5-[2,7-diazaspiro[3.5]nonan-7-YL]-5-[4-phenoxyphenyl]hexahydropyrimidine-2,4,6-trione derivatives as MMP9 inhibitors for the treatment of dry eye disease

Abstract

The present invention relates to spirocyclic barbiturates of the general formula (I) or a pharmaceutically acceptable salt thereof, as MMP9 inhibitors for the treatment of ocular surface diseases, such as e.g. dry eye disease.

Description

[0001] 5-[2,7-DIAZASPIRO[3.5]NONAN-7-YL]-5-

[0002] [4-PHENOXYPHENYLJHEXAHYDROPYRIMIDINE-2, 4, 6-TRIONE DERIVATIVES AS MMP9 INHIBITORS

[0003] FOR THE TREATMENT OF DRY EYE DISEASE

[0004] Field of the invention

[0005] The present invention relates to spirocyclic barbiturates derivatives useful as MMP9 inhibitors, their manufacture, pharmaceutical compositions comprising said derivatives and their use as medicaments for the therapeutic and / or prophylactic treatment of an ocular surface disease.

[0006] Background of the invention

[0007] Matrix metalloproteases (MMPs) were intensively investigated as drug targets for the treatment of a variety of diseases in the past decades. MMPs are zinc dependent metallo- endopeptidases that are involved in many important biological processes such as for example tissue remodelling, wound healing, embryonic development, nerve growth or cell migration. In humans, about 24 different MMPs subdivided into several different subclasses with different substrate specificity are known as of today.

[0008] Imbalanced activity of MMP9 was associated with a number of different diseases in the past and hence this target was subject to different drug discovery programs, related for example to cardiovascular diseases, cancer, inflammatory and neurodegenerative disorders as well as lung diseases (for a more recent review, notably on MMP9 and cancer, see Mondal et al., Eur J Med Chem 194 (2020), 112260, and references cited therein). In the context of these programs, many compounds with various degrees of specificity towards other MMPs were made and are described in the literature. Several of them were investigated in clinical trials. For example, to name just a few, AZD-1236 was investigated for chronic obstructive pulmonary disease (COPD) up to clinical phase II, S-3304 for lung cancer in Ph I / II or tanomastat up to Ph III for rheumatoid arthritis and solid tumor. However, all clinical trials were stopped due to lack of efficacy or side effects.

[0009] Topical administration of classical small molecule MMP inhibitors originating from different compound series for ocular surface diseases was not widely investigated. An experiment with the hydroxamate inhibitor tool compound PES 103 was described by Mori et al. (Basic Clin Pharmacol Toxicol 111 (2012), 289), and some data on tear production, but not on comeal surface integrity, were provided. Also, a number of approaches for indirect modulation of MMP9 activity were described in the literature. For a recent review see Alireza et al., Exp Eye Res 205 (2021), 108523, and references cited therein. The topical route of administration is believed to reduce systemic drug exposure which may alter safety or specificity requirements for the new MMP9 inhibitors that - in cases of systemic administration - may have been limiting before. This invention describes the synthesis and use of new and structurally distinct MMP9 inhibitors that are suitable for the topical ocular treatment of front of the eye diseases such Dry Eye Disease (DED).

[0010] Dry Eye Disease (DED) is the most common reason for seeking medical eye care and affects 5-30% of the population worldwide. DED impairs patient’s visual function and quality of life resulting in global costs of $4.9bn by 2029. The condition is defined as a multifactorial disease of the ocular surface characterized by a “loss of tear film homeostasis, and is accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles” (TFOS DEWS II report). Patients frequently experience ocular grittiness, discomfort, pain and loss of low contrast visual acuity, which can impact some visual functions such as reading. Symptoms and signs of the condition occur more frequently with advanced age and female sex. Risk factors include contact lens usage, laser-eye surgery, prolonged use of computer screens and certain low humidity environmental conditions.

[0011] Currently, mild forms of dry-eye can be treated using over-the-counter tear replacement drops. Standard of care (SoC) for more severe or chronic forms of the disease are two types of approved drugs targeting ocular surface inflammation. Cyclosporin-based drugs (usually given l-2x daily) like Restasis, Ikervis or Cequa inhibit calcineurin activity and thereby reduce T-cell activation and hence inflammatory cytokine production. Unfortunately, these drugs are only effective in certain patient subpopulations, have a delayed onset (up to 6 months) and induce ocular irritation / buming in a significant number of patients. Xiidra (Lifitegrast solution dosed through eye drops 2x daily), has been approved in the USA as an additional SoC. The drug is an LFA-1 inhibitor, which prevents T-cell trafficking to the ocular surface. Although safe, Xiidra showed variable results in two Phase 3 trials and efficacy of the drug on the market remains to be demonstrated. Very recently, FDA approved Tyrvaya, a nasal spray of a nicotinic acetylcholine receptor agonist (varenicline solution), stimulating basal tear production.

[0012] In summary, there is a clear unmet medical need for developing new DED therapies targeting mechanisms of action beyond T-cell inhibition or lubrication with faster onset and better efficacy, tolerability and durability. The matrix metalloproteinase (MMP) family of 24 (in human) zinc-dependent endoproteinases together play important roles in the degradation of extracellular matrix proteins. MMP9 and MMP2 (both also known as gelatinases) are 92 kDa enzymes capable of binding and disrupting collagen types I, IV, V, VII, X, IX, elastin, fibronectin, aggrecan, vitronectin, laminin, occludin and many non-ECM molecules including pro-TNF-a, transforming growth factor (TGF)-P, pro-IL-ip, pro-IL-8 and monocyte chemoattractant protein (MCP)-3. Elevated protein and mRNA levels of MMP9 have been correlated with increased severity of human dry-eye disease. A point of care test measuring MMP9 level above 40 ng / ml within the tear film of dryeye patients is currently marketed as a diagnostic tool for the condition (Inflammadry™).

[0013] Elevated expression and activity of MMP9 has also been observed in multiple mouse models of the condition (scopolamine-induced dry eye and concanavalin A-induced dry-eye) and these models have been used to investigate the role of MMP9 in the disease. MMP9 knock-out mice are protected from experimental induction of dry-eye-dependent phenotypes, as measured by disruption of the comeal epithelial barrier by the fluorescein staining method. In these models, the protective effect of MMP9 inhibition was associated with preservation of epithelial occludin level, suggesting maintenance of the tight junction structure comprising the epithelial surface. In vitro, induction of MMP9 in comeal epithelial cells has been shown to occur in response to hyperosmolar or inflammatory stress along with decreased barrier function of the comeal epithelium as measured by transepithelial electrical resistance (TEER). In conclusion, MMP9 is a target with strong link to DED, good druggability on the ocular surface and a differentiated MoA (epithelial barrier break down, aggravation of inflammation) compared to the standard of care (SoC).

[0014] Therefore, inhibiting the MMP9 activity is a promising therapeutic strategy for the treatment or prevention of MMP9-mediated diseases or disorders, such as ocular surface diseases, in particular dry eye disease.

[0015] There is a need for new compounds, formulations, treatments and therapies to treat or prevent MMP9-mediated diseases or disorders. It is, therefore, an object of this invention to provide compounds useful for the treatment or prevention or amelioration of such diseases and disorders with improved therapeutic properties, in particular improved pharmacokinetic properties. Summary of the invention

[0016] A first object of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0017] L is -O-, -NH-, -C=C~, -CONH-, -NHCO- or a covalent bond; is phenyl or a 6-membered heteroaryl;

[0018] R1is selected from Ce-u-aryl, 5-6-membered heteroaryl, Cs-s-cycloalkyl and 3-11 membered heterocyclyl, wherein R1is optionally substituted with one or more R2which can be the same or different; spiro radical i is a 3-6 membered heterocyclyl which may contain one or two identical or different heteroatoms selected from O, N and S and may be substituted with one or more R3which can be the same or different; and the sub-ring a) a 3-11 membered heterocyclyl which may contain one, two, three or four identical or different heteroatoms selected from O, N and S and may be substituted with one or more R4which can be the same or different; or b) a C3-6-cycloalkyl optionally substituted with one or more R5which can be the same or different;

[0019] R2is selected from halo-Ci-6-alkoxy, C3-6-cycloalkyl, Ci-6-alkyl, halo- Ci-6-alkyl and halogen;

[0020] R3, R4and R5are each independently selected from oxo, Ci-6-alkyl, C2-8-alkoxy alkyl, hydroxy - Ci-6-alkyl, -COR6, -S(O)2R7, -NR8R8, -CO2R9, 3-10 membered Co-6-alkyl-heterocyclyl, C3-6- cycloalkyl, 5-6 membered Co-6-alkyl-heteroaryl and Co-6-alkyl-C6-i4-aryl; wherein the 3-10 membered Co-6-alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl or - CO2(Ci-6-alkyl); C2-8-alkoxyalkyl is optionally substituted with hydroxy; and Co-6-alkyl-C6-i4- aryl is optionally substituted with -B(OH)2;

[0021] R6is selected from Ci-6-alkyl, hydroxy-Ci-6-alkyl, amino-Ci-6-alkyl, -Co-6-alkyl-N(RloR10’), C3-6- cycloalkyl, 3-6 membered Co-6-alkyl-heterocyclyl and -Co-6-alkyl-OC(0)(Ci-6-alkyl); wherein the 3-6 membered Co-6-alkyl-heterocyclyl is optionally substituted with -CO2(Ci-6- alkyl), and hydroxy-Ci-6-alkyl is optionally substituted with amino, -NHCO2(Ci-6-alkyl) or - C(O)(C 1-6-al kyl);

[0022] R7is 3-6 membered Co-6-alkyl-heterocyclyl optionally substituted with Ci-6-alkyl;

[0023] R8and R8are each independently selected from hydrogen, -CO2(Ci-6-alkyl), 3-10 membered Co- 6-alkyl-heterocyclyl optionally substituted with Ci-6-alkyl;

[0024] R9is Ci-6-alkyl;

[0025] R10and R10are each independently selected from hydrogen, Ci-6-alkyl, hydroxy-Ci-6-alkyl and - CO2(Ci-6-alkyl).

[0026] A further object of the present invention is a process for the preparation of a compound as described herein, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (II) with a compound of formula (III) wherein L, Ar, R1and are as described herein and X is halogen, in the presence of a base to form said compound of formula (I).

[0027] A further object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to the process as described above.

[0028] A further object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0029] A further object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

[0030] A further object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of an ocular surface disease. A further object of the present invention is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of an ocular surface disease.

[0031] A further object of the present invention is a method for the therapeutic and / or prophylactic treatment of an ocular surface disease, which method comprises administering an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0032] Detailed description of the invention

[0033] The following definitions of the general terms used in the present description apply irrespectively of whether the terms in question appear alone or in combination with other groups.

[0034] The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“Ci-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms. Some non-limiting examples of alkyl include methyl (Me), ethyl (Et), propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particular alkyl groups have 1 to 4 carbon atoms (“Ci-4-alkyl”). A particularly preferred, yet non-limiting example of alkyl is methyl. “Co-alkyl” means a covalent bond.

[0035] The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“Ci-6-alkoxy”). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet non-limiting example of alkoxy is methoxy.

[0036] The term “alkoxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Preferably, “alkoxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably one hydrogen atom of the alkyl group have been replaced by an alkoxy group. Particularly preferred, yet non-limiting examples of alkoxyalkyl is methoxymethyl and 2-methoxyethyl.

[0037] The term “amino” refers to a -NH2 group.

[0038] The term “aminoalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group have been replaced by an amino moiety.

[0039] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members (“Ce-u-aryl”), preferably, 6 to 12 ring members, and more preferably 6 to 10 ring members, and wherein at least one ring in the system is aromatic. A particularly preferred, yet non-limiting example of aryl is phenyl.

[0040] The terms “asymmetric carbon atom” and “asymmetric center” mean a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can be of the “R” or “S” configuration.

[0041] The term “cyano” refers to a -CN (nitrile) group.

[0042] The term “cycloalkyl” as used herein refers to a saturated or partly unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“Cs-io-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms, in particular 3 to 6 ring carbon atoms. “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and spiro[2.3]hexan-5-yl.

[0043] The terms “halogen” or “halo”, alone or in combination, denotes fluoro, chloro, bromo or iodo and particularly fluoro, chloro or bromo, more particularly fluoro and chloro. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to four halogens, i.e. one, two, three or four halogens.

[0044] The term “haloalkyl” refers to an alkyl group, as previously defined, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl and trifluoroethyl.

[0045] The term “haloalkoxy” refers to an alkoxy group, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet nonlimiting examples of haloalkoxy are difluoromethoxy and trifluoromethoxy.

[0046] The term "heteroaryl" refers to a mono- or multivalent, monocyclic or bicyclic, preferably bicyclic ring system having a total of 5 to 12 ring members, preferably, 5 to 10 ring members, more preferably 5 to 6 ring members, even more preferably 5 to 8 ring members wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl include 2-pyridyl, 3-pyridyl, 4-pyridyl, indol-l-yl, lH-indol-2-yl, lH-indol-3-yl, lH-indol-4-yl, lH-indol-5-yl, lH-indol-6-yl, lH-indol-7-yl, 1,2- benzoxazol-3-yl, l,2-benzoxazol-4-yl, l,2-benzoxazol-5-yl, l,2-benzoxazol-6-yl, 1,2- benzoxazol-7-yl, lH-indazol-3-yl, lH-indazol-4-yl, lH-indazol-5-yl, lH-indazol-6-yl, 1H- indazol-7-yl, pyrazol-l-yl, lH-pyrazol-3-yl, lH-pyrazol-4-yl, lH-pyrazol-5-yl, imidazol-l-yl, lH-imidazol-2-yl, lH-imidazol-4-yl, lH-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-4-yl, and l,2,4-oxadiazol-3-yl. Most preferably, “heteroaryl” refers to 3-pyridyl, 4- pyridyl, lH-pyrazol-5-yl, thiazol-4-yl, or l,2,4-oxadiazol-3-yl.

[0047] The term “heterocyclyl” refers to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. “Bicyclic heterocyclyl” refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Some non-limiting examples of heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 2-oxopyrrolidin-l-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5-oxopyrrolidin-3-yl, 2-oxo-l -piperidyl, 2-oxo-3 -piperidyl, 2-oxo-4- piperidyl, 6-oxo-2-piperidyl, 6-oxo-3-piperidyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- piperidinyl, morpholino, morpholin-2-yl, morpholin-3-yl, pyrrolidinyl (e.g., pyrrolidin-3-yl), 3- azabicyclo[3.1.0]hexan-6-yl, or 2,5-diazabicyclo[2.2. l]heptan-2-yl.

[0048] The term “heterocyclyl” also includes an aryl or heteroaryl group fused to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 10 ring atoms, ring system of 3 to 10 ring atoms wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon as described above. Examples include quinoline, benzothiophene, indole, and benzofuran.

[0049] The term “hydroxy” refers to an -OH group.

[0050] The term “hydroxyalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group have been replaced by a hydroxy moiety. Examples include alcohols and diols.

[0051] The term “oxo”, alone or in combination with other groups, refers to =0.

[0052] The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein.

[0053] Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid. The term “protecting group” (PG) denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protective groups can be removed at the appropriate point. Exemplary protective groups are amino-protective groups, carboxy-protective groups or hydroxy-protective groups. Particular protective groups are the tert-butoxy carbonyl (Boc), benzyloxy carbonyl (Cbz), fluorenylmethoxy carbonyl (Fmoc) and benzyl (Bn). Further particular protective groups are the tert-butoxy carbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc). More particular protective group is the tert-butoxy carbonyl (Boc). Exemplary protective groups and their application in organic synthesis are described, for example, in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.

[0054] The term “prophylaxis” as used herein includes preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

[0055] The terms “moiety” and “substituent” refer to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule.

[0056] The term "optionally substituted" means unsubstituted or substituted. Generally, but not limited to, "one or more substituents" means one, two or three, preferably one or two substituents. Generally these substituents can be the same or different.

[0057] The term “substituted” refers to the replacement of at least one of hydrogen atoms of a compound or moiety with another substituent or moiety. Examples of such substituents include, without limitation, halogen, -OH, -CN, oxo, alkoxy, alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl and heterocycle. For example, the term “haloalkyl” refers to the fact that one or more hydrogen atoms of an alkyl (as defined below) is replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one aspect, substituted as used herein can refer to replacement of at least one hydrogen atom of a compound or moiety described herein with halogen or alkyl. The term “ECX” is the half maximal effective concentration and denotes the plasma concentration of a particular compound required for obtaining x% of the maximum of a particular effect in vivo. Examples of “ECX” are EC 20, EC50 and EC100 denoting the plasma concentration of a particular compound required for obtaining 20%, 50% and 100%, respectively, of the maximum of a particular effect in vivo.

[0058] The term “treatment” as used herein includes: (1) inhibiting the state, disease, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (2) relieving the condition or disease (i. e. , causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.

[0059] The following abbreviations are used in the present text:

[0060] ACN: Acetonitrile

[0061] BOC:tertButyloxy carbonyl protecting group

[0062] BP: Boiling point

[0063] CBZ: Benzyloxycarbonyl protecting group

[0064] DBU: l,8-Diazabicyclo[5.4.0]undec-7-ene

[0065] DCM: Dichloromethane

[0066] DIPEA: Diisopropylethylamine

[0067] DMF: Dimethylformamide

[0068] DMSO: Dimethylsolfoxide

[0069] ESI: Electrospray ionization

[0070] FA: Formic acid

[0071] HATU : O-(7 -Azabenzotri azol- 1 -yl)-N,N,N',N'-tetramethyluronium-hexafluorphosphate

[0072] HPLC: High pressure liquid chromatography LCMS: Liquid chromatography coupled with a mass spectrometer

[0073] LDA: Lithium diisopropylamide

[0074] MS: Mass spectrometry

[0075] NBS: N-Bromosuccinimide

[0076] NMR: Nuclear magnetic resonance

[0077] PE: Petroleum ether

[0078] PG: Protecting group

[0079] RT : Room temperature

[0080] SFC: Supercritical fluid chromatography (CO2 as eluent)

[0081] TCEP: Tris(2-carboxyethyl)phosphin

[0082] TEA: Triethylamine

[0083] TLC: Thin layer chromatography

[0084] TLCK: Na-Tosyl-Lys-chloromethylketone, HC1 salt

[0085] TFA: Trifluoroacetic acid

[0086] THF: Tetrahydrofurane

[0087] Compounds of the invention

[0088] In a first aspect, the present invention provides a compound of formula (I)

[0089] or a pharmaceutically acceptable salt thereof, wherein:

[0090] L is -O-, -NH-, -C=C~, -CONH-, -NHCO- or a covalent bond;

[0091] Ar is phenyl or a 6-membered heteroaryl;

[0092] R1is selected from Ce-u-aryl, 5-6-membered heteroaryl, Cs-s-cycloalkyl and 3-11 membered heterocyclyl, wherein R1is optionally substituted with one or more R2which can be the same or different; spiro radical i is a 3-6 membered heterocyclyl which may contain one or two identical or different heteroatoms selected from O, N and S and may be substituted with one or more R3which can be the same or different; and the sub-ring

[0093] IS: c) a 3-11 membered heterocyclyl which may contain one, two, three or four identical or different heteroatoms selected from O, N and S and may be substituted with one or more R4which can be the same or different; or d) a C3-6-cycloalkyl optionally substituted with one or more R5which can be the same or different;

[0094] R2is selected from halo-Ci-6-alkoxy, C3-6-cycloalkyl, Ci-6-alkyl, halo- Ci-6-alkyl and halogen;

[0095] R3, R4and R5are each independently selected from oxo, Ci-6-alkyl, C2-8-alkoxy alkyl, hydroxy - Ci-6-alkyl, -COR6, -S(O)2R7, -NR8R8, -CO2R9, 3-10 membered Co-6-alkyl-heterocyclyl, C3-6- cycloalkyl, 5-6 membered Co-6-alkyl-heteroaryl and Co-6-alkyl-C6-i4-aryl; wherein the 3-10 membered Co-6-alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl or - CO2(Ci-6-alkyl); C2-8-alkoxyalkyl is optionally substituted with hydroxy; and Co-6-alkyl-C6-i4- aryl is optionally substituted with -B(OH)2;

[0096] R6is selected from Ci-6-alkyl, hydroxy-Ci-6-alkyl, amino-Ci-6-alkyl, -Co-6-alkyl-N(RloR10’), C3-6- cycloalkyl, 3-6 membered Co-6-alkyl-heterocyclyl and -Co-6-alkyl-OC(0)(Ci-6-alkyl); wherein the 3-6 membered Co-6-alkyl-heterocyclyl is optionally substituted with -CO2(Ci-6- alkyl), and hydroxy-Ci-6-alkyl is optionally substituted with amino, -NHCO2(Ci-6-alkyl) or - C(O)(C 1-6-al kyl);

[0097] R7is 3-6 membered Co-6-alkyl-heterocyclyl optionally substituted with Ci-6-alkyl;

[0098] R8and R8are each independently selected from hydrogen, -CO2(Ci-6-alkyl), 3-10 membered Co- 6-alkyl-heterocyclyl optionally substituted with Ci-6-alkyl;

[0099] R9is Ci-6-alkyl;

[0100] R10and R10are each independently selected from hydrogen, Ci-6-alkyl, hydroxy-Ci-6-alkyl and - CO2(Ci-6-alkyl).

[0101] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is -O-, -CONH- or a covalent bond.

[0102] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl, pyridinyl or pyrazinyl. In a preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl or pyridinyl.

[0103] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is Ce-u-aryl or 3-11 membered heterocyclyl, optionally substituted with one or more R2which can be the same or different.

[0104] In a preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl or dihydrobenzofuranyl.

[0105] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is halo-Ci-6-alkoxy or halogen.

[0106] In a preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is trifluoromethoxy or chlorine.

[0107] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein is a spiro radical in which the sub-ring is 4-6 membered heterocyclyl which may contain one or two identical or different heteroatoms selected from O and N and may be substituted with one or more R3which can be the same or different; and the sub-ring a) a 4-9 membered heterocyclyl which may contain one or two identical or different heteroatoms selected from O and N and may be substituted with one or more R4which can be the same or different; or b) a C3-6-cycloalkyl optionally substituted with one or more R5which can be the same or different. In a preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein In a particularly preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0108] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is -C(O)(Ci-6-alkyl).

[0109] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from oxo, Ci-6-alkyl, hydroxy - Ci-6-alkyl, -COR6, -S(O)2R7, -NR8R8, -CO2R9, 3-10 membered Co-6-alkyl-heterocyclyl and Co-6- alkyl-Ce-u-aryl, wherein the 3-10 membered Co-6-alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl.

[0110] In a preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from Ci-6-alkyl, hydroxy-Ci-6- alkyl, -COR6, -S(O)2R7, -NR8R8and 3-10 membered Co-6-alkyl-heterocyclyl, wherein the 3-10 membered Co-6-alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl.

