.49 - 2.43 (m, 2H); LCMS m / z = 496 [M+Na]+.

[0266] Example 4 (S)-3-(2-(5-Chlorothiophen-2-yl)-5,7-difluoro-1H-indol-3-yl)-N-(2-oxopyrrolidin-3- yl)propenamide (E4)

[0267] To a stirred solution of Intermediate 2 (45.0 mg, 0.13 mmol) in DMF (0.50 mL) were added DIPEA (0.11 mL, 0.66 mmol), HATU (75.0 mg, 0.20 mmol) and (S)-3-aminopyrrolidin-2-one hydrochloride (36.0 mg, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours, then diluted with ice cold H2O (10 mL). Organics were extracted with 3 x CH2CI2, then dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by reversed-phase HPLC purification (CI8 column; MeCN : MeOH : IPA gradient with 0.1% formic acid in H2O) to afford the title compound as an off- white solid (18.3 mg, 33%).1H NMR (400 MHz, DMSO-d6) 6 11.81 (s, 1 H), 8.19 (d, J = 8.0 Hz, 1 H), 7.84 (s, 1 H), 7.47 (d, J = 3.5 Hz, 1 H), 7.28 - 7.27 (m, 2H), 7.02 (t, J = 9.5 Hz ,1 H), 4.28 (q, J = 9.0 Hz, 1 H), 3.16 - 3.15 (m, 2H), 3.09 - 3.05 (m, 2H), 2.43 - 2.39 (m, 2H), 2.29 - 2.26 (m, 1 H), 1.69 - 1.64 (m, 1 H); LCMS m / z 424 [M+H]+.

[0268] Example 5 (S)-3-(5,7-Difluoro-2-(5-fluorothiophen-2-yl)-1 / - / -indol-3-yl)-A / -(2-oxopyrrolidin-3- yljpropenamide (E5)

[0269] To a stirred solution of Intermediate 3 (0.020 g, 0.06 mmol) in DMF (1 .0 mL) were added DIPEA (0.024 g, 0.18 mmol) and HATU (0.035 g, 0.092 mmol) at 0°C and the mixture held at this temperature for 10 minutes. A solution of (S)-3-aminopyrrolidin-2-one hydrochloride (6.70 mg, 0.067 mmol) in DMF (0.20 mL) was added dropwise at 0°C, and the resulting mixture allowed to warm to room temperature and stirred for a further 1 hour. The reaction mixture was diluted with H2O and organics extracted with 3 x EtOAc, then washed with ice cold water (2 x 30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (MeOH : CH2CI2 (1 :24)) to give the title compound as a white solid (0.015 g, 60%).1H NMR (400 MHz, DMSO-de) 6 11 .77 (s, 1 H), 8.18 (d, J = 8.0 Hz, 1 H), 7.82 (s, 1 H), 7.27 - 7.24 (m, 2H), 7.03 - 6.97 (m, 1 H), 6.89 (q, J = 2.0 Hz, 1 H), 4.31 - 4.25 (m, 1 H), 3.17 - 3.14 (m, 2H), 3.07 - 3.02 (m, 2H), 2.43 - 2.38 (m, 2H), 2.30 - 2.22 (m, 1 H), 1 .69 - 1 .62 (m, 1 H); LCMS m / z 408 [M+H]+.

[0270] Example 6 (S)-3-(5,7-Difluoro-2-(5-(trifluoromethyl)thiophen-2-yl)-1 H-indol-3-yl)-N-(2- oxopyrrolidin-3-yl)propenamide (E6)

[0271] To a stirred solution of Intermediate 4 (0.03 g, 0.08 mmol) in DMF (1.50 ml_) were added DIPEA (0.031 g, 0.24 mmol) and HATU (0.045 g, 0.12 mmol) at 0°C and the mixture held at this temperature for 10 minutes. A solution of (S)-3-aminopyrrolidin-2-one hydrochloride (8.0 mg, 0.088 mmol) in DMF (0.2 mL) was added dropwise at 0°C, and resulting mixture was further stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O and organics extracted with 3 x EtOAc, washed with ice cold water (2 x 20 mL), then dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (MeOH : CH2CI2 (1 :24)) to give the title compound as a white solid (0.02 g, 55%).1H NMR(400 MHz, DMSO-d6) 611.98 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.85-7.82 (m, 2H), 7.69-7.68 (m, 1H), 7.32 (dd, J= 9.5, 2.0 Hz, 1H), 7.10-7.04 (m, 1H), 4.32-4.23 (m, 1H), 3.16-3.11 (m, 4H), 2.47-2.43 (m, 2H), 2.28-2.21 (m, 1H), 1.69 - 1.58 (m, 1 H); LCMS 458 [M+H]+.

