5-[2,7-diazaspiro[3,5]nonane-7-yl]-5-[4-phenoxyphenyl]hexahydropyrimidine-2,4,6-trione derivatives used as MMP9 inhibitors for the treatment of dry eye disease

Abstract

This invention relates to spirocyclic barbiturates of general formula (I) or pharmaceutically acceptable salts thereof as MMP9 inhibitors for the treatment of ocular surface diseases, such as, for example, dry eye disease.

Description

Technical Field

[0001] This invention relates to spirocyclic barbiturate compound derivatives that can be used as MMP9 inhibitors, their manufacture, pharmaceutical compositions comprising said derivatives, and their use as medicaments for the therapeutic and / or preventive treatment of ocular surface diseases. Background Technology

[0002] Over the past few decades, matrix metalloproteinases (MMPs) have been extensively studied as drug targets for the treatment of various diseases. MMPs are zinc-dependent metalloendopeptidases involved in many important biological processes, such as tissue remodeling, wound healing, embryonic development, nerve growth, or cell migration. In humans, approximately 24 different MMPs are known to date, and they are further subdivided into several distinct subclasses with different substrate specificities.

[0003] In the past, the imbalance of MMP9 activity has been associated with many different diseases, thus leading to various drug discovery projects targeting this target, such as those related to cardiovascular disease, cancer, inflammatory and neurodegenerative diseases, and lung diseases (for more recent reviews, particularly those on MMP9 and cancer, see Mondal et al., Eur J Med Chem 194 (2020), 112260, and the references cited therein). Against the backdrop of these projects, many compounds with varying degrees of specificity for other MMPs have been prepared and described in the literature. Several of these compounds have been investigated in clinical trials. For example, to name a few, a Phase II clinical trial of AZD-1236 for chronic obstructive pulmonary disease (COPD), a Phase I / II trial of S-3304 for lung cancer, and a Phase III trial of tanomastat for rheumatoid arthritis and solid tumors. However, all clinical trials were discontinued due to poor efficacy or side effects.

[0004] Topical application of classic small-molecule MMP inhibitors derived from different compound families for ocular surface diseases has not been extensively studied. Mori et al. described an experiment using the hydroxamic acid inhibitor tool compound PES 103 (BasicClin Pharmacol Toxicol 111 (2012), 289) and provided some data on tear production, but no data on corneal surface integrity. Additionally, many methods for indirectly modulating MMP9 activity have been described in the literature. For a recent review, see Alireza et al., Exp Eye Res 205 (2021), 108523, and the references cited therein. Topical application is considered to reduce systemic drug exposure, which may alter the safety or specificity requirements for novel MMP9 inhibitors that may have previously been limited by systemic application. This invention describes the synthesis and use of novel structurally different MMP9 inhibitors suitable for topical ocular treatment of anterior segment diseases such as dry eye disease (DED).

[0005] Dry eye disease (DED) is the most common cause of seeking medical eye care and affects 5% to 30% of the global population. DED impairs patients' visual function and quality of life, resulting in a global cost of $4.9 billion by 2029. The condition is defined as a multifactorial disease of the ocular surface characterized by “loss of tear film homeostasis with ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play a causative role” (TFOS DEWS II report). Patients frequently experience a gritty sensation, discomfort, pain, and loss of low-contrast vision, which can affect some visual functions, such as reading. Symptoms and signs of the condition are more frequent in older adults and women. Risk factors include contact lens use, laser eye surgery, prolonged computer screen use, and certain low-humidity environmental conditions.

[0006] Currently, over-the-counter tear drops can be used to treat mild forms of dry eye. The standard of care (SoC) for more severe or chronic forms of the disease consists of two types of approved medications targeting ocular surface inflammation. Cyclosporine-based medications (usually administered once or twice daily) such as Restasis, Ikervis, or Cequa inhibit calcineurin activity, thereby reducing T-cell activation and thus reducing the production of inflammatory cytokines. Unfortunately, these medications are only effective in certain patient subgroups, have a delayed onset of action (up to 6 months), and cause eye irritation / burning in a large number of patients. Xiidra (Lifitegrast solution administered twice daily as eye drops) has been approved in the US as another SoC. This drug is an LFA-1 inhibitor that prevents T-cell transport to the ocular surface. While safe, Xiidra showed mixed results in two phase 3 trials, and its market efficacy remains to be proven. Recently, the FDA approved Tyrvaya, a nasal spray containing a nicotinic acetylcholine receptor agonist (varenicline solution) that stimulates basal tear production.

[0007] In summary, there is a clear unmet medical need for the development of new DED therapies that target mechanisms beyond T-cell inhibition or lubrication, with faster onset of action and better efficacy, tolerability, and durability.

[0008] The matrix metalloproteinase (MMP) family of 24 zinc-dependent endopeptidases (in humans) plays a collectively important role in the degradation of extracellular matrix proteins. MMP9 and MMP2 (both also known as gelatinases) are 92 kDa enzymes capable of binding to and disrupting molecules I, IV, V, VII, X, IX, elastin, fibronectin, agglutinin, hydatidin, laminin, occlusion proteins, and many non-ECM molecules, including pre-TNF-α, transforming growth factor (TGF)-β, pre-IL-1β, pre-IL-8, and monocyte chemoattractant protein (MCP)-3. Elevated protein and mRNA levels of MMP9 have been associated with increased severity of dry eye disease in humans. A point of care test measuring intratear MMP9 levels above 40 ng / ml in dry eye patients is currently marketed as a diagnostic tool for this condition (Inflammadry™).

[0009] Elevated expression and activity of MMP9 have been observed in multiple mouse models (scopolamine-induced dry eye and concanavalin A-induced dry eye), and these models have been used to investigate the role of MMP9 in disease. For example, experimental protection of MMP9 knockout mice from the dry eye-dependent phenotype has been demonstrated by disrupting the corneal epithelial barrier via fluorescein staining. In these models, the protective effect of MMP9 inhibition is associated with the maintenance of epithelial occlusive protein levels, suggesting the maintenance of tight junction structures that constitute the epithelial surface. In vitro, MMP9 induction in corneal epithelial cells has been shown to occur in response to hyperosmolar or inflammatory stress and reduced corneal epithelial barrier function, as measured by transepithelial electrical resistance (TEER). In conclusion, compared to standard of care (SoC), MMP9 is a target for dry eye with a strong association with DED, good druggability on the ocular surface, and differential MoA (epithelial barrier disruption, exacerbation of inflammation).

[0010] Therefore, inhibiting MMP9 activity is a promising therapeutic strategy for treating or preventing MMP9-mediated diseases or disorders, such as ocular surface diseases, especially dry eye.

[0011] There is a need for novel compounds, formulations, treatments, and therapies for the treatment or prevention of MMP9-mediated diseases or disorders. Therefore, the object of this invention is to provide compounds for the treatment, prevention, or relief of such diseases and disorders, which possess improved therapeutic properties, particularly improved pharmacokinetic properties. Summary of the Invention

[0012] The first object of this invention is a compound of formula (I).

[0013] (I)

[0014] Or its pharmaceutically acceptable salt, wherein:

[0015] L can be –O-, -NH-, –C≡C-, -CONH-, -NHCO-, or a covalent bond;

[0016] Ar is a phenyl or a 6-membered heteroaryl group;

[0017] R 1 Selected from C 6-14 -Aryl, 5- to 6-membered heteroaryl, C 3-8 -cycloalkyl and 3- to 11-membered heterocyclic groups, wherein R 1 Optionally by one or more R that may be the same or different 2 replace;

[0018] Spiro group

[0019] Sub-ring

[0020]

[0021] It is a 3- to 6-membered heterocyclic group, which may contain one or two identical or different heteroatoms selected from O, N, and S, and may be composed of one or more identical or different R atoms. 3 Replace; and

[0022] sub-ring

[0023]

[0024] for:

[0025] a) A 3- to 11-membered heterocyclic group, which may contain one, two, three, or four identical or different heteroatoms selected from O, N, and S, and may be composed of one or more identical or different R atoms. 4 Replace; or

[0026] b)C 3-6 -cycloalkyl group, which is optionally surrounded by one or more R groups that may be the same or different 5 replace;

[0027] R 2 Selected from halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkyl, C 1-6 -alkyl, halo-C 1-6 -alkyl and halogen;

[0028] R 3 R 4 and R 5 Each is independently selected from oxygen, C 1-6 -alkyl, C 2-8 -alkoxyalkyl, hydroxy-C 1-6 -alkyl, -COR 6 -S(O)2R 7 -NR 8 R 8' -CO2R 9 3 to 10 yuan C 0-6 -alkyl-heterocyclic group, C 3-6 -Cycloalkyl, 5- to 6-membered C 0-6 -alkyl-heteroaryl and C 0-6 -alkyl-C 6-14 -Aryl; wherein the 3 to 10 C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6-alkyl or –CO2(C 1-6 -alkyl) substitution; C 2-8 -Alkoxyalkyl groups are optionally substituted with hydroxyl groups; and C 0-6 -alkyl-C 6-14 -The aryl group is optionally substituted by –B(OH)2;

[0029] R 6 Selected from C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, amino-C 1-6 -alkyl, -C 0-6 -alkyl-N(R) 10 R 10' C 3-6 -cycloalkyl, 3- to 6-membered C 0-6 -alkyl-heterocyclic groups and -C 0-6 -alkyl-OC(O)(C 1-6 -alkyl); wherein the 3- to 6-membered C 0-6 -alkyl-heterocyclic groups are optionally replaced by –CO2(C 1-6 -alkyl) substitution, and hydroxy-C 1-6 -Alkyl group optionally surrounded by amino group, –NHCO2(C 1-6 -alkyl) or -C(O)(C 1-6 -alkyl) substitution;

[0030] R 7 For optional use by C 1-6 -alkyl-substituted 3- to 6-membered C 0-6 -alkyl-heterocyclic group;

[0031] R 8 and R 8' Each is independently selected from hydrogen, –CO2(C 1-6 -alkyl), optionally C 1-6 -alkyl-substituted 3- to 10-membered C 0-6 -alkyl-heterocyclic group;

[0032] R 9 C 1-6 -alkyl;

[0033] R 10 and R 10' Each is independently selected from hydrogen and C. 1-6 -alkyl, hydroxy-C 1-6 -alkyl and -CO2(C 1-6 -alkyl).

[0034] Another object of the present invention is a method for preparing compounds as described herein or pharmaceutically acceptable salts thereof, said method comprising preparing a compound of formula (II).

[0035] (II)

[0036] With compound of formula (III)

[0037] (III)

[0038] Among them, L, Ar, R 1 and As described herein, and X is a halogen, the reaction occurs in the presence of a base to form the compound of formula (I).

[0039] Another object of the present invention is the production of compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, by the method described above.

[0040] Another object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, which is used as a therapeutically active substance.

[0041] 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 therapeutically inert carrier.

[0042] Another object of the present invention is a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for the therapeutic and / or preventive treatment of ocular surface diseases.

[0043] Another object of the present invention is the use of compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of ocular surface diseases.

[0044] Another object of the present invention is a method for the therapeutic and / or preventive treatment of ocular surface diseases, the method comprising administering an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof. Detailed Implementation

[0045] The following definitions apply to the general terms used in this specification, whether the term in question appears alone or in combination with other groups.

[0046] The term "alkyl" refers to a monovalent or polyvalent (e.g., monovalent or divalent) linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms ("C1-6-alkyl") (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). In some embodiments, the alkyl group contains 1 to 3 carbon atoms, such as 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl (Me), ethyl (Et), propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Certain alkyl groups have 1 to 4 carbon atoms ("C1-6-alkyl"). 1-4 "-alkyl"). A particularly preferred, but not limiting, example of an alkyl group is methyl. "CO-alkyl" means covalent bond.

[0047] The term "alkoxy group" refers to an alkyl group as defined above, attached to the parent molecule via an oxygen atom. Unless otherwise stated, an alkoxy group contains 1 to 6 carbon atoms ("C"). 1-6 (-alkoxy group”). 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 the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of the alkoxy group is methoxy.

[0048] The term "alkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms, and most preferably one hydrogen atom, have been replaced by an alkoxy group. Particularly preferred, but non-limiting, examples of alkoxyalkyl are methoxymethyl and 2-methoxyethyl.

[0049] The term "amino" refers to the –NH2 group.

[0050] The term "aminoalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced by an amino group.

[0051] The term "aryl" refers to a group of members having a total of 6 to 14 rings ("C"). 6-14 -aryl", preferably a monocyclic, bicyclic or tricyclic carbocyclic system with 6 to 12 ring members and more preferably 6 to 10 ring members, wherein at least one ring in the system is aromatic. A particularly preferred, but not limiting, example of aryl is phenyl.

[0052] The terms "asymmetric carbon atom" and "asymmetric center" refer to a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog specification, an asymmetric carbon atom can be either "R" or "S" configuration.

[0053] The term "cyano" refers to the –CN (nitrile) group.

[0054] As used herein, the term "cycloalkyl" refers to a ring of 3 to 10 carbon atoms ("C10") 3-10 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon group. In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group with 3 to 8 ring carbon atoms (particularly 3 to 6 ring carbon atoms). "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having two common carbon atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) and a spirocyclic moiety (i.e., the two rings are connected via a common ring atom). Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group with 3 to 6 ring carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms). Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and spiro[2.3]hexane-5-yl.

[0055] The terms "halogen" or "halogenated" used alone or in combination indicate fluorination, chlorination, bromination, or iodination, especially fluorination, chlorination, or bromination, and more particularly fluorination and chlorination. The term "halogenated" in combination with another group indicates that the group is substituted by at least one halogen, especially by one to five halogens, particularly one to four halogens, i.e., one, two, three, or four halogens.

[0056] The term "haloalkyl" refers to an alkyl group as defined above, wherein at least one hydrogen atom of the alkyl group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group wherein one, two, or three hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluorine. Particularly preferred, but non-limiting, examples of haloalkyl are trifluoromethyl and trifluoroethyl.

[0057] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluorine. Particularly preferred, but non-limiting, examples of haloalkoxy groups are difluoromethoxy and trifluoromethoxy.

[0058] The term "heteroaryl" refers to a monovalent 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, and even more preferably 5 to 8 ring members, wherein at least one ring in the system is aromatic and contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, indole-1-yl, 1H-indole-2-yl, 1H-indole-3-yl, 1H-indole-4-yl, 1H-indole-5-yl, 1H-indole-6-yl, 1H-indole-7-yl, 1,2-benzoxazole-3-yl, 1,2-benzoxazole-4-yl, 1,2-benzoxazole-5-yl, 1,2-benzoxazole-6-yl, 1,2-benzoxazole-7-yl, 1 H-indazole-3-yl, 1H-indazole-4-yl, 1H-indazole-5-yl, 1H-indazole-6-yl, 1H-indazole-7-yl, pyrazole-1-yl, 1H-pyrazole-3-yl, 1H-pyrazole-4-yl, 1H-pyrazole-5-yl, imidazole-1-yl, 1H-imidazole-2-yl, 1H-imidazole-4-yl, 1H-imidazole-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazole-4-yl, and 1,2,4-oxadiazole-3-yl. Most preferably, "heteroaryl" refers to 3-pyridyl, 4-pyridyl, 1H-pyrazole-5-yl, thiazole-4-yl, or 1,2,4-oxadiazole-3-yl.

[0059] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system having 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclic group" refers to a heterocyclic portion consisting of two rings sharing two common ring atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) and a spirocyclic portion (i.e., the two rings are connected via a common ring atom). Some non-limiting examples of heterocyclic groups include azirbutan-3-yl, azirbutan-2-yl, oxetane-3-yl, oxetane-2-yl, 2-oxopyrrolidone-1-yl, 2-oxopyrrolidone-3-yl, 5-oxopyrrolidone-2-yl, 5-oxopyrrolidone-3-yl, 2-oxo-1-piperidinyl, 2-oxo-3-piperidinyl, 2-oxo... -4-piperidinyl, 6-oxo-2-piperidinyl, 6-oxo-3-piperidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, morpholine, morpholin-2-yl, morpholin-3-yl, pyrrolylyl (e.g., pyrrolidine-3-yl), 3-azabicyclo[3.1.0]hexane-6-yl, or 2,5-diazabicyclo[2.2.1]heptane-2-yl.

[0060] The term "heterocyclic group" also includes aryl or heteroaryl groups fused with a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system having 3 to 10 ring atoms, wherein one, two, or three of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon, as described above. Examples include quinoline, benzothiophene, indole, and benzofuran.

[0061] The term "hydroxyl group" refers to the –OH group.

[0062] The term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been partially replaced by hydroxyl groups. Examples include alcohols and diols.

[0063] The term "oxo" refers to =O, whether used alone or in combination with other groups.

[0064] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a free base or free acid, which is not biologically or otherwise undesirable. These salts are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (especially 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, and N-acetylcysteine.

[0065] Particularly preferred, the pharmaceutically acceptable salts of the compound of formula (I) are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

[0066] The term "protecting group" (PG) refers to a group that selectively blocks a reaction site in a multifunctional compound so that a chemical reaction can selectively occur at another unprotected reaction site that is typically associated with it in synthetic chemistry. The protecting group can be removed at an appropriate site. Exemplary protecting groups are amino, carboxyl, or hydroxyl protecting groups. Specific protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further specific protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their applications in organic synthesis are described, for example, in: TW Greene and PGM Wutts, Protective Groups in Organic Chemistry, 5th Edition, 2014, John Wiley & Sons, NY.

[0067] As used herein, the term “prevention” includes preventing or delaying the onset of clinical symptoms of a disease, disorder, or symptom that develops in mammals, and particularly humans, who may have or be susceptible to the disease, disorder, or symptom but have not yet experienced or exhibited clinical or subclinical symptoms of the disease, disorder, or symptom.

[0068] The terms "part" and "substituent" refer to an atom or group that is chemically bonded to another atom or molecule through one or more chemical bonds, thus forming a part of the molecule.

[0069] The term "optionally substituted" means either unsubstituted or substituted. Generally, but not limited to, "one or more substituents" means one, two, or three, preferably one or two substituents. Typically, these substituents can be the same or different.

[0070] The term "substituted" means that at least one hydrogen atom of a compound or part is replaced by another substituent or part. Examples of such substituents include, without limitation, halogens, -OH, -CN, oxo, alkoxy, alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, and heterocyclic. For example, the term "haloalkyl" refers to the fact that one or more hydrogen atoms of an alkyl group (as defined below) are replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one aspect, substitution as used herein may refer to the substitution of at least one hydrogen atom of a compound or part described herein with a halogen or alkyl group.

[0071] The term "EC" x "This is the half-maximal effective concentration and represents the plasma concentration of a specific compound required to achieve x% of its maximum specific effect in vivo." (EC) x An example of "EC" is 20 EC 50 and EC 100 , respectively, represent the plasma concentrations of a specific compound required to achieve 20%, 50%, and 100% of its maximum specific effect in vivo.

[0072] As used herein, the term "treatment" includes: (1) a state, condition, or illness that suppresses at least one clinical or subclinical symptom of a symptom, disease, ailment, or symptom (e.g.,, in the case of maintenance therapy, preventing, reducing, or delaying the development of a disease or its recurrence); and / or (2) alleviating a condition or illness (i.e., the resolution of a state, ailment, or symptom, or at least one clinical or subclinical symptom). The benefit of treatment to a patient is statistically significant or at least perceptible to the patient or physician. However, it should be understood that when a patient is given medication to treat a disease, the outcome may not always be an effective treatment.

[0073] The following abbreviations are used in this text:

[0074]

[0075] The compounds of the present invention

[0076] In a first aspect, the present invention provides a compound of formula (I).

