Cycloalkyl- and piperidinyl-containing diaminomethylene pyrimidine-2,4,6-trione agonists of parathyroid hormone 1 and incretin receptors

Abstract

Disclosed are compounds that are parathyroid hormone receptor 1 agonists, and methods useful for preventing or treating osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis. Also disclosed are agonists of GLP-1R, GCGR, and / or GIPR, and methods of treating various therapeutic indications by administering an effective amount of an agonist of GLP-1R, GCGR, and / or GIPR.

Description

[0001] CYCLOALKYL AND PIPERIDINYL-CONTAINING DIAMINOMETHYLENE PYRIMIDINE-2, 4, 6-TRIONE AGONISTS OF PARATHYROID HORMONE 1 AND INCRETIN RECEPTORS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application Nos. 63 / 715,068, filed November 1, 2024; and 63 / 638,001, filed April 24, 2024; each of which is incorporated herein by reference in its entirety.

[0004] BACKGROUND

[0005] Regulation of calcium concentration is important to normal function of the gastrointestinal tract, skeletal system, nervous system, muscular nervous system and cardiovascular system. Parathyroid hormone (PTH) synthesis and release is primarily controlled by serum calcium levels.

[0006] Osteoporosis is characterized by bone loss resulting in an increased incidence of fracture. This condition, which is most prevalent in the spine and hip, affects 1 in 3 postmenopausal women, a lesser but significant number of aging men, and is also caused by other conditions including hypogonadism and prolonged glucocorticoid use. Current therapies to treat osteoporosis, such as bisphosphonates, hormone replacement therapy, SERMs and calcitonin, serve to arrest further bone loss by inhibiting bone resorption. Although these treatments may slow or even prevent continued bone loss, new bone formation leading to increased bone mass and strength, does not occur. Consequently, there is still a need for a therapeutic agent capable of stimulating bone formation. Such a therapeutic agent would be beneficial both to patients who are at risk of developing osteoporosis or who present with established osteoporosis.

[0007] Parathyroid hormone (PTH) is a significant regulator of calcium homeostasis and acts, in part, by mobilizing calcium from the skeleton through increased bone resorption. Additionally, pulsatile administration of PTH can stimulate new bone formation, both in laboratory animals and in humans. Thus, there is evidence to suggest that targeting of the receptor for PTH with a small molecule agonist mimicking the actions of PTH, would be a suitable approach for generating an anabolic response in bone. PTH elicits its effects by binding and activating a class B, G protein-coupled receptor of the 7 transmembrane superfamily, designated PTH1R. PTH1R activates multiple signaling pathways, but predominantly the adenylyl cyclase / cyclic AMP and the phospholipase C / calcium mobilization pathways.

[0008] The glucagon- like peptide- 1 receptor (GLP-1R) is a receptor protein found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. Glucagon-like peptide- 1 (GLP-1) is a hormone consisting of 30 amino acids. It is released by intestinal L cells when nutrients are consumed. GLP-1 has multiple effects, including enhancing insulin secretion from pancreatic beta cells in response to glucose, increasing insulin expression, preventing beta-cell apoptosis, promoting the formation of new beta cells, reducing glucagon secretion, slowing down stomach emptying, promoting satiety, and improving glucose disposal in peripheral tissues. GLP-1 R is also expressed in the brain, where it is involved in the control of appetite. Furthermore, mice that over express GLP-1 R display improved memory and learning.

[0009] Due to these diverse effects, there has been significant interest in developing long- lasting agonists of the GLP-1 receptor (GLP-1R) for the treatment of type 2 diabetes and other conditions. Indeed, glucagon-like peptide- 1 receptor agonists gained approval as drugs to treat diabetes and obesity starting in the 2000s.

[0010] The gastric inhibitory polypeptide receptor (GIPR), also known as the glucosedependent insulinotropic polypeptide receptor, is a protein that in humans is encoded by the GIPR gene. GIPR is a member of the class B family of G protein coupled receptors. GIPR is found on beta-cells in the pancreas where it serves as the receptor for the hormone Gastric inhibitory polypeptide (GIP). Gastric inhibitory polypeptide, also called glucose-dependent insulinotropic polypeptide, is a 42-amino acid polypeptide synthesized by K cells of the duodenum and small intestine. It was originally identified as an activity in gut extracts that inhibited gastric acid secretion and gastrin release, but subsequently was demonstrated to stimulate insulin release potently in the presence of elevated glucose. The insulinotropic effect on pancreatic islet beta-cells was then recognized to be the principal physiologic action of GIP. Together with glucagon-like peptide- 1, GIP is largely responsible for the secretion of insulin after eating. It is involved in several other facets of the anabolic response.

[0011] The glucagon receptor (GCGR) is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors, coupled to G alpha i, Gs and to a lesser extent G alpha q. Stimulation of the receptor results in the activation of adenylate cyclase and phospholipase C and in increased levels of the secondary messengers intracellular cAMP and calcium. Through interaction with GCGR, glucagon has been shown to increase hepatic glucose output in hypoglycemic state, reduce body weight and appetite, stimulate insulin secretion under certain circumstances and as a key hormone that modulates postprandial amino acid metabolism. In humans, the glucagon receptor is encoded by the GCGR gene.

[0012] Inactivating mutation of glucagon receptor in humans causes resistance to glucagon and is associated with pancreatic alpha cell hyperplasia, nesidioblastosis, hyperglucagonemia, and pancreatic neuroendocrine tumors, also known as Mahvash disease. Glucagon receptors are mainly expressed in liver and in kidney with lesser amounts found in heart, adipose tissue, spleen, thymus, adrenal glands, pancreas, cerebral cortex, and gastrointestinal tract.

[0013] Accordingly, there is a need in the art to provide small molecule therapeutics that treat or prevent hypoparathyroidism, osteoporosis and related conditions. In particular, there is a need for providing compounds that act as PTH1R agonists.

[0014] Additionally, there is a need in the art to provide small molecule modulators of the GLP-1R, GIPR, and / or GCGR in order to provide treatments for conditions such as diabetes, obesity or overweight, liver disease, and heart disease. More particularly, there is a need for GLP-1R / GIPR / GCGR triagonists to treat these conditions, which should be more efficacious compared to currently available GLP-1 agonists.

[0015] SUMMARY

[0016] The present invention provides in some embodiments a compound according to formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0017] R1is selected from:

[0018] 5-oxo-l,4-dihydro-l,2,4-triazol-4-yl, optionally substituted with one or more instances of (Ci-Ce)alkyl, and

[0019] 2-oxo-4-pyridyl, optionally substituted with one or more instances of (Ci-Ce)alkyl;

[0020] R2is (Ci-C6)alkyl,

[0021] R3is alkyl optionally substituted with (C CsJcycloalkyl;

[0022] R4is hydrogen;

[0023] R5is (Ci-Ce)alkyl or (Ci-Ce)alkoxy alkyl, or R4and R5taken together with the carbon atom to which they are attached form a 5- to 7-membered heterocycloalkyl;

[0024] R6is hydrogen or alkyl; and

[0025] R7and R8are each alkyl; or R7and R8are taken together with the carbon atom to which they are attached form 4- to 7-membered heterocycloalkyl; provided that the compound is not:

[0026] The present invention also provides a compound according to Formula (II): or a pharmaceutically acceptable salt thereof, wherein:

[0027] R9is selected from:

[0028] 2-oxo-l,3-dihydro-l,3,4-triaza-3-indenyl,

[0029] 2.5-dioxo-l-imidazolidinyl optionally substituted with one or more is (Ci-Ce)alkyl, and

[0030] 2.6-dioxo-l,3,4,5-tetrahydro-4-pyrimidinyl;

[0031] R10is (Ci-C6)alkyl;

[0032] R11and R12taken together with the carbon atom to which they are attached form 4- to 7-membered heterocycloalkyl;

[0033] R13is (Ci-C6)alkyl; and

[0034] R14is (Ci-Ce)alkyl optionally substituted with (CvCs)cycloalkyL provided that the compound is not:

[0035] The present invention also provides a compound according to Formula (III): or a pharmaceutically acceptable salt thereof, wherein:

[0036] R16is hydroxy or cyano;

[0037] R17is (Ci-C6)alkyl; and

[0038] R18and R19taken together with the carbon atom to which they are attached form (C3- Csjcycloalkyl.

[0039] The present invention also provides a compound according to Formula (IV): or a pharmaceuticall acceptable salt thereof, wherein:

[0040] R20is:

[0041] R21is (Ci-Ce)hydroxyalkyl;

[0042] R22is (Ci-C6) alkyl;

[0043] R23is (Ci-C6) alkyl; and

[0044] R24is (C3-Cs)cycloalkyl.

[0045] The present invention also provides a compound according to Formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein

[0046] R25is (Ci-Ce)hydroxyalkyl;

[0047] R26is (C1-C3) alkyl; and

[0048] R27and R28taken together with the carbon atom to which they are attached form (C3- Cs)cycloalkyl.

[0049] Other aspects of the disclosure provide a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0050] In still other aspects, provided herein is a method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof an effective amount of a compound of compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0051] In still other aspects, provided herein is a method of: a) reducing of HbAlc; b) treating or preventing type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin dependent diabetes, and / or obesity; c) reducing body weight and / or food intake, and / or inducing satiety; and / or d) treating or preventing Alzheimer’s disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and / or cardiovascular diseases; comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0053] Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims.

[0054] BRIEF DESCRIPTION OF THE FIGURES

[0055] Figure 1 tabulates exemplary compounds of the invention, and their characterization data and PTH1R activity.

[0056] DETAILED DESCRIPTION

[0057] Definitions

[0058] For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0059] In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0060] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0061] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0062] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0063] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0064] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0065] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0066] “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

[0067] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0068] Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure.

[0069] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

[0070] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or deenriched carbon are within the scope of this invention.

[0071] The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[0072] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non- toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.)

[0073] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

[0074] The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule.

[0075] A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0076] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0077] The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human.

[0078] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0079] “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl groups may be substituted or unsubstituted.

[0080] As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.

[0081] As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen.

[0082] As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein substituted with at least one halogen atom. For example, haloalkoxy groups include fluoroalkoxy groups, such as trifluoromethoxy, difluoromethoxy, and the like.

[0083] As used herein, the term “hydroxyalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl.

[0084] As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0085] "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.

[0086] “1,2-Disubstituted cyclohexyl” as used herein refers to a cyclohexane ring that contains points of attachment at the 1 and 2 positions of the cyclohexane ring to the rest of the compound. Similarly, “1,2-disubstituted cyclopentyl” as used herein refers to a cyclopentane ring that contains points of attachment at the 1 and 2 positions of the cyclopentane ring to the rest of the compound. 1 ,2-Disubstituted cyclohexyl and 1 ,2- disubstituted cyclopentyl can also be referred to as 1 ,2-cyclohexylene and 1 ,2- cyclopentylene, respectively.

[0087] As used herein, the term “halocyclo alkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen.

[0088] "Cycloheteroalkyl" refers to a cycloalkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted.

[0089] Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0090] “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

[0091] “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.

[0092] The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, indazole, quinoline, benzofuran, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0093] The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo. The terms “heterocyclyl” or “heterocyclic group” or “heterocycloalkyl” refer to 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. Heterocycloalkyl groups can be fully saturated or partially saturated. Heterocycloalkyl groups include, for example, bicyclic ring systems having either or both constituent rings saturated (e.g., 2,3-dihydroindole, 4, 5,6,7- tetrahydro-benzofuran, decahydroquinoline, and the like) or partially saturated (e.g., octahydroquinoline and the like).

[0094] The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0095] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0096] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0097] As used herein, “small molecules” refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da). The small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).

[0098] In some embodiments, a “small molecule” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound, with a size on the order of 1 nm. In some embodiments, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0099] An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments.

[0100] The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter as compared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment.

[0101] The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.

[0102] As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response.

[0103] A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and / or therapy of various diseases. The radiolabeled pharmaceutical agent, for example, a radiolabeled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

[0104] Compounds of the Invention

[0105] The present invention provides in some embodiments a compound according to formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0106] R1is selected from:

[0107] 5-oxo-l,4-dihydro-l,2,4-triazol-4-yl, optionally substituted with one or more instances of (Ci-Ce)alkyl, and

[0108] 2-oxo-4-pyridyl, optionally substituted with one or more instances of (Ci-Ce)alkyl;

[0109] R2is (Ci-C6)alkyl,

[0110] R3is alkyl optionally substituted with (C Cs)cycloalkyl;

[0111] R4is hydrogen;

[0112] R5is (Ci-Ce)alkyl or (Ci-Ce)alkoxy alkyl, or R4and R5taken together with the carbon atom to which they are attached form a 5- to 7-membered heterocycloalkyl;

[0113] R6is hydrogen or alkyl; and

[0114] R7and R8are each alkyl; or R7and R8are taken together with the carbon atom to which they are attached form 4- to 7-membered heterocycloalkyl; provided that the compound is not:

[0115] In some embodiments, the compound has the structure of formula (la) or (lb): or a pharmacemtucally acceptable salt thereof.

[0116] In some embodiments,

[0117] In some embodiments, R4and R5taken together with the carbon atom to which they are attached form

[0118] In other embodiments, R4is hydrogen and R5is methyl.

[0119] In still other embodiments, R4is hydrogen and R5is ethoxymethyl.

[0120] In some embodiments,

[0121] In some embodiments, R6is hydrogen, while in other embodiments, R6is methyl.

[0122] In some embodiments, R7and R8are each methyl.

[0123] In other embodiments, R7and R8taken together with the carbon atom to which they are attached form:

[0124] In some embodiments, R2is methyl.

[0125] In some embodiments, R3is n-butyl.

[0126] The present invention also provides a compound according to Formula (II): or a pharmaceutically acceptable salt thereof, wherein:

[0127] R9is selected from:

[0128] 2-oxo-l,3-dihydro-l,3,4-triaza-3-indenyl,

[0129] 2.5-dioxo-l-imidazolidinyl optionally substituted with one or more is (Ci-Ce)alkyl, and

[0130] 2.6-dioxo-l,3,4,5-tetrahydro-4-pyrimidinyl;

[0131] R10is (Ci-C6)alkyl;

[0132] R11and R12taken together with the carbon atom to which they are attached form 4- to 7-membered heterocycloalkyl;

[0133] R13is (Ci-C6)alkyl; and

[0134] R14is (Ci-Ce)alkyl optionally substituted with (C3-Cs)cycloalkyl, provided that the compound is not:

[0135] In some embodiments, the compound has the structure of Formula (Ila): or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, R11and R12taken together with the carbon atom to which they are attached form:

[0137] In some embodiments, R13is methyl.

[0138] In some embodiments, R14is cyclopropylmethyl.

[0139] In some embodiments, R10is n-butyl.

[0140] The present invention also provides a compound according to Formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein:

[0141] R16is hydroxy or cyano;

[0142] R17is (Ci-C6)alkyl; and R18and R19taken together with the carbon atom to which they are attached form (C3- Csjcycloalkyl.

[0143] In some embodiments, the compound has the structure of Formula (Illa) or (Illb): (Illb), or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, R17is n-butyl.

[0145] In some embodiments, R18and R19taken together with the carbon atom to which they are attached form cyclobutyl.

[0146] The present invention also provides a compound according to Formula (IV): (IV), or a pharmaceuticall acceptable salt thereof, wherein:

[0147] R20is:

[0148] R21is (Ci-Ce)hydroxyalkyl;

[0149] R22is (Ci-C6) alkyl;

[0150] R23is (Ci-C6) alkyl; and

[0151] R24is (C3-Cs)cycloalkyl.

[0152] In some embodiments, the compound has a structure of Formula (IVa) or (IVb): or a pharmaceutically acceptable salt thereof. In some embodiments, R21is hydroxymethyl.

[0153] In some embodiments, R22is n-butyl.

[0154] In some embodiments, R23is methyl.

[0155] In some embodiments, R24is cyclopropyl.

[0156] The present invention also provides a compound according to Formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein

[0157] R25is (Ci-Ce)hydroxyalkyl;

[0158] R26is (C1-C3) alkyl; and

[0159] R27and R28taken together with the carbon atom to which they are attached form (C3- Cs)cycloalkyl.

[0160] In some embodiments, the compound has the structure of Formula (Va) or (Vb): or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, R25is hydroxymethyl.

[0162] In some embodiments, R26is n-propyl.

[0163] In some embodiments, R27and R28taken together with the carbon atom to which they are attached form cyclobutyl.

[0164] The present invention also provides a compound having a structure selected from the following table: or a pharmaceutically acceptable salt thereof.

[0165] Methods of Treatment

[0166] One aspect of the invention provides a method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof an effective amount of a compound according to the present invention, or a pharmaceutically acceptable salt thereof.

[0167] Another aspect of this invention is a method for preventing or treating a condition mediated by PTH which comprises administering to a mammal in need thereof an effective amount of a compound a compound according to the present invention, or a pharmaceutically acceptable salt thereof, either alone or in admixture with a pharmaceutically excipient. Another aspect of the invention includes compounds of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment and prevention of diseases and conditions characterized by loss of bone mineral density, mass, or strength, as well as in conditions wherein PTH would have a beneficial pharmacological effect. The invention includes administering compounds of formula (I) or (II) for use as a PTH mimetic. Another aspect of the invention includes use of the compounds of the present invention in the manufacture of a medicament for use in the treatment of osteopenia and osteoporosis in men and women for reduction in the risk of fractures, both vertebral and nonvertebral.

[0168] Another aspect of the invention provides a method of: a) reducing of HbAlc; b) treating or preventing type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin dependent diabetes, and / or obesity; c) reducing body weight and / or food intake, and / or inducing satiety; and / or d) treating or preventing Alzheimer’s disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and / or cardiovascular diseases; comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the present invention.

[0169] In certain embodiments, the compound is administered orally to the subject.

[0170] In certain embodiments, the compound is administered parenterally to the subject.

[0171] In certain embodiments, the disease is prevented. In other embodiments, the disease is treated.

[0172] Pharmaceutical Compositions, Routes of Administration, and Dosing

[0173] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention, e.g. a compound according to the present invention, and a pharmaceutically acceptable carrier.

[0174] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier.

[0175] In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.

[0176] Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0177] As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein.

[0178] In certain embodiments, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 10 mg / kg / day.

[0179] Generally, daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams / kg per day to 1000 milligrams / kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound.

[0180] For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.

[0181] The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0182] For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.

[0183] For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.

[0184] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.

[0185] Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that could be used are poly- 1,3 -dioxolane and poly-l,3,6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable.

[0186] For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.

[0187] To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films.

[0188] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.

[0189] The therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression.

[0190] Colorants and flavoring agents may all be included. For example, the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.

[0191] One may dilute or increase the volume of the therapeutic with an inert material. These diluents could include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

[0192] Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0193] Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.

[0194] An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.

[0195] Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.

[0196] To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios.

[0197] Pharmaceutical preparations which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[0198] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0199] For topical administration, the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.

[0200] For administration by inhalation, compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro tetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0201] Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (al- antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a- 1 -proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Pat. No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569 (incorporated by reference), issued Sep. 19, 1995 to Wong et al.

[0202] Contemplated for use in the practice of this invention are mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0203] Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

[0204] All such devices require the use of formulations suitable for the dispensing of the compounds of the invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.

[0205] Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.

[0206] Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.

[0207] Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing a compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers (pm), most preferably 0.5 to 5 pm, for most effective delivery to the deep lung.

[0208] Nasal delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.

[0209] For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[0210] Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.

[0211] The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0212] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0213] Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0214] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0215] In addition to the formulations described above, a compound may also be formulated as a depot preparation. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0216] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0217] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990).

[0218] The compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicine the salts or cocrystals should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

[0219] Suitable buffering agents include: acetic acid and a salt (1-2% w / v); citric acid and a salt (1-3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphoric acid and a salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v) and thimerosal (0.004-0.02% w / v).

[0220] Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0221] The therapeutic agent(s), including specifically but not limited to a compound of the invention, may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state. The particles may be of virtually any shape.

[0222] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, poly anhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly (butylmethacrylate), poly (isobutyl methacrylate), poly (hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly (octadecyl acrylate). The therapeutic agent(s) may be contained in controlled release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”

[0223] Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.

[0224] It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention.

[0225] EXAMPLES

[0226] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0227] Abbreviations:

[0228] ]

[0229] General Scheme 1

[0230] General Scheme 2:

[0231]

[0232] Example 1 : l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((4,4-dimethyl-2,5- dioxoimidazolidin-l-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (1)

[0233] Synthetic scheme:

[0234] Tert-butyl (( ls,4s)-4-((4,4-dimethyl-2,5-dioxoimidazolidin- 1- yl)methyl)cyclohexyl)carbamate

[0235] To a solution of tert-butyl (( 1 s,4. )-4-(bromomethyl)cyclohexyl)carbamate (2.5 g, 8.56 mmol) and 5,5-dimethyl hydantoin (1.8 mL, 10.3 mmol) in DMF (42.8 mL) was added KI (1.43 g, 8.56 mmol) followed by K2CO3 (1.54 g, 11.1 mmol). The suspension was stirred at 60 °C for 16 h. The reaction was quenched with water (80 mL) and diluted with EtOAc (80 mL). After the layer was separated, the aqueous layer was extracted with EtOAc (3 X 80 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica, 0-10%, EtOAc / DCM) to afford the title compound (2.31 g, 80%). MS (ESI): mass calcd. for C17H29N3O4: 339.22, found: 362.5 [M+Na]+.

[0236] 3-(((ls,4s)-4-aminocyclohexyl)methyl)-5,5-dimethylimidazolidine-2, 4-dione

[0237] Tert-butyl ((15',45')-4-((4,4-dimethyl-2,5-dioxoimidazolidin-l- yl)methyl)cyclohexyl)carbamate (2.0 g, 5.89 mmol) was dissolved in a solution of TFA in HFIP (5% w / w) (63.1 mL, 41.2 mmol) and the solution was stirred at rt for 2 h. To the resulting mixture was added z'-PrOH (50 mL) and all was concentrated by azeotropic distillation (repeated twice) to give the crude title compound. MS (ESI): mass calcd. for C12H21N3O2: 239.16, found: 240.4 [M+H]+. l-butyl-3-((ls,4s)-4-((4,4-dimethyl-2,5-dioxoimidazolidin-l-yl)methyl)cyclohexyl)urea

[0238] To a solution of 3-((( 11v,41v)-4-aminocyclohcxyl)mcthyl)-5.5-dimcthylimidazolidinc- 2, 4-dione (2.61 g, 7.39 mmol) in DCM (36.9 mL) was added triethylamine (3.1 mL, 22.2 mmol) followed by butyl isocyanate (892 pL, 7.76 mmol). The mixture was stirred at rt for 15 min and was concentrated. The crude residue was purified by flash column chromatography (silica, 0-10%, MeOH / DCM) to afford the title compound (2.5 g, 100%). MS (ESI): mass calcd. for C17H30N4O3: 338.23, found: 339.4 [M+H]+. l-butyl-3-((ls,4s)-4-((4,4-dimethyl-2,5-dioxoimidazolidin-l- yl)methyl)cyclohexyl)pyrimidine-2,4,6(17Z,37Z,57Z)-trione

[0239] To a solution of Lbutyl-3-((l. ,4. )-4-((4,4-dimethyl-2,5-dioxoimidazolidin-l- yl)methyl)cyclohexyl)urea (800 mg, 2.36 mmol) in AcOH (4.7 mL) was added malonic acid (286 mg, 2.72 mmol). The reaction was heated to 90 °C and when the temperature reached 60 °C, acetic anhydride (894 pL, 9.45 mmol) was added. The reaction was sealed and stirred at 90 °C for 4.5 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and concentrated. The crude was purified by flash column chromatography (silica, 10-80%, EtOAc / heptane) to provide the title compound (431 mg, 45%) as a pale-yellow gummy oil. MS (ESI): mass calcd. for C20H30N4O5: 406.22, found: 407.5 [M+H]+. l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((4,4-dimethyl-2,5-dioxoimidazolidin-l- yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (1)

[0240] To a solution of l-butyl-3-((15',45')-4-((4,4-dimethyl-2,5-dioxoimidazolidin-l- yl)methyl)cyclohexyl)pyrimidine-2,4,6(177,3Z7,5H)-trione (224 mg, 551 pmol) in THF (5.5 mL) in a sealed tube was added cyanamide (234 mg, 5.51 mmol) followed by nickel(II) acetylacetonate (28.3 mg, 110 p mol). The dark green mixture was stirred at 80 °C for 17.5 h. Further portions of cyanamide (209 mg, 4.92 mmol) and nickel(II) acetylacetonate (28.3 mg, 110 pmol) were added at rt and the reaction mixture was then stirred at 80 °C for 5 h. The resulting mixture was cooled down to rt, filtered through a pad of Celite, and concentrated. The residue was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (x3). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (silica, 0-5%, MeOH / DCM) to afford the title compound (7.3 mg, 3%) as a white solid. MS (ESI): mass calcd. for C21H32N6O5: 448.24, found: 449,5 [M+H]+.1H NMR (400 MHz, CD3OD) 5 4.77 - 4.89 (m, 1H), 4.65 (s, 1H), 3.85 - 4.00 (m, 2H), 3.74 (d, J = 7.7 Hz, 2H), 2.72 - 2.92 (m, 2H), 2.15 (s, J = 31.3 Hz, 1H), 1.55 - 1.83 (m, 6H), 1.34 - 1.51 (m, 10H), 1.03 0. 7 = 7.4 Hz, 3H).

[0241] Example 2: l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((8,8-dioxido-2,4-dioxo-8-thia- l,3-diazaspiro[4.5]decan-l-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (2) Synthetic scheme:

[0242] 8-thia-l,3-diazaspiro[4.5]decane-2, 4-dione 8,8-dioxide

[0243] Ammonium carbonate (999 mg, 10.4 mmol) was dissolved in MeOH (23.6 mL) and potassium cyanide (349 mg, 5.2 mmol) was added. The mixture was heated to 40 °C for 30 min. Tetrahydrothiopyran-4-one 1,1 -dioxide (700 mg, 4.72 mmol) was added, and the mixture was stirred over the weekend at rt. The solvent was removed, and the residue was treated with 6 N aqueous HC1 solution until pH 1. The solid formed was filtered and washed with water to afford the title compound (1.0 g, 97%). MS (ESI): mass calcd. for C7H10N2O4S: 218.4, found: 217.3 [M-H]’.

[0244] 3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia-l,3-diazaspiro[4.5]decane-2, 4-dione 8,8- dioxide

[0245] To 8-thia-l,3-diazaspiro[4.5]decane-2, 4-dione 8,8-dioxide (1.00 g, 4.58 mmol) in DMF (9.2 mL) was added A,A-diisopropylethylamine (1.20 mL, 6.87 mmol) followed by (2- chloromethoxyethyl)trimethylsilane (993 pL, 5.5 mmol) and the solution was stirred for 1 h. Water was added and the mixture was extracted with EtOAc (3x). The combined organic phase was washed with brine, dried over Na2SC>4, filtered, and concentrated. The crude was purified by flash column chromatography (silica, 0-10% MeOH / DCM) to provide the title compound (1.18 g, 74%). MS (ESI): mass calcd. for Ci3H24N2O5SSi: 348.12, found: 347.4 [M-H]’.

[0246] / ( / • / -butyl (( Is, 4s )-4-((8,8-dioxido-2,4-dioxo-3-((2-(trimethylsilyl )ethoxy )methyl )-8-thia- 1 ,3-diazaspiro[4.5] decan- 1 -yl)methyl)cyclohexyl)carbamate

[0247] To 3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia-l,3-diazaspiro[4.5]decane-2, 4-dione 8,8-dioxide (200 mg, 574 pmol) in DMF (3.2 mL) was added tert-butyl ((ls,4s)-4- (bromomethyl)cyclohexyl)carbamate (168 mg, 574 pmol) followed by cesium carbonate (283 mg, 861 pmol) and the suspension was stirred at 80 °C for 17 h. Water was added and the mixture was extracted with EtOAc (3x). The combined organic phase was washed with 10% aqueous LiCl and brine, dried over Na2SC>4, filtered and concentrated. The crude was purified by flash column chromatography (silica, 0-100% EtOAc / heptanes) to give the title compound (100 mg, 31%). MS (ESI): mass calcd. for C25H45N3O?SSi: 559.25 found: 582.5 [M+Na]+, 604.5 [M+HC02]’. l-(((ls,4s)-4-aminocyclohexyl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia-l,3- diazaspiro[4.5]decane-2, 4-dione 8,8-dioxide

[0248] To tert-butyl ((ls,4s)-4-((8,8-dioxido-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)- 8-thia-l,3-diazaspiro[4.5]decan-l-yl)methyl)cyclohexyl)carbamate (500 mg, 893 pmol) in DCM (8.9 mL) was added formic acid (1.0 mL, 26.8 mmol). The reaction was stirred for 17 h and then was concentrated. The residue was diluted with saturated aqueous Na2COs solution and extracted with DCM. The organic layer was separated, dried over Na2SC>4, filtered, and concentrated to give the crude title compound (157 mg, 38%). MS (ESI): mass calcd. for C2oH37N305SSi: 459.22 found: 460.4 [M+H]+. l-butyl-3-((ls,4s)-4-((8,8-dioxido-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia- l,3-diazaspiro[4.5]decan-l-yl)methyl)cyclohexyl)urea

[0249] To l-(((15',45')-4-aminocyclohexyl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-8- thia-l,3-diazaspiro[4.5]decane-2, 4-dione 8,8-dioxide (157 mg, 342 pmol) in DCM (1.7 mL) was added triethylamine (71.4 pL, 512 pmol) followed by butyl isocyanate (43.2 pL, 376 pmol) and the solution was stirred at rt for 30 min. Water was added and the mixture was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na2SC>4, filtered, and concentrated. The crude was purified by flash column chromatography (silica, 0-10% MeOH / DCM) to provide the title compound (191 mg, 100%). MS (ESI): mass calcd. for C25H46N4O6SSi: 558.29, found: 559.5 [M+H]+. l-butyl-3-((ls,4s)-4-((8,8-dioxido-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia- l,3-diazaspiro[4.5]decan-l-yl)methyl)cyclohexyl)pyrimidine-2,4,6(17Z,37Z,57Z)-trione

[0250] To l-butyl-3-((l.v,4.v)-4-((8,8-dioxido-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)- 8-thia-l,3-diazaspiro[4.5]decan-l-yl)methyl)cyclohexyl)urea (191 mg, 342 pmol) in DCM (3.4 mL) was added malonyl chloride (68.6 pL, 684 pmol) and the mixture was stirred at rt for 1 h. Water was added and the mixture was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography (silica, 20-50% EtOAc / heptanes) to provide the title compound (181 mg, 84%). MS (ESI): mass calcd. for C28H4eN40sSSi: 626.28 found: 625.4 [M-H]’ l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((8,8-dioxido-2,4-dioxo-3-((2-(trimethylsilyl) ethoxy)methyl)-8-thia-l,3-diazaspiro[4.5]decan-l-yl)methyl)cyclohexyl)pyrimidine-

[0251] 2,4,6(17 / ,37 / ,57 / )-trione

[0252] To a solution of l-butyl-3-((lMs)-4-((8,8-dioxido-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-8-thia-l,3-diazaspiro[4.5]decan-l- yl)methyl)cyclohexyl)pyrimidine-2,4,6(177,3Z7,5Zr)-trione (180 mg, 287 pmol) and cyanamide (122 mg, 2.27 mmol) in THF (2.9 mL) was added nickel(II) acetylacetonate (15.8 mg, 57.4 pmol). The mixture was stirred at 80 °C for 18 h. The resulting mixture was filtered with a syringe filter, and concentrated. The crude residue was purified by flash column chromatography (silica, 20-60%, EtOAc / heptane) to provide the title compound (134 mg, 70%). MS (ESI): mass calcd. for C29H48N6O8SSi: 668.30 found: 667.4 [M-H]’. l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((8,8-dioxido-2,4-dioxo-8-thia-l,3- diazaspiro[4.5]decan-l-yI)methyI)cycIohexyI)pyrimidine-2,4,6(lH,3H,5H)-trione (2)

[0253] To l-butyl-5-(diaminomethylene)-3-((l.v,4.v)-4-((8,8-dioxido-2,4-dioxo-3-((2-

[0254] (trimethylsilyl)ethoxy)methyl)-8-thia-l,3-diazaspiro[4.5]decan-l-yl)methyl)cyclohexyl) pyrimidine-2,4,6(177,3Z7,5Zr)-trione (134 mg, 200 pmol) in DCM (2 mL) was added trifluoroacetic acid (460 pL, 6.01 mmol) and the solution was stirred for 30 min. Saturated aqueous bicarbonate solution was added, and the biphasic solution was stirred for 10 min, then extracted with DCM (3x). The combined organic phase was dried over Na2SO4, filtered and concentrated. The crude was purified by reverse phase chromatography (Cl 8, 10-40% MeCN / 10 mM AmB buffer) to provide the title compound (30 mg, 28%). MS (ESI): mass calcd. for C23H34N6O7S: 538.22, found: 539.5 [M+H]+. ' H NMR (400 MHz, DMSO-t / 6) 5 11.09 (bs, 1H), 9.55 (s, 2H), 7.29 (s, 2H), 4.56 - 4.74 (m, 1H), 3.70 - 3.77 (m, 2H), 3.58 - 3.70 (m, 2H), 3.07 - 3.28 (m, 5H), 2.51 - 2.61 (m, 2H), 2.39 - 2.46 (m, 2H), 2.15 - 2.25 (m, 2H), 1.58 - 1.80 (m, 2H), 1.36 - 1.52 (m, 4H), 1.17 - 1.33 (m, 4H), 0.86 (t. J = 7.3 Hz, 3H).