[0272] The compounds of Examples 7 to 13 and 15 to 16 were prepared in an analogous manner to the preparation of Examples 1 to 6:

[0273] Example 14 (S)-3-(2-(3,5-Dichlorothiophen-2-yl)-5,7-difluoro-1H-indol-3-yl)-N-(2-oxopyrrolidin-3- yl)propenamide (E14)

[0274] Step 1 :

[0275] To a stirred solution 2-bromo-3,5-dichlorothiophene (0.400 g, 1.72 mmol, 1.00 eq.) in tetrahydrofuran (4 mL) was added ethyl pent-4-ynoate (0.650 g, 5.17 mmol, 3.00 eq.) and triethylamine (0.430 g, 4.31 mmol, 2.50 eq.), under nitrogen. The reaction was stirred for 30 minutes under nitrogen. To the above reaction mixture PdCl2(PPh3)2 (0.120 g, 0.170 mmol, 0.100 eq.) and copper iodide (0.065 g, 0.340 mmol, 0.200 eq.) were added. The reaction was stirred at 90 °C for another four hours. The progress of the reaction was monitored by TLC (1% ethyl acetate in hexane) and LCMS analysis. After completion, the reaction was quenched using DI water (80 mL) and extracted with ethyl acetate (2 X 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography using 230-400 silica mesh (eluted at 2% ethyl acetate in hexane as eluent) to give ethyl 5-(3,5- dichlorothiophen-2-yl) pent-4-ynoate as a colourless liquid (0.370 g, 77%).

[0276] Step 2:

[0277] To a stirred solution ethyl 5-(3,5-dichlorothiophen-2-yl) pent-4-ynoate (0.350 g, 1.26 mmol, 1.0 eq.) in 1 ,4 dioxane (3.5 mL) was added 2,4-difluoro-6-iodoaniline (0.380 g, 1.51 mmol, 1.20 eq.) and caesium carbonate (0.610 g, 1.89 mmol, 1.50 eq.), under nitrogen. The reaction was stirred for 10 minutes then Pd(dppf)Ch (0.092 g, 0.126 mmol, 0.100 eq.) was added. The reaction mixture was stirred at 100 °C for another 16 hours. The progress of the reaction was monitored by TLC (1% ethyl acetate in hexane) and LCMS analysis. After completion of the reaction, the obtained material was poured into water (70 mL) and extracted with ethyl acetate (2 X 90 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography using 230-400 silica mesh (eluted at 1% ethyl acetate in hexane as eluent) to give ethyl 3-(2-(3,5-dichlorothiophen-2-yl)-5,7- difluoro-1 H-indol-3-yl) propanoate as yellow liquid (0.230 g, 45%).

[0278] Step 3:

[0279] To a stirred solution (S)-3-aminopyrrolidin-2-one (0.02 g, 0.20 mmol, 1.20 eq.) in toluene (1.4 mL) was added trimethylaluminum (2M in toluene) (0.25 mL, 0.52 mmol) dropwise at 0 °C. The reaction was stirred for 30 min at 0 °C then ethyl 3-(2-(3,5-dichlorothiophen-2-yl)-5,7- difluoro-1 H-indol-3-yl) propanoate (0.07 g, 0.17 mmol, 1.00 eq.) was added. The reaction mixture was stirred at 70 °C for another two hours. The progress of the reaction was monitored by TLC (5% methanol in dichloromethane) and LCMS analysis. After completion, the reaction mixture was quenched using saturated NaHCOa (35 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography using 230-400 silica mesh (eluted at 3% methanol in dichloromethane as eluent). The obtained material was lyophilized to give the title compound as a white solid (47 mg, 59%).1H NMR (400 MHz, DMSO-de) 5 111 .90 (s, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 7.82 (s, 1 H), 7.47 (s, 1 H), 7.35-7.32 (m, 1 H), 7.10-7.04 (m, 1 H), 4.26 (q, J = 8.4 Hz, 1 H), 3.17-3.14 (m, 2H), 2.89-2.86 (m, 2H), 2.39-2.33 (m, 2H), 2.29-2.24 (m, 1 H), 1 .67 (p, J = 9.2 Hz, 1 H); LCMS m / z 460.1 [M+1]+. BIOLOGICAL ASSAYS

[0280] APOL1 Potency Data (FLIPR Method)

[0281] Reagents and Materials

[0282] APOL1 Cell Line; a stable inducible (tetracycline (TET)) HEK293 mammalian expression system with APOL1 G1 gene; clone is APOL1 G1 2A8.