[0111] In a particularly preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydroxyethyl, - C(O)(CH2OH), (lR,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino, 4-piperidylsulfonyl, 4- piperidylacetyl, azetidin-3-ylmethyl, (l-methyl-4-piperidyl)amino and methyl. In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5is -NR8R8, wherein R8and R8are each independently selected from hydrogen and -CO2(Ci-6-alkyl).

[0112] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R6is hydroxy-Ci-6-alkyl or 3-6 membered Co- 6-alkyl-heterocyclyl. In a preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R6is hydroxymethyl or -CH2-4-piperidyl.

[0113] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R7is 3-6 membered Co-6-alkyl-heterocyclyl substituted with Ci-6-alkyl.

[0114] In a preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R7is 4-piperidyl. In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R8and R8are selected from hydrogen and 3- 10 membered Co-6-alkyl-heterocyclyl optionally substituted with Ci-6-alkyl.

[0115] In a preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R8and R8are selected from hydrogen,

[0116] (lR,5S)-8-methyl-8-azabicyclo[3.2. l]octan-3-yl]amino and l-methyl-4-piperidyl.

[0117] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: L is -O-, -NH-, -C=C~, -CONH-, -NHCO- or a covalent bond;

[0118] Ar is phenyl, pyridinyl or pyrazinyl,

[0119] R1is Ce-u-aryl or 3-11 membered heterocyclyl, optionally substituted with one or more R2which can be the same or different;

[0120] R2is halo-Ci-6-alkoxy or halogen; R3is selected from -C(O)(Ci-6-alkyl); and

[0121] R4is selected from oxo, Ci-6-alkyl, hydroxy-Ci-6-alkyl, -COR6, -S(O)2R7, -NR8R8, -CO2R9, 3-10 membered Co-6-alkyl-heterocyclyl and Co-6-alkyl-Ce-i4-aryl, wherein the 3-10 membered Co-6- alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl; R5is -NR8R8, wherein R8and R8are each independently selected from hydrogen and -CC>2(Ci- 6-alkyl);

[0122] R6is hydroxy-Ci-6-alkyl or 3-6 membered Co-6-alkyl-heterocyclyl;

[0123] R7is 3-6 membered Co-6-alkyl-heterocyclyl substituted with Ci-6-alkyl;

[0124] R8and R8are each independently selected from hydrogen and 3-10 membered Co-6-alkyl- heterocyclyl optionally substituted with Ci-6-alkyl.

[0125] In a preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0126] L is -O-, -CONH- or a covalent bond;

[0127] Ar is phenyl or pyridinyl;

[0128] R1is Ce-u-aryl or 3-11 membered heterocyclyl, optionally substituted with one or more R2which can be the same or different;

[0129] R2is halo-Ci-6-alkoxy or halogen;

[0130] R4is selected from Ci-6-alkyl, hydroxy-Ci-6-alkyl, -COR6, -S(O)2R7, -NR8R8and 3-10 membered

[0131] Co-6-alkyl-heterocyclyl, wherein the 3-10 membered Co-6-alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl;

[0132] R6is hydroxy-Ci-6-alkyl or 3-6 membered Co-6-alkyl-heterocyclyl;

[0133] R7is 3-6 membered Co-6-alkyl-heterocyclyl substituted with Ci-6-alkyl; R8and R8are selected from hydrogen and 3-10 membered Co-6-alkyl-heterocyclyl optionally substituted with Ci-6-alkyl.

[0134] In a particularly preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0135] L is -O-, -CONH- or a covalent bond;

[0136] Ar is phenyl or pyridinyl,

[0137] R1is phenyl or dihydrobenzofuranyl;

[0138] R2is trifluoromethoxy or chlorine;

[0139] R4is selected from hydroxyethyl, -C(O)(CH2OH), (lR,5S)-8-methyl-8-azabicyclo[3.2. l]octan-3- yl] amino, 4-piperidylsulfonyl, 4-piperidylacetyl, azetidin-3-ylmethyl, (l-methyl-4- piperidyl)amino, methyl and (l-methyl-4-piperidyl)amino;

[0140] R6is hydroxymethyl or methyl-4-piperidyl;

[0141] R7is 4-piperidyl;

[0142] R8and R8are selected from hydrogen, (lR,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino and l-methyl-4-piperidyl.

[0143] In one embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 5-[2-(2-Hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-[4-[4-

[0144] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione;

[0145] 5-[2-(2-phenylethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-[4-[4-

[0146] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione;

[0147] 5- [2-(2-hy droxy acetyl)-2, 7 -diazaspiro [3.5]nonan-7 -yl] -5 - [4 - [4 -

[0148] (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0149] 5-[4-(3-cyclopropylphenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;

[0150] 5- [2-(2-hy droxy acetyl)-2, 7 -diazaspiro [3.5]nonan-7 -yl] -5 - [4 - (3 - methylphenoxy )phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0151] 5-[4-(2,3-dihydrobenzofuran-5-yloxy)phenyl]-5-[2-(2-hy droxy acetyl)-2,7-diazaspiro[3.5]nonan- 7-y 1] hexahy dropy rimi dine-2, 4, 6-trione;

[0152] 5-[4-(2,3-dihydrobenzofuran-6-yloxy)phenyl]-5-[2-(2-hy droxy acetyl)-2,7-diazaspiro[3.5]nonan- 7- yl]hexahydropyrimidine-2, 4, 6-trione;

[0153] 5-[4-(l,3-benzodioxol-5-yloxy)phenyl]-5-[2-(2-hy droxy acetyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimi dine-2, 4, 6-trione;

[0154] 5-[4-(l,3-benzodioxol-5-yloxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimi dine-2, 4, 6-trione;

[0155] 5-[4-[3-(difluoromethoxy)phenoxy]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimi dine-2, 4, 6-trione;

[0156] 5-[4-[3-(difluoromethoxy)phenoxy]phenyl]-5-[2-(2-hy droxy ethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimi dine-2, 4, 6-trione;

[0157] 5-[2-(2-hy droxy acetyl)-2, 7-diazaspiro[3.5]nonan-7-yl]-5-(4-phenoxyphenyl)-l, 3-diazinane-

[0158] 2, 4, 6-trione;

[0159] 5-(2-(2 -hy droxy ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-5-(4-phenoxyphenyl)pyrimi dine- 2,4,6(lH,3H,5H)-trione; 5-[2-(l,4-dioxane-2-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-(4-phenoxyphenyl)-l,3- diazinane-2, 4, 6-trione;

[0160] 5-[4-(benzofuran-5-yloxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimi dine-2, 4, 6-trione;

[0161] 5-[4-(4-cyclopropylphenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;

[0162] 5-[4-(4-chlorophenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;

[0163] 5- [2-(2-hy droxy acetyl)-2, 7 -diazaspiro [3.5]nonan-7 -yl] -5 - [4 - [4 - (trifluoromethoxy )phenyl]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0164] 5- [2-(2-hy droxy acetyl)-2, 7 -diazaspiro [3.5]nonan-7 -yl] -5 - [3 - [4 - (trifluoromethoxy)anilino]phenyl]hexahydropyri mi dine-2, 4, 6-trione;

[0165] 5- [2-(2-hy droxy ethyl)-2,7-diazaspiro[3.5] nonan-7-yl] -5 - [3 - [4 -

[0166] (trifluoromethoxy)anilino]phenyl]hexahydropyri mi dine-2, 4, 6-trione;

[0167] 5- [2-(2-hy droxy ethyl)-2,7-diazaspiro[3.5] nonan-7-yl] -5 - [4 - [4 -

[0168] (trifluoromethoxy )phenyl]phenyl]hexahydropyrimi dine-2, 4, 6-trione;

[0169] 5-[ 1 -(2-hy droxy ethyl)- 1 ,8-diazaspiro[4.5] decan-8-yl] -5 - [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione;

[0170] 5-(l -ethyl- 1 ,9-diazaspiro[4.5] decan-9-yl)-5-[4-[4-

[0171] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione, TFA salt;

[0172] 5-(4-acetyl-4,7-diazaspiro[2.5] octan-7 -y 1) -5 - [4- [4-

[0173] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione;

[0174] 5-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)-5-[4-[4-

[0175] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione; rac-5-[7-[[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino]-5-oxa-2-azaspiro[3.4]octan-2- yl]-5-[4-[4-(trifhioromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione; rac-5-[7-[[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino]-5-oxa-2-azaspiro[3.4]octan- 2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0176] 5-(3-methylspiro[7H-furo[3,4-b]pyridine-5,4'-piperidine]-r-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0177] 5-(6-oxo-7 -oxa-2,5 -diazaspiro[3.4] octan-2-yl)-5- [4- [4-

[0178] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0179] 5-[4-(2,3-dihydrobenzofuran-6-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,8-diazaspiro[3.5]nonan- 8-yl]hexahydropyrimidine-2, 4, 6-trione;

[0180] N-[7-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-7- azaspiro[3.5]nonan-3-yl]carbamic acid tert-butyl ester;

[0181] 2-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-2,7- diazaspiro[3.4]octane-7-carboxylic acid tert-butyl ester;

[0182] 7-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-l,7- diazaspiro[3.5]nonane-l-carboxylic acid tert-butyl ester;

[0183] 6-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-l,6- diazaspiro[3.3]heptane-l-carboxylic acid tert-butyl ester;

[0184] 5-spiro[lH-isobenzofuran-3,4'-piperidine]-l'-yl-5-[4-[4-

[0185] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0186] 5-[4-[2-(4-chlorophenyl)ethynyl]phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt;

[0187] 5-[4-[2-(4-chlorophenyl)ethynyl]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;

[0188] N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-2,4,6-trioxo- hexahydropyrimidin-5-yl]benzamide;

[0189] N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonan-7-yl]-2,4,6-trioxo- hexahydropyrimidin-5-yl]benzamide; N-(4-chlorophenyl)-4-[5-[8-[(l-methyl-4-piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2- yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide;

[0190] 5- [4-(4-Piperidylsulfonyl)- 1 -oxa-4, 9-diazaspiro[5.5] undecan-9-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;

[0191] 5- [4- [2-(4-Piperidyl)acetyl] - 1 -oxa-4, 9-diazaspiro [5.5] undecan-9-yl] -5 - [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0192] 5-[8-(Azetidin-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4-

[0193] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;

[0194] 5-[8-[(l-Methyl-4-piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;

[0195] 5-(8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)-5-[4-[4-

[0196] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0197] 5-(3-amino-7-azaspiro[3.5]nonan-7-yl)-5-[4-[4-

[0198] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione hydrogen chloride;

[0199] 5- [7-(2-hy droxy ethyl)-2,7-diazaspiro[4.4] nonan-2-yl] -5 - [4 - [4 -

[0200] (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0201] 5-(7-Methyl-2,7-diazaspiro[4.4]nonan-2-yl)-5-[4-[4-

[0202] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt;

[0203] 5-(l-Methyl-l,9-diazaspiro[4.5]decan-9-yl)-5-[4-[4-

[0204] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0205] 5-(5-Oxa-2,8-diazaspiro[3.5]nonan-8-yl)-5-[4-[4-

[0206] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione bis p-toluenesulfonic acid salt;

[0207] 5- [ 1 -(2-Hy droxy ethyl)- 1 , 9-diazaspiro[4.5] decan-9-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione; 5-[8-[[(3R)-Tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0208] 5-[8-[[(3S)-tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0209] 5-[7-[(l-Methyl-4-piperidyl)amino]-5-oxa-2-azaspiro[3.4]octan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0210] 5-[8-(l,4-Dioxan-2-ylmethyl)-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0211] 5-[5-(l,4-Dioxan-2-ylmethyl)-2,5-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0212] 5-[8-(2-Hydroxyacetyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4-

[0213] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione hydrochloric acid;

[0214] 5-[5-(2-hydroxyacetyl)-2,5-diazaspiro[3.4]octan-2-yl]-5-[4-[4-

[0215] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0216] 5-[5-[(4-Methylmorpholin-2-yl)methyl]-8-oxa-2,5-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0217] 5-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)-5-[4-[4-

[0218] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione, TFA salt;

[0219] 5-[5-(4-ethylphenoxy)pyrazin-2-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione

[0220] 5-[4-[(6-ethyl-3-pyridyl)oxy]phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;

[0221] 5-[5-(4-ethylphenoxy)-2-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione, formic acid salt;

[0222] 5-[6-(4-ethylphenoxy)pyridazin-3-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;

[0223] 5-[6-(4-ethylphenoxy)-3-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione; 5-[8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[[5- (trifluoromethoxy)-2-pyridyl]oxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione, 2,2,2- trifluoroacetic acid salt;

[0224] N-(6-chloro-3-pyridyl)-4-[5-[2-(2 -hydroxy ethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-2, 4, 6-trioxo- hexahydropyrimidin-5-yl]benzamide;

[0225] 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-[3-[[5-(trifluoromethyl)pyrazin-2- yl]amino]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0226] 5-[3-[(5-chloro-2-pyridyl)amino]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;

[0227] 5-[2-(4-ethylphenoxy)pyrimidin-5-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione; and

[0228] 5-[4-(5-ethylpyrazin-2-yl)oxyphenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione.

[0229] In a preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0230] 5-[2-(2-Hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0231] 5-[4-(2,3-dihydrobenzofuran-5-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonan- 7-y 1] hexahy dropy rimi dine-2, 4, 6-trione;

[0232] 5- [2-(2-hy droxy ethyl)-2,7-diazaspiro[3.5] nonan-7-yl] -5 - [4 - [4 -

[0233] (trifluoromethoxy )phenyl]phenyl]hexahydropyrimi dine-2, 4, 6-trione; rac-5-[7-[[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino]-5-oxa-2-azaspiro[3.4]octan-2- yl]-5-[4-[4-(trifhioromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione;

[0234] N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-2,4,6-trioxo- hexahydropyrimidin-5-yl]benzamide;

[0235] 5- [4-(4-Piperidylsulfonyl)- 1 -oxa-4, 9-diazaspiro[5.5] undecan-9-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt; 5- [4- [2 -(4 -Pip eri dy 1 ) acety 1] - 1 -oxa-4,9-diazaspiro [5.5] undecan-9-yl] -5 - [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0236] 5-[8-(Azetidin-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;

[0237] 5-[8-[(l-Methyl-4-piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;

[0238] 5-(8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0239] 5- [7-(2-hy droxy ethyl)-2,7-diazaspiro[4.4] nonan-2-yl] -5 - [4 - [4 - (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;

[0240] 5-(7-Methyl-2,7-diazaspiro[4.4]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt;

[0241] 5-[5-(4-ethylphenoxy)-2-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;

[0242] 5-[6-(4-ethylphenoxy)-3-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione; and

[0243] 5-[2-(4-ethylphenoxy)pyrimidin-5-yl]-5-[2-(2-hy droxy ethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione.

[0244] In the description herein, if there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold wedged, or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry.

[0245] Unless otherwise indicated, the terms “a compound of the formula” or “a compound of formula” or “compounds of the formula” or “compounds of formula” refer to any compound selected from the genus of compounds as defined by the formula (including any pharmaceutically acceptable salt of any such compound if not otherwise noted).

[0246] Furthermore, the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates of the compounds of formula (I).

[0247] The compounds of formula (I) may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

[0248] In the embodiments, where optically pure enantiomers are provided, optically pure enantiomer means that the compound contains > 90% of the desired isomer by weight, particularly > 95% of the desired isomer by weight, or more particularly > 99% of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.

[0249] In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i. e. , radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to,2H,3H,1'C.13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0250] Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0251] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled 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 Examples as set out below using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0252] Processes of manufacturing

[0253] Processes for the manufacture of compounds of formula (I), or pharmaceutically acceptable salts thereof, as described herein are also an object of the present invention.

[0254] The preparation of compounds of formula (I) as described herein may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary. If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rd Ed., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxy carbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

[0255] If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can, for example, be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0256] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0257] In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

[0258] If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section.

[0259] In one embodiment, compounds of formula (I), as described herein or a pharmaceutically acceptable salt thereof, are prepared by a process comprising reacting a compound of formula (II) with a compound of formula (III) wherein L, Ar, R1and are as defined herein and X is halogen, in the presence of a base to form said compound of formula (I).

[0260] A general description of the synthesis of the examples provided in this invention is given in the section below.

[0261] General procedure for the assembly of 5,5-di-substituted spirocyclic barbituric acid derivatives The key step of the synthetic approach is shown in Scheme 1 and involves the treatment of an aryl barbituric acid intermediate with the general structure (i) (in essence the intermediates A, B, C, etc., described in the experimental part) with a brominating agent such as NBS or HBr / bromine in a solvent like DMF, THF, or water, or similar, which is dependent on the choice of the brominating agent, at temperatures ranging from -20 °C to the boiling point of the solvent. The brominated intermediate (ii) may be used in situ without further purification or can be isolated in a purer form for example by precipitation or trituration with an appropriate solvent.

[0262] Intermediate (ii) is then treated with a spirocyclic amine (iii-a, iii-b or iii-c) (referred to as Intermediates 1, 2, 3, etc. in the experimental part) in the presence of a base such as NEts, DIPEA, DBU, Na2COs or similar, in the solvents mentioned above, at temperatures ranging from -20 °C to the boiling point of the solvent, to provide examples or intermediates with the general structure (iv-a, iv-b or iv-c). Reaction times for the coupling can vary and can be in the range of minutes to days.

[0263]

[0264] Intermediates A, B, C, ... Intermediates 1 , 2, 3, spirocyclic hetrocycles, with:

[0265] Ra= R4, protected R4or a protecting group (PG)

[0266] Rb= R5, protected R5or a protecting group (PG), when ring B is a carbocyle

[0267] Rb= R4, protected R4or a protecting group (PG), when ring B is a heterocycle with R3, R4and R5as defined in the claims.

[0268] Examples of this invention; or Intermediates A1 , A2, A3, etc. in case of post modifications ...

[0269] Scheme 1

[0270] The general approach to obtain suitably substituted aryl barbiturate intermediates with the general structure (i) is described in Scheme 2. General approaches to suitable spirocyclic intermediates with the general structure (iii-a), (iii-b) or (iii-c) are outlined in Scheme 3.

[0271] General synthesis of barbiturate intermediates A, B, C, etc., with the general structure (i) v

[0272] As shown in Scheme 2, Sequence A, appropriately substituted aryl acetic acid ester derivatives (v) (Rc= lower alkyl), which are either commercially available or can be made according to the literature, where X is for example halogen such as Cl, Br or I can be treated with a base such as LDA, KOlBu, NaH or similar followed by a suitable carbonic acid ester (Xa= ORd, where Rdis for example lower alkyl) or a chloroformic acid ester (Xa= Cl) in a solvent such as DMF, THF or the like at temperatures ranging from -78 °C to the boiling point of the solvent to provide an aryl mal onate intermediate with the general structure (vi). Intermediate (iv) can then be treated with urea in the presence of a suitable base such as NaOMe, NaOEt, KCFBu or similar in solvents such as MeOH, EtOH or the like at temperatures ranging from -20 °C to the boiling point of the solvent to provide an aryl barbiturate intermediate with the general structure (vii). This material can then be subjected to further modification for example with phenols (Re-0H), anilines (Rf-NH2), aryl acetylenes (Rg-C=C) or aryl boronic acid derivatives (Rh-B(0H)2, or similar; where Re, Rf, Rgand Rhare appropriate subsets of R1as defined in the claims) under suitable reaction conditions which are dependent on the reagent used. Suitable conditions for such coupling reactions include for example Chan-Lam, Suzuki, Buchwald, Sonogashira or Ullmann-type coupling conditions. Conditions for such individual reaction types can vary and are dependent on the choice of solvent, catalyst, base and the corresponding stoichiometries. Suitable options for the choice of conditions can be found in the literature or are well known to those skilled in the art.

[0273] In the case of L representing a -C(O)NH- linker, an intermediate of structure (vii) can be subjected to carbonylation conditions by treatment with CO and suitable catalyst such as Pd(dppf)C12 or similar, in the presence of an alcohol RC-OH, where Rcis for example Me or Et, at temperatures ranging from RT to the boiling point of the solvent, and at CO pressures ranging from 1 to 50 bar. To obtain a carboxylic acid intermediate of structure (vii-b), the ester can be hydrolyzed for example with LiOH, NaOH or KOH in a solvent like water, THF or the like at temperatures ranging from -20 °C to the boiling point of the solvent. Then, an amide coupling reaction can be used in the presence of an aniline Rf-NH2, a suitable coupling reagent such as for example HATU, and an amine base such as NEts, DIPEA or similar in DMF or THF or the like. Many possible coupling reagents and associated reaction conditions exist and are known in the art.

[0274] A reversal of the synthetic steps is also possible (Scheme 2, Sequence 2). In this approach, the modifications at the aryl ring to introduce the residues R'-L are conducted as the first reaction step, which is based on the same reagents as described above (substituted phenols (Re-OH), anilines (Rf-NH2), aryl acetylenes (Rg-C=C) or aryl boronic acid derivatives (Rh-B(OH)2)) and the same conditions. Subsequently, formation of the appropriately substituted malonate (ix) followed by cyclization with urea to provide intermediates of structure (i) can be based on the same conditions as described above for Sequence 1. Sequence 1 :

[0275] Scheme 2

[0276] General description of the synthesis of spirocyclic building blocks and intermediates Suitable modifications at the various spirocyclic building blocks to introduce the desired residues Raor Rbin the general structures (iv-a) or (iv-b), where Raare Rbare defined above as in Scheme 1, are either possible prior to the coupling with a barbiturate intermediate with the general structure (i) or, alternatively, thereafter.

[0277] Scheme 3 shows the general approaches for the synthesis of suitably substituted spirocyclic intermediates prior to the coupling with a barbiturate intermediate (i). Modification of suitably protected spirocyclic starting materials with the general structure (x-a) or (x-b), which are either commercially available or can be made according to the literature, can for example be accomplished by amide bond formation, sulfonamide bond formation, reductive amination or N- alkylation. Appropriate protecting groups PG of the structures (x-a) and (x-b) are for example a BOC group, CBZ, benzyl or substituted benzyl or many others. A good overview on possible protecting groups and the chemistry associated with them for both protection and de-protection as well as compatibility with reaction conditions can be found in T. M. Greene, P. G. M. Wuts, Protecting Groups in Organic Synthesis, John Wiley & Sons, 4thEdition 2006.

[0278] Suitable conditions for such transformations can be found in the literature and are well known to those skilled in the art. In case of an amide bond formation, (x-a) or (x-b) can be treated with a carboxylic acid (YCOR1; Y = OH) or a carboxylic acid halide (Y = Cl, Br). The latter is done in the presence of a base such as NEts, DIPEA, Na2COs, whereas the former can be done in the presence of a base such a s NEts or DIPEA and a coupling reagent such as for example HATU or similar. The choice of the solvent and the temperature depends on the reaction conditions. The substituents C(O)-R‘ and N-C(O)-R‘ are a subset of and are defined by R4and R5given in the claims.