[0077] (I)

[0078] Or its pharmaceutically acceptable salt, wherein:

[0079] L can be –O-, -NH-, –C≡C-, -CONH-, -NHCO-, or a covalent bond;

[0080] Ar is a phenyl or a 6-membered heteroaryl group;

[0081] R 1 Selected from C 6-14 -Aryl, 5- to 6-membered heteroaryl, C 3-8 -cycloalkyl and 3- to 11-membered heterocyclic groups, wherein R 1 Optionally by one or more R that may be the same or different 2 replace;

[0082] Spiro group

[0083] Sub-ring

[0084]

[0085] It is a 3- to 6-membered heterocyclic group, which may contain one or two identical or different heteroatoms selected from O, N, and S, and may be composed of one or more identical or different R atoms. 3 Replace; and

[0086] sub-ring

[0087]

[0088] for:

[0089] c) A 3- to 11-membered heterocyclic group, which may contain one, two, three, or four identical or different heteroatoms selected from O, N, and S, and may be composed of one or more identical or different R atoms. 4 Replace; or

[0090] d)C 3-6 -cycloalkyl group, which is optionally surrounded by one or more R groups that may be the same or different 5 replace;

[0091] R 2 Selected from halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkyl, C 1-6 -alkyl, halo-C 1-6 -alkyl and halogen;

[0092] R 3 R 4 and R 5 Each is independently selected from oxygen, C 1-6 -alkyl, C 2-8 -alkoxyalkyl, hydroxy-C 1-6 -alkyl, -COR 6-S(O)2R 7 -NR 8 R 8' -CO2R 9 3 to 10 yuan C 0-6 -alkyl-heterocyclic group, C 3-6 -Cycloalkyl, 5- to 6-membered C 0-6 -alkyl-heteroaryl and C 0-6 -alkyl-C 6-14 -Aryl; of which 3 to 10 yuan C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6 -alkyl or –CO2(C 1-6 -alkyl) substitution; C 2-8 -Alkoxyalkyl groups are optionally substituted with hydroxyl groups; and C 0-6 -alkyl-C 6-14 -The aryl group is optionally substituted by –B(OH)2;

[0093] R 6 Selected from C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, amino-C 1-6 -alkyl, -C 0-6 -alkyl-N(R) 10 R 10' C 3-6 -cycloalkyl, 3- to 6-membered C 0-6 -alkyl-heterocyclic groups and -C 0-6 -alkyl-OC(O)(C 1-6 -alkyl); wherein the 3- to 6-membered C 0-6 -alkyl-heterocyclic groups are optionally replaced by –CO2(C 1-6 -alkyl) substitution, and hydroxy-C 1-6 -Alkyl group optionally surrounded by amino group, –NHCO2(C 1-6 -alkyl) or -C(O)(C 1-6 -alkyl) substitution;

[0094] R 7 For optional use by C 1-6 -alkyl-substituted 3- to 6-membered C 0-6 -alkyl-heterocyclic group;

[0095] R 8 and R 8' Each is independently selected from hydrogen, –CO2(C 1-6 -alkyl), optionally C 1-6 -alkyl-substituted 3- to 10-membered C 0-6-alkyl-heterocyclic group;

[0096] R 9 C 1-6 -alkyl;

[0097] R 10 and R 10' Each is independently selected from hydrogen and C. 1-6 -alkyl, hydroxy-C 1-6 -alkyl and -CO2(C 1-6 -alkyl).

[0098] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein L is –O-, -CONH- or a covalent bond.

[0099] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl, pyridyl or pyrazinyl.

[0100] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl or pyridyl.

[0101] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 C 6-14 -Aryl or 3- to 11-membered heterocyclic group, optionally surrounded by one or more R groups that may be identical or different. 2 replace.

[0102] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 It is phenyl or dihydrobenzofuranyl.

[0103] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 Halogenated-C 1-6 -Alkyl or halogen.

[0104] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 It is trifluoromethoxy or chlorine.

[0105] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0106] It is a spiro group, in which the daughter ring

[0107] It is a 4- to 6-membered heterocyclic group, which may contain one or two identical or different heteroatoms selected from O and N, and may be composed of one or more identical or different R atoms. 3 Replace; and

[0108] sub-ring

[0109] for

[0110] a) A 4- to 9-membered heterocyclic group, which may contain one or two identical or different heteroatoms selected from O and N, and may be composed of one or more identical or different R atoms. 4 Replace; or

[0111] b)C 3-6 -cycloalkyl group, which is optionally surrounded by one or more R groups that may be the same or different 5 replace.

[0112] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0113] Selected from:

[0114] , , , , , , , , , , , , , , , , and .

[0115] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0116] Selected from:

[0117] , , , , and .

[0118] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 -C(O)(C 1-6 -alkyl).

[0119] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from oxo, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, -COR 6 -S(O)2R 7 -NR 8 R 8' -CO2R 9 3 to 10 yuan C 0-6 -alkyl-heterocyclic groups and C 0-6 -alkyl-C 6-14 -Aryl, wherein the 3 to 10 C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6 -Alkyl substitution.

[0120] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, -COR 6 -S(O)2R 7 -NR 8 R 8' And 3 to 10 yuan C 0-6 -alkyl-heterocyclic group, wherein the 3- to 10-membered C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6 -Alkyl substitution.

[0121] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4It is selected from hydroxyethyl, -C(O)(CH2OH), (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino, 4-piperidinylsulfonyl, 4-piperidinylacetyl, azabicyclobutane-3-ylmethyl, (1-methyl-4-piperidinyl)amino and methyl.

[0122] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 For -NR 8 R 8' , where R 8 and R 8' Each is independently selected from hydrogen and –CO2(C 1-6 -alkyl).

[0123] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 Hydroxyl-C 1-6 -alkyl or 3 to 6 C 0-6 -alkyl-heterocyclic group.

[0124] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 It is hydroxymethyl or -CH2-4-piperidinyl.

[0125] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 For being C 1-6 -alkyl-substituted 3- to 6-membered C 0-6 -alkyl-heterocyclic group.

[0126] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 It is 4-piperidinyl.

[0127] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 8' Selected from hydrogen and optionally C 1-6 -alkyl-substituted 3- to 10-membered C 0-6 -alkyl-heterocyclic group.

[0128] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 8' It is selected from hydrogen, (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino and 1-methyl-4-piperidinyl.

[0129] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0130] L can be –O-, -NH-, –C≡C-, -CONH-, -NHCO-, or a covalent bond;

[0131] Ar is phenyl, pyridyl, or pyrazinyl.

[0132] R 1 C 6-14 -Aryl or 3- to 11-membered heterocyclic group, optionally surrounded by one or more R groups that may be identical or different. 2 replace;

[0133] R 2 Halogenated-C 1-6 -alkoxy or halogen;

[0134] R 3 Selected from -C(O)(C 1-6 -alkyl);

[0135] Selected from:

[0136] , , , , , , , , , , , , , , , , and ,

[0137] R 4 Selected from oxo, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, -COR 6-S(O)2R 7 -NR 8 R 8' -CO2R 9 3 to 10 yuan C 0-6 -alkyl-heterocyclic groups and C 0-6 -alkyl-C 6-14 -Aryl, wherein the 3 to 10 C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6 -alkyl substitution;

[0138] R 5 For -NR 8 R 8' , where R 8 and R 8' Each is independently selected from hydrogen and –CO2(C 1-6 -alkyl);

[0139] R 6 Hydroxyl-C 1-6 -alkyl or 3 to 6 C 0-6 -alkyl-heterocyclic group;

[0140] R 7 For being C 1-6 -alkyl-substituted 3- to 6-membered C 0-6 -alkyl-heterocyclic group;

[0141] R 8 and R 8' Each is independently selected from hydrogen and optionally by C 1-6 -alkyl-substituted 3- to 10-membered C 0-6 -alkyl-heterocyclic group.

[0142] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0143] L represents –O-, -CONH-, or a covalent bond;

[0144] Ar is either phenyl or pyridinyl;

[0145] R 1 C 6-14 -Aryl or 3- to 11-membered heterocyclic group, optionally surrounded by one or more R groups that may be identical or different. 2 replace;

[0146] R 2 Halogenated-C 1-6 -alkoxy or halogen;

[0147] Selected from:

[0148] , , , , ,

[0149] R 4 Selected from C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, -COR 6 -S(O)2R 7 -NR 8 R 8' And 3 to 10 yuan C 0-6 -alkyl-heterocyclic group, wherein the 3- to 10-membered C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6 -alkyl substitution;

[0150] R 6 Hydroxyl-C 1-6 -alkyl or 3 to 6 C 0-6 -alkyl-heterocyclic group;

[0151] R 7 For being C 1-6 -alkyl-substituted 3- to 6-membered C 0-6 -alkyl-heterocyclic group;

[0152] R 8 and R 8' Selected from hydrogen and optionally C 1-6 -alkyl-substituted 3- to 10-membered C 0-6 -alkyl-heterocyclic group.

[0153] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0154] L represents –O-, -CONH-, or a covalent bond;

[0155] Ar is phenyl or pyridyl.

[0156] R 1 It is phenyl or dihydrobenzofuranyl;

[0157] R 2 It is trifluoromethoxy or chlorine;

[0158] Selected from:

[0159] , , , , ,

[0160] R 4 Selected from hydroxyethyl, -C(O)(CH2OH), (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino, 4-piperidinylsulfonyl, 4-piperidinylacetyl, azabicyclobutane-3-ylmethyl, (1-methyl-4-piperidinyl)amino, methyl and (1-methyl-4-piperidinyl)amino;

[0161] R 6 It is hydroxymethyl or methyl-4-piperidinyl;

[0162] R 7 It is 4-piperidinyl;

[0163] R 8 and R 8' It is selected from hydrogen, (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino and 1-methyl-4-piperidinyl.

[0164] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0165] 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0166] 5-[2-(2-phenylethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0167] 5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0168] 5-[4-(3-cyclopropylphenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0169] 5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-(3-methylphenoxy)phenyl]hexahydropyrimidine-2,4,6-trione;

[0170] 5-[4-(2,3-dihydrobenzofuran-5-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0171] 5-[4-(2,3-dihydrobenzofuran-6-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0172] 5-[4-(1,3-benzodioxane-5-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0173] 5-[4-(1,3-benzodioxacyclopenten-5-yloxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0174] 5-[4-[3-(difluoromethoxy)phenoxy]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0175] 5-[4-[3-(difluoromethoxy)phenoxy]phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0176] 5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-(4-phenoxyphenyl)-1,3-diazacyclohexane-2,4,6-trione;

[0177] 5-(2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl)-5-(4-phenoxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione;

[0178] 5-[2-(1,4-dioxane-2-carbonyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-(4-phenoxyphenyl)-1,3-diazacyclohexane-2,4,6-trione;

[0179] 5-[4-(benzofuran-5-yloxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0180] 5-[4-(4-cyclopropylphenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0181] 5-[4-(4-chlorophenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0182] 5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenyl]phenyl]hexahydropyrimidine-2,4,6-trione;

[0183] 5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[3-[4-(trifluoromethoxy)anilino]phenyl]hexahydropyrimidine-2,4,6-trione;

[0184] 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[3-[4-(trifluoromethoxy)anilino]phenyl]hexahydropyrimidine-2,4,6-trione;

[0185] 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenyl]phenyl]hexahydropyrimidine-2,4,6-trione;

[0186] 5-[1-(2-hydroxyethyl)-1,8-diazaspiro[4.5]decane-8-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0187] 5-(1-Ethyl-1,9-diazaspiro[4.5]decane-9-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione, TFA salt;

[0188] 5-(4-acetyl-4,7-diazaspiro[2.5]octane-7-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0189] 5-(2,5-dioxa-8-azaspiro[3.5]nonane-8-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0190] Racemic-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;

[0191] Racemic-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;

[0192] 5-(3-methylspiro[7H-furano[3,4-b]pyridin-5,4'-piperidin]-1'-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0193] 5-(6-oxo-7-oxa-2,5-diazaspiro[3,4]octane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0194] 5-[4-(2,3-dihydrobenzofuran-6-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,8-diazaspiro[3.5]nonane-8-yl]hexahydropyrimidine-2,4,6-trione;

[0195] N-[7-[2,4,6-triketone-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-7-azaspiro[3,5]nonane-3-yl]tert-butyl carbamate;

[0196] 2-[2,4,6-triketone-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-2,7-diazaspiro[3,4]octane-7-carboxylic acid tert-butyl ester;

[0197] 7-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-1,7-diazaspiro[3.5]nonane-1-carboxylic acid tert-butyl ester;

[0198] 6-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylic acid tert-butyl ester;

[0199] 5-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-yl-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0200] 5-[4-[2-(4-chlorophenyl)ethynyl]phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate;

[0201] 5-[4-[2-(4-chlorophenyl)ethynyl]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0202] N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide;

[0203] N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide;

[0204] N-(4-chlorophenyl)-4-[5-[8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide;

[0205] 5-[4-(4-piperidinylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate;

[0206] 5-[4-[2-(4-piperidinyl)acetyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0207] 5-[8-(azacyclobutane-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate;

[0208] 5-[8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate;

[0209] 5-(8-oxa-2,5-diazaspiro[3.5]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0210] 5-(3-amino-7-azaspiro[3.5]nonane-7-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione hydrochloride;

[0211] 5-[7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0212] 5-(7-methyl-2,7-diazaspiro[4.4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate;

[0213] 5-(1-Methyl-1,9-diazaspiro[4.5]decane-9-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0214] 5-(5-oxa-2,8-diazaspiro[3.5]nonane-8-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione di-toluenesulfonate;

[0215] 5-[1-(2-hydroxyethyl)-1,9-diazaspiro[4.5]decane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0216] 5-[8-[[(3R)-tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0217] 5-[8-[[(3S)-tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0218] 5-[7-[(1-methyl-4-piperidinyl)amino]-5-oxa-2-azaspiro[3,4]octane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0219] 5-[8-(1,4-dioxane-2-ylmethyl)-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0220] 5-[5-(1,4-dioxane-2-ylmethyl)-2,5-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0221] 5-[8-(2-hydroxyacetyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione hydrochloride;

[0222] 5-[5-(2-hydroxyacetyl)-2,5-diazaspiro[3,4]octane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0223] 5-[5-[(4-methylmorpholin-2-yl)methyl]-8-oxa-2,5-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0224] 5-(5-oxa-2,8-diazaspiro[3.5]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione, TFA salt;

[0225] 5-[5-(4-ethylphenoxy)pyrazin-2-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione

[0226] 5-[4-[(6-ethyl-3-pyridyl)oxy]phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0227] 5-[5-(4-ethylphenoxy)-2-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione, formate;

[0228] 5-[6-(4-ethylphenoxy)pyridazin-3-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0229] 5-[6-(4-ethylphenoxy)-3-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0230] 5-[8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[[5-(trifluoromethoxy)-2-pyridinyl]oxy]phenyl]hexahydropyrimidine-2,4,6-trione, 2,2,2-trifluoroacetate;

[0231] N-(6-chloro-3-pyridyl)-4-[5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide;

[0232] 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[3-[[5-(trifluoromethyl)pyrazin-2-yl]amino]phenyl]hexahydropyrimidine-2,4,6-trione;

[0233] 5-[3-[(5-chloro-2-pyridyl)amino]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0234] 5-[2-(4-ethylphenoxy)pyrimidin-5-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidin-2,4,6-trione; and

[0235] 5-[4-(5-ethylpyrazin-2-yl)oxyphenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione.

[0236] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0237] 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0238] 5-[4-(2,3-dihydrobenzofuran-5-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione;

[0239] 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenyl]phenyl]hexahydropyrimidine-2,4,6-trione;

[0240] Racemic-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;

[0241] N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide;

[0242] 5-[4-(4-piperidinylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate;

[0243] 5-[4-[2-(4-piperidinyl)acetyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0244] 5-[8-(azacyclobutane-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate;

[0245] 5-[8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate;

[0246] 5-(8-oxa-2,5-diazaspiro[3.5]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0247] 5-[7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione;

[0248] 5-(7-methyl-2,7-diazaspiro[4.4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate;

[0249] 5-[5-(4-ethylphenoxy)-2-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione carboxylate;

[0250] 5-[6-(4-ethylphenoxy)-3-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; and

[0251] 5-[2-(4-ethylphenoxy)pyrimidin-5-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidin-2,4,6-trione.

[0252] In this description, if there is a discrepancy between the described structure and the name given to that structure, the described structure shall prevail. Furthermore, if the stereochemistry of a structure or part thereof is not indicated by, for example, a thick wedge or dashed line, the structure or part thereof shall be interpreted as encompassing all its stereoisomers. However, in cases where more than one chiral center exists, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry.

[0253] Unless otherwise stated, the terms “compound of the formula” or “compound of the formula” or “multiple compounds of the formula” or “multiple compounds of the formula” mean any compound selected from the genus of compounds as defined by the formula (including any pharmaceutically acceptable salt of any such compound unless otherwise stated).

[0254] Furthermore, the present invention includes all optical isomers of the compound of formula (I), namely diastereomers, diastereomer mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers, and their solvates.

[0255] Compounds of formula (I) may contain one or more asymmetric centers and thus may exist as racemates, racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. Additional asymmetric centers may exist depending on 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 possible optical and diastereomers, in mixture form and as pure or partially purified compounds, be included within this invention. This invention is intended to cover all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be achieved by suitable modifications to the methods disclosed herein, as known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or intermediates, and, if necessary, these products or intermediates can be derivatized using reagents containing asymmetric centers of known absolute configurations. If desired, racemic mixtures of compounds can be separated so that individual enantiomers are isolated. Separation can be carried out by methods well known in the art, such as coupling a racemic mixture of compounds to an enantiomerically pure compound to form a mixture of diastereomers, and then separating the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0256] In embodiments where optically pure enantiomers are provided, optically pure enantiomers mean that the compound contains >90% by weight of the desired isomer, particularly >95% by weight of the desired isomer, or more particularly >99% by weight of the desired isomer, said weight percentage based on the total weight of the compound's isomers. Chiral pure compounds or chiral enriched compounds can be prepared by chiral selective synthesis or by enantiomer separation. Enantiomer separation can be performed on the final product, or alternatively on suitable intermediates.

[0257] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radioactively labeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, isotopes of these elements. 2 H, 3 H, 11 C 13 C14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Certain isotope-labeled compounds of formula (I) (e.g., those containing a radioactive isotope) can be used for drug and / or matrix tissue distribution studies. Radioactive isotope tritium (i.e....) 3 H) and carbon-14 (i.e. 14 C) This is particularly useful because they are easy to incorporate and detection methods are readily available. For example, compounds of formula (I) can be enriched with a given isotope of 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or 99%.

[0258] Using heavier isotopes (such as deuterium, i.e.) 2 H) Substitution can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[0259] Using positron emission isotopes (such as 11 C 18 F, 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the examples set forth below, using an appropriate isotopically labeled reagent instead of the previously used unlabeled reagent.

[0260] Manufacturing method

[0261] A method for producing compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof is also an object of this invention.

[0262] The preparation of compounds of formula (I) as described herein can be carried out via sequential or convergent synthetic routes. The synthesis of the present invention is illustrated in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. Unless otherwise stated, the substituents and labels used in the following description of the methods have the meanings given above herein.

[0263] If any of the starting material, intermediate, or compound of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (as described, for example, in TW Greene and PGM Wuts, “Protective Groups in Organic Chemistry,” 3rd ed., 1999, Wiley, New York) can be introduced prior to a critical step using methods well-known in the art. Such protecting groups can be removed later in the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbonylbenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0264] If the starting material or intermediate contains a stereoisomeric center, the compound of formula (I) can be obtained as a diastereomer or a mixture of enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemic compounds can be separated as their corresponding enantiomers, for example, by diastereomer salts, which are separated by crystallization with optically pure acids, or by specific chromatographic methods using chiral adsorbents or chiral eluents. Similarly, starting materials and intermediates containing stereoisomeric centers can be separated to provide diastereomer / enantiomer-enriched starting materials and intermediates. The use of such diastereomer / enantiomer-enriched starting materials and intermediates in the synthesis of compounds of formula (I) will generally yield the corresponding diastereomer / enantiomer-enriched compound of formula (I).

[0265] Those skilled in the art will recognize that the reaction sequence can vary depending on the reactivity and properties of the intermediate.

[0266] More specifically, the compound of formula (I) can be prepared by the methods given below, by the methods given in the examples, or by similar methods. Appropriate reaction conditions for each reaction step are known to those skilled in the art. Likewise, for information on reaction conditions reported in the literature affecting the reactions described, 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 has been found convenient to carry out the reaction with or without a solvent. There are no particular limitations on the nature of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and is at least partially capable of dissolving the reagents. The described reactions can occur over a wide temperature range, and precise reaction temperatures are not critical to the invention. The above reactions can be conveniently carried out in the temperature range from -78°C to reflux. The reaction time required can also vary considerably depending on many factors, particularly the reaction temperature and the nature of the reagents. However, typically 0.5 hours to several days are sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to the order shown in the scheme; however, the order of reaction steps can be freely changed depending on the starting materials and their corresponding reactivity.