[0255] Example 3: l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((2-oxo-l,2-dihydro-3H- imidazo[4,5-b]pyridin-3-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (3)

[0256] The title compound (3) was synthesized following the same steps of example (1) using tert-butyl 2-oxo-2,3-dihydro- 1 / f-imidazo[4,5- / ?]pyridine- 1 -carboxylate instead of 5,5- dimethylimidazolidine-2, 4-dione. The last step of the synthesis employed sodium hydroxide (3 M in water, 130 pL) and THF (500 pL). The reaction was stirred at ambient temperature for 6 h and was extracted with EtOAc, dried and concentrated. The crude product was purified by reverse phase chromatography (Cl 8, 60% MeCN / 10 mM AmF buffer) to provide the title compound. MS (ESI): mass calcd. for C22H29N7O4: 455.23, found: 456.4 [M+H]+. ' H NMR (400 MHz, DMSO-t / 6) 5 11.06 (bs, 1H), 9.55 (s, 2H), 7.91 (d, J = 4.9 Hz, 1H), 7.35 (s, 2H), 7.26 (d, J = 6.1 Hz, 1H), 6.94 - 7.00 (m, 1H), 4.60 - 4.74 (m, 1H), 3.94 (d, J = 7.4 Hz, 2H), 3.71 - 3.81 (m, 2H), 2.88 - 2.98 (m, 1H), 2.59 - 2.77 (m, 2H), 1.53 - 1.66 (m, 2H), 1.38 - 1.52 (m, 4H), 1.24 - 1.35 (m, 4H), 0.88 (t, J = 7.4 Hz, 3H).

[0257] Example 4: l-butyl-5-(diaminomethylene)-3-(4-((6,6-dimethyl-2,4- dioxotetrahydropyrimidin-l(2H)-yl)methyl)-4-methylcyclohexyl)pyrimidine-

[0258] 2,4,6(lH,3H,5H)-trione (4)

[0259] Ethyl 3-methyl-3-(((8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)amino)butanoate

[0260] To a suspension of 8-methyl-l,4-dioxaspiro[4.5]decane-8-carbaldehyde (3.00 g, 16.3 mmol) and ethyl 3-amino-3-methylbutanoate hydrochloride (9.34 g, 48.9 mmol) in DCE (81 mL) was added AcOH (3.7 mL, 65.1 mmol). One portion of sodium triacetoxyborohydride (10.4 g, 48.9 mmol) was added and the mixture was stirred at rt for 23 h. The resulting mixture was quenched with a 1 M aqueous NUTCO? solution (90 mL) then a 2 M aqueous NUTCO? solution (60 mL) until the aqueous layer showed pH 7-8. The quenched mixture was diluted with water (100 mL) and DCM (100 mL). After the layer was separated, the aqueous layer was extracted with DCM (100 mL x3). The combined organic phase was dried over Na2SC>4, filtered and concentrated. The crude residue was purified by flash column chromatography (silica, DCM) to afford the title compound (3.07 g, 60%). MS (ESI): mass calcd. for C17H31NO4: 313.23, found: 314.4 [M+H]+.

[0261] 3-(4-methoxybenzyl)-6,6-dimethyl-l-((l-methyl-4- oxocyclohexyl)methyl)dihydropyrimidine-2,4(l / Z,3 / )-dione

[0262] To a solution of ethyl 3-methyl-3-(((8-methyl-l,4-dioxaspiro[4.5]decan-8- yl)methyl)amino)butanoate (1.62 g, 5.17 mmol) in MeCN (51.7 mL) was added 4- methoxybenzyl isocyanate (904 pL, 6.2 mmol). The mixture was stirred at rt for 2 h, then at 60 °C for 20 min. To the mixture was added CS2CO3 (5.16 g, 15.5 mmol) and the suspension was stirred at 60 °C for 30 min. The mixture was acidified with aqueous 2 N HC1 (50 mL) at 0 °C to pH -1. The resulting solution was stirred vigorously at rt for 60 min and then rendered alkaline using aqueous 2 N NaOH (53 mL, 5.17 mmol) at 0 °C to pH 12-13. To the quenched mixture was added EtOAc (100 mL), phase was separated, the aqueous layer was extracted with EtOAc (50 mL x3). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (silica, 5-60%, EtOAc / heptanes) to afford the title compound (0.902 g, 45%). MS (ESI): mass calcd. for C22H30N2O4: 386.22 found: 387.5 [M+H]+.

[0263] 6,6-dimethyl-l-((l-methyl-4-oxocyclohexyl)methyl)dihydropyrimidine-2,4(l / Z,3 / Z)-dione

[0264] 3-(4-methoxybenzyl)-6,6-dimethyl-l-((l-methyl-4-oxocyclohexyl)methyl) dihydropyrimidine-2, 4(1 / / , 3H) -dione (663 mg, 1.72 mmol) was dissolved in TFA (17.2 mL) and TfOH (1.52 mL, 17.2 mmol) was slowly added to the solution at 0 °C. The red color reaction solution was stirred at rt for 2.5 h. The resulting reddish-purple mixture was slowly poured into a mixture of aqueous 2 M NaOH (155 mL) / ice at 0 °C. The mixture was diluted with EtOAc (100 mL), phase was separated, and the aqueous layer was extracted with EtOAc (80 mL x3). The combined organic layer was dried over Na2SC>4, filtered and concentrated. The crude was purified by reverse phase chromatography (C18, 0-30% MeCN / 10 mM AmB buffer) to provide the title compound (286 mg, 63%) as a white solid. MS (ESI): mass calcd. for C14H22N2O3: 266.16 found: 267.4 [M+H]+. l-((4-amino-l-methylcyclohexyl)methyl)-6,6-dimethyldihydropyrimidine-2, 4(177, 377)- dione

[0265] To a suspension of 6,6-dimethyl-l-((l-methyl-4- oxocyclohexyl)methyl)dihydropyrimidine-2, 4(177, 377)-dione (286 mg, 1.07 mmol) in MeOH (10.7 mL) were added ammonium formate (684 mg, 10.7 mmol), 8 -hydroxyquinoline (46.8 mg, 322 pmol), [Cp*IrC12]2 (131 mg, 164 pmol), and AcOH (61.5 pL, 1.07 mmol). The mixture was stirred at 60 °C for 1 h. The reaction was cooled down to rt, quenched with aqueous 0.5 N NaOH (10 mL) and was extracted with a 4:1 CHCL / z-PrOH. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase chromatography (C18, 0-40% MeCN / 10 mM AmB buffer). Appropriate fractions were partially concentrated, frozen, and lyophilized to provide the title compound (287 mg, 100%) as a brown solid with a cis / trans ratio of 69 / 31. MS (ESI): mass calcd. for C14H25N3O2: 267.19 found: 268.5 [M+H]+. l-butyl-3-(4-((6,6-dimethyl-2,4-dioxotetrahydropyrimidin-l(277)-yl)methyl)-4- methylcyclohexyl)urea

[0266] To a solution of l-((4-amino-l-methylcyclohexyl)methyl)-6,6- dimethyldihydropyrimidine-2, 4(177, 377)-dione (370 mg, 1.38 mmol) in DCM (6.9 mL) was added butyl isocyanate (186.1 pL, 1.64 mmol). The mixture was stirred at rt for 1.5 h. The resulting mixture was quenched with water and the phase was separated. The aqueous layer was extracted with DCM (x6) and the combined organic layer was dried over Na2SC>4, filtered, and concentrated to give the crude title compound (451.3 mg, 89%) as a yellow solid. MS (ESI): mass calcd. for C19H34N4O3: 366.26 found: 367.5 [M+H]+. l-butyl-3-(4-((6,6-dimethyl-2,4-dioxotetrahydropyrimidin-l(2 / Z)-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(l / Z,3 / Z,5 / Z)-trione

[0267] To a solution of l-butyl-3-(4-((6,6-dimethyl-2,4-dioxotetrahydropyrimidin- 1(2 / 7)- yl)methyl)-4-methylcyclohexyl)urea (506 mg, 1.38 mmol) in AcOH (2.8 mL) was added malonic acid (167 mg, 1.59 mmol). The reaction was heated to 60 °C and acetic anhydride (522 pL, 5.52 mmol) was added. The reaction was sealed and stirred at 90 °C for 2 h. The mixture was cooled to rt and concentrated after adding MeOH (20 mL). The residue was purified by flash column chromatography (silica, 0-8%, McOH / CtLCF) to afford the title compound (390 mg, 65%) with an observed cis / trans ratio of 68 / 32, as a dark brown oil. MS (ESI): mass calcd. for C22H34N4O5: 434.25 found: 435.5 [M+H]+. l-butyl-5-(diaminomethylene)-3-(4-((6,6-dimethyl-2,4-dioxotetrahydropyrimidin-l(2H)- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (4)

[0268] To a solution of l-butyl-3-(4-((6,6-dimethyl-2,4-dioxotetrahydropyrimidin-l(2 / 7)- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(l / 7,3 / 7,5 / 7)-trione (390 mg, 898 pmol) and cyanamide (381 mg, 8.98 mmol) in THF (9 mL) was added nickel(II) acetylacetonate (15.3 mg, 59.6 pmol). The mixture was stirred at 80 °C for 18 h. Further cyanamide (127 mg, 2.99 mmol) and nickel(II) acetylacetonate (15.3 mg, 59.6 pmol) were added, and the stirring continued at 80 °C for 2 h. The resulting mixture was filtered through a pad of Celite by aid of EtOAc and concentrated. The crude residue was purified by flash column chromatography (silica, 0-5%, MeOH / DCM) and then by reverse phase chromatography (C18, 0-70% MeCN / 10 mM AmB buffer) to provide the title compound (90.3 mg, 21%) as a white solid with a cis / trans ratio of 68 / 32. MS (ESI): mass calcd. for C23H36N6O5: 476.27 found: 477.5 [M+H]+. NMR is a complex mixture of the separated stereoisomers Example 5 and Example 6.

[0269] Example 5 & Example 6: l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((6,6-dimethyl-2,4- dioxotetrahydropyrimidin-l(2H)-yl)methyl)-4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (5), and l-butyl-5-(diaminomethylene)-3-((lr,4r)-4-((6,6- dimethyl-2,4-dioxotetrahydropyrimidin-l(2H)-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (6)

[0270] The racemic mixture of was subjected to chiral separation (Phenomenex, z-Amylose-3, 30% MeCN / MeOH). The first peak to elute (5) was collected as a white solid. MS (ESI): mass calcd. for C23H36N6O5: 476.27 found: 477.5 [M+H]+’H NMR (400 MHz, DMSO-r / 6) 5 10.21 (s, 1H), 9.56 (s, 2H), 7.31 (s, 2H), 4.66 (br s, 1H), 3.69 - 3.80 (m, 2H), 3.34 (s, 2H), 2.54 - 2.71 (m, 4H), 1.76 (d, J = 13.8 Hz, 2H), 2.54 - 2.71 (m, 2H), 1.21 - 1.33 (m, 10H), 1.14 (t, J - 11.7 Hz, 2H), 0.88 (t, J - 7.3 Hz, 3H), 0.85 (s, 3H). The second peak to elute (6) was collected as a white solid. MS (ESI): mass calcd. for C23H36N6O5: 476.27 found: 477.5 [M+H]+. ' H NMR (400 MHz, DMSO-r / 6) 5 10.23 (s, 1H), 9.55 (s, 2H), 7.31 (s, 2H), 4.52 - 4.67 (m, 1H), 3.67 - 3.81 (m, 2H), 3.12 (s, 2H), 2.58 (s, 2H), 2.40 - 2.55 (m, 2H), 1.09 - 1.56 (m, 16H), 0.98 (s, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[0271] Example 7 : l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-methyl-4-((3,6,6-trimethyl-2,4- dioxotetrahydropyrimidin-l(2H)-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)- trione (7)

[0272]

[0273] To a solution of Example 5 (21.2 mg, 44.5 pmol) and Mel (3 pL, 46.6 pmol) in DMF (265 pL) was added K2CO3 (29.3 mg, 212 pmol). The mixture was wrapped with aluminum foil and stirred at rt for 18 h. The resulting mixture was diluted with water and extracted with EtOAc (x5). The combined organic layer was dried over Na2SC>4, filtered, and concentrated. The crude was purified by reverse phase chromatography (C18, 5-80% MeCN / 10 mM AmB buffer) to provide the title compound (13.3 mg, 61%). MS (ESI): mass calcd. for C24H38N6O5: 490.29 found: 491.5 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6) 5 9.56 (s, 2H), 7.32 (s, 2H), 4.55 - 4.78 (m, 1H), 3.65 - 3.82 (m, 2H), 3.39 (s, 2H), 3.03 (s, 3H), 2.57 - 2.73 (m, 4H), 1.77 (d, J = 12.5 Hz, 2H), 1.37 - 1.53 (m, 2H), 1.20 - 1.37 (m, 10H), 1.15 (dt, 7 = 13.5, 3.4 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H), 0.85 (s, 3H).

[0274] Example 8: l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((7,9-dioxo-2-oxa-6,8- diazaspiro[4.5]decan-6-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)- trione (8)

[0275]

[0276] A solution of dihydrofuran-3(2H)-one (5.0 g, 56.3 mmol) and methyl (triphenylphosphoranylidene)acetate (19.2 g, 56.3 mmol) in toluene (50.0 mL) was stirred under nitrogen at 105 °C for 19 h. Toluene was removed by concentration and the residue was diluted with a 1:1 mixture of EtOAc / heptanes (150 mL) and the solid was filtered. The filtrate was concentrated to get a brown oil. The crude was purified by flash column chromatography (silica, 0-30% EtOAc / heptanes to give the title compound (5.40 g, 67%) as a clear oil. NMR showed a mixture of E / Z isomers;1H NMR (400 MHz, CDCh) 5 5.78 - 5.90 (m, 1H), 4.36 -

[0277] 4.75 (m, 2H), 3.85 - 4.01 (m, 2H), 3.71 (d, J = 5.7 Hz, 3H), 2.67 - 3.09 (m, 2H).

[0278] Methyl 2-(3-aminotetrahydrofuran-3-yl)acetate The material was split into 6 x 20 mL microwave vials. To methyl 2-(dihydrofuran- 3(2H)-ylidene)acetate (5.4 g, 38 mmol) was added ammonia (110 mL, 771 mmol) 7 M in MeOH and the vials were heated at 110 °C for 3 h in the microwave. The 4 vials were concentrated, and the crude was purified by flash column chromatography (silica, 0-15% MeOH / DCM) to give the title compound (1.11 g, 18%) as a pale orange oil. ' H NMR (400 MHz, CDCh) 5 3.93 - 4.04 (m, 1H), 3.80 - 3.93 (m, 1H), 3.70 (s, 3H), 3.63 (dd, J = 21.8, 8.9 Hz, 2H), 2.52 - 2.68 (m, 2H), 1.83 - 2.02 (m, 2H), 1.72 (s, 2H).

[0279] Methyl 2-(3-(((8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)amino)tetrahydrofuran-3- yl)acetate

[0280] To a solution of 8-methyl-l,4-dioxaspiro[4.5]decane-8-carbaldehyde (1.10 g, 5.97 mmol) and methyl 2-(3-aminotetrahydrofuran-3-yl)acetate (1.11 g, 6.97 mmol) in DCM (30 mL) was added AcOH (1.4 mL, 23.9 mmol) and the mixture was stirred for 16 h. At 0 °C, sodium triacetoxyborohydride (3.91 g, 17.9 mmol) was added to the mixture and slowly warmed up to rt and stirred for 6 h. The resulting mixture was cooled to 0 °C and quenched with saturated aqueous NaHCCL solution until the aqueous layer showed pH 7~8. The quenched mixture was diluted with water and DCM. The layer was separated, and the aqueous layer was extracted twice with DCM. The combined organic layer was dried over Na2SC>4, filtered, and concentrated. The crude residue was purified by flash column chromatography (silica, 5-100% of a solution mix of 20% MeOH / EtOAc in heptanes) to give the title compound (907 mg, 48%) as a clear oil. MS (ESI): mass calcd. for C17H29NO5: 327.20, found: 328.4 [M+H]+.

[0281] 6-((8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-2-oxa-6,8-diazaspiro[4.5]decane-7,9- dione

[0282] To a solution of methyl 2-(3-(((8-methyl-l,4-dioxaspiro[4.5]decan-8- yl)methyl)amino)tetrahydrofuran-3-yl)acetate (680 mg, 2.08 mmol) in THF (7.9 mL) was added triethylamine (582 pL, 4.15 mmol) followed by trichloroacetyl isocyanate (300 pL, 2.39 mmol). The mixture was stirred at 60 °C for 17 h and was then concentrated to dryness. To the crude residue in MeOH (1.4 mL) was added ammonia 7 M in MeOH (9.08 mL, 63.6 mmol), and the mixture was stirred in the micro wave at 70 °C for 1 h and was concentrated with silica gel. The crude was purified by flash column chromatography (silica, 40 g, 5-20% of a solution mix of 20% MeOH / EtOAc in heptanes) to give the title compound (158 mg, 22%) as a white solid. MS (ESI): mass calcd. for C17H26N2O5: 338.18, found: 339.4 [M+H]+.

[0283] 6-((l-methyl-4-oxocyclohexyl)methyl)-2-oxa-6,8-diazaspiro[4.5]decane-7, 9-dione

[0284] To 6-((8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-2-oxa-6,8- diazaspiro[4.5]decane-7, 9-dione (305 mg, 901 pmol) in acetone (4.3 mL) and water (427 pL) was added p-toluenesulfonic acid monohydrate (272 mg, 1.41 mmol) and the mixture was stirred at 50 °C for 3 h. The solution was cooled down to rt and neutralized with saturated aqueous NaHCCL- DCM was added, and the phases were separated. The aqueous phase was extracted twice with DCM, and the combined organic phase was dried over Na2SC>4, filtered, and concentrated to give the crude title compound (259 mg, 98%), which was used as such for the next step. MS (ESI): mass calcd. for C15H22N2O4: 294.16, found: 295.3 [M+H]+.

[0285] 6-((4-amino-l-methylcyclohexyl)methyl)-2-oxa-6,8-diazaspiro[4.5]decane-7, 9-dione

[0286] To 6-((l-methyl-4-oxocyclohexyl)methyl)-2-oxa-6,8-diazaspiro[4.5]decane-7, 9-dione (259 mg, 880 pmol) in MeOH (8.8 mL) was added ammonium formate (560 mg, 8.80 mmol), 8 -hydroxyquinoline (38.3 mg, 264 pmol), [Cp*IrC12]2 (108 mg, 135 pmol), and AcOH (50.4 pL, 880 pmol). The mixture was stirred at 60 °C for 1 h. The reaction was concentrated to give the crude title compound with a trans / cis ratio of 35 / 65. MS (ESI): mass calcd. for C15H25N3O3: 295.10, found: 296.4 [M+H]+. l-butyl-3-(4-((7,9-dioxo-2-oxa-6,8-diazaspiro[4.5]decan-6-yl)methyl)-4- methylcyclohexyl)urea

[0287] To a solution of crude 6-((4-amino-l-methylcyclohexyl)methyl)-2-oxa-6,8- diazaspiro[4.5]decane-7, 9-dione (260 mg, 880 pmol) in DCM (8.8 mL) was added triethylamine (136 pL, 968 pmol) and butyl isocyanate (106 pL, 924 pmol) and the mixture was stirred at rt for 1.5 h. Silica gel was added, and the mixture was concentrated. The crude was purified by flash column chromatography (silica, 15-100% of 20% MeOH / EtOAc in heptanes) to give the title compound (255 mg, 73%) as a yellow foam. MS (ESI): mass calcd. for C20H34N4O4: 394.26, found: 395.4 [M+H]+. l-butyl-3-((ls,4s)-4-((7,9-dioxo-2-oxa-6,8-diazaspiro[4.5]decan-6-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(177,377,5£f)-trione

[0288] To l-butyl-3-(4-((7,9-dioxo-2-oxa-6,8-diazaspiro[4.5]decan-6-yl)methyl)-4- methylcyclohexyl)urea (205 mg, 520 pmol) in AcOH (3.0 mL) was added malonic acid (62.8 mg, 598 pmol) and the flask was heated to 60 °C. Acetic anhydride (147 pL, 1.56 mmol) was added and the reaction was heated at 90 °C for 19 h. The reaction was diluted with EtOAc, concentrated with silica gel, and purified by flash column chromatography (silica, 15-100% of a solution of 20% MeOH / EtOAc in heptanes) to give the title compound (43.2 mg, 18 %). MS (ESI): mass calcd. for C23H34N4O6: 462.25, found: 463.4 [M+H]+. Fractions corresponding to the trans product (second product to elute) were concentrated to give the trans isomer of title compound (29.7 mg, 12%). A fraction of cis / trans mixture was also collected (98 mg, 40%). l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((7,9-dioxo-2-oxa-6,8-diazaspiro[4.5]decan-6- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (8)

[0289] To a solution of l-butyl-3-((l.v,4.v)-4-((7,9-dioxo-2-oxa-6,8-diazaspiro[4.5]decan-6- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(l / f,3 / f,5H)-trione (43.2 mg, 93.4 pmmol) in THF (934 pL) was added cyanamide (39.7 mg, 934 pmol) and nickel(II) acetylacetonate (4.80 mg, 18.7 pmol). The reaction was heated to 80 °C for 17 h. The crude was cooled down to rt, filtered with a syringe filter, and concentrated. The crude was purified by preparative column chromatography (CSH-C18, 25-45% MeCN / AmB 10 mM buffer) to provide the title compound (11.1 mg, 23%) as a white solid. MS (ESI): mass calcd. for C24H36N6O6: 504.27, found: 505.4 [M+H]+. ’H NMR (400 MHz, CD3OD) 5 4.70 - 4.82 (m, 1H), 4.02 - 4.11 (m, 1H), 4.00 (d, J = 9.9 Hz, 1H), 3.80 - 3.92 (m, 3H), 3.68 - 3.78 (m, 1H), 3.60 (d, J = 9.9 Hz, 1H), 2.85 - 2.95 (m, 1H), 2.70 - 2.80 (m, 2H), 2.21 - 2.34 (m, 1H), 2.06 - 2.20 (m, 1H), 1.98 - 1.98 (m, 1H), 1.74 - 1.88 (m, 1H), 1.50 - 1.59 (m, 2H), 1.21 - 1.46 (m, 8H), 1.01 - 0.91 (m, 6H).

[0290] Example 9 and Example 10: l-butyl-5-(diaminomethylene)-3-((lR,4s)-4-(((S)-7,9-dioxo- 2-oxa-6,8-diazaspiro[4.5]decan-6-yl)methyl)-4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (9) l-butyl-5-(diaminomethylene)-3-((lS,4s)-4-(((R)-7,9-dioxo-2- oxa-6,8-diazaspiro[4.5]decan-6-yl)methyl)-4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (10)

[0291] The title compound (9) was the first peak to elute from the chiral SFC separation (i- Amylose, 25% (ACN:EtOH (1:1) + 0.1% NH4OH ) / 75% supercritical CO2), from example 8. MS (ESI): mass calcd. for C24H36N6O6: 504.27, found: 505.1 [M+H]+. ' H NMR (400 MHz, CD3CN) 5 9.89 (s, 2H), 8.18 (s, 1H), 6.10 (s, 2H), 4.65 - 4.85 (m, 1H), 3.95 (td, J = 8.9, 5.0 Hz, 1H), 3.88 (d, J = 9.8 Hz, 1H), 3.74 - 3.85 (m, 3H), 3.39 - 3.67 (m, 3H), 2.62 - 2.81 (m, 4H), 2.17 - 2.27 (m, 1H), 1.99 - 2.08 (m, 1H), 1.66 - 1.82 (m, 2H), 1.45 - 1.58 (m, 2H), 1.16

[0292] - 1.44 (m, 6H), 0.92 (t, J - 7.3 Hz, 3H), 0.89 (s, 3H). The title compound (10) was the second peak to elute from the chiral SFC separation (i-Amylose, 25% ( ACN:EtOH (1:1) + 0.1% NH4OH ) / 75% supercritical CC>2).MS (ESI): mass calcd. for C24H36N6O6: 504.27, found: 505.1 [M+H]+. ' H NMR (400 MHz, CD3CN) 59.89 (s, 2H), 8.18 (s, 1H), 6.16 (s, 2H), 4.65 - 4.80 (m, 1H), 3.95 (td, 7 = 8.9, 5.0 Hz, 1H), 3.88 (d, 7 = 9.8 Hz, 1H), 3.75 - 3.84 (m, 3H), 3.38

[0293] - 3.69 (m, 3H), 2.60 - 2.82 (m, 4H), 2.18 - 2.26 (m, 1H), 1.99 - 2.08 (m, 1H), 1.62 - 1.83 (m, 2H), 1.44 - 1.57 (m, 2H), 1.19 - 1.43 (m, 6H), 0.92 (t, J = 7.3 Hz, 3H), 0.89 (s, 3H).

[0294] Example (11) was synthesized following the last step of example (8) and by using the trans isomer l-butyl-3-((lr,4r)-4-((7,9-dioxo-2-oxa-6,8-diazaspiro[4.5]decan-6-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(177,3 / 7,5 / 7)-trione as starting materiel instead of cis 1- butyl-3-((l.v,4.v)-4-((7,9-dioxo-2-oxa-6,8-diazaspiro[4.5]decan—yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(177,3 / 7,5 / 7)-trione.

[0295] Example 12: l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((8,8-dioxido-2,4-dioxo-8-thia- l,3-diazaspiro[4.5]decan-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)- trione (12)

[0296] Synthetic scheme

[0297]

[0298] 8-thia-l,3-diazaspiro[4.5]decane-2, 4-dione

[0299] Ammonium carbonate (9.1 g, 94.7 mmol) was dissolved in MeOH (215 mL) and potassium cyanide (3.18 g, 47.3 mmol) was added. The mixture was heated to 40 °C for 30 min. Tetrahydro-4Z7-thiopyran-4-one (5.0 g, 43 mmol) was added, and the mixture was stirred over the weekend at rt. The solvent was removed, and the residue was treated with 6 M aqueous HC1 solution until pH 1. The solid formed was filtered and washed with water to afford the title compound (5.6 g, 70 %). MS (ESI): mass calcd. for C7H10N2O2S: 186.05, found: 185.3 [M-H]’.

[0300] 4-aminotetrahydro-27Z-thiopyran-4-carboxylic acid

[0301] To sodium hydroxide (13.2 g, 331 mmol) in water (100 mL) was added 8-thia-l,3- diazaspiro[4.5]decane-2, 4-dione (5.6 g, 30.1 mmol) and the solution was heated at reflux for 17 h. The solution was cooled to 0 °C and acidified with 6 M aqueous HC1 and was concentrated to dryness to give the crude title compound (4.85 g, 100%) which was used as such for the next step.

[0302] Methyl 4-aminotetrahydro-27Z-thiopyran-4-carboxylate

[0303] To 4-aminotetrahydro-2Z7-thiopyran-4-carboxylic acid (4.85 g, 30.1 mmol) in MeOH (60.2 mL) at 0 °C was added thionyl chloride (22.1 mL, 301 mmol) dropwise and the solution was heated to reflux for 6 h. The mixture was concentrated, the residue was diluted with EtOAc and the solid formed was filtered to give the title compound (4.10 g, 64%) as a white solid. MS (ESI): mass calcd. for C7H13NO2S: 175.07, found: 176.3 [M+H]+.