[0279] N-alkylation of (x-a) or (x-b) can be achieved by treatment with a suitable residue R' carrying a leaving group X which can be a halide such as Cl, Br or I, or alternatively for example a mesilate or tosylate. Usually, a base such as NEts, DIPEA, Na2COs, CS2CO3 or similar in a solvent like DMF or THF is added and the reaction can be carried out at various temperatures. Again, the substituents R) and N-R) are a subset of and are defined by R4and R5given in the claims.

[0280] Reductive amination of (x-a) or (x-b) can be achieved by treatment with a suitable aldehyde or ketone RklC(O)Rk2. In case of an aldehyde, Rklcorresponds to H. Such a transformation is usually done in the presence a weak acid such as AcOH or NH4OAC and a reducing agent such as NaCNBHs or NaBH(OAc)s in a solvent like THF, MeOH or EtOH or similar. However, many other conditions can be taken from the literature. Again, the substituents RklCHRk2and N- CHRklRk2are a subset of and are defined by R4and R5given in the claims.

[0281] Finally, formation of a sulfonamide (xvii-a), (xvii-b) can be done by treatment of (x-a) or (x-b) with a sulfonyl halide YS(O2)R*, where Y corresponds to Cl or Br, in the presence of a base such as NEts, DIPEA, Na2COs, CS2CO3 in a solvent like DCM, THF or others, at various temperatures. Again, the substituents S(O2)R* and NS(O2)R* are a subset of and are defined by R4and R5given in the claims.

[0282] In all cases, the conditions for final de-protection step to remove PG are dependent on the protecting group PG used. If PG is for example a BOC group, treatment with TFA in DCM or HC1 in water or MeOH can be used. If PG is a benzyl group or CBZ group, then hydrogenation can be used for removal of PG to obtain the structures (xii-a), (xii-b), (xiv-a), (xiv-b), (xvi-a), (xvi-b), (xviii-a) and (xviii-b), respectively, containing a free cyclic amine for coupling with a barbiturate intermediate (i).

[0283] Scheme 3 It is also possible that the intermediates (xx-a) and (xx-b) contain a suitable orthogonal protecting group PG2 as outlined in Scheme 4 if any of the residues R1, R>, Rk, or R1, which are part of the substituents A in intermediates (xix-a) or (xix-b), contain an additional functional group such as NHXor OH that might interfere with the coupling step with an intermediate (i). If PG at the spirocyclic ring A of starting materials (x-a) or (x-b)is a BOC group, then suitable orthogonal protecting groups PG2 are for example for amines NHXCBZ, trifluoro acetyl, benzyl, or many others, and for O, for example, a stable silyl protecting group, benzyl or a carboxylic acid ester. Many other options or permutations of protecting groups are possible which are well described in the literature and are known to those skilled in the art.

[0284] (x-a) (x-b) (xix-a) (xix-b) (xx-a) (xx-b)

[0285] Scheme 4

[0286] General description of optional post modifications of 5,5-di-substituted barbituric acid derivatives

[0287] Optional post modifications which are essentially the same as the ones outlined in Scheme 3 for the corresponding building blocks (x-a) and (x-b) may also be carried out after the coupling step described above in Scheme 1. In this case, 5,5-disubstituted barbiturate examples or intermediates with the general structure (xxii-a) or (xxii-b) are modified as summarized in Scheme 5. To achieve the latter, the appropriate protecting group PG at the spirocyclic building blocks (xxi-a) and (xxi-b) needs to be in a different position at the beginning of the synthesis. Suitable starting materials (xxi-a) and (xxi-b) are commercially available or are readily accessible from starting materials (iii-a) or (iii-b) based on standard protecting group chemistry. Suitable protecting groups PG are for example BOC, CBZ, benzyl or substituted benzyl and many others. Coupling conditions of (xxi-a) and (xxi-b) with (i) via the brominated intermediate (ii) are the same as described above in Scheme 1.

[0288]

[0289] Scheme 5

[0290] The protected 5,5-substituted barbiturate intermediates (xxii-a ) or (xxii-b) are then de-protected using standard conditions which are dependent on the protecting group PG. For example, if PG in (xxii-a) or (xxii-b) is a BOC group, then suitable conditions for its removal include for example treatment with TFA in DCM, HC1 in dioxane or MeOH or similar, at temperatures ranging from -20°C to the boiling point of the solvent. Following de-protection, intermediates (xxiii-a) or (xxiii-b) can then be further modified using a choice of the same reactions and reaction conditions (amide bond formation, N-alkylation, reductive amination or sulfonamide formation) that are outlined above in Scheme 3 and Scheme 4, respectively. If the reactants for these modifications do not carry an orthogonal protecting group PG2, then the examples of structure (xxv-a) or structure (xxv-b) are obtained directly. In case of the reactants carrying an additional protecting group PG2which will result in protected intermediates (xxiv-a) or (xxiv-b), then an additional de-protection step is required to form the final examples of structure (xxv-a) or (xxv-b). Conditions for the removal of PG2are depending on the nature of the protecting group and can be taken from the literature. The definitions of A, R1, R>, Rkl, Rk2and R1in Scheme 5 correspond to the ones given in the text above for Schemes 3 and 4. General description of the synthesis of heterocyclic 5,5-disubstituted barbituric acid derivatives

[0291] This part of the general description provides an outline of the access to barbiturate derivatives in which any of the two 6-membered phenyl rings are replaced with a nitrogen containing 6- membered aromatic heterocycle such as pyridine, pyrimidine, pyridazine or pyrazine which are represented by a phenyl ring with an N in the center ( ) in the following Schemes. In some cases, the methods outlined in the previous sections are still appropriate, but in other cases new routes had to be followed which are described for the corresponding intermediates in Scheme 6 and for the final examples in Scheme 7.

[0292] Sequence A in Scheme 6 outlines the synthesis of heterocyclic intermediates of structure (xxx). In this case, a benzyl protected halo-phenol (xxvi) where X is for example Br or I can be coupled with dimethylmalonate in the presence of Cui and L-proline and a base such as CS2CO3 in a solvent like DMSO at temperatures ranging from RT to 120°C according to Xie et. al., Or g Lett 2005, 7 (21), 4693, to provide an aryl malonate of structure (xxvii). The latter is then cyclized with urea in the presence of a base such as NaOEt or NaOMe or similar in ethanol or methanol at temperatures ranging from RT to the boiling point of the solvent to provide intermediate (xxviii) and then, following de-protection with catalytic hydrogenation, phenol (xxix). This material is then subjected to a nucleophilic aromatic substitution with a suitably substituted 6-membered halo nitrogen heterocycle (e.g. pyridine or similar), where X is Cl, Br, I or F and Rmis a subset of R2as defined in the claims, in the presence of a base such as CS2CO3 or the like, for example in DMF at temperatures ranging from RT to the boiling point of the solvent to provide a key intermediate of structure (xxx).

[0293] Sequence B in Scheme 6 shows an approach to make intermediates (xxxiii) where the heterocycle is attached directly to the barbituric acid. In this case, a nucleophilic aromatic substitution between a suitably substituted phenol reagent, where Rmis again a subset of R2as defined in the claims, with a 6-membered heterocycle (xxxi) (e.g. pyridine, pyrazine, pyridazine and pyrimidine) carrying one Br as well as second halogen (X = Cl, Br, I, F) in the appropriate positions, is performed. This coupling providing bromo intermediate (xxxii) can be done under similar conditions as described above in Sequence A for the final step, (xxxii) is then coupled directly with barbituric acid under specific conditions such as Me4-tBu-XPhos-Pd-G3 and DBU in DMSO at temperatures ranging from 50 to 160 °C to give the desired intermediates of structure (xxxiii).

[0294] In Sequence C in Scheme 6 a synthetic approach to certain heterocyclic di-arylamine intermediates (xxxiv) is described. A suitable material of structure (vii) which can be obtained as described in Scheme 2 Sequence 1, is coupled with a suitable heterocyclic aryl amine (Rm= subset of R2) under Buchwald type conditions (e.g. tBu-XPhos-PG-G3, BuONa in DMF at elevated temperatures) to provide the key intermediates of structure (xxxiv).

[0295] Sequence D shows an approach for making certain heterocyclic diaryl carboxamides of structure (xxxv). In analogy to Scheme 2, Sequence 1, a carboxylic acid intermediate of structure (vii-b) can be coupled with suitably substituted heterocyclic arylamine (Rm= subset of R2) using amide bond coupling conditions which can be based on many possible coupling reagents (e.g. HATU, etc.) and conditions that are described well in the literature.

[0296] Sequence C: Sequence

[0297] Scheme 6

[0298] The final steps to make the desired heterocyclic examples of structures (xxxviii) and (xli), respectively, are outlined in Scheme 7. Starting from intermediates of structures (xxxvi) and (xxxix), bromination under the same conditions as described before in Scheme 1 (e.g. NBS or HBr / bromine in a solvent like DMF, THF, or water, or similar) provides bromo intermediates (xxxvii) or (xl), respectively, which are usually not isolated, and are then coupled for example with a spirocyclic building block (iii-a) in the presence of a base such as NEts, DIPEA, DBU, Na2CC>3 or similar, in the solvents mentioned above, at temperatures ranging from -20 °C to the boiling point of the solvent. This way, the examples containing an aromatic heterocycle represented by general structures (xxxviii) and (xli) are obtained. Structures (xxxviii) and (xli) vary by the position of the heterocycle in combination with the linkers Laor Lb, respectively, which are defined in Scheme 7.

[0299] Scheme 7

[0300] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to any one of the processes described herein.

[0301] Pharmaceutical compositions and administration

[0302] Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0303] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions). The administration can also be effected topically, e.g. transdermal administration, or in form of eye drops or ear drops.

[0304] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations, such as tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations. Lactose, com starch or derivatives thereof, talc, stearic acids or salts thereof, and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules.

[0305] Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatin capsules.

[0306] Suitable carriers for the production of solutions and syrups are, for example, water, alcohols, polyols, saccharose, glucose, invert sugar, vegetable oil, etc.

[0307] Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0308] Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc. Suitable carriers for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

[0309] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

[0310] Medicaments containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula (I) and / or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable excipients.

[0311] The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. In the case of topical administration, the formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.1 and 25 mg, and can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week. It will, however, be clear that the upper or lower limit given herein can be exceeded when this is shown to be indicated.

[0312] The pharmaceutical composition according to the invention may be prepared as follows.

[0313] Preparation of pharmaceutical compositions comprising compounds of the invention

[0314] Tablet Formulation (Wet Granulation) Manufacturing Procedure:

[0315] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[0316] 2. Dry the granules at 50°C.

[0317] 3. Pass the granules through suitable milling equipment.

[0318] 4. Add ingredient 5 and mix for three minutes; compress on a suitable press.

[0319] Capsule Formulation Manufacturing Procedure:

[0320] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0321] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[0322] 3. Fill into a suitable capsule.

[0323] Injection Solutions

[0324] Manufacturing Procedure:

[0325] A compound of formula (I) is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

[0326] Indications

[0327] An object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.

[0328] As described above, compounds of formula (I) and their pharmaceutically acceptable salts are useful as MMP9 inhibitors.

[0329] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of an ocular surface disease.

[0330] In one embodiment, the ocular surface disease is dry eye disease. In a further aspect, the present invention provides the use of compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of an ocular surface disease.

[0331] In one embodiment, the ocular surface disease is dry eye disease.

[0332] In a further aspect, the present invention provides the use of compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of an ocular surface disease.

[0333] In one embodiment, the ocular surface disease is dry eye disease.

[0334] In a further aspect, the present invention provides a method for the therapeutic and / or prophylactic treatment of an ocular surface disease, which method comprises administering an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the ocular surface disease is dry eye disease.

[0335] The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

[0336] 1) Preparative examples

[0337] 1.1) Preparation of intermediates

[0338] 1.1.1) 5-Aryl Barbiturate Intermediates

[0339] Intermediate A

[0340] 5- [4- [4-(T rifluoromethoxy)phenoxy] phenyl] hexahydro pyrimidine-2, 4, 6-trione

[0341] Step 1 : Dimethyl 2-(4-bromophenyl)propanedioate

[0342] Methyl 4-bromophenylacetate (6.00 g, 26.2 mmol, 1.0 eq) was dissolved in THF (60 mL), sodium hydride, 60% in oil (2.10 g, 52.4 mmol, 2.0 eq) was added and the mixture was stirred at 30 °C for 1 h. Then, dimethyl carbonate (9.44 g, 105 mmol, 4.0 eq) was added and the mixture was stirred at 30 °C for 11 h. LCMS showed that the desired mass was present.

[0343] The mixture was concentrated in vacuo to give a crude material, which was triturated with petroleum ether, filtered and dried in vacuo to give the title compound dimethyl 2-(4- bromophenyl)propanedioate (2.40 g, 8.36 mmol, 28.6% yield) as a white solid.

[0344] LCMS (ESC): 286.9 [M+H]+.

[0345] Sodium (1.57 g, 68.4 mmol, 1.96 eq) was dissolved in ethanol (300 mL). Then, urea (5.00 g,

[0346] 83.3 mmol, 1.71 eq) was added to the solution in batches and the reaction was stirred for 30 min, followed by addition of dimethyl 2-(4-bromophenyl)propanedioate (10.0 g, 34.8 mmol, 1.0 eq). The reaction mixture was heated to 90 °C and was stirred for 15.5 h. LCMS showed that the desired mass was present. Then, the mixture was poured into ice water and the pH was adjusted to 3 with 2N HC1. A solid appeared which was filtered and dried in vacuo to afford the title compound 5-(4-bromophenyl)hexahydropyrimidine-2, 4, 6-trione (3.50 g, 12.4 mmol, 35.1% yield) as a yellow solid.

[0347] LCMS (ESC): 284.9 [M+H]+.

[0348] Step 3 : 5-14-14-(Tri fluoromethoxy )phenoxy I phenyl |hexahvdropyrimidine-2.4.6-trione

[0349] To a solution of 5-(4-bromophenyl)hexahydropyrimidine-2, 4, 6-trione (10.0 g, 35.3 mmol, 1.0 eq) and 4-(trifluoromethoxy)phenol (6.0 mL, 46.3 mmol, 1.31 eq), cesium carbonate (23.5 g, 72.1 mmol, 2.04 eq), copper(I) iodide (1.00 g, 5.25 mmol, 0.15 eq) in DMF (50 mL) was added N, N-dimethylglycine hydrochloride (1.50 g, 10.8 mmol, 0.3 eq). Then, the mixture was stirred at 130 °C for 48 h. LCMS showed that the desired mass was present. The mixture was cooled to 25°C, filtered, and concentrated to afford a crude material, which was triturated with water and ethyl acetate to afford the title compound 5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (4.60 g, 12.1 mmol, 30.9% yield) as a yellow solid.

[0350] LCMS (ESC): 381.0 [M+H]+.

[0351] The following intermediates were made in analogy to Intermediate A, steps 1 to 3, by using the appropriate starting materials in Step 3.

[0352] Intermediate H 5-(4-Phenoxyphenyl)hexahydropyrimidine-2, 4, 6-trione Step 1: Ol-Ethyl 03-methyl 2-(4-phenoxyphenyl)propanedioate

[0353] To a solution of ethyl 2-(4-phenoxyphenyl)acetate (10.5 g, 41.0 mmol, 1.0 eq) in THF (120 mL) was added LDA (41.0 mL, 81.9 mmol, 2.0 eq) while the temperature was kept at -78 °C. 1 hour later, methyl chloroformate (6.35 mL, 81.9 mmol, 2.0 eq) was added and the reaction was stirred at 30 °C for 11 h. LCMS showed that the desired product mass was present. Then, the mixture was quenched with saturated aqueous NH4CI (50 mL), concentrated in vacuo to remove THF, and extracted with EtOAc (3 x 70 mL). The concentrated residue was purified by column chromatography (SiCL, PE:EtOAc = 9:1, UV detection) to give 01-ethyl 03-methyl 2-(4- phenoxyphenyl)propanedioate (9.70 g, 30.9 mmol, 73.7% yield) as a light brown oil.

[0354] LCMS (ESH): 315.1 [M+H]+.

[0355] Step 2: 5-(4-Phenoxyphenyl)hexahydropyrimidine-2,4.6-trione

[0356] Ol-Ethyl 03-methyl 2-(4-phenoxyphenyl)propanedioate (5.00 g, 15.9 mmol, 1.0 eq) and urea (1.62 g, 27.0 mmol, 1.7 eq) were added to a solution of sodium (731 mg, 31.1 mmol, 2.0 eq) dissolved in ethanol (175 mL). Then, the mixture was stirred at reflux at 80 °C for 8 h. LCMS showed that the desired product mass was formed. The resulting suspension was concentrated to be half-dry and was then poured into ice water. IN HC1 was added to adjust to pH 2~3, then the precipitate was filtered and the filter cake was triturated with EtOAc (15 mL), filtered again and washed with more EtOAc (3 x 6 mL). The material was then dried under reduced pressure to give 5-(4-phenoxyphenyl)hexahydropyrimidine-2, 4, 6-trione (1.90 g, 6.41 mmol, 40.2% yield) as a white solid.

[0357] LCMS (ESC): 297.2 [M+H]+.

[0358] Intermediate J 5-(4-Phenoxyphenyl)hexahydropyrimidine-2, 4, 6-trione

[0359] Step 1: Methyl 2- [4-(4-cyclopropylphenoxy)phenyl] acetate

[0360] 2-(4-Hydroxyphenyl)acetic acid methyl ester (300 mg, 1.81 mmol, 1.0 eq) was dissolved in dichloromethane extra dry (10 mL). Then, pyridine (714 mg, 726 uL, 9.03 mmol, 5.0 eq), molecular sieves (0.4 g), (4-cyclopropylphenyl)boronic acid (585 mg, 3.61 mmol, 2.0 eq) and copper (II) acetate (328 mg, 1.81 mmol, 1.0 eq) were added. The reaction mixture was then stirred at RT overnight. TLC after 15 hrs showed that the reaction was complete. The reaction mixture was filtered and the filtrate was washed 2 times with water and the water layer was extracted with DCM. The organic layers were combined, dried with Na2SC>4, filtered and concentrated in vacuo. The residue was dissolved in a minimal amount of EtOAc and was transferred to a silica gel column. Purification was done on an ISCO CombiFlash Companion, SILICYCLE FLH-R10095D-A-IS040, SiliaSep premium, 25pm 40 g, by elution with a gradient of 0% EtOAc to 22% EtOAc in heptane. The product fractions were combined and concentrated to give 209 mg (40.2%) of the title compound as a white foam.

[0361] LCMS (ESE): 283.1 [M+H]+.

[0362] Step 2: Dimethyl 2- [4-(4-cyclopropylphenoxy)phenyl1 propanedioate

[0363] The reaction was conducted under an argon atmosphere. 2-[4-(4- Cyclopropylphenoxy)phenyl] acetic acid methyl ester (203 mg, 717 umol, 1.0 eq) and carbonic acid dimethyl ester (549 mg, 513 uL, 6.1 mmol, 8.5 eq) were dissolved in THF extra dry (2 mL) and 1 M potassium tertbutoxide solution (1.51 mL, 1.51 mmol, 2.1 eq) was added rapidly. The addition was slightly exothermic, the temperature rose from 24°C to 29°C to give a pink reaction mixture. After addition, the reaction mixture was heated to 76 °C, resulting in a light yellow mixture that was stirred overnight. LCMS after 18 hours showed that the reaction was complete. The reaction was quenched at 5 °C with acetic acid (129 mg, 123 uL, 2.15 mmol, 3.0 eq) and the resulting suspension was concentrated in vacuo. The residue was taken up in EtOAc and was washed with H2O. After back-extraction, the combined organic extracts were washed with brine, dried over anhydrous NaiSO-i. filtered and concentrated under reduced pressure to afford the crude product as a yellow oil. This material was dissolved in a minimal amount of EtOAc and was transferred to a silica gel column. Purification was done on an ISCO CombiFlash Companion, SILICYCLE FLH-R10095D-A-IS040, SiliaSep premium, 25pm 40g, by elution with a gradient of 0% EtOAc to 28% EtOAc in heptane. The fractions containing the product were combined and concentrated to give 172 mg (69.1%) of the title compound as a light yellow oil.

[0364] LCMS (ESE): 341.1 [M+H]+.

[0365] :-2,4, 6-trione

[0366] Sodium ethoxide (350 mg, 402 uL, 1.08 mmol, 2.2 eq) was dissolved in ethanol (3 mL), then urea (50.1 mg, 834 umol, 1.7 eq) was added to the solution and the mixture was stirred for 30min. Then, a solution of 2-[4-(4-cyclopropylphenoxy)phenyl]malonic acid dimethyl ester (167 mg, 491 umol, 1.0 eq) in ethanol (1.0 mL) was added and the reaction mixture was heated to reflux. Formation of an off-white suspension was observed at reflux temperature. LCMS after 2.5 hours showed that the reaction was complete. The mixture was cooled to RT and was then poured into ice water (16 mL + ice) and the pH was adjusted to 3 with 2 M HC1 (736 uL, 1.47 mmol, 3.0 eq). The fine solid that appeared was filtered and dried in vacuo to provide 87.7mg of a yellow material, which was triturated 3 times with 3.6 mL petroleum ether (60-80°C BP) : EtOAc (3: 1). The suspension was filtered over a Sartorius funnel and the off-white solid was washed 2 times with 1 mL PE / EtOAc and was dried in vacuo to provide the title compound: 72.3 mg off-white solid (42.6%).

[0367] LCMS (ESI+): 337.0 [M+H]+.

[0368] Intermediate K

[0369] The following Intermediate was made in analogy to Intermediate J, steps 1 to 3, by using the appropriate starting material in Step 1.

[0370] Intermediate L

[0371] 5- [4- [4-(T rifluoromethoxy)phenyl] phenyl] hexahydropyrimidine-2,4,6-trione

[0372] To a solution of 5-(4-bromophenyl)hexahydropyrimidine-2, 4, 6-trione (3.00 g, 10.6 mmol, 1.0 eq), obtained in Step 2 for the synthesis of intermediate A, in DMF (20 mL) and water (4 mL) were added 4-(trifluoromethoxy)phenylboronic acid (3.27 mg, 15.9 mmol, 1.5 eq) and [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (775 mg, 1.06 mmol, 0.1 eq) and K2CO3 (2.93 g, 21.2 mmol, 2.0 eq). The mixture was stirred at 90 °C for 12 h under N2. LCMS showed the formation of the desired product. The mixture was poured into water (70 mL), extracted with EtOAc (3 times 70 mL), and the water phase was concentrated to give a crude material which was triturated with PE:EtOAc 10:1, filtered and dried in vacuo. This material was again triturated with EtOAc (3 times 20 mL), filtered and dried in vacuo to give the title compound 5- [4-[4-(trifluoromethoxy)phenyl]phenyl]hexahydropyrimidine-2, 4, 6-trione (1.60 g, 4.39 mmol, 40.6% yield) as a grey solid.

[0373] LCMS (ESC): 365.0 [M+H]+.