[0267] If the starting materials or intermediates are not commercially available, or their synthesis is not described in the literature, they can be prepared in a manner similar to existing procedures for closely analogous substances or as outlined in the experimental section.

[0268] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, is prepared by a method comprising the steps of: making a compound of formula (II)

[0269] (II)

[0270] With compound of formula (III)

[0271] (III)

[0272] Among them, L, Ar, R 1 and As defined herein, and X is a halogen, reacts in the presence of a base to form the compound of formula (I).

[0273] The following sections provide a general description of the synthesis of the examples provided in this invention.

[0274] General procedure for assembling 5,5-disubstituted spirocyclic barbituric acid derivatives

[0275] The key steps of the synthetic method are shown in Scheme 1 and involve treating an aryl barbituric acid intermediate with a common structure (i) (essentially intermediates A, B, C, etc., described in the experimental section) with a brominating agent such as NBS or HBr / bromine in a solvent such as DMF, THF, or water or the like (depending on the choice of brominating agent) at a temperature ranging from -20°C to the boiling point of the solvent. The brominating intermediate (ii) can be used in situ without further purification, or can be separated in a purer form, for example, by precipitation or grinding with a suitable solvent.

[0276] Then, in the presence of a base such as NET3, DIPEA, DBU, Na2CO3, or the like, in the aforementioned solvent, at a temperature ranging from -20°C to the boiling point of the solvent, intermediate (ii) is treated with a spirocyclic amine (iii-a, iii-b, or iii-c) (referred to as intermediates 1, 2, 3, etc. in the experimental section) to provide an example or intermediate having a universal structure (iv-a, iv-b, or iv-c). The coupling reaction time can vary and can range from minutes to days.

[0277]

[0278] Option 1

[0279] A general method for obtaining appropriately substituted aryl barbiturate intermediates having a general structure (i) is described in Scheme 2. A general method for obtaining suitable spirocyclic intermediates having a general structure (iii-a), (iii-b), or (iii-c) is outlined in Scheme 3.

[0280] General synthesis of barbiturate intermediates A, B, C, etc., with common structure (i)v

[0281] As shown in Scheme 2, Sequence A, commercially available or appropriately substituted aryl acetate derivatives (v) (R) can be prepared according to literature. c =lower alkyl groups (where X is a halogen such as Cl, Br, or I) can be used in solvents such as DMF, THF, etc., at temperatures ranging from −78°C to the boiling point of the solvent, using solvents such as LDA, KO t Treatment with a base of Bu, NaH, or similar substances, followed by treatment with a suitable carbonate (X). a = OR d , where R dFor example, lower alkyl groups) or chloroformates (X) a =Cl) treatment to provide aryl malonate intermediates with a general structure (vi). These can then be processed using substances such as NaOMe, NaOEt, and KO. t The intermediate (iv) is treated with urea in the presence of a suitable base such as Bu or similar, in a solvent such as MeOH, EtOH, etc., at a temperature ranging from -20°C to the boiling point of the solvent, to provide an aryl barbiturate intermediate having a universal structure (vii). Then, under suitable reaction conditions depending on the reagents used, such as with phenol (R... e -OH), aniline (R) f -NH2), arylacetylene (R g -C≡C) or aryl organoboronic acid derivatives (R h -B(OH)2, or similar compounds; wherein R e R f R g and R h R as defined in the claims 1 (A suitable subset thereof) allows the material to undergo further modification. Suitable conditions for such coupling reactions include, for example, Chan-Lam, Suzuki, Buchwald, Sonogashira, or Ullmann type coupling conditions. Conditions for such a single reaction type can vary and depend on the selection of the solvent, catalyst, base, and corresponding stoichiometry. Suitable options for selecting conditions are available in the literature or are well known to those skilled in the art.

[0282] In the case where L represents the -C(O)NH- connector, it can be achieved by connecting the alcohol R... c -OH (where R) c The intermediate of structure (vii) is subjected to carbonylation conditions by treatment with CO and a suitable catalyst such as Pd(dppf)Cl2 or the like in the presence of, for example, Me or Et, at a temperature ranging from RT to the boiling point of the solvent and at a CO pressure of 1 bar to 50 bar. To obtain the carboxylic acid intermediate of structure (vii-b), the ester can be hydrolyzed, for example, with LiOH, NaOH, or KOH in a solvent such as water, THF, etc., at a temperature ranging from -20°C to the boiling point of the solvent. Then, the amide coupling reaction can be carried out on aniline R. f-NH2, suitable coupling agents such as HATU, and amine bases such as NET3, DIPEA, or similar compounds are used in DMF or THF, etc. Many possible coupling agents and associated reaction conditions exist and are known in the art.

[0283] Reversing the synthetic steps is also possible (Scheme 2, Sequence 2). In this method, modification is performed at the aryl ring to introduce residue R. 1 -L is carried out as the first reaction step, which is based on the same reagent as described above (the substituted phenol (R)). e -OH), aniline (R) f -NH2), arylacetylene (R g -C≡C) or aryl organoboronic acid derivatives (R h -B(OH)2)) and the same conditions. Subsequently, the formation of a suitably substituted malonate (ix), followed by urea cyclization to provide an intermediate for structure (i), can be carried out under the same conditions as described above for sequence 1.

[0284]

[0285] Option 2

[0286] General description of the synthesis of helical structural units and intermediates

[0287] Appropriate modifications at various spirocyclic structural units are made to introduce desired residues R into the general structure (iv-a) or (iv-b). a Or R b (where R) a and R b As defined in Scheme 1 above, this can be done before or alternatively after coupling with a barbiturate intermediate having a common structure (i).

[0288] Scheme 3 illustrates a general method for synthesizing a suitably substituted spirocyclic intermediate prior to coupling with a barbiturate intermediate (i). Modification of a suitably protected spirocyclic starting material with a common structure (xa) or (xb), which is commercially available or can be prepared according to literature, can be accomplished, for example, by amide bond formation, sulfonamide bond formation, reductive amination, or N-alkylation. Suitable protecting groups PG for structures (xa) and (xb) are, for example, BOC, CBZ, benzyl, or substituted benzyl, or many other groups. A good overview of possible protecting groups and their associated protecting and deprotecting chemistry, as well as their compatibility with reaction conditions, can be found in TM Greene, PGMWuts, Protecting Groups in Organic Synthesis, John Wiley & Sons, 4th edition, 2006.

[0289] Suitable conditions for such a transformation are available in the literature and are well known to those skilled in the art. In the case of amide bond formation, carboxylic acids (YCOR) can be used. i Treatment with (xa) or (xb) carboxylic acid halides (Y = Cl, Br) or carboxylic acid halides (Y = Cl, Br). The latter is carried out in the presence of bases such as NET3, DIPEA, or Na2CO3, while the former can be carried out in the presence of bases such as NET3 or DIPEA and coupling agents such as HATU or similar substances. The choice of solvent and temperature depends on the reaction conditions. Substituent C(O)-R i and NC(O)-R i R as given in the claims 4 and R 5 A subset of and given in the claims R 4 and R 5 definition.

[0290] N-alkylation of (xa) or (xb) can be achieved by using a suitable residue R carrying a leaving group X (which can be a halide such as Cl, Br, or I). j Alternatively, treatment with methanesulfonates or toluenesulfonates may be used. Typically, a base such as NET3, DIPEA, Na2CO3, Cs2CO3, or similar substances is added to a solvent such as DMF or THF, and the reaction can be carried out at different temperatures. Similarly, the substituent R... j and NR j R as given in the claims 4 and R 5A subset of and given in the claims R 4 and R 5 definition.

[0291] The reductive amination of (xa) or (xb) can be achieved by using a suitable aldehyde or ketone R. k1 C(O)R k2 This is achieved through processing. In the case of aldehydes, R k1 Corresponding to H. Such transformations are typically carried out in solvents such as THF, MeOH, or EtOH, or similar compounds, in the presence of weak acids such as AcOH or NH4OAc and reducing agents such as NaCNBH3 or NaBH(OAc)3. However, many other conditions can be obtained from the literature. Similarly, the substituent R k1 CHR k2 and N-CHR k1 R k2 R as given in the claims 4 and R 5 A subset of and given in the claims R 4 and R 5 definition.

[0292] Finally, the formation of sulfonamides (xvii-a) and (xvii-b) can be achieved using the sulfonyl halide YS(O2)R l (Where Y corresponds to Cl or Br) This is accomplished by treatment (xa) or (xb) at different temperatures in the presence of a base such as NET3, DIPEA, Na2CO3, or Cs2CO3 in a solvent such as DCM, THF, or other solvents. Similarly, the substituent S(O2)R l and NS(O2)R l R as given in the claims 4 and R 5 A subset of and given in the claims R 4 and R 5 definition.

[0293] In all cases, the conditions for the final deprotection step of removing PG depend on the protecting group PG used. If PG is, for example, a BOC group, it can be treated with TFA in DCM or HCl in water or MeOH. If PG is a benzyl or CBZ group, hydrogenation can be used to remove PG to obtain 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 barbiturate intermediate (i).

[0294]

[0295] Option 3

[0296] If residue R is part of substituent A in intermediate (xix-a) or (xix-b) i R j R k Or R l Any of them contains additional functional groups such as NH that may interfere with the coupling step with intermediate (i). x If OH or , then intermediates (xx-a) and (xx-b) may also contain a suitable orthorhombic protecting group PG2 as outlined in Scheme 4. If the PG at the spirocyclic A of the starting material (xa) or (xb) is a BOC group, then a suitable orthorhombic protecting group PG2 is, for example, for amine NH x The protecting group can be CBZ, trifluoroacetyl, benzyl, or many other groups, and for O, it can be, for example, a stable silyl protecting group, benzyl, or formate. Many other choices or arrangements of protecting groups are possible, as well as are well described in the literature and known to those skilled in the art.

[0297]

[0298] Option 4

[0299] General description of optional post-modifications of 5,5-disubstituted barbituric acid derivatives

[0300] For the corresponding structural units (xa) and (xb), optional post-modifications, substantially the same as those outlined in Scheme 3, can be performed after the coupling step described in Scheme 1 above. In this case, examples of 5,5-disubstituted barbiturates or intermediates having the general structure (xxii-a) or (xxii-b) as summarized in Scheme 5 are modified. To achieve the latter, at the start of the synthesis, the appropriate protecting groups PG at the spirocyclic structural units (xxi-a) and (xxi-b) need to be in different positions. Suitable starting materials (xxi-a) and (xxi-b) are commercially available or readily available 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 other groups. The coupling conditions of (xxi-a) and (xxi-b) with (i) via brominated intermediate (ii) are the same as those described in Scheme 1 above.

[0301]

[0302] Option 5

[0303] The protected 5,5-substituted barbiturate intermediate (xxii-a) or (xxii-b) is then deprotected using standard conditions depending on the protecting group PG. For example, if PG in (xxii-a) or (xxii-b) is a BOC group, suitable conditions for its removal include treatment with TFA in DCM, dioxane, or HCl in MeOH, or similar substances, at temperatures ranging from -20°C to the boiling point of the solvent. After deprotection, intermediate (xxiii-a) or (xxiii-b) can then be further modified using the same reactions and reaction conditions (amide bond formation, N-alkylation, reductive amination, or sulfonamide formation) outlined in Schemes 3 and 4 above, respectively. If the reactants used for these modifications do not carry the orthogonal protecting group PG... 2 This directly yields an instance of structure (xxv-a) or structure (xxv-b). The formation of a protected intermediate (xxiv-a) or (xxiv-b) by adding an additional protecting group PG... 2 In the case of reactants, an additional deprotection step is required to form the final instance of structure (xxv-a) or (xxv-b). Removal of PG 2 The conditions depend on the nature of the protecting group and can be obtained from the literature. In Scheme 5, A and R...i R j R k1 R k2 and R l The definition corresponds to the definitions given in the texts above for Scheme 3 and Scheme 4.

[0304] General description of the synthesis of heterocyclic 5,5-disubstituted barbituric acid derivatives

[0305] This general description provides an overview of the pathways to obtain barbiturate derivatives, wherein either of the two 6-membered benzene rings is replaced by a nitrogen-containing 6-membered aromatic heterocycle such as pyridine, pyrimidine, pyridazine, or pyrazine (which in the following schemes is composed of a benzene ring having an N at the center). () indicates a substitution. In some cases, the methods outlined in the previous sections remain appropriate, but in others, the new paths described for the corresponding intermediates in scheme 6 and for the final instance in scheme 7 must be followed.

[0306] Sequence A in Scheme 6 outlines the synthesis of the heterocyclic intermediate of structure (xxx). In this case, a benzyl-protected halophenol (xxvi) (where X is, for example, Br or I) can be coupled with dimethyl malonate in the presence of CuI and L-proline and a base such as Cs2CO3 in a solvent such as DMSO at a temperature ranging from RT to 120 °C to provide an aryl malonate of structure (xxvii). The latter is then cyclized with urea in ethanol or methanol in the presence of a base such as NaOEt or NaOMe or the like at a temperature ranging from RT to the boiling point of the solvent to provide intermediate (xxviii), followed by deprotection with catalytic hydrogenation to provide phenol (xxix). The material is then subjected to a suitable substituted 6-membered halocyanine heterocycle (e.g., pyridine or the like) in the presence of a base such as Cs₂CO₃, for example in DMF, at a temperature ranging from RT to the boiling point of the solvent (where X is Cl, Br, I, or F, and R...). m R as defined in the claims 2 Nucleophilic aromatic substitutions of a subset of (xxx) are used to provide key intermediates for the structure (xxx).

[0307] Sequence B in Scheme 6 illustrates a method for preparing intermediate (xxxiii), wherein the heterocycle is directly linked to barbituric acid. In this case, a suitably substituted phenolic reagent (where R...) is used... mAgain, R as defined in the claims 2 Nucleophilic aromatic substitution is performed between a subset of the bromine intermediate (xxxi) and a 6-membered heterocycle (xxxi) (e.g., pyridine, pyrazine, pyridazine, and pyrimidine) carrying a Br and a second halogen (X = Cl, Br, I, F) at the appropriate position. This coupling, providing the bromine intermediate (xxxii), can be carried out under similar conditions as described in sequence A above for the final step. (xxxii) is then directly coupled with barbituric acid under specific conditions such as Me4-tBu-XPhos-Pd-G3 and DBU in DMSO at temperatures ranging from 50 °C to 160 °C to obtain the intermediate with the desired structure (xxxiii).

[0308] In sequence C of scheme 6, a method for synthesizing certain heterocyclic diarylamine intermediates (xxxiv) is described. Suitable materials with structures (vii) that can be obtained as described in sequence 1 of scheme 2 are reacted with suitable heterocyclic arylamines (R) under Buchwald-type conditions (e.g., tBu-XPhos-PG-G3, BuONa in DMF at elevated temperatures). m = R 2 A subset of the subset is coupled to provide the key intermediate of the structure (xxxiv).

[0309] Sequence D illustrates a method for preparing heterocyclic diarylformamides of certain structures (xxxv). Similar to scheme 2, sequence 1, the carboxylic acid intermediate of structure (vii-b) can be prepared using amide bond coupling conditions (which can be based on many possible coupling agents (e.g., HATU, etc.) and conditions well described in the literature) with a suitably substituted heterocyclic arylamine (R... m = R 2 (a subset of) coupled.

[0310]

[0311] Option 6

[0312] Scheme 7 outlines the final steps for preparing heterocyclic examples of the desired structures (xxxviii) and (xli), respectively. Starting with intermediates of structures (xxxvi) and (xxxix), bromination under the same conditions described in Scheme 1 (e.g., NBS or HBr / bromine in solvents such as DMF, THF, or water or similar substances) provides bromine intermediates (xxxvii) or (xli) that are not normally separated. These are then coupled, for example, with a spirocyclic structural unit (iii-a) in the presence of a base such as NET3, DIPEA, DBU, Na2CO3, or similar substances in the aforementioned solvents at temperatures ranging from -20°C to the boiling point of the solvent. In this way, examples containing aromatic heterocycles represented by the general structures (xxxviii) and (xli) are obtained. Structures (xxxviii) and (xli) are respectively based on the heterocycle and the linker L defined in Scheme 7. a or L b It varies depending on the location of the combination.

[0313]

[0314] Option 7

[0315] 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 of the methods described herein.

[0316] Pharmaceutical composition and administration

[0317] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0318] Compounds of formula (I) and their pharmaceutically acceptable salts may be used as pharmaceutical preparations. Pharmaceutical preparations may be administered orally, such as orally (e.g., in the form of tablets, coated tablets, sugar-coated pills, hard and soft gelatin capsules, solutions, emulsions, or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration may also be parenteral, such as intramuscularly or intravenously (e.g., in the form of injections). Administration may also be administered topically, such as percutaneously, or in the form of eye drops or ear drops.

[0319] Compounds of formula (I) and their pharmaceutically acceptable salts may be processed with pharmaceutically inert inorganic or organic carriers to prepare pharmaceutical preparations such as tablets, coated tablets, sugar-coated pills, hard gelatin capsules, injections, or topical formulations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof may be used as such carriers for tablets, coated tablets, sugar-coated pills, and hard gelatin capsules.

[0320] Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols. However, depending on the characteristics of the active ingredient, a carrier is often not required in soft gelatin capsules.

[0321] Suitable carriers for preparing solutions and syrups include, for example, water, alcohol, polyol, sucrose, glucose, invert sugar, and vegetable oil.

[0322] Suitable carriers for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0323] Suitable carriers for suppositories include, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols.

[0324] Suitable carriers for topical ophthalmic formulations include, for example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0325] In addition, pharmaceutical preparations may contain preservatives, solubilizers, thickeners, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts that alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances with therapeutic value.

[0326] The invention also aims to produce a medicament comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, as well as a method of producing such a medicament comprising causing one or more compounds of formula (I) and / or a pharmaceutically acceptable salt thereof, if desired, and one or more other substances of therapeutic value together with one or more pharmaceutically acceptable excipients to form a galenical form.

[0327] Dosage can vary over a wide range, but will of course have to be adjusted according to individual needs in each specific situation. Generally, in the case of oral administration, a daily dose of about 0.1 mg to 20 mg / kg body weight, preferably 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / individual), divided into 1 to 3 independent doses (which may consist of, for example, the same amount), should be appropriate. In the case of topical administration, the formulation may contain 0.001% to 15% of the drug by weight, and the required dose may be between 0.1 mg and 25 mg, and may be administered as a single daily or weekly dose, or as multiple daily doses (2 to 4 times), or as multiple weekly doses. However, it will be apparent that the upper or lower limits given herein may be exceeded when necessary.

[0328] The pharmaceutical composition according to the present invention can be prepared as follows.

[0329] Preparation of pharmaceutical compositions comprising the compounds of the present invention

[0330] Tablet formulations (wet granulation)

[0331]

[0332] Manufacturing process:

[0333] 1. Mix components 1, 2, 3 and 4 and granulate them together with purified water.

[0334] 2. Dry the granules at 50℃.

[0335] 3. Pass the particles through suitable grinding equipment.

[0336] 4. Add ingredient 5 and mix for three minutes; press on a suitable press.

[0337] Capsule formulation

[0338]

[0339] Manufacturing process:

[0340] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0341] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[0342] 3. Fill into the appropriate capsules.

[0343] Injection

[0344]

[0345] Manufacturing process:

[0346] The compound of formula (I) was dissolved in a mixture of polyethylene glycol 400 and water for injection (partial). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0 ml by adding the remaining water. The solution was filtered, filled into vials using appropriate overfilling, and sterilized.

[0347] Indications

[0348] One object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, which is used as a therapeutically active substance.

[0349] As described above, compounds of formula (I) and their pharmaceutically acceptable salts can be used as MMP9 inhibitors.

[0350] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for therapeutic and / or preventive treatment of ocular surface diseases.

[0351] In one embodiment, the ocular surface disease is dry eye disease.