[0283] Cell culture

[0284] 1. Cells scaled up from frozen vials.

[0285] 2. APOL1 G1 2A8 frozen vials: 1.5 million cells per vial.

[0286] Scale up procedure and cell line maintenance

[0287] 1. Day 1 : Defrost frozen vial into T-175 flask.

[0288] 2. Day 4: (when 85% confluent): Split into T175 at 3 x 106cells per flask and split repeatedly every 48 - 72 hours (see medium details below) for continued propagation, cells are kept in continued culture up to passage 40. Assay plates are prepared as described below.

[0289] Cell Culture Medium

[0290] 1. DMEM (Gibco, Cat. No. #41965) + 10% TET free FBS (Gibco, Cat. No. A47362-01) + 1% P / S + 1% L-Glut + 5 pg / ml blasticidin + 100 pg / ml Zeocin.

[0291] Instruments and Equipment

[0292] 1. Esco, Airstream® Class II, Biological Safety Cabinet (Esco, Cat. No. CAB7522).

[0293] 2. Cellometer Auto T4 Bright Field Cell Counter (Nexcelom).

[0294] 3. E1 -ClipTip Multichannel Pipettes, 8-channel, 15 to 1250 pL (Thermo Fisher Scientific, Cat. No. 15613046).

[0295] 4. FLIPR PENTA High throughput cellular screening system (Molecular Devices, Cat. No. FLIPR PENTA).

[0296] Assay Procedure

[0297] Cell Assay Medium

[0298] 1. DMEM (Gibco, Cat. No. #41965) + 10% TET free FBS (Gibco, Cat. No. A47362-01 + 1% P / S + 1% L-Glut.

[0299] Preparation of Tetracycline

[0300] 1. Tetracycline stock is prepared at 2 mM in H2O, aliquoted and stored at -20°C. Day 1

[0301] Preparation of Cell Assay Plates

[0302] 1. Culture medium is aspirated from the T 175 cm2flasks.

[0303] 2. The cell monolayer is rinsed with PBS 1x at room temperature and is removed by aspiration.

[0304] 3. Cells are dissociated from flasks using TrypLE (Gibco, Cat. No. 12563011).

[0305] 4. The flasks are incubated with TrypLE for 3 minutes at 37°C.

[0306] 5. Cell Assay Medium is then added. Cell suspension is then transferred to an 50 mL Falcon polypropylene tube.

[0307] 6. Cells are then counted using a Nexcelom Cellometer Auto T4 Bright Field Cell Counter.

[0308] 7. Cells are diluted to achieve 7.5 x 105cells / mL.

[0309] 8. Using a E1 -ClipTip Multichannel Pipettes, 8-channel, 15 to 1250 pL (Thermo Fisher Scientific, Cat. No. 15613046) 20 L of cell suspension is added to each well (corresponds to 15,000 cells total per well) of a 384-well black walled, transparent flat bottom Poly-D-lysine coated plate (Greiner Bio-One, Cat. No. 781948).

[0310] 9. Plates are placed into humidified 37°C and 5% CO2 incubator (Thermo Fisher Scientific, Cat. No. 51026282) and left to equilibrate and adhere for 3 hours.

[0311] 10. Tetracycline is prepared in Cell Assay Medium at 2x, (4 pM).

[0312] 11 . 20 pL of media containing TET is added to each well of prepared 384-well cell plate.

[0313] 12. Plates are placed into humidified 30°C and 5% CO2 incubator (Thermo Fisher Scientific, Cat. No. 51026282) and left to equilibrate overnight.

[0314] Day 2

[0315] Preparation of dye kit

[0316] FLIPR Potassium Assay Bulk Kit (Molecular Devices, Cat. No. MLDVR8223).

[0317] 1. Remove one vial each of Component A (Dye) and Component C from the freezer, and then equilibrate to room temperature.