[0374] Intermediate N

[0375] The following Intermediate was made in analogy to Intermediate L by using the appropriate starting material.

[0376] Intermediate M

[0377] 5-[3-[4-(Trifluoromethoxy)anilino]phenyl]hexahydropyrimidine-2,4,6-trione

[0378] Step 1 : Dimethyl 2-(3-bromophenyl)propanedioate

[0379] Methyl 2-(3-bromophenyl)acetate (100 g, 437 mmol, 1.0 eq) was dissolved in THF (800 mL) and the mixture was cooled to 0°C. Sodium hydride, 60% in oil (32.5 g, 812 mmol, 1.86 eq) was added to the mixture, which was then stirred at 0°C for 0.5 h. Then, dimethyl carbonate (113 g, 1249 mmol, 2.7 eq) was added to the mixture and the mixture was warmed to 70°C and stirred at 70 °C for 15.5 h. LCMS showed that the desired product was formed. The mixture was poured into water, extracted with EtOAc (3 times 800 mL) and the combined organic layers were dried with Na2SO4, filtered and concentrated to give a crude material. This material was triturated with petroleum ether to give the title compound dimethyl 2-(3-bromophenyl)propanedioate (80.0 g, 279 mmol, 57.3 % yield) as a yellow oil, which was used directly in the next step.

[0380] LCMS (ESC): 288.9 [M+H]+.

[0381] Step 2: 5-(3-Bromophenyl)hexahvdropyrimidine-2,4.6-trione

[0382] Sodium (8.17 g, 355 mmol, 1.96 eq) was dissolved in ethanol (400 mL), then urea (18.6 g, 309 mmol, 1.7 eq) was added to the solution in batches and the mixture was stirred for 30 min. Dimethyl 2-(3-bromophenyl)propanedioate (52.0 g, 181 mmol, 1.0 eq) was added and the reaction mixture was heated to 90 °C and stirred for 15.5 h. LCMS confirmed the formation of the desired product. The mixture was poured into ice water and the pH was adjusted to 3 with 2N HC1. A solid appeared which was filtered and dried in vacuo to afford the title compound 5-(3- bromophenyl)hexahydropyrimidine-2, 4, 6-trione (18.0 g, 63.6 mmol, 34.9% yield) as a yellow solid.

[0383] LCMS (ESC): 282.9[M+H]+.

[0384] Step 3 : 5-[3-[4-(Trifluoromethoxy)anilino1phenyl1hexahydropyrimidine-2.4.6-trione

[0385] To a mixture of 5-(3-bromophenyl)hexahydropyrimidine-2, 4, 6-trione (1.0 g, 3.53 mmol, 1.0 eq), 2-(trifluoromethoxy)aniline (0.72 mL, 5.30 mmol, 1.5 eq) andtertBuONa (2 M in THF, 5.3 mL, 10.6 mmol, 3.0 eq) in DMF (30 mL) was added TBUXPHOS PD G3 (225 mg, 0.28 mmol, 0.08 eq) under N2 at 20 °C. Then, the mixture was heated to 100 °C and was stirred for 12 h. LCMS confirmed the presence of the desired product and the mixture was then cooled to 20°C, filtered, and concentrated. The crude material was triturated with EtOAc and then filtered and dried in vacuo to afford a material containing the title compound 5-[3-[4- (trifluoromethoxy)anilino]phenyl]hexahydropyrimidine-2, 4, 6-trione (720 mg, 1.9 mmol, 43% yield) as a grey solid with a purity of about 80%.

[0386] LCMS (ESC): 380.0 [M+H]+.

[0387] Intermediate O

[0388] 5- [4- [2-(4-Chlorophenyl)ethynyl] phenyl] hexahydropyrimidine-2,4,6-trione

[0389] Step 1: Methyl 2- [4- [2-(4-chlorophenyl)ethynyl] phenyl] acetate

[0390] To a solution of methyl 4-bromophenylacetate (2.00 g, 8.7 mmol, 1.0 eq), copper(l) iodide (0.17 g, 0.87 mmol, 0.1 eq) and bis-triphenylphosphine-palladium(II) chloride (0.61 g, 0.87 mmol, 0.1 eq) in DMF (2.0 mL) were added 1 -chloro-4-ethynylbenzene (3.58 g, 26.2 mmol, 3.0 eq) and N,N-diisopropylethylamine (3.04 mL, 17.5 mmol, 2.0 eq). The reaction mixture was then stirred at 90 °C for 12 h. TLC (PE:EtOAc=5: 1) showed that the starting material was consumed completely and a new spot was present (staining with aq. KMnCh). The reaction mixture was diluted with water (50 mL) and was extracted with ethyl acetate (3 times 50 mL) and the organic extracts were washed with brine (2 times 50 mL). The combined organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluted with a gradient of petroleum ether : ethyl acetate (0% to 20% EtOAc) to give the title compound methyl 2-[4-[2-(4- chlorophenyl)ethynyl] phenyl] acetate (2.10 g, 7.38 mmol, 84.5 % yield) as a green solid. 'H-NMR (400 MHz, CDCh): 5 = 7.53 - 7.42 (m, 4H), 7.27 (s, 5H), 3.72 (s, 3H), 3.65 (s, 2H).

[0391] Step 2: Dimethyl 2-|4-|2-(4-chloroDhenyl )ethvnyl Iphenyl Ipropanedioate

[0392] To a solution of methyl 2- [4- [2-(4-chlorophenyl)ethynyl] phenyl] acetate (6.89 g, 24.2 mmol, 1.0 eq) and dimethyl carbonate (8.72 g, 96.8 mmol, 4.0 eq) in THF (30 mL) was added sodium hydride, 60% in oil (1.94 g, 48.4 mmol, 2.0 eq) in portions with ice bath cooling. Then, the mixture was stirred under reflux at 80 °C for 12 h. LCMS showed the presence of the desired product mass. The mixture was poured into water and was extracted with EtOAc (3 times 100 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography (SiCh. gradient of PE:EtOAc=80:l to 20:1, UV detection). Fractions containing the desired product were combined and evaporated to provide the title compound dimethyl 2-[4-[2-(4-chlorophenyl)ethynyl]phenyl]propanedioate (5.20 g, 15.2 mmol, 62.7 % yield) as a yellow solid.

[0393] LCMS (ESC): 343.1 [M+H]+.

[0394] Step 3 : 5-[4-[2-(4-Chlorophenyl)ethynyl]phenyl]hexahydropyrimidine-2.4.6-trione

[0395] Dimethyl 2-[4-[2-(4-chlorophenyl)ethynyl]phenyl]propanedioate (5.20 g, 15.2 mmol, 1.0 eq) and urea (1.55 g, 25.8 mmol, 1.7 eq) were added to a solution of sodium (698 mg, 30.3 mmol, 2.0 eq) dissolved in ethanol (10 mL), prepared previously. Then, the mixture was stirred under reflux at 80 °C for 12 h under an N2 atmosphere. LCMS confirmed formation of the desired material. The suspension was concentrated in vacuo to about half of the initial volume, and the mixture was then then cooled to room temperature and poured into ice water. 1 N HC1 was added to adjust to pH to 2 to 3. The resulting precipitate was filtered and the filter cake was triturated with EtOAc (10 mL), filtered again and washed with additional EtOAc (3 times 2 mL). The material was dried under reduced pressure to give a crude product. This material was further triturated with EtOH (10 mL), filtered and washed with water (3 times 2 mL). Then the filter cake was dried to give the title compound 5-[4-[2-(4- chlorophenyl)ethynyl]phenyl]hexahydropyrimidine-2, 4, 6-trione (1.20 g, 3.54 mmol, 20 % yield) as a brown solid.

[0396] LCMS (ESE): 339.1 [M+H]+.

[0397] Intermediate P

[0398] N-(4-Chlorophenyl)-4-(2,4,6-trioxohexahydropyrimidin-5-yl)benzamide

[0399] Step 1: Methyl 4-(2.4.6-trioxohexahydropyrimidin-5-yl)benzoate

[0400] To a solution of 5-(4-bromophenyl)hexahydropyrimidine-2, 4, 6-trione (Intermediate A, step 2) (3.00 g, 10.6 mmol, 1.0 eq.) and Pd(dppl C12 (1.73 g, 2.12 mmol, 0.2 Eq.) in methanol (20 mL) and DMF (20 mL) was added triethylamine (4.43 mL, 31.8 mmol, 3.0 eq). The mixture was stirred at 80 °C for 48 h under a CO atmosphere (50 psi). The mixture was cooled to 25°C, filtered and concentrated. The crude product was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100 * 25 mm * 4 pm; gradient: water (containing 0.1% FA) : CH3CN (20%-40%); gradient time: 7 min), followed by lyophilisation of the fractions containing the desired product, to afford methyl 4-(2,4,6-trioxohexahydropyrimidin-5-yl)benzoate (3.00 g, 11.4 mmol, quant.) as a white solid with a purity of 97%.

[0401] LCMS (ESI+): 263.0 [M+H]+.

[0402] Step 2: 4-(2.4.6-Trioxohexahydropyrimidin-5-yl)benzoic acid

[0403] Methyl 4-(2,4,6-trioxohexahydropyrimidin-5-yl)benzoate (300 mg, 1.14 mmol, 1.0 eq.) was dissolved in H2O (10 mL) and THF (10 mL) and LiOH (82 mg, 3.42 mmol, 3.0 eq.) was added. The mixture was stirred at 20 °C for 12 h. Then, the mixture was adjusted to pH 2 by addition of IN HC1 and was extracted with EtOAc (3 x 20mL). The organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the 4-(2,4,6- trioxohexahydropyrimidin-5-yl)benzoic acid (80 mg, 0.32 mmol, 28% yield) as a yellow oil which was used without further purification.

[0404] LCMS (ESI+): 249.0 [M+H]+.

[0405] Step 3 : N-(4-Chlorophenyl)-4-(2.4.6-trioxohexahydropyrimidin-5-yl)benzamide

[0406] To a solution of 4-(2,4,6-trioxohexahydropyrimidin-5-yl)benzoic acid (290 mg, 1.17 mmol, 1.0 eq.) and DIPEA (1.35 mL, 3.51 mmol, 3.0 Eq.) in DMF (5 mL) was added O-(7-azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (550 mg, 2.34 mmol, 2.0 eq,) and the mixture was stirred for 10 min at RT. 4-Chloroaniline (298 mg, 2.34 mmol, 2.0 eq.) was added and the mixture was stirred at RT for 12h. The mixture was concentrated in vacuo and the crude was triturated with EtOAc, filtered, dried in vacuo to afford the N-(4-chlorophenyl)-4-(2,4,6- trioxohexahydropyrimidin-5-yl)benzamide (220 mg, 0.61 mmol, 53% yield) as a pink solid. LCMS (ESE): 358.1 [M+H]+.

[0407] The following Intermediate was made in analogy to Intermediate P, Step 3 by using the appropriate starting materials and conditions as indicated in the table below:

[0408] Intermediate Q 5-[5-(4-Ethylphenoxy)pyrazin-2-yl]hexahydropyrimidine-2, 4, 6-trione Step 1: 2-Bromo-5-(4-ethylphenoxy)pyrazine

[0409] To a solution of 2-bromo-5 -chloropyrazine (5.0 g), 4-ethylphenol (4.0 g) in ACN (100 mL) was added K2CO3 (12.0 g) at 25 °C. Then, the mixture was stirred at 90 °C for 12 h. LCMS showed formation of the desired product. The mixture was then filtered and concentrated in vacuo to afford a residue which was then purified by flash column chromatography eluting with 30% EtOAc in petroleum ether. The desired fractions were combined and concentrated to afford 2- bromo-5-(4-ethylphenoxy)pyrazine (8.0 g, 111% yield) as a colorless oil. This material which was used for the next step contained about 25% of 2-chloro-5-(4-ethylphenoxy)pyrazine as a side product.

[0410] 'H NMR (400 MHz, DMSO- 6): 6 = 8.39 (m, 2H), 7.27 (d, J=8.38 Hz, 2H), 7.12 (d, J=8.50 Hz, 2H), 2.54 - 2.70 (m, 2H), 1.19 (t, J=7.63 Hz, 3H).

[0411] An extra signal at 8.33 ppm was associated with the 2-chloro-pyrazine side product.

[0412] Step 1 : 5-[5-(4-Ethylphenoxy)pyrazin-2-yl]hexahydropyrimidine-2.4.6-trione

[0413] Me4-tBu-XPhos-Pd-G3 (CAS 1507403-85-1, 305 mg) was added to a stirred mixture of 2- bromo-5-(4-ethylphenoxy)pyrazine (2.00 g), barbituric acid (1.19 g) and DBU (3.27 g) in DMSO (8 mL) and the mixture was purged with N2. Then, the mixture was stirred at 100 °C under nitrogen for 12 h. LCMS showed the presence of a new peak with the desired mass. The mixture was diluted with 80 mL EtOAc and was washed three times with 60 mL brine. The organic layer was dried over Na2SO4 and was concentrated in vacuo. The residue was purified by reverse MPLC (240 g C18 column SepaFlash prefill domestic amorphous spherical Cl 8 silicone, 20-45 pm; eluent A: Water containing 0.5% FA; B: ACN; gradient of B 1% - 80%) to afford a still impure fraction of 5-[5-(4-ethylphenoxy)pyrazin-2-yl]hexahydropyrimidine-2, 4, 6-trione (200 mg, 8.6% yield) as a yellow solid.

[0414] This material was used without further detailed analysis in the next step. The following Intermediates were made in analogy to Intermediate Q by using the appropriate starting materials and conditions.

[0415] Intermediate U

[0416] 5-[6-(4-Ethylphenoxy)-3-pyridyl]hexahydropyrimidine-2, 4, 6-trione

[0417] Step 1: 5-Bromo-2-(4-ethylphenoxy)pyridine tBuOK (35.0 mL, IM solution in THF) was added to a mixture of 4-ethylphenol (3.0 g) and 5- bromo-2-fluoropyridine (5.0 g) in THF (60 mL) at 5 °C and the mixture was then stirred for 1 h at RT and then at 50 °C for another 11 h. TLC analysis (PE / EtOAc = 5 / 1) showed a new spot being formed. The reaction mixture was then concentrated and the residue was diluted with 50 ml water and was extracted 3 times with 50 mL EtOAc. The organics were dried over NaiSO-i before being concentrated to dryness. The crude material was then purified by flash column chromatography eluting with 20% EtOAc in PE. The desired fractions were combined and concentrated to afford 5-bromo-2-(4-ethylphenoxy)pyridine (3.80 g, 56% yield) as a white solid. 'H NMR (400 MHz, CDCh): 8 = 8.23 (d, J = 2.5 Hz, 1H), 7.75 (dd, J = 2.6, 8.7 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.08 - 7.02 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 2.68 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H).

[0418] Step 2: Dimethyl 2-[6-(4-ethylphenoxy)-3-pyridyl1propanedioate

[0419] CS2CO3 (13.0 g) was added to a stirred mixture of 5-bromo-2-(4-ethylphenoxy)pyridine (3.6 g), Cui (630 mg), dimethyl malonate (8.65 mL) and L-proline (900 mg) and the reaction was then stirred at 60 °C for 12 h. LCMS showed formation of a peak with the desired mass.

[0420] A second reaction with 200 mg of 5-bromo-2-(4-ethylphenoxy)pyridine was carried out in the same way.

[0421] Both reaction mixtures were combined, poured into 100 mL of ice water and the solution was neutralized with IM HC1. The mixture was then extracted 3 times with 50 mL EtOAc and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 25% EtOAc in PE and the desired fractions were combined and concentrated to afford dimethyl 2-[6-(4-ethylphenoxy)-3- pyridyl] propanedioate (1.6 g, 38% yield) as a yellow solid.

[0422] 'H NMR (400 MHz, CDCI3): 8 = 8.11 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 2.5, 8.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.10 - 7.01 (m, 2H), 6.91 (d, J = 8.6 Hz, 1H), 4.61 (s, 1H), 3.77 (s, 6H), 2.67 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H). Step 3: 5-[6-(4-Ethylphenoxy)-3-pyridyl1hexahydropyrimidine-2.4.6-trione

[0423] Dimethyl 2-[6-(4-ethylphenoxy)-3-pyridyl]propanedioate (1.6 g) was added to a solution of urea (450 mg) in MeOH (30 mL) and NaOEt in EtOH (20% by weight, 8 mL) and then the mixture was heated to 80 °C and stirred for 16 h. LCMS showed a new peak with the desired mass. The mixture was then poured into ice water (30 mL) and the mixture was neutralized with IM HC1. It was then concentrated in vacuo to afford a residue which was purified by reverse MPLC (elution with A: water containing 0.5% FA, and B: ACN, gradient of B 5% - 45%). The desired fractions were combined and lyophilized to afford 5-[6-(4-ethylphenoxy)-3-pyridyl]hexahydropyrimidine- 2, 4, 6-trione (300 mg, 19% yield) as a yellow solid.

[0424] LCMS (ESC): 326.1 [M+H]+.

[0425] Intermediate V

[0426] 5- [4- [ [5-(T rifluoromethoxy)-2- pyridyl] oxy] phenyl] hexahydro pyrimidine-2, 4, 6- trione

[0427] Step 1 : Dimethyl 2-(4-benzyloxyphenyl)propanedioate

[0428] CS2CO3 (180 g) was added to a stirred mixture of 4-benzyloxybromobenzene (50.0 g), Cui (7.0 g), dimethyl mal onate (103.8 mL) and L-proline (9.0 g) in DMSO (600 mL) and the mixture was purged with N2. Then, the reaction was stirred at 90 °C for 12 h. LCMS showed a new peak with the desired product mass. The mixture was poured into ice-water (500 mL) and the pH was adjusted to 6 with 6M HC1. The mixture was then extracted 4 times with 300 mL EtOAc and the organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was then purified by column chromatography on a Biotage apparatus eluting with 15% EtOAc in PE and the desired fractions were combined and concentrated to afford dimethyl 2-(4- benzyloxyphenyljpropanedioate (38.0 g, 64% yield) as a white solid. 'H-NMR (400 MHz, CDC13): 7.48-7.28 (m, 7H), 6.98 (d, J=8.8 Hz, 2H), 5.07 (s, 2H), 4.60 (s, 1H), 3.76 (s, 6H).

[0429] >-2,4, 6-trione

[0430] Sodium (0.92 g) was dissolved in ethanol (200 mL) and urea (3.21 g) was added to the mixture, followed by dimethyl 2-(4-benzyloxyphenyl)propanedioate (12.0 g). Then, the mixture was stirred at 80 °C for 16 h. LCMS showed formation of a peak with the desired mass. The mixture was cooled to 20°C and was poured into ice water. Then, the pH was adjusted to 2 with IN HC1. The resulting suspension was filtered and the solid was triturated with EA to afford after filtration 5-(4-benzyloxyphenyl)hexahydropyrimidine-2, 4, 6-trione (6.2 g, 60% yield) as a yellow solid with a purity of about 80% (by UV).

[0431] LCMS (ESC): 311.0 [M+H]+.

[0432] :-2, 4, 6-trione

[0433] 5-(4-Benzyloxyphenyl)hexahydropyrimidine-2, 4, 6-trione (6.2 g) was dissolved in DMF (200 mL), Pd / C (482 mg) was added to the mixture and then the reaction was stirred at 20 °C for 12 h under an atmosphere of H2. LCMS confirmed formation of a product with the desired mass. The mixture was filtered and concentrated to afford a crude material which was triturated with EtOAc, filtered again and dried in vacuo to afford 5-(4-hydroxyphenyl)hexahydropyrimidine- 2, 4, 6-trione (1.8 g, 41% yield) as a grey solid.

[0434] LCMS (ESH): 221.1 [M+H]+.

[0435] Step 4: 5-[4-[[5-(Trifluoromethoxy)-2-pyridyl1oxy1phenyl1hexahvdropyrimidine-2.4.6-trione

[0436] Potassium carbonate (168 mg) was added to a mixture of 2-chloro-5-(trifluoromethoxy)pyridine (80.0 mg) and 5-(4-hydroxyphenyl)hexahydropyrimidine-2, 4, 6-trione (89.2 mg) in DMSO (6 mL) and then the mixture was heated to 100 °C and stirred for 12 h under N2. LCMS showed that the desired product was formed. The reaction mixture was purified directly by prep-HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase A: water (0.225% TFA), B: ACN; gradient of B 35%-65%) and the desired fractions were lyophilized to afford the 5-[4-[[5- (trifluoromethoxy)-2-pyridyl]oxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (15.0 mg, 10% yield) as a white solid.

[0437] LCMS (ESC): 382.0 [M+H]+.

[0438] Intermediate X

[0439] 5- [3- [ [5-(trifluoromethyl)pyrazin-2-yl] amino] phenyl] hexahydropyrimidine-2,4,6-trione

[0440] To a solution of 5-(3-bromophenyl)hexahydropyrimidine-2, 4, 6-trione (500 mg, obtained in Intermediate M, Step 2) and 5-(trifluoromethyl)pyrazin-2-amine (346 mg), Tbuxphos PD G3 (140 mg) in DMF (20 mL) kept under nitrogen was added tBuONa (2.65 mL, 2M in THF) and then the mixture was stirred at 90 °C for 12 h. LCMS showed formation of a peak with the desired product mass. The mixture was filtered and concentrated in vacuo to afford a crude material which was triturated with EtOAc and MeOH to afford after filtration a 5-[3-[[5- (trifluoromethyl)pyrazin-2-yl]amino]phenyl]hexahydropyrimidine-2, 4, 6-trione (430 mg, 40% yield) as a brown solid with a purity of about 60% ( by UV). This material was suitable for the next step and was used without further purification.

[0441] LCMS (ESC): 366.0 [M+H]+.

[0442] Intermediate Y

[0443] 5- [3- [(5-Chloro-2-pyridyl)amino] phenyl] hexahydro pyrimidine-2, 4, 6-trione

[0444] Xantphos (409 mg) was added to a mixture of 2-amino-5-chloropyridine (1.36 g), cesium carbonate (4.60 g), Pd2(dba)s (388 mg), 5-(3-bromophenyl)hexahydropyrimidine-2, 4, 6-trione (2.00 g, obtained in Intermediate M, Step 2) in DMF (20 mL) under N2 at 20 °C. Then, the mixture was heated to 100 °C under N2 and was stirred for 12 h. In process LCMS showed a peak with the desired product mass. The mixture was cooled to 25°C, filtered and concentrated in vacuo to give a residue which was triturated with EtOAc to afford after filtration a crude crop of 5-[3-[(5-chloro-2-pyridyl)amino]phenyl]hexahydropyrimidine-2, 4, 6-trione (800 mg, 15% yield) as a yellow solid which was used without further purification and analysis in the next reaction step.

[0445] LCMS (ESL, in process): 330.9 [M+H]+.