[0352] In another aspect, the present invention provides the use of compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of ocular surface diseases.

[0353] In one embodiment, the ocular surface disease is dry eye disease.

[0354] In another aspect, the present invention provides the use of compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof for the preparation of medicaments for the therapeutic and / or preventive treatment of ocular surface diseases.

[0355] In one embodiment, the ocular surface disease is dry eye disease.

[0356] In another aspect, the present invention provides a method for the therapeutic and / or preventive treatment of ocular surface diseases, the method comprising administering an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0357] In one embodiment, the ocular surface disease is dry eye disease.

[0358] Example

[0359] The invention will be more fully understood by referring to the following examples. However, the claims should not be construed as limiting the scope of the examples.

[0360] 1) Preparation Examples

[0361] 1.1) Preparation of intermediates

[0362] 1.1.1) 5-Arylbarbiturate intermediates

[0363] Intermediate A

[0364] 5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0365] Step 1: Dimethyl 2-(4-bromophenyl)malonate

[0366]

[0367] Methyl 4-bromophenylacetate (6.00 g, 26.2 mmol, 1.0 eq) was dissolved in THF (60 mL), and 60% sodium hydride from the oil (2.10 g, 52.4 mmol, 2.0 eq) was added. 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 the presence of the desired mass. The mixture was concentrated under vacuum to obtain a crude substance, which was milled with petroleum ether, filtered, and dried under vacuum to give the title compound, dimethyl 2-(4-bromophenyl)malonate (2.40 g, 8.36 mmol, 28.6% yield), as a white solid.

[0368] LCMS (ESI + ): 286.9 [M+H] + .

[0369] Step 2: 5-(4-bromophenyl)hexahydropyrimidine-2,4,6-trione

[0370]

[0371] Sodium (1.57 g, 68.4 mmol, 1.96 eq) was dissolved in ethanol (300 mL). Urea (5.00 g, 83.3 mmol, 1.71 eq) was then added in portions to the solution, and the reaction was stirred for 30 min, followed by the addition of dimethyl 2-(4-bromophenyl)malonate (10.0 g, 34.8 mmol, 1.0 eq). The reaction mixture was heated to 90 °C and stirred for 15.5 h. LC-MS showed the presence of the desired mass. The mixture was then poured into ice water and the pH was adjusted to 3 with 2N HCl. A solid was formed, which was filtered and dried under vacuum to give the title compound 5-(4-bromophenyl)hexahydropyrimidine-2,4,6-trione (3.50 g, 12.4 mmol, 35.1% yield) as a yellow solid.

[0372] LCMS (ESI + ): 284.9 [M+H] + .

[0373] Step 3: 5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0374]

[0375] N,N-dimethylglycine hydrochloride (1.50 g, 10.8 mmol, 0.3 eq) was added 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), and cuprous iodide(I) (1.00 g, 5.25 mmol, 0.15 eq) in DMF (50 mL). The mixture was then stirred at 130 °C for 48 h. LCMS showed the desired mass. The mixture was cooled to 25°C, filtered, and concentrated to obtain a crude substance, which was then ground with water and ethyl acetate to give 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.

[0376] LCMS (ESI + ): 381.0 [M+H] + .

[0377] The following intermediates are similar to intermediate A, steps 1 to 3, and are manufactured by using a suitable starting material in step 3.

[0378]

[0379] intermediate H

[0380] 5-(4-phenoxyphenyl)hexahydropyrimidine-2,4,6-trione

[0381] Step 1: O1-ethyl-O3-methyl-2-(4-phenoxyphenyl)malonate

[0382]

[0383] LDA (41.0 mL, 81.9 mmol, 2.0 eq) was added to a solution of ethyl 2-(4-phenoxyphenyl)acetate (10.5 g, 41.0 mmol, 1.0 eq) in THF (120 mL) while maintaining the temperature at −78 °C. After 1 h, 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 the presence of the desired product mass. The mixture was then quenched with saturated aqueous NH4Cl (50 mL), concentrated under vacuum to remove THF, and extracted with EtOAc (3 x 70 mL). The concentrated residue was purified by column chromatography (SiO2, PE:EtOAc = 9:1, UV detection) to give O1-ethylO3-methyl 2-(4-phenoxyphenyl)malonate as a light brown oil (9.70 g, 30.9 mmol, 73.7% yield).

[0384] LCMS (ESI + ): 315.1 [M+H] + .

[0385] Step 2: 5-(4-phenoxyphenyl)hexahydropyrimidine-2,4,6-trione

[0386]

[0387] O1-ethyl-O3-methyl-2-(4-phenoxyphenyl)malonate (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). The mixture was then refluxed and stirred at 80 °C for 8 h. LC-MS showed the formation of the desired product mass. The resulting suspension was concentrated to semi-dryness and then poured into ice water. 1 N HCl was added to adjust the pH to 2 to 3, and the precipitate was then filtered. The filter cake was ground 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 as a white solid (1.90 g, 6.41 mmol, 40.2% yield).

[0388] LCMS (ESI + ): 297.2 [M+H] + .

[0389] Intermediate J

[0390] 5-(4-phenoxyphenyl)hexahydropyrimidine-2,4,6-trione

[0391] Step 1: Methyl 2-[4-(4-cyclopropylphenoxy)phenyl]acetate

[0392]

[0393] Methyl 2-(4-hydroxyphenyl)acetate (300 mg, 1.81 mmol, 1.0 eq) was dissolved in specially dried dichloromethane (10 mL). Then, pyridine (714 mg, 726 μL, 9.03 mmol, 5.0 eq), molecular sieve (0.4 g), (4-cyclopropylphenyl)organoboronic 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 overnight at RT. TLC after 15 hours showed the reaction was complete. The reaction mixture was filtered, and the filtrate was washed twice with water. The aqueous layer was extracted with DCM. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was dissolved in a minimal amount of EtOAc and transferred to a silica gel column. Purification was performed by gradient elution in heptane from 0% to 22% EtOAc on an ISCO CombiFlash Companion, SILICYCLE FLH-R10095D-A-ISO40, SiliaSep premium, 25µm 40 g. The product fractions were combined and concentrated to give 209 mg (40.2%) of the title compound as a white foam.

[0394] LCMS (ESI + ): 283.1 [M+H] + .

[0395] Step 2: Dimethyl 2-[4-(4-cyclopropylphenoxy)phenyl]malonate

[0396]

[0397] The reaction was carried out under an argon atmosphere. Methyl 2-[4-(4-cyclopropylphenoxy)phenyl]acetate (203 mg, 717 μmol, 1.0 eq) and dimethyl carbonate (549 mg, 513 μL, 6.1 mmol, 8.5 eq) were dissolved in specially dried THF (2 mL) and rapidly added with 1 M potassium tert-butoxide solution (1.51 mL, 1.51 mmol, 2.1 eq). The addition was slightly exothermic, and the temperature was increased from 24 °C to 29 °C to give a pink reaction mixture. After the addition, the reaction mixture was heated to 76 °C, producing a pale yellow mixture, which was stirred overnight. LCMS showed the reaction was complete after 18 hours. The reaction was quenched at 5 °C with acetic acid (129 mg, 123 μL, 2.15 mmol, 3.0 eq), and the resulting suspension was concentrated under vacuum. The residue was placed in EtOAc and washed with H2O. After back-extraction, the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product as a yellow oil. This material was dissolved in a minimal amount of EtOAc and transferred to a silica gel column. Purification was performed by elution in heptane with a gradient of 0% to 28% EtOAc on an ISCO CombiFlash Companion, SILICYCLE FLH-R10095D-A-ISO40, SiliaSep premium, 25µm 40g. The fractions containing the product were combined and concentrated to give 172 mg (69.1%) of the title compound as a pale yellow oil.

[0398] LCMS (ESI + ): 341.1 [M+H] + .

[0399] Step 3: 5-[4-(4-cyclopropylphenoxy)phenyl]hexahydropyrimidine-2,4,6-trione

[0400]

[0401] Sodium ethoxide (350 mg, 402 μL, 1.08 mmol, 2.2 eq) was dissolved in ethanol (3 mL), and then urea (50.1 mg, 834 μmol, 1.7 eq) was added to the solution, and the mixture was stirred for 30 min. Then, a solution of dimethyl 2-[4-(4-cyclopropylphenoxy)phenyl]malonate (167 mg, 491 μmol, 1.0 eq) in ethanol (1.0 mL) was added, and the reaction mixture was heated to reflux. A grayish-white suspension was observed to form at reflux. LCMS after 2.5 h showed the reaction was complete. The mixture was cooled to RT and then poured into ice water (16 mL + ice), and the pH was adjusted to 3 with 2 M HCl (736 μL, 1.47 mmol, 3.0 eq). The resulting fine solid was filtered and dried under vacuum to provide 87.7 mg of a yellow substance, which was then milled three times with 3.6 mL of petroleum ether (60°C to 80°C BP): EtOAc (3:1). The suspension was filtered over a Sartorius funnel and the off-white solid was washed twice with 1 mL of PE / EtOAc and dried under vacuum to provide the title compound: 72.3 mg of off-white solid (42.6%).

[0402] LCMS (ESI + ): 337.0 [M+H] + .

[0403] intermediate K

[0404] The following intermediates are similar to intermediate J, and are produced in steps 1 to 3 by using a suitable starting material in step 1.

[0405]

[0406] intermediate L

[0407] 5-[4-[4-(trifluoromethoxy)phenyl]phenyl]hexahydropyrimidine-2,4,6-trione

[0408]

[0409] 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), 4-(trifluoromethoxy)phenyl organoboronic acid (3.27 mg, 15.9 mmol, 1.5 eq), [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) were added. The mixture was stirred at 90 °C under N₂ for 12 h. LCMS showed the formation of the desired product. The mixture was poured into water (70 mL), extracted with EtOAc (3 × 70 mL), and the aqueous phase was concentrated to obtain a crude material that was ground with PE:EtOAc at a ratio of 10:1, filtered, and dried under vacuum. The material was ground again with EtOAc (3 × 20 mL), filtered, and dried under vacuum 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 gray solid.

[0410] LCMS (ESI + ): 365.0 [M+H] + .

[0411] intermediate N

[0412] The following intermediates are similar to intermediate L and are manufactured using appropriate starting materials.

[0413]

[0414] intermediate M

[0415] 5-[3-[4-(trifluoromethoxy)anilino]phenyl]hexahydropyrimidine-2,4,6-trione

[0416] Step 1: Dimethyl 2-(3-bromophenyl)malonate

[0417]

[0418] 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 (32.5 g, 812 mmol, 1.86 eq) of 60% of the oil was added to the mixture, and it was 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 heated to 70 °C and stirred at 70 °C for 15.5 h. LCMS showed the formation of the desired product. The mixture was poured into water, extracted with EtOAc (3 × 800 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. The material was ground with petroleum ether to obtain the title compound 2-(3-bromophenyl)malonate dimethyl ester (80.0 g, 279 mmol, 57.3% yield) as a yellow oil, which was used directly in the next step.

[0419] LCMS (ESI + ): 288.9 [M+H] + .

[0420] Step 2: 5-(3-bromophenyl)hexahydropyrimidine-2,4,6-trione

[0421]

[0422] Sodium (8.17 g, 355 mmol, 1.96 eq) was dissolved in ethanol (400 mL), and then urea (18.6 g, 309 mmol, 1.7 eq) was added in portions to the solution, and the mixture was stirred for 30 min. Dimethyl 2-(3-bromophenyl)malonate (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 HCl. A solid appeared, which was filtered and dried under vacuum to give the title compound 5-(3-bromophenyl)hexahydropyrimidine-2,4,6-trione (18.0 g, 63.6 mmol, 34.9% yield) as a yellow solid.

[0423] LCMS (ESI + ): 282.9 [M+H] + .

[0424] Step 3: 5-[3-[4-(trifluoromethoxy)anilino]phenyl]hexahydropyrimidine-2,4,6-trione

[0425]

[0426] TBUXPHOS PDG3 (225 mg, 0.28 mmol, 0.08 eq) was added 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), and sodium tert-butoxide (2 M in THF, 5.3 mL, 10.6 mmol, 3.0 eq) in DMF (30 mL) at 20 °C under N2. The mixture was then heated to 100 °C and stirred for 12 h. The presence of the desired product was confirmed by LCMS, and the mixture was then cooled to 20 °C, filtered, and concentrated. The crude material was ground with EtOAc, then filtered and dried under vacuum to obtain 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 gray solid, with a purity of about 80%.

[0427] LCMS (ESI + ): 380.0 [M+H] + .

[0428] Intermediate O

[0429] 5-[4-[2-(4-chlorophenyl)ethynyl]phenyl]hexahydropyrimidine-2,4,6-trione

[0430] Step 1: Methyl 2-[4-[2-(4-chlorophenyl)ethynyl]phenyl]acetate

[0431]

[0432] To a solution of methyl 4-bromophenylacetate (2.00 g, 8.7 mmol, 1.0 eq), copper iodide (l) (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), 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) were added. The reaction mixture was then stirred at 90 °C for 12 h. TLC (PE:EtOAc = 5:1) showed that the starting materials were completely consumed and new spots were present (stained with KMnO4 aqueous solution). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL), and the organic extract was washed with brine (2 × 50 mL). The combined organic phases were 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 with a gradient elution 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.

[0433] 1 H-NMR (400 MHz, CDCl3): δ = 7.53 - 7.42 (m, 4H), 7.27 (s, 5H), 3.72 (s, 3H), 3.65 (s, 2H).

[0434] Step 2: Dimethyl 2-[4-[2-(4-chlorophenyl)ethynyl]phenyl]malonate

[0435]

[0436] Under ice bath cooling, sodium hydride (1.94 g, 48.4 mmol, 2.0 eq) of 60% of the oil was added fractionally 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). The mixture was then stirred under reflux at 80 °C for 12 h. LC-MS showed the presence of the desired product mass. The mixture was poured into water and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by column chromatography (SiO2, PE:EtOAc gradient = 80:1 to 20:1, UV detection). The fractions containing the desired product were combined and evaporated to provide the title compound, dimethyl 2-[4-[2-(4-chlorophenyl)ethynyl]phenyl]malonate, as a yellow solid (5.20 g, 15.2 mmol, 62.7% yield).

[0437] LCMS (ESI + ): 343.1 [M+H] + .

[0438] Step 3: 5-[4-[2-(4-chlorophenyl)ethynyl]phenyl]hexahydropyrimidine-2,4,6-trione

[0439]

[0440] Dimethyl 2-[4-[2-(4-chlorophenyl)ethynyl]phenyl]malonate (5.20 g, 15.2 mmol, 1.0 eq) and urea (1.55 g, 25.8 mmol, 1.7 eq) were added to a previously prepared solution of sodium (698 mg, 30.3 mmol, 2.0 eq) dissolved in ethanol (10 mL). The mixture was then stirred under reflux at 80 °C for 12 h in a N2 atmosphere. LCMS confirmed the formation of the desired material. The suspension was concentrated to approximately half its initial volume under vacuum, and the mixture was then cooled to room temperature and poured into ice water. 1 N HCl was added to adjust the pH to 2 to 3. The resulting precipitate was filtered, and the filter cake was ground with EtOAc (10 mL), filtered again, and washed with additional EtOAc (3 × 2 mL). The material was dried under reduced pressure to obtain the crude product. The material was further ground with EtOH (10 mL), filtered, and washed with water (3 × 2 mL). The filter cake was then 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.

[0441] LCMS (ESI + ): 339.1 [M+H] + .

[0442] intermediate P

[0443] N-(4-Chlorophenyl)-4-(2,4,6-trioxohexahydropyrimidin-5-yl)benzamide

[0444] Step 1: Methyl 4-(2,4,6-trioxohexahydropyrimidin-5-yl)benzoate

[0445]

[0446] Triethylamine (4.43 mL, 31.8 mmol, 3.0 eq.) was added 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(dppf)Cl2 (1.73 g, 2.12 mmol, 0.2 Eq.) in methanol (20 mL) and DMF (20 mL). 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 passed through a preparative HPLC (column: Phenomenex Synergi Polar-RP 100 * 25 mm * 4 µm; gradient: water (containing 0.1% FA): CH3CN (20%-40%); gradient time: 7 min), followed by freeze-drying of the fraction containing the desired product to obtain methyl 4-(2,4,6-trioxohexahydropyrimidin-5-yl)benzoate (3.00 g, 11.4 mmol, quantified) as a white solid with a purity of 97%.

[0447] LCMS (ESI + ): 263.0 [M+H] + .

[0448] Step 2: 4-(2,4,6-trioxohexahydropyrimidin-5-yl)benzoic acid

[0449]

[0450] 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. The mixture was then adjusted to pH 2 by adding 1 N HCl and extracted with EtOAc (3 x 20 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to give 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.

[0451] LCMS (ESI + ): 249.0 [M+H] + .

[0452] Step 3: N-(4-chlorophenyl)-4-(2,4,6-trioxohexahydropyrimidin-5-yl)benzamide

[0453]

[0454] O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (550 mg, 2.34 mmol, 2.0 eq.) was added 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), and the mixture was stirred at RT for 10 min. Then 4-chloroaniline (298 mg, 2.34 mmol, 2.0 eq.) was added, and the mixture was stirred at RT for 12 h. The mixture was concentrated under vacuum and the crude product was ground with EtOAc, filtered, and dried under vacuum to give N-(4-chlorophenyl)-4-(2,4,6-trioxohexahydropyrimidin-5-yl)benzamide (220 mg, 0.61 mmol, 53% yield) as a pink solid.

[0455] LCMS (ESI + ): 358.1 [M+H] + .

[0456] The following intermediates are similar to intermediate P, and are produced in step 3 by using the appropriate starting materials and conditions shown in the table below:

[0457]

[0458] intermediate Q

[0459] 5-[5-(4-ethylphenoxy)pyrazin-2-yl]hexahydropyrimidine-2,4,6-trione

[0460] Step 1: 2-Bromo-5-(4-ethylphenoxy)pyrazine

[0461]

[0462] K₂CO₃ (12.0 g) was added to a solution of 2-bromo-5-chloropyrazine (5.0 g) and 4-ethylphenol (4.0 g) in ACN (100 mL) at 25 °C. The mixture was then stirred at 90 °C for 12 h. LCMS showed the formation of the desired product. The mixture was then filtered and concentrated under vacuum to obtain a residue, which was then purified by rapid column chromatography eluting with 30% EtOAc in petroleum ether. The desired fractions were combined and concentrated to give 2-bromo-5-(4-ethylphenoxy)pyrazine (8.0 g, 111% yield) as a colorless oil. This material used in the next step contained about 25% 2-chloro-5-(4-ethylphenoxy)pyrazine as a byproduct.

[0463] 1 H NMR (400 MHz, DMSO-d6): δ = 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).

[0464] The additional signal at 8.33 ppm is associated with 2-chloro-pyrazine byproducts.

[0465] Step 1: 5-[5-(4-ethylphenoxy)pyrazin-2-yl]hexahydropyrimidine-2,4,6-trione

[0466]

[0467] Me4-tBu-XPhos-Pd-G3 (CAS 1507403-85-1, 305 mg) was added to a 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) under stirring, and the mixture was purged with N2. The mixture was then stirred at 100 °C for 12 h under nitrogen. LCMS showed the presence of a new peak with the desired mass. The mixture was diluted with 80 mL of EtOAc and washed three times with 60 mL of brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by reversed-phase MPLC (240 g C18 column SepaFlash pre-packed with domestic amorphous spherical C18 silica gel, 20 μm to 45 μm; eluent A: water containing 0.5% FA; B: ACN; gradient of B 1%–80%) to obtain 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.

[0468] This material will be used in the next step without further detailed analysis.

[0469] The following intermediates are similar to intermediate Q and are manufactured using appropriate starting materials and conditions.