[0304] Methyl 4-(((8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)amino)tetrahydro-27Z- thiopyran-4-carboxylate

[0305] To a mixture of 8-methyl-l,4-dioxaspiro[4.5]decane-8-carbaldehyde (2.0 g, 10.9 mmol) and methyl 4-aminotetrahydro-2Z7-thiopyran-4-carboxylate (2.53 g, 11.9 mmol) in DCM (36.2 mL) at 0 °C was added sodium triacetoxyborohydride (7.27 g, 32.6 mmol) and the reaction was stirred at rt for 17 h. The reaction was quenched with saturated aqueous Na2COs (30 mL) solution, diluted with water (80 mL) and extracted with DCM (100 mL 2x). The combined organic layer was washed with brine, dried over Na2SC>4, filtered, and concentrated. The crude was purified by flash column chromatography (silica, DCM to 1 / 19 / 80 NPLOH / McOH / DCM) to provide the title compound (2.6 g, 70%). MS (ESI): mass calcd. for C17H29NO4S: 343.18, found: 344.4 [M+H]+. l-((l-Methyl-4-oxocyclohexyl)methyl)-8-thia-l,3-diazaspiro[4.5]decane-2, 4-dione

[0306] To ethyl 4-(((8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)amino)tetrahydro-2Z7- thiopyran-4-carboxylate (830 mg, 2.42 mmol) in AcOH (8.1 mL) was added potassium cyanate (619 mg, 7.25 mmol) and the reaction was heated at 60 °C for 16 h. Starting material was still present, so more potassium cyanate (619 mg, 7.25 mmol) was added and the vial was sealed and heated to 100 °C for 21 h. Water was added and the solution was stirred for 30 min then cooled down to rt and extracted with DCM (3x). The combined organic phase was dried over Na2SC>4, filtered, and concentrated to provide the title compound (750 mg, 100%) which was used as crude in the next step. MS (ESI): mass calcd. for C15H22N2O3S: 310.14, found: 311.4 [M+H]+. l-((l-Methyl-4-oxocyclohexyl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia-l,3- diazaspiro[4.5]decane-2, 4-dione

[0307] To a solution of l-((l-methyl-4-oxocyclohexyl)methyl)-8-thia-l,3- diazaspiro[4.5]decane-2, 4-dione (800 mg, 2.58 mmol) in a mixture of DMF (1.1 mL) and DCM (1.1 mL) at 0 °C was added A,A-diisopropylethylamine (680 pL, 3.87 mmol) followed by (2- chloromethoxyethyl)trimethylsilane (559 pL, 3.09 mmol) and the resulting was stirred at rt for 1 h. Water was added and the mixture was extracted with DCM (3x), the combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated. The crude residue was purified by flash column chromatography (silica, 10-50%, EtOAc / heptanes) to provide the title compound (350 mg, 31%). MS (ESI): mass calcd. for C2iH36N2O4SSi: 440.22, found: 439.3 [M-H]’. l-((4-Amino-l-methylcyclohexyl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia- l,3-diazaspiro[4.5]decane-2, 4-dione

[0308] To a suspension of l-((l-methyl-4-oxocyclohexyl)methyl)-3-((2- (trimethylsilyl)ethoxy)methyl)-8-thia-l,3-diazaspiro[4.5]decane-2, 4-dione (350 mg, 794 pmol) in MeOH (2.7 mL) was added ammonium formate (304 mg, 4.77 mmol), 8- hydroxyquinoline (2.9 mg, 19.9 pmol), [CpMrChh (6.33 mg, 7.94 pmol), and AcOH (45.5 pL, 794 pmol). The mixture was stirred at 50 °C for 17 h. The reaction was cooled down to rt, diluted with DCM and 1 N aqueous NaOH. Phase was separated and the aqueous phase was extracted with DCM (3x). The organic phase was dried over Na2SO4. filtered, and concentrated to give the crude title compound (350 mg, 100%) which was used as such in the next step. MS (ESI): mass calcd. for C2iH39N3O3SSi: 441.24, found: 442.4 [M+H]+. l-Butyl-3-(4-((2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia-l,3- diazaspiro[4.5]decan-l-yl)methyl)-4-methylcyclohexyl)urea

[0309] To l-((4-amino-l-methylcyclohexyl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-8- thia-l,3-diazaspiro[4.5]decane-2, 4-dione (350 mg, 792 pmol) in DCM (4.0 mL) was added triethylamine (333 pL, 2.38 mmol) followed by butyl isocyanate (100 pL, 872 p mol) and the solution was stirred for 30 min. Water was added the mixture was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na2SC>4, filtered, and concentrated. The crude was purified by flash column chromatography (silica, 0-10% MeOH / DCM) to provide the title compound (333 mg, 78%). MS (ESI): mass calcd. for C26H48N4O4SSi: 540.32, found: 541.4 [M+H]+. l-Butyl-3-(4-((8,8-dioxido-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia-l,3- diazaspiro[4.5]decan-l-yI)methyI)-4-methy!cycIohexyI)urea

[0310] To l-butyl-5-(diaminomethylene)-3-(4-((2,4-dioxo-3-((2-

[0311] (trimethylsilyl)ethoxy)methyl)-8-thia-l,3-diazaspiro[4.5]decan-l-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(l / 7,3 / 7,5 / r)-trione (170 mg, 314 pmol) in DCM (3.1 mL) at 0 °C was added 3 -chloroperbenzoic acid (108 mg, 629 pmol) and the mixture was stirred for 1 h. The reaction was quenched with the addition of saturated aqueous NaHCCL solution and extracted with DCM (x 2). The combined organic layer was dried over Na2SC>4, filtered, and concentrated. The crude was purified by flash column chromatography (silica, 0-10% MeOH / DCM) to provide the title compound (160 mg, 89%). MS (ESI): mass calcd. for C26H48N4O6SSi: 572.31 found: 617.4 [M+HC02]’ l-Butyl-3-(4-((8,8-dioxido-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia-l,3- diazaspiro[4.5]decan- l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6( trione

[0312] To l-butyl-3-(4-((8,8-dioxido-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-8-thia- l,3-diazaspiro[4.5]decan-l-yl)methyl)-4-methylcyclohexyl)urea (160 mg, 279 pmol) in DCM (2.8 mL) was added malonyl chloride (56 pL, 559 pmol) and the mixture was stirred for 1 h. Water was added and the mixture was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated. The crude was purified by flash column chromatography (silica, 20-50% EtOAc / heptanes) to provide the title compound (40 mg, 22%). MS (ESI): mass calcd. for C29H48N40sSSi: 664.30 found: 663.3 [M- H]- l-Butyl-5-(diaminomethylene)-3-(4-((8,8-dioxido-2,4-dioxo-3-((2-

[0313] (trimethylsilyl)ethoxy)methyl)-8-thia-l,3-diazaspiro[4.5]decan-l-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(17Z,37Z,57Z)-trione

[0314] To a solution of l-butyl-3-(4-((8,8-dioxido-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-8-thia-l,3-diazaspiro[4.5]decan-l-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(177,3Z7,5Zr)-trione (42.1 mg, 65.7 pmol) in THF (657 pL) was added cyanamide (27.9 mg, 657 pmol) and nickel(II) acetylacetonate (3.4 mg, 13.1 pmol). The reaction was heated to 80 °C for 17 h. The mixture was cooled down to rt, filtered with a syringe filter, and concentrated. The crude was purified by flash column chromatography (silica, 20-60% EtOAc / heptanes) to provide the title compound (45 mg, 100%). MS (ESI): mass calcd. for CaoHsoNeOsSSi: 682.32 found: 681.3 [M-H]" l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((8,8-dioxido-2,4-dioxo-8-thia-l,3- diazaspiro[4.5]decan-l-yI)methyI)-4-methyIcycIohexyI)pyrimidine-2,4,6(lH,3H,5H)- trione (12)

[0315] To l-butyl-5-(diaminomethylene)-3-(4-((8,8-dioxido-2,4-dioxo-3-((2-

[0316] (trimethylsilyl)ethoxy)methyl)-8-thia-l,3-diazaspiro[4.5]decan-l-yl)methyl)-4- mcthylcyclohcxyl)pyi'imidinc-2,4,6( 17 / ,3f / ,5f / )-ti ionc (45 mg, 65.9 pmol) in DCM (659 pL) was added trifluoroacetic acid (151 pL, 1.98 mmol) and the solution was stirred for 30 min. Saturated aqueous bicarbonate solution was added, and the biphasic solution was stirred for 10 min then was extracted with DCM (3x). The combined organic phase was dried over Na2SC>4, filtered and concentrated. The crude was purified by preparative column chromatography (CSH-C18, 25-45% MeCN / AmF 10 mM buffer) to give a white solid as a racemate. The racemic mixture was subjected to chiral separation (Phenomenex i-Amylose-3, 4% MeCN+0.1%CHO2H / MeOH), and the first peak to elute gave the title compound (4.2 mg, 12%). MS (ESI): mass calcd. for C24H36N6O7S: 552.24 found: 553.3 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 5 11.18 (bs, 1H), 9.54 (s, 2H), 7.34 (s, 2H), 4.56 - 4.81 (m, 1H), 3.59 - 3.77 (m, 4H), 3.22 (s, 2H), 3.06 - 3.16 (m, 2H), 2.53 - 2.72 (m, 2H), 2.38 - 2.45 (m, 2H), 2.21 (d, J = 13.2 Hz, 2H), 1.64 - 1.78 (m, 2H), 1.41 - 1.50 (m, 2H), 1.10 - 1.35 (m, 6H), 0.79 - 0.92 (m, 6H).

[0317] Example 13: l-butyl-5-(diaminomethylene)-3-((lr,4r)-4-((8,8-dioxido-2,4-dioxo-8-thia- l,3-diazaspiro[4.5]decan-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)- trione (13)

[0318] The title compound (13) was the second peak to elute from the reverse phase chromatography (trans product) from the example (12)

[0319] Example 14 was synthesized following the same steps as in Example 12 but without the oxidation step of the sulfide (m-CPBA). The last step was purified by prep HPLC, and the product was isolated as a cis / trans mixture.

[0320] Example 15: l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((2,2-dioxido-6,8-dioxo-2-thia-

[0321] 5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (15)

[0322]

[0323] 2-thia-5,7-diazaspiro[3.4]octane-6, 8-dione

[0324] Ammonium carbonate (12.0 g, 125 mmol) was dissolved in MeOH (284 mL) and potassium cyanide (4.19 g, 62.4 mmol) was added. The mixture was heated to 40 °C for 30 min. Thietan-3-one (5.00 g, 56.7 mmol) was added, and the mixture was stirred over the weekend at rt. The solvent was removed, and the residue was treated with 6 N aqueous HC1 solution until pH 1. The solid formed was filtered and washed with water to afford the title compound (2.7 g, 30%). MS (ESI): mass calcd. for C5H6N2O2S: 158.01, found: 157.2 [M-H]".

[0325] 7-((2-(trimethylsilyl)ethoxy)methyl)-2-thia-5,7-diazaspiro[3.4]octane-6, 8-dione To a solution of 2-thia-5,7-diazaspiro[3.4]octane-6, 8-dione (1.00 g, 6.32 mmol) in (12.6 mL) at 0 °C was added A,A-diisopropylethylamine (1.66 mL, 9.48 mmol) followed by (2- chloromethoxyethyl)trimethylsilane (1.4 mL, 9.48 mmol). After stirring at rt for 1 h, water was added and the mixture was extracted with EtOAc (3x). The combined organic phase was washed with 10% aqueous LiCl solution, dried over Na2SC>4, filtered and concentrated. The crude residue was purified by flash column chromatography (silica, 0-60%, EtOAc / heptanes) to provide the title compound (1.13 g, 62%). MS (ESI): mass calcd. for CnEbo^ChSSi: 288.10, found: 287.3 [M-H]’.

[0326] 7-((2-(Trimethylsilyl)ethoxy)methyl)-2-thia-5,7-diazaspiro[3.4]octane-6, 8-dione 2-oxide

[0327] To 7-((2-(trimethylsilyl)ethoxy)methyl)-2-thia-5,7-diazaspiro[3.4]octane-6, 8-dione (1.13 g, 3.92 mmol) in DCM (39.2 mL) at 0 °C was added 3-chloroperbenzoic acid (1.35 g, 7.84 mmol) and the mixture was stirred for 1 h. The reaction was quenched by the addition of saturated aqueous NaHCCL solution and extracted with DCM (x 2). The combined organic layer was dried over Na2SC>4, filtered, and concentrated. The crude was purified by flash column chromatography (silica, 0-10% MeOH / DCM) to provide the title compound (1.06 g, 84%). MS (ESI): mass calcd. for CnH2oN204SSi: 304.09 found: 303.2 [M-H]’

[0328] Tert-butyl ((ls,4s)-4-((2-oxido-6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2-thia-5,7- diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)carbamate

[0329] To 7-((2-(trimethylsilyl)ethoxy)methyl)-2-thia-5,7-diazaspiro[3.4]octane-6, 8-dione 2- oxide (1.06 g, 3.31 mmo) in DMF (18.7 mL) was added tert-butyl ((ls,4s)-4- (bromomethyl)cyclohexyl)carbamate (967 mg, 3.31 mmol) and cesium carbonate (1.63 g, 4.96 mmol) and the suspension was stirred at 80 °C for 17 h. Water was added and the mixture was extracted with EtOAc (3x). The combined organic phase was washed with 10% aqueous LiCl and brine, dried over Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography (silica, 20-80% EtOAc / heptanes) to give the title compound (1.10 g, 63%). MS (ESI): mass calcd. for C23H4iN30eSSi: 515.25 found: 416.3 [M-Boc+H]+

[0330] 5-(((ls,4s)-4-Aminocyclohexyl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-2-thia-5,7- diazaspiro[3.4]octane-6, 8-dione 2-oxide

[0331] To tert-butyl (( ls,4.v)-4-((2-oxido-6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2- thia-5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)carbamate (1.07 g, 2.07 mmol) in DCM (10.3 mL) was added formic acid (2.3 mL, 62.1 mmol). The reaction was stirred for 17 h and then was concentrated to give the crude title compound (860 mg, 100%). MS (ESI): mass calcd. for CisH^fCCLSSi: 415.20 found: 416.4 [M+H]+. l-Butyl-3-((ls,4s)-4-((2-oxido-6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2-thia-5,7- diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)urea

[0332] To a solution of butylamine (308 pL, 3.1 mmol) in a mixture of DCM (10.3 mL) and saturated aqueous bicarbonate (10.3 mL) solution was added triphosgene (313 mg, 1.03 mmol) in a minimal solution of DCM. The biphasic mixture was stirred for 1 h. The DCM layer was separated, dried over Na2SC>4, filtered, and concentrated slightly to give the crude isocyanate which was used as a solution.

[0333] To 5-(((ls,4.v)-4-aminocyclohexyl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-2- thia-5,7-diazaspiro[3.4]octane-6, 8-dione 2-oxide (860 mg, 2.07 mmol) in DCM (10.3 mL) was added triethylamine (433 p L, 3.1 mmol) followed by the isocyanate solution and the solution was stirred for 30 min. Water was added and the mixture was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated. The crude was purified by flash column chromatography (silica, 0-10% MeOH / DCM) to provide the title compound (800 mg, 75%). MS (ESI): mass calcd. for C23H42N4O5SSE 514.26 found: 515.3 [M+H]+. l-butyl-3-((ls,4s)-4-((2,2-dioxido-6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2-thia-

[0334] 5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)urea

[0335] To l-butyl-3-((15',45')-4-((2-oxido-6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2- thia-5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)urea (400 mg, 777 pmol) in DCM (7.8 mL) at 0 °C was added 3 -chloroperbenzoic acid (148 mg, 855 pmol) and the mixture was stirred for 1 h. The reaction was quenched with saturated aqueous NaHCCL solution and extracted with DCM (x 2). The combined organic layer was dried over Na2SC>4, filtered, and concentrated. The crude was purified by flash column chromatography (silica, 0-10% MeOH / DCM) to provide the title compound (275 mg, 67%). MS (ESI): mass calcd. for C23H42N4O6SSi: 530.26 found: 531.3 [M+H]+l-butyl-3-((ls,4s)-4-((2,2-dioxido-6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2-thia-

[0336] 5,7-diazaspiro| 3.4|octan-5-yl (methyl )cycloliexyl)pyriinidine-2,4,6( l / / ,3 / / ,5 / / )-trione

[0337] To l-butyl-3-((l.v,4.v)-4-((2,2-dioxido-6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)- 2-thia-5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)urea (275 mg, 518 pmol) in DCM (5.2 mL) was added malonyl chloride (104 pL, 1.04 mmol) and the mixture was stirred for 1 h. Water was added and the mixture was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated. The crude was purified by flash column chromatography (silica, 20-50% EtOAc / heptanes) to provide the title compound (60 mg, 19%). MS (ESI): mass calcd. for C26H42N40sSSi: 598.25 found: 597.2 [M- H]- l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((2,2-dioxido-6,8-dioxo-7-((2-(trimethylsilyl) ethoxy)methyl)-2-thia-5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)pyrimidine-

[0338] 2,4,6(177,377,577)-trione l-butyl-3-((15,45)-4-((2,2-dioxido-6,8-dioxo-7-((2-

[0339] (trimethylsilyl)ethoxy)methyl)-2-thia-5 ,7 -diazaspiro [3.4]octan-5 -yl)methyl)cyclohexyl) pyi imidinc-2,4,6( I f / ,37 / ,5f / )-ti'ionc (60 mg, 100 pmol) in THF (1 mL) was added cyanamide (42.6 mg, 1.0 mmol) and nickel(II) acetylacetonate (5.2 mg, 20 pmol). The reaction was heated to 80 °C for 42 h and then was cooled down to rt, filtered with a syringe filter, and concentrated to provide the crude title compound (16 mg, 25%). MS (ESI): mass calcd. for C27H44NeOsSSi: 640.27 found: 639.2 [M-H]’ l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((2,2-dioxido-6,8-dioxo-2-thia-5,7- diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (15)

[0340] To l-butyl-5-(diaminomethylene)-3-((l.v,4.v)-4-((2,2-dioxido-6,8-dioxo-7-((2-

[0341] (trimethylsilyl)ethoxy)methyl)-2-thia-5 ,7 -diazaspiro [3.4]octan-5 -yl)methyl)cyclohexyl) pyrimidine-2,4,6(177,3Z7,5H)-trione (15.8 mg, 24.7 pmol) in DCM (246 pL) was added trifluoroacetic acid (56.5 pL, 737 pmol) and the solution was stirred for 30 min. Saturated aqueous bicarbonate solution was added, and the biphasic solution was stirred for 10 min then was extracted with DCM (3x). The combined organic phase was dried over Na2SC>4, filtered and concentrated. The crude was purified by reverse phase chromatography (Cl 8, 5-60% MeCN / 10 mM AmF buffer) to provide the title compound (8 mg, 64%). MS (ESI): mass calcd. for C21H30N6O7S: 510.19 found: 511.2 [M+H]+. ' H NMR (400 MHz, DMSO-D6) 5 11.36 (bs, 1H), 9.56 (s, 2H), 7.31 (s, 2H), 4.52 - 4.75 (m, 5H), 3.67 - 3.79 (m, 2H), 3.51 - 3.62 (m, 2H), 2.55 - 2.63 (m, 2H), 2.02 - 2.12 (m, 1H), 1.66 - 1.76 (m, 2H), 1.38 - 1.55 (m, 4H), 1.18 - 1.34 (m, 4H), 0.87 (t, J = 7.3 Hz, 3H). Example 16: l-butyl-5-(diaminomethylene)-3-((lR,3S)-3-((5,5-dimethyl-2,4- dioxoimidazolidin-l-yl)methyl)cyclopentyl)pyrimidine-2,4,6(lH,3H,5H)-trione (16)

[0342] Tert-butyl (( l / ?.3.S)-3-(liydroxyinethyl)cyclopentyl )carbamate

[0343] To (15\3r)-(+)-3-(boc-amino)cyclopentanecarboxylic acid (1.0 g, 4.19 mmol) in anhydrous THF (12.5 mL) at -15 °C was slowly added borane dimethylsulfide complex (660 pL, 6.95 mmol) over 15 min and the solution was warmed to rt and stirred for 17 h. The reaction was quenched with the slow addition of MeOH (1 mL) and diluted with DCM (50 mL). The DCM phase was washed with saturated aqueous NaHCCL solution, dried over Na2SC>4, filtered, and concentrated to give the crude title compound (901 mg, 100%) as a clear oil that solidified upon standing. Tert-butyl (( ll?,3S)-3-(bromomethyl)cyclopentyl)carbamate

[0344] To a crude solution of tert-butyl (( 1 / ?,3.S')-3-(hydroxymcthyl)cyclopcntyl)cai'bamatc (900 mg, 4.18 mmol) in DCM (16.7 mL) was added CBia (1.66 g, 5.02 mmol). The solution was cooled to 0 °C and PPh? (1.22 g, 4.6 mmol) was slowly added. The reaction was then stirred at rt for 16 h. 30 mL of EtOAc was added and the slurry was stirred for 15 min. The white solid (triphenylphosphine oxide) was filtered and rinsed with EtOAc. The filtrate was concentrated onto silica gel and the crude was purified by flash column chromatography (silica, 0-60% EtOAc / Heptanes) to give the title compound (710 mg, 61%) as a clear colorless oil.

[0345] Tert-butyl (( ll?,3S)-3-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl) imidazolidin-l-yl)methyl)cyclopentyl)carbamate

[0346] To tert-butyl (( 1 / ?,3.S')-3-(bromomcthyl)cyclopcntyl)cai'bamatc (710 mg, 2.55 mmol) in DMF (14.4 mL) was added 5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine- 2, 4-dione (659 mg, 2.55 mmol) followed by cesium carbonate (1.26 g, 3.83 mmol) and the mixture was heated at 80 °C for 17 h then cooled down to rt. Water was added and the mixture was extracted with EtOAc (3x). The combined organic phase was washed with 10% aqueous LiCl and brine, dried over Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography (silica, DCM) to give the title compound (530 mg, 46%). MS (ESI): mass calcd. for C22H4iN30sSi: 455.28 found: 356.5 [M-Boc+H]+l-(((lS,31?)-3-aminocyclopentyl)methyl)-5,5-dimethyl-3-((2-

[0347] (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione To tert-butyl ((17?,35')-3-((5,5-dimethyl-2,4-dioxo-3-((2-

[0348] (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)cyclopentyl)carbamate (530 mg, 1.16 mmol) in DCM (11.6 mL) was added formic acid (1.32 mL, 34.9 mmol) and the reaction was stirred at rt for 17 h. The reaction was concentrated, diluted with saturated aqueous Na2CO3, and extracted with DCM. The organic layer was separated, dried over Na2SC>4, filtered, and concentrated to give the crude title compound (137 mg, 33 %). MS (ESI): mass calcd. for Ci7H33N3O3Si: 355.23 found: 356.4 [M+H]+l-butyl-3-((ll?,3S)-3-((5,5-dimethyl-2,4-dioxo-3-((2-

[0349] (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)cyclopentyl)urea

[0350] To l-(((lS,37?)-3-aminocyclopentyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl) ethoxy)methyl)imidazolidine-2, 4-dione (137 mg, 385 pmol) in DCM (1.9 mL) was added triethylamine (80.6 p L, 578 pmol) and butyl isocyanate (48.7 pL, 424 pmol) and the reaction was stirred for 30 min. Water was added and the mixture was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na3SO4, filtered and concentrated. The crude was purified by flash column chromatography (silica, 0-10% MeOH / DCM) to provide the title compound (125 mg, 71 %). MS (ESI): mass calcd. for C22H42N4O4SE 454.30 found: 455.5 [M+H]+l-butyl-3-((ll?,3S)-3-((5,5-dimethyl-2,4-dioxo-3-((2-

[0351] (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)cyclopentyl)pyrimidine-

[0352] 2,4,6(17 / ,37 / ,57 / )-trione

[0353] To l-butyl-3-((17?,3S')-3-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl) ethoxy)methyl)imidazolidin-l-yl) methyl)cyclopentyl)urea (125 mg, 275 pmol) in DCM (2.8 mL) was added malonyl chloride (55.1 pL, 550 pmol) and the mixture was stirred at rt for 1 h. Water was added and the mixture was extracted with DCM (3x). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography (silica, 20-50% EtOAc / heptanes) to provide the title compound (70 mg, 49 %). MS (ESI): mass calcd. for C25H42N4O6SE 522.29 found: 521.4 [M- H]- l-butyl-5-(diaminomethylene)-3-((ll?,3S)-3-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)cyclopentyl)pyrimidine- 2,4,6(17 / ,37 / ,57 / )-trione l-butyl-3-((17?,3S')-3-((5,5-dimethyl-2,4-dioxo-3-((2-

[0354] (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)cyclopentyl)pyrimidine-

[0355] 2,4,6(l / 7,3 / 7,5 / r)-trione (70 mg, 134 pmol), cyanamide (56.9 mg, 1.34 mmol), and nickel(II) acetylacetonate (6.9 mg, 26.8 pmol) were dissolved in THF (1.3 mL) and the mixture was heated to 80 °C for 17 h. The reaction was cooled down to rt, filtered and concentrated. The crude was purified by flash column chromatography (silica, 20-60% EtOAc / heptanes) to give the title compound (34 mg, 45%). MS (ESI): mass calcd. for C26H44N60eSi: 564.31 found:

[0356] 563.4 [M-H]- l-butyl-5-(diaminomethylene)-3-((lR,3S)-3-((5,5-dimethyl-2,4-dioxoimidazolidin-l- yI)methyI)cycIopentyI)pyrimidine-2,4,6(lH,3H,5H)-trione (16)

[0357] To l-butyl-5-(diaminomethylene)-3-((17?,3S')-3-((5,5-dimethyl-2,4-dioxo-3-((2-

[0358] (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)cyclopentyl)pyrimidine- 2,4,6(177,3Z7,5H)-trione (31 mg, 54.9 p mol) in DCM (549 p L) was added trifluoroacetic acid (126 |iL, 1.65 mmol) and the solution was stirred for 30 min. Saturated aqueous bicarbonate solution was added, and the biphasic solution was stirred for 10 min then was extracted with DCM (3x). The combined organic phase was dried over Na2SC>4, filtered and concentrated. The crude was purified by reverse phase chromatography (Cl 8, 20-40% MeCN / 10 mM AmF buffer) to provide the title compound (8.4 mg, 35 %). MS (ESI): mass calcd. for C20H30N6O5: 434.23 found: 435.4 [M+H]+, 433.4 [M-H]’.1H NMR (400 MHz, DMSO-d6) 5 10.69 (s, 1H), 9.53 (s, 2H), 7.32 (s, 2H), 5.14 - 5.31 (m, 1H), 3.63 - 3.80 (m, 2H), 3.26 (dd, J = 14.2, 7.7 Hz, 1H), 3.15 (dd, 7 = 14.3, 7.4 Hz, 1H), 2.17 - 2.27 (m, 1H), 1.98 - 2.09 (m, 1H), 1.87 (q, 7 = 10.9 Hz, 1H), 1.59 - 1.77 (m, 4H), 1.37 - 1.51 (m, 2H), 1.16 - 1.31 (m, 8H), 0.86 0. 7 = 7.3 Hz, 3H).

[0359] Example 17 was synthesized following the same sequence of steps as in the Example 16 and by using (17?,3S')-3-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid as starting materiel instead of (lS',37?)-3-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid. The last step was purified by reverse phase chromatography (C18, 20-40% MeCN / 10 mM AmF buffer).

[0360] Example 18: l-butyl-3-(4-((3-cyclopropyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4- yl)methyl)-4-(hydroxymethyl)cyclohexyl)-5-(diaminomethylene)pyrimidine- 2,4,6(lH,3H,5H)-trione (18)

[0361] Synthetic Scheme:

[0362] 5-cyclopropyl-l,3,4-oxadiazol-2(3H)-one

[0363] To a solution of cyclopropanecarbohydrazide (5 g, 49.94 mmol) in THF (50 mL) was added diphenyl carbonate (10.7 g, 50 mmol) and DBU (1.52 g, 10 mmol, 1.51 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried with anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 20 : 1 to 1 : 1) to give the title compound (2.6 g, 41%) as a colorless oil. ' H NMR (400 MHz, CDCh): 5 ppm 9.72 (s, 1H), 1.81-1.88 (m, 1H), 1.01-1.04 (m, 4H). 8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carbonitrile o OBn

[0364] To a solution of l,4-dioxaspiro[4.5]decane-8-carbonitrile (25 g, 149.5 mmol) in THF (125 mL) was added dropwise LDA (2.0 M, 149.5 mL) at 0 °C over 30 min and the mixture was stirred at 25 °C for 30 min. The mixture was cooled to 0 °C, and chloromethoxymethylbenzene (28.10 g, 179.42 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was quenched with saturated aqueous NH4CI (100 mL) and was extracted with ethyl acetate (90 mL x 3). The organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 20 : 1 to 1 : 1) to give the title compound (22 g, 51%) as a white solid. MS (ESI): mass calcd. C17H21NO3: 287.15, found: 288.1 [M+H]+.

[0365] [8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8-yl]methanamine

[0366] To a solution of 8-(benzyloxymethyl)-l,4-dioxaspiro[4.5]decane-8-carbonitrile (26 g, 90.48 mmol) in THF (260 mL) was added dropwise LiAlEL (2.5 M in THF, 54.3 mL) at 0 °C over 1 h. The mixture was stirred at 20 °C for 11 h. The reaction was quenched with H2O (5 mL), 15% aqueous NaOH (5 mL) and H2O (15 mL). The mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 20 : 1 to 1 : 1) to give the title compound (16 g, 61%) as a yellow oil. MS (ESI): mass calcd. C17H25NO3: 291.18, found: 292.2 [M+H]+.

[0367] 4-[[8-(benzyloxymethyl)-l,4-dioxaspiro[4.5]decan-8-yl]methyl]-3-cyclopropyl-lH-l,2,4- triazol-5-one

[0368] To a solution of [8-(benzyloxymethyl)-l,4-dioxaspiro[4.5]decan-8-yl]methanamine (3 g, 10.3 mmol) in MeOH (30 mL) was added 5-cyclopropyl-3H-l,3,4-oxadiazol-2-one (1.3 g, 10.3 mmol). After stirring at 70 °C for 12 h, the reaction was concentrated under reduced pressure. The residue was dissolved in NaOH (30 mL, 1 N) and stirred at 100 °C for 12 h. The reaction was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 20 : 1 to 0 : 1) to give the title compound (2.7 g, 94%) as a white solid. MS (ESI): mass calcd. C22H29N3O4: 399.22, found: 400.2 [M+H]+.

[0369] 4-[[8-(benzyloxymethyl)-l,4-dioxaspiro[4.5]decan-8-yl]methyl]-5-cyclopropyl-2-(2- trimethyIsiIyIethoxymethyI)-l,2,4-triazoI-3-one

[0370] To a solution of 4-[[8-(benzyloxymethyl)-l,4-dioxaspiro[4.5]decan-8-yl]methyl]-3- cyclopropyl-lH-l,2,4-triazol-5-one (2.7 g, 6.26 mmol) in DCM (27 mL) was added DIPEA (2.43 g, 18.77 mmol) and SEM-C1 (1.57 g, 9.39 mmol). The mixture was stirred at 25 °C for 12 h, poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried with anhydrous Na2SC>4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 20 : 1 to 1 : 1) to give the title compound (2.6 g, 78%) as a colorless oil. MS (ESI): mass calcd. C28H43N30sSi: 529.30, found: 530.2 [M+H]+

[0371] 4-[[l-(benzyloxymethyl)-4-oxo-cyclohexyl]methyl]-5-cyclopropyl-2-(2- trimethylsilylethoxymethyl)-l,2,4-triazol-3-one

[0372] To a solution of 4-[[8-(benzyloxymethyl)-l,4-dioxaspiro[4.5]decan-8-yl]methyl]-5- cyclopropyl-2-(2-trimethylsilylethoxymethyl)-l,2,4-triazol-3-one (2.3 g, 4.34 mmol) in H2O (10 mL) and acetone (23 mL) was added TsOH-EhO (1.65 g, 8.68 mmol). The mixture was stirred at 50 °C for 3 h. The mixture was adjusted to pH ~6 with saturated aqueous NaHCCL (20 mL) and extracted with DCM (25 mL x 3). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. Petroleum ether : Ethyl acctatc= 20 : 1 to 1 : 1) to give the title compound (1.6 g, 90%) as a white solid. MS (ESI): mass calcd. C26H39N3O4Si: 485.27, found: 508.3 [M+Na]+.