[0318] 2. Prepare Component A (Dye) by adding 10 mL chloride free EBSS (140 mM sodium gluconate, 2.5 mM potassium gluconate, 6 mM calcium gluconate, 2 mM magnesium sulfate, 5 mM glucose and 10 mM HEPES at pH 7.0). 3. Aliquot dye into 1 mL micro centrifuge tubes, one to be used for each plate on day of assay.

[0319] 4. Prepare Component C by adding 300 pL DMSO.

[0320] 5. Aliquot Component C into 0.3 mL Glass Screw Top Microvial (Thermo Fisher Scientific, Cat. No 6PSV9-03FIVP), one to be used for each plate on day of assay.

[0321] Dye loading for 1 cell plate

[0322] 1. Remove one aliquot of both Component A (Dye) and Component C from the freezer, and then equilibrate to room temperature.

[0323] 2. Dilute one aliquot of Component A (dye) (1 mL) into 14 mL of chloride free EBSS.

[0324] 3. Add 30 pL of Component C to 15 mL Component A (dye).

[0325] 4. Prepare 0.5 M Probenecid (Merck Life Science, Cat. No. P8761) using 1 M NaOH prepared in H2O.

[0326] 5. Add 50 pL 0.5 M Probenecid to 15 mL dye.

[0327] 6. Mix using a vortex for 1 to 2 minutes until the contents of the vial are combined.

[0328] 7. Remove Cell Assay Media from 384-well by inversion and gentle tapping.

[0329] 8. Add 30 pL dye to each well of cell plate with E 1 -ClipTip Multichannel Pipettes, 8-channel.

[0330] 9. Incubate for 30 minutes using a humidified 37°C and 5% CO2incubator.

[0331] Compound plate preparation for 1 cell plate

[0332] Two compound plates are prepared in 384 V Well Microplate Polypropylene (Greiner Bio- One, Cat. No. 781280).

[0333] 1. Plate 1 , preincubation drug plate. i. A 10-point concentration response curve is dispensed using Tecan D300e (Tecan UK, Cat. No. 30100152). A total of 16 concentration response curves (CRC’s) are dispensed into 384 V well Microplate. Maximum and Minimum relative fluorescence unit (RFU) control wells are dispensed using Tecan D300e. ii. The preincubation drug plate is hydrated with 70 pL chloride free EBSS. iii. The preincubation drug plate contents are transferred to the cell plate 30 minutes after loading with thallium sensitive dye (as described in Dye loading described above). iv. The compound transfer is performed using FLIPR. Mix: 3 strokes, 10 pL with speed© 10 pL / sec, Height 4.6 pL. Aspirate: 10 pL with speed© 10 pL / sec, Height 4.6 pL; Tip up speed of 20 mm / sec. Dispense: 10 pL with speed @ 15 pL / sec, Height 28 pL; liquid removal speed of 20 mm / sec. v. Incubate cell plate for a further 30 minutes in a humidified 37°C and 5% CO2 incubator. Plate 2, Thallium drug plate.

[0334] I. Prepare a 6.25 mM concentration of thallium sulfate (TI2SO4) from the 50 mM thallium sulfate stock (provided in the kit) in chloride free EBSS.

[0335] II. Compound CRC’s, maximum and minimum relative fluorescence unit (RFU) control wells are dispensed using Tecan D300e into 384 V Well Microplates.

[0336] III. Following dispense of compound and controls; the thallium drug plate is hydrated with 70 pL chloride free EBSS containing 6.25 mM thallium sulfate.

[0337] IV. The preincubation and thallium drug plates are prepared so that a final DMSO concentration of 0.3% v / v is maintained.

[0338] V. FLIPR PENTA is used to add the thallium drug plate to the cell plate, following the final 30-minute period with preincubation plate.

[0339] VI. Read parameters: Excitation: 470-495 nm; Emission: 515-575 nm, read every second for 290 seconds.

[0340] VII. The compound transfer is performed using FLIPR. Mix: 3 strokes, 10 pL with speed @ 10 pL / sec, Height 4.6 pL. Aspirate: 10 pL with speed @ 10 pL / sec, Height 4.6 pL; Tip up speed of 20 mm / sec. Dispense: 10 pL with speed @ 15 pL / sec, Height 28 pL; liquid removal speed of 20 mm / sec.

[0341] VIII. Start FLIPR PENTA. Data Analysis

[0342] I. Stat file: Export area under the curve between 14 and 42 seconds.

[0343] II. Well inhibition response is calculated by normalizing to the positive and negative controls.