[0470]

[0471] intermediate U

[0472] 5-[6-(4-ethylphenoxy)-3-pyridyl]hexahydropyrimidine-2,4,6-trione

[0473] Step 1: 5-Bromo-2-(4-Ethylphenoxy)pyridine

[0474]

[0475] tBuOK (35.0 mL, 1 M 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. The mixture was then stirred at RT for 1 h, followed by stirring at 50 °C for an additional 11 h. TLC analysis (PE / EtOAc = 5 / 1) showed new spots forming. The reaction mixture was then concentrated and the residue was diluted with 50 mL of water and extracted three times with 50 mL of EtOAc. The organic matter was dried over Na2SO4 and then concentrated to dryness. The crude substance was then purified by rapid column chromatography eluting with 20% EtOAc in PE. The desired fractions were combined and concentrated to provide 5-bromo-2-(4-ethylphenoxy)pyridine (3.80 g, 56% yield) as a white solid.

[0476] 1 H NMR (400 MHz, CDCl3): δ = 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).

[0477] Step 2: Dimethyl 2-[6-(4-ethylphenoxy)-3-pyridyl]malonate

[0478]

[0479] 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 the formation of peaks with the desired quality.

[0480] The second reaction with 200 mg of 5-bromo-2-(4-ethylphenoxy)pyridine was carried out in the same manner.

[0481] The two reaction mixtures were combined, poured into 100 mL of ice water, and the solution was neutralized with 1 M HCl. The mixture was then extracted three times with 50 mL of EtOAc, and the combined organic extracts were dried over Na2SO4 and concentrated under vacuum. The residue was purified by rapid column chromatography eluting with 25% EtOAc in PE, and the desired fractions were combined and concentrated to give dimethyl 2-[6-(4-ethylphenoxy)-3-pyridyl]malonate (1.6 g, 38% yield) as a yellow solid.

[0482] 1 H NMR (400 MHz, CDCl3): δ = 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).

[0483] Step 3: 5-[6-(4-ethylphenoxy)-3-pyridyl]hexahydropyrimidine-2,4,6-trione

[0484]

[0485] Dimethyl 2-[6-(4-ethylphenoxy)-3-pyridyl]malonate (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). The mixture was then heated to 80 °C and stirred for 16 h. LCMS showed a new peak with the desired quality. The mixture was then poured into ice water (30 mL) and neutralized with 1 M HCl. It was then concentrated under vacuum to give a residue, which was purified by reversed-phase MPLC (eluted with a gradient of A: water containing 0.5% FA and B: ACN, B eluting 5%–45%). The desired fractions were combined and lyophilized to give 5-[6-(4-ethylphenoxy)-3-pyridyl]hexahydropyrimidine-2,4,6-trione (300 mg, 19% yield) as a yellow solid.

[0486] LCMS (ESI + ): 326.1 [M+H] + .

[0487] intermediate V

[0488] 5-[4-[[5-(trifluoromethoxy)-2-pyridyl]oxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0489] Step 1: Dimethyl 2-(4-benzyloxyphenyl)malonate

[0490]

[0491] Cs₂CO₃ (180 g) was added to a stirred mixture of 4-benzyloxybromobenzene (50.0 g), CuI (7.0 g), dimethyl malonate (103.8 mL), and L-proline (9.0 g) in DMSO (600 mL), and the mixture was purged with N₂. The reaction was then stirred at 90 °C for 12 h. LCMS showed a new peak with the desired product quality. The mixture was poured into ice water (500 mL) and the pH was adjusted to 6 with 6 M HCl. The mixture was then extracted four times with 300 mL of EtOAc, and the organic extract was dried over Na₂SO₄ and concentrated under vacuum. The residue was then purified by column chromatography on a Biotage device using 15% EtOAc in PE, and the desired fractions were combined and concentrated to give dimethyl 2-(4-benzyloxyphenyl)malonate as a white solid (38.0 g, 64% yield).

[0492] 1 H-NMR (400 MHz, CDCl3): 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).

[0493] Step 2: 5-(4-benzyloxyphenyl)hexahydropyrimidine-2,4,6-trione

[0494]

[0495] 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)malonate (12.0 g). The mixture was then stirred at 80 °C for 16 h. LCMS showed the formation of a peak with the desired quality. The mixture was cooled to 20 °C and poured into ice water. The pH was then adjusted to 2 with 1 N HCl. The resulting suspension was filtered, and the solid was milled with EA to obtain 5-(4-benzyloxyphenyl)hexahydropyrimidine-2,4,6-trione (6.2 g, 60% yield) as a yellow solid with a purity of approximately 80% (via UV).

[0496] LCMS (ESI + ): 311.0 [M+H] + .

[0497] Step 3: 5-(4-hydroxyphenyl)hexahydropyrimidine-2,4,6-trione

[0498]

[0499] 6.2 g of 5-(4-benzyloxyphenyl)hexahydropyrimidine-2,4,6-trione was dissolved in DMF (200 mL), and Pd / C (482 mg) was added to the mixture. The reaction was then stirred at 20 °C for 12 h under a H2 atmosphere. LC-MS confirmed the formation of the product with the desired quality. The mixture was filtered and concentrated to obtain a crude substance, which was milled with EtOAc, filtered again, and dried under vacuum to give 1.8 g (41% yield) of 5-(4-hydroxyphenyl)hexahydropyrimidine-2,4,6-trione as a gray solid.

[0500] LCMS (ESI + ): 221.1 [M+H] + .

[0501] Step 4: 5-[4-[[5-(trifluoromethoxy)-2-pyridyl]oxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0502]

[0503] 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 the mixture was then heated to 100 °C and stirred under N2 for 12 h. LCMS showed the formation of the desired product. The reaction mixture was directly purified by preparative HPLC (column: Phenomenex luna C18 150 * 40 mm * 15 μm; mobile phase A: water (0.225% TFA), B: ACN; gradient of B 35%–65%) and the desired fraction was lyophilized to give 5-[4-[[5-(trifluoromethoxy)-2-pyridyl]oxy]phenyl]hexahydropyrimidine-2,4,6-trione (15.0 mg, 10% yield) as a white solid.

[0504] LCMS (ESI + ): 382.0 [M+H] + .

[0505] Intermediate X

[0506] 5-[3-[[5-(trifluoromethyl)pyrazin-2-yl]amino]phenyl]hexahydropyrimidine-2,4,6-trione

[0507]

[0508] tBuONa (2.65 mL, 2M in THF) was added to a solution of 5-(3-bromophenyl)hexahydropyrimidine-2,4,6-trione (500 mg, obtained in intermediate M, step 2) and 5-(trifluoromethyl)pyrazine-2-amine (346 mg), Tbuxphos PD G3 (140 mg) in DMF (20 mL) (stored under nitrogen). The mixture was then stirred at 90 °C for 12 h. LCMS showed the formation of peaks with the desired product mass. The mixture was filtered and concentrated under vacuum to provide a crude substance, which was milled with EtOAc and MeOH to provide, after filtration, 5-[3-[[5-(trifluoromethyl)pyrazine-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 is suitable for the next step and can be used without further purification.

[0509] LCMS (ESI + ): 366.0 [M+H] + .

[0510] intermediate Y

[0511] 5-[3-[(5-chloro-2-pyridyl)amino]phenyl]hexahydropyrimidine-2,4,6-trione

[0512]

[0513] Xantphos (409 mg) was added to a mixture of 2-amino-5-chloropyridine (1.36 g), cesium carbonate (4.60 g), Pd2(dba)3 (388 mg), and 5-(3-bromophenyl)hexahydropyrimidine-2,4,6-trione (2.00 g, obtained in intermediate M, step 2) in DMF (20 mL) at 20 °C under N2. The mixture was then heated to 100 °C under N2 and stirred for 12 h. LCMS during the process showed peaks with the desired product quality. The mixture was cooled to 25°C, filtered, and concentrated under vacuum to obtain a residue, which was then ground with EtOAc to obtain, 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 in the next reaction step without further purification and analysis.

[0514] LCMS (ESI) + (during the process): 330.9 [M+H) + .

[0515] Intermediate AA

[0516] 5-[4-(5-ethylpyrazin-2-yl)oxyphenyl]hexahydropyrimidine-2,4,6-trione

[0517]

[0518] A solution of 5-(4-hydroxyphenyl)hexahydropyrimidine-2,4,6-trione (60 mg, obtained in intermediate V, step 3) and 2-chloro-5-ethylpyrazine (389 mg) in DMSO (7.5 mL) was mixed with K₂CO₃ (1.32 g), and the mixture was stirred at 120 °C for 12 h. LCMS showed that the desired product was forming. The reaction mixture was then filtered, and the filtrate was poured into water (45 mL) and extracted three times with EtOAc (30 mL). The aqueous phase was then concentrated under vacuum and the residue was purified by reversed-phase chromatography (column: Welch Ultimate XB_C18 20 μm to 40 μm; eluent A: water (0.1% NH3*H2O); eluent B: ACN; gradient of B: 0%–37% B) to give the title compound 5-[4-(5-ethylpyrazin-2-yl)oxyphenyl]hexahydropyrimidine-2,4,6-trione (295 mg, 32% yield) as a gray solid after lyophilization of the desired fraction.

[0519] LCMS (ESI + ): 327.1 [M+H] + .

[0520] 1.1.2) Spiral ring intermediate

[0521] Intermediate 1

[0522] 2-(2,7-diazaspiro[3.5]nonane-2-yl)ethanol 2,2,2-trifluoroacetate

[0523] Step 1: 2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0524]

[0525] 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl 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-bromoethanol (787 mg, 445 µL, 6.30 mol, 0.95 Eq.) in acetonitrile (5 mL) was added dropwise, and the reaction mixture was stirred under reflux for 4 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by rapid chromatography (0%-10% gradient of SiO2, DCM:MeOH, UV detection) to obtain tert-butyl 2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1069 mg, 3.96 mmol, 61% yield) as a white oil.

[0526] LCMS (ESI + ): 271.0 [M+H] + .

[0527] Step 2: 2,2,2-trifluoroacetate of 2-(2,7-diazaspiro[3.5]nonane-2-yl)ethanol

[0528]

[0529] 2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (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 heated to room temperature. The colorless reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under reduced pressure and diluted with toluene and concentrated (3 x 10 mL) to remove any excess TFA to give 2-(2,7-diazaspiro[3.5]nonane-2-yl)ethanol 2,2,2-trifluoroacetate (1.23 g, quantitative yield), which was used in the next step without further purification.

[0530] LCMS (ESI + ): 171.2 [M+H] + .

[0531] Intermediate 2

[0532] 2-(2-Phenylacetyl)-2,7-diazaspiro[3.5]nonane 2,2,2-trifluoroacetate

[0533] Step 1: tert-butyl 2-(2-phenylethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0534]

[0535] Similar to intermediate 1, step 1 was prepared using tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (500 mg, 1.9 mmol, 1.0 Eq.) and 2-bromoethylbenzene (260 µL, 1.9 mmol, 1.0 Eq.) to obtain 2-(2-phenylethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate tert-butyl ester as a colorless oil (465 mg, 1.41 mmol, 67% yield).

[0536] LCMS (ESI + ): 331.3 [M+H] + .

[0537] Step 2: 2-(2-phenylethyl)-2,7-diazaspiro[3.5]nonane 2,2,2-trifluoroacetate

[0538]

[0539] Similar to intermediate 1, step 2 was prepared 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 µL, 9.15 mmol, 15 Eq.) to obtain 2-(2-phenylethyl)-2,7-diazaspiro[3.5]nonane 2,2,2-trifluoroacetate as a colorless oil (250 mg, quantitative yield).

[0540] LCMS (ESI + ): 231.3 [M+H] + .

[0541] Intermediate 3

[0542] 1-(2,7-diazaspiro[3.5]nonane-2-yl)-2-hydroxy-acetone 2,2,2-trifluoroacetate

[0543] Step 1: 2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0544]

[0545] To a solution of glycolic acid (1.74 g, 22.8 mmol, 2.0 eq), 1-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), 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) was added. The mixture was then stirred at 25 °C for 12 h. LCMS confirmed the presence of the desired product mass. The mixture was concentrated under vacuum and the crude material was purified by MPLC (ISCO CombiFlash; column: 330 g Welch Ultimate XB C18 flash column 20 μm to 40 μm; 120 A; flow rate: 100 ml / min; gradient of CH3CN in H2O (containing 0.1% TFA) from 0% to 35% for 30 min, followed by isocratic elution in 35% CH3CN for 10 min). Fractions containing the desired material were combined and lyophilized to give tert-butyl 2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.50 g, 5.28 mmol, 46.1%) as a white solid. LCMS (ESI) + ): 285.1 [M+H] + 229.1 [M+H-isobutylene] + .

[0546] Step 2: 1-(2,7-diazaspiro[3.5]nonane-2-yl)-2-hydroxy-acetone 2,2,2-trifluoroacetate

[0547]

[0548] Similar to intermediate 1, step 2 was prepared 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 obtain 1-(2,7-diazaspiro[3.5]nonane-2-yl)-2-hydroxy-acetone 2,2,2-trifluoroacetate (650 mg, quantitative yield) as a pale yellow oil.

[0549] LCMS (ESI + ): 185.0 [M+H] + .

[0550] Intermediate 4

[0551] 2,7-diazaspiro[3.5]nonane-2-yl(1,4-dioxane-2-yl)methyl ketone 2,2,2-trifluoroacetate

[0552] Step 1: 2-(1,4-dioxane-2-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0553]

[0554] Similar to intermediate 3, step 1, prepared using 1,4-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.), 1-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 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl hydrochloride (100 mg, 0.38 mmol, 1.0 Eq.), to obtain 2-(1,4-dioxane-2-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl hydrochloride (109 mg, 0.38 mmol, 1.0 Eq.). (mg, 0.32 mmol, 84% yield)

[0555] LCMS (ESI + ): 341.1 [M+H] + .

[0556] Step 2: 2,7-diazaspiro[3.5]nonane-2-yl(1,4-dioxane-2-yl)methyl ketone 2,2,2-trifluoroacetic acid Salt

[0557]

[0558] Similar to intermediate 1, in step 2, this intermediate was prepared using tert-butyl 2-(1,4-dioxane-2-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (160 mg, 0.47 mmol, 1.0 Eq.) and TFA (333 µL, 7.05 mmol, 15 Eq.) to obtain 2,7-diazaspiro[3.5]nonane-2-yl(1,4-dioxane-2-yl)methyl ketone 2,2,2-trifluoroacetate (120 mg, quantitative yield) as a pale yellow oil.

[0559] LCMS (ESI + ): 241.2 [M+H] + .

[0560] Intermediate 5

[0561] 4-(1-oxa-4,9-diazaspiro[5.5]undecane-4-ylsulfonyl)piperidine-1-carboxylic acid benzyl ester hydrochloride

[0562] Step 1: 4-[(1-benzyloxycarbonyl-4-piperidinyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5] eleven tert-butyl alkyl-9-carboxylate

[0563]

[0564] N,N-diisopropylethylamine (1.53 mL, 8.82 mmol, 2.0 eq) was added to a solution of 4-(chlorosulfonyl)piperidine-1-carboxylate (1.40 g, 4.41 mmol, 1.0 Eq.) in DMF (15 mL), 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 obtain tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidinyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1.92 g, 3.57 mmol, 81% yield) as a yellow oil.

[0565] LCMS (ESI + ): 438.3 [M-BOC+H] + .

[0566] Step 2: 4-(1-oxa-4,9-diazaspiro[5.5]undecane-4-ylsulfonyl)piperidine-1-carboxylic acid benzyl ester salt Salt

[0567]

[0568] 4-[(1-benzyloxycarbonyl-4-piperidinyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (1.92 g, 3.57 mmol, 1.0 Eq.) was dissolved in MeOH (10 mL). HCl in MeOH (3.0 M, 5.95 mL, 17.85 mmol, 5.0 Eq.) and the reaction mixture were stirred at RT for 1.5 h. The reaction mixture was concentrated and the residue was purified by column chromatography (SiO2, DCM:MeOH gradient 0%–10%, UV detection) to give 4-(1-oxa-4,9-diazaspiro[5.5]undecane-4-ylsulfonyl)piperidin-1-carboxylic acid benzyl ester hydrochloride (1.64 g, 3.46 mmol, 97% yield) as a white solid.

[0569] LCMS (ESI + ): 438.3 [M+H] + .

[0570] Intermediate 6

[0571] 4-[2-(1-oxa-4,9-diazaspiro[5.5]undecane-4-yl)-2-oxo-ethyl]piperidine-1-carboxylic acid benzyl ester hydrochloride

[0572] Step 1: 4-[2-(1-benzyloxycarbonyl-4-piperidinyl)acetyl]-1-oxa-4,9-diazaspiro[5.5]+ tert-butyl 9-carboxylate

[0573]

[0574] N,N-diisopropylethylamine (2.51 mL, 14.4 mmol, 2.0 eq.) and HATU (2.55 g, 10.8 mmol, 1.5 eq.) were added to a solution of 2-(1-benzyloxycarbonyl-4-piperidinyl)acetic acid (2.0 g, 7.21 mmol, 1.0 eq.) in DMF (30 mL). The mixture was stirred at RT for 10 min, followed by the addition of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (2.03 g, 7.93 mmol, 1.1 eq.) and stirring at RT for 12 h. 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) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, PE:EtOAc 5:1, UV detection) to obtain tert-butyl 4-[2-(1-benzyloxycarbonyl-4-piperidinyl)acetyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (3.13 g, 6.06 mmol, 54% yield) as a yellow oil.

[0575] LCMS (ESI + ): 516.4 [M+H] + .

[0576] Step 2: 4-[2-(1-oxa-4,9-diazaspiro[5.5]undecane-4-yl)-2-oxo-ethyl]piperidine-1- Benzyl formate hydrochloride

[0577]

[0578] Similar to intermediate 5, step 2 was prepared using tert-butyl 4-[2-(1-benzyloxycarbonyl-4-piperidinyl)acetyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (5.10 g, 9.89 mmol, 1.0 eq) and HCl in MeOH (3.0 M, 1.48 mL, 49.45 mmol, 5 Eq.) to give 4-[2-(1-oxa-4,9-diazaspiro[5.5]undecane-4-yl)-2-oxo-ethyl]piperidin-1-carboxylate hydrochloride (2.30 g, 5.09 mmol, 55% yield) as a yellow solid.

[0579] LCMS (ESI + ): 416.2 [M+H] + .

[0580] Intermediate 7

[0581] 5-Oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoroacetate

[0582]

[0583] Similar to intermediate 1, in step 2, this intermediate was prepared 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 obtain 2,2,2-trifluoroacetate of 5-oxa-2,8-diazaspiro[3.5]nonane as a white solid. This substance was used without further characterization.

[0584] LCMS (ESI + ): 129.1 [M+H] + .

[0585] Intermediate 8

[0586] 2-(1,8-diazaspiro[4.5]decane-1-yl)ethanol hydrochloride

[0587] Step 1: 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1,8-diazaspiro[4,5]decane- tert-butyl 8-carboxylate

[0588]

[0589] (tert-butyldimethylsilyloxy)acetaldehyde (145 mg, 0.83 mmol, 2.0 eq) was dissolved in MeOH (4 mL). 8-(Boc)-1,8-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 9 h. 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 Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, PE:EtOAc 5:1, UV detection) to obtain tert-butyl 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1,8-diazaspiro[4.5]decane-8-carboxylate (120 mg, 0.30 mmol, 72% yield) as a light yellow oil.

[0590] LCMS (ESI + ): 399.4 [M+H] + .

[0591] Step 2: 2-(1,8-diazaspiro[4.5]decane-1-yl)ethanol hydrochloride

[0592]

[0593] Similar to intermediate 5, step 2 was prepared using tert-butyl 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1,8-diazaspiro[4.5]decane-8-carboxylate (120 mg, 0.301 mmol, 1.0 eq) and HCl in MeOH (3.0 M, 50 µL mL, 1.51 mmol, 5 Eq.) to obtain 2-(1,8-diazaspiro[4.5]decane-1-yl)ethanol hydrochloride (70 mg, quantitative yield) as a light brown solid, which was used without further purification.

[0594] LCMS (ESI + ): 185.4 [M+H] + .

[0595] Intermediate 9

[0596] 1-Ethyl-1,8-diazaspiro[4.5]decane 2,2,2-trifluoroacetate

[0597] Step 1: 1-Ethyl-1,8-diazaspiro[4,5]decane-8-carboxylic acid tert-butyl ester

[0598]

[0599] Iodine ethane (0.06 mL, 0.76 mmol, 0.91 eq) was added to a suspension of tert-butyl 1,9-diazaspiro[4.5]decane-9-carboxylate (200 mg, 0.83 mmol, 1.0 Eq.) and potassium carbonate (230 mg, 1.66 mmol, 2.0 Eq.), and the mixture was stirred at RT for 12 h. The mixture was filtered and concentrated to give tert-butyl 1-ethyl-1,9-diazaspiro[4.5]decane-9-carboxylate as a yellow oil, TFA salt (209 mg, 0.78 mmol, 94% yield), which was used without further purification.