[0373] 4-[[4-amino-l-(benzyloxymethyl)cyclohexyl]methyl]-5-cyclopropyl-2-(2- trimethylsilylethoxymethyl) - 1 ,2,4-triazol-3-one

[0374] To a solution of 4-[[l-(benzyloxymethyl)-4-oxo-cyclohexyl]methyl]-5-cyclopropyl-2- (2-trimethylsilylethoxymethyl)-l,2,4-triazol-3-one (1.5 g, 3.09 mmol) in MeOH (50 mL) was added ammonium acetate (4.76 g, 61.77 mmol) and sodium triacetoxyborohydride (1.64 g, 7.72 mmol). The mixture was stirred at 25 °C for 1 h, poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (1.5 g, 99%) as a white solid. MS (ESI): mass calcd. C26H42N4O3Si: 486.30, found: 487.3 [M+H]+. l-[4-(benzyloxymethyl)-4-[[3-cyclopropyl-5-oxo-l-(2-trimethylsilylethoxymethyl)-l,2,4- triazol-4-yl]methyl] cyclohexyl]-3-butyl-urea To a solution of 4-[[4-amino-l-(benzyloxymethyl)cyclohexyl]methyl]-5-cyclopropyl- 2-(2-trimethylsilylethoxymethyl)-l,2,4-triazol-3-one (1.5 g, 3.08 mmol) in DCM (15 mL) was added 1-isocyanatobutane (306 mg, 3.08 mmol) and TEA (312 mg, 3.08 mmol). After stirring at 25 °C for 2 h, the reaction was added H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 20 : 1 to 0 : 1) to give the title compound (1.5 g, 83%) as a colorless oil. MS (ESI): mass calcd. CsiHsiNsCLSi: 585.37, found: 586.4 [M+H]+. l-[4-(benzyloxymethyl)-4-[[3-cyclopropyl-5-oxo-l-(2-trimethylsilylethoxymethyl)-l,2,4- triazoI-4-yI]methyI] cyclohexyl]-3-butyl-hexahydropyrimidine-2, 4, 6-trione

[0375] To a solution of l-[4-(benzyloxymethyl)-4-[[3-cyclopropyl-5-oxo-l-(2- trimethylsilylethoxymethyl)-l,2,4-triazol-4-yl]methyl]cyclohexyl]-3-butyl-urea (1.5 g, 2.56 mmol) in AcOH (15 mL) was added malonic acid (266 mg, 2.56 mmol) and AC2O (1.83 g, 17.92 mmol). The mixture was stirred at 80 °C for 2 h. Upon completion, the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 20 : 1 to 1 : 1) to give the title compound (900 mg, 1.38 mmol, 54%) as a yellow oil. MS (ESI): mass calcd. C34HsiNsO6Si: 653.36, found: 676.4 [M+Na]+. l-[4-(benzyloxymethyl)-4-[[3-cyclopropyl-5-oxo-l-(2-trimethylsilylethoxymethyl)-l,2,4- triazol-4-yl]methyl] cyclohexyl]-3-butyl-5-(diaminomethylene)hexahydropyrimidine- 2, 4, 6- trione

[0376] To a solution of l-[4-(benzyloxymethyl)-4-[[3-cyclopropyl-5-oxo-l-(2- trimethylsilylethoxymethyl)- 1 ,2 ,4-triazol-4-yl] methyl] cyclohexyl] -3 -propyl- hexahydropyrimidine-2, 4, 6-trione (750 mg, 1.17 mmol) in THF (8 mL) was added Ni(acac)2 (90 mg, 352 pmol) and cyanamide (493 mg, 11.72 mmol). The mixture was stirred at 80 °C for 12 h and filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 20 : 1 to 1 : 1) to give the title compound (350 mg, 43%) as a yellow solid. MS (ESI): mass calcd. C sHs NvOeSi: 695.38, found: 696.5 [M+H]+. l-butyl-3-(4-((3-cyclopropyl-5-oxo-l-((2-(trimethylsilyl)ethoxy)methyl)-l,5-dihydro-4H- l,2,4-triazol-4-yl)methyl)-4-(hydroxymethyl)cyclohexyl)-5-

[0377] (diaminomethylene)pyrimidine-2,4,6(lH,3H,5H)-trione

[0378] To a solution of l-[4-(benzyloxymethyl)-4-[[3-cyclopropyl-5-oxo-l-(2- trimethylsilylethoxymethyl)-l,2,4-triazol-4-yl]methyl]cyclohexyl]-3-butyl-5- (diaminomethylene)hexahydropyrimidine-2, 4, 6-trione (320 mg, 460 pmol) in EtOH (2 mL) was added Pd(OH)2 / C (10%, 1 g) under N2. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (50 psi) at 50 °C for 12 h and filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiCL, petroleum ether : ethyl acetate = 1 : 2) to give the title compound (170 mg, 61%) as a white solid. MS (ESI): mass calcd. C28H47N?O6Si: 605.34, found: 628.4 [M+Na]+. l-butyl-3-(4-((3-cyclopropyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)methyl)-4-

[0379] (hydroxymethyl)cyclohexyl)-5-(diaminomethylene)pyrimidine-2,4,6(lH,3H,5H)-trione

[0380]

[0381] A solution of 1 -butyl-3- [4-[[3-cyclopropyl-5-oxo- 1 -(2-trimethylsilylethoxymethyl)- l,2,4-triazol-4-yl]methyl]-4-(hydroxymethyl)cyclohexyl]-5- (diaminomethylene)hexahydropyrimidine-2, 4, 6-trione (5 mg, 8.25 pmol), TFA (0.5 mL) and H2O (0.2 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure. To the residue was added MeOH (1 mL) and K2CO3 (1.14 mg, 8.25 pmol) and stirred at 25 °C for 1 h. Aqueous citric acid (15%) was added to the reaction until pH = 6-7, and the solution was extracted with DCM (3 mL x 3). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep- HPLC (H2O (10 mM NH4HCC>3)-ACN; gradient: 20-50%) to give the title compound (3 mg, 76.4%) as a white solid. MS (ESI): mass calcd. C22H33N7O5: 475.25, found: 476.3 [M+H]+. ’H NMR (400 MHz, DMSO-rfo): 5 ppm 9.54 (s, 2H), 7.39 (s, 2H), 4.90-4.96 (m, 1H), 4.62- 4.67 (m, 1H), 3.74 (t. J = 7.2 Hz, 2H), 3.51 (d, 7 = 7.6 Hz, 2H), 3.44 (s, 2H), 2.44 (s, 2H), 1.94- 1.98 (m, 1H), 1.60-1.64 (m, 2H), 1.43-1.46 (m, 2H), 1.22-1.31 (m, 6H), 0.86-0.91 (m, 5H),

[0382] 0.76-0.80 (m, 2H).

[0383] Example 19: l-butyl-5-(diaminomethylene)-3-(4-((3-isopropyl-5-oxo-l,5-dihydro-4H- l,2,4-triazol-4-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (19)

[0384] 8-methyl-l,4-dioxaspiro[4.5]decane-8-carbonitrile

[0385] OCX

[0386] To a solution of l,4-dioxaspiro[4.5]decane-8-carbonitrile (10 g, 59.81 mmol) in THF (100 mL) was added LiHMDS (1 M in THF, 68.8 mL) at 0 °C under N2 and was stirred for 1 h. Mel (8.91 g, 62.8 mmol) was then added at 0 °C. The reaction was stirred at 0 °C for 1 h. After completion, the reaction was added saturated aqueous NH4CI (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 1 : 0 to 20 : 1) to give the title compound (9.5 g, 88%) as a white solid.1H NMR (400 MHz; DMSO-rfc) 5 ppm 3.77-3.98 (m, 4H), 1.89 (d, 7 = 12.4 Hz, 2H), 1.48-1.77 (m, 6H), 1.33 (s, 3H). l-bicyclo[2.1.1]hexanylmethyl 4-methylbenzenesulfonate

[0387] To a solution of 8-methyl-l,4-dioxaspiro[4.5]decane-8-carbonitrile (8.5 g, 46.9 mmol) in THF (85 mL) was added LAH (2.5 M, 22.5 mL) dropwise at 0 °C under N2. The reaction was stirred at 25 °C for 16 h. After completion, the reaction was quenched with H2O (2.2 mL), 15% NaOH (2.2 mL) and H2O (7 mL). The mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (7.25 g, 83%) as a white solid. ' H NMR (400 MHz, DMSO-rfc) 5 ppm 3.82 (s, 4H), 2.33 (s, 2H), 1.45-1.55 (m, 4H), 1.34-1.43 (m, 2H), 1.18-1.28 (m, 2H), 0.81 (s, 3H).

[0388] 3-isopropyl-4-[(8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl]-lH-l,2,4-triazol-5-one

[0389] A mixture of (8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methanamine (6 g, 32.4 mmol) and 5-isopropyl-3H-l,3,4-oxadiazol-2-one (4.15 g, 32.4 mmol) in MeOH (60 mL) was stirred at 70 °C for 16 h. The mixture was concentrated under reduced pressure, and NaOH (1 N, 100 mL) was added and stirred at 100 °C for 16 h. After completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si CL. petroleum ether : ethyl acetate = 1 : 0 to 3 : 7) to give the title compound (5.3 g, 55%) as a yellow solid. ' H NMR (400 MHz, DMSO-rfc) 5 ppm 11.35-11.42 (m, 1H), 3.82 (s, 4H), 3.41 (s, 2H), 2.83-2.91 (m, 1H), 1.46-1.60 (m, 6H), 1.26-1.34 (m, 2H), 1.15 (d, 7 = 6.8 Hz, 6H), 0.88 (s, 3H).

[0390] 5-isopropyl-4-[(8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl]-2-(2- trimethylsilylethoxymethyl)-!, 2, 4-triazol-3-one

[0391] To a mixture of 3-isopropyl-4-[(8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl]-lH- l,2,4-triazol-5-one (5.3 g, 17.94 mmol) and DIPEA (9.28 g, 71.8 mmol) in DCM (60 mL) was added SEM-C1 (5.98 g, 35.9 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 16 h. After completion, the mixture was poured into water (50 mL) and extracted with DCM (50 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 1 : 0 to 7 : 3) to give the title compound (5.6 g, 73%) as a yellow oil. ’H NMR (400 MHz, DMSO-rfc) 5 ppm 4.99 (s, 2H), 3.83 (s, 4H), 3.53 (t, 7 = 8.0 Hz, 2H), 3.48 (s, 2H), 2.89-3.00 (m, 1H), 1.45-1.66 (m, 6H), 1.26-1.37 (m, 2H), 1.18 (d, J = 6.8 Hz, 6H), 0.89 (s, 3H), 0.83 (t, J = 8.0 Hz, 2H), -0.05 (s, 9H).

[0392] 5-isopropyl-4-[(l-methyl-4-oxo-cyclohexyl)methyl]-2-(2-trimethylsilylethoxymethyl)- 1 ,2,4- triazol-3 -one

[0393] To a solution of 5-isopropyl-4-[(8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl]-2-(2- trimethylsilylethoxymethyl)-l,2,4-triazol-3-one (5.6 g, 13.16 mmol) in acetone (40 mL) and H2O (20 mL) was added TsOH- fLO (5.01 g, 26.3 mmol) under N2. The mixture was stirred at 50 °C for 3 h, poured into water (50 mL). and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (5 g, 99%) as a yellow oil.1H NMR (400 MHz, DMSO-rfc) 5 ppm 4.99 (s, 2H), 3.63 (s, 2H), 3.54 (t, J = 8.0 Hz, 2H), 2.92- 3.06 (m, 1H), 2.25-2.41 (m, 4H), 1.67-1.79 (m, 2H), 1.56-1.67 (m, 2H), 1.18 (d, 7 = 6.8 Hz, 6H), 1.05 (s, 3H), 0.77-0.86 (m, 2H), -0.06 (s, 9H).

[0394] 4-[(4-amino-l-methyl-cyclohexyl)methyl]-5-isopropyl-2-(2-trimethylsilylethoxymethyl)- 1 ,2,4- triazol-3 -one

[0395] To a solution of 5-isopropyl-4-[(l-methyl-4-oxo-cyclohexyl)methyl]-2-(2- trimethylsilylethoxymethyl)-l,2,4-triazol-3-one (5 g, 13.1 mmol) in MeOH (50 mL) was added NH4OAC (20.2 g, 262 mmol) and NaBH(OAc)3 (6.94 g, 32.8 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 16 h. After completion, the mixture was added saturated NaHCCL (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (5 g, crude) as a yellow oil. MS (ESI): mass calcd. Ci9H38N4O2Si: 382.28, found: 383.3 [M+H]+. l-butyl-3-[4-[[3-isopropyl-5-oxo-l-(2-trimethylsilylethoxymethyl)-l,2,4-triazol-4- yl]methyl]-4-methyl-cyclohexyl]urea

[0396] To a solution of 4-[(4-amino-l-methyl-cyclohexyl)methyl]-5-isopropyl-2-(2- trimethylsilylethoxymethyl)-l,2,4-triazol-3-one (5 g, 13.07 mmol) in DCM (50 mL) was added TEA (1.32 g, 13.07 mmol) and 1-isocyanatobutane (1.30 g, 13.07 mmol) in one portion at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. After completion, the mixture was quenched with MeOH (1 mL), diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 1 : 0 to 7 : 3) to give the title compound (4.7 g, 76%) as a yellow oil. ’H NMR (400 MHz, DMSO-rfc) 5 ppm 5.59-5.82 (m, 1H), 4.98 (s, 2H), 3.46-3.60 (m, 3H), 3.40-3.46 (m, 1H), 3.14-3.27 (m, 1H), 2.87-3.02 (m, 3H), 1.40-1.69 (m, 4H), 1.06-1.40 (m, 15H), 0.76-0.92 (m, 8H), -0.06 (s, 9H). l-butyl-3-[4-[[3-isopropyl-5-oxo-l-(2-trimethylsilylethoxymethyl)-l,2,4-triazol-4- yl]methyl]-4-methyl-cyclohexyl]hexahydropyrimidine-2, 4, 6-trione

[0397] To a mixture of l-butyl-3-[4-[[3-isopropyl-5-oxo-l-(2-trimethylsilylethoxymethyl)- l,2,4-triazol-4-yl]methyl]-4-methyl-cyclohexyl]urea (4.6 g, 9.55 mmol) and malonic acid (994 mg, 9.55 mmol) in AcOH (45 mL) was added AC2O (6.82 g, 66.84 mmol) at 25 °C under N2. The mixture was stirred at 80 °C for 8 h. After completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 1 : 0 to 4 : 1) to give the title compound (3.4 g, 64.8%) as a yellow oil. ’H NMR (400 MHz, DMSO-rfc) 5 ppm 4.98 (d, J = 2.4 Hz, 2H), 4.31-4.60 (m, 1H), 3.66-3.74 (m, 4H), 3.50-3.58 (m, 2H), 2.88-3.05 (m, 1H), 2.60-2.71 (m, 1H), 2.27-2.41 (m, 1H), 1.63-1.75 (m, 1H), 1.16- 1.51 (m, 17H), 0.98 (s, 1H), 0.80-0.94 (m, 6H), 0.77 (s, 1H), -0.05 (s, 9H). l-butyl-5-(diaminomethylene)-3-[4-[[3-isopropyl-5-oxo-l-(2- trimethylsilylethoxymethyl)-l,2,4-triazol-4-yl]methyl]-4-methyl- cyclohexyl]hexahydropyrimidine-2, 4, 6-trione

[0398] To a solution of l-butyl-3-[4-[[3-isopropyl-5-oxo-l-(2-trimethylsilylethoxymethyl)- 1, 2, 4-triazol-4-yl]methyl]-4-methyl-cyclohexyl]hexahydropyrimidine-2, 4, 6-trione (1 g, 1.82 mmol) in THF (10 mL) was added cyanamide (765 mg, 18.19 mmol) and Ni(acac)2 (140.19 mg, 546 pmol) under N2. The mixture was stirred at 80 °C for 16 h. After completion, the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 1 : 0 to 3 : 1) to provide the title compound (0.6 g, 56%) as a yellow oil.1H NMR (400 MHz, DMSO-rfc) 5 ppm 9.55 (d, J = 10.4 Hz, 2H), 7.32 (s, 2H), 4.98 (d, 7 = 3.2 Hz, 2H), 4.49-4.76 (m, 1H), 3.66-3.80 (m, 3H), 3.50-3.59 (m, 2H), 2.89-3.04 (m, 1H), 1.69 (d, 7 = 12.0 Hz, 1H), 1.17-1.51 (m, 17H), 0.99 (s, 2H), 0.74-0.92 (m, 7H), -0.05 (s, 9H). l-butyl-5-(diaminomethylene)-3-(4-((3-isopropyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (19) A solution of l-butyl-5-(diaminomethylene)-3-[4-[[3-isopropyl-5-oxo-l-(2- trimethylsilylethoxymethyl)- 1 ,2 ,4-triazol-4-yl] methyl] -4-methyl- cyclohexyl]hexahydropyrimidine-2, 4, 6-trione (0.15 g, 253 pmol) in H2O (0.2 mL) and TFA (1 mL) was stirred at 25 °C for 30 min. The mixture was concentrated under reduced pressure and dissolved in MeOH (2 mL). K2CO3 (210 mg, 1.52 mmol) was added. After stirring at 25 °C for 30 min, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (15 mg, 12%) as a white solid. MS (ESI): mass calcd. C22H35N7O4: 461.28, found: m / z (ESI, +ve ion) = 462.3 [M+H]+. ' H NMR (400 MHz, DMSO- dd) 5 ppm 11.38 (d, 7 = 8.4 Hz, IH), 9.55 (s, 2H), 7.33 (s, 2H), 4.56-4.70 (m, IH), 3.65-3.75 (m, 3H), 3.38 (s, IH), 2.86-2.92 (m, IH), 2.73-2.77 (m, IH), 2.47 (s, IH), 1.69 (d, 7 = 12.0 Hz, IH), 1.11-1.52 (m, 15H), 0.70-1.04 (m, 6H).

[0399] Example 20 and Example 21. l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((3-isopropyl-5- oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)methyl)-4-methylcyclohexyl)pyrimidine-

[0400] 2,4,6(lH,3H,5H)-trione & l-butyl-5-(diaminomethylene)-3-((lr,4r)-4-((3-isopropyl-5- oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)methyl)-4-methylcyclohexyl)pyrimidine-

[0401] 2,4,6(lH,3H,5H)-trione l-butyl-5-(diaminomethylene)-3-[4-[(3-isopropyl-5-oxo-lH-l,2,4-triazol-4-yl)methyl]-4- methyl-cyclohexyl]hexahydropyrimidine-2, 4, 6-trione (60 mg) was separated by chiral SFC (column: ChiralPak IH, 250*30mm, 10 um; mobile phase: CO2-IPA (0.1% NH3H2O); 35% B with isocratic elution) to give 20 (12.34 mg) as a white solid as the first eluting peak. MS (ESI): mass calcd. C22H35N7O4: 461.28, found: 462.3 [M+H]+. ’H NMR (400 MHz, DMSO- dd) 5 ppm 11.38 (s, IH), 9.56 (s, 2H), 7.34 (s, 2H), 4.69 (s, IH), 3.76 0. 7 = 7.2 Hz, 2H), 3.66 (s, 2H), 2.87-2.91 (m, IH), 2.73-2.79 (m, 2H), 1.69 (d, 7 = 12.8 Hz, 2H), 1.42-1.48 (m, 2H), 1.14-1.35 (m, 12H), 0.88 (t, J - 7.2 Hz, 3H), 0.75 (s, 3H). The second eluting peak was collected to give 21, (15.66 mg) as a white solid. MS (ESI): mass calcd. C22H35N7O4: 461.28, found: 462.3 [M+H]+. ' H NMR (400 MHz, DMSO-rfc) 5 ppm 11.40 (s, IH), 9.54 (s, 2H), 7.32 (s, 2H), 4.57 (t, J = 12.8 Hz, IH), 3.73 (t, J = 7.2 Hz, 2H), 3.38 (s, 2H), 2.90-2.94 (m, IH), 2.40-2.49 (m, 2H), 1.37-1.52 (m, 4H), 1.21-1.36 (m, 6H), 1.16 (d, J = 6.8 Hz, 6H), 0.98 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H).

[0402] Example 22 was prepared in an identical fashion to Example 19 starting from 5 -ethyl- 1,3,4- oxadiazol-2(3H)-one.

[0403] Example 23 and Example 24 were obtained from the first eluting peak from chiral SFC separation of Example 22 using similar SFC conditions to those used to separate Example 20 and Example 21.

[0404] Example 25. l-butyl-5-(diaminomethylene)-3-(4-methyl-4-((3-methyl-2-oxo-l,2- dihydropyridin-4-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (25)

[0405] To a solution of (8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methanol (7.6 g, 40.81 mmol) in toluene (73 mL) was added PPI13 (16.05 g, 61.2 mmol), imidazole (5.56 g, 81.6 mmol) and I2 (15.54 g, 61.2 mmol). The mixture was stirred at 100 °C for 1 h under N2. The reaction was quenched with saturated Na2SC>3, diluted with H2O (80 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 94 : 6) to afford the title compound (10.8 g, 80%) as a white solid. ’H NMR (400 MHz, DMSO-rfo): 5 ppm 3.84 (s, 4H), 3.34 (s, 2H), 1.43- 1.55 (m, 8H), 0.96 (s, 3H).

[0406] 2-methoxy-3-methyl-4-[(8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl]pyridine

[0407] To a solution of 8-(iodomethyl)-8-methyl-l,4-dioxaspiro[4.5]decane (2.5 g, 8.44 mmol) and 4-bromo-2-methoxy-3-methyl-pyridine (1.71 g, 8.44 mmol) in DMA (25 mL) was added NiC12(DME) (185.5 mg, 844 pmol), 1,10-phenanthroline (152 mg, 844 pmol), Zn (1.10 g, 16.88 mmol), Nal (316 mg, 2.11 mmol), and TFA (97 mg, 844 pmol). After heating at 60 °C for 16 h under N2, the reaction was quenched with saturated NH4CI (5 mL), diluted with H2O (50 mL) and extracted with ethyl acetate (45 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (2 g, 81%) as a white solid.:H NMR (400 MHz, DMSO- d6) 5 ppm 7.77-7.91 (m, 1H), 6.69 (d, J = 5.2 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 4H), 2.58 (s, 2H), 2.09 (s, 3H), 1.43-1.60 (m, 6H), 1.27-1.37 (m, 2H), 0.85 (s, 3H).

[0408] 4-[(2-methoxy-3-methyl-4-pyridyl)methyl]-4-methyl-cyclohexanone of 2-methoxy-3-methyl-4-[(8-methyl-l,4-dioxaspiro[4.5]decan-8- yl)methyl]pyridine (2 g, 6.86 mmol), TSOH H2O (3.79 g, 19.9 mmol) in acetone (16 mL) and H2O (8 mL) was degassed and purged with N2 3 times. The mixture was stirred at 50 °C for 16h under N2. The reaction was diluted with H2O (50 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layer was washed with saturated NaHCCh, brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (1.47 g, 86.6%) as a white solid. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 7.94 (d, J = 5.2 Hz, 1H), 6.81 (d, 7 = 5.6 Hz, 1H), 3.92 (s, 3H), 2.78 (s, 2H), 2.41-2.44 (m, 2H), 2.25-2.35 (m, 2H), 2.19 (s, 3H), 1.63-1.86 (m, 4H), 1.08 (s, 3H).

[0409] 4-[(2-methoxy-3-methyl-4-pyridyl)methyl]-4-methyl-cyclohexanamine

[0410] A mixture of 4-[(2-methoxy-3-methyl-4-pyridyl)methyl]-4-methyl-cyclohexanone (1.47 g, 5.94 mmol), NaBH(OAc)3 (3.78 g, 17.83 mmol), NH4OAC (9.16 g, 118.87 mmol) in MeOH (15 mL) was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 1 h under N2. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM : IPA (3 : 1) (45 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (1.4 g, crude) as a white solid. MS (ESI): mass calcd. for C15H24N2O: 248.19, found: 249.1 [M+H]+. l-butyl-3-[4-[(2-methoxy-3-methyl-4-pyridyl)methyl]-4-methyl-cyclohexyl]urea

[0411] A mixture of 4-[(2-methoxy-3-methyl-4-pyridyl)methyl]-4-methyl-cyclohexanamine (1.4 g, 5.64 mmol), 1-isocyanatobutane (559 mg, 5.64 mmol), TEA (570 mg, 5.64 mmol) in DCM (15 mL) was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 30 min under N2. The reaction was quenched with MeOH (2mL), diluted with H2O (50 mL) and extracted with DCM (45 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to give the title compound (1.1 g, 56%) as a white solid.:H NMR (400 MHz, DMSO-rfo) 5 ppm 7.85 (t, J = 5.2 Hz, 1H), 6.65-6.71 (m, 1H), 5.68-5.76 (m, 1H), 5.56-5.66 (m, 1H), 3.84 (s, 3H), 3.39- 3.47 (m, 1H), 2.92-2.97 (m, 2H), 2.61 (s, 2H), 2.10 (d, J = 4.8 Hz, 3H), 1.56-1.65 (m, 2H), 1.49-1.55 (m, 1H), 1.22-1.35 (m, 9H), 0.83-0.88 (m, 6H). l-butyl-3-[4-[(2-methoxy-3-methyl-4-pyridyl)methyl]-4-methyl- cyclohexyl]hexahydropyrimidine-2, 4, 6-trione

[0412] A mixture of l-butyl-3-[4-[(2-methoxy-3-methyl-4-pyridyl)methyl]-4-methyl- cyclohexyl]urea (1.07 g, 3.08 mmol), malonic acid (320 mg, 3.08 mmol) in AC2O (5 mL) and AcOH (5 mL) was degassed and purged with N2 3 times. The mixture was stirred at 80 °C for 0.5 h. The reaction was diluted with H2O (40 mL) and extracted with DCM (40 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (550 mg, 43%) as a white solid.1!! NMR (400 MHz, DMSO-rfo) 5 ppm 7.87 (t, J = 5.6 Hz, 1H), 6.60-6.77 (m, 1H), 4.54 (s, 1H), 3.85 (s, 3H), 3.61-3.76 (m, 4H), 2.56 (s, 2H), 2.12 (d, J = 4.0 Hz, 3H), 1.11-1.67 (m, 12H), 0.64-0.98 (m, 6H). l-butyl-5-(diaminomethylene)-3-[4-[(2-methoxy-3-methyl-4-pyridyl)methyl]-4-methyl- cyclohexyl]hexahydropyrimidine-2, 4, 6-trione

[0413] To a solution of l-butyl-3-[4-[(2-methoxy-3-methyl-4-pyridyl)methyl]-4-methyl- cyclohexyl]hexahydropyrimidine-2, 4, 6-trione (550 mg, 1.32 mmol) in THF (5 mL) was added cyanamide (556 mg, 13.24 mmol) and Ni(acac)2 (102 mg, 397 pmol). The mixture was stirred at 80 °C for 16 h. The reaction was filtered, diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 1 : 10 to 1 : 1) to give the title compound (450 mg, 74%) as a white solid.:H NMR (400 MHz, DMSO-rfo) 5 ppm 9.50-9.63 (m, 2H), 7.86 (t, J = 5.2 Hz, 1H), 7.22-7.37 (m, 2H), 6.65-6.77 (m, 1H), 4.50-4.75 (m, 1H), 3.85 (s, 3H), 3.71-3.79 (m, 2H), 2.70-2.81 (m, 2H), 2.12 (d, J = 5.2 Hz, 3H), 1.21-1.71 (m, 12H), 0.96 (s, 1.5H), 0.87-0.91 (m, 3H), 0.69 (s, 1.5H). l-butyl-5-(diaminomethylene)-3-(4-methyl-4-((3-methyl-2-oxo-l,2-dihydropyridin-4- yI)methyI)cycIohexyI)pyrimidine-2,4,6(lH,3H,5H)-trione (25)

[0414] To a solution of l-butyl-5-(diaminomethylene)-3-[4-[(2-methoxy-3-methyl-4- pyridyl)methyl]-4-methyl-cyclohexyl]hexahydropyrimidine-2, 4, 6-trione (100 mg, 219 pmol), LiCl (46 mg, 1.09 mmol) in DMF (1 mL) was added PTSA (188 mg, 1.09 mmol). The mixture was stirred at 120 °C for 1 h under N2. The reaction was diluted with H2O (20 mL) and extracted with DCM (25 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (37 mg, 38%) as a white solid. MS (ESI): mass calcd. for C23H33N5O4: 443.25, found: 444.2 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 11.29 (s, 1H), 9.54-9.55 (m, 2H), 7.31 (s, 2H), 7.05-7.10 (m, 1H), 5.85-5.97 (m, 1H), 4.53-4.81 (m, 1H), 3.71-3.78 (m, 2H), 2.61-2.76 (m, 2H), 2.43 (s, 1H), 1.95 (d, J = 6.0 Hz, 3H), 1.63 (d, J = 12.8 Hz, 1H), 1.17-1.52 (m, 10H), 0.75-0.98 (m, 6H).

[0415] Example 26 and Example 27 were synthesized through chiral separation of Example 25 (45 mg) (column: DAICEL CHIRALCEL OD (250mm*30mm, 10 um); mobile phase: CCL-MeOH (0.1% NH3H2O); 45% B with isocratic elution) to give 26 (10.17 mg) from the first eluting peak as a white solid, and 27 (5.07 mg) from the second eluting peak as a white solid.

[0416] Example 28 and Example 29. l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((l,3-dimethyl- 2-oxo-l,2-dihydropyridin-4-yI)methyI)-4-methyIcycIohexyI)pyrimidine-

[0417] 2,4,6(lH,3H,5H)-trione (28) and l-butyl-5-(diaminomethylene)-3-((lr,4r)-4-((l,3- dimethyI-2-oxo-l,2-dihydropyridin-4-yI)methyI)-4-methyIcydohexyI)pyrimidine- 2,4,6(lH,3H,5H)-trione (29)

[0418] l-butyl-5-(diaminomethylene)-3-[4-[(l,3-dimethyl-2-oxo-4-pyridyl)methyl]-4-methyl- cyclohexyl]hexahydropyrimidine-2, 4, 6-trione

[0419] To a solution of Example 25 (100 mg, 225 pmol), CS2CO3 (80.8 mg, 248 pmol) in DMF (1 mL) was added Mel (64 mg, 451 pmol) at 0 °C. The mixture was stirred at 25 °C for 1 h under N2. The reaction was diluted with saturated NaHCCL (20 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (40 mg, 37%) as a white solid.1H NMR (400 MHz, DMSO-rL) 5 ppm 9.55 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 6.4 Hz, 1H), 7.32 (s, 2H), 5.90-6.00 (m, 1H), 4.52-4.78 (m, 1H), 3.70-3.80 (m, 2H), 3.39 (s, 3H), 2.61-2.78 (m, 3H), 2.43 (s, 1H), 1.99 (d, 7 = 6.8 Hz, 3H), 1.63 (d, 7 = 13.2 Hz, 1H), 1.18-1.52 (m, 9H), 0.74-1.00 (m, 6H). l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((l,3-dimethyl-2-oxo-l,2-dihydropyridin-4- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (28) and l-butyl-5- (diaminomethylene)-3-((lr,4r)-4-((l,3-dimethyl-2-oxo-l,2-dihydropyridin-4-yl)methyl)- 4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (29) l-butyl-5-(diaminomethylene)-3-[4-[(l,3-dimethyl-2-oxo-4-pyridyl)methyl]-4- methyl-cyclohexyl]hexahydropyrimidine-2, 4, 6-trione (20 mg) was separated by chiral SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10 um); mobile phase: CCh-MeOH (0.1% NH3H2O); 35% B with isocratic elution) to give 28 (10 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C24H35N5O4: 457.27, found: 458.2 [M+H]+. 'H NMR (400 MHz, DMSO-rfo) 5 ppm 9.56 (s, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.38 (s, 2H), 5.92 (d, J = 7.2Hz, 1H), 4.65-4.82 (m, 1H), 3.72-3.81 (m, 2H), 3.39 (s, 3H), 2.61-2.77 (m, 4H), 2.00 (s, 3H), 1.64 (d, 7 = 13.2 Hz, 2H), 1.42-1.53 (m, 2H), 1.37 (d, 7 = 11.2 Hz, 2H), 1.19-1.30 (m, 4H), 0.89 (t, J - 7.6 Hz, 3H), 0.76 (s, 3H). 29 (5.12 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C24H35N5O4: 457.27, found: 458.2 [M+H]+. ’H NMR (400 MHz, DMSO-rfc) 5 ppm 9.53 (s, 2H), 7.31-7.45 (m, 3H), 5.99 (d, J = 7.2 Hz, 1H), 4.50-4.67 (m, 1H), 3.73 (t. 7 = 7.2 Hz, 2H), 3.38 (s, 3H), 2.46-2.48 (m, 1H), 2.43 (s, 2H), 1.98 (s, 3H), 1.22-1.49 (m, 11H), 0.98 (s, 3H), 0.83-0.92 (m, 3H).

[0420] Example 30. (S)-l-butyl-5-(diaminomethylene)-3-(4-((2,4-dioxo-7-oxa-l,3- diazaspiro[4.4]nonan-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)- trione (30)

[0421] 7-oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione

[0422] To a solution of tetrahydrofuran-3-one (50 g, 580.8 mmol), (NEU^CCh (111.6 g, 1.16 mol) in EtOH (200 mL) and H2O (50 mL) was added KCN (34 g, 522.7 mmol) in H2O (150 mL) at 60 °C under N2. The mixture was stirred at 60 °C for 12 h under N2. The reaction was cooled to 25 °C and concentrated to remove the organic solvents under reduced pressure. The residual aqueous phase was filtered to give a white solid. The solid was washed with H2O (10 mL x 3) and dried under reduced pressure to give the title compound (18 g, 20%) as a white solid. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 10.76 (s, 1H), 8.42 (s, 1H), 3.76-3.95 (m, 3H), 3.71 (d, J = 7.2 Hz, 1H), 2.22-2.28 (m, 1H), 1.98-2.03 (m, 1H). 3-(2-trimethylsilylethoxymethyl)-7-oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione

[0423] A solution of 7-oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione (18 g, 115.3 mmol), DIPEA (59.6 g, 461.1 mmol) in DCM (320 mL) and DMF (80 mL) was degassed and purged with N2 3 times. SEM-C1 (31.7 g, 190.2 mmol) was added to the mixture at 0 °C and it was stirred at 20 °C for 16 h under N2. The mixture was poured into water (300 mL) and extracted with DCM (500 mL x 2). The combined organic layer was washed with saturated NH4CI, brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 95 : 5 to 70 : 30) to give the title compound (30 g, 91%) as a colorless oil. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 8.87 (s, 1H), 4.77 (s, 2H), 3.92 (t, J = 7.6 Hz, 2H), 3.85 (d, J = 9.2 Hz, 1H), 3.71-3.77 (m, 1H), 3.56 (t, J = 7.6 Hz, 2H), 2.28-2.34 (m, 1H), 2.04-2.07 (m, 1H), 0.81-0.94 (m, 2H), 0.00 (s, 9H). l-[(8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl]-3-(2-trimethylsilylethoxymethyl)-7- oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione

[0424] To a solution of 3-(2-trimethylsilylethoxymethyl)-7-oxa-l,3-diazaspiro[4.4]nonane- 2, 4-dione (17.55 g, 61.3 mmol), 8-(iodomethyl)-8-methyl-l,4-dioxaspiro[4.5]decane (18.15 g, 61.3 mmol) in DMF (180 mL) was added CS2CO3 (39.94 g, 123 mmol). The mixture was stirred at 80 °C for 60 h. The reaction was diluted with H2O (100 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 10 : 1 to 1 : 1) to give the title compound (13.2 g, 45%) as a white solid. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 4.81 (s, 2H), 4.04-4.17 (m, 2H), 3.87 (s, 4H), 3.77-3.85 (m, 1H), 3.68 (d, J = 10.4 Hz, 1H), 3.57 (t, J = 8.0 Hz, 2H), 3.02-3.28 (m, 2H), 2.29-2.38 (m, 2H), 2.02 (s, 2H), 1.53-1.65 (m, 6H), 1.35-1.43 (m, 2H), 0.98 (s, 3H), 0.87 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H). l-[(l-methyl-4-oxo-cyclohexyl)methyl]-3-(2-trimethylsilylethoxymethyl)-7-oxa-l,3- diazaspiro[4.4]nonane-2, 4-dione

[0425] To a solution of l-[(8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl]-3-(2- trimethylsilylethoxymethyl)-7-oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione (13.2 g, 29 mmol) in acetone (180 mL), H2O (90 mL) was added TsOH.JfcO (16.57 g, 87.1 mmol). The mixture was stirred at 50 °C for 12 h. The reaction was diluted with H2O (80 mL) and extracted with ethyl acetate (250 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (14.4 g, crude) as a white solid.