[0344] III. Data is reported as IC50 (half maximum inhibitory concentration) and maximum percent inhibition.

[0345] The compounds of the invention were tested in the above referenced assay and the results are shown in Table 1 :

[0346] Table 1: APOL1 Potency Values he data in the above table were obtained from at least 3 separate tests.

Claims

CLAIMS1 . A compound of formula (I):or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein:R1represents: halogen; hydroxy; thiol; amino; cyano; -OC(O)Ci-6 linear, branched, or cyclic alkyl; -C(0)0Ci-6 linear, branched, or cyclic alkyl; -NHC(O)CI-6 linear, branched, or cyclic alkyl; -C(O)NHCI-6 linear, branched, or cyclic alkyl; -NHC(O)aryl; -C(O)NHaryl; -NHC(O)heteroaryl; -C(O)NHheteroaryl; -NHS(O)2CI-6 linear, branched, or cyclic alkyl; -S(O)2NHCI-6linear, branched, or cyclic alkyl; -NHS(O)2aryl; -S(O)2NHaryl;-NHS(O)2heteroaryl; -S(O)2NHheteroaryl; -NHC(O)NHCI-6 linear, branched, or cyclic alkyl; - NHC(O)NHaryl; -NHC(O)NHheteroaryl; C1-6 linear, branched, or cyclic alkyl; C2-6 linear, branched, or cyclic alkenyl; C1-6 linear, branched, or cyclic hydroxyalkyl; C1-6 linear, branched, or cyclic alkoxy; C1-6 linear, branched, or cyclic thioalkyl; C1-6 linear, branched, or cyclic haloalkyl; C1-6 linear, branched, or cyclic haloaminoalkyl; C1-6 linear, branched, or cyclic halothioalkyl; C1-6 linear, branched, or cyclic haloalkoxy; benzyloxy; benzylamino; benzylthio; 3 to 6-membered heterocycloalkenyl; 3 to 6-membered heterocycloalkyl; or 5 and 6-membered heteroaryl; m represents an integer selected from 0 to 4, such that when m represents 2, two R1groups together with the carbon atom to which they are attached may join to form a C4-8 cycloalkyl, aryl, or heteroaryl ring;R2represents halogen; hydroxy; thiol; amino; cyano; -NHC(O)CI-6 linear, branched, or cyclic alkyl; -C(O)NHCI-6 linear, branched, or cyclic alkyl; -NHC(O)aryl; -C(O)NHaryl;-NHC(O)heteroaryl; -C(O)NHheteroaryl; -NHS(O)2CI-6 linear, branched, or cyclic alkyl;-S(O)2NHCI-6 linear, branched, or cyclic alkyl; -NHS(O)2aryl; -S(O)2NHaryl; -NHS(O)2heteroaryl; -S(O)2NHheteroaryl; -NHC(O)NHCI-6 linear, branched, or cyclic alkyl; - NHC(O)NHaryl; -NHC(O)NHheteroaryl; C1-4 linear, branched, or cyclic alkyl; C2-4 linear, branched, or cyclic alkenyl; C1-4 linear, branched, or cyclic hydroxyalkyl; C1-4 linear, branched, or cyclic alkoxy; C1-4 linear, branched, or cyclic thioalkyl; C1-4 linear, branched, or cyclic haloalkyl; C1-4 linear, branched, or cyclic haloaminoalkyl; C1-4 linear, branched, or cyclic halothioalkyl; or C1-4 linear, branched, or cyclic haloalkoxy; n represents an integer selected from 0 to 3;Y is selected from: divalent C1-8 linear or branched cyclic alkyl; divalent C1-8 linear or branched alkoxy; divalent C1-8 linear or branched aminoalkyl; or divalent C1-8 linear or branched thioalkyl; wherein the divalent alkyl, divalent alkoxy, divalent aminoalkyl, and divalent thioalkyl are optionally substituted with one or more groups chosen from: C1-6 alkyl; aryl; heteroaryl; halogen; hydroxy; or amino;R3and R4are independently selected from: hydrogen; hydroxy; thiol; amino; halogen; C1-6 linear, branched, or cyclic alkyl; C1-6 linear, branched, or cyclic hydroxyalkyl; C1-6 linear, branched, or cyclic alkoxy; C1-6 linear, branched, or cyclic thioalkyl; C1-6 linear, branched, or cyclic haloalkyl; C1-6 linear, branched, or cyclic haloaminoalkyl; C1-6 linear, branched, or cyclic halothioalkyl; or C1-6 linear, branched, or cyclic haloalkoxy; or R3and R4, together with the carbon atom to which they are attached, may form a C3-6 cycloalkyl or carbonyl group; R5and R6are independently selected from: hydrogen; thiol; amino; halogen; hydroxy, C1-6 linear, branched, or cyclic alkyl; C1-6 linear, branched, or cyclic hydroxyalkyl; C1-6 linear, branched, or cyclic alkoxy; C1-6 linear, branched, or cyclic thioalkyl; C1-6 linear, branched, or cyclic haloalkyl; C1-6 linear, branched, or cyclic haloaminoalkyl; C1-6 linear, branched, or cyclic halothioalkyl;C1-6 linear, branched, or cyclic haloalkoxy; -OC(O)Ci-6 linear, branched, or cyclic alkyl; -C(O)OCi-6 linear, branched, or cyclic alkyl; -NHC(O)CI-6 linear, branched, or cyclic alkyl; - C(0)NHCI-6 linear, branched, or cyclic alkyl; -NHC(O)aryl; -C(O)NHaryl;-NHC(O)heteroaryl; -C(O)NHheteroaryl; -NHS(O)2CI-6 linear, branched, or cyclic alkyl; -S(O)2NHCI-6linear, branched, or cyclic alkyl; -NHS(O)2aryl; -S(O)2NHaryl;-NHS(O)2heteroaryl; -S(O)2NHheteroaryl; -NHC(O)NHCI-6 linear, branched, or cyclic alkyl; - NHC(O)NH aryl; or -NHC(O)NH heteroaryl; andR7, R8and R9are independently selected from: hydrogen; C1-6 linear, branched, or cyclic alkyl; C1-6 linear, branched, or cyclic hydroxyalkyl; C1-6 linear, branched, or cyclic alkoxy; C1-6 linear, branched, or cyclic thioalkyl; C1-6 linear, branched, or cyclic haloalkyl; C1-6 linear, branched, or cyclic haloaminoalkyl; C1-6 linear, branched, or cyclic halothioalkyl; or C1-6 linear, branched, or cyclic haloalkoxy.