[0446] Intermediate AA

[0447] 5-[4-(5-Ethylpyrazin-2-yl)oxyphenyl]hexahydropyrimidine-2,4,6-trione

[0448] A solution of 5-(4-hydroxyphenyl)hexahydropyrimidine-2, 4, 6-trione (60 mg, obtained in Intermediate V, Step 3) and 2-chloro-5-ethyl-pyrazine (389 mg) in DMSO (7.5 mL) was added K2CO3 (1.32 g) and then the mixture was stirred at 120 °C for 12 h. LCMS showed the desired product being formed. Then, the reaction mixture was filtered and the filtrate was poured into water (45 mL) which was then extracted 3 times with EtOAc (30 mL). Then the water phase was concentrated in vacuo and the residue was purified by reverse phase chromatography (Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1% NH3*H2O); eluent B: ACN; gradient of B: 0-37% B) to give after lyophilization of the desired fractions the title compound 5-[4-(5- ethylpyrazin-2-yl)oxyphenyl]hexahydropyrimidine-2, 4, 6-trione (295 mg, 32% yield) as a grey solid.

[0449] LCMS (ESC): 327.1 [M+H]+. 1.1.2) Spirocyclic Intermediates

[0450] Intermediate 1 2-(2,7-Diazaspiro[3.5]nonan-2-yl)ethanol 2,2,2-trifluoroacetic acid salt

[0451] Step 1: tert-Butyl 2-(2-hydroxyethyl)-2.7-diazaspiro[3.5]nonane-7-carboxylate

[0452] Tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (1.70 g, 6.49 mmol, 1.0 Eq.) was dissolved in acetonitrile (35 mL) and K2CO3 (1.74 g, 12.6 mmol, 2.0 Eq.) was added. The white suspension was heated under reflux. 2-Bromoethan-l-ol (787 mg, 445 pL, 6.30 mol, 0.95 Eq.) in acetonitrile (5 mL) was added dr op wise at reflux and the reaction mixture was stirred under reflux for 4 hours. The mixture was cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by flash chromatography (SiCh. gradient of DCM:MeOH 0-10%, UV detection) to afford tert-butyl 2-(2- hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1069 mg, 3.96 mmol, 61 % yield) as white oil.

[0453] LCMS (ESI+): 271.0 [M+H]+.

[0454] Step 2: 2-(2.7-Diazaspiro[3.5]nonan-2-yl)ethanol 2.2.2-trifluoroacetic acid salt

[0455] Tert-butyl 2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.06 g, 3.92 mmol, 1.0 Eq.) was dissolved in dry DCM (30 mL) and cooled to 0 °C. TFA (6.71 g, 4.53 mL, 58.8 mmol, 15 Eq.) was added dropwise and the reaction mixture was allowed to warm up to room temperature. The colourless reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and diluted with toluene and concentrated (3 x 10 mL) to remove any excess of TFA to give 2-(2,7-diazaspiro[3.5]nonan-2-yl)ethanol 2,2,2- trifluoroacetic acid salt (1.23 g, quant, yield) which was used in the next step without further purification.

[0456] LCMS (ESI+): 171.2 [M+H]+. 10

[0457] Intermediate 2 2-(2-Phenylethyl)-2,7-diazaspiro [3.5] nonane 2,2,2-trifluoroacetic acid salt

[0458] Step 1: tert-Butyl 2-(2-phenylethyl)-2.7-diazaspiro[3.51nonane-7-carboxylate

[0459] Prepared in analogy to Intermediate 1, step 1, using tert-butyl 2,7-diazaspiro[3.5]nonane-7- carboxylate hydrochloride (500 mg, 1.9 mmol, 1.0 Eq.) and 2-bromoethylbenzene (260 pL, 1.9 mmol, 1.0 Eq.) to give the tert-butyl 2-(2-phenylethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (465 mg, 1.41 mmol, 67 % yield) as a colorless oil.

[0460] LCMS (ESI+): 331.3 [M+H]+.

[0461] Step 2: 2-(2-Phenylethyl)-2,7-diazaspiro[3.5]nonane 2.2.2-trifluoroacetic acid salt

[0462] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 2-(2-phenylethyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (200 mg, 0.61 mmol, 1.0 Eq.) and TFA (430 pL, 9.15 mmol, 15 Eq.) to give 2-(2-phenylethyl)-2,7-diazaspiro[3.5]nonane 2,2,2-trifluoroacetic acid salt (250 mg, quant, yield) as a colorless oil.

[0463] LCMS (ESI+): 231.3 [M+H]+.

[0464] Intermediate 3 l-(2,7-Diazaspiro[3.5]nonan-2-yl)-2-hydroxy-ethanone 2,2,2-trifluoroacetic acid salt

[0465] Step 1: tert-Butyl 2-(2-hydroxyacetyl)-2,7-diazaspiro[3.51nonane-7-carboxylate

[0466] To a solution of glycolic acid (1.74 g, 22.8 mmol, 2.0 eq) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (3.28 g, 17.1 mmol, 1.5 eq) and 1- hydroxybenzotriazole (2.31 g, 17.1 mmol, 1.5 eq) in DMF (30 mL) were added tert-butyl 2,7- diazaspiro[3.5]nonane-7-carboxylate hydrochloride (3.0 g, 11.4 mmol, 1.0 eq) and N,N- diisopropylethylamine (7.95 mL, 45.7 mmol, 4.0 eq). Then, the mixture was stirred at 25 °C for 12 h. LCMS confirmed that the desired product mass was present. The mixture was concentrated in vacuo and the crude material was purified by MPLC (ISCO CombiFlash; column: 330g flash column Welch Ultimate XB C18 20-40 pm; 120 A; flow rate: lOOml / min; gradient of CH3CN in H2O (containing 0.1% TFA) 0-35% over 30 min, then isocratic elution at 35% CH3CN for lOmin). Fractions containing the desired material were combined and lyophilized to give tertbutyl 2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.50 g, 5.28 mmol, 46.1 %) as a white solid.LCMS (ESU): 285.1 [M+H]+, 229.1 [M+H-isobutylene]+.

[0467] Step 2: l-(2.7-Diazaspiro[3.5]nonan-2-yl)-2-hydroxy-ethanone 2.2.2-trifluoroacetic acid salt

[0468] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 2-(2-hydroxyacetyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (600 mg, 2.11 mmol, 1.0 Eq.) and TFA (1.50 mL, 31.7 mmol, 15 Eq.) to give l-(2,7-diazaspiro[3.5]nonan-2-yl)-2-hydroxy-ethanone 2,2,2- trifluoroacetic acid salt (650 mg, quant, yield) as a light yellow oil.

[0469] LCMS (ESI+): 185.0 [M+H]+.

[0470] Intermediate 4 2,7-Diazaspiro[3.5]nonan-2-yl(l,4-dioxan-2-yl)methanone 2,2,2-trifluroacetic acid salt

[0471] Step 1: tert-Butyl 2-(1.4-dioxane-2-carbonyl)-2.7-diazaspiro[3.51nonane-7-carboxylate

[0472] Prepared in analogy to Intermediate 3, step 1, using l,4-dioxane-2-carboxylic acid (99.2 mg, 0.75 mmol, 2.0 eq), N,N-diisopropylethylamine (0.26 mL, 1.5 mmol, 4.0 Eq.), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (144 mg, 0.75 mmol, 2.0 Eq.), 1- hydroxybenzotriazole (33.5 mg, 0.25 mmol, 0.66 Eq.) and tert-butyl 2,7-diazaspiro[3.5]nonane- 7-carboxylate hydrochloride (100 mg, 0.38 mmol, 1.0 Eq.) to give tert-butyl 2-(l,4-dioxane-2- carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (109 mg, 0.32 mmol, 84% yield) LCMS (ESC): 341.1 [M+H]+.

[0473] Step 2: 2.7-Diazaspiro[3.5]nonan-2-yl(l,4-dioxan-2-yl)methanone 2.2.2-trifluoroacetic acid salt

[0474] This intermediate was prepared in analogy to Intermediate 1, step 2, using tert-butyl 2-(l,4- dioxane-2-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (160 mg, 0.47 mmol, 1.0 Eq.) and TFA (333 pL, 7.05 mmol, 15 Eq.) to give 2,7-diazaspiro[3.5]nonan-2-yl(l,4-dioxan-2- yl)methanone 2,2,2-trifluoroacetic acid salt (120 mg, quant, yield) as a light yellow oil.

[0475] LCMS (ESC): 241.2 [M+H]+.

[0476] Intermediate 5

[0477] Benzyl 4-(l-oxa-4,9-diazaspiro[5.5]undecan-4-ylsulfonyl)piperidine-l-carboxylate hydrochloride salt

[0478] Step 1: tert-Butyl 4- [(1 -benzyloxy carbonyl-4-piperi dvDsulfonyl]- l-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate

[0479] To a solution of benzyl 4-(chlorosulfonyl)piperidine-l -carboxylate (1.40 g, 4.41 mmol, 1.0 Eq.) and tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1.129 g, 4.41 mmol, 1.0 Eq.) in DMF (15 mL) was added N,N-diisopropylethylamine (1.53 mL, 8.82 mmol, 2.0 eq) and the mixture was stirred at RT for 12 h. The mixture was concentrated and EtOAc (50 mL) and H2O (50 mL) were added. The aqueous layer was extracted with EtOAc (2 x 3 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, PE:EtOAc 5:1, UV detection) to afford tert-butyl 4-[(l-benzyloxycarbonyl-4-piperidyl)sulfonyl]-l-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate (1.92 g, 3.57 mmol, 81% yield) as a yellow oil.

[0480] LCMS (ESC): 438.3 [M-BOC+H]+. Step 2: Benzyl 4-(l-oxa-4.9-diazaspiro(5.51undecan-4-ylsulfonyl)piperidine-l-carboxylate hydrochloride salt

[0481] Tert-butyl 4-[(l-benzyloxycarbonyl-4-piperidyl)sulfonyl]-l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate (1.92 g, 3.57 mmol, 1.0 Eq.) was dissolved in MeOH (10 mL). HC1 in MeOH (3.0 M, 5.95 mL, 17.85 mmol, 5.0 Eq.) and the reaction mixture was stirred at RT for 1.5 h. The reaction mixture was concentrated and the residue was purified by column chromatography (SiCh, gradient of DCM:MeOH 0-10%, UV detection) to give benzyl 4-(l-oxa-4,9- diazaspiro[5.5]undecan-4-ylsulfonyl)piperidine-l-carboxylate hydrochloride salt (1.64 g, 3.46 mmol, 97% yield) as a white solid.

[0482] LCMS (ESI+): 438.3 [M+H]+.

[0483] Intermediate 6

[0484] Benzyl 4-[2-(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxo-ethyl]piperidine-l-carboxylate hydrochloride salt

[0485] Step 1: tert-Butyl 4-(2-(l-benzyloxycarbonyl-4-piperidyl)acetyl1-l-oxa-4.9- diazaspiro(5.51undecane-9-carboxylate

[0486] To a solution of 2-(l-benzyloxycarbonyl-4-piperidyl)acetic acid (2.0 g, 7.21 mmol, 1.0 eq) in DMF (30 mL) were added N,N-diisopropylethylamine (2.51 mL, 14.4 mmol, 2.0 eq) and HATU (2.55 g, 10.8 mmol, 1.5 eq). The mixture was stirred at RT for 10 min followed by the addition of tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (2.03 g, 7.93 mmol, 1.1 eq) and stirred for 12h at RT. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with H2O (3 x 20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiCB, PE:EtOAc 5:1, UV detection) to afford tert-butyl 4-[2-(l- benzyloxycarbonyl-4-piperidyl)acetyl]-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (3.13 g, 6.06 mmol, 54% yield) as a yellow oil.

[0487] LCMS (ESB): 516.4 [M+H]+.

[0488] Step 2: Benzyl 4-[2-(l-oxa-4.9-diazaspiro[5.51undecan-4-yl)-2-oxo-ethyl1piperidine-l- carboxylate hydrochloride salt

[0489] Prepared in analogy to Intermediate 5, step 2, using tert-butyl 4-[2-(l-benzyloxycarbonyl-4- piperidyl)acetyl]-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (5.10 g, 9.89 mmol, 1.0 eq) and HC1 in MeOH (3.0 M, 1.48 mL, 49.45 mmol, 5 Eq.) to give benzyl 4-[2-(l-oxa-4,9- diazaspiro[5.5]undecan-4-yl)-2-oxo-ethyl]piperidine-l-carboxylate hydrochloride salt (2.30 g, 5.09 mmol, 55% yield) as a yellow solid.

[0490] LCMS (ESB): 416.2 [M+H]+.

[0491] Intermediate 7 5-Oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoro acetic acid salt

[0492] This intermediate was prepared in analogy to Intermediate 1, step 2, using tert-butyl 5-oxa-2,8- diazaspiro[3.5]nonane-8-carboxylate (200 mg, 0.876 mmol, 15 Eq.) and TFA (4.0 mL) to give 5- oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoroacetic acid salt (180 mg, 60%) as a white solid.

[0493] This material was used without further characterization.

[0494] LCMS (ESB): 129.1 [M+H]+.

[0495] Intermediate 8 2-(l,8-Diazaspiro[4.5]decan-l-yl)ethanol hydrochloride salt

[0496] Step 1: tert-Butyl l-(2-(tert-butyl(dimethyl)silyl1oxyethyl1-l,8-diazaspiro(4.51decane-8- carboxylate

[0497] (Tert-butyldimethylsilyloxy)acetaldehyde (145 mg, 0.83 mmol, 2.0 eq) was dissolved in MeOH (4 mL). 8-(Boc)-l,8-diazaspiro(4,5)decane oxalate (100 mg, 0.42 mmol, 1.0 eq), sodium cyanoborohydride (78 mg, 1.25 mmol, 3.0 eq) and acetic acid (0.2 mL) were added sequentially and the reaction mixture was stirred at RT for 9h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated. The crude product was purified by column chromatography (SiCh. PE:EtOAc 5:1, UV detection) to give tert-butyl l-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-l,8-diazaspiro[4.5]decane-8-carboxylate (120 mg, 0.30 mmol, 72% yield) as light yellow oil.

[0498] LCMS (ESC): 399.4 [M+H]+.

[0499] Step 2: 2-(1.8-Diazaspiro[4.5]decan-l-yl)ethanol hydrochloride salt

[0500] Prepared in analogy to Intermediate 5, step 2, using tert-butyl l-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-l,8-diazaspiro[4.5]decane-8-carboxylate (120 mg, 0.301 mmol, 1.0 eq) and HCI in MeOH (3.0 M, 50 pL mL, 1.51 mmol, 5 Eq.) to give 2-(l,8- diazaspiro[4.5]decan-l-yl)ethanol hydrochloride salt (70 mg, quant, yield) as a light brown solid which was used without further purification.

[0501] LCMS (ESC): 185.4 [M+H]+.

[0502] Intermediate 9 l-Ethyl-l,8-diazaspiro[4.5]decane 2,2,2-trifluoroacetic acid salt

[0503] Step 1: tert-Butyl l-ethyl-1.8-diazaspiro[4.51decane-8-carboxylate

[0504] To a suspension of tert-butyl l,9-diazaspiro[4.5]decane-9-carboxylate (200 mg, 0.83 mmol, 1.0

[0505] Eq.) and potassium carbonate (230 mg, 1.66 mmol, 2.0 Eq.) was added iodoethane (0.06 mL, 0.76 mmol, 0.91 eq) and the mixture was stirred at RT for 12h. The mixture was filtered and concentrated to afford the tert-butyl l-ethyl-l,9-diazaspiro[4.5]decane-9-carboxylate, TFA salt (209 mg, 0.78 mmol, 94% yield) as a yellow oil which was used without further purification. LCMS (ESC): 268.9 [M+H]+.

[0506] Step 2: l-Ethyl-1.8-diazaspiro[4.5]decane 2.2.2-trifluoroacetic acid salt

[0507] Prepared in analogy to Intermediate 1, step 2, using tert-butyl l-ethyl-l,9-diazaspiro[4.5]decane- 9-carboxylate (161 mg, 0.60 mmol, 1.0 Eq.) and TFA (57 pL, 1.20 mmol, 2.0 Eq.) to give 1- (2,7-diazaspiro[3.5]nonan-2-yl)-2-hydroxy-ethanone 2,2,2-trifluoroacetic acid salt (650 mg, quant, yield) as a light yellow oil.

[0508] LCMS (ESC): 168.8 [M+H]+.

[0509] Intermediate 10 tert-Butyl N-(7-azaspiro[3.5]nonan-3-yl)carbamate

[0510] Commercially available: CAS# 1354950-49-4

[0511] Intermediate 11 tert-Butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate

[0512] Commercially available: CAS# 236406-49-8

[0513] Intermediate 12 l-(4,7-Diazaspiro[2.5]octan-4-yl)ethanone 2,2,2-trifluoroacetic acid salt

[0514] Step 1: tert-Butyl 4-acetyl-4.7-diazaspiro[2.51octane-7-carboxylate

[0515] Tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate (300 mg, 1.41 mmol, 1.0 Eq.) was dissolved in DCM (2 mL). Triethylamine (207 pL, 2.83 mmol, 2.0 Eq.) and acetyl chloride (201 pL, 2.83 mmol, 2.0 eq) were added. The mixture was stirred at 0 °C for 1.5 h. The mixture was concentrated and diluted with EtOAc (25 mL) and H2O (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give tert-butyl 4-acetyl-4,7- diazaspiro[2.5]octane-7-carboxylate (366 mg, quant, yield) as colorless oil.

[0516] LCMS (ESC): 199.2 [M-tBu+H]+.

[0517] Step 2: l-(2,7-Diazaspiro[3.51nonan-2-yl)-2-hydroxy-ethanone 2.2.2-trifluoroacetic acid salt

[0518] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 4-acetyl-4,7-diazaspiro[2.5]octane- 7-carboxylate (316 mg, 1.24 mmol, 1.0 Eq.) and TFA (118 pL, 2.48 mmol, 2.0 Eq.) to give 1- (2,7-diazaspiro[3.5]nonan-2-yl)-2-hydroxy-ethanone 2,2,2-trifluoroacetic acid salt (350 mg, quant, yield) as a light brown oil.

[0519] LCMS (ESC): 155.2 [M+H]+.

[0520] Intermediate 13 tert-Butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate

[0521] Commercially available: CAS# 236406-49-8

[0522] Intermediate 14 l-(l,9-Diazaspiro[4.5]decan-l-yl)-2,2,2-trifluoro-ethanone 2, 2, 2- trifluoroacetic acid salt

[0523] 1: tert-Butvl l-(2,2,2-trifluoroacetvl)-L9-di :-9-carboxvlate

[0524] To a solution of tert-butyl l,9-diazaspiro[4.5]decane-9-carboxylate (200 mg, 0.83 mmol, 1.0 Eq.) and trifluoroacetic anhydride (0.24 mL, 1.66 mmol, 2.0 Eq.) in DCM (10 mL) was added triethylamine (0.35 mL, 2.5 mmol, 3.0 Eq.) and the mixture was stirred at RT for 12 h. The mixture was concentrated and the crude was purified by column chromatograph (SiCh.

[0525] PE / EtOAc 8:1, UV detection) to give tert-butyl l-(2,2,2-trifluoroacetyl)-l,9- diazaspiro[4.5]decane-9-carboxylate (260 mg, 0.77 mmol, 90% yield) as a yellow oil.

[0526] LCMS (ESC): 281.1 [M-tBu+H]+.

[0527] Step 2: l-(1.9-Diazaspiro[4.5]decan-l-yl)-2.2.2-trifluoro-ethanone 2.2.2-trifluoroacetic acid salt

[0528] Prepared in analogy to Intermediate 1, step 2, using tert-butyl l-(2,2,2-trifluoroacetyl)-l,9- diazaspiro[4.5]decane-9-carboxylate (260 mg, 0.77 mmol, 1.0 Eq.) and TFA (366 pL, 7.70 mmol, 10 Eq.) to give l-(l,9-diazaspiro[4.5]decan-l-yl)-2,2,2-trifluoro-ethanone 2,2,2- trifluoroacetic acid salt (185 mg, quant, yield) as a yellow oil.

[0529] LCMS (ESC): 237.1 [M+H]+.

[0530] Intermediate 15

[0531] 2,5-Dioxa-8-azaspiro[3.5]nonane hemioxalate

[0532] Commercially available: CAS# 1184185-17-8

[0533] Intermediate 16 tert-Butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate

[0534] Commercially available: CAS# 1251011-05-8 Intermediate 18 rac-N-[(3-exo)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl]-5-oxa-2-azaspiro[3.4]octan-7-amine 2,2,2-trifluoroacetic acid salt .2.1] octan-3-yl] amino] -5-oxa-2- -2-carboxylate

[0535] Prepared in analogy to Intermediate 8, step 1, using (3-exo)-8-methyl-8-azabicyclo[3.2.1]octan- 3-amine (150 mg, 1.07 mmol , 1.0 Eq.) and tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2- carboxylate (513 mg, 2.14 mmol, 2.0 Eq.) to give rac-tert-butyl 7-[[(3-exo)-8-methyl-8- azabicyclo[3.2. l]octan-3-yl]amino]-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (260 mg, 0.74 mmol, 69% yield) as a colorless oil.

[0536] LCMS (ESI+): 352.2 [M+H]+.

[0537] Step 2: rac-N-[(3-exo)-8-Methyl-8-azabicyclo[3.2. l]octan-3-yl]-5-oxa-2-azaspiro[3.4]octan-7- amine 2,2,2-trifluoroacetic acid salt

[0538] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 7-[[(3-exo)-8-methyl-8- azabicyclo[3.2. l]octan-3-yl]amino]-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (260 mg, 0.74 mmol, 1.0 Eq.) and TFA (140 pL, 2.96 mmol, 4 Eq.) to give rac-N-[(3-exo)-8-methyl-8- azabicyclo[3.2. l]octan-3-yl]-5-oxa-2-azaspiro[3.4]octan-7-amine 2,2,2-trifluoroacetic acid salt (192 mg, quant, yield) as a yellow oil.

[0539] LCMS (ESI+): 252.2 [M+H]+.

[0540] Intermediate 19 rac-N- [(3-enrfo)-8-Methyl-8- azabicyclo [3.2.1] octan-3-yl] -5-oxa-2- azaspiro [3.4] octaneamine 2,2,2-trifluoroacetic acid salt .2. l]octan-3-yl]amino]-5-oxa-2- -2-carboxylate

[0541] Prepared in analogy to Intermediate 8, step 1, using (3-e«<7o)-8-methyl-8-azabicyclo[3.2.1]octan- 3-amine (70 mg, 0.50 mmol , 1.0 Eq.) and tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2- carboxylate (227 mg, 1.00 mmol, 2.0 Eq.) to give rac-tert-butyl 7-[[(3-e«<7o)-8-methyl-8- azabicyclo[3.2. l]octan-3-yl]amino]-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (125 mg, 0.36 mmol, 71% yield) as a colorless oil.