[0426] (S)-l-((l-methyl-4-oxocyclohexyl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-7-oxa- l,3-diazaspiro[4.4]nonane-2, 4-dione and (R)-l-((l-methyl-4-oxocyclohexyl)methyl)-3- ((2-(trimethylsilyl)ethoxy)methyl)-7-oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione l-[(l-methyl-4-oxo-cyclohexyl)methyl]-3-(2-trimethylsilylethoxymethyl)-7-oxa-l,3- diazaspiro[4.4]nonane-2, 4-dione (14.4 g) was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250mm*50mm,10 um); mobile phase: CO2-MeOH (0.1% NH3H2O); 35% B with isocratic elution) to give rac-(S)-l-((l-methyl-4-oxocyclohexyl)methyl)-3-((2- (trimethylsilyl)ethoxy)methyl)-7-oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione (7.3 g) as a white solid from the first eluting peak. MS (ESI): mass calcd. C20H34N2O5SL 410.22, found: 433.2 [M+Na]+. Rac-(R)-l-((l-methyl-4-oxocyclohexyl)methyl)-3-((2- (trimethylsilyl)ethoxy)methyl)-7-oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione (6.3 g) was obtained as a white solid from the second eluting peak. MS (ESI): mass calcd. C2oH34N20sSi: 410.22, found: 433.2 [M+Na]+. The stereochemistry was arbitrarily assigned. rac-(5S)-l-[(4-amino-l-methyl-cyclohexyl)methyl]-3-(2-trimethylsilylethoxymethyl)-7- oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione

[0427] A mixture of rac-(5S)-l-[(l-methyl-4-oxo-cyclohexyl)methyl]-3-(2- trimethylsilylethoxymethyl)-7-oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione (825 mg, 2.01 mmol), NH4OAC (3.87 g, 50.23 mmol), NaBH(OAc)3 (1.70 g, 8.04 mmol) in MeOH (8 mL) was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 1 h under N2. The reaction was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and extracted with DCM (40 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (880 mg, crude) as a white solid. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 4.77 (d, J - 2.4 Hz, 2H), 4.03-4.18 (m, 2H), 3.76-3.81 (m, 1H), 3.53-3.57 (m, 2H), 3.04 (d. 7 = 7.6 Hz, 2H), 2.23- 2.37 (m, 3H), 1.88 (s, 3H), 1.59-1.79 (m, 4H), 1.29-1.53 (m, 4H), 1.13-1.28 (m, 1H), 0.91-0.95 (m, 2H), 0.83 (t, J = 7.6 Hz, 2H), -0.05 (s, 9H). l-butyl-3-[4-methyl-4-[[rac-(5S)-2,4-dioxo-3-(2-trimethylsilylethoxymethyl)-7-oxa-l,3- diazaspiro[4.4]nonan-l-yl]methyl]cyclohexyl]urea

[0428] A mixture of rac-(5S)-l-[(4-amino-l-methyl-cyclohexyl)methyl]-3-(2- trimethylsilylethoxymethyl)-7-oxa-l,3-diazaspiro[4.4]nonane-2, 4-dione (880 mg, 2.14 mmol), 1-isocyanatobutane (317.9 mg, 3.21 mmol), TEA (216 mg, 2.14 mmol) in DCM (8.8 mL) was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 1 h under N2. The reaction was quenched with MeOH (2 mL), diluted with H2O (20 mL) and extracted with DCM (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 0 : 1 to 1 : 1) to give the title compound (680 mg, 63%) as a white solid. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 5.69-5.85 (m, 2H), 4.81 (s, 2H), 4.08- 4.18 (m, 2H), 3.80-3.85 (m, 1H), 3.68 (d, 7 = 10.0 Hz, 1H), 3.57 (t, 7 = 8.0 Hz, 2H), 3.24-3.31 (m, 1H), 3.10-3.19 (m, 1H), 2.92-3.08 (m, 3H), 2.29-2.38 (m, 2H), 1.54-1.71 (m, 3H), 1.23- 1.46 (m, 9H), 0.84-0.99 (m, 8H), 0.00 (s, 9H). l-butyl-3-[4-methyl-4-[[rac-(5S)-2,4-dioxo-3-(2-trimethylsilylethoxymethyl)-7-oxa-l,3- diazaspiro[4.4]nonan-l-yl]methyl]cyclohexyl]hexahydropyrimidine-2, 4, 6-trione

[0429] A mixture of l-butyl-3-[4-methyl-4-[[rac-(5S)-2,4-dioxo-3-(2- trimethylsilylethoxymethyl)-7-oxa-l,3-diazaspiro[4.4]nonan-l-yl]methyl]cyclohexyl]urea (420 mg, 822.34 pmol), malonic acid (86 mg, 822 pmol), AC2O (588 mg, 5.76 mmol) in AcOH (4.4 mL) was degassed and purged with N2 3 times. The mixture was stirred at 80 °C for 4 h under N2. The reaction was diluted with H2O (40 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 1 : 0 to 3 : 1) to give the title compound (220 mg, 46%) as a white solid. MS (ESI): mass calcd. C28H46N4O?Si: 578.31, found: 601.3 [M+Na]+. l-butyl-5-(diaminomethylene)-3-[4-methyl-4-[[rac-(5S)-2,4-dioxo-7-oxa-l,3- diazaspiro[4.4]nonan-l-yI]methyI]cycIohexyI]hexahydropyrimidine-2, 4, 6-trione

[0430] A mixture of l-butyl-3-[4-methyl-4-[[rac-(5S)-2,4-dioxo-3-(2- trimethylsilylethoxymethyl)-7-oxa-l,3-diazaspiro[4.4]nonan-l- yl]methyl]cyclohexyl]hexahydropyrimidine-2, 4, 6-trione (220 mg, 380 pmol), cyanamide (160 mg, 3.8 mmol), Ni(acac)2 (29 mg, 114 pmol) in THF (2.2 mL) was degassed and purged with N2 3 times. The mixture was stirred at 80 °C for 16 h under N2. The reaction was filtered. The filtrate was diluted with H2O (30 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiCL. petroleum ether : ethyl acetate = 1 : 1 , Rf = 0.34) to give the title compound (120 mg, 51 %) as a white solid. MS (ESI): mass calcd. C29H48N6O?Si: 620.34, found: 643.4 [M+Na]+. (S)-l-butyl-5-(diaminomethylene)-3-(4-((2,4-dioxo-7-oxa-l,3-diazaspiro[4.4]nonan-l- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (30)

[0431] A solution of l-butyl-5-(diaminomethylene)-3-[4-methyl-4-[[rac-(5S)-2,4-dioxo-3-(2- trimethylsilylethoxymethyl)-7-oxa-l,3-diazaspiro[4.4]nonan-l- yl]methyl]cyclohexyl]hexahydropyrimidine-2, 4, 6-trione (120 mg, 193 pmol) in TFA (1 mL) and H2O (0.2 mL) was stirred at 25 °C for 40 min. The mixture was concentrated under reduced pressure. The residue was added MeOH (1.2 mL), adjusted pH to 9 by adding potassium carbonate. The mixture was stirred at 25 °C for 20 min and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (35 mg, 37%) as a white solid. MS (ESI): mass calcd. C23H34N6O6: 490.25, found: 491.3 [M+H]+. ' H NMR (400 MHz, DMSO-rfo) 8 ppm 10.81 (s, 1H), 9.57 (s, 2H), 7.33 (s, 2H), 4.56-4.73 (m, 1H), 4.00- 4.13 (m, 2H), 3.81-3.87 (m, 3H), 3.63-3.66 (m, 1H), 3.20-3.38 (m, 1H), 2.89-3.13 (m, 1H), 2.55-2.75 (m, 1H), 2.21-2.37 (m, 2H), 1.67-1.77 (m, 1H), 1.11-1.41 (m, 10H), 0.87-1.02 (m, 6H).

[0432] Example 31 and Example 32. l-butyl-5-(diaminomethylene)-3-((lS,4r)-4-(((S)-2,4-dioxo-

[0433] 7-oxa-l,3-diazaspiro[4.4]nonan-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-

[0434] 2,4,6(lH,3H,5H)-trione (31) and l-butyl-5-(diaminomethylene)-3-((lR,4s)-4-(((S)-2,4- dioxo-7-oxa-l,3-diazaspiro[4.4]nonan-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-

[0435] 2,4,6(lH,3H,5H)-trione (32) elution) to give 31 (17.69 mg) as a white solid from the first eluting peak. MS (ESI): mass calcd. for C23H34N6O6: 490.25, found: 491.3 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 10.97 (s, 1H), 9.56 (s, 2H), 7.32 (s, 2H), 4.61-4.76 (m, 1H), 4.01-4.12 (m, 2H), 3.70-3.80 (m, 3H), 3.63 (d, J = 10.0 Hz, 1H), 3.36 (s, 1H), 3.18-3.24 (m, 1H), 2.51-2.53 (m, 2H), 2.21-2.37 (m, 2H), 1.65-1.71 (m, 2H), 1.42-1.48 (m, 2H), 1.11-1.34 (m, 6H), 0.82-0.94 (m, 6H). 32 was obtained from the second eluting peak (17.39 mg) as a white solid. MS (ESI): mass calcd. for C23H34N6O6: 490.25, found: 491.3 [M+H]+. 'H NMR (400 MHz, DMSO-rfo) 5 ppm 10.99 (s, 1H), 9.55 (s, 2H), 7.32 (s, 2H), 4.55-4.75 (m, 1H), 4.01-4.10 (m, 2H), 3.71-3.79 (m, 3H), 3.62 (d, J = 10.0 Hz, 1H), 3.03-3.10 (m, 1H), 2.92 (d, J = 14.4 Hz, 1H), 2.54-2.57 (m, 1H), 2.46 (s, 1H), 2.18-2.34 (m, 2H), 1.41-1.50 (m, 4H), 1.21-1.39 (m, 6H), 1.01 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H).

[0436] Example 33 was prepared in a similar fashion to Example 30 from (R)-l-((l-methyl-4- oxocyclohexyl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-7-oxa-l,3- diazaspiro [4.4] nonane-2 ,4-dione .

[0437] Example 34 and Example 35. l-butyl-5-(diaminomethylene)-3-((lR,4r)-4-(((R)-2,4-dioxo-

[0438] 7-oxa-l,3-diazaspiro[4.4]nonan-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-

[0439] 2,4,6(lH,3H,5H)-trione (34) and l-butyl-5-(diaminomethylene)-3-((lS,4s)-4-(((R)-2,4- dioxo-7-oxa-l,3-diazaspiro[4.4]nonan-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-

[0440] 2,4,6(lH,3H,5H)-trione (35)

[0441] Example 33 (55 mg) was separated by chiral SFC (column: REGIS (s,s) WHELK-01 (250mm*30mm, 5 um); mobile phase: CO2-MeOH (0.1% NH3H2O); 40% B with isocratic elution) to give 34 (18.5 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C23H34N6O6: 490.25, found: 491.3 [M+H]+. 'H NMR (400 MHz, DMSO-rfo) 5 ppm 10.96 (s, 1H), 9.56 (s, 2H), 7.33 (s, 2H), 4.55-4.75 (m, 1H), 4.00-4.13 (m, 2H), 3.70-3.81 (m, 3H), 3.64 (d, J = 10.0 Hz, 1H), 3.38-3.33 (m, 1H), 3.19-3.25 (m, 1H), 2.63 (q, J = 12.0 Hz, 2H), 2.19-2.35 (m, 2H), 1.71 (d, J = 12.0 Hz, 2H), 1.46 (quin. J = 7.2 Hz, 2H), 1.13-1.35 (m, 6H), 0.83-0.93 (m, 6H). 35 was obtained from the second eluting peak (18.83 mg) as a white solid. MS (ESI): mass calcd. for C23H34N6O6: 490.25, found: 491.3 [M+H]+. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 10.86 (s, 1H), 9.56 (s, 2H), 7.33 (s, 2H), 4.53-4.70 (m, 1H), 4.02-4.13 (m, 2H), 3.70-3.84 (m, 3H), 3.63 (d, J = 10.0 Hz, 1H), 3.04-3.13 (m, 1H), 2.93 (d, J = 14.4 Hz, 1H), 2.51-2.56 (m, 1H), 2.46 (s, 1H), 2.19-2.37 (m, 2H), 1.41-1.52 (m, 4H), 1.21-1.41 (m, 6H), 1.02 (s, 3H), 0.89 (t, J - 7.2 Hz, 3H). Stereochemistry was arbitrarily assigned.

[0442] Example 36 was obtained in a similar fashion to Example 30 using propyl isocyanate instead of butyl isocyanate for the urea synthesis.

[0443] Example 37 and Example 38. 5-(diaminomethylene)-l-((lR,4s)-4-(((S)-2,4-dioxo-7-oxa- l,3-diazaspiro[4.4]nonan-l-yl)methyl)-4-methylcyclohexyl)-3-propylpyrimidine- 2,4,6(lH,3H,5H)-trione (37) and 5-(diaminomethylene)-l-((lS,4r)-4-(((S)-2,4-dioxo-7- oxa- 1 ,3-diazaspiro[4.4] nonan- 1 -yl)methyl)-4-methylcyclohexyl) -3-propylpyrimidine- 2,4,6(lH,3H,5H)-trione (38)

[0444] Example 36 (90 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10 um); mobile phase: CCh-EtOH (0.1% NH3H2O); 50% B with isocratic elution) to give 37 (15.81 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 477.3 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 10.98 (s, 1H), 9.56 (s, 2H), 7.32 (s, 2H), 4.60-4.80 (m, 1H), 4.00-4.13 (m, 2H), 3.60-3.83 (m, 4H), 3.33-3.40 (m, 1H), 3.18-3.25 (m, 1H), 2.56- 2.71 (m, 2H), 2.23-2.35 (m, 2H), 1.66-1.77 (m, 2H), 1.34-1.44 (m, 2H), 1.10-1.28 (m, 4H), 0.79-0.93 (m, 6H). 38 (23.31 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 477.3 [M+H]+.1H NMR (400 MHz, DMSO-rfo): 5 ppm 10.99 (s, 1H), 9.55 (s, 2H), 7.32 (s, 2H), 4.54-4.68 (m, 1H), 4.00-4.10 (m, 2H), 3.56-3.83 (m, 4H), 2.88-3.13 (m, 2H), 2.51-2.59 (m, 2H), 2.19-2.36 (m, 2H), 1.23-1.59 (m, 8H), 1.01 (s, 3H), 0.83 (t, J = 7.2 Hz, 3H). Stereochemistry was arbitrarily assigned. Example 39 was obtained in a similar fashion to Example 33 using propyl isocyanate instead of butyl isocyanate for the urea synthesis. MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 477.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 ppm 10.98 (s, 1H), 9.56 (s, 2H), 7.32 (s, 2H), 4.50-4.72 (m, 1H), 4.00-4.13 (m, 2H), 3.60-3.83 (m, 4H), 3.33- 3.40 (m, 1H), 3.18- 3.25 (m, 1H), 2.56- 2.71 (m, 2H), 2.23-2.35 (m, 2H), 1.65-1.80 (m, 1H), 1.40-1.61 (m, 3H), 1.12-1.12 (m, 4H), 0.79- 0.93 (m, 6H).

[0445] Example 40 and Example 41. 5-(diaminomethylene)-l-((lS,4s)-4-(((R)-2,4-dioxo-7-oxa- l,3-diazaspiro[4.4]nonan-l-yl)methyl)-4-methylcyclohexyl)-3-propylpyrimidine- 2,4,6(lH,3H,5H)-trione (40) and 5-(diaminomethylene)-l-((lR,4r)-4-(((R)-2,4-dioxo-7- oxa- 1 ,3-diazaspiro[4.4] nonan- 1 -yl)methyl)-4-methylcyclohexyl) -3-propylpyrimidine-

[0446] 2,4,6(lH,3H,5H)-trione (41)

[0447] Example 39 (50 mg) was separated by chiral SFC (column: REGIS (s,s) WHELK-01 (250mm*30mm, 5 um); mobile phase: CO2- MeOH(0.1% NH3H2O); 40% B with isocratic elution) to give 40 (11.9 mg) as a white solid from the first eluting peak. MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 477.3 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 10.98 (s, 1H), 9.57 (s, 2H), 7.36 (s, 2H), 4.56-4.84 (m, 1H), 4.02-4.13 (m, 2H), 3.60-3.82 (m, 4H), 3.38 (s, 1H), 3.14-3.26 (m, 1H), 2.64 (q, 7 = 12.0 Hz, 2H), 2.19-2.37 (m, 2H), 1.72 (d, 7 = 12.0 Hz, 2H), 1.43-1.54 (m, 2H), 1.11-1.36 (m, 4H), 0.77-0.96 (m, 6H). 41 (11.8 mg) as a white solid from the second eluting peak. MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 477.3 [M+H]+. ’H NMR (400 MHz, DMSO-rfo): 5 ppm 10.98 (s, 1H), 9.56 (s, 2H), 7.36 (s, 2H), 4.52-4.72 (m, 1H), 4.02-4.13 (m, 2H), 3.57-3.82 (m, 4H), 2.88-3.12 (m, 2H), 2.59 (s, 1H), 2.47 (s, 1H), 2.20-2.37 (m, 2H), 1.42-1.58 (m, 4H), 1.26-1.41 (m, 4H), 1.02 (s, 3H), 0.84 (t, J - 7.2 Hz, 3H). Stereochemistry was arbitrarily assigned.

[0448] Example 42 was obtained in a similar fashion to Example 30 starting from rac-(5S)-l-[(l- methyl-4-oxo-cyclohexyl)methyl]-3-(2-trimethylsilylethoxymethyl)-7-oxa-l,3-

[0449] - I l l - diazaspiro[4.4]nonane-2, 4-dione and using (isocyanatomethyl)cyclopropane instead of butyl isocyanate

[0450] Example 43 and Example 44. l-(cyclopropylmethyl)-5-(diaminomethylene)-3-((lR,4s)-4- (((S)-2,4-dioxo-7-oxa-l,3-diazaspiro[4.4]nonan-l-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (43) and l-(cyclopropylmethyl)-5- (diaminomethylene)-3-((lS,4r)-4-(((S)-2,4-dioxo-7-oxa-l,3-diazaspiro[4.4]nonan-l- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6 (lH,3H,5H)-trione (44)

[0451] Example 42 (70 mg) was separated by chiral SFC (column: REGIS (s,s) WHELK-01 (250mm30mm, 5 um); mobile phase: CO2-MeOH (0.1% NH3H2O); 40% B with isocratic elution) to give 43 (25.1 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C23H32N6O6: 488.24, found: 489.2 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 10.99 (s, 1H), 9.56 (s, 2H), 7.36 (s, 2H), 4.60-4.80 (m, 1H), 4.01-4.14 (m, 2H), 3.73-3.77 (m, 1H), 3.60-3.69 (m, 3H), 3.37 (s, 1H), 3.15-3.25 (m, 1H), 2.57-2.72 (m, 2H), 2.22-2.35 (m, 2H), 1.67- 1.77 (m, 2H), 1.05-1.35 (m, 5H), 0.90 (s, 3H), 0.35-0.42 (m, 2H), 0.26-0.31 (m, 2H). 44 (20.47 mg) was obtained as the second eluting peak from SFC separation as a white solid. MS (ESI): mass calcd. for C23H32N6O6: 488.24, found: 489.2 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 11.01 (s, 1H), 9.55 (s, 2H), 7.35 (s, 2H), 4.55-4.70 (m, 1H), 4.02-4.11 (m, 2H), 3.72-3.80 (m, 1H), 3.59-3.68 (m, 3H), 3.03-3.10 (m, 1H), 2.93 (d, 7 = 14.8 Hz, 1H), 2.53 (s, 1H), 2.47 (s, 1H), 2.19-2.35 (m, 2H), 1.28-1.50 (m, 6H), 1.07-1.17 (m, 1H), 1.01 (s, 3H), 0.36-0.42 (m, 2H), 0.26-0.31 (m, 2H).

[0452] Example 45. l-butyl-5-(diaminomethylene)-3-(4-((2,4-dioxo-8-oxa-l,3- diazaspiro[4.5]decan-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)- trione (45)

[0453]

[0454] 8-oxa-l,3-diazaspiro[4.5]decane-2, 4-dione

[0455] To a solution of tetrahydropyran-4-one (5 g, 49.94 mmol, 4.59 mL) in H2O (50 mL) and EtOH (50 mL) was added (NH 2CO3 (9.6 g, 99.88 mmol) and KCN (2.93 g, 44.95 mmol) under N2 at 25 °C. The reaction was stirred at 60 °C for 12 h under N2. The reaction was cooled down and concentrated under reduced pressure. The solid was collected by filter, washed with H2O (15 mL x 3) and dried under reduced pressure to provide the title compound (4.47 g, 53%) as a white solid.1H NMR (400 MHz, DMSO-rfo) 5 ppm 10.67 (s, 1H), 8.57 (s, 1H), 3.78-3.82 (m, 2H), 3.57-3.63 (m, 2H) 1.72-1.93 (m, 2H) 1.48 (d, 7 = 13.6 Hz, 2H).

[0456] 3-((2-(trimethylsilyl)ethoxy)methyl)-8-oxa-l,3-diazaspiro[4.5]decane-2, 4-dione

[0457] To a solution of 8-oxa-l,3-diazaspiro[4.5]decane-2, 4-dione (2 g, 11.75 mmol) and DIPEA (6.08 g, 47 mmol) in DCM (16 mL) and DMF (4 mL) was added SEM-C1 (3.92 g, 23.5 mmol). The reaction was stirred at 25 °C for 1 h, poured into saturated NH4CI (50 mL) and extracted with DCM (50 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 100 : 1 to 95 : 5) to give the title compound (2.6 g, 74%) as a colorless oil. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 9.03 (s, 1H), 4.73 (s, 2H), 3.78-3.90 (m, 2H), 3.58-3.71 (m, 2H), 3.52 (t, 7 = 8.0 Hz, 2H), 1.78-1.95 (m, 2H), 1.50 (d, 7 = 13.6 Hz, 2H), 0.83 (t, 7 = 8.0 Hz, 2H), -0.04 (s, 9H). l-((8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-

[0458] 8-oxa-l,3-diazaspiro[4.5]decane-2, 4-dione

[0459] A mixture of 8-(iodomethyl)-8-methyl-l,4-dioxaspiro[4.5]decane (1.48 g, 4.99 mmol), 3-(2-trimethylsilylethoxymethyl)-8-oxa-l,3-diazaspiro[4.5]decane-2, 4-dione (1.5 g, 4.99 mmol), CS2CO3 (3.25 g, 9.99 mmol) in DMF (21 mL) was degassed and purged with N2 3 times. The mixture was stirred at 80 °C for 30 h under N2. The reaction was diluted with H2O (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC to give the title compound (470 mg, 20%) as a white solid. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 4.77 (s, 2H), 3.89-4.00 (m, 2H), 3.83 (s, 6H), 3.53 (t, 7 = 8.0 Hz, 2H), 3.07 (s, 2H), 1.99-2.07 (m, 2H), 1.49-1.64 (m, 8H), 1.27-1.41 (m, 2H), 0.91 (s, 3H), 0.83 (t, J = 7.6 Hz, 2H), -0.04 (s, 9H). l-((l-methyl-4-oxocyclohexyl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-8-oxa-l,3- diazaspiro[4.5]decane-2, 4-dione

[0460] To a solution of l-[(8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl]-3-(2- trimethylsilylethoxymethyl)-8-oxa-l,3-diazaspiro[4.5]decane-2, 4-dione (470 mg, 1.00 mmol) in acetone (2.5 mL), H2O (2.5 mL) was added TsOH-EhO (382 mg, 2.01 mmol). The mixture was stirred at 25 °C for 5 h, poured into water (40 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic phase was washed with NaHCCL. brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (420 mg, crude) as a white solid. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 4.78 (s, 2H), 3.90-4.00 (m, 2H), 3.79-3.87 (m, 2H), 3.53 (t, 7 = 8.0 Hz, 2H), 3.22 (s, 2H), 2.21-2.41 (m, 4H), 2.01-2.14 (m, 2H), 1.73-1.86 (m, 2H), 1.55-1.68 (m, 4H), 1.10 (s, 3H), 0.87-0.92 (m, 2H), 0.00 (s, 9H). l-((4-amino-l-methylcyclohexyl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-8-oxa-l,3- diazaspiro[4.5]decane-2, 4-dione

[0461] To a solution of l-[(l-methyl-4-oxo-cyclohexyl)methyl]-3-(2- trimethylsilylethoxymethyl)-8-oxa-l,3-diazaspiro[4.5]decane-2, 4-dione (420 mg, 990 pmol) in MeOH (5 mL) was added NH4OAC (1.91 g, 24.73 mmol) and NaBH(OAc)3 (839mg, 3.96 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (20 mL) and extracted with DCM / IPA = 3 / 1 (25 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (380 mg, crude) as a white solid. MS (ESI): mass calcd. for C21H39N3O4SE 425.27, found: 426.2 [M+H]+. l-butyl-3-(4-((2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-8-oxa-l,3- diazaspiro[4.5]decan-l-yI)methyI)-4-methyIcydohexyI)urethyI acetate trimethylsilylethoxymethyl)-8-oxa-l,3-diazaspiro[4.5]decane-2, 4-dione (380 mg, 893 pmol) in DCM (5 mL) was added TEA (362 mg, 3.57 mmol), 1-isocyanatobutane (115 mg, 1.16 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with H2O (10 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 80 : 20 to 70 : 30) to give the title compound (320 mg, 56%) as a white solid. MS (ESI): mass calcd. for C26H48N40sSi: 524.34, found: 525.4 [M+H]+. l-butyl-3-(4-((2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-8-oxa-l,3- diazaspiro[4.5]decan-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)- trione

[0462] To a solution of l-butyl-3-[4-[[2,4-dioxo-3-(2-trimethylsilylethoxymethyl)-8-oxa-l,3- diazaspiro[4.5]decan-l-yl]methyl]-4-methyl-cyclohexyl]urethyl acetate (0.32 g, 610 pmol) and malonic acid (69.8 mg, 671 pmol) in AcOH (3 mL) was added AC2O (436 mg, 4.27 mmol). The mixture was stirred at 80 °C for 12 h, cooled down and concentrated under reduced pressure. The residue was poured into H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 100 : 1 to 1 : 1) to give the title compound (0.22 g, 61%) as a white solid. MS (ESI): mass calcd. for C29H48N4O?Si: 592.33, found: 615.3 [M+Na]+. l-butyl-5-(diaminomethylene)-3-(4-((2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-8- oxa- 1 ,3-diazaspiro[4.5] decan- 1 -yl)methyl)-4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione To a solution of l-butyl-3-[4-[[2,4-dioxo-3-(2-trimethylsilylethoxymethyl)-8-oxa-l,3- diazaspiro[4.5]decan-l-yl]methyl]-4-methyl-cyclohexyl]hexahydropyrimidine-2, 4, 6-trione (0.2 g, 338 pmol) and cyanamide (289 mg, 6.75 mmol) in THF (2.5 mL) was added Ni(acac)2 (26 mg, 101 pmol). The mixture was stirred at 80 °C for 12 h, cooled down and concentrated under reduced pressure. The residue was poured into H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 100 : 1 to 7 : 3) to give the title compound (0.16 g, 74.7%) as a white solid. MS (ESI): mass calcd. for CsoHsoNeChSi: 634.35, found: 657.3 [M+Na]+. l-butyl-5-(diaminomethylene)-3-(4-((2,4-dioxo-8-oxa-l,3-diazaspiro[4.5]decan-l- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (45) l-butyl-5-(diaminomethylene)-3-[4-[[2,4-dioxo-3-(2- trimethylsilylethoxymethyl)-8-oxa-l,3-diazaspiro[4.5]decan-l-yl]methyl]-4-methyl- cyclohexyl]hexahydropyrimidine-2, 4, 6-trione (0.14 g, 220.5 pmol) in TFA (2 mL) and H2O (0.4 mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated and K2CO3 (91 mg, 662 pmol) in MeOH (2 mL) was added. The resulting mixture was stirred at 25 °C for 0.5 h. The residue was purified by prep-HPLC to give the title compound (36 mg, 32%) as a white solid. MS (ESI): mass calcd. for C24H36N6O6: 504.27, found: 505.3 [M+H]+. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 10.85 (s, 1H), 9.56 (s, 2H), 7.31 (s, 2H), 4.51-4.77 (m, 1H), 3.90-4.03 (m, 2H), 3.69-3.86 (m, 4H), 2.91-3.27 (m, 2H), 2.57-2.74 (m, 1H), 2.42-2.49 (m, 1H), 1.91-2.03 (m, 2H), 1.72-1.85 (m, 1H), 1.58-1.70 (m, 2H), 1.41-1.50 (m, 3H), 1.23-1.40 (m, 5H), 1.12- 1.22 (m, 1H), 0.82-1.03 (m, 6H).

[0463] Example 46 and Example 47. l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((2,4-dioxo-8- oxa- 1 ,3-diazaspiro[4.5] decan- 1 -yl)methyl)-4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (46) & l-butyl-5-(diaminomethylene)-3-((lr,4r)-4-((2,4-dioxo-8- oxa- 1 ,3-diazaspiro[4.5] decan- 1 -yl)methyl)-4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (47)

[0464] Example 45 (36 mg) was separated by SFC separation (column: DAICEL CHIRALPAK IG (250mm*30mm, 10 um); mobile phase: CCh-EtOH; 55% B with isocratic elution) to give the title compound (46) (15.5 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C24H36N6O6: 504.27, found: 505.3 [M+H]+. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 10.86 (s, 1H), 9.56 (s, 2H), 7.32 (s, 2H), 4.60-4.77 (m, 1H), 3.89-4.05 (m, 2H), 3.70-3.84 (m, 4H), 3.23 (s, 2H), 2.57-2.74 (m, 2H), 1.90-2.05 (m, 2H), 1.78 (d, 7 = 12.8 Hz, 2H), 1.66 (d, 7 = 13.2 Hz, 2H), 1.41-1.51 (m, 2H), 1.23-1.35 (m, 4H), 1.12-1.22 (m, 2H), 0.82-0.93 (m, 6H). The title compound (47) was obtained (17.6 mg) as a white solid from the second eluting peak. MS (ESI): mass calcd. for C24H36N6O6: 504.27, found: 505.3 [M+H]+.:H NMR (400 MHz, DMSO-rfo) 5 ppm 10.86 (s, 1H), 9.56 (s, 2H), 7.33 (s, 2H), 4.53-4.69 (m, 1H), 3.88-4.03 (m, 2H), 3.68-3.85 (m, 4H), 2.96 (s, 2H), 2.53-2.61 (m, 1H), 2.46 (s, 1H), 1.89- 2.07 (m, 2H), 1.62 (d, 7 = 13.2 Hz, 2H), 1.38-1.51 (m, 5H), 1.23-1.37 (m, 5H), 1.00 (s, 3H), 0.89 (t, J = 7.2 Hz, 3H).