2. The compound of formula (I) as defined in claim 1 , wherein: m represents an integer selected from 0 to 2; or m represents an integer selected from 1 or 2; or m represents an integer which is 2.

3. The compound of formula (I) as defined in claim 1 or claim 2, wherein: R1represents halogen; orR1represents fluorine.

4. The compound of formula (I) as defined in any one of claims 1 to 3, wherein: m represents 2 and both R1groups represent halogen; or m represents 2 and both R1groups represent fluorine.

5. The compound of formula (I) as defined in any one of claims 1 to 4, wherein: n represents an integer selected from 0 to 2; or n represents an integer selected from 0 or 1 ; or n represents an integer selected from 1 or 2; or n represents an integer which is 1 .

6. The compound of formula (I) as defined in any one of claims 1 to 5, wherein: R2represents halogen; C1-4 linear, branched, or cyclic haloalkyl; C1-4 linear, branched, or cyclic alkyl; or cyano; orR2represents halogen, C1-4 linear haloalkyl, C1-4 linear alkyl or cyano; or R2represents halogen; orR2represents fluorine, chlorine, bromine, trifluoromethyl, methyl or cyano; or R2represents fluorine.

7. The compound of formula (I) as defined in any one of claims 1 to 6, wherein:Y represents a divalent C1-8 linear or branched cyclic alkyl; orY represents a divalent C1-8 linear cyclic alkyl; orY represents an unsubstituted divalent C1-8 linear cyclic alkyl; orY represents an unsubstituted divalent C2-4 linear cyclic alkyl; orY represents an unsubstituted divalent C2 linear cyclic alkyl; orY represents -(CH2)2-.

8. The compound of formula (I) as defined in any one of claims 1 to 7, wherein: R3represents hydrogen or a C1-6 linear, branched, or cyclic alkyl; orR3represents hydrogen or a C1-6 linear alkyl; orR3represents hydrogen or a C1-4 linear alkyl; orR3represents hydrogen or methyl; or R3represents hydrogen.

9. The compound of formula (I) as defined in any one of claims 1 to 8, wherein:R4represents hydrogen or a C1-6 linear, branched, or cyclic alkyl; orR4represents hydrogen or a C1-6 linear alkyl; orR4represents hydrogen or a C1-4 linear alkyl; orR4represents hydrogen or methyl; orR4represents hydrogen.