[0542] LCMS (ESE): 352.1 [M+H]+. -7- amine 2,2,2-trifluoroacetic acid salt

[0543] Prepared in analogy to Intermediate 1, step 2, using rac-tert-butyl 7-[[(3-e«<7o)-8-methyl-8- azabicyclo[3.2. l]octan-3-yl]amino]-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (125 mg, 0.36 mmol, 1.0 Eq.) and TFA (68 pL, 1.44 mmol, 4 Eq.) to give rac-N-[(3-e«<7o)-8-methyl-8- azabicyclo[3.2. l]octan-3-yl]-5-oxa-2-azaspiro[3.4]octan-7-amine 2,2,2-trifluoroacetic acid salt (95 mg, quant.) as a yellow oil.

[0544] LCMS (ESI+): 252.3 [M+H]+.

[0545] Intermediate 20

[0546] 3-Methylspiro [7H-furo [3,4-b] pyridine-5,4'-piperidine]

[0547] Intermediate 20 was prepared as described in WO 2015 / 091411A1. Intermediate 21 8-(Tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoroacetic acid salt

[0548] Step 1: tert-Butyl 8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2.8-diazaspiro[3.51nonane-2- carboxylate

[0549] Prepared in analogy to Intermediate 8, step 1, using tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane- 2-carboxylate (200 mg, 0.88 mmol, 1.0 Eq.) and tetrahydrofuran-3-carbaldehyde (175 mg, 1.75 mmol, 2.0 Eq.) to give tert-butyl 8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8- diazaspiro[3.5]nonane-2-carboxylate (410 mg, 1.31 mmol, 52% yield) as ayellow oil.

[0550] LCMS (ESC): 313.2 [M+H]+.

[0551] Step 2: 8-(Tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.51nonane 2,2.2-trifluoroacetic acid salt

[0552] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 8-(tetrahydrofuran-3-ylmethyl)-5- oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (410 mg, 1.31 mmol, 1.0 Eq.) and TFA (923 pL, 19.65 mmol, 15 Eq.) to give 8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoroacetic acid salt (300 mg, quant, yield) as a colorless oil.

[0553] LCMS (ESC): 231.3 [M+H]+.

[0554] Intermediate 22

[0555] 7-Oxa-2,5-diazaspiro [3.4] octan-6-one

[0556] Commercially available: CAS# 1780174-72-2

[0557] Intermediate 23 5-Oxa-2-azaspiro[3.4]octan-7-one 2,2,2-trifluoroacetic acid salt

[0558] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 7-oxo-5-oxa-2- azaspiro[3.4]octane-2-carboxylate (500 mg, 2.20 mmol, 1.0 Eq.) and TFA (680 pL, 8.80 mmol, 4 Eq.) to give 5-oxa-2-azaspiro[3.4]octan-7-one 2,2,2-trifluoroacetic acid salt (295 mg, quant.) as a colorless oil.

[0559] LCMS (ESC): 128.1 [M+H]+.

[0560] Intermediate 24 tert-Butyl 2,8-Diazaspiro[3.5]nonane-8-carboxylate

[0561] Commercially available: CAS# 885272-17-3

[0562] Intermediate 25 l-(2,8-Diazaspiro[3.5]nonan-2-yl)-2-hydroxy-ethanone 2,2,2-trifluoroacetic acid salt

[0563] Step 1: tert-Butyl 2-(2-hydroxyacetyl)-2.8-diazaspiro[3.51nonane-8-carboxylate

[0564] Prepared in analogy to Intermediate 3, step 1, using glycolic acid (145 mg, 1.9 mmol, 2.0 Eq.), N,N-diisopropylethylamine (0.66 mL, 3.81 mmol, 4.0 Eq.), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (274 mg, 1.43 mmol, 1.5 Eq.), 1- hydroxybenzotriazole (193 mg, 1.43 mmol, 1.5 Eq.) and tert-butyl 2,6-diazaspiro[3.5]nonane-6- carboxylate hydrochloride (250.0 mg, 0.95 mmol, 1.0 Eq.) to give tert-butyl 2-(2- hydroxyacetyl)-2,8-diazaspiro[3.5]nonane-8-carboxylate (155 mg, 0.55 mmol, 56% yield). LCMS (ESC): 258.4 [M+H]+.

[0565] Step 2: l-(2,8-Diazaspiro[3.51nonan-2-yl)-2-hydroxy-ethanone 2.2.2-trifluoroacetic acid salt Prepared in analogy to Intermediate 1, step 2, using tert-butyl 2-(2-hydroxyacetyl)-2,8- diazaspiro[3.5]nonane-8-carboxylate (150 mg, 0.53 mmol, 1.0 Eq.) and TFA (163 pL, 2.12 mmol, 4 Eq.) to give l-(2,8-diazaspiro[3.5]nonan-2-yl)-2-hydroxy-ethanone 2,2,2-trifluoroacetic acid salt(166 mg, quant, yield) as a colorless oil.

[0566] LCMS (ESE): 185.2 [M+H]+.

[0567] Intermediate 26

[0568] 2,5-Diazaspiro[3.5]nonane 2,2,2-trifluoroacetic acid salt

[0569] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 2,5-diazaspiro[3.5]nonane-2- carboxylate (225 mg, 0.99 mmol, 1.0 Eq.) and TFA (306 pL, 3.96 mmol, 4 Eq.) to give 2,5- diazaspiro[3.5]nonane 2,2,2-trifluoroacetic acid salt (130 mg, quant, yield) as a colorless oil.

[0570] LCMS (ESE): 185.2 [M+H]+.

[0571] Intermediate 27 tert-Butyl 7-azaspiro[3.5]non-l-ylcarbamate

[0572] Commercially available: CAS# 1354950-49-4

[0573] Intermediate 28 tert-Butyl 2,5-diazaspiro [3.4] octane-5-carboxylate

[0574] Commercially available: CAS# 1086398-04-0

[0575] Intermediate 29 tert-Butyl 2,6-diazaspiro [3.4] octane-6-carboxylate

[0576] Commercially available: CAS# 885270-86-0 Intermediate 30 tert-Butyl l,7-diazaspiro[3.5]nonane-l-carboxylate

[0577] Commercially available: CAS# 1216936-29-6

[0578] Intermediate 31 tert-Butyl 1,6-diazaspiro [3.3] heptane- 1-carboxylate

[0579] Commercially available: CAS# 1330763-95-5

[0580] Intermediate 32

[0581] Spiro| / / / -is()beiizoliiran-3.4'-piperidine|

[0582] Commercially available: CAS# 38309-60-3

[0583] Intermediate 33

[0584] 8-Oxa-2,5-diazaspiro [3.5] nonane 2,2,2-trifluoroacetic acid salt tert-Butyl 8-oxa-2,5-diazaspiro[3.5]nonane-2-carboxylate (400 mg, 1.75 mmol, 1.0 eq) was dissolved in DCM (4 mL) and TFA (1.0 mL) and the reaction mixture was stirred at 20 °C for 2 h. Then, the reaction mixture was concentrated in vacuo to remove the solvents and the concentrated residue was purified by silica gel chromatography, eluting first with PE, then with EtOAc to remove impurities and excess reagents, and finally with MeOH to elute the polar product. Fractions containing the desired product were combined and evaporated to provide the title compound 8-oxa-2,5-diazaspiro[3.5]nonane 2,2,2-trifluoroacetic acid salt (580 mg, 4.53 mmol, 93% yield calculated based on a bis-TFA salt) as a colorless oil. 'H-NMR (<5, MeOD): 3.291(m, 2H), 3.842 (m, 2H), 4.046 (s, 2H), 4.169 (d, 2H, J=13.2Hz), 4.432 (d, 2H, J=13.2Hz).

[0585] Intermediate 34

[0586] 8- [(l-Methyl-4-piperidyl)methyl] -5-oxa-2,8-diazaspiro [3.5] nonane 2,2,2-trifluoroacetic acid salt

[0587] Step 1: tert-Butyl 8-[(l-benzyloxycarbonyl-4-piperidyl)methyl1-5-oxa-2.8- diazaspiro[3.5]nonane-2-carboxylate

[0588] A solution of tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (100 mg, 0.44 mmol, 1.0 eq) and 4-formyl-N-CBZ-piperidine (114 mg, 0.46 mmol, 1.05 eq) in methanol (2 mL) / acetic acid (0.5 mL) was stirred at 20 °C for 1 h. Sodium cyanoborohydride (55.1 mg, 0.88 mmol, 2.0 eq) was added. Then, the mixture was stirred at 20 °C for 11 h. LCMS showed the presence of the desired product mass. The mixture was diluted with aqueous NH4CI solution and was extracted with EtOAc(3 x 30 mL). The combined organic layers were dried with Na2SC>4, filtered, and concentrated to give a residue, which was purified by column chromatography (SiCh, PE:EtOAc=l:l, UV detection) to give tert-butyl 8-[(l-benzyloxycarbonyl-4- piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (230.0 mg, 0.5 mmol, quant, yield) as a colorless oil.

[0589] LCMS (ESI+): 460.3 [M+H]+, 404.3 [M-isobutylene+H]+.

[0590] Step 2: tert-Butyl 8-[(l-methyl-4-piperidyl)methyl]-5-oxa-2.8-diazaspiro[3.5]nonane-2- carboxylate tert-Butyl 8-[(l-benzyloxycarbonyl-4-piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2- carboxylate (200 mg, 0.44 mmol, 1.0 eq) was dissolved in methanol (10 mL). Pd / C (20.0 mg) was added and the reaction mixture was degassed and purged with H2. Then, the mixture was stirred at 20 °C under a H2 atmosphere for 12 h. LCMS showed the a desired mono-deprotected intermediate as the main peak. Then, formaldehyde (50 pL) was added and the mixture was stirred at 20 °C for another 12 h. LCMS indicated the presence of the methylated product. The mixture was filtered and the filtrate was concentrated to give tert-butyl 8-[(l-methyl-4- piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (110 mg, 0.32 mmol, 74.5% yield) as a light yellow oil.

[0591] LCMS (ESC): 340.3 [M+H]+.

[0592] Step 3: 8-[(l-Methyl-4-piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane 2,2.2-trifluoroacetic acid salt tert-Butyl 8-[(l-methyl-4-piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (110 mg, 0.32 mmol, 1.0 eq) was dissolved in DCM (2 mL) / TFA (0.5 mL) and the reaction mixture was stirred at 20 °C for 2 h. The mixture was then concentrated to give a residue which was filtered through Si O2 (PE, EtOAc, MeOH, UV detection) to give 8-[(l-methyl-4- piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoroacetic acid salt (90.0 mg, 0.38 mmol, 118%) as a colorless oil, that was used without further purification.

[0593] LCMS (ESC): 240.3 [M+H]+.

[0594] 1.2) Preparation of examples

[0595] 1.2,1) General purification methods

[0596] The compounds prepared in the examples were purified according to one of the following methods.

[0597] Methods A: HPLC, TFA condition Mobile phase: A - water / 0.1% TFA (v / v); B - ACN.

[0598] Al: Column: Phenomenex Luna C18 150 x 40mm x 15pm.

[0599] For example: Gradient of B 20% - 50%, 10 min gradient time.

[0600] A2: Column: Phenomenex Synergi C18 150 x 25mm x 10pm.

[0601] For example: Gradient of B 40% - 70%, 40 min gradient time.

[0602] A3: Column: Phenomenex Luna Cl 8 75 x 30mm x 3pm.

[0603] For example: Gradient of B 34% - 54%, 7 min gradient time.

[0604] A4: Column: Phenomenex Synergi Polar-RP 100 x 25 mm x 4pm.

[0605] For example: Gradient of B 30% - 60%, 7 min gradient time.

[0606] Methods B; HPLC, neutral condition

[0607] Mobile phase: A - water containing 10 mM NH4HCO3; B - ACN.

[0608] Bl: Column: Waters Xbridge C18 150 x 50mm x 10pm.

[0609] For example: Gradient of B 26% - 56%, 10 min gradient time.

[0610] B2: Column: Waters Xbridge 150 x 25mm x 5um.

[0611] For example: Gradient of B 10% - 40%, 1 min gradient time.

[0612] B3: Column: Phenomenex Gemini-NX Cl 8 75 x 30mm x 3pm.

[0613] For example: Gradient of B 12% - 42%, 8 min gradient time.

[0614] Methods C: HPLC, formic acid (FA) condition

[0615] Mobile phase: A - water / 0.1% FA (v / v); B - ACN.

[0616] Cl: Column: Phenomenex Synergi C18 150 x 25mm x 10pm.

[0617] For example: Gradient of B 20% - 53%, 11 min gradient time.

[0618] C2: Column: Unisil 3-100 Cl 8 Ultra 150 x 50mm x 3pm.

[0619] For example: Gradient of B 35% - 65%, 7 min gradient time.

[0620] C3: Column: Phenomenex luna C18 150 x 40mm x 15pm.

[0621] For example: Gradient of B 10% - 40%, 10 min gradient time.

[0622] C4: Column: YMC Triart C18 150 x 25mm x 5pm.

[0623] For example: Gradient of B 51% - 51%, 10 min gradient time.

[0624] C5: Column: Phenomenex Cl 8 75 x 30mm x 3pm.

[0625] For example: Gradient of B 18% - 48%, 7 min gradient time.

[0626] C6: Column: Phenomenex luna C18 150 x 25mm x 10pm.

[0627] For example: Gradient of B 14% - 44%, 10 min gradient time. Method D: SFC, neutral condition

[0628] Column: Achiral 2-EPI, 12 nm, 5 pm, 250 x 20 mm. Mobile phase: SFC / 25% MeOH, 140 bar. For example, run time 6 min.

[0629] Method E: HPLC, TEA condition

[0630] Column: Gemini NX, 12 nm, 5 pm, 100 x 30 mm. Mobile phase: A - water / 0.1% TEA (v / v); B - ACN.

[0631] For example: isocratic conditions with A 27%, B 73%, run time 4.5 min.

[0632] Methods F: Silica gel chromatography

[0633] For example, a reaction on a scale of approx. 0.1 mmol was purified on a 12 g SiliaSep HP column (or an alternative silica gel cartridge) with elution either isocratically with an appropriate solvent mixture, or with a gradient of appropriate eluents, for example over a period of 20 minutes. Fractions containing pure product were combined and evaporated in vacuo to provide the title compound.

[0634] F 1 : Gradient of MeOH in DCM (0% - 10% MeOH)

[0635] F2: Isocratic elution with EtOAc:heptane 3:1

[0636] F3: Isocratic elution with DCM:MeOH 19: 1

[0637] F4: Isocratic elution with DCM:MeOH 9: 1

[0638] F5: Isocratic elution with petroleum ether:EtOAc 1 : 1

[0639] F6: Gradient of EtOAc in petroleum ether (20% - 80% EtOAc)

[0640] Method G: HPLC, NH4QH condition

[0641] Column: Waters Xbridge 150 x 25mm x 5 pm. Mobile phase: A - water (0.1% NH4OH); B - ACN.

[0642] For example: Gradient of B 18% - 48%; gradient time 9 min.

[0643] 1.2,1) Synthetic procedures

[0644] Example 1

[0645] 5- [2-(2-Hydroxyethyl)-2,7-diazaspiro [3.5] nonan-7-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0646] To a solution of 5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (Intermediate A, 700 mg, 1.84 mmol, 1.0 eq) in DMF (20 mL) was added N-bromosuccinimi de (393 mg, 2.21 mmol, 1.2 eq) at 0°C. The reaction mixture was stirred at 0 °C for 0.5 h. Then, 2- (2,7-Diazaspiro[3.5]nonan-2-yl)ethanol trifluoroacetic acid salt (Intermediate 1, 313 mg, 1.8 mmol, 1.0 eq) and N,N-diisopropylethylamine (0.42 mL, 2.4 mmol, 1.3 eq) were added and the reaction mixture was stirred at 25 °C for 0.5 h. LCMS showed the formation of a product with the desired mass of 549.1, [M+H]+. The mixture was concentrated to give a residue, which was purified by preparative HPLC (Method Al) to give the product as 2 crops (220 mg, 84 % purity and 70 mg, 45% purity, respectively). The combined materials were further purified by preparative HPLC (Method G) and then lyophilized to give the title compound 5-[2-(2- hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (175 mg, 0.32 mmol, 17.3 % yield) as a white solid.

[0647] MS (ESC): 549.0 [M+H]+.

[0648] The following examples were made in an analogous coupling step as described above for Example 1, by using the appropriate starting materials and purification conditions summarized in the following table:

[0649] Some examples required the synthesis of the appropriate 5, 5, -disubstituted barbiturate intermediates. The following intermediates were made in an analogous coupling step as described above for Example 1, by using the appropriate starting materials and purification conditions summarized in the following table:

[0650]

[0651] The following examples were synthesized form 5,5 disubstituted barbiturate intermediates Ax, summarized in the table above, by subsequent transformations.

[0652] Example 41

[0653] 5- [4-(4-Piperidylsulfonyl)- l-oxa-4,9-diazaspiro [5.5]undecan-9-yl] -5- [4- [4- (trifluoromethoxy)phenoxy] phenyl] hexahydropyrimidine-2, 4, 6- trione formic acid salt

[0654] Benzyl 4-[[9-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5- yl] -l-oxa-4,9-diazaspiro [5.5] undecan-4-yl] sulf onyl]piperi dine- 1 -carboxylate (Intermediate A5) (450 mg, 0.55 mmol, 1.0 Eq.) in a mixture of HBr (48% in H2O) (1.0 mL, 8.84 mmol, 16 Eq.) and acetic acid (2 mL) was stirred at RT for 12 h. The reaction mixture diluted with sat. NaHCCL (20 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with H2O (40 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC (Method C3) to give 5-[4-(4-piperidylsulfonyl)-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 2, 4, 6-trione formic acid salt (110 mg, 0.15 mmol, 26% yield) as yellow solid.

[0655] LCMS (ESI+): 682.3 [M+H]+.

[0656] Example 42

[0657] 5- [4- [2-(4-Piperidyl)acetyl] - l-oxa-4,9-diazaspiro [5.5]undecan-9-yl]-5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0658] Benzyl 4-[2-oxo-2-[9-[2,4,6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-l-oxa-4,9- diazaspiro[5.5]undecan-4-yl]ethyl]piperidine-l-carboxylate (Intermediate A6) (480 mg, 0.51 mmol, 1.0 Eq.) was dissolved in EtOAc (20 mL). Pd / C (wet) (100 mg) was added and the mixture was stirred at 20 °C for 4 h under H2 (balloon). The mixture was filtered, concentrated to give 5-[4-[2-(4-piperidyl)acetyl]-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl]-5-[4-[4

[0659] (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (170 mg, 0.26 mmol, 50% yield) as a white solid.

[0660] LCMS (ESI+): 660.2 [M+H]+.

[0661] Example 43

[0662] 5- [8-(Azetidin-3-ylmethyl)-5-oxa-2,8-diazaspiro [3.5] nonan-2-yl] -5- [4- [4- (trifluoromethoxy)phenoxy] phenyl] hexahydropyrimidine-2, 4, 6- trione formic acid salt

[0663] Step 1: tert-Butyl 3-[[2-[2,4.6-trioxo-5-[4-[4-

[0664] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-5-oxa-2.8-diazaspiro[3.5]nonan-8- y 1 methyl] azetidine- 1 -carboxylate 5-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (Example 60) (200 mg, 0.39 mmol, 1.0 Eq.) and tert-butyl 3-formylazetidine-l -carboxylate (219 mg, 1.18 mmol, 3.0 Eq.) were dissolved in a mixture of MeOH (8 mL) and acetic acid (0.5 mL). Sodium cyanoborohydride (74 mg, 1.18 mmol, 3.0 Eq.) was added and the mixture was stirred at RT for 12 h. (676.1, [M+H]+) was detected as main peak. The reaction mixture was concentrated and the residue was diluted with EtOAc (30 mL) and H2O (10 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give tert-butyl 3-[[2-[2,4,6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-5-oxa-2,8-diazaspiro[3.5]nonan-8- yl] methyl] azetidine- 1 -carboxylate (215 mg, 0.32 mmol, 80% yield) as white gum which was used without further purification.

[0665] LCMS (ESE): 676.1 [M+H]+.

[0666] Step 2: 5-[8-(Azetidin-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4-

[0667] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2.4.6-trione formic acid salt

[0668] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 3-[[2-[2,4,6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-5-oxa-2,8-diazaspiro[3.5]nonan-8- yl] methyl] azetidine- 1 -carboxylate (400 mg, 0.6 mmol, 1.0 Eq.) and TFA (2 mL) in DCM (8 mL).

[0669] The crude product was purified by preparative HPLC (Method C2) to give 5-[8-(azetidin-3- ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt (44 mg, 0.08 mmol, 12% yield).

[0670] LCMS (ESI+): 576.2 [M+H]+.

[0671] Example 44

[0672] 5- [8- [(l-Methyl-4-piperidyl)methyl] -5-oxa-2,8-diazaspiro [3.5] nonan-2-yl] -5- [4- [4- (trifluoromethoxy)phenoxy] phenyl] hexahydropyrimidine-2, 4, 6- trione formic acid salt

[0673] Step 1: tert-Butyl 4-[[2-[2,4.6-trioxo-5-[4-[4-

[0674] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-5-oxa-2.8-diazaspiro[3.5]nonan-8- yl] methyl] piperidine- 1 -carboxylate

[0675] Prepared in analogy to Example 43, step 2, using 5-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)-5-[4- [4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (Example 60) (100 mg, 0.20 mmol, 1.0 Eq.), tert-butyl 4-formylpiperidine-l-carboxylate (84 mg, 0.40 mmol, 2.0 Eq.) and sodium cyanoborohydride (37 mg, 0.60 mmol, 3.0 Eq.) to give tert-butyl 4-[[2-[2,4,6-trioxo- 5- [4- [4-(trifluoromethoxy)phenoxy] phenyl]hexahy dropy rimi din-5 -yl] -5 -oxa-2, 8- diazaspiro[3.5]nonan-8-yl]methyl]piperidine-l-carboxylate (130 mg, 0.18 mmol, 88% yield) as a yellow oil

[0676] LCMS (ESI+): 704.0 [M+H]+.

[0677] Step 2: 5-[8-(4-PiperidylmethyD-5-oxa-2.8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4-

[0678] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2.4.6-trione formic acid salt

[0679] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 4-[[2-[2,4,6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-5-oxa-2,8-diazaspiro[3.5]nonan-8- yl] methyl] piperidine- 1 -carboxylate (130 mg, 0.18 mmol, 1.0 Eq.) and TFA (56 pL, 0.72 mmol, 4 Eq.). The crude product was purified by preparative HPLC (Method C3) and lyophilized to afford the 5-[8-(4-piperidylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt (85 mg, 0.14 mmol, 76% yield) as a white solid.

[0680] LCMS (ESC): 604.3 [M+H]+.