[0465] Example 48 and Example 49. l-butyl-5-(diaminomethylene)-3-((lR,4s)-4-(((S)-5- (ethoxymethyl)-2,4-dioxoimidazolidin-l-yl)methyl)-4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (48) and l-butyl-5-(diaminomethylene)-3-((lS,4s)-4-(((R)-5- (ethoxymethyl)-2,4-dioxoimidazolidin-l-yl)methyl)-4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (49) Synthetic Scheme: ate hydrochloride

[0466] A mixture of (2S)-2-(tert-butoxycarbonylamino)-3-ethoxy-propanoic acid (4.2 g, 18 mmol) in HCl / MeOH (4M, 40 mL) was stirred at 25 °C for 12 h under N2. The reaction was filtered, and the filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE (20 mL) to give the title compound (3 g, 91%) as a brown solid.1H NMR (400 MHz, DMSO-rfo) 5 ppm 8.76 (s, 3H), 4.27 (s, 1H), 3.68-3.87 (m, 5H), 3.39-3.57 (m, 2H), 1.03-1.18 (m, 3H). methyl O-ethyl-N-((8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-L-serinate To a solution of 8-methyl-l,4-dioxaspiro[4.5]decane-8-carbaldehyde (1.8 g, 9.77 mmol), methyl (2S)-2-amino-3-ethoxy-propanoate (1.73 g, 11.72 mmol) and AcOH (704.05 mg, 11.72 mmol, 671.16 pL) in DCM (30 mL) was added NaBH(OAc)3 (6.21 g, 29.3 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was poured into saturated NaHCCL (150 mL) and extracted with DCM (150 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si CL. petroleum ether : ethyl acetate = 100 : 1 to 7 : 3) to give the title compound (2.5 g, 81%) as a colorless oil. MS (ESI): mass calcd. for C16H29NO5: 315.20, found: 316.1 [M+H]+.

[0467] 5-(ethoxymethyl)-l-((8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)imidazolidine-2,4- dione

[0468] To a mixture of methyl (2S)-3-ethoxy-2-[(8-methyl-l,4-dioxaspiro[4.5]decan-8- yl)methylamino]propanoate (2.5 g, 7.93 mmol) in AcOH (20 mL) was added potassium cyanate (6.43 g, 79.3 mmol) under N2. The reaction was stirred at 100 °C for 2 h under N2, cooled down and concentrated under reduced pressure. The residue was poured into saturated NaHCCL (200 mL) and extracted with DCM (200 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.8 g, 70%) as a yellow solid. MS (ESI): mass calcd. for C16H26N2O5: 326.18, found: 327.2 [M+H]+.

[0469] 5-(ethoxymethyl)-l-((l-methyl-4-oxocyclohexyl)methyl)imidazolidine-2, 4-dione

[0470] To a mixture of 5-(ethoxymethyl)-l-((8-methyl-l,4-dioxaspiro[4.5]decan-8- yl)methyl)imidazolidine-2, 4-dione (1.8 g, 5.5 mmol) in acetone (12 mL) and H2O (6 mL) was added TsOH- H2O (2.1 g, 11.0 mmol) under N2. The mixture was stirred at 50 °C for 2 h under N2. The reaction was concentrated under reduced pressure to remove the organic solvents. The residue was poured into saturated NaHCCL (100 mL) and extracted with DCM (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (1.5 g, 96%) as a yellow solid. MS (ESI): mass calcd. for C14H22N2O4: 282.16, found: 283.1 [M+H]+.

[0471] 5-(ethoxymethyl)-l-((l-methyl-4-oxocyclohexyl)methyl)-3-((2-

[0472] (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione

[0473] To a mixture of 5-(ethoxymethyl)-l-((l-methyl-4- oxocyclohexyl)methyl)imidazolidine-2, 4-dione (1.5 g, 5.31 mmol) and DIPEA (2.75 g, 21.25 mmol) in DCM (20 mL) was added SEM-C1 (1.77 g, 10.63 mmol) under N2. The reaction was stirred at 25 °C for 1 h under N2, poured into H2O (100 mL) and extracted with DCM (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 100 : 1 to 7 : 3) to give the title compound (1.6 g, 73%) as a yellow oil. l-((4-amino-l-methylcyclohexyl)methyl)-5-(ethoxymethyl)-3-((2-

[0474] (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione

[0475] To a mixture of 5-(ethoxymethyl)-l-((l-methyl-4-oxocyclohexyl)methyl)-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione (1.6 g, 3.88 mmol) and NH4OAC (5.98 g, 77.56 mmol) in MeOH (32 mL) was added NaBH(OAc)3 (2.05 g, 9.69 mmol). The mixture was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure, poured into H2O (50 mL) and extracted with DCM : i-PrOH = 3 : 1 (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (1.6 g, crude) as a yellow oil, which was used directly without further purification. l-butyl-3-(4-((5-(ethoxymethyl)-2,4-dioxo-3-((2-

[0476] (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)-4-methylcyclohexyl)urea

[0477] To a mixture of l-((4-amino-l-methylcyclohexyl)methyl)-5-(ethoxymethyl)-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione (1.6 g, 3.87 mmol) and TEA (782.9 mg, 7.74 mmol) in DCM (16 mL) was added 1-isocyanatobutane (383.46 mg, 3.87 mmol). The mixture was stirred at 25 °C for 1 h, poured into H2O (100 mL) and extracted with DCM (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 100 : 1 to 0 : 1) to give the title compound (1.4 g, 71%) as a yellow solid. ' H NMR (400 MHz, CDC13): 5 ppm 4.91-4.98 (m, 2H), 4.14 (s, 1H), 3.99 (d, J = 14.8 Hz, 1 H), 3.78-3.90 (m, 2H), 3.68 (d, J = 14.4 Hz, 1 H), 3.61 (t, J = 8.4 Hz, 2H), 3.40-3.56 (m, 4H), 3.13-3.15 (m, 2H), 2.68-2.82 (m, 1H), 1.72-1.92 (m, 2H), 1.54-1.69 (m, 1H), 1.23-1.51 (m, 9H), 1.09-1.18 (m, 3H), 0.85-1.03 (m, 8H), 0.00 (s, 9H). l-butyl-3-(4-((5-(ethoxymethyl)-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[0478] To a mixture of l-butyl-3-(4-((5-(ethoxymethyl)-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin- l-yl)methyl)-4-methylcyclohexyl)urea (1.2 g, 2.34 mmol) in AcOH (12 mL) and acetyl acetate (1.67 g, 16.38 mmol, 1.54 mL) was added malonic acid (267.89 mg, 2.57 mmol) under N2. The mixture was stirred at 80 °C for 4 h. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 : 1 to 1 : 1) to give the title compound (0.9 g, 66.2%) as a white solid. MS (ESI): mass calcd. for C28H48N4O?Si: 580.33, found: 603.3 [M+Na]+. l-butyl-5-(diaminomethylene)-3-(4-((5-(ethoxymethyl)-2,4-dioxo-3-((2- (trimethyIsiIyI)ethoxy)methyI)imidazoIidin-l-yI)methyI)-4- methyIcycIohexyI)pyrimidine-2,4,6(lH,3H,5H)-trione

[0479] To a mixture of l-butyl-3-(4-((5-(ethoxymethyl)-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)-4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (0.9 g, 1.55 mmol) in THF (10 mL) was added cyanamide (1.3 g, 31 mmol) and Ni(acac)2 (119.43 mg, 465 pmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was poured into H2O (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 100 : 1 to 7 : 3) to give the title compound (0.7 g, 73%) as a colorless oil. MS (ESI): mass calcd. for C29H5oNe07Si: 622.35, found: 645.3 [M+Na]+. l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((5-(ethoxymethyl)-2,4-dioxoimidazolidin-l- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione and l-butyl-5- (diaminomethylene)-3-((lr,4r)-4-((5-(ethoxymethyl)-2,4-dioxoimidazolidin-l-yl)methyl)- 4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[0480] A mixture of l-butyl-5-(diaminomethylene)-3-(4-((5-(ethoxymethyl)-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)-4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (0.68 g, 1.09 mmol) in TFA (5 mL) and H2O (1 mL) was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and added K2CO3 (905.4 mg, 6.55 mmol). The mixture was stirred at 25 °C for 0.5 h and concentrated under reduced pressure. The residue was purified by prep-HPLC to give l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((5-(ethoxymethyl)-2,4- dioxoimidazolidin-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (0.1 g, 18%) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C23H36N6O6: 492.27, found: 493.2 [M+H]+. l-butyl-5-(diaminomethylene)-3-((lr,4r)-4-((5- (ethoxymethyl) -2 ,4-dioxoimidazolidin- 1 -yl)methyl) -4-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (0.1 g, 18.2%) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C23H36N6O6: 492.27, found: 493.2 [M+H]+. Each compound contained two stereoisomers. l-butyl-5-(diaminomethylene)-3-((lR,4s)-4-(((S)-5-(ethoxymethyl)-2,4- dioxoimidazolidin-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[0481] (48) and l-butyl-5-(diaminomethylene)-3-((lS,4s)-4-(((R)-5-(ethoxymethyl)-2,4- dioxoimidazolidin-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[0482] (49) l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((5-(ethoxymethyl)-2,4- dioxoimidazolidin- l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (0.1 g) was purified by SFC (column: DAICEL CHIRALPAK IE (50*250mm, 10 um); mobile phase: CCh-MeOH; 55% B with isocratic elution) to give 48 (20.6 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C23H36N6O6: 492.27, found: 493.2 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 10.75 (s, 1H), 9.56 (s, 2H), 7.36 (s, 2H), 4.77-4.60 (m, 1H), 4.17 (s, 1H), 4.01-3.90 (m, 1H), 3.76 0. 7 = 7.2 Hz, 2H), 3.67 (d, 7= 9.2 Hz, 1H), 3.58 (d, J = 14.4 Hz, 1H), 3.54-3.45 (m, 2H), 3.06 (d, J = 14.8 Hz, 1H), 2.75-2.60 (m, 1H), 2.58-2.52 (m, 1H), 1.68-1.54 (m, 2H), 1.53-1.41 (m, 2H), 1.37-1.15 (m, 6H), 1.10 (t, J = 7.2 Hz, 3H), 0.95-0.83 (m, 6H). 49 (22 mg) was isolated from the second eluting peak as a white solid. MS (ESI): mass calcd. for C23H36N6O6: 492.27, found: 493.2 [M+H]+. ’H NMR (400 MHz, DMSO- d6) 5 ppm 10.75 (s, 1H), 9.56 (s, 2H), 7.36 (s, 2H), 4.77-4.60 (m, 1H), 4.17 (s, 1H), 4.01-3.90 (m, 1H), 3.76 (t, J = 7.2 Hz, 2H), 3.67 (d, J = 9.2 Hz, 1H), 3.58 (d, J = 14.4 Hz, 1H), 3.54-3.45 (m, 2H), 3.06 (d, 7 = 14.8 Hz, 1H), 2.75-2.60 (m, 1H), 2.58-2.52 (m, 1H), 1.68-1.54 (m, 2H), 1.53-1.41 (m, 2H), 1.37-1.15 (m, 6H), 1.10 (t, J = 7.2 Hz, 3H), 0.95-0.83 (m, 6H). Stereochemistry is arbitrarily assigned. l-butyl-5-(diaminomethylene)-3-((lS,4r)-4-(((S)-5-(ethoxymethyl)-2,4- dioxoimidazolidin-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[0483] (50) l-butyl-5-(diaminomethylene)-3-((lR,4r)-4-(((R)-5-(ethoxymethyl)-2,4- dioxoimidazolidin-l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[0484] (51) l-butyl-5-(diaminomethylene)-3-((lr,4r)-4-((5-(ethoxymethyl)-2,4- dioxoimidazolidin- l-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (0.1 g) was purified by SFC (column: DAICEL CHIRALPAK IE (50*250mm, 10 um); mobile phase: CCh-MeOH; 60% B with isocratic elution) to give 50 (28 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C23H36N6O6: 492.27, found: 493.2 [M+H]+. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 10.75 (s, 1H), 9.55 (s, 2H), 7.31 (s, 2H), 4.71-4.56 (m, 1H), 4.25 (s, 1H), 3.89-3.80 (m, 1H), 3.74 (t, J = 7.2 Hz, 2H), 3.65 (d, J = 9.2 Hz, 1H), 3.50- 3.35 (m, 3H), 2.75-2.65 (m, 1H), 2.58-2.51 (m, 1H), 2.48-2.39 (m, 1H), 1.52-1.37 (m, 4H), 1.36-1.21 (m, 6H), 1.06 0. 7 = 7.2 Hz, 3H), 0.98 (s, 3H), 0.88 (t, 7 = 7.2 Hz, 3H). 51 (36 mg) was isolated from the second eluting peak as a white solid. MS (ESI): mass calcd. for C23H36N6O6: 492.27, found: 493.2 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 10.75 (s, 1H), 9.55 (s, 2H), 7.31 (s, 2H), 4.71-4.56 (m, 1H), 4.25 (s, 1H), 3.89-3.80 (m, 1H), 3.74 (t, 7 = 7.2 Hz, 2H), 3.65 (d, 7= 9.2 Hz, 1H), 3.50-3.35 (m, 3H), 2.75-2.65 (m, 1H), 2.58-2.51 (m, 1H), 2.48-2.39 (m, 1H), 1.52-1.37 (m, 4H), 1.36-1.21 (m, 6H), 1.06 (t, 7 = 7.2 Hz, 3H), 0.98 (s, 3H), 0.88 (t, J - 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned.

[0485] Example 52 and 53 were prepared using an identical route to Example 48 and Example 49 using methyl L-alaninate hydrochloride as a starting material, with separation by chiral SFC (column: DAICEL CHIRALPAK IC (250mm*30mm,10 um); mobile phase: CCh-EtOH (0.1% NH3H2O); 40% B with isocratic elution mode) to give 52 (7.33 mg) from the first eluting peak as a white solid. 53 (5.23 mg) was isolated from the second eluting peak from SFC separation as a white solid. Stereochemistry is arbitrarily assigned.

[0486] Example 54 and 55 were prepared using an identical route to Example 50 and Example 51, with separation by chiral SFC (column: DAICEE CHIRAEPAK IC (250mm*30mm,10 um); mobile phase: CCh-EtOH (0.1% NH3H2O); 30% B with isocratic elution) to give 54 (16.85 mg) from the first eluting peak from SFC separation as a white solid. 55 (12.08 mg) was isolated from the second eluting peak from SFC separation as a white solid.

[0487] Example 56. l-butyl-5-(diaminomethylene)-3-(4-((6,8-dioxo-5,7-diazaspiro[3.4]octan-5- yl)methyl)-4-hydroxycyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (56)

[0488] 8-hydroxy-l,4-dioxaspiro[4.5]decane-8-carbonitrile

[0489] To a solution of l,4-dioxaspiro[4.5]decan-8-one (30 g, 192.1 mmol) in DMSO (300 mL) was added TMSCN (26.68 g, 269 mmol) and H2O (60 mL). The mixture was stirred at 25 °C for 1 h under N2. After completion, the mixture was diluted with H2O (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography CSiCL. petroleum ether: ethyl acetate = 100: 1 to 0: 1) to afford the title compound (33 g, 92%) as a white solid.1H NMR (400 MHz, DMSO-rfo) 5 ppm 6.56 (s, 1H), 3.86 (s, 4H), 1.91-1.99 (m, 2H), 1.80-1.88 (m, 2H), 1.69-1.77 (m, 2H), 1.52-1.62 (m, 2H). 8-benzyloxy-l,4-dioxaspiro[4.5]decane-8-carbonitrile

[0490] To a solution of 8-hydroxy-l,4-dioxaspiro[4.5]decane-8-carbonitrile (33 g, 180 mmol) in DCM (300 mL) was added TMSOTf (8.01 g, 36.0 mmol) and benzyl 2,2,2- trichloroethanimidate (54.58 g, 216 mmol) at 0 °C. The mixture was stirred at 15 °C for 1 h. After completion, the reaction was quenched with H2O (200 mL) and extracted with DCM (300 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether : ethyl acetate = 100 : 1 to 0 : 1) to afford the title compound (10 g, crude) as a yellow oil.1H NMR (400 MHz, DMSO-rfo) 5 ppm 7.19-7.44 (m, 5H), 4.53-4.77 (m, 2H), 3.82-3.96 (m, 4H), 2.01-2.21 (m, 4H), 1.69-1.83 (m, 2H), 1.57-1.67 (m, 2H).

[0491] 8-benzyloxy- l,4-dioxaspiro[4.5]decane-8-carboxylic acid

[0492] To a solution of 8-benzyloxy-l,4-dioxaspiro[4.5]decane-8-carbonitrile (9.8 g, 35.85 mmol) in EtOH (50 mL) and H2O (50 mL) was added LiOH H2O (25.58 g, 609.5 mmol) at 25 °C. The mixture was stirred at 90 °C for 16 h under N2. After completion, the pH was adjusted to around 4-5 by progressively adding 1 N HC1, diluted with H2O (200 mL) and extracted with ethyl acetate (600 mL). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep- HPLC to give the title compound (9.6 g, 79%) as a yellow solid. MS (ESI): mass calcd. for C16H20O5: 292.13, found: 293.2 [M+H]+.

[0493] (8-benzyloxy- 1 ,4-dioxaspiro[4.5] decan-8-yl)methanol

[0494] To a solution of 8-benzyloxy-l,4-dioxaspiro[4.5]decane-8-carboxylic acid (6.5 g, 22.24 mmol) in THF (10 mL) was added BH3-Me2S (10 M, 6.67 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h under N2. The reaction was quenched with methanol (10 mL) at 0 °C slowly, stirred at 25 °C for 2 h and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiCh, petroleum ether : ethyl acetate = 100 : 1 to 94 : 6) to afford the title compound (5.9 g, 67%) as a colorless oil. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 7.20-7.38 (m, 5H), 4.64 (t, J = 5.6 Hz, 1H), 4.44 (s, 2H), 3.85 (s, 4H), 3.44 (d, J = 5.6 Hz, 2H), 1.81 (d, 7 = 13.6 Hz, 2H), 1.64-1.73 (m, 2H), 1.46-1.58 (m, 4H).

[0495] 8-benzyloxy-l,4-dioxaspiro[4.5]decane-8-carbaldehyde

[0496] To a solution of oxalyl dichloride (1.78 g, 14.05 mmol) in DCM (5 mL) was added dropwise DMSO (1.1 g, 14.1 mmol) in DCM (5 mL) at -70 °C. After addition, the mixture was stirred at this temperature for 15 min. (8-benzyloxy-l,4-dioxaspiro[4.5]decan-8- yl)methanol (2.3 g, 8.26 mmol) in DCM (23 mL) was added dropwise at -70 °C. The resulting mixture was stirred for 0.5 h and TEA (4.18 g, 41.3 mmol) was added. After an additional 15 min stirring at -70 °C, the cooling bath was removed, and the reaction mixture was allowed to slowly warm to 20 °C for 30 min. The residue was poured into H2O (30 mL) and extracted with DCM (30 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford the title compound (3.2 g, crude) as a colorless oil. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 9.66 (s, 1H), 7.19-7.48 (m, 5H), 4.45 (s, 2H), 3.87 (s, 4H), 1.85-1.93 (m, 2H), 1.57-1.78 (m, 6H). methyl l-[(8-benzyloxy-l,4-dioxaspiro[4.5]decan-8- yl)methylamino]cyclobutanecarboxylate

[0497] To a solution of 8-benzyloxy-l,4-dioxaspiro[4.5]decane-8-carbaldehyde (3.2 g, 11.58 mmol) and methyl 1 -aminocyclobutanecarboxylate (1.94 g, 15.05 mmol) in DCM (30 mL) was added AcOH (695.43 mg, 11.58 mmol), followed by NaBH(OAc)3 (7.36 g, 34.74 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction was quenched with saturated NaHCCL (30 mL). The aqueous layer was extracted with DCM (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to afford the title compound (4.5 g, crude) as a yellow oil.1H NMR (400 MHz, DMSO-rfc) 5 ppm 7.31-7.44 (m, 5H), 4.41 (s, 2H), 3.92 (s, 4H), 3.71 (s, 3H), 2.54-2.63 (m, 2H), 2.31-2.38 (m, 2H), 1.97-2.02 (m, 4H), 1.93-1.96 (m, 1H), 1.71-1.90 (m, 4H), 1.53- 1.63 (m, 4H). l-[[5,5-dimethyl-2,4-dioxo-3-(2-trimethylsilylethoxymethyl)imidazolidin-l-yl]methyl]-4- oxo-cyclohexanecarbonitrile

[0498] To a solution of methyl l-[(8-benzyloxy-l,4-dioxaspiro[4.5]decan-8- yl)methylamino]cyclobutanecarboxylate (4.5 g, 11.55 mmol) in AcOH (45 mb) was added potassium cyanate (9.37 g, 115.54 mmol). The reaction was stirred at 100 °C for 12 h. After completion, the reaction was quenched with saturated NaHCCL (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si CL. petroleum ether : ethyl acetate = 100 : 1 to 0 : 1) to afford the title compound (2.9 g, 75.9%) as a white solid. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 10.84 (s, 1H), 7.25-7.47 (m, 5H), 4.68 (s, 2H), 3.65 (s, 2H), 2.66-2.77 (m, 2H), 2.41-2.49 (m, 2H), 2.15- 2.23 (m, 4H), 2.07-2.10 (m, 2H), 1.79-1.87 (m, 3H), 1.34-1.43 (m, 1H).

[0499] 5-[(l-benzyloxy-4-oxo-cyclohexyl)methyl]-7-(2-trimethylsilylethoxymethyl)-5,7- diazaspiro[3.4]octane-6, 8-dione

[0500] To a solution of 5-[(l-benzyloxy-4-oxo-cyclohexyl)methyl]-5,7-diazaspiro[3.4]octane- 6, 8-dione (2.9 g, 8.14 mmol) in DCM (29 mL) was added DIP EA (4.21 g, 32.55 mmol) and SEM-C1 (2.71 g, 16.27 mmol) at 0 °C. The reaction was stirred at 25 °C for 12 h. After completion, the reaction was quenched with saturated NH4CI (30 mL) and extracted with DCM (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 : 1 to 0 : 1) to give the title compound (3.7 g, 92%) as a yellow oil. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 7.26-7.47 (m, 5H), 4.76 (s, 2H), 4.70 (s, 2H), 3.74 (s, 2H), 3.50 (t, 7 = 8.0 Hz, 2H), 2.72-2.83 (m, 2H), 2.45-2.46 (m, 2H), 2.08-2.22 (m, 6H), 1.82-1.94 (m, 3H), 1.39-1.48 (m, 1H), 0.80 0. 7 = 7.6 Hz, 2H), -0.06 (s, 9H).

[0501] 5- [(4-amino- 1 -benzyloxy-cyclohexyl)methyl] -7-(2-trimethylsilylethoxymethyl)-5,7 - diazaspiro[3.4]octane-6, 8-dione

[0502] To a solution of 5-[(l-benzyloxy-4-oxo-cyclohexyl)methyl]-7-(2- trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octane-6, 8-dione (3.7 g, 7.60 mmol) in MeOH (38 mL) was added NaBH(OAc)3 (4.03 g, 19 mmol) and ammonium acetate (11.72 g, 152.1 mmol). The mixture was stirred at 25 °C for 1 h. After completion, the reaction was quenched with saturated NaHCCL (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (3.7 g, crude) as a colorless oil. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 7.22-7.50 (m, 5H), 4.76 (d, J = 5.2 Hz, 2H), 4.54 (d, J = 8.0 Hz, 2H), 3.59-3.66 (m, 2H), 3.50-3.55 (m, 2H), 2.67-2.91 (m, 3H), 1.98-2.10 (m, 2H), 1.85-1.95 (m, 2H), 1.83 (s, 3H), 1.64-1.73 (m, 3H), 1.23-1.47 (m, 4H), 0.82 (m, 2H), -0.05 (s, 9H). l-[4-benzyloxy-4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octan- 5-yl]methyl]cyclohexyl]-3-butyl-urea

[0503] To a solution of 5-[(4-amino-l-benzyloxy-cyclohexyl)methyl]-7-(2- trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octane-6, 8-dione (3.7 g, 7.59 mmol) in DCM (37 mL) was added 1-isocyanatobutane (752.1 mg, 7.59 mmol) and TEA (767.68 mg, 7.59 mmol). The mixture was stirred at 25 °C for 1 h. After completion, the reaction was quenched with MeOH (10 mL) and H2O (40 mL) and extracted with DCM (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 : 1 to 0 : 1) to afford the title compound (3 g, 54%) as a white solid.1H NMR (400 MHz, DMSO-rfo) 5 ppm 7.23-7.46 (m, 5H), 5.56-5.94 (m, 2H), 4.76 (d, J = 3.2 Hz, 2H), 4.56 (d, 7 = 4.8 Hz, 2H), 3.58-3.68 (m, 2H), 3.49-3.55 (m, 2H), 2.95-2.98 (m, 2H), 2.71- 2.84 (m, 2H), 2.01-2.11 (m, 2H), 1.82-1.91 (m, 2H), 1.49-1.79 (m, 4H), 1.23-1.26 (m, 6H), 1.21-1.28 (m, 2H), 0.78-0.90 (m, 5H), -0.07 (s, 9H). l-[4-benzyloxy-4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octan-

[0504] 5-yl]methyl]cyclohexyl]-3-butyl-hexahydropyrimidine-2, 4, 6-trione

[0505] To a solution of l-[4-benzyloxy-4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7- diazaspiro[3.4]octan-5-yl]methyl]cyclohexyl]-3-butyl-urea (1 g, 1.70 mmol) in AcOH (10 mL) was added AC2O (1.22 g, 11.93 mmol) and malonic acid (355 mg, 3.41 mmol). The mixture was stirred at 80 °C for 4 h. After completion, the reaction was quenched with H2O (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiCL, etroleum ether : ethyl acetate = 100 : 1 to 0 : 1) to afford the title compound (480 mg, 38.7%) as a yellow oil.1H NMR (400 MHz, DMSO-rfo) 5 ppm 7.20-7.61 (m, 5H), 4.75-4.77 (m, 2H), 4.56 (d, 7 = 14.8 Hz, 2H), 3.67-3.77 (m, 4H), 3.62 (s, 1H), 3.50-3.54 (m, 2H), 2.53-2.84 (m, 5H), 2.05-2.13 (m, 1H), 1.70-2.03 (m, 5H), 1.38-1.59 (m, 6H), 1.29 (m, 3H), 0.79-0.93 (m, 5H), -0.06 (s, 9H). l-[4-benzyloxy-4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octan-

[0506] 5-yl]methyl]cyclohexyl]-3-butyl-5-(diaminomethylene)hexahydropyrimidine-2, 4, 6-trione

[0507] To a solution of l-[4-benzyloxy-4-[[6,8-dioxo-7-(2-trimethylsilylethoxy methyl)-5,7- diazaspiro[3.4]octan-5-yl]methyl]cyclohexyl]-3-butyl-hexahydropyrimidine-2, 4, 6-trione (0.48 g, 733 pmol) in THF (5 mL) was added cyanamide (308.1 mg, 7.33 mmol) and Ni(acac)2 (56.5 mg, 220 pmol). The mixture was stirred at 80 °C for 16 h under N2. After completion, the reaction was quenched with addition of H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 100 : 1 to 0 : 1) to give the title compound (0.3 g, 53%) as a colorless oil. MS (ESI): mass calcd. for CsiHsoN-iOsSi: 586.36, found: 587.4 [M+H]+. l-butyl-5-(diaminomethylene)-3-[4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7- diazaspiro[3.4]octan-5-yl]methyl]-4-hydroxy-cyclohexyl]hexahydropyrimidine-2, 4,6- trione

[0508] To a solution of l-[4-benzyloxy-4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7- diazaspiro [3.4] octan-5 -yl] methyl] cyclohexyl] -3 -buty 1-5 -(diaminomethylene)hexahydro pyrimidine-2, 4, 6-trione (0.3 g, 430 pmol) in EtOH (2 mL) was added Pd(OH)2 (300 mg, 2.14 mmol) and HC1 (12 M, 108 pL). The mixture was stirred at 25 °C for 12 h under H2 (50 psi). After completion, the reaction was filtered and concentrated under reduced pressure to give the title compound (0.26 g, 90%) as a white solid. MS (ESI): mass calcd. for C28H46N6O?Si: 606.32, found: 607.5 [M+H]+. l-butyl-5-(diaminomethylene)-3-(4-((6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)methyl)-4- hydroxycyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (56)

[0509] A solution of l-butyl-5-(diaminomethylene)-3-[4-[[6,8-dioxo-7-(2- trimethylsilylethoxymethyl)-5 ,7 -diazaspiro [3.4]octan-5-yl]methyl] -4-hydroxy- cyclohexyl]hexahydropyrimidine-2,4,6-tri one (0.26 g, 428.49 pmol) in TFA (2 mL) and H2O (0.4 mL) was stirred at 25 °C for 1 h. The reaction was concentrated, dissolved with methanol and added potassium carbonate to achieve a pH of 7-8. Then 15% aqueous citric acid solution was added to adjust reaction pH to 5-6 and the mixture was extracted with ethyl acetate (3 mL x 2). The combined organic layer was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to provide the title compound (0.1 g, 50%) as a white solid. MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 477.3 [M+HJ+JH NMR (400 MHz, DMSO-rfo) 5 ppm 10.69 (s, 1H), 9.56 (s, 2H), 7.31 (s, 2H), 4.53-4.81 (m, 2H), 3.74 (t, J = 7.2 Hz, 2H), 3.48 (s, 1H), 3.28 (s, 1H), 2.62-2.85 (m, 4H), 2.10-2.20 (m, 2H), 1.87-2.00 (m, 1H), 1.81 (d, J = 11.2 Hz, 1H), 1.65-1.75 (m, 1H), 1.61 (d, 7 = 13.2 Hz, 1H), 1.31-1.52 (m, 5H), 1.21-1.29 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H).

[0510] Example 57 and Example 58. l-butyl-5-(diaminomethylene)-3-((lr,4r)-4-((6,8-dioxo-5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-hydroxycyclohexyl)pyrimidine-2,4,6(lH,3H,5H)- trione (57) and l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((6,8-dioxo-5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-hydroxycyclohexyl)pyrimidine-2,4,6(lH,3H,5H)- trione (58)

[0511] Example 56 (100 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 um); mobile phase: CO2-IPA (0.1% NH3H2O); 40% B with isocratic elution) to give 57 (29.55 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 459.2 [M-18+H]+. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 10.71 (s, 1H), 9.56 (s, 2H), 7.33 (s, 2H), 4.68-4.77 (m, 2H), 3.74 (t. 7 = 7.2 Hz, 2H), 3.48 (s, 2H), 2.76-2.87 (m, 2H), 2.62-2.70 (m, 2H), 2.15 (t, 7 = 9.2 Hz, 2H), 1.87-1.97 (m, 1H), 1.81 (d, J = 12.0 Hz, 2H), 1.63-1.73 (m, 1H), 1.33-1.50 (m, 6H), 1.23-1.29 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). 58 (41.02 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 477.2 [M+H]+. ’H NMR (400 MHz, DMSO-rfc) 5 ppm 10.76 (s, 1H), 9.57 (s, 2H), 7.30 (s, 2H), 4.63 (t, 7 = 11.2 Hz, 1H), 4.51 (s, 1H), 3.74 (t, J = 7.2 Hz, 2H), 3.28 (s, 2H), 2.65-2.81 (m, 4H), 2.16 (t, J = 9.6 Hz, 2H), 1.88-1.99 (m, 1 H), 1.66-1.75 (m, 1H), 1.62 (d, J = 12.4 Hz, 2H). 1.33-1.50 (m, 4H), 1.21-1.29 (m, 4H), 0.88 (t, J = 7.6 Hz, 3H).