10. The compound of formula (I) as defined in any one of claims 1 to 9, wherein R3and R4both represent hydrogen.

11. The compound of formula (I) as defined in any one of claims 1 to 10, wherein:R5represents hydrogen, a C1-6 linear, branched, or cyclic alkyl or hydroxy;R5represents hydrogen, a C1-6 linear alkyl or hydroxy; orR5represents hydrogen, a C1-4 linear alkyl or hydroxy; orR5represents hydrogen, methyl or hydroxy; orR5represents hydrogen or hydroxy; orR5represents hydrogen; orR5represents hydroxy.

12. The compound of formula (I) as defined in any one of claims 1 to 11 , wherein:R6represents hydrogen or a C1-6 linear, branched, or cyclic alkyl; orR6represents hydrogen or a C1-6 linear alkyl; orR6represents hydrogen or a C1-4 linear alkyl; orR6represents hydrogen or methyl; orR6represents hydrogen.

13. The compound of formula (I) as defined in any one of claims 1 to 12, wherein:R5and R6both represent hydrogen; orR5represents hydroxy and R6represents hydrogen.

14. The compound of formula (I) as defined in any one of claims 1 to 13, wherein:R7represents hydrogen or a C1-6 linear, branched, or cyclic alkyl; orR7represents hydrogen or a C1-6 linear alkyl; orR7represents hydrogen or a C1-4 linear alkyl; orR7represents hydrogen or methyl; orR7represents hydrogen.

15. The compound of formula (I) as defined in any one of claims 1 to 14, wherein:R8represents hydrogen or a C1-6 linear, branched, or cyclic alkyl; orR8represents hydrogen or a C1-6 linear alkyl; orR8represents hydrogen or a C1-4 linear alkyl; orR8represents hydrogen or methyl; orR8represents hydrogen.

16. The compound of formula (I) as defined in any one of claims 1 to 15, wherein:R9represents hydrogen or a C1-6 linear, branched, or cyclic alkyl; orR9represents hydrogen or a C1-6 linear alkyl; orR9represents hydrogen or a C1-4 linear alkyl; orR9represents hydrogen or methyl; orR9represents hydrogen.

17. The compound of formula (I) as defined in claim 1 wherein:R1represents halogen; m represents an integer selected from 0 to 2;R2represents halogen; cyano; C1-4 linear, branched, or cyclic alkyl; or C1-4 linear, branched, or cyclic haloalkyl; n represents an integer selected from 1 or 2;Y is divalent C1-8 linear or branched cyclic alkyl;R3and R4are both hydrogen;R5and R6are either both hydrogen or one of R5and R6represents hydrogen and the other represents hydroxy; andR7, R8and R9each represent hydrogen.

18. The compound of formula (I) as defined in any one of claims 1 to 17, wherein the compound of formula (I) is a compound of formula (IA)-(IH):wherein R1, R2, R3, R4, R5, R6, R7, R8and R9are as defined in claim 1 ; orwherein R1, R2and R5are as defined in claim 1 ; orwherein R1, R2, n, and R5are as defined herein, such as: wherein R1represents hydrogen or halogen, in particular both R1groups represent hydrogen or both R1groups represent halogen (i.e. fluorine); n represents 1 or 2;R2represents halogen; cyano; C1-4 linear, branched, or cyclic alkyl; or C1-4 linear, branched, or cyclic haloalkyl, in particular R2represents chlorine, fluorine, bromine, cyano, methyl or trifluoromethyl; and R5represents hydrogen or hydroxy; orwherein R2and R5are as defined in claim 1 ; orwherein R2and R5are as defined in claim 1 ; orwherein R2and R5are as defined in claim 1 ; orwherein R1, R2, R3, R4, R5, R6, R7, R8and R9are as defined in claim 1 ; orwherein R1, R2, R3, R4, R5, R6, R7, R8and R9are as defined in claim 1 ; orwherein R1, R2, R3, R4, R5, R6, R7, R8and R9are as defined in claim 1.