[0600] LCMS (ESI + ): 268.9 [M+H] + .

[0601] Step 2: 1-Ethyl-1,8-diazaspiro[4.5]decane 2,2,2-trifluoroacetate

[0602]

[0603] Similar to intermediate 1, step 2 was prepared using tert-butyl 1-ethyl-1,9-diazaspiro[4.5]decane-9-carboxylate (161 mg, 0.60 mmol, 1.0 Eq.) and TFA (57 µL, 1.20 mmol, 2.0 Eq.) to obtain 1-(2,7-diazaspiro[3.5]nonane-2-yl)-2-hydroxy-acetone 2,2,2-trifluoroacetate (650 mg, quantitative yield) as a pale yellow oil.

[0604] LCMS (ESI + ): 168.8 [M+H] + .

[0605] Intermediate 10

[0606] N-(7-azaspiro[3.5]nonane-3-yl)carbamate tert-butyl

[0607]

[0608] Available for commercial purchase: CAS# 1354950-49-4

[0609] Intermediate 11

[0610] 2,7-Diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester

[0611]

[0612] Available for commercial purchase: CAS# 236406-49-8

[0613] Intermediate 12

[0614] 1-(4,7-diazaspiro[2.5]octane-4-yl)acetone 2,2,2-trifluoroacetate

[0615] Step 1: 4-Acetyl-4,7-diazaspiro[2,5]octane-7-carboxylic acid tert-butyl ester

[0616]

[0617] 4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester (300 mg, 1.41 mmol, 1.0 Eq.) was dissolved in DCM (2 mL). Triethylamine (207 µL, 2.83 mmol, 2.0 Eq.) and acetyl chloride (201 µL, 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 4-acetyl-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester (366 mg, quantitative yield) as a colorless oil.

[0618] LCMS (ESI + ): 199.2 [M-tBu+H] + .

[0619] Step 2: 1-(2,7-diazaspiro[3.5]nonane-2-yl)-2-hydroxy-acetone 2,2,2-trifluoroacetate

[0620]

[0621] Similar to intermediate 1, step 2 was prepared using tert-butyl 4-acetyl-4,7-diazaspiro[2.5]octane-7-carboxylate (316 mg, 1.24 mmol, 1.0 Eq.) and TFA (118 µL, 2.48 mmol, 2.0 Eq.) to obtain 1-(2,7-diazaspiro[3.5]nonane-2-yl)-2-hydroxy-acetone 2,2,2-trifluoroacetate (350 mg, quantitative yield) as a light brown oil.

[0622] LCMS (ESI + ): 155.2 [M+H] + .

[0623] Intermediate 13

[0624] 2,7-Diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester

[0625]

[0626] Available for commercial purchase: CAS# 236406-49-8

[0627] Intermediate 14

[0628] 1-(1,9-diazaspiro[4.5]decane-1-yl)-2,2,2-trifluoro-ethyl ketone 2,2,2-trifluoroacetate

[0629] Step 1: 1-(2,2,2-trifluoroacetyl)-1,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester

[0630]

[0631] Triethylamine (0.35 mL, 2.5 mmol, 3.0 Eq.) was added to a solution of 1,9-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), and the mixture was stirred at RT for 12 h. The mixture was concentrated and the crude product was purified by column chromatography (SiO2, PE / EtOAc 8:1, UV detection) to give 1-(2,2,2-trifluoroacetyl)-1,9-diazaspiro[4.5]decane-9-carboxylate tert-butyl ester (260 mg, 0.77 mmol, 90% yield) as a yellow oil.

[0632] LCMS (ESI + ): 281.1 [M-tBu+H] + .

[0633] Step 2: 1-(1,9-diazaspiro[4.5]decane-1-yl)-2,2,2-trifluoro-ethyl ketone, 2,2,2-trifluoroacetic acid Salt

[0634]

[0635] Similar to intermediate 1, step 2 was prepared using tert-butyl 1-(2,2,2-trifluoroacetyl)-1,9-diazaspiro[4.5]decane-9-carboxylate (260 mg, 0.77 mmol, 1.0 Eq.) and TFA (366 µL, 7.70 mmol, 10 Eq.) to obtain 1-(1,9-diazaspiro[4.5]decane-1-yl)-2,2,2-trifluoro-ethyl ketone 2,2,2-trifluoroacetate (185 mg, quantitative yield) as a yellow oil.

[0636] LCMS (ESI + ): 237.1 [M+H] + .

[0637] Intermediate 15

[0638] 2,5-Dioxa-8-azaspiro[3,5]nonane hemioxalate

[0639]

[0640] Available for commercial purchase: CAS# 1184185-17-8

[0641] Intermediate 16

[0642] 5-Oxa-2,8-diazaspiro[3,5]nonane-2-carboxylic acid tert-butyl ester

[0643]

[0644] Available for commercial purchase: CAS# 1251011-05-8

[0645] Intermediate 18

[0646] Racemic-N-[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]-5-oxa-2-azaspiro[3.4]octane-7-amine 2,2,2-trifluoroacetate

[0647] Step 1: Racemic-7-[[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino]-5- tert-butyl oxa-2-azaspiro[3,4]octane-2-carboxylate

[0648]

[0649] Similar to intermediate 8, step 1 was prepared using (3-exo)-8-methyl-8-azabicyclo[3.2.1]octane-3-amine (150 mg, 1.07 mmol, 1.0 Eq.) and 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (513 mg, 2.14 mmol, 2.0 Eq.) to obtain racemic-7-[[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino]-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (260 mg, 0.74 mmol, 69% yield) as a colorless oil.

[0650] LCMS (ESI + ): 352.2 [M+H] + .

[0651] Step 2: Racemic -N-[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]-5-oxa- 2-azaspiro[3.4]octane-7-amine 2,2,2-trifluoroacetate

[0652]

[0653] Similar to intermediate 1, step 2 was prepared using 7-[[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino]-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (260 mg, 0.74 mmol, 1.0 Eq.) and TFA (140 µL, 2.96 mmol, 4 Eq.) to obtain racemic-N-[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]-5-oxa-2-azaspiro[3.4]octane-7-amine 2,2,2-trifluoroacetate (192 mg, quantitative yield) as a yellow oil.

[0654] LCMS (ESI + ): 252.2 [M+H] + .

[0655] Intermediate 19

[0656] Racemic-N-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]-5-oxa-2-azaspiro[3.4]octane-7-amine 2,2,2-trifluoroacetate

[0657] Step 1: Racemic-7-[[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino]-5- tert-butyl oxa-2-azaspiro[3,4]octane-2-carboxylate

[0658]

[0659] Similar to intermediate 8, step 1 was prepared using (3-endo)-8-methyl-8-azabicyclo[3.2.1]octane-3-amine (70 mg, 0.50 mmol, 1.0 Eq.) and 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (227 mg, 1.00 mmol, 2.0 Eq.) to obtain racemic-7-[[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino]-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (125 mg, 0.36 mmol, 71% yield) as a colorless oil.

[0660] LCMS (ESI + ): 352.1 [M+H] + .

[0661] Step 2: Racemic -N-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]-5-oxa- 2-azaspiro[3.4]octane-7-amine 2,2,2-trifluoroacetate

[0662]

[0663] Similar to intermediate 1, step 2 was prepared using racemic-7-[[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]amino]-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (125 mg, 0.36 mmol, 1.0 Eq.) and TFA (68 µL, 1.44 mmol, 4 Eq.) to obtain racemic-N-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]-5-oxa-2-azaspiro[3.4]octane-7-amine 2,2,2-trifluoroacetate (95 mg, quantified) as a yellow oil.

[0664] LCMS (ESI + ): 252.3 [M+H] + .

[0665] Intermediate 20

[0666] 3-Methylspiro[7H-furano[3,4-b]pyridine-5,4'-piperidine]

[0667]

[0668] Intermediate 20 is prepared as described in WO 2015 / 091411A1.

[0669] Intermediate 21

[0670] 8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoroacetate

[0671] Step 1: 8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0672]

[0673] Similar to intermediate 8, step 1 was prepared using tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (200 mg, 0.88 mmol, 1.0 Eq.) and tetrahydrofuran-3-carboxaldehyde (175 mg, 1.75 mmol, 2.0 Eq.) to obtain tert-butyl 8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (410 mg, 1.31 mmol, 52% yield) as a yellow oil.

[0674] LCMS (ESI + ): 313.2 [M+H]+ .

[0675] Step 2: 8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoro Acetate

[0676]

[0677] Similar to intermediate 1, step 2 was prepared 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 µL, 19.65 mmol, 15 Eq.) to obtain 8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoroacetate (300 mg, quantitative yield) as a colorless oil.

[0678] LCMS (ESI + ): 231.3 [M+H] + .

[0679] Intermediate 22

[0680] 7-Oxa-2,5-diazaspiro[3,4]octane-6-one

[0681]

[0682] Available for commercial purchase: CAS# 1780174-72-2

[0683] Intermediate 23

[0684] 5-oxa-2-azaspiro[3.4]octane-7-one 2,2,2-trifluoroacetate

[0685]

[0686] Similar to intermediate 1, step 2 was prepared using tert-butyl 7-oxa-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (500 mg, 2.20 mmol, 1.0 Eq.) and TFA (680 µL, 8.80 mmol, 4 Eq.) to obtain 2,2,2-trifluoroacetate of 5-oxa-2-azaspiro[3.4]octane-7-one (295 mg, quantified) as a colorless oil.

[0687] LCMS (ESI + ): 128.1 [M+H] + .

[0688] Intermediate 24

[0689] 2,8-diazaspiro[3.5]nonane-8-carboxylic acid tert-butyl ester

[0690]

[0691] Available for commercial purchase: CAS# 885272-17-3

[0692] Intermediate 25

[0693] 1-(2,8-diazaspiro[3.5]nonane-2-yl)-2-hydroxy-acetone 2,2,2-trifluoroacetate

[0694] Step 1: 2-(2-hydroxyacetyl)-2,8-diazaspiro[3.5]nonane-8-carboxylic acid tert-butyl ester

[0695]

[0696] Similar to intermediate 3, step 1 was prepared using glycolic acid (145 mg, 1.9 mmol, 2.0 Eq.), N,N-diisopropylethylamine (0.66 mL, 3.81 mmol, 4.0 Eq.), 1-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 2,6-diazaspiro[3.5]nonane-6-carboxylic acid tert-butyl hydrochloride (250.0 mg, 0.95 mmol, 1.0 Eq.) to obtain 2-(2-hydroxyacetyl)-2,8-diazaspiro[3.5]nonane-8-carboxylic acid tert-butyl ester (155 mg, 0.55 mmol, 56% yield).

[0697] LCMS (ESI + ): 258.4 [M+H] + .

[0698] Step 2: 1-(2,8-diazaspiro[3.5]nonane-2-yl)-2-hydroxy-acetone 2,2,2-trifluoroacetate

[0699]

[0700] Similar to intermediate 1, step 2 was prepared 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 µL, 2.12 mmol, 4 Eq.) to obtain 1-(2,8-diazaspiro[3.5]nonane-2-yl)-2-hydroxy-acetone 2,2,2-trifluoroacetate (166 mg, quantitative yield) as a colorless oil.

[0701] LCMS (ESI + ): 185.2 [M+H] + .

[0702] Intermediate 26

[0703] 2,5-Dazaspiro[3.5]nonane 2,2,2-trifluoroacetate

[0704]

[0705] Similar to intermediate 1, step 2 was prepared using tert-butyl 2,5-diazaspiro[3.5]nonane-2-carboxylate (225 mg, 0.99 mmol, 1.0 Eq.) and TFA (306 µL, 3.96 mmol, 4 Eq.) to obtain 2,5-diazaspiro[3.5]nonane 2,2,2-trifluoroacetate as a colorless oil (130 mg, quantitative yield).

[0706] LCMS (ESI + ): 185.2 [M+H] + .

[0707] Intermediate 27

[0708] 7-Zazaspiro[3.5]nonane-1-ylcarbamate tert-butyl ester

[0709]

[0710] Available for commercial purchase: CAS# 1354950-49-4

[0711] Intermediate 28

[0712] 2,5-Dazaspiro[3,4]octane-5-carboxylic acid tert-butyl ester

[0713]

[0714] Available for commercial purchase: CAS# 1086398-04-0

[0715] Intermediate 29

[0716] 2,6-Dazaspiro[3,4]octane-6-carboxylic acid tert-butyl ester

[0717]

[0718] Available for commercial purchase: CAS# 885270-86-0

[0719] Intermediate 30

[0720] 1,7-Diazaspiro[3.5]nonane-1-carboxylic acid tert-butyl ester

[0721]

[0722] Available for commercial purchase: CAS# 1216936-29-6

[0723] Intermediate 31

[0724] 1,6-diazaspiro[3.3]heptane-1-carboxylic acid tert-butyl ester

[0725]

[0726] Available for commercial purchase: CAS# 1330763-95-5

[0727] Intermediate 32

[0728] Spiro[1H-isobenzofuran-3,4'-piperidine]

[0729]

[0730] Available for commercial purchase: CAS# 38309-60-3

[0731] Intermediate 33

[0732] 2,2,2-trifluoroacetate of 8-oxa-2,5-diazaspiro[3,5]nonane

[0733]

[0734] 8-oxa-2,5-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (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. The reaction mixture was then concentrated under vacuum to remove the solvent, and the concentrated residue was purified by silica gel chromatography, first eluting with PE, then with EtOAc to remove impurities and excess reagent, and finally with MeOH to elute the polar products. 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-trifluoroacetate as a colorless oil (580 mg, 4.53 mmol, 93% yield based on bis-TFA salt).

[0735] 1 H-NMR (δ, 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).

[0736] Intermediate 34

[0737] 8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoroacetate

[0738] Step 1: 8-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane- tert-butyl 2-formate

[0739]

[0740] 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. The mixture was then stirred at 20 °C for 11 h. LCMS showed the presence of the desired product mass. The mixture was diluted with aqueous NH4Cl solution and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated to obtain a residue, which was purified by column chromatography (SiO2, PE:EtOAc = 1:1, UV detection) to obtain tert-butyl 8-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (230.0 mg, 0.5 mmol, quantitative yield) as a colorless oil.

[0741] LCMS (ESI + ): 460.3 [M+H] + 404.3 [M-Isobutylene + H] + .

[0742] Step 2: 8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3,5]nonane-2-carboxylic acid tert-butyl ester

[0743]

[0744] 8-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (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. The mixture was then stirred at 20 °C for 12 h under H2 atmosphere. LCMS showed the expected single deprotected intermediate as the main peak. Formaldehyde (50 µL) was then added, and the mixture was stirred at 20 °C for another 12 h. LCMS showed the presence of a methylated product. The mixture was filtered and the filtrate was concentrated to give tert-butyl 8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (110 mg, 0.32 mmol, 74.5% yield) as a pale yellow oil.

[0745] LCMS (ESI + ): 340.3 [M+H] + .

[0746] Step 3: 8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane 2,2,2- Trifluoroacetate

[0747]

[0748] 8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (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 obtain a residue, which was filtered through SiO2 (PE, EtOAc, MeOH, UV detection) to obtain 8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane 2,2,2-trifluoroacetate (90.0 mg, 0.38 mmol, 118%) as a colorless oil, which was used without further purification.

[0749] LCMS (ESI + ): 240.3 [M+H] + .

[0750] 1.2) Instance preparation

[0751] 1.2.1) General purification methods

[0752] The compound prepared in the example was purified according to one of the following methods.

[0753] Method A: HPLC, TFA conditions

[0754] Mobile phase: A - Water / 0.1% TFA (v / v); B - ACN.

[0755] A1: Column: Phenomenex Luna C18 150 x 40mm x 15µm.

[0756] For example: gradient of B from 20% to 50%, gradient time 10 min.

[0757] A2: Column: Phenomenex Synergi C18 150 x 25mm x 10µm.

[0758] For example: gradient of B from 40% to 70%, gradient time 40 min.

[0759] A3: Column: Phenomenex Luna C18 75 x 30mm x 3µm.

[0760] For example: gradient of B from 34% to 54%, gradient time 7 min.

[0761] A4: Column: Phenomenex Synergi Polar-RP 100 x 25 mm x 4µm.

[0762] For example: gradient of B from 30% to 60%, gradient time 7 min.

[0763] Method B: HPLC, neutral conditions

[0764] Mobile phase: A - water containing 10 mM NH4HCO3; B - ACN.

[0765] B1: Column: Waters Xbridge C18 150 x 50mm x 10µm.

[0766] For example: gradient of B from 26% to 56%, gradient time 10 min.

[0767] B2: Column: Waters Xbridge 150 x 25mm x 5um.

[0768] For example: gradient of B from 10% to 40%, gradient time 1 min.

[0769] B3: Column: Phenomenex Gemini-NX C18 75 x 30mm x 3µm.

[0770] For example: the gradient of B is 12% to 42%, with a gradient time of 8 min.

[0771] Method C: HPLC, formic acid (FA) conditions

[0772] Mobile phase: A - Water / 0.1% FA (v / v); B - ACN.

[0773] C1: Column: Phenomenex Synergi C18 150 x 25mm x 10µm.

[0774] For example: gradient of B from 20% to 53%, gradient time 11 min.

[0775] C2: Column: Unisil 3-100 C18 Ultra 150 x 50mm x 3µm.

[0776] For example: gradient of B from 35% to 65%, gradient time 7 min.

[0777] C3: Column: Phenomenex luna C18 150 x 40mm x 15µm.

[0778] For example: gradient of B from 10% to 40%, gradient time 10 min.

[0779] C4: Column: YMC Triart C18 150 x 25mm x 5µm.

[0780] For example: gradient of B is 51%–51%, gradient time is 10 min.

[0781] C5: Column: Phenomenex C18 75 x 30mm x 3µm.

[0782] For example: gradient of B from 18% to 48%, gradient time 7 min.

[0783] C6: Column: Phenomenex luna C18 150 x 25mm x 10µm.

[0784] For example: gradient of B from 14% to 44%, gradient time 10 min.

[0785] Method D: SFC, Neutral Condition

[0786] Column: Chiral 2-EPI, 12 nm, 5 µm, 250 x 20 mm. Mobile phase: SFC / 25% MeOH, 140 bar. Run time: 6 min (e.g., 6 min).

[0787] Method E: HPLC, TEA conditions

[0788] Column: Gemini NX, 12 nm, 5 µm, 100 x 30 mm. Mobile phase: A - water / 0.1% TEA (v / v); B - ACN.

[0789] For example: isothermal conditions, where A 27%, B 73%, and running time 4.5 min.

[0790] Method F: Silica gel chromatography

[0791] For example, a reaction at a scale of approximately 0.1 mmol is purified on a 12 g SiliaSep HP column (or an alternative silica gel column) by isocratic elution with a suitable solvent mixture or by gradient elution with a suitable eluent, for a duration of approximately 20 minutes. Fractions containing the purified product are combined and evaporated under vacuum to provide the title compound.

[0792] F1: Gradient of MeOH (0% to 10% MeOH) in DCM

[0793] F2: Elute with EtOAc:heptanine 3:1 isocratic

[0794] F3: Elution with DCM:MeOH at a ratio of 19:1

[0795] F4: Elute with DCM:MeOH 9:1 isocratic ratio

[0796] F5: Elute with petroleum ether:EtOAc 1:1 isocratic.

[0797] F6: Gradient of EtOAc (20% to 80% EtOAc) in petroleum ether

[0798] Method G: HPLC, NH4OH conditions

[0799] Column: Waters Xbridge 150 x 25mm x 5 µm. Mobile phase: A - Water (0.1% NH4OH); B - ACN.

[0800] For example: gradient B from 18% to 48%; gradient time 9 min.