[0512] Example 59. 4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-l(2H)- yl)-l-((6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexane-l-carbonitrile (59) ethyl 8-cyano-l,4-dioxaspiro[4.5]decane-8-carboxylate

[0513] To a mixture of l,4-dioxaspiro[4.5]decane-8-carbonitrile (10 g, 59.81 mmol) in THF (100 mL) was added LiHMDS (1 M, 119.6 mL) in one portion at -78 °C under N2. The mixture was stirred at -78 °C for 30 min, then was added ethyl chloroformate (12.98 g, 119.6 mmol) and stirred for 2 h at -78 °C. After completion, the reaction was poured into saturated NH4CI (100 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiCL, petroleum ether : ethyl acetate = 100 : 1 to 0 : 1) to afford the title compound (12.5 g, 73%) as a yellow solid. MS (ESI): mass calcd. for C12H17NO4: 239.12, found: 240.1 [M+H]+.

[0514] 8-(hydroxymethyl)-l,4-dioxaspiro[4.5]decane-8-carbonitrile

[0515] To a solution of ethyl 8-cyano-l,4-dioxaspiro[4.5]decane-8-carboxylate (12.5 g, 52.24 mmol) in THF (120 mL) and MeOH (30 mL) was added NaBH4 (3.95 g, 104.49 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 h. After completion, the reaction was poured into saturated NH4CI (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude product was triturated with petroleum ether at 25 °C for 1 h to afford the title compound (9.8 g, 86%) as a white solid. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 5.42 (t, J = 5.6 Hz, 1H), 3.86-3.88 (m, 4H), 3.45 (d, 7 = 5.6 Hz, 2H), 1.87 (d, 7 = 12.8 Hz, 2H), 1.68-1.77 (m, 2H), 1.46-1.66 (m, 4H).

[0516] 8-formyl-l,4-dioxaspiro[4.5]decane-8-carbonitrile

[0517] To a solution of oxalyl dichloride (6.44 g, 50.70 mmol) in DCM (100 mL) was added DMSO (5.94 mL, 76 mmol) at -78 °C in 30 min followed by addition of 8-(hydroxymethyl)- l,4-dioxaspiro[4.5]decane-8-carbonitrile (5 g, 25.35 mmol) in DCM (100 mL) at -78 °C in 30 min. TEA (21.17 mL, 152.1 mmol) was added. The reaction was stirred at -78 °C for 1 h. After completion, the mixture was poured into H2O (100 mL) and extracted with DCM (100 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (6 g, crude) as a white solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C10H13NO3: 195.09, found: 196.1 [M+H]+. methyl l-[(8-cyano-l,4-dioxaspiro[4.5]decan-8-yl)methylamino]cyclobutanecarboxylate

[0518] To a solution of 8-formyl-l,4-dioxaspiro[4.5]decane-8-carbonitrile (6 g, 30.7 mmol) and methyl 1-aminocyclobutanecarboxylate (5.16 g, 40 mmol) in DCM (30 mb) and AcOH (1.85 g, 30.74 mmol) was added sodium triacetoxyborohydride (19.54 g, 92.21 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h. After completion, the reaction was quenched with saturated NaHCCL (30 mL) and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiCL, petroleum ether : ethyl acetate = 100 : 1 to 0 : 1) to afford the title compound (5.3 g, 50%) as a yellow oil. ’H NMR (400 MHz, CDCI3) 5 ppm 3.89-3.99 (m, 4H), 3.73 (s, 3H), 2.55 (s, 2H), 2.34-2.43 (m, 2H), 2.03-2.10 (m, 3H), 1.86-1.98 (m, 6H), 1.71-1.78 (m, 2H), 1.54-1.63 (m, 2H).

[0519] 8-[(6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)methyl]-l,4-dioxaspiro[4.5]decane-8- carbonitrile

[0520] To a solution of methyl l-[(8-cyano-l,4-dioxaspiro[4.5]decan-8- yl)methylamino]cyclobutanecarboxylate (4.8 g, 15.57 mmol) in HOAc (48 mL) was added potassium cyanate (18.94 g, 233.5 mmol). The mixture was stirred at 100 °C for 16 h under N2. The pH was adjusted to around 7 with saturated aqueous Na2CC>3, diluted with H2O (80 mL) and extracted with DCM (150 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 0 : 1 to 1 : 0) to give the title compound (4.65 g, 93.5%) as a yellow oil.:H NMR (400 MHz, CDCh) 5 ppm 7.93 (s, 1H), 3.94-3.98 (m, 4H), 3.56 (s, 2H), 2.66-2.70 (m, 2H), 2.45-2.55 (m, 2H), 2.19-2.29 (m, 1H), 2.01-2.07 (m, 2H), 1.78-1.94 (m, 7H). l-[(6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)methyl]-4-oxo-cyclohexanecarbonitrile

[0521] A mixture of 8-[(6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)methyl]-l,4- dioxaspiro[4.5]decane-8-carbonitrile (4.65 g, 14.56 mmol), TSOH H2O (6.92 g, 36.4 mmol) in acetone (32 mL) and H2O (16 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 50 °C for 16 h under N2. The reaction was diluted with H2O (60 mL) and extracted with DCM (120 mL x 2). The combined organic layer was washed with NaHCCL. brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 0 : 1 to 1 : 0) to give the title compound (3 g, 75%) as a yellow oil. ' H NMR (400 MHz, CDCh) 5 ppm 8.01-8.14 (m, 1H), 3.66 (s, 2H), 2.64-2.78 (m, 4H), 2.47-2.60 (m, 4H), 2.23-2.40 (m, 3H), 1.89-2.06 (m, 3H). l-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octan-5-yl]methyl]-4- oxo-cyclohexanecarbonitrile

[0522] To a solution of l-[(6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)methyl]-4-oxo- cyclohexanecarbonitrile (3 g, 10.9 mmol), DIPEA (5.63 g, 43.6 mmol) in DCM (30 mL) was added SEM-C1 (3.63 g, 21.8 mmol). The mixture was stirred at 25 °C for 1 h under N2. The reaction was diluted with H2O (50 mL) and extracted with DCM (75 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 0 : 1 to 1 : 0) to give the title compound (3.1 g, 70%) as a white solid.1H NMR (400 MHz, CDCh) 5 ppm 4.94 (s, 2H), 3.60-3.71 (m, 4H), 2.66-2.72 (m, 4H), 2.51-2.56 (m, 4H), 2.27-2.43 (m, 3H), 2.01-2.05 (m, 3H), 0.93-0.97 (m, 2H), 0.05 (s, 9H).

[0523] 4-amino-l-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octan-5- yl]methyl]cyclohexanecarbonitrile

[0524] A mixture of 1 - [ [6,8-dioxo-7 -(2-trimethylsilylethoxymethyl)-5 ,7 - diazaspiro[3.4]octan-5-yl]methyl]-4-oxo-cyclohexanecarbonitrile (3.1 g, 7.64 mmol), NH4OAC (11.78 g, 152.87 mmol), NaBH(OAc)3 (4.05 g, 19.11 mmol) in MeOH (31 mL) was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 1 h under N2. The reaction was concentrated under reduced pressure. The residue was diluted with H2O (30 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.22 g, crude) as a white solid.1H NMR (400 MHz, DMSO-rfo) 5 ppm 4.77 (s, 2H), 3.67 (s, 2H), 3.55 (s, 2H), 2.97-3.05 (m, 1H), 2.69-2.75 (m, 2H), 1.96-2.35 (m, 8H), 1.70-1.84 (m, 3H),

[0525] 1.45-1.68 (m, 3H), 0.83 (t, 7 = 8.0 Hz, 2H), -0.05 (s, 9H). l-butyl-3-[4-cyano-4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7- diazaspiro[3.4]octan-5-yl]methyl]cyclohexyl]urea

[0526] To a solution of 4-amino-l-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7- diazaspiro[3.4]octan-5-yl]methyl]cyclohexanecarbonitrile (3.22 g, 7.92 mmol), 1- isocyanatobutane (1.18 g, 11.88 mmol) in DCM (32 mL) was added TEA (801.4 mg, 7.92 mmol). The reaction was stirred at 25 °C for 1 h under N2. The reaction was quenched with MeOH (0.5 mL), diluted with H2O (30 mL) and extracted with DCM (60 mL). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to give the title compound (2.7 g, 67%) as a white solid.1H NMR (400 MHz, CDCh) 5 ppm 4.93 (s, 2H), 3.57-3.69 (m, 5H), 3.12-3.17 (m, 2H), 2.60-2.65 (m, 2H), 2.48-2.65 (m, 2H), 2.23-2.34 (m, 1H), 2.06-2.11 (m, 4H), 1.87-1.98 (m, 3H), 1.37-1.54 (m, 4H), 1.33-1.41 (m, 2H), 0.92-0.97 (m, 5H), 0.01 (s, 9H).

[0527] 4-(3-butyl-2,4,6-trioxo-hexahydropyrimidin-l-yl)-l-[[6,8-dioxo-7-(2- trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octan-5- yl]methyl]cyclohexanecarbonitrile

[0528] A mixture of l-butyl-3-[4-cyano-4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7- diazaspiro[3.4]octan-5-yl]methyl]cyclohexyl]urea (2.7 g, 5.34 mmol), malonic acid (555.57 mg, 5.34 mmol), AC2O (3.82 g, 37.37 mmol) in AcOH (27 mL) was degassed and purged with N2 3 times. The mixture was stirred at 80 °C for 4 h under N2. The mixture was poured into water (60 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (1.6 g, 52%) as a white solid. ’H NMR (400 MHz, CDCh): 5 ppm 4.93-4.95 (m, 2H), 4.62-4.81 (m, 1H), 3.78-3.87 (m, 3H), 3.61-3.67 (m, 5H), 2.69-2.72 (m, 4H), 2.44-2.54 (m, 2H), 2.32-2.33 (m, 2H), 2.12-2.22 (m, 1H), 1.86-2.02

[0529] (m, 2H), 1.65-1.82 (m, 3H), 1.55-1.58 (m, 2H), 1.32-1.39 (m, 2H), 0.95 (t, J = 7.6 Hz, 5H), 0.01 (s, 9H).

[0530] 4-[3-butyl-5-(diaminomethylene)-2,4,6-trioxo-hexahydropyrimidin-l-yl]-l-[[6,8-dioxo-7- (2-trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octan-5- yl]methyl]cyclohexanecarbonitrile

[0531] A mixture of 4-(3-butyl-2,4,6-trioxo-hexahydropyrimidin-l-yl)-l-[[6,8-dioxo-7-(2- trimethylsilylethoxymethyl)-5 ,7 -diazaspiro [3.4]octan-5 -yl] methyl]cyclohexanecarbonitrile (1.6 g, 2.79 mmol), cyanamide (1.17 g, 27.89 mmol), Ni(acac)2 (214.93 mg, 836.59 pmol) in THF (16 mL) was degassed and purged with N2 3 times. The mixture was stirred at 80 °C for 16 h under N2. The reaction was filtered, diluted with H2O (50 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (S i O2, petroleum ether : ethyl acetate = I : 0 to 0 : 1) to give the title compound (1.4 g, 82%) as a white solid. ' H NMR (400 MHz, CDCh) 5 ppm 10.22-10.29 (m, 1H), 5.39- 5.45 (m, 1H), 4.93-4.95 (m, 2H), 3.86-3.89 (m, 3H), 3.60-3.65 (m, 6H), 2.80-2.95 (m, 2H), 2.62-2.75 (m, 2H), 2.43-2.53 (m, 2H), 2.32-2.33 (m, 2H), 2.11-2.20 (m, 1H), 1.85-2.04 (m, 3H), 1.72-1.73 (m, 4H), 1.34-1.38 (m, 2H), 0.92-0.98 (m, 5H), 0.01 (s, 9H).

[0532] 4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-l(2H)-yl)-l-((6,8- dioxo-5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexane-l-carbonitrile (59)

[0533] A mixture of 4-[3-butyl-5-(diaminomethylene)-2,4,6-trioxo-hexahydropyrimidin-l- yl]-l-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octan-5- yl] methyl] cyclo hexanecarbonitrile (1.4 g, 2.27 mmol) in TFA (10 mL) and H2O (2.5 mL) was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure. MeOH (14 mL) was added to the residue and the reaction was adjusted to pH = 9 by adding potassium carbonate. The mixture was stirred at 25 °C for 0.5 h, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (400 mg, 36%) as a white solid. MS (ESI): mass calcd. for C23H31N7O5: 485.24, found: 486.2 [M+H]+. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 10.95 (s, 1H), 9.53 (s, 2H), 7.34 (s, 2H), 4.62-4.86 (m, 1H), 3.70-3.80 (m, 2H), 3.58 (s, 2H), 2.58-2.74 (m, 4H), 2.20-2.23 (m, 2H), 1.68-2.11 (m, 3H), 1.44-1.60 (m, 7H), 1.19-1.34 (m, 2H), 0.88 0. 7 = 7.2 Hz, 3H).

[0534] (lr,4r)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-l(2H)-yl)-l- ((6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexane-l-carbonitrile (60) and (ls,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-l(2H)-yl)-l- ((6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexane-l-carbonitrile (61)

[0535]

[0536] Example 59 (200 mg) was separated by chiral SFC (column: REGIS (s,s) WHELK-01 (250mm*30mm,5 um); mobile phase: CO2-EtOH (0.1% NH3H2O); 40% B with isocratic elution) to give 60 (80 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C23H31N7O5: 485.24, found: 486.3 [M+H]+. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 10.96 (s, 1H), 9.54 (s, 2H), 7.37 (s, 2H), 4.65-4.85 (m, 1H), 3.68-3.84 (m, 4H), 2.61-2.77 (m, 4H), 2.32 (d, J = 12.4 Hz, 2H), 2.22 (t, 7 = 8.8 Hz, 2H), 1.93-2.06 (m, 1H), 1.69-1.88 (m, 3H), 1.42- 1.54 (m, 4H), 1.20-1.30 (m, 2H), 0.89 (t, J - 7.2 Hz, 3H). 61 (100 mg) was obtained as the second eluting peak from SFC separation as a white solid. MS (ESI): mass calcd. for C23H31N7O5: 485.24, found: 486.3 [M+H]+. ' H NMR (400 MHz, DMSO-rfo) 5 ppm 10.94 (s, 1H), 9.53 (s, 2H), 7.33 (s, 2H), 4.60-4.77 (m, 1H), 3.75 0. 7 = 7.2 Hz, 2H), 3.58 (s, 2H), 2.57- 2.71 (m, 4H), 2.23 (t, J = 9.2 Hz, 2H), 1.92-2.11 (m, 3H), 1.60-1.85 (m, 1H), 1.52-1.65 (m, 4H), 1.40-1.50 (m, 2H), 1.26 (d, 7 = 7.2 Hz, 2H), 0.88 (t, 7 = 7.2 Hz, 3H).

[0537] Example 62. 5-(diaminomethylene)-l-(4-((6,8-dioxo-5,7-diazaspiro[3.4]octan-5- yl)methyl)-4-(hydroxymethyl)cyclohexyl)-3-propylpyrimidine-2,4,6(lH,3H,5H)-trione

[0538] Synthetic scheme:

[0539] ethyl 8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate

[0540] To a solution of ethyl ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (80 g, 373.38 mmol) in THF (800 mL) was added drop wise LDA (2 M in THF / n-heptane, 373.4 mL) at 0 °C. After addition, the reaction was stirred at this temperature for 30 min. Chloromethoxymethylbenzene (70.17 g, 448.06 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction was partitioned between ethyl acetate (300 mL x 3), NH4CI (300 mL) and H2O (100 mL). The organic layer was separated, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, petroleum ether : ethyl acetate = 100 : 1 to 3 : 1) to give the title compound (80 g) as a yellow oil.1H NMR (400 MHz, DMSO-rfo) 5 ppm 7.23-7.38 (m, 5H), 4.44 (s, 2H), 4.03-4.11 (m, 2H), 3.80-3.84 (m, 4H), 3.43 (s, 2H), 1.96-2.04 (m, 2H), 1.53-1.70 (m, 2H), 1.41-1.53 (m, 4H), 1.12-1.18 (m, 3H). (8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8-yl)methanol

[0541] To a solution of ethyl ethyl 8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decane-8- carboxylate (60 g, 179.42 mmol) in THF (600 mL) was added LiAlFLi (2.5 M in THF, 86.1 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with H2O (8 mL) 15% NaOH (8 mL) and H2O (24 mL). The mixture was filtered through a celite pad and was washed with ethyl acetate (600 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, petroleum ether : ethyl acetate = 100 : 1 to 1 : 1) to give the title compound as a colorless oil. MS (ESI): mass calcd. for C17H24O4: 292.17, found: 293.1 [M+H]+.

[0542] 8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carbaldehyde

[0543] To a solution of (COC1)2 (25.83 g, 203.51 mmol) in DCM (350 mL) was added DMSO (203.5 mmol, 15.9 mL) at -70 °C. The mixture was stirred at -70 °C for 1 h. (8- ((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8-yl)methanol (35 g, 119.71 mmol) was added and the mixture was stirred at -70 °C for 1 h. TEA (60.57 g, 598.56 mmol) was added to quench the reaction. The mixture was stirred at -70 °C for 0.5 h, allowed to warm to 20 °C and stirred for 20 min. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound, which was used directly the next step without further purification.1H NMR (400 MHz, DMSO-rfo) 5 ppm 9.52 (s, 1H), 7.24-7.38 (m, 5H), 4.44 (s, 2H), 3.83 (s, 4H), 3.73 (s, 2H), 1.84-1.96 (m, 2H), 1.35-1.60 (m, 6H). methyl l-(((8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8- yl)methyl)amino)cyclobutane-l-carboxylate

[0544] To a solution of 8-(benzyloxymethyl)-l,4-dioxaspiro[4.5]decane-8-carbaldehyde (35 g, 120.54 mmol) and methyl 1-aminocyclobutanecarboxylate (20.24 g, 156.7 mmol) in DCM (300 mL) was added NaBH(OAc)3 (76.64 g, 361.63 mmol) at 0 °C. The mixture was stirred at 0-25 °C for 16 h. The mixture was poured into H2O (100 mL) and saturated NaHCCL (100 mL) and extracted with DCM (300 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 100 : 1 to 30 : 1) to give the title compound as a white solid. MS (ESI): mass calcd. for C23H33NO5: 403.24, found: 404.1 [M+H]+.

[0545] 5-((l-((benzyloxy)methyl)-4-oxocyclohexyl)methyl)-5,7-diazaspiro[3.4]octane-6, 8-dione

[0546] To a solution of methyl l-[[8-(benzyloxymethyl)-l,4-dioxaspiro[4.5]decan-8- yl]methylamino]cyclobutanecarboxylate (35 g, 86.74 mmol) in AcOH (350 mL) was added potassium cyanate (70.36 g, 867.39 mmol). The mixture was stirred at 100 °C for 16 h, cooled down and concentrated under reduced pressure. The residue was quenched with saturated NaHCCL (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 100 : 1 to 10 : 1) to give the title compound as a white solid. MS (ESI): mass calcd. for C21H26N2O4: 370.19, found: 371.1 [M+H]+.

[0547] 5-((l-((benzyloxy)methyl)-4-oxocyclohexyl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-

[0548] 5,7-diazaspiro[3.4] octane-6, 8-dione To a solution of 5-((l-((benzyloxy)methyl)-4-oxocyclohexyl)methyl)-5,7- diazaspiro[3.4]octane-6, 8-dione (37 g, 99.88 mmol) in DCM (400 mL) was added SEM-C1 (19.98 g, 119.86 mmol) and DIPEA (38.73 g, 299.64 mmol). After stirring at 25 °C for 16 h, the reaction was poured into H2O (100 mL) and extracted with DCM (100 mL x 2). The combined organic layer was dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 100 : 1 to 1 : 1) to give the title compound (38 g, 76%) as a colorless oil. MS (ESI): mass calcd. for C27H4oN20sSi: 500.27, found: 523.2 [M+Na]+.

[0549] 5-[[4-amino-l-(benzyloxymethyl)cyclohexyl]methyl]-7-(2-trimethylsilylethoxymethyl)-

[0550] 5,7-diazaspiro[3.4] octane-6, 8-dione

[0551] A mixture of 5-[[l-(benzyloxymethyl)-4-oxo-cyclohexyl]methyl]-7-(2- trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octane-6, 8-dione (2.9 g, 5.79 mmol), NaBH(OAc)3 (3.68 g, 17.38 mmol) and NH4OAC (8.93 g, 115.84 mmol) in MeOH (30 mL) was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 16 h under N2. The reaction was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and extracted with DCM (45 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (2.89 g, 99%) as a white solid. MS (ESI): mass calcd. for C27H43N3O4SE 501.30, found: 502.4 [M+H]+.

[0552] 1 - [4-(benzyloxymethyl)-4- [[6,8-dioxo-7 - (2-trimethylsilylethoxymethyl)-5,7 - diazaspiro[3.4]octan-5-yl]methyl]cyclohexyl]-3-propyl-urea

[0553] A mixture of 5-[[4-amino-l-(benzyloxymethyl)cyclohexyl]methyl]-7-(2- trimethylsilylethoxymethyl)-5,7-diazaspiro[3.4]octane-6, 8-dione (2.89 g, 5.76 mmol), 1- isocyanatopropane (490.2 mg, 5.76 mmol) and TEA (582.85 mg, 5.76 mmol) in DCM (30 mL) was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 1 h under N2. The reaction was quenched by MeOH (2 mL), diluted with H2O (50 mL) and extracted with DCM (45 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 10 : 90 to 17 : 83) to give the title compound (1.8 g, 53.3%) as a colorless oil. MS (ESI): mass calcd. for C3iHsoN40sSi: 586.36, found: 587.4 [M+H]+.

[0554] 1 - [4-(benzyloxymethyl)-4- [[6,8-dioxo-7 - (2-trimethylsilylethoxymethyl)-5,7 - diazaspiro[3.4]octan-5-yl]methyl]cyclohexyl]-3-propyl-hexahydropyrimidine-2, 4,6- trione

[0555] A mixture of l-[4-(benzyloxymethyl)-4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)- 5,7-diazaspiro[3.4]octan-5-yl]methyl]cyclohexyl]-3-propyl-urea (1.6 g, 2.73 mmol) and malonic acid (283.72 mg, 2.73 mmol) in AcOH (8 mL) and AC2O (8 mL) was degassed and stirred at 80 °C for 1 h. The reaction was diluted with H2O (40 mL) and extracted with DCM (45 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 10 : 1 to 1 : 1) to give the title compound (1 g, 56% ) as a yellow oil. MS (ESI): mass calcd. for Cs-iHsoN-iChSi: 654.34, found: 677.4 [M+Na]+.

[0556] 1 - [4-(benzyloxymethyl)-4- [[6,8-dioxo-7 - (2-trimethylsilylethoxymethyl)-5,7 - diazaspiro[3.4]octan-5-yl]methyl]cyclohexyl]-5-(diaminomethylene)-3-propyl- hexahydropyrimidine-2, 4, 6-trione

[0557] A mixture of l-[4-(benzyloxymethyl)-4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)- 5, 7-diazaspiro[3.4]octan-5-yl]methyl]cyclohexyl]-3-propyl-hexahydropyrimidine-2, 4, 6-trione (1 g, 1.53 mmol), cyanamide (641.96 mg, 15.27 mmol) and Ni(acac)2 (117.7 mg, 458.11 pmol) in THF (10 mL) was degassed and purged with N2 3 times. The mixture was stirred at 80 °C for 16 h under N2. The reaction was filtered through a celite pad. The filtrate was diluted with H2O (60 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL. petroleum ether : ethyl acetate = 15 : 85 to 1 : 1) to afford the title compound (508 mg, 48%) as a white solid. MS (ESI): mass calcd. for C35H52N6O7Si: 696.37, found: 719.4 [M+Na]+.

[0558] 5-(diaminomethylene)-l-[4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-5,7- diazaspiro[3.4]octan-5-yl]methyl]-4-(hydroxymethyl)cyclohexyl]-3-propyl- hexahydropyrimidine-2, 4, 6-trione

[0559] A mixture of l-[4-(benzyloxymethyl)-4-[[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)- 5 ,7-diazaspiro [3.4] octan-5-yl]methyl]cyclohexyl] -5-(diaminomethylene)-3-propyl- hexahydropyrimidine-2, 4, 6-trione (508 mg, 728.9 pmol), Pd / C (1.5 g, 1.41 mmol, 10% w / w) in EtOH (5 mL) was degassed and purged with H2 3 times. After stirring at 25 °C for 16 h under H2 (50 psi), the reaction was filtered through a celite pad and washed with EtOH (20 mL). The filtrate was concentrated under reduced pressure to give the title compound (285 mg, 52%) as a white solid. MS (ESI): mass calcd. for C28H46N6O?Si: 606.32, found: 629.4 / 629.3 [M+Na]+.

[0560] 5-(diaminomethylene)-l-(4-((6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)methyl)-4-

[0561] (hydroxymethyl)cyclohexyl)-3-propylpyrimidine-2,4,6(lH,3H,5H)-trione (62)

[0562] A mixture of 5-(diaminomethylene)-l-[4-[[6,8-dioxo-7-(2-trimethylsilylethoxy methyl)-5 ,7-diazaspiro [3.4] octan-5 -yl] methyl] -4-(hydroxymethyl)cyclohexyl] -3 -propyl- hexahydropyrimidine-2, 4, 6-trione (285 mg, 470 pmol) in TFA (2.5 mL) and H2O (0.5 mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure. The residue was dissolved into MeOH (3 mL), and potassium carbonate was added to adjust to pH = 9. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (40 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (120 mg, 54%) as a white solid. MS (ESI): mass calcd. for C22H32N6O4: 476.24, found: 477.3 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 10.53-10.93 (m, 1H), 9.55 (s, 2H), 7.26-7.37 (m, 2H), 4.70-4.75 (m, 1H), 4.59-4.69 (m, 1H), 3.66-3.77 (m, 2H), 3.38-3.46 (m, 2H), 3.05-3.18 (m, 2H), 2.60-2.75(m, 3H), 2.43 (s, 1H), 2.11- 2.25 (m, 2H), 1.90-2.03 (m, 1H), 1.45-1.70 (m, 5H), 1.20-1.39 (m, 4H), 0.82 (t, J = 7.2 Hz, 3H).

[0563] Example 63 and Example 64. 5-(diaminomethylene)-l-((lr,4r)-4-((6,8-dioxo-5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-(hydroxymethyl) cyclohexyl)-3-propylpyrimidine- 2,4,6(lH,3H,5H)-trione (63) and 5-(diaminomethylene)-l-((ls,4s)-4-((6,8-dioxo-5,7-diazaspiro[3.4]octan-5- yl)methyl)-4-(hydroxymethyl)cyclohexyl)-3-propylpyrimidine-2,4,6(lH,3H,5H)-trione

[0564] Example 62 (120 mg) was separated by chiral SFC (condition: column: DAICEL CHIRALPAK IG (250mm*30mm,10 um); mobile phase: CO2-IPA (0.1% NH3H2O); 50% B with isocratic elution) to give 63 (30 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 477.2 [M+H]+. 'H NMR (400 MHz, DMSO-rfc) 5 ppm 10.86 (s, 1H), 9.56 (s, 2H), 7.34 (s, 2H), 4.59-4.92 (m, 2H), 3.67-3.78 (m, 2H), 3.38 (s, 2H), 3.07 (d, J = 5.6 Hz, 2H), 2.59-2.78 (m, 4H), 2.19 (t, J = 9.2 Hz, 2H), 1.91-2.04 (m, 1H), 1.58-1.73 (m, 3H), 1.44-1.56 (m, 2H), 1.35 (d, J = 10.0 Hz, 2H), 1.15-1.27 (m, 2H), 0.82 (t, J - 7.6 Hz, 3H). 64 (40 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 477.2 [M+H]+. ’H NMR (400 MHz, DMSO- d6) 5 ppm 10.83 (s, 1H), 9.55 (s, 2H), 7.26-7.40 (m, 2H), 4.73 (s, 1H), 4.59-4.70 (m, 1H), 3.67- 3.75 (m, 2H), 3.45 (d, 7 = 5.6 Hz, 2H), 3.13 (s, 2H), 2.57-2.67 (m, 2H), 2.36-2.47 (m, 2H), 2.16 (t, J = 8.8 Hz, 2H), 1.88-2.01 (m, 1H), 1.44-1.72 (m, 5H), 1.22-1.34 (m, 4H), 0.82 (t, J = 7.6 Hz, 3H).

[0565] Example 65. l-butyl-3-((ls,4s)-4-((3-(cyclopropylmethyl)-4-methyl-2,5- dioxoimidazolidin-4-yl)methyl)cyclohexyl)-5-(diaminomethylene)pyrimidine- 2,4,6(lH,3H,5H)-trione (65)

[0566] Synthetic scheme: tert-butyl ((ls,4s)-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate

[0567] To a solution of 2-((ls,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (4.8 g, 18.65 mmol) in DCM (50 mL) was added N-methoxymethanamine;hydrochloride (2.00 g, 20.52 mmol) and DIPEA (7.23 g, 55.96 mmol, 9.75 mL) followed by the addition of HATU (8.51 g, 22.38 mmol) at 0 °C under N2. The reaction was stirred at 25 °C for 12 h under N2. The reaction mixture was quenched with H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 100 : 1 to 5 : 1). The resulting product was triturated with MTBE (20 mL) at 25 °C for 30 min. The precipitate was collected by filtration and dried over vacuum to give the title compound (4.5 g, 79%) as a white solid. MS (ESI): mass calcd. for C15H28N2O4: 300.20, found: 323.2 [M+Na]+. tert-butyl ((ls,4s)-4-(2-oxopropyl)cyclohexyl)carbamate

[0568] To a solution of tert-butyl ((ls,4s)-4-(2-(methoxy(methyl)amino)-2- oxoethyl)cyclohexyl)carbamate (4.5 g, 14.98 mmol) in THF (45 mL) was added MeMgBr (3 M, 9.99 mL) at -20 °C under N2. The reaction mixture was stirred at 25 °C for 12 h under N2. The reaction was quenched with H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 100 : 1 to 3 : 1) to give the title compound (3 g, 78%) as a white solid.1H NMR (400 MHz, CDCh) 5 ppm 4.60 (s, 1 H), 3.70 (s, 1 H), 2.36 (d, J = 6.8 Hz, 2 H), 2.12 (s, 3 H), 1.94-1.97 (m, 1 H), 1.54-1.63 (m, 6 H), 1.44 (s, 9 H), 1.17-1.21 (m, 2 H). tert-butyl ((ls,4s)-4-((4-methyl-2,5-dioxoimidazolidin-4-yl)methyl)cyclohexyl)carbamate

[0569] To a solution of tert-butyl ((ls,4s)-4-(2-oxopropyl)cyclohexyl)carbamate (3 g, 11.75 mmol) in MeOH (2 mL) and H2O (2 mL) was added TMSCN (2.33 g, 23.50 mmol) and (NEL^hCCh (4.52 g, 46.99 mmol). The reaction was stirred at 90 °C for 12 h, cooled down and concentrated under reduced pressure. The residue was triturated with H2O at 25 °C for 30 min. The precipitate was collected by filter and dried over vacuum to give the title compound (3.8 g, 95%) as a white solid. MS (ESI): mass calcd. for C16H27N3O4: 325.20, found: 348.2 [M+Na]+. tert-butyl ((ls,4s)-4-((4-methyl-2,5-dioxo-l-((2-

[0570] (trimethylsilyl)ethoxy)methyl)imidazolidin-4-yl)methyl)cyclohexyl)carbamate

[0571] To a solution of tert-butyl tert-butyl ((ls,4s)-4-((4-methyl-2,5-dioxoimidazolidin-4- yl)methyl)cyclohexyl)carbamate (1 g, 3.07 mmol) in DCM (10 mL) was added SEM-C1 (1.02 g, 6.15 mmol) and DIPEA (1.59 g, 12.29 mmol) dropwise at 0 °C under N2. The reaction was stirred at 40 °C for 12 h under N2. The reaction was quenched with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 100 : 1 to 3 : 1) to give the title compound (687 mg, 48%) as a white solid. MS (ESI): mass calcd. for C22H4iN30sSi: 455.28, found: 478.2 [M+Na]+. tert-butyl ((ls,4s)-4-((3-(cyclopropylmethyl)-4-methyl-2,5-dioxo-l-((2-

[0572] (trimethylsilyl)ethoxy)methyl) imidazolidin-4-yl)methyl)cyclohexyl)carbamate

[0573] To a solution of tert-butyl ((ls,4s)-4-((4-methyl-2,5-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-4-yl)methyl)cyclohexyl)carbamate (540 mg, 1.19 mmol) in DMF (5 mL) was added CS2CO3 (386.1 mg, 1.19 mmol) and iodomethylcyclopropane (237.3 mg, 1.3 mmol). The mixture was stirred at 25 °C for 12 h. The residue was poured into H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether : ethyl acetate = 96 : 4 to 1 : 1) to give the title compound (400 mg, 66%) as white solid. MS (ESI): mass calcd. for C26H47N3O5Si: 509.33, found: 532.6 [M+Na]+.