19. The compound of formula (I) as defined in any one of claims 1 to 18, which is the free base of a compound of Examples 1-16:Example 13-(2-(5-Chlorothiophen-2-yl)-5,7-difluoro-1H-indol-3-yl)-A / -((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propenamide (E1)Example 2 3-(5,7-Difluoro-2-(5-fluorothiophen-2-yl)-1H-indol-3-yl)-N-((3S,4A?)-4-hydroxy-2- oxopyrrolidin-3-yl)propenamide (E2)Example 3 3-(5,7-Difluoro-2-(5-(trifluoromethyl)thiophen-2-yl)-1 / 7-indol-3-yl)-N-((3S,4R)-4-hydroxy- 2-oxopyrrolidin-3-yl)propenamide (E3)Example 4 (S)-3-(2-(5-Chlorothiophen-2-yl)-5,7-difluoro-1H-indol-3-yl)-N-(2-oxopyrrolidin-3- yl)propenamide (E4)Example 5(S)-3-(5,7-Difluoro-2-(5-fluorothiophen-2-yl)-1 / 7-indol-3-yl)-N-(2-oxopyrrolidin-3- yl)propenamide (E5)Example 6 (S)-3-(5,7-Difluoro-2-(5-(trifluoromethyl)thiophen-2-yl)-1 H-indol-3-yl)-N-(2- oxopyrrolidin-3-yl)propenamide (E6)Example 73-(5,7-Difluoro-2-(5-methylthiophen-2-yl)-1 H-indol-3-yl)-N-((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide (E7)Example 83-(5,7-Difluoro-2-(4-methylthiophen-2-yl)-1 H-indol-3-yl)-N-((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide (E8)Example 9 (S)-3-(2-(5-Chlorothiophen-2-yl)-1 H-indol-3-yl)-N-(2-oxopyrrolidin-3-yl)propenamide(E9)Example 10 (S)-3-(5,7-Difluoro-2-(5-methylthiophen-2-yl)-1H-indol-3-yl)-N-(2-oxopyrrolidin-3- yl)propanamide (E10)Example 11 (S)-3-(2-(5-Cyanothiophen-2-yl)-5,7-difluoro-1H-indol-3-yl)-N-(2-oxopyrrolidin-3- yl)propenamide (E11)Example 12(S)-3-(2-(5-Bromothiophen-2-yl)-5,7-difluoro-1 H-indol-3-yl)-N-(2-oxopyrrolidin-3- yl)propanamide (E12)Example 13(S)-3-(5,7-Difluoro-2-(4-methylthiophen-2-yl)-1 H-indol-3-yl)-N-(2-oxopyrrolidin-3- yl)propanamide (E13)Example 14(S)-3-(2-(3,5-Dichlorothiophen-2-yl)-5,7-difluoro-1H-indol-3-yl)-N-(2-oxopyrrolidin-3- yl)propenamide (E14)Example 15(S)-3-(2-(5-Chloro-4-methylthiophen-2-yl)-5,7-difluoro-1H-indol-3-yl)-N-(2- oxopyrrolidin-3-yl)propenamide (E 15)Example 16(S)-3-(5,7-Difluoro-2-(5-fluoro-4-methylthiophen-2-yl)-1 H-indol-3-yl)-N-(2-oxopyrrolidin-3-yl)propanamide (E16)or a pharmaceutically acceptable salt or solvate thereof.

20. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 19.

21. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 19, in combination with one or more therapeutic agents.

22. A compound as defined in any of claims 1 to 19 for use in therapy.

23. A compound as defined in any of claims 1 to 19 for use in the prophylaxis or treatment of a disease or condition alleviated by APOL1 inhibition.

24. A compound as defined in any of claims 1 to 19 for use in the prophylaxis or treatment of an APOL1 mediated kidney disease.

25. A compound as defined in any of claims 1 to 19 for use in the prophylaxis or treatment of end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal and segmental glomerulosclerosis (FSGS), HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

26. A process for preparing a compound of formula (I) as herein defined in claim 1 which comprises:(a) reacting a compound of formula (II):wherein R1, R2, m, n and Y are as defined in claim 1 , with a compound of formula (III):(Ill) wherein R3, R4, R5, R6, R7, R8and R9are as defined in claim 1 ; or(b) reacting a compound of formula (IV):wherein R1, R2, m, n and Y are as defined in claim 1 and L1represents a suitable leaving group, such as an -0-0-6 alkyl group, in particular -O-ethyl, with a compound of formula (HI):wherein R3, R4, R5, R6, R7, R8and R9are as defined in claim 1 ; or(c) deprotection of a protected derivative of a compound of formula (I); or(d) interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof; and(e) optional formation of a pharmaceutically acceptable salt of a compound of formula (I).

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