[0801] 1.2.1) Synthesis Procedure

[0802] Example 1

[0803] 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0804]

[0805] N-bromosuccinimide (393 mg, 2.21 mmol, 1.2 eq) was added 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) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then, 2-(2,7-diazaspiro[3.5]nonane-2-yl)ethanol trifluoroacetate (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 solution with 549.1 [M+H]. + The product was concentrated to obtain a residue, which was purified by preparative HPLC (Method A1) to obtain two portions of the product (220 mg, 84% purity and 70 mg, 45% purity, respectively). The combined material was further purified by preparative HPLC (Method G) and then lyophilized to give the title compound 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-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.

[0806] MS (ESI + ): 549.0 [M+H] + .

[0807] The following examples were produced by using the appropriate starting materials and purification conditions summarized in the table below, in a similar coupling step as described above for Example 1:

[0808]

[0809] Some examples require the synthesis of suitable 5,5-disubstituted barbiturate intermediates. The following intermediates were prepared using appropriate starting materials and purification conditions summarized in the table below, in a coupling step similar to that described above for Example 1:

[0810]

[0811] The following examples were synthesized from the 5,5-disubstituted barbiturate intermediate Ax summarized in the table above through subsequent transformations.

[0812] Example 41

[0813] 5-[4-(4-piperidinylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carbamate

[0814]

[0815] 4-[[9-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]sulfonyl]piperidin-1-carboxylic acid benzyl ester (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 was diluted with saturated NaHCO3 (20 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with H2O (40 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (method C3) to give 5-[4-(4-piperidinylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carbamate as a yellow solid (110 mg, 0.15 mmol, 26% yield).

[0816] LCMS (ESI + ): 682.3 [M+H] + .

[0817] Example 42

[0818] 5-[4-[2-(4-piperidinyl)acetyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0819]

[0820] 4-[2-oxo-2-[9-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]ethyl]piperidin-1-carboxylic acid benzyl ester (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 and concentrated to give 5-[4-[2-(4-piperidinyl)acetyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (170 mg, 0.26 mmol, 50% yield) as a white solid.

[0821] LCMS (ESI + ): 660.2 [M+H] + .

[0822] Example 43

[0823] 5-[8-(azacyclobutane-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate

[0824]

[0825] Step 1: 3-[[2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 5-yl]-5-oxa-2,8-diazaspiro[3,5]nonane-8-yl]methyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0826]

[0827] 5-(5-oxa-2,8-diazaspiro[3.5]nonane-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-formylazacyclobutane-1-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. A concentration of (676.1, [M+H]) was detected. +The main peak was α. 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]nonane-8-yl]methyl]azacyclobutane-1-carboxylate (215 mg, 0.32 mmol, 80% yield) as a white gel, which was used without further purification.

[0828] LCMS (ESI + ): 676.1 [M+H] + .

[0829] Step 2: 5-[8-(azacyclobutane-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]- 5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trionecarbamate

[0830]

[0831] Similar to intermediate 1, step 2 was prepared 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]nonane-8-yl]methyl]azacyclobutane-1-carboxylate (400 mg, 0.6 mmol, 1.0 Eq.) and TFA (2 mL) in DCM (8 mL).

[0832] The crude product was purified by preparative HPLC (method C2) to obtain 5-[8-(azacyclobutane-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carbamate (44 mg, 0.08 mmol, 12% yield).

[0833] LCMS (ESI + ): 576.2 [M+H] + .

[0834] Example 44

[0835] 5-[8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3,5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate

[0836]

[0837] Step 1: 4-[[2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 5-yl]-5-oxa-2,8-diazaspiro[3,5]nonane-8-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester

[0838]

[0839] Similar to Example 43, step 2 uses 5-(5-oxa-2,8-diazaspiro[3.5]nonane-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-formylpiperidin-1-carboxylate (84 mg, 0.40 mmol, 2.0 Eq.), and sodium cyanoborohydride (37 mg, 0.60 mmol, 3.0 Eq.). Preparation was carried out to obtain tert-butyl 4-[[2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-5-oxa-2,8-diazaspiro[3,5]nonane-8-yl]methyl]piperidine-1-carboxylate as a yellow oil (130 mg, 0.18 mmol, 88% yield).

[0840] LCMS (ESI + ): 704.0 [M+H] + .

[0841] Step 2: 5-[8-(4-piperidinylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4- [4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trionecarbamate

[0842]

[0843] Similar to intermediate 1, step 2 was prepared 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]nonane-8-yl]methyl]piperidine-1-carboxylate (130 mg, 0.18 mmol, 1.0 Eq.) and TFA (56 µL, 0.72 mmol, 4 Eq.).

[0844] The crude product was purified by preparative HPLC (method C3) and lyophilized to give 5-[8-(4-piperidinylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carbamate as a white solid (85 mg, 0.14 mmol, 76% yield).

[0845] LCMS (ESI + ): 604.3 [M+H] + .

[0846] Step 3: 5-[8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2- [4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carbamate]

[0847]

[0848] Similar to Example 43, step 2, is prepared using 5-[8-(4-piperidinylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-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 C1) to give 5-[8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carbamate as a white solid (20 mg, 0.03 mmol, 38% yield).

[0849] LCMS (ESI + ): 618.3 [M+H] + .

[0850] Example 46

[0851] 5-(3-amino-7-azaspiro[3.5]nonane-7-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione hydrochloride

[0852]

[0853] N-[7-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-7-azaspiro[3.5]nonane-3-yl]tert-butyl carbamate (intermediate A10) (15 mg, 0.024 mmol, 1.0 Eq.) was dissolved in DCM (100 µL) and hydrochloric acid (4M in dioxane) (30 µL, 0.121 mmol, 5.0 Eq.) was added at RT. The mixture was stirred for 2 hours. The reaction mixture was concentrated to dryness to give 5-(3-amino-7-azaspiro[3.5]nonane-7-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione hydrochloride (13 mg, 0.021 mmol, 88% yield) as a white solid.

[0854] LCMS (ESI + ): 519.4 [M+H] + .

[0855] Example 47

[0856] 5-[7-(2-hydroxyethyl)-2,7-diazaspiro[4,4]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0857]

[0858] Step 1: 5-(2,7-diazaspiro[4,4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]benzene [Hydroxypyrimidine-2,4,6-trione 2,2,2-trifluoroacetate]

[0859]

[0860] Similar to intermediate 1, step 2 was prepared 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 A11), 380 mg, 0.63 mmol, 1.0 Eq.) and TFA (196 µL, 2.52 mmol, 4 Eq.) to obtain 5-(2,7-diazaspiro[4.4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-2,4,6-trione 2,2,2-trifluoroacetate salt (365 mg, quantitative yield) as a light brown oil.

[0861] LCMS (ESI + ): 505.3 [M+H] +.

[0862] Step 2: 5-[7-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2,7-diazaspiro[4.4]nonyl [alkyl-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0863]

[0864] Similar to Example 43, step 2, using 5-(2,7-diazaspiro[4.4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate (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.). Preparation was carried out to obtain 5-[7-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2,7-diazaspiro[4,4]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (400 mg, 0.60 mmol, 88% yield) as a colorless oil.

[0865] LCMS (ESI + ): 663.4 [M+H] + .

[0866] Step 3: 5-[7-(2-hydroxyethyl)-2,7-diazaspiro[4,4]nonane-2-yl]-5-[4-[4-(trifluoromethyl) [Oxyphenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0867]

[0868] Similar to intermediate 1, step 2 was prepared using 5-[7-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2,7-diazaspiro[4,4]nonane-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 B1) and lyophilized to give 5-[7-(2-hydroxyethyl)-2,7-diazaspiro[4,4]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (126 mg, 0.23 mmol, 39% yield) as a white solid.

[0869] LCMS (ESI + ): 549.4 [M+H] + .

[0870] Example 48

[0871] 5-(7-methyl-2,7-diazaspiro[4,4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate

[0872]

[0873] Step 1: 5-(2,7-diazaspiro[4,4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]benzene [Hydroxypyrimidine-2,4,6-trione 2,2,2-trifluoroacetate]

[0874]

[0875] Similar to intermediate 1, step 2 was prepared using 2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-2,7-diazaspiro[4.4]nonane-7-carboxylate tert-butyl ester TFA salt (intermediate A11, 380 mg, 0.63 mmol, 1.0 Eq.) and TFA (196 µL, 2.52 mmol, 4 Eq.) to obtain 5-(2,7-diazaspiro[4.4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-2,4,6-trione 2,2,2-trifluoroacetate salt (365.0 mg, quantified) as a light brown oil.

[0876] LCMS (ESI + ): 505.3 [M+H] + .

[0877] Step 2: 5-(7-methyl-2,7-diazaspiro[4.4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy [Hydroxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate

[0878]

[0879] Similar to Example 43, step 2, 5-(2,7-diazaspiro[4.4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate (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.) were used to prepare 5-(7-methyl-2,7-diazaspiro[4.4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate (39.9 Eq.) as a white solid after purification by preparative HPLC (Method A4). mg, 0.063 mmol, 30.4% yield).

[0880] LCMS (ESI + ): 518.9 [M+H] + .

[0881] Example 49

[0882] 5-(1-Methyl-1,9-diazaspiro[4,5]decane-9-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0883]

[0884] Step 1: 5-(1,9-diazaspiro[4,5]decane-9-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]benzene [Hexanediol-2,4,6-trione]

[0885]

[0886] The mixture of 5-[1-(2,2,2-trifluoroacetyl)-1,9-diazaspiro[4.5]decane-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. The mixture was then concentrated and the resulting crude material was dissolved in EtOAc (20 mL), washed with H2O (10 mL), dried over Na2SO4, filtered and concentrated to give 5-(1,9-diazaspiro[4.5]decane-9-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (110 mg, 0.21 mmol, 90% yield) as a yellow solid.

[0887] LCMS (ESI+): 519.2 [M+H] + .

[0888] Step 2: 5-(1-methyl-1,9-diazaspiro[4.5]decane-9-yl)-5-[4-[4-(trifluoromethoxy)phenoxy [Hydroxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0889]

[0890] Similar to Example 43, step 2, was prepared using 5-(1,9-diazaspiro[4.5]decane-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 5-(1-methyl-1,9-diazaspiro[4.5]decane-9-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (5.0 mg, 0.01 mmol, 5% yield).

[0891] LCMS (ESI + ): 533.1 [M+H] + .

[0892] Example 50

[0893] 5-(5-oxa-2,8-diazaspiro[3.5]nonane-8-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione di-p-toluenesulfonate

[0894]

[0895] 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 A16) was dissolved in EtOAc (250 µL), 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 washed with Et2O to give 5-(5-oxa-2,8-diazaspiro[3.5]nonane-8-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione bis(p-toluenesulfonate) as a white solid (20 mg, 0.023 mmol, 43% yield).

[0896] LCMS (ESI + ): 507.5 [M+H] + .

[0897] Example 51

[0898] 5-[1-(2-hydroxyethyl)-1,9-diazaspiro[4.5]decane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0899]

[0900] Step 1: 5-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1,9-diazaspiro[4,5]decane [alkyl-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0901]

[0902] Similar to Example 43, step 1, 5-(1,9-diazaspiro[4.5]decane-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.) were used. Preparation was carried out to obtain 5-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1,9-diazaspiro[4.5]decane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (75 mg, 0.11 mmol, 74% yield) as a yellow oil.

[0903] LCMS (ESI + ): 677.5 [M+H] + .

[0904] Step 2: 5-[1-(2-hydroxyethyl)-1,9-diazaspiro[4.5]decane-9-yl]-5-[4-[4-(trifluoromethyl) [Oxyphenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0905]

[0906] 5-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1,9-diazaspiro[4.5]decane-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. 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-[1-(2-hydroxyethyl)-1,9-diazaspiro[4.5]decane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (13 mg, 0.02 mmol, 21% yield) as a white solid.

[0907] LCMS (ESI + ): 563.2 [M+H] + .

[0908] Examples 52 and 53

[0909] 5-[8-[[(3R)-tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3,5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0910] and

[0911] 5-[8-[[(3S)-tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3,5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0912]

[0913] 5-(5-oxa-2,8-diazaspiro[3.5]nonane-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-carboxaldehyde (8 mg, 7.5 µL, 0.04 mmol, 1.3 Eq.) were dissolved in methanol (150 µL) and stirred for 30 min. Sodium cyanoborohydride (3 mg, 0.04 mmol, 1.5 Eq.) was added in a single batch and the mixture was stirred at RT for 1 h. 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 substance was purified by rapid chromatography (method F4) to give racemic 5-[8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-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.

[0914] LCMS (ESI + ): 591.4 [M+H] + .

[0915] A racemic mixture of 5-[8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-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 (250 mm x 20 mm x 5 µm) in scCO2 with 25% MeOH to obtain:

[0916] ● 5-[8-[[(3S or 3R)-tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3,5]nonane-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) + ): 591.3 [M+H] + ,and

[0917] ● 5-[8-[[(3R or 3S)-tetrahydrofuran-3-yl]methyl]-5-oxa-2,8-diazaspiro[3,5]nonane-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) + ): 591.4 [M+H] + .

[0918] The absolute configuration of the structure assigned to each peak is not determined.

[0919] Example 54

[0920] 5-[7-[(1-methyl-4-piperidinyl)amino]-5-oxa-2-azaspiro[3,4]octane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0921]

[0922] Similar to Example 43, step 1 was prepared using 5-(7-oxo-5-oxa-2-azaspiro[3.4]octane-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-1-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-[(1-methyl-4-piperidinyl)amino]-5-oxa-2-azaspiro[3,4]octane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (3 mg, 0.005 mmol, 12% yield) as a white solid.

[0923] LCMS (ESI + ): 604.2 [M+H] + .

[0924] Example 55

[0925] 5-[8-(1,4-dioxane-2-ylmethyl)-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0926]

[0927] Step 1: 5-(2,8-diazaspiro[3.5]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]benzene [Hexanediol-2,4,6-trione]

[0928]

[0929] 2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-2,8-diazaspiro[3.5]nonane-8-carboxylic acid tert-butyl ester (intermediate A24, 250 mg, 0.41 mmol, 1.0 eq) was dissolved in DCM (15 mL). TFA (3 mL) was added and the mixture was stirred at 25 °C for 2 h. LCMS showed the presence of the desired product mass. The mixture was concentrated under vacuum to obtain a crude substance, which was purified by filtration via silica gel (1: elution with EtOAc to remove excess TFA and impurities, then 2: elution with MeOH) to give 5-(2,8-diazaspiro[3.5]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (230 mg, 0.46 mmol, 107% yield based on parent MW) as a yellow oil. This material can be used as a TFA salt without further purification.

[0930] LCMS (ESI + ): 505.2 [M+H] + .

[0931] Step 2: 5-8-(1,4-dioxane-2-ylmethyl)-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4- [(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0932]

[0933] Similar to Example 43, step 1 was prepared using 5-(2,8-diazaspiro[3.5]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (40 mg, 0.08 mmol, 1.0 eq.), 1,4-dioxane-2-carboxaldehyde (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-(1,4-dioxane-2-ylmethyl)-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (2 mg, 0.004 mmol, 5% yield) as a white solid.

[0934] LCMS (ESI + ): 605.3 [M+H] + .

[0935] Example 56

[0936] 5-[5-(1,4-dioxane-2-ylmethyl)-2,5-diazaspiro[3,5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0937]

[0938] Similar to Example 43, step 1 was prepared using 5-(2,5-diazaspiro[3.5]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (intermediate A26) (20 mg, 0.04 mmol, 1.0 Eq.), 1,4-dioxane-2-carboxaldehyde (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 obtain 5-[5-(1,4-dioxane-2-ylmethyl)-2,5-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (2 mg, 0.003 mmol, 8% yield) as a colorless oil.

[0939] LCMS (ESI + ): 605.3 [M+H] + .

[0940] Example 57

[0941] 5-[8-(2-hydroxyacetyl)-5-oxa-2,8-diazaspiro[3,5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione hydrochloride

[0942]

[0943] Step 1: [2-oxo-2-[2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexadecyl [Hydropyrimidin-5-yl]-5-oxa-2,8-diazaspiro[3,5]nonane-8-yl]ethyl]acetate

[0944]

[0945] 5-(5-oxa-2,8-diazaspiro[3.5]nonane-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 µL) with acetoxyacetyl chloride (5 mg, 4 µL, 0.037 mmol, 1.05 Eq.) and DIPEA (23 mg, 31 µL, 0.176 mmol, 5.0 Eq.) under 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 rapid 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]nonane-8-yl]ethyl]acetate as a white solid (8 mg, 0.013 mmol, 32% yield).

[0946] LCMS (ESI + ): 607.5 [M+H] + .

[0947] Step 2: 5-[8-(2-hydroxyacetyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4- [4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione hydrochloride

[0948]

[0949] [2-oxo-2-[2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-5-oxa-2,8-diazaspiro[3,5]nonane-8-yl]ethyl]acetate (8 mg, 0.013 mmol, 1.0 Eq.) was dissolved in methanol (0.100 mL) under RT and 2 M NaOH (18 µL, 0.040 mmol, 3.0 Eq.) was added. The mixture was stirred for 1 hour. The reaction mixture was acidified with 1N HCl (100 µL) and the precipitate was filtered and dried under vacuum to give 5-[8-(2-hydroxyacetyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione hydrochloride (6 mg, 0.009 mmol, 69% yield) as a white solid.

[0950] LCMS (ESI + ): 565.4 [M+H] + .

[0951] Example 58

[0952] 5-[5-(2-hydroxyacetyl)-2,5-diazaspiro[3,4]octane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0953]

[0954] Step 1: 5-(2,5-diazaspiro[3,4]octane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]benzene [Hydroxypyrimidine-2,4,6-trione 2,2,2-trifluoroacetate]

[0955]

[0956] Similar to intermediate 1, step 2 was prepared using 2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-2,5-diazaspiro[3,4]octane-5-carboxylic acid tert-butyl ester (intermediate A28) (80 mg, 0.136 mmol, 1.0 Eq.) and TFA (42 µL, 0.544 mmol, 4 Eq.) to obtain 5-(2,5-diazaspiro[3,4]octane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-2,4,6-trione 2,2,2-trifluoroacetate (70 mg, quantitative yield) as a pale yellow oil, which was used without further purification.

[0957] LCMS (ESI + ): 491.1 [M+H] + .

[0958] Step 2: 5-[5-(2-hydroxyacetyl)-2,5-diazaspiro[3,4]octane-2-yl]-5-[4-[4-(trifluoro [Methoxy]phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0959]

[0960] Add 5-(2,5-diazaspiro[3,4]octane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate (59 mg, 0.10 mmol, 1.0 Eq.) and DIPEA (70 µL, 0.41 mmol, 4.0 Eq.) to a solution of glycolic acid (16 mg, 0.20 mmol, 2.0 Eq.), 1-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). 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]octane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (1.0 mg, 0.003 mmol, 2% yield) as a white solid.

[0961] LCMS (ESI + ): 549.3 [M+H] + .

[0962] Example 59

[0963] 5-[5-[(4-methylmorpholin-2-yl)methyl]-8-oxa-2,5-diazaspiro[3,5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione

[0964]

[0965] Step 1: 2-[[2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine- 5-yl]-8-oxa-2,5-diazaspiro[3,5]nonane-5-yl]methyl]morpholine-4-carboxylic acid tert-butyl ester

[0966]

[0967] Similar to Example 43, step 1 was prepared using 5-(8-oxa-2,5-diazaspiro[3.5]nonane-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 C1) to obtain tert-butyl 2-[[2-[2,4,6-trioxo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-8-oxa-2,5-diazaspiro[3,5]nonane-5-yl]methyl]morpholine-4-carboxylate as a white solid (25 mg, 0.04 mmol, 30% yield).

[0968] LCMS (ESI + ): 620.2 [M+H] + .

[0969] Step 2: 5-[5-(morpholin-2-ylmethyl)-8-oxa-2,5-diazaspiro[3.5]nonane-2-yl]-5-[4- [4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate

[0970]

[0971] Similar to intermediate 1, step 2 was prepared 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]nonane-5-yl]methyl]morpholine-4-carboxylate (25 mg, 0.04 mmol, 1.0 eq.) and TFA (1 mL) to obtain 5-[5-(morpholino-2-ylmethyl)-8-oxa-2,5-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-2,4,6-trione 2,2,2-trifluoroacetate (30 mg, quantitative yield) as a pale yellow oil, which was used without further purification.