[0681] Step 3: 5-18-l(l-Methyl-4-piperidyl)methyl1-5-oxa-2,8-diazaspirol3.51nonan-2-yl1-5-14-14-

[0682] (trifluoromethoxy)phenoxy1phenyl1hexahydropyrimidine-2.4.6-trione formic acid salt

[0683] Prepared in analogy to Example 43, step 2, using 5-[8-(4-piperidylmethyl)-5-oxa-2,8- diazaspiro[3.5]nonan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 2,4,6-trione;formic acid (50 mg, 0.08 mmol, 1.0 Eq.), formaldehyde (5 mg, 0.17 mmol, 2.0 Eq.) and sodium cyanoborohydride (16 mg, 0.25 mmol, 3.0 Eq.). The crude product was purified by HPLC (Method Cl) to give the product 5-[8-[(l-methyl-4-piperidyl)methyl]-5-oxa- 2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt (20 mg, 0.03 mmol, 38% yield) as a white solid.

[0684] LCMS (ESC): 618.3 [M+H]+.

[0685] Example 46 5-(3-amino-7-azaspiro[3.5]nonan-7-yl)-5-[4-[4- (trifluoromethoxy)phenoxy] phenyl] hexahydro pyrimidine-2, 4, 6-trione hydrogen chloride salt

[0686] N-[7-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-7- azaspiro[3.5]nonan-3-yl]carbamic acid tert-butyl ester (Intermediate A10) (15 mg, 0.024 mmol, 1.0 Eq.) was dissolved in DCM (100 pL) and hydrochloric acid (4M in dioxane) (30 pL, 0.121 mmol, 5.0 Eq.) was added at RT. The mixture was stirred for 2 hour. The reaction mixture was concentrated to dryness to give 5-(3-amino-7-azaspiro[3.5]nonan-7-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione hydrogen chloride salt (13 mg, 0.021 mmol, 88% yield) as a white solid.

[0687] LCMS (ESI+): 519.4 [M+H]+.

[0688] Example 47

[0689] 5- [7-(2-hydroxyethyl)-2,7-diazaspiro [4.4] nonan-2-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0690] Prepared in analogy to Intermediate 1, step 2, using (tert-butyl 2-[2,4,6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-2,7-diazaspiro[4.4]nonane-7- carboxylate TFA salt (Intermediate All), 380 mg, 0.63 mmol, 1.0 Eq.) and TFA (196 pL, 2.52 mmol, 4 Eq.) to give 5-(2,7-diazaspiro[4.4]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt (365 mg, quant, yield) as a light brown oil.

[0691] LCMS (ESI+): 505.3 [M+H]+.

[0692] Step 2: 5-[7-[2-[tert-Butyl(dimethyl)silyl1oxyethyl1-2.7-diazaspiro[4.41nonan-2-yl1-5-[4-[4-

[0693] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2.4.6-trione

[0694] Prepared in analogy to Example 43, step 2, using 5-(2,7-diazaspiro[4.4]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt (345 mg, 0.68 mmol, 1.0 Eq.), (tert-butyldimethylsilyloxy)acetaldehyde (125 mg, 0.72 mmol, 1.1 Eq.) and sodium cyanoborohydride (96 mg, 1.37 mmol, 2.0 Eq.) to give 5-[7-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-2,7-diazaspiro[4.4]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (400 mg, 0.60 mmol, 88% yield) as a colorless oil.

[0695] LCMS (ESI+): 663.4 [M+H]+.

[0696] Step 3: 5-[7-(2-Hydroxyethyl)-2,7-diazaspiro[4.41nonan-2-yl1-5-[4-[4-

[0697] (trifluoroiTiethoxy)phenoxylphenyl |hexahvdropyrimidine-2.4.6-trione

[0698] Prepared in analogy to Intermediate 1, step 2, using 5-[7-[2-[tert-butyl(dimethyl)silyl]oxyethyl]- 2,7-diazaspiro[4.4]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (385 mg, 0.58 mmol, 1.0 eq) and TFA (1.5 mL). The crude product was purified by preparative HPLC (Method Bl) and lyophilized to give 5-[7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (126 mg, 0.23 mmol, 39% yield) as a white solid.

[0699] LCMS (ESI+): 549.4 [M+H]+.

[0700] Example 48 5-(7-Methyl-2,7-diazaspiro [4.4] nonan-2-yl)-5- [4- [4- (trifluoromethoxy)phenoxy] phenyl] hexahydro pyrimidine-2, 4, 6-trione 2, 2, 2- trifluoroacetic acid salt Il l

[0701] Step 1: 5-(2,7-Diazaspiro[4.41nonan-2-yl)-5-[4-[4-

[0702] (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2.4.6-tri one 2.2,2-trifluoroacetic acid salt

[0703] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 2-[2,4,6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-2,7-diazaspiro[4.4]nonane-7- carboxylate TFA salt (Intermediate All, 380 mg, 0.63 mmol, 1.0 Eq.) and TFA (196 pL, 2.52 mmol, 4 Eq.) to give 5-(2,7-diazaspiro[4.4]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine -2,4,6-trione 2,2,2-trifluoroacetic acid salt (365.0 mg, quant.) as a light brown oil.

[0704] LCMS (ESI+): 505.3 [M+H]+.

[0705] Step 2: 5-(7-Methyl-2,7-diazaspiro[4.41nonan-2-yl)-5-[4-[4-

[0706] (trifluoromethoxy)phenoxy1phenyl1hexahydropyrimidine-2.4.6-trione 2.2.2-trifluoroacetic acid salt

[0707] Prepared in analogy to Example 43, step 2, using 5-(2,7-diazaspiro[4.4]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt (124 mg, 0.2 mmol, 1.0 Eq.), formaldehyde (30 mg, 0.99 mmol, 5.0 Eq.) and sodium cyanoborohydride (37 mg, 0.59 mmol, 3.0 Eq.) to give after purification by preparative HPLC (Method A4) 5-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-5-[4-[4- (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt (39.9 mg, 0.063 mmol, 30.4% yield) as a white solid.

[0708] LCMS (ESI+): 518.9 [M+H]+.

[0709] Example 49

[0710] 5-(l-Methyl-l,9-diazaspiro[4.5]decan-9-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0711] Step 1: 5-(1.9-diazaspiro[4.51decan-9-yl)-5-[4-[4-

[0712] (trifluoromethoxy)phenoxy1phenyl1hexahydropyrimidine-2.4.6-trione

[0713] A mixture of 5-[l-(2,2,2-trifluoroacetyl)-l,9-diazaspiro[4.5]decan-9-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (Intermediate A14, 140 mg, 0.23 mmol, 1.0 Eq.) and K2CO3 (94 mg, 0.68 mmol, 3.0 Eq.) in MeOH (20 mL) was stirred at 50 °C for 48 h. Then the mixture was concentrated and the resulting crude material was dissolved in EtOAc (20 mL), washed with H2O (10 mL), dried over Na2SC>4, filtered and concentrated to give 5-(l,9-diazaspiro[4.5]decan-9-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (110 mg, 0.21 mmol, 90% yield) as a yellow solid.

[0714] LCMS (ESI+): 519.2 [M+H]+.

[0715] Step 2: 5-(l-Methyl-l,9-diazaspiro[4.51decan-9-yl)-5-[4-[4-

[0716] (trifluoromethoxy)phenoxy1phenyl1hexahydropyrimidine-2.4.6-trione

[0717] Prepared in analogy to Example 43, step 2, using 5-(l,9-diazaspiro[4.5]decan-9-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (100 mg, 0.19 mmol, 1.0 Eq.), formaldehyde (29 mg, 0.96 mmol, 5.0 Eq.) and sodium cyanoborohydride (36 mg, 0.58 mmol, 3.0 Eq.). The crude product was purified by preparative HPLC (Method C5) to give the 5- (l-methyl-l,9-diazaspiro[4.5]decan-9-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (5.0 mg, 0.01 mmol, 5% yield).

[0718] LCMS (ESE): 533.1 [M+H]+.

[0719] Example 50

[0720] 5-(5-Oxa-2,8-diazaspiro [3.5] nonan-8-yl)-5- [4- [4-

[0721] (trifluoromethoxy)phenoxy] phenyl] hexahydropyrimidine-2,4,6-trione bis p-toluenesulfonic acid salt

[0722] 8-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-5-oxa-2,8- diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (35 mg, 0.055 mmol, 1.0 Eq.) (Intermediate Al 6) was dissolved in EtOAc (250 pL) and p-toluenesulfonic acid monohydrate (21 mg, 0.110 mmol, 2.0 Eq.) was added at RT. The reaction mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was concentrated to dryness, suspended in EtOAc, filtered and rinsed with Et20 to give 5-(5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione bis p-toluenesulfonic acid salt (20 mg, 0.023 mmol, 43% yield) as a white solid.

[0723] LCMS (ESI+): 507.5 [M+H]+.

[0724] Example 51 5- [ l-(2-Hydroxy ethyl)- 1,9-diazaspiro [4.5] decan-9-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0725] Step 1 : 5-[l-[2-[tert-Butyl(dimethyl)silyl1oxyethyl1-l,9-diazaspiro[4.51decan-9-yl1-5-[4-[4-

[0726] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2.4.6-trione

[0727] Prepared in analogy to Example 43, step 1, using 5-(l,9-diazaspiro[4.5]decan-9-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (obtained in Example 49, step 1, 60 mg, 0.12 mmol, 1.0 Eq.), (tert-butyldimethylsilyloxy)acetaldehyde (61 mg, 0.35 mmol, 3.0 Eq.) and sodium cyanoborohydride (29 mg, 0.46 mmol, 4.0 Eq.) to give 5-[l-[2-[tert- butyl(dimethyl)silyl] oxy ethyl] - 1 ,9-diazaspiro[4.5] decan-9-yl] -5 - [4 - [4 - (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (75 mg, 0.11 mmol, 74% yield) as a yellow oil.

[0728] LCMS (ESI+): 677.5 [M+H]+.

[0729] Step 2: 5-[l-(2-Hydroxyethyl)-l,9-diazaspiro[4.51decan-9-yl1-5-[4-[4-

[0730] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2.4.6-trione

[0731] 5-[l-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-l,9-diazaspiro[4.5]decan-9-yl]-5-[4-[4- (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (75 mg, 0.11 mmol, 1.0 Eq.) was dissolved in DCM (10 mL) and TFA (3.0 mL) was added and the mixture was stirred at RT for 12 h. The reaction mixture was concentrated and the crude material was purified by preparative HPLC (Method C6) followed by preparative HPLC (Method G) to give 5-[l-(2- hydroxy ethyl)- 1 ,9-diazaspiro [4.5] decan-9-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (13 mg, 0.02 mmol, 21% yield) as a white solid.

[0732] LCMS (ESI+): 563.2 [M+H]+.

[0733] Examples 52 and 53

[0734] 5- [8- [ [(3R)-T etrahydrofuran-3-yl] methyl]-5-oxa-2,8-diazaspiro [3.5] nonan-2-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione and

[0735] 5- [8- [ [(3S)-tetrahydrofuran-3-yl] methyl] -5-oxa-2,8-diazaspiro [3.5] nonan-2-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0736] 5-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl] hexahydropyrimidine-2, 4, 6-trione TFA salt (Example 60) (15 mg, 0.03 mmol, 1.0 eq.) and tetrahydrofuran-3-carbaldehyde (8 mg, 7.5 pL, 0.04 mmol, 1.3 Eq.) were dissolved in methanol (150 pL) and stirred for 30 minutes. Sodium cyanoborohydride (3 mg, 0.04 mmol, 1.5 Eq.) was added in one portion and the mixture was stirred at RT for Ih. The reaction mixture was diluted with EtOAc (5 mL) and H2O (2 mL). The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (Method F4) to give racemic 5-[8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (9.3 mg, 0.02 mmol, 48% yield) as a white solid.

[0737] LCMS (ESI+): 591.4 [M+H]+.

[0738] The racemic mixture of 5-[8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]- 5-[4-[4-(trifluoromethoxy)phenoxy]phenyl] hexahydropyrimidine-2, 4, 6-trione (52 mg, 0.075 mmol) was separated by chiral SFC: Column Chiral AD-H (250mm x 20mm x 5pm). 25% MeOH in scCCh to give:

[0739] • 5-[8-[[(3S or 3R)-tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5- [4- [4-(trifluoromethoxy)phenoxy] phenyl] hexahydropyrimidine-2, 4, 6-trione (20 mg, 0.033 mmol, 45% yield) as a white solid. Retention time SFC: 2.41 min. LC-MS (ESI+):

[0740] 591.3 [M+H]+, and

[0741] • 5-[8-[[(3R or 3S)-tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5- [4- [4-(trifluoromethoxy)phenoxy] phenyl] hexahydropyrimidine-2, 4, 6-trione (21 mg, 0.036 mmol, 48% yield) as a white solid. Retention time SFC: 2.93 min. LC-MS (ESI+):

[0742] 591.4 [M+H]+.

[0743] Absolute configuration of the structure assigned to each peak was not established.

[0744] Example 54

[0745] 5- [7- [(l-Methyl-4-piperidyl)amino]-5-oxa-2-azaspiro [3.4] octan-2-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0746] Prepared in analogy to Example 43, step 1, using 5-(7-oxo-5-oxa-2-azaspiro[3.4]octan-2-yl)-5- [4- [4-(trifluoromethoxy)phenoxy] phenyl] hexahydropyrimidine-2, 4, 6-trione TFA salt (Intermediate A23, 20 mg, 0.04 mmol, 1.0 eq.), 4-amino-l -methylpiperidine (14 mg, 0.12 mmol, 3.0 eq.) and sodium cyanoborohydride (8 mg, 0.12 mmol, 3.0 eq.). The crude product was purified by preparative HPLC (Method A4) followed by another round of preparative HPLC (Method B2) to give 5-[7-[(l-methyl-4-piperidyl)amino]-5-oxa-2-azaspiro[3.4]octan-2-yl]-5-[4- [4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (3 mg, 0.005 mmol, 12% yield) as a white solid.

[0747] LCMS (ESI+): 604.2 [M+H]+.

[0748] Example 55 5-[8-(l,4-Dioxan-2-ylmethyl)-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0749] Step 1: 5-(2,8-Diazaspiro[3.51nonan-2-yl)-5-[4-[4-

[0750] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2.4.6-trione tert-Butyl 2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]- 2,8-diazaspiro[3.5]nonane-8-carboxylate (Intermediate A24, 250 mg, 0.41 mmol, 1.0 eq) was dissolved in DCM (15 mL). TFA (3mL) was added and the mixture was stirred at 25 °C for 2 h. LCMS showed that the desired product mass was present. The mixture was concentrated in vacuo to afford a crude material which was purified by filtration through silica gel (1: elution with EtOAc to remove excess TFA and impurities, and then 2: elution with MeOH) to afford 5- (2, 8-diazaspiro [3.5]nonan-2-yl)-5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (230 mg, 0.46 mmol, 107% yield based on the parent MW) as a yellow oil. This material, which could be a TFA salt, was used without further purification.

[0751] LCMS (ESL): 505.2 [M+H]+.

[0752] Step 2: 5-8-(1.4-Dioxan-2-ylmethyl)-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4-

[0753] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2.4.6-trione Prepared in analogy to Example 43, step 1, using 5-(2,8-diazaspiro[3.5]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (40 mg, 0.08 mmol, 1.0 eq.), l,4-dioxane-2-carbaldehyde (46 mg, 0.40 mmol, 5.0 Eq.) and sodium cyanoborohydride (15 mg, 0.24 mmol, 3.0 Eq.). The crude product was purified by preparative HPLC (Method A4) followed by preparative HPLC (Method G) to give 5-[8-(l,4-dioxan-2-ylmethyl)-2,8- diazaspiro[3.5]nonan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 2, 4, 6-trione (2 mg, 0.004 mmol, 5% yield) as a white solid.

[0754] LCMS (ESC): 605.3 [M+H]+.

[0755] Example 56 5-[5-(l,4-Dioxan-2-ylmethyl)-2,5-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0756] Prepared in analogy to Example 43, step 1, using 5-(2,5-diazaspiro[3.5]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (Intermediate A26) (20 mg, 0.04 mmol, 1.0 Eq.), l,4-dioxane-2-carbaldehyde (18 mg, 0.08 mmol, 2.0 eq) and sodium cyanoborohydride (8 mg, 0.12 mmol, 3.0 Eq.). The crude product was purified by preparative HPLC (Method G) to give 5-[5-(l,4-dioxan-2-ylmethyl)-2,5-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (2 mg, 0.003 mmol, 8% yield) as a colorless oil.

[0757] LCMS (ESC): 605.3 [M+H]+.

[0758] Example 57

[0759] 5- [8-(2-Hydroxyacetyl)-5-oxa-2,8-diazaspiro [3.5] nonan-2-yl] -5- [4- [4- (trifluoromethoxy)phenoxy] phenyl]hexahydropyrimidine-2,4,6-trione hydrochloric acid salt

[0760] Step 1: [2-Oxo-2-[2-[2,4.6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-5-oxa-2.8-diazaspiro[3.5]nonan-8- yllethyl] acetate

[0761] 5-(5-Oxa-2,8-diazaspiro[3.5]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione TFA salt (Example 60) (30 mg, 0.035 mmol, 1.0 Eq.) was dissolved in DCM (150 pL) with acetoxyacetyl chloride (5 mg, 4 pL, 0.037 mmol, 1.05 Eq.) and DIPEA (23 mg, 31 pL, 0.176 mmol, 5.0 Eq.) at RT. The mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc (5 mL) and water (2 mL). The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (SiO2, MeOH in DCM, 0% to 10%) to give [2-oxo-2-[2-[2,4,6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-5-oxa-2,8-diazaspiro[3.5]nonan-8- yl] ethyl] acetate (8 mg, 0.013 mmol, 32% yield) as a white solid.

[0762] LCMS (ESI+): 607.5 [M+H]+.

[0763] Step 2: 5-[8-(2-Hydroxyacetyl)-5-oxa-2,8-diazaspiro[3.51nonan-2-yl1-5-[4-[4-

[0764] (trifluoromethoxy)phenoxy1phenyl1hexahydropyrimidine-2.4.6-trione hydrochloride salt [2-oxo-2- [2- [2,4, 6-tri oxo-5- [4- [4-(trifluoromethoxy)phenoxy] phenyl]hexahy dropyrimidin-5-yl] - 5-oxa-2,8-diazaspiro[3.5]nonan-8-yl]ethyl] acetate (8 mg, 0.013 mmol, 1.0 Eq.) was dissolved in methanol (0.100 mL) and 2 M NaOH (18 pL, 0.040 mmol, 3.0 Eq.) was added at RT. The mixture was stirred for 1 hour. The reaction mixture was acidified with IN HC1 (100 pL) and the precipitate was filtered and dried in vacuo to give 5-[8-(2-hydroxyacetyl)-5-oxa-2,8- diazaspiro[3.5]nonan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 2, 4, 6-trione hydrochloride salt (6 mg, 0.009 mmol, 69% yield) as a white solid.

[0765] LCMS (ESI+): 565.4 [M+H]+.

[0766] Example 58

[0767] 5- [5-(2-hydroxyacetyl)-2,5-diazaspiro [3.4] octan-2-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0768] Step 1: 5-(2,5-Diazaspirol3.41octan-2-yl)-5-14-14-

[0769] (trifluoromethoxy)phenoxy1phenyl1hexahvdropyrimidine-2.4.6-trione 2.2.2-trifluoroacetic acid salt

[0770] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 2-[2,4,6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-2,5-diazaspiro[3.4]octane-5- carboxylate (Intermediate A28) (80 mg, 0.136 mmol, 1.0 Eq.) and TFA (42 pL, 0.544 mmol, 4 Eq.) to give 5-(2,5-diazaspiro[3.4]octan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetic acid salt (70 mg, quant, yield) as a light yellow oil that was used without further purification. LCMS (ESC): 491.1 [M+H]+.

[0771] Step 2: 5-(5-(2-Hydroxyacetyl)-2,5-diazaspiro(3.4]octan-2-yl]-5-(4-(4-

[0772] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2.4.6-trione

[0773] To a solution of glycolic acid (16 mg, 0.20 mmol, 2.0 Eq.), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (29 mg, 0.15 mmol, 1.5 Eq.) and 1- hydroxybenzotriazole (21 mg, 0.15 mmol, 1.5 Eq.) in DMF (2 mL) were added 5-(2,5- diazaspiro[3.4]octan-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 2,4,6-trione 2,2,2-trifluoroacetic acid salt (59 mg, 0.10 mmol, 1.0 Eq.) and DIPEA (70 pL, 0.41 mmol, 4.0 Eq.). The mixture was stirred at RT for 12 h. The mixture was filtered and concentrated and the residue was purified by preparative HPLC (Method A3) followed by preparative HPLC (Method G) to give 5-[5-(2-hydroxyacetyl)-2,5-diazaspiro[3.4]octan-2-yl]-5- [4- [4-(trifluoromethoxy)phenoxy] phenyl] hexahydropyrimidine-2, 4, 6-trione (1.0 mg, 0.003 mmol, 2% yield) as white solid.

[0774] LCMS (ESC): 549.3 [M+H]+.

[0775] Example 59

[0776] 5- [5- [(4-Methylmorpholin-2-yl)methyl] -8-oxa-2,5-diazaspiro [3.5]nonan-2-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0777] Step 1: tert-Butyl 2-((2-(2,4.6-trioxo-5-(4-(4-

[0778] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-8-oxa-2.5-diazaspiro(3.5]nonan-5- y 11 methyl] morpholine-4-carboxy 1 ate

[0779] Prepared in analogy to Example 43, step 1, using 5-(8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)-5-[4- [4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (Example 45, 60 mg, 0.119 mmol, 1.0 eq.), tert-butyl 2-formylmorpholine-4-carboxylate (77 mg, 0.355 mmol, 3.0 eq.) and sodium cyanoborohydride (22 mg, 0.355 mmol, 3.0 eq.). The crude product was purified by preparative HPLC (Method Cl) to give tert-butyl 2-[[2-[2,4,6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-8-oxa-2,5-diazaspiro [3.5]nonan- 5-yl]methyl]morpholine-4-carboxylate (25 mg, 0.04 mmol, 30% yield) as a white solid.

[0780] LCMS (ESC): 620.2 [M+H]+.

[0781] Step 2: 5-[5-(Morpholin-2-ylmethyl)-8-oxa-2,5-diazaspiro[3.51nonan-2-yl1-5-[4-[4- (trifluoromethoxy)phenoxy1phenyl1hexahydropyrimidine-2.4.6-trione 2,2.2-trifluoroacetic acid salt

[0782] Prepared in analogy to Intermediate 1, step 2, using tert-butyl 2-[[2-[2,4,6-trioxo-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-8-oxa-2,5-diazaspiro[3.5]nonan-5- yl]methyl]morpholine-4-carboxylate (25 mg, 0.04 mmol, 1.0 eq.) and TFA (1 mL) to give 5-[5- (morpholin-2-ylmethyl)-8-oxa-2,5 -diazaspiro [3.5]nonan-2-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt (30 mg, quant, yield) as a light yellow oil which was used without further purification LCMS (ESC): 606.2 [M+H]+.