[0972] LCMS (ESI + ): 606.2 [M+H] + .

[0973] Step 3: 5-[5-[(4-methylmorpholin-2-yl)methyl]-8-oxa-2,5-diazaspiro[3,5]nonane-2- [4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione]

[0974]

[0975] Similar to Example 43, step 1, is prepared using 5-[5-(morpholin-2-ylmethyl)-8-oxa-2,5-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate (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]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione (13 mg, 0.02 mmol, 49% yield) as a white solid. 1 H-NMR showed that the material contained a small amount of residual formic acid.

[0976] LCMS (ESI + ): 620.2 [M+H] + .

[0977] 2) Biological Examples

[0978] 2.1) MMP protein used in activity assays

[0979] Full-length human MMP9 (19-707) was cloned into pExpreS2.1, carrying a C-terminal Avi-10-His-EPEA tag and a TEV cleavage site. The endogenous signaling sequence was replaced with a Drosophila immunoglobulin heavy chain-binding protein (BiP) sequence to obtain the final construct BiP-hMMP9 (19-707)WT_C-TEV-Avi-10His-EPEA. Stable polyclonal S2 cell lines were generated using the manufacturer's instructions (Expres2ion Biotechnologies). After culturing, the cell culture medium containing the recombinant protein was concentrated and treated with AKTA Crossflow (30K MWCO, 3 x 100cm). 2The buffer was replaced with buffer A (50 mM HEPES pH 7.8, 0.5 M NaCl, 10% glycerol, 0.35% CHAPS, 0.02% NaN3). The His-labeled protein was purified via a HisTRAP column (Cytiva) and eluted with buffer A supplemented with 0.5 M imidazole. The elution fraction was concentrated and further purified by size exclusion chromatography (Superdex200 IncreaseGL10 / 300) in 50 mM TRIS / Cl pH 8, 0.5 M NaCl, 5 mM CaCl2, 0.1 mM Zn acetate, 0.35% CHAPS, 0.02% NaN3. To activate the enzyme, MMP9 was incubated with trypsin (Thermo) at a 100:1 w / w ratio at room temperature for approximately 17 hours. The reaction was terminated with TLCK at a final concentration of 0.5 mM. To remove trypsin and TLCK, activated MMP9 was further purified in a second size exclusion chromatography step using Superdex 200 IncreaseGL10 / 300 in 50 mM TRIS / Cl pH 8, 0.5 M NaCl, 5 mM CaCl2, 0.1 mM Zn acetate, 0.35% CHAPS, and 0.02% NaN3.

[0980] hMMP10: This enzyme was purchased from Aviva Systems Biology (product number OPED00091).

[0981] hMMP14: This enzyme was purchased from Biovision (product number: 8009-50).

[0982] 2.2) MMP determination

[0983] The inhibitory potential of the compounds was determined by an activity assay based on fluorescence readouts from the fluorescence released after cleavage of the peptide substrate with an MMP enzyme. Due to the coplanar stacking of tryptophan and the MR121 fluorophore on each side of the peptide substrate, the fluorescence of MR121 was statically quenched. An increase in MR121 fluorescence was observed after substrate cleavage with an MMP enzyme.

[0984] The 6-amino acid peptide substrate Cys-Pro-Leu-Gly-Leu-Trp was synthesized by Biosyntan GmbH, Berlin, Germany, with a purity of 95% (to improve the yield of the synthesis, the carboxyl group of tryptophan was replaced with an amide group (CO-NH2)). The reactive form of the fluorophore, MR121-maleimide, is described in patent EP 0747447 A3. MR121-maleimide was covalently coupled to the thiol group of the cysteine ​​residue of the substrate peptide (Derek G. Smyth, Atsuo Nagamatsu, Joseph S. Fruton; Some Reactions of N-Ethylmaleimide; J. Am. Chem. Soc. (1960); 82 (17): 4600-4604) and purified by analytical HPLC on a C18 column (Marchery-Nagel, CCL25 / 4, Nucleosil 100-5, Protect 1) on a Merck Hitachi D-6000, Merck USA.

[0985] All measurements were performed in 384-well microtiter plates. MMP enzymes were pre-incubated for 15 min with various concentrations of inhibitors, followed by the addition of 1 µM of MR121-cPLGLW peptide substrate to the following assay buffers: 25 mM Hepes, 100 mM NaCl, 10 mM CaCl2, 0.1% Chaps, 1 mm TCEP, and 2% final DMSO. Kinetic measurements were conducted by excitation at 630 nm and fluorescence emission measured at 695 nm. Calculations of the slope within the linear range of kinetics provide robust values ​​for enzyme activity and the effect of small compounds on this activity.

[0986] The table below summarizes detailed information about the materials and methods.

[0987] plate

[0988]

[0989] reagents

[0990]

[0991] Determination methods

[0992]

[0993] 2.3) Results

[0994] The data in the table below show the inhibitory efficacy of the samples against human MMP9 and the observed selectivity factors for related MMP10 and MMP14.

[0995]

Claims

1. A compound of formula (I) (I) Or its pharmaceutically acceptable salt, wherein: L can be –O-, -NH-, –C≡C-, -CONH-, -NHCO-, or a covalent bond; Ar is a phenyl or a 6-membered heteroaryl group; R 1 Selected from C 6-14 -Aryl, 5- to 6-membered heteroaryl, C 3-8 -cycloalkyl and 3- to 11-membered heterocyclic groups, wherein R 1 Optionally by one or more R that may be the same or different 2 replace; Spiro group Sub-ring It is a 3- to 6-membered heterocyclic group, which may contain one or two identical or different heteroatoms selected from O, N, and S, and may be substituted by one or more identical or different R atoms. 3 Replace; and sub-ring for: a) A 3- to 11-membered heterocyclic group, which may contain one, two, three, or four identical or different heteroatoms selected from O, N, and S, and may be composed of one or more identical or different R atoms. 4 Replace; or b)C 3-6 -cycloalkyl group, which is optionally surrounded by one or more R groups that may be the same or different 5 replace; R 2 Selected from halogenated-C 1-6 -alkoxy group, C 3-6 -cycloalkyl, C 1-6 -alkyl, halo-C 1-6 -alkyl and halogen; R 3 R 4 and R 5 Each is independently selected from oxygen, C 1-6 -alkyl, C 2-8 -alkoxyalkyl, hydroxy-C 1-6 -alkyl, -COR 6 -S(O)2R 7 -NR 8 R 8' -CO2R 9 3 to 10 yuan C 0-6 -alkyl-heterocyclic group, C 3-6 -Cycloalkyl, 5- to 6-membered C 0-6 -alkyl-heteroaryl and C 0-6 -alkyl-C 6-14 -Aryl; wherein the 3 to 10 C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6 -alkyl or –CO2(C 1-6 -alkyl) substitution; C 2-8 -Alkoxyalkyl groups are optionally substituted with hydroxyl groups; and C 0-6 -alkyl-C 6-14 -The aryl group is optionally substituted by –B(OH)2; R 6 Selected from C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, amino-C 1-6 -alkyl, -C 0-6 -alkyl-N(R) 10 R 10' C 3-6 -cycloalkyl, 3- to 6-membered C 0-6 -alkyl-heterocyclic groups and -C 0-6 -alkyl-OC(O)(C 1-6 -alkyl); wherein the 3- to 6-membered C 0-6 -alkyl-heterocyclic groups are optionally replaced by –CO2(C 1-6 -alkyl) substitution, and hydroxy-C 1-6 -Alkyl group optionally surrounded by amino group, –NHCO2(C 1-6 -alkyl) or -C(O)(C 1-6 -alkyl) substitution; R 7 For optional use by C 1-6 -alkyl-substituted 3- to 6-membered C 0-6 -alkyl-heterocyclic group; R 8 and R 8' Each is independently selected from hydrogen, –CO2(C 1-6 -alkyl), optionally C 1-6 -alkyl-substituted 3 to 10 C 0-6 -alkyl-heterocyclic group; R 9 C 1-6 -alkyl; R 10 and R 10' Each is independently selected from hydrogen and C. 1-6 -alkyl, hydroxy-C 1-6 -alkyl and -CO2(C 1-6 -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, pyridyl 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 pyridyl.

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 C 6-14 -Aryl or 3- to 11-membered heterocyclic group, optionally surrounded by one or more R groups that may be identical or different. 2 replace.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 1 It is 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 R 2 Halogenated-C 1-6 -Alkyl or halogen.

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 It is trifluoromethoxy or chlorine.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein It is a spiro group, in which the daughter ring It is a 4- to 6-membered heterocyclic group, which may contain one or two identical or different heteroatoms selected from O and N, and may be substituted by one or more identical or different R atoms. 3 Replace; and sub-ring for a) A 4- to 9-membered heterocyclic group, which may contain one or two identical or different heteroatoms selected from O and N, and may be composed of one or more identical or different R atoms. 4 Replace; or b)C 3-6 -cycloalkyl group, which is optionally surrounded by one or more R groups that may be the same or different 5 replace.

10. The compound of formula (I) according to any one of claims 1 to 9, wherein... Selected from: , , , , , , , , , , , , , , , , and .

11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Selected from: , , , , and .

12. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 3 -C(O)(C 1-6 -alkyl).

13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from oxo, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, -COR 6 -S(O)2R 7 -NR 8 R 8' -CO2R 9 3 to 10 yuan C 0-6 -alkyl-heterocyclic groups and C 0-6 -alkyl-C 6-14 -Aryl, wherein the 3 to 10 C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6 -Alkyl substitution.

14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, -COR 6 -S(O)2R 7 -NR 8 R 8' And 3 to 10 yuan C 0-6 -alkyl-heterocyclic group, wherein the 3- to 10-membered C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6 -Alkyl substitution.

15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 4 It is selected from hydroxyethyl, -C(O)(CH2OH), (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino, 4-piperidinylsulfonyl, 4-piperidinylacetyl, azabicyclobutane-3-ylmethyl, (1-methyl-4-piperidinyl)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 R 5 For -NR 8 R 8' , where R 8 and R 8' Each is independently selected from hydrogen and –CO2(C 1-6 -alkyl).

17. The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 6 Hydroxyl-C 1-6 -alkyl or 3 to 6 C 0-6 -alkyl-heterocyclic group.

18. The compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 6 It is hydroxymethyl or -CH2-4-piperidinyl.

19. The compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 7 For being C 1-6 -alkyl-substituted 3- to 6-membered C 0-6 -alkyl-heterocyclic group.

20. The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R 7 It is 4-piperidinyl.

21. The compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 8' Selected from hydrogen and optionally C 1-6 -alkyl-substituted 3- to 10-membered C 0-6 -alkyl-heterocyclic group.

22. The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 8' It is selected from hydrogen, (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino and 1-methyl-4-piperidinyl.

23. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: L can be –O-, -NH-, –C≡C-, -CONH-, -NHCO-, or a covalent bond; Ar is phenyl, pyridyl, or pyrazinyl. R 1 C 6-14 -Aryl or 3- to 11-membered heterocyclic group, optionally surrounded by one or more R groups that may be identical or different. 2 replace; R 2 Halogenated-C 1-6 -alkoxy or halogen; R 3 Selected from -C(O)(C 1-6 -alkyl); Selected from: , , , , , , , , , , , , , , , , and , R 4 Selected from oxo, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, -COR 6 -S(O)2R 7 -NR 8 R 8' -CO2R 9 3 to 10 yuan C 0-6 -alkyl-heterocyclic groups and C 0-6 -alkyl-C 6-14 -Aryl, wherein the 3 to 10 C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6 -alkyl substitution; R 5 For -NR 8 R 8' , where R 8 and R 8' Each is independently selected from hydrogen and –CO2(C 1-6 -alkyl); R 6 Hydroxyl-C 1-6 -alkyl or 3 to 6 C 0-6 -alkyl-heterocyclic group; R 7 For being C 1-6 -alkyl-substituted 3- to 6-membered C 0-6 -alkyl-heterocyclic group; R 8 and R 8' Each is independently selected from hydrogen and optionally by C 1-6 -alkyl-substituted 3- to 10-membered C 0-6 -alkyl-heterocyclic group.

24. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: L represents –O-, -CONH-, or a covalent bond; Ar is either phenyl or pyridinyl; R 1 C 6-14 -Aryl or 3- to 11-membered heterocyclic group, optionally surrounded by one or more R groups that may be identical or different. 2 replace; R 2 Halogenated-C 1-6 -alkoxy or halogen; Selected from: 、 、 、 、 、 R 4 Selected from C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, -COR 6 -S(O)2R 7 -NR 8 R 8' And 3 to 10 yuan C 0-6 -alkyl-heterocyclic group, wherein the 3- to 10-membered C 0-6 -alkyl-heterocyclic group is optionally replaced by C 1-6 -alkyl substitution; R 6 Hydroxyl-C 1-6 -alkyl or 3 to 6 C 0-6 -alkyl-heterocyclic group; R 7 For being C 1-6 -alkyl-substituted 3- to 6-membered C 0-6 -alkyl-heterocyclic group; R 8 and R 8' Selected from hydrogen and optionally C 1-6 -alkyl-substituted 3- to 10-membered C 0-6 -alkyl-heterocyclic group.

25. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: L represents –O-, -CONH-, or a covalent bond; Ar is phenyl or pyridyl. R 1 It is phenyl or dihydrobenzofuranyl; R 2 It is trifluoromethoxy or chlorine; Selected from: 、 、 、 、 、 R 4 Selected from hydroxyethyl, -C(O)(CH2OH), (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino, 4-piperidinylsulfonyl, 4-piperidinylacetyl, azabicyclobutane-3-ylmethyl, (1-methyl-4-piperidinyl)amino, methyl and (1-methyl-4-piperidinyl)amino; R 6 It is hydroxymethyl or methyl-4-piperidinyl; R 7 It is 4-piperidinyl; R 8 and R 8' It is selected from hydrogen, (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl]amino and 1-methyl-4-piperidinyl.

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 from... 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[2-(2-phenylethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-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]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-(3-methylphenoxy)phenyl]hexahydropyrimidine-2,4,6-trione; 5-[4-(2,3-dihydrobenzofuran-5-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[4-(2,3-dihydrobenzofuran-6-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[4-(1,3-benzodioxane-5-yloxy)phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[4-(1,3-benzodioxacyclopenten-5-yloxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[4-[3-(difluoromethoxy)phenoxy]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[4-[3-(difluoromethoxy)phenoxy]phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-(4-phenoxyphenyl)-1,3-diazacyclohexane-2,4,6-trione; 5-(2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl)-5-(4-phenoxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione; 5-[2-(1,4-dioxane-2-carbonyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-(4-phenoxyphenyl)-1,3-diazacyclohexane-2,4,6-trione; 5-[4-(benzofuran-5-yloxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[4-(4-cyclopropylphenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[4-(4-chlorophenoxy)phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenyl]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[3-[4-(trifluoromethoxy)anilino]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[3-[4-(trifluoromethoxy)anilino]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenyl]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[1-(2-hydroxyethyl)-1,8-diazaspiro[4.5]decane-8-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-(1-Ethyl-1,9-diazaspiro[4.5]decane-9-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione, TFA salt; 5-(4-acetyl-4,7-diazaspiro[2.5]octane-7-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-(2,5-dioxa-8-azaspiro[3.5]nonane-8-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; Racemic-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; Racemic-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-furano[3,4-b]pyridin-5,4'-piperidin]-1'-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-(6-oxo-7-oxa-2,5-diazaspiro[3,4]octane-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]nonane-8-yl]hexahydropyrimidine-2,4,6-trione; N-[7-[2,4,6-triketone-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-7-azaspiro[3,5]nonane-3-yl]tert-butyl carbamate; 2-[2,4,6-triketone-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]-1,7-diazaspiro[3.5]nonane-1-carboxylic acid tert-butyl ester; 6-[2,4,6-triketo-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidin-5-yl]-1,6-diazaspiro[3.3]heptane-1-carboxylic acid tert-butyl ester; 5-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-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]nonane-7-yl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate; 5-[4-[2-(4-chlorophenyl)ethynyl]phenyl]-5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide; N-(4-chlorophenyl)-4-[5-[2-(2-hydroxyacetyl)-2,7-diazaspiro[3.5]nonane-7-yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide; N-(4-chlorophenyl)-4-[5-[8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide; 5-[4-(4-piperidinylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate; 5-[4-[2-(4-piperidinyl)acetyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[8-(azacyclobutane-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate; 5-[8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate; 5-(8-oxa-2,5-diazaspiro[3.5]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-(3-amino-7-azaspiro[3.5]nonane-7-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione hydrochloride; 5-[7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-(7-methyl-2,7-diazaspiro[4.4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate; 5-(1-Methyl-1,9-diazaspiro[4.5]decane-9-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-(5-oxa-2,8-diazaspiro[3.5]nonane-8-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione di-toluenesulfonate; 5-[1-(2-hydroxyethyl)-1,9-diazaspiro[4.5]decane-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]nonane-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]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[7-[(1-methyl-4-piperidinyl)amino]-5-oxa-2-azaspiro[3,4]octane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[8-(1,4-dioxane-2-ylmethyl)-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[5-(1,4-dioxane-2-ylmethyl)-2,5-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[8-(2-hydroxyacetyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione hydrochloride; 5-[5-(2-hydroxyacetyl)-2,5-diazaspiro[3,4]octane-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]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-(5-oxa-2,8-diazaspiro[3.5]nonane-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]nonane-7-yl]hexahydropyrimidine-2,4,6-trione 5-[4-[(6-ethyl-3-pyridyl)oxy]phenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[5-(4-ethylphenoxy)-2-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione, formate; 5-[6-(4-ethylphenoxy)pyridazin-3-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[6-(4-ethylphenoxy)-3-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[8-(tetrahydrofuran-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[[5-(trifluoromethoxy)-2-pyridinyl]oxy]phenyl]hexahydropyrimidine-2,4,6-trione, 2,2,2-trifluoroacetate; N-(6-chloro-3-pyridyl)-4-[5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide; 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-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]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[2-(4-ethylphenoxy)pyrimidin-5-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidin-2,4,6-trione; and 5-[4-(5-ethylpyrazin-2-yl)oxyphenyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-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]nonane-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]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; 5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]-5-[4-[4-(trifluoromethoxy)phenyl]phenyl]hexahydropyrimidine-2,4,6-trione; Racemic-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]nonane-7-yl]-2,4,6-trioxo-hexahydropyrimidin-5-yl]benzamide; 5-[4-(4-piperidinylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate; 5-[4-[2-(4-piperidinyl)acetyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[8-(azacyclobutane-3-ylmethyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate; 5-[8-[(1-methyl-4-piperidinyl)methyl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione carboxylate; 5-(8-oxa-2,5-diazaspiro[3.5]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-[7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]nonane-2-yl]-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione; 5-(7-methyl-2,7-diazaspiro[4.4]nonane-2-yl)-5-[4-[4-(trifluoromethoxy)phenoxy]phenyl]hexahydropyrimidine-2,4,6-trione 2,2,2-trifluoroacetate; 5-[5-(4-ethylphenoxy)-2-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione carboxylate; 5-[6-(4-ethylphenoxy)-3-pyridyl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidine-2,4,6-trione; and 5-[2-(4-ethylphenoxy)pyrimidin-5-yl]-5-[2-(2-hydroxyethyl)-2,7-diazaspiro[3.5]nonane-7-yl]hexahydropyrimidin-2,4,6-trione.

28. A method for preparing a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, the method comprising: Compound of formula (II) (II) With compound of formula (III) (III) Among them, L, Ar, R 1 and As defined in any one of claims 1 to 25, and X is a halogen. The reaction takes place in the presence of a base to form the compound of formula (I).

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

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, used 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. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, for therapeutic and / or preventive treatment of ocular surface diseases.

33. The compound used according to claim 32, wherein the ocular surface disease is dry eye disease.

34. Use of any compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof for the therapeutic and / or preventive treatment of ocular surface diseases.

35. A method for the therapeutic and / or preventive treatment of ocular surface diseases, the method comprising 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 present invention as described above.

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