[0783] Step 3: 5-[5-[(4-Methylmorpholin-2-yl)methyl1-8-oxa-2.5-diazaspiro[3.51nonan-2-yl1-5-[4-[4-

[0784] (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2.4.6-trione

[0785] Prepared in analogy to Example 43, step 1, using 5-[5-(morpholin-2-ylmethyl)-8-oxa-2,5- diazaspiro[3.5]nonan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 2,4,6-trione 2,2,2-trifluoroacetic acid salt (25 mg, 0.04 mmol, 1.0 Eq.), formaldehyde (3 mg, 0.08 mmol, 2.0 Eq.) and sodium cyanoborohydride (8 mg, 0.12 mmol, 3.0 Eq.). The crude product was purified by preparative HPLC (Method C2) to give 5-[5-[(4-methylmorpholin-2- yl)methyl]-8-oxa-2,5-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione (13 mg, 0.02 mmol, 49% yield) as a white solid. This material contained a small, residual amount of formic acid based on 'H-NMR.

[0786] LCMS (ESI+): 620.2 [M+H]+.

[0787] 2) Biological examples

[0788] 2. 1) MMP proteins used in the activity assays

[0789] Full-length human MMP9 (19-707) was cloned into pExpreS2.1 with C-terminal Avi-10-His- EPEA tag and a TEV cleavage site. The endogenous signal sequence was replaced by the Drosophila immunoglobulin heavy chain-binding protein (BiP) sequence resulting in the final construct BiP-hMMP9 (19-707)WT_C-TEV-Avi-10His-EPEA. Stable, polyclonal S2 cell lines were generated using manufacturer’s instructions (Expres2ion Biotechnologies). After cultivation, the cell culture media containing the recombinant protein was concentrated and buffer exchanged using an AKTA Crossflow (30K MWCO, 3 x 100cm2) into Buffer A (50 mM HEPES pH 7.8, 0.5 M NaCl, 10% glycerol, 0.35% CHAPS, 0.02% NaN3). The His-tagged protein was purified via a HisTRAP column (Cytiva) and eluted with buffer A supplemented with 0.5 M imidazole. The elution fractions were concentrated and further purified on size exclusion chromatography (Superdex200 increase GL10 / 300) in 50 mM TRIS / C1 pH 8, 0.5 M NaCl, 5 mM CaCh, 0.1 mM Zn acetate, 0.35% CHAPS, 0.02% NaN3. In order to activate the enzyme, MMP9 is incubated with Trypsin (Thermo) for ca. 17 hours at room temperature at a 100:1 w / w ratio. The reaction is stopped with TLCK at 0.5 mM end concentration. To remove trypsin and TLCK, activated MMP9 is further purified on a second size exclusion chromatography step using a Superdex 200 Increase GL10 / 300 in 50 mM TRIS / C1 pH 8, 0.5 M NaCl, 5 mM CaCl2, 0.1 mM Zn acetate, 0.35% CHAPS, 0.02% NaN3.

[0790] AMMPIO: This enzyme was purchased from Aviva Systems Biology (product number GPED00091).

[0791] AMMP14: This enzyme was purchased from Biovision (product number: 8009-50).

[0792] 22) MMP assays

[0793] The inhibition potential of compounds is determined via an activity assay based on a fluorescence read out coming from the released fluorescence upon cleaving of the peptidic substrate by the MMP enzyme. Due to co-planar stacking of the tryptophan and MR121 fluorophore at each side of the peptidic substrate, the fluorescence of MR121 is statically quenched. Upon cleavage of the substrate by the MMP enzyme, an increase of MR121 fluorescence is observed.

[0794] The 6 amino acid peptide substrate Cys-Pro-Leu-Gly-Leu-Trp was synthesized with a purity of 95% by Biosyntan GmbH, Berlin, DE (for improved yield of synthesis the carboxyl group of the tryptophan was replaced by an amide group (CO-NH2)). The reactive form of the fluorophore, MR121-maleimide, described in the patent EP 0747447 A3. The MR121-mal eimide was attached to the sulfhydryl group of the cysteine residue of the substrate peptide by covalent coupling (Derek G. Smyth, Atsuo Nagamatsu, Joseph S. Fruton; Some Reactions ofN- Ethylmaleimide; J. Am. Chem. Soc. (1960); 82(17): 4600-4604) and purified on an analytical HPLC (Merck Hitachi D-6000, Merck USA) using a Cl 8 column (Marchery -Nagel, ccl25 / 4, Nucleosil 100-5, protect 1)

[0795] All measurements were performed in 384 well microtiter plates. MMP enzyme is pre-incubated with various concentrations of inhibitor for 15 min, after which IpM of the MR121-cPLGLW peptide substrate is added in the following assay buffer: 25 mM Hepes, 100 mM NaCl, 10 mM CaCh, 0.1% Chaps and 1 mm TCEP and a final DMSO concentration of 2%. The enzymatic reaction was monitored in a kinetic measurement, by exciting at 630 nm and measuring fluorescence emission at 695 nm. The calculation of the slope in the linear range of the kinetic provides a robust value for the activity of the enzyme and the effect of the small compound on this activity. The following tables summarize the details on material and methods.

[0796] Plates Reagents

[0797] Assay Method

[0798] 2.3) Results The data in the table below show the inhibitory potency of the examples against human MMP9 and the observed selectivity factors against the related MMP10 and MMP14.

Claims

1. A compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein:L is -O-, -NH-, -C=C~, -CONH-, -NHCO- or a covalent bond; is phenyl or a 6-membered heteroaryl;R1is selected from Ce-u-aryl, 5-6-membered heteroaryl, Cs-s-cycloalkyl and 3-11 membered heterocyclyl, wherein R1is optionally substituted with one or more R2which can be the same or different; spiro radical iis a 3-6 membered heterocyclyl which may contain one or two identical or different heteroatoms selected from O, N and S and may be substituted with one or more R3which can be the same or different; and the sub-ringa) a 3-11 membered heterocyclyl which may contain one, two, three or four identical or different heteroatoms selected from O, N and S and may be substituted with one or more R4which can be the same or different; or b) a C3-6-cycloalkyl optionally substituted with one or more R5which can be the same or different;R2is selected from halo-Ci-6-alkoxy, C3-6-cycloalkyl, Ci-6-alkyl, halo- Ci-6-alkyl and halogen;R3, R4and R5are each independently selected from oxo, Ci-6-alkyl, C2-8-alkoxy alkyl, hydroxy-Ci-6-alkyl, -COR6, -S(O)2R7, -NR8R8, -CO2R9, 3-10 membered Co-6-alkyl- heterocyclyl, C3-6-cycloalkyl, 5-6 membered Co-6-alkyl-heteroaryl and Co-6-alkyl-C6-i4-aryl; wherein the 3-10 membered Co-6-alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl or -CO2(Ci-6-alkyl); C2-8-alkoxyalkyl is optionally substituted with hydroxy; and Co-6-alkyl-Ce- 14-aryl is optionally substituted with -B(OH)2;R6is selected from Ci-6-alkyl, hydroxy-Ci-6-alkyl, amino-Ci-6-alkyl, -Co-6-alkyl-N(RloR10’), C3-6-cycloalkyl, 3-6 membered Co-6-alkyl-heterocyclyl and -Co-6-alkyl-OC(0)(Ci-6-alkyl); wherein the 3-6 membered Co-6-alkyl-heterocyclyl is optionally substituted with -CO2(Ci-6- alkyl), and hydroxy-Ci-6-alkyl is optionally substituted with amino, -NHCO2(Ci-6-alkyl) or - C(O)(C 1-6-al kyl);R7is 3-6 membered Co-6-alkyl-heterocyclyl optionally substituted with Ci-6-alkyl;R8and R8are each independently selected from hydrogen, -CO2(Ci-6-alkyl), 3-10 membered Co-6-alkyl-heterocyclyl optionally substituted with Ci-6-alkyl;R9is Ci-6-alkyl;R10and R10are each independently selected from hydrogen, Ci-6-alkyl, hydroxy-Ci-6-alkyl and -CO2(Ci-6-alkyl).

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is -O-, -CONH- or a covalent bond.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl, pyridinyl or pyrazinyl.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl or pyridinyl.

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1is Ce-u-aryl or 3-11 membered heterocyclyl, optionally substituted with one or more R2which can be the same or different.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl or dihydrobenzofuranyl.

7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2is halo-Ci-6-alkoxy or halogen.

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R2is trifluoromethoxy or chlorine.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, whereinis a spiro radical in which the sub-ringis 4-6 membered heterocyclyl which may contain one or two identical or different heteroatoms selected from O and N and may be substituted with one or more R3which can be the same or different; and the sub-ringa) a 4-9 membered heterocyclyl which may contain one or two identical or different heteroatoms selected from O and N and may be substituted with one or more R4which can be the same or different; or b) a C3-6-cycloalkyl optionally substituted with one or more R5which can be the same or different.

10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein12. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R3is -C(O)(Ci-6-alkyl).

13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R4is selected from oxo, Ci-6-alkyl, hydroxy-Ci-6-alkyl, -COR6, -S(O)2R7, -NR8R8, -CO2R9, 3-10 membered Co-6-alkyl-heterocyclyl and Co-6-alkyl-C6-i4-aryl, wherein the 3-10 membered Co-6-alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl.

14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R4is selected from Ci-6-alkyl, hydroxy-Ci- 6-alkyl, -COR6, -S(O)2R7, -NR8R8’ and 3-10 membered Co-6-alkyl-heterocyclyl, wherein the 3- 10 membered Co-6-alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl.

15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydroxyethyl, - C(O)(CH2OH), (lR,5S)-8-methyl-8-azabicyclo[3.

2. l]octan-3-yl] amino, 4-piperidylsulfonyl, 4-piperidylacetyl, azetidin-3-ylmethyl, (l-methyl-4-piperidyl)amino and methyl.

16. The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R5is -NR8R8, wherein R8and R8are each independently selected from hydrogen and -CO2(Ci-6-alkyl).

17. The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R6is hydroxy-Ci-6-alkyl or 3-6 membered Co-6-alkyl-heterocyclyl.

18. The compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R6is hydroxymethyl or -CH2-4-piperidyl.

19. The compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R7is 3-6 membered Co-6-alkyl-heterocyclyl substituted with Ci-6-alkyl20. The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R7is 4-piperidyl.

21. The compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R8and R8are selected from hydrogen and 3-10 membered Co-6-alkyl-heterocyclyl optionally substituted with Ci-6-alkyl.

22. The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R8and R8are selected from hydrogen, (lR,5S)-8-methyl-8-azabicyclo[3.

2. l]octan-3-yl]amino and l-methyl-4-piperidyl.

23. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:L is -O-, -NH-, -C=C~, -CONH-, -NHCO- or a covalent bond;Ar is phenyl, pyridinyl or pyrazinyl, R1is Ce-u-aryl or 3-11 membered heterocyclyl, optionally substituted with one or more R2which can be the same or different;R2is halo-Ci-6-alkoxy or halogen;R3is selected from -C(O)(Ci-6-alkyl);R4is selected from oxo, Ci-6-alkyl, hydroxy-Ci-6-alkyl, -COR6, -S(O)2R7, -NR8R8, -CO2R9, 3- 10 membered Co-6-alkyl-heterocyclyl and Co-6-alkyl-C6-i4-aryl, wherein the 3-10 membered Co-6-alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl;R5is -NR8R8, wherein R8and R8are each independently selected from hydrogen and - CO2(Ci-6-alkyl);R6is hydroxy-Ci-6-alkyl or 3-6 membered Co-6-alkyl-heterocyclyl;R7is 3-6 membered Co-6-alkyl-heterocyclyl substituted with Ci-6-alkyl;R8and R8are each independently selected from hydrogen and 3-10 membered Co-6-alkyl- heterocyclyl optionally substituted with Ci-6-alkyl.

24. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:L is -O-, -CONH- or a covalent bond;Ar is phenyl or pyridinyl;R1is Ce-u-aryl or 3-11 membered heterocyclyl, optionally substituted with one or more R2which can be the same or different;R2is halo-Ci-6-alkoxy or halogen;R4is selected from Ci-6-alkyl, hydroxy-Ci-6-alkyl, -COR6, -S(O)2R7, -NR8R8’and 3-10 membered Co-6-alkyl-heterocyclyl, wherein the 3-10 membered Co-6-alkyl-heterocyclyl is optionally substituted with Ci-6-alkyl;R6is hydroxy-Ci-6-alkyl or 3-6 membered Co-6-alkyl-heterocyclyl;R7is 3-6 membered Co-6-alkyl-heterocyclyl substituted with Ci-6-alkyl;R8and R8are selected from hydrogen and 3-10 membered Co-6-alkyl-heterocyclyl optionally substituted with Ci-6-alkyl.

25. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:L is -O-, -CONH- or a covalent bond;Ar is phenyl or pyridinyl,R1is phenyl or dihydrobenzofuranyl;R2is trifluoromethoxy or chlorine;R4is selected from hydroxyethyl, -C(0)(CH20H), (lR,5S)-8-methyl-8- azabicyclo[3.

2. l]octan-3-yl] amino, 4-piperidylsulfonyl, 4-piperidylacetyl, azetidin-3- ylmethyl, (l-methyl-4-piperidyl)amino, methyl and (l-methyl-4-piperidyl)amino;R6is hydroxymethyl or methyl-4-piperidyl;R7is 4-piperidyl;R8and R8are selected from hydrogen, (lR,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino and l-methyl-4-piperidyl.

26. The compound of formula (I) according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from5-[2-(2-Hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[2-(2-phenylethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5- [2-(2-hy droxy acetyl)-2, 7 -diazaspiro [3.5]nonan-7 -yl] -5 - [4 - [4 - (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[4-(3-cyclopropylphenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimi dine-2, 4, 6-trione;5- [2-(2-hy droxy acetyl)-2, 7 -diazaspiro [3.5]nonan-7 -yl] -5 - [4 - (3 - methylphenoxy )phenyl]hexahydropyrimi dine-2, 4, 6-trione;5-[4-(2,3-dihydrobenzofuran-5-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7- diazaspiro[3.5]nonan-7-yl]hexahydropyrimi dine-2, 4, 6-trione;5-[4-(2,3-dihydrobenzofuran-6-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7- diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;5-[4-(l,3-benzodioxol-5-yloxy)phenyl]-5-[2-(2-hy droxy acetyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;5-[4-(l,3-benzodioxol-5-yloxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;5-[4-[3-(difluoromethoxy)phenoxy]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonan- 7-y 1] hexahy dropy rimi dine-2, 4, 6-trione;5-[4-[3-(difluoromethoxy)phenoxy]phenyl]-5-[2-(2-hy droxy ethyl)-2,7-di azaspiro[3.5]nonan- 7-y 1] hexahy dropy rimi dine-2, 4, 6-trione;5-[2-(2-hy droxy acetyl)-2, 7-diazaspiro[3.5]nonan-7-yl]-5-(4-phenoxyphenyl)-l, 3-diazinane- 2, 4, 6-trione;5-(2-(2 -hy droxy ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-5-(4-phenoxyphenyl)pyrimi dine- 2,4,6(lH,3H,5H)-trione;5-[2-(l,4-dioxane-2-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-(4-phenoxyphenyl)-l,3- diazinane-2, 4, 6-trione;5-[4-(benzofuran-5-yloxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimi dine-2, 4, 6-trione;5-[4-(4-cyclopropylphenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimi dine-2, 4, 6-trione;5-[4-(4-chlorophenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimi dine-2, 4, 6-trione;5- [2-(2-hy droxy acetyl)-2, 7 -diazaspiro [3.5]nonan-7 -yl] -5 - [4 - [4 - (trifluoromethoxy )phenyl]phenyl]hexahydropyrimi dine-2, 4, 6-trione;5- [2-(2-hy droxy acetyl)-2, 7 -diazaspiro [3.5]nonan-7 -yl] -5 - [3 - [4 - (trifluoromethoxy)anilino]phenyl]hexahydropyri mi dine-2, 4, 6-trione;5- [2-(2-hy droxy ethyl)-2,7-diazaspiro[3.5] nonan-7-yl] -5 - [3 - [4 - (trifluoromethoxy)anilino]phenyl]hexahydropyrimi dine-2, 4, 6-trione;5- [2-(2-hy droxy ethyl)-2,7-diazaspiro[3.5] nonan-7-yl] -5 - [4 - [4 - (trifluoromethoxy )phenyl]phenyl]hexahydropyrimi dine-2, 4, 6-trione;5-[ 1 -(2-hy droxy ethyl)- 1 ,8-diazaspiro[4.5] decan-8-yl] -5 - [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione;5-(l -ethyl- 1 ,9-diazaspiro[4.5] decan-9-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione, TFA salt;5-(4-acetyl-4,7-diazaspiro[2.5] octan-7 -y 1) -5 - [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione;5-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione; rac-5-[7-[[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino]-5-oxa-2- azaspiro[3.4]octan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 2, 4, 6-trione; rac-5-[7-[[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino]-5-oxa-2- azaspiro[3.4]octan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 2, 4, 6-trione;5-(3-methylspiro[7H-furo[3,4-b]pyridine-5,4'-piperidine]-l'-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimi dine-2, 4, 6-trione;5-(6-oxo-7 -oxa-2,5 -diazaspiro[3.4] octan-2-yl)-5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[4-(2,3-dihydrobenzofuran-6-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,8- diazaspiro[3.5]nonan-8-yl]hexahydropyrimidine-2, 4, 6-trione;N-[7-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-7- azaspiro[3.5]nonan-3-yl]carbamic acid tert-butyl ester;2-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-2,7- diazaspiro[3.4]octane-7-carboxylic acid tert-butyl ester;7-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-l,7- diazaspiro[3.5]nonane-l-carboxylic acid tert-butyl ester;6-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-l,6- diazaspiro[3.3]heptane-l-carboxylic acid tert-butyl ester;5-spiro[lH-isobenzofuran-3,4'-piperidine]-l'-yl-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[4-[2-(4-chlorophenyl)ethynyl]phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt;5-[4-[2-(4-chlorophenyl)ethynyl]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-2,4,6-trioxo- hexahydropyrimidin-5-yl]benzamide;N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonan-7-yl]-2,4,6-trioxo- hexahydropyrimidin-5-yl]benzamide;N-(4-chlorophenyl)-4-[5-[8-[(l-methyl-4-piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonan- 2- yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide;5- [4-(4-Piperidylsulfonyl)- 1 -oxa-4, 9-diazaspiro[5.5] undecan-9-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;5- [4- [2 -(4 -Pip eri dy 1 ) acety 1] - 1 -oxa-4,9-diazaspiro [5.5] undecan-9-yl] -5 - [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[8-(Azetidin-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;5-[8-[(l-Methyl-4-piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;5-(8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-(3-amino-7-azaspiro[3.5]nonan-7-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione hydrogen chloride;5- [7-(2-hy droxy ethyl)-2,7-diazaspiro[4.4] nonan-2-yl] -5 - [4 - [4 -(trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-(7-Methyl-2,7-diazaspiro[4.4]nonan-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt;5-(l-Methyl-l,9-diazaspiro[4.5]decan-9-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-(5-Oxa-2,8-diazaspiro[3.5]nonan-8-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione bis p-toluenesulfonic acid salt;5- [ 1 -(2-Hy droxy ethyl)- 1 , 9-diazaspiro[4.5] decan-9-yl] -5- [4- [4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[8-[[(3R)-Tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[8-[[(3S)-tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4-(trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[7-[(l-Methyl-4-piperidyl)amino]-5-oxa-2-azaspiro[3.4]octan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[8-(l,4-Dioxan-2-ylmethyl)-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[5-(l,4-Dioxan-2-ylmethyl)-2,5-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[8-(2-Hydroxyacetyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione hydrochloric acid;5-[5-(2-hydroxyacetyl)-2,5-diazaspiro[3.4]octan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[5-[(4-Methylmorpholin-2-yl)methyl]-8-oxa-2,5-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione, TFA salt;5-[5-(4-ethylphenoxy)pyrazin-2-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione5-[4-[(6-ethyl-3-pyridyl)oxy]phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;5-[5-(4-ethylphenoxy)-2-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione, formic acid salt;5-[6-(4-ethylphenoxy)pyridazin-3-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;5-[6-(4-ethylphenoxy)-3-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;5-[8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[[5- (trifluoromethoxy)-2-pyridyl]oxy]phenyl]hexahydropyrimidine-2, 4, 6-trione, 2,2,2- trifluoroacetic acid salt;N-(6-chloro-3-pyridyl)-4-[5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-2,4,6-trioxo- hexahydropyrimidin-5-yl]benzamide;5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-[3-[[5-(trifluoromethyl)pyrazin-2- yl]amino]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[3-[(5-chloro-2-pyridyl)amino]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione;5-[2-(4-ethylphenoxy)pyrimidin-5-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione; and5-[4-(5-ethylpyrazin-2-yl)oxyphenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione.

27. The compound of formula (I) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:5-[2-(2-Hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-5-[4-[4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[4-(2,3-dihydrobenzofuran-5-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7- diazaspiro[3.5]nonan-7-yl]hexahydropyrimidine-2, 4, 6-trione;5- [2-(2-hy droxy ethyl)-2,7-diazaspiro[3.5] nonan-7-yl] -5 - [4 - [4 - (trifluoromethoxy )phenyl]phenyl]hexahydropyrimidine-2, 4, 6-trione; rac-5-[7-[[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino]-5-oxa-2- azaspiro[3.4]octan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 2, 4, 6-trione;N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-2,4,6-trioxo- hexahydropyrimidin-5-yl]benzamide;5- [4-(4-Piperidylsulfonyl)- 1 -oxa-4, 9-diazaspiro[5.5] undecan-9-yl] -5- [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;5- [4- [2-(4-Piperidyl)acetyl] - 1 -oxa-4, 9-diazaspiro [5.5] undecan-9-yl] -5 - [4- [4- (trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-[8-(Azetidin-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;5-[8-[(l-Methyl-4-piperidyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]-5-[4-[4- (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;5-(8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5- [7-(2-hy droxy ethyl)-2,7-diazaspiro[4.4] nonan-2-yl] -5 - [4 - [4 - (trifluoromethoxy )phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione;5-(7-Methyl-2,7-diazaspiro[4.4]nonan-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2, 4, 6-trione 2,2,2-trifluoroacetic acid salt;5-[5-(4-ethylphenoxy)-2-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione formic acid salt;5-[6-(4-ethylphenoxy)-3-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione; and5-[2-(4-ethylphenoxy)pyrimidin-5-yl]-5-[2-(2-hy droxy ethyl)-2,7-diazaspiro[3.5]nonan-7- yl]hexahydropyrimidine-2, 4, 6-trione.

28. A process for the preparation of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (II)with a compound of formula (III)wherein L, Ar, R1andare as defined in any one of claims 1 to 25 and X is halogen, in the presence of a base to form said compound of formula (I).

29. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, when manufactured according to the process of claim 28.

30. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

32. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of an ocular surface disease.

33. A compound for use according to claim 32, wherein the ocular surface disease is dry eye disease.

34. The use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of an ocular surface disease.

35. A method for the therapeutic and / or prophylactic treatment of an ocular surface disease, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

36. The invention as hereinbefore described.5

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