[0574] 5-(((ls,4s)-4-aminocyclohexyl)methyl)-l-(cyclopropylmethyl)-5-methyl-3-((2-

[0575] (trimethylsilyl)ethoxy)methyl) imidazolidine-2, 4-dione

[0576] To a solution of tert-butyl ((ls,4s)-4-((3-(cyclopropylmethyl)-4-methyl-2,5-dioxo-l- ((2-(trimethylsilyl)ethoxy)methyl) imidazolidin-4-yl)methyl)cyclohexyl)carbamate (350 mg, 686.6 pmol) in DCM (3 mL) was added formic acid (3 mL). The reaction was stirred at 25 °C for 12 h and concentrated under reduced pressure. The residue was poured into H2O (20 mL), adjusted to pH = 8-9 with saturated NaHCCL and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (260 mg, 93%) as colorless oil. MS (ESI): mass calcd. for C21H39N3O3SE 409.28, found: 410.2 [M+H]+. l-butyl-3-((ls,4s)-4-((3-(cyclopropylmethyl)-4-methyl-2,5-dioxo-l-((2-

[0577] (trimethyIsiIyI)ethoxy)methyI)imidazoIidin-4-yI)methyI)cycIohexyI)urea

[0578] The title compound was prepared using an identical method to the urea synthesis in

[0579] Example 1. l-butyl-3-((ls,4s)-4-((3-(cyclopropylmethyl)-4-methyl-2,5-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-4-yl)methyl)cyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione

[0580] The title compound was prepared using an identical method to the barbiturate synthesis in Example 1. l-butyl-3-((ls,4s)-4-((3-(cyclopropylmethyl)-4-methyl-2,5-dioxo-l-((2-

[0581] (trimethylsilyl)ethoxy)methyl)imidazolidin-4-yl)methyl)cyclohexyl)-5-

[0582] (diaminomethylene)pyrimidine-2,4,6(lH,3H,5H)-trione The title compound was prepared using an identical method to the diaminomethylene barbiturate synthesis in Example 1. l-butyl-3-((ls,4s)-4-((3-(cyclopropylmethyl)-4-methyl-2,5-dioxoimidazolidin-4- yI)methyI)cycIohexyI)-5-(diaminomethyIene)pyrimidine-2,4,6(lH,3H,5H)-trione (65)

[0583] A solution of l-butyl-3-((ls,4s)-4-((3-(cyclopropylmethyl)-4-methyl-2,5-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-4-yl)methyl)cyclohexyl)-5- (diaminomethylene)pyrimidine-2,4,6(lH,3H,5H)-trione (30 mg, 48 pmol) in H2O (0.2 mL) and TFA (1 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (1 mL) and K2CO3 (46.9 mg, 339 pmol) was added. The mixture was stirred at 25 °C for 1 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (7.8 mg, 33%) as a white solid. MS (ESI): mass calcd. for C24H36N6O5: 488.27, found: 489.3 [M+H]+. ' H NMR (400 MHz, DMSO-tfo) 5 ppm 10.80 (s, 1H), 9.55 (s, 2H), 7.30 (s, 2H), 4.61 (t, J = 12.0 Hz, 1H), 3.74 (t, J = 7.2 Hz, 2H), 3.15 (dd, J = 6.4, 14.4 Hz, 1H), 2.92 (dd, J = 7.2, 14.8 Hz, 1H), 2.32-2.47 (m, 2H), 2.04 (dd, 7 = 8.0, 14.8 Hz, 1H), 1.63-1.74 (m, 1H), 1.53 (s, 1H), 1.41- 1.51 (m, 5H), 1.37 (s, 4H), 1.16-1.31 (m, 4H), 0.96-1.07 (m, 1H), 0.88 (t, 7 = 7.2 Hz, 3H), 0.47 (d, J = 8.0 Hz, 2H), 0.21-0.35 (m, 2H). l-butyI-5-(diaminomethyIene)-3-((ls,4s)-4-((2,6-dioxohexahydropyrimidin-4- yI)methyI)cycIohexyI)pyrimidine-2,4,6(lH,3H,5H)-trione (66) tert-butyl ((ls,4s)-4-(2-oxoethyl)cyclohexyl)carbamate

[0584] To a solution of tert-butyl ((ls,4s)-4-(2-(methoxy(methyl)amino)-2- oxoethyl)cyclohexyl)carbamate (5 g, 16.64 mmol) in DCM (25 mL) was added sodium bis(2- methoxyethoxy)aluminum hydride (49.93 mmol, 13.9 mL, 70% in DCM). The mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated NH4CI (15 mL), diluted with H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Si CL. petroleum ether : ethyl acetate = 99 : 1 to 3 : 1) to give the title compound (3.2 g, 80%) as a white solid. ’H NMR (400 MHz, CDCh) 5 ppm 9.77 (s, 1H), 4.60 (s, 1H), 3.73 (s, 1H), 2.38 (dd. J = 2.0. 6.8 Hz, 2H), 2.05 (s, 1H), 1.60-1.70 (m, 6H), 1.45 (s, 9H), 1.17-1.35 (m, 2H). tert-butyl ((ls,4s)-4-((E)-2-((tert-butylsulfinyl)imino)ethyl)cyclohexyl)carbamate

[0585] To a solution of tert-butyl ((ls,4s)-4-(2-oxoethyl)cyclohexyl)carbamate (5 g, 20.72 mmol) and 2-methylpropane-2-sulfinamide (3.01 g, 24.86 mmol) in DCM (100 mL) was added Ti(i-PrO)4 (11.78 g, 41.44 mmol). The mixture was stirred at 20 °C for 12 h. The residue was poured into H2O (20 mL) and stirred for 5 min. The mixture was filtered through a celite pad. The filtrate was extracted with DCM (20 mL). The organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 88 : 12 to 3 : 1) to give the title compound (3 g, 42%) as a white solid.1H NMR (400 MHz, CDCh) 5 ppm 8.05 (t, J = 5.2 Hz, 1H), 4.62 (d, J = 1.2 Hz, 1H), 3.73 (s, 1H), 2.48 (dd, J = 5.6, 6.8 Hz, 2H), 1.90 (s, 1H), 1.60-1.68 (m, 6H), 1.45 (s, 9H), 1.25-1.37 (m, 2H), 1.20 (s, 9H). methyl 4-((ls,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-((tert- butylsulfinyl)amino)butanoate

[0586] To a solution of methyl acetate (1.12 g, 15.09 mmol) in THF (15 mL) was added dropwise LDA (2 M, 7.92 mL) at -70 °C. After addition, the mixture was stirred at this temperature for 30 min. A solution of TiCl(OiPr)3 (8.26 g, 31.7 mmol) in THF (15 mL) was added dropwise and the resulting mixture was stirred at -70 °C for 30 min. Then a solution of tert-butyl ((ls,4s)-4-((E)-2-((tert-butylsulfinyl)imino)ethyl)cyclohexyl)carbamate (2.6 g, 7.55 mmol) in THF (15 mL) was added dropwise and the resulting mixture was stirred at -70 °C for 3 h. The reaction mixture was quenched with saturated NH4CI (12 mL). The mixture was filtered through a celite pad. The filtrate was extracted with ethyl acetate (50 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 88 : 12 to 1 : 1) to give the title compound (2.2 g, 70%) as a yellow oil. MS (ESI): mass calcd. for C20H38N2O5S: 418.25, found: 419.1 [M+H]+. methyl 3-amino-4-((ls,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)butanoate

[0587] To a solution of methyl 4-((ls,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-3-((tert- butylsulfinyl)amino)butanoate (1.5 g, 3.58 mmol) in THF (13 mL) was added HC1 (1 N, 3.58 mL) in H2O (3.2 mL). The mixture was stirred at 20 °C for 6 h. The mixture was poured into H2O (5 mL) and extracted with ethyl acetate (10 mL). The aqueous phase was adjusted to pH = 8-9 with saturated NaHCCL and extracted with ethyl acetate (10 mL). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (0.75 g, 67%) as a colorless oil. MS (ESI): mass calcd. for C16H30N2O4: 314.22, found: 315.0 [M+H]+. tert-butyl ((ls,4s)-4-((2,6-dioxohexahydropyrimidin-4-yl)methyl)cyclohexyl)carbamate methyl 3-amino-4-((ls,4s)-4-((tert- butoxycarbonyl)amino)cyclohexyl)butanoate (400 mg, 1.27 mmol) in DCM (8 mL) was added 2,2,2-trichloroacetyl isocyanate (240 mg, 1.27 mmol). The mixture was stirred at 25 °C for 1 h and concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and NH4OH (32.46 mmol, 5 mL, 25% purity). The mixture was stirred at 70 °C for 1 h and concentrated under reduced pressure. The crude product was triturated with CH3CN (3 mL) at 25 °C for 5 min to give the title compound (470 mg, crude) as a colorless oil. MS (ESI): mass calcd. for C16H27N3O4: 325.20, found: 270.0 [M-56+l]+. tert-butyl ((ls,4s)-4-((l-(3,4-dimethoxybenzyl)-2,6-dioxohexahydropyrimidin-4- yl)methyl)cyclohexyl)carbamate

[0588] To a solution of tert-butyl ((ls,4s)-4-((2,6-dioxohexahydropyrimidin-4- yl)methyl)cyclohexyl)carbamate (300 mg, 921.9 pmol) in CH3CN (3 mL) was added CS2CO3 (600.8 mg, 1.84 mmol) and 4-(chloromethyl)-l,2-dimethoxy-benzene (172.1 mg, 921.9 pmol). The mixture was stirred at 20 °C for 12 h. The residue was poured into H2O (5 mL) and stirred for 5 min. The mixture was filtered. The filter cake was dried over vacuum to give the title compound (200 mg, crude) as a white solid. MS (ESI): mass calcd. for C25H37N3O6: 475.27, found: 476.2 [M+H]+.

[0589] 6-(((ls,4s)-4-aminocyclohexyl)methyl)-3-(3,4-dimethoxybenzyl)dihydropyrimidine-

[0590] 2,4(lH,3H)-dione

[0591] To a solution of tert-butyl ((ls,4s)-4-((l-(3,4-dimethoxybenzyl)-2,6- dioxohexahydropyrimidin-4-yl)methyl)cyclohexyl)carbamate (200 mg, 420.5 pmol) in DCM (2 mL) was added HCOOH (20.20 mg, 420.5 pmol). The mixture was stirred at 20 °C for 12 h. The residue was poured into H2O (10 mL) and extracted with ethyl acetate (20 mL). The aqueous phase was concentrated under reduced pressure to give the title compound (140 mg, crude) as a yellow oil. MS (ESI): mass calcd. for C20H29N3O4: 375.22, found: 376.1 [M+H]+. l-butyl-3-((ls,4s)-4-((l-(3,4-dimethylbenzyl)-2,6-dioxohexahydropyrimidin-4- yl)methyl)cyclohexyl)urea

[0592] The title compound was prepared using an identical method to the urea synthesis in Example 1. l-butyl-3-((ls,4s)-4-((l-(3,4-dimethylbenzyl)-2,6-dioxohexahydropyrimidin-4- yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[0593] The title compound was prepared using an identical method to the barbiturate synthesis in Example 1. l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((l-(3,4-dimethylbenzyl)-2,6- dioxohexahydropyrimidin-4-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[0594] The title compound was prepared using an identical method to the diaminomethylene synthesis in Example 1. l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((2,6-dioxohexahydropyrimidin-4- yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (66)

[0595] To a solution of l-butyl-5-(diaminomethylene)-3-((ls,4s)-4-((l-(3,4- dimethoxybenzyl)-2,6-dioxohexahydropyrimidin-4-yl)methyl)cyclohexyl)pyrimidine-

[0596] 2,4,6(lH,3H,5H)-trione (30 mg, 51 pmol) in TFA (0.5 mL) was added methanesulfonic acid (0.2 mL). The mixture was stirred at 70 °C for 16 h, cooled down and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (4.71 mg, 20%) as a yellow solid. MS (ESI): mass calcd. for C20H30N6O5: 434.23.21, found: 435.2 [M+H]+.1H NMR (400 MHz, DMSO-rfo) 5 ppm 9.96 (s, 1H), 9.55 (s, 2H), 7.55-7.79 (m, 1H), 7.30 (s, 2H), 4.65 (t, J = 12.4 Hz, 1H), 3.69-3.79 (m, 2H), 3.42-3.48 (m, 1H), 2.60 (dd, J = 5.2, 16.4 Hz, 2H), 2.42 (d, J = 12.8 Hz, 1H), 2.27 (dd, J = 6.0, 16.4 Hz, 1H), 1.80 (s, 1H), 1.54-

[0597] 1.66 (m, 3H), 1.40-1.52 (m, 5H), 1.27 (quin, 7 = 7.6 Hz, 4H), 0.88 (t. 7 = 7.6 Hz, 3H).

[0598] Example 67. l-butyl-5-(diaminomethylene)-3-(cis-4-((5,5-dimethyl-2,4- dioxoimidazolidin-l-yl)methyl)-3-methylcyclohexyl) pyrimidine-2,4,6(lH,3H,5H)-trione (67) cis-ethyl -2-methyl-4-oxocyclohexane-l-carboxylate

[0599] To a solution of ethyl 2-methyl-4-oxo-cyclohex-2-ene-l -carboxylate (36 g, 197.6 mmol) in EtOH (360 mL) was added Pd / C (5.76 g, 5.41 mmol, 10% w / w) under N2. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (15 psi) at 25 °C for 6 h. The reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure to give a mixture of cis / trans isomers (7:1) of title compound (35 g, 96%) as colorless oil.1H NMR (400 MHz, CDCh) 5 ppm 4.06-4.27 (m, 2H), 2.83-2.87 (m, 1H), 2.42-2.65 (m, 4H), 2.25-2.38 (m, 1H), 2.05-2.21 (m, 2H), 1.15-1.33 (m, 3H), 0.85-1.08 (m, 3H). ethyl (7 / ?,8.S)-7-methyl- L4-dioxaspiro|4.5|decane-8-carboxylate

[0600] A mixture of ethyl cis-2-methyl-4-oxo-cyclohexanecarboxylate (35 g, 189.98 mmol, 7:1 cis / trans isomer mix), ethylene glycol (23.58 g, 380 mmol), PTS A (3.27 g, 19.0 mmol) in toluene (400 mL) was degassed and purged with N2 3 times. The mixture was stirred at 120 °C for 12 h under N2, cooled down and concentrated under reduced pressure. The reaction was diluted with saturated NaHCCL (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 1 : 0 to 19 : 1) to give the title compound (16.8 g, 39%) as a light yellow oil. MS (ESI): mass calcd. for C12H20O4: 228.14, found: 229.1 [M+H]+. cis-7-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylic acid

[0601] A mixture of ethyl cis-7-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (9.6 g, 42.1 mmol) and LiOH H2O (5.29 g, 126.2 mmol) in EtOH (57.6 mL) and H2O (32.4 mL) was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 24 h under N2. The reaction was concentrated under reduced pressure. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL x 3). The aqueous layer was cooled to 0 °C, adjusted to pH to 3 - 4 with saturated citric acid solution and extracted with DCM (30 mL). The organic phase was separated, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (8.34 g, 99%) as a colorless oil. MS (ESI): mass calcd. for C10H16O4: 200.10, found: 201.1 [M+H]+. cis-7-methyl-l,4-dioxaspiro[4.5]decane-8-carboxamide

[0602] To a solution of cis-7-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylic acid (4.3 g, 21.48 mmol) in THF (86 mL) was added TEA (20.64 g, 204.01 mmol) and isobutyl chloroformate (3.23 g, 23.62 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. NH4OH (273.59 mmol, 42.15 mL, 25% w / w) in THF (43 mL) was added dropwise at 0 °C for 5 min. After addition, the mixture was stirred at 0 °C for 30 min and then at 25 °C for 2 h. The reaction was concentrated under reduced pressure. The residue was diluted with saturated NH4CI (50 mL) and extracted with DCM (50 mL x 8). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (2 g, 48%) as a white solid.1H NMR (400 MHz, METHANOL-^): 5 ppm 7.40 (s, 1H), 6.55 (s, 1H), 3.80-4.00 (m, 4H), 2.43 (q, J = 4.8 Hz, 1H), 2.04-2.16 (m, 1H), 1.93-2.04 (m, 2H), 1.82-1.92 (m, 1H), 1.71-1.82 (m, 1H), 1.44-1.65 (m, 2H), 1.01 (d. 7 = 7.2 Hz, 3H).

[0603] (cis-7 -methyl- 1 ,4-dioxaspiro[4.5] decan-8-yl)me thanamine

[0604] To a solution of cis-7-methyl-l,4-dioxaspiro[4.5]decane-8-carboxamide (3.3 g, 16.56 mmol) in THF (33 mL) was added dropwise LiAIFU (2.5 M in THF, 9.94 mL) at 0 °C. The mixture was stirred at 70 °C for 4 h and quenched with H2O (0.9 mL), NaOH (15%) (0.9 mL) and H2O (2.7 mL) at 0 °C. The mixture was filtered through a celite pad and washed with THF (150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 1 : 0 to 7 : 3, then ethyl acetate : methanol : NH3.H2O = 50 : 50 : 1) to give the title compound (2.86 g, 93%) as a yellow oil. ’H NMR (400 MHz, METHANOL-^) 5 ppm 3.83-3.99 (m, 4 H), 2.48-2.71 (m, 2 H), 1.96- 2.15 (m, 1 H), 1.39-1.77 (m, 7 H), 0.87-1.04 (m, 3 H). methyl 2-methyl-2-(((cis-7-methyl-l,4-dioxaspiro[4.5]decan-8- yl)methyl)amino)propanoate

[0605] A mixture of [cis-7-methyl-l,4-dioxaspiro[4.5]decan-8-yl]methanamine (3.4 g, 18.35 mmol) and K2CO3 (5.07 g, 36.7 mmol) in methyl 2-bromo-2-methyl-propanoate (47.57 g, 262.8 mmol) was degassed and purged with N2 3 times. The mixture was stirred at 80 °C for 16 h under N2. The reaction was filtered through a celite pad and washed with THF (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, petroleum ether : ethyl acetate = 1 : 0 to 3 : 1) to give the title compound (3.5 g, 67%) as a colorless oil. ’H NMR (400 MHz, CDCI3) ppm 3.84-4.03 (m, 4H), 3.63-3.80 (m, 3H), 2.28-2.54 (m, 1H), 2.00-2.13 (m, 1H), 1.46-1.85 (m, 9H), 1.19-1.41 (m, 6H), 0.84- 1.06 (m, 3H).

[0606] 5,5-dimethyl-l-((cis-7-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)imidazolidine-2,4- dione

[0607] To a solution of methyl 2-methyl-2-[[cis-7-methyl-l,4-dioxaspiro[4.5]decan-8- yl]methylamino]propanoate (3.6 g, 12.6 mmol) in DCM (36 mL) was added 2,2,2- trichloroacetyl isocyanate (3.56 g, 18.9 mmol). The mixture was stirred at 45 °C for 1 h and concentrated under reduced pressure. The residue was dissolved in MeOH (36 mL) and NH3 H2O (36 mL) and further stirred at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 1 : 0 to 7 : 3) to give the title compound (3 g, 80%) as a white solid. ’H NMR (400 MHz, CDCh) 5 ppm 8.01 (s, 1H), 3.89-4.00 (m, 4H), 3.32-3.48 (m, 1H), 2.95-3.17 (m, 1H), 2.04-2.16 (m, 1H), 1.93-2.03 (m, 1H), 1.76-1.93 (m, 1H), 1.60-1.72 (m, 3H), 1.49-1.58 (m, 2H), 1.38-1.48 (m, 6H), 0.98-1.08 (m, 3H).

[0608] 5,5-dimethyl-l-((cis-7-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-3-((2-

[0609] (trimethylsilyl)ethoxy)methyl) imidazolidine-2, 4-dione

[0610] A mixture of 5,5-dimethyl-l-[[cis-7-methyl-l,4-dioxaspiro[4.5]decan-8- yl]methyl]imidazolidine-2, 4-dione (3 g, 10.1 mmol), SEMC1 (16.96 g, 101.7 mmol) and DIPEA (6.68 g, 51.7 mmol) in DCM (30 mL) was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 1 h under N2 and concentrated. The reaction was partitioned between ethyl acetate (20 mL) and H2O (20 mL). The organic phase was separated, washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 1 : 0 to 9 : 1) to give the title compound (3.2 g, 74%) as a colorless oil. ’H NMR (400 MHz, CDCh) 5 ppm 4.93 (s, 2H), 3.86-4.02 (m, 4H), 3.62 (t, 7 = 8.0 Hz, 2H), 3.36-3.51 (m, 1H), 3.17 (dd, 7 = 4.4, 14.4 Hz, 1H), 1.96-2.16 (m, 2H), 1.83-1.94 (m, 1H), 1.48-1.82 (m, 6H), 1.38-1.47 (m, 7H), 1.00-1.08 (m, 3H), 0.94 (t, 7 = 8.0 Hz, 2H), 0.00 (s, 9H). 5,5-dimethyl-l-((cis-2-methyl-4-oxocyclohexyl)methyl)-3-((2-

[0611] (trimethyIsiIyI)ethoxy)methyI)imidazo!idine-2, 4-dione

[0612] A mixture of 5,5-dimethyl-l-[[cis-7-methyl-l,4-dioxaspiro[4.5]decan-8-yl]methyl]-3- (2-trimethylsilylethoxymethyl)imidazolidine-2, 4-dione (3 g, 7.03 mmol), TSOH.H2O (1.74 g, 9.14 mmol) in acetone (30 mL) and H2O (15 mL) was degassed and purged with N2 3 times. The mixture was stirred at 30 °C for 3 h under N2. The reaction mixture was quenched with H2O (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was separated, washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 93 : 7 to 3 : 2) to give the title compound (1.7 g, 4.44 mmol, 63%) as a colorless oil. MS (ESI): mass calcd. for Ci9H34N2O4Si: 382.23, found: 405.2 [M+Na]+. l-((cis-4-amino-2-methylcyclohexyl)methyl)-5,5-dimethyl-3-((2-

[0613] (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione

[0614] A solution of 5,5-dimethyl-l-[[cis-2-methyl-4-oxo-cyclohexyl]methyl]-3-(2- trimethylsilylethoxymethyl)imidazolidine-2, 4-dione (1 g, 2.61 mmol) in NHVMcOH (7 M, 10 mL) was stirred at 25 °C for 1 h under N2. Raney Ni (112 mg) was added in one portion. The mixture was stirred at 25 °C for 15 h under H2 (15 psi). The reaction mixture was filtered through a celite pad, washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to give the title compound (1 g, 99%) as a green oil. MS (ESI): mass calcd. for Ci9H37N3O3Si: 383.26, found: 384.3 [M+H]+. l-butyl-3-(cis-4-((5, 5-dimethyl-2, 4-dioxo-3-((2-(trimethylsilyl) ethoxy) methyl) imidazolidin-l-yl) methyl)-3-methylcyclohexyl) urea and l-butyl-3-(trans-4-((5,5- dimethyI-2,4-dioxo-3-((2-(trimethyIsiIyI)ethoxy)methyI)imidazoIidin-l-yI)methyI)-3- methylcyclohexyl)urea

[0615] A mixture of l-[[cis-4-amino-2-methyl-cyclohexyl]methyl]-5,5-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2, 4-dione (0.9 g, 2.35 mmol), 1-isocyanatobutane (1.16 g, 11.73 mmol) and TEA (712.2 mg, 7.04 mmol) in DCM (9 mL) was degassed and purged with N2 3 times. The mixture was stirred at 30 °C for 2 h under N2. The reaction was concentrated under reduced pressure and partitioned between ethyl acetate (30 mL) and H2O (10 mL). The organic phase was separated, washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- butyl-3-(cis-4-((5, 5-dimethyl-2, 4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-l- yl)methyl)-3-methylcyclohexyl)urea (0.56 g, 31.11% ) from the first eluting peak from HPLC separation as a light yellow oil. MS (ESI): mass calcd. for C24H4eN4O4Si: 482.33, found: 483.4 [M+H]+. l-butyl-3-(trans-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin- 1 -yl)methyl)-3-methylcyclohexyl)urea (0.4 g, 22%) was from the second eluting peak as a light yellow oil. MS (ESI): mass calcd. for C24H46N4O4Si: 482.33, found: 483.4 [M+H]+. l-butyl-3-(cis-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)-3- methylcyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[0616] To a solution of l-butyl-3-(cis-4-((5, 5-dimethyl-2, 4-dioxo-3-((2-(trimethylsilyl) ethoxy) methyl) imidazolidin-l-yl) methyl)-3-methylcyclohexyl) urea (0.56 g, 1.16 mmol) in acetic acid (12 mL) was added AC2O (2.99 g, 29.3 mmol) and malonic acid (241.44 mg, 2.32 mmol). The mixture was stirred at 80 °C for 1 h, cooled down, quenched with H2O (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 1 : 0 to 7 : 3) to give the title compound (0.58 g, 91%) as a light yellow oil. MS (ESI): mass calcd. for C27H46N40eSi: 550.32, found: 523.4 [M-28+H]+. l-butyl-5-(diaminomethylene)-3-(cis-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl) ethoxy)methyl)imidazolidin-l-yl)methyl)-3-methylcyclohexyl)pyrimidine-

[0617] 2,4,6(lH,3H,5H)-trione

[0618] To a solution of l-butyl-3-(cis-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidin- 1 -yl)methyl)-3-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (580 mg, 1.05 mmol) in THF (30 mL) was added Ni(acac)2 (270.55 mg, 1.05 mmol) and cyanamide (1.33 g, 31.59 mmol). The mixture was stirred at 80 °C for 16 h. The reaction was cooled to 25 °C, filtered through a celite pad and washed with THF (30 mL). The filtrate was concentrated under reduced pressure. The reaction was partitioned between H2O (40 mL) and ethyl acetate (40 mL). The organic phase was separated, washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, petroleum ether : ethyl acetate = 1 : 0 to 7 : 3) to give the title compound (0.624 g, crude) as a white solid. MS (ESI): mass calcd. for C28H48N6O6Si: 592.34, found: 593.4 [M+H]+. l-butyl-5-(diaminomethylene)-3-(cis-4-((5,5-dimethyl-2,4-dioxoimidazolidin-l- yl)methyl)-3-methylcyclohexyl) pyrimidine-2,4,6(lH,3H,5H)-trione (67)

[0619] A solution of l-butyl-5-(diaminomethylene)-3-(cis-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-l-yl)methyl)-3-methylcyclohexyl)pyrimidine- 2,4,6(lH,3H,5H)-trione (0.42 g, 708.5 pmol) in H2O (0.8 mL) and TFA (4 mL) was stirred at 25 °C for 2 h. The reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (4 mL), added K2CO3 (648.17 mg, 4.69 mmol) and stirred at 25 °C for 1 h. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (5.2 mg, 2%) as a white solid. MS (ESI): mass calcd. for C22H34N6O5: 462.26, found: 463.4 [M+H]+.1H NMR (400 MHz, DMSO-tfo) 5 ppm 10.77 (s, 1H), 9.56 (s, 2H), 7.36 (s, 2H), 4.57-4.90 (m, 1H), 3.75 (s, 2H), 3.44-3.61 (m, 1H), 3.06 (d, J = 13.6 Hz, 1H), 2.56-2.81 (m, 2H), 2.12-2.37 (m, 1H), 1.89 (d, 7 = 4.4 Hz, 1H), 1.70-1.84 (m, 2H), 1.45 (d, J = 5.2 Hz, 2H), 1.31 (s, 6H), 1.26 (d, 7 = 6.4 Hz, 4H), 1.00 (d, J = 5.6 Hz, 3H) 0.88 (t, J = 6.4 Hz, 3H).

[0620] Example 68 and Example 69. l-butyl-5-(diaminomethylene)-3-((lS,4r)-4- (hydroxymethyl)-4-(((S)-4-methyl-2,5-dioxoimidazolidin-4- yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (68) and l-butyl-5- (diaminomethylene)-3-((lR,4s)-4-(hydroxymethyl)-4-(((S)-4-methyl-2,5- dioxoimidazolidin-4-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (69)

[0621] Synthetic scheme:

[0622] ethyl 8-allyl-l,4-dioxaspiro[4.5]decane-8-carboxylate

[0623] To a solution of ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (20 g, 93.4 mmol) in

[0624] THF (300 mL) was added dropwise LiHMDS (1 M in THF, 112 mL) at -70 °C. The mixture was stirred at -70 °C for 1.5 h. A solution of 3-bromoprop-l-ene (16.94 g, 140.02 mmol) in THF (10 mL) was added dropwise at -70 °C. The reaction was stirred at 20 °C for 16 h under N2. After completion, the reaction was quenched with saturated NH4CI (100 mL), diluted with H2O (50 mL) and extracted with ethyl acetate (250 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 99 : 1 to 10 : 1) to give the title compound (18.94 g, 76%) as a light yellow oil. ’H NMR (400 MHz, CDC13): 5 ppm 5.62-5.77 (m, 1H), 4.97-5.07 (m, 2H), 4.14 (q, 7 = 7.2 Hz, 2H), 3.93 (s, 4H), 2.26 (d. 7 = 7.2 Hz, 2H), 2.14 (d, 7 = 12.4 Hz, 2H), 1.47-1.70 (m, 6H), 1.25 (t, 7 = 7.2 Hz, 3H).

[0625] (8-allyl-l,4-dioxaspiro[4.5]decan-8-yl)methanol

[0626] To a solution of ethyl 8-allyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (8 g, 31.46 mmol) in THF (80 mL) was added DIBAL-H (1 M in THF, 94.4 mL) dropwise at 0 °C under N2. The mixture was warmed up to 20 °C and stirred at 20 °C for 2 h under N2. After completion, the reaction was diluted with ethyl acetate (30 mL), quenched slowly with saturated potassium sodium tartrate (10 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, petroleum ether : ethyl acetate = 99 : 1 to 10 : 1) to provide the title compound (5.5 g, 74%) as a light yellow oil. ' H NMR (400 MHz, CDCh) 5 ppm 5.85-5.90 (m, 1H), 5.04-5.15 (m, 2H), 3.95 (s, 4H), 3.46 (s, 2H), 2.16 (d, 7 = 7.2 Hz, 2H), 1.61-1.67 (m, 4H), 1.48-1.57 (m, 5H).

[0627] 8-allyl-8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decane

[0628] To a solution of (8-allyl-l,4-dioxaspiro[4.5]decan-8-yl)methanol (5.5 g, 25.91 mmol) in THF (55 mL) was added NaH (2.07 g, 51.82 mmol, 60% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. Bromomethylbenzene (8.86 g, 51.82 mmol) was added to the reaction. The mixture was stirred at 50 °C for 12 h under N2. After completion, the mixture was quenched with saturated NH4CI (40 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (5 g, 57%) as a colorless oil.1H NMR (400 MHz, CDCh) 5 ppm 7.29-7.38 (m, 5H), 5.73-5.84 (m, 1H), 4.99-5.07 (m, 2H), 4.50 (s, 2H), 3.94 (s, 4H), 3.25 (s, 2H), 2.20 (d. 7 = 7.6 Hz, 2H), 1.59-1.68 (m, 4H), 1.48-1.56 (m, 4H). l-(8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8-yl)propan-2-one

[0629] A mixture of PdCh (366.5 mg, 2.07 mmol) and Cu(OAc)2 (1.8 g, 9.92 mmol) in DMA (48 mL) and H2O (8 mL) was stirred at 20 °C for 3 h. 8-allyl-8-(benzyloxymethyl)-l,4- dioxaspiro[4.5]decane (2.5 g, 8.27 mmol) was added and the reaction was stirred at 20 °C for 16 h. The reaction was poured into H2O (100 mL) and extracted with ethyl acetate (120 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, petroleum ether : ethyl acetate = 99 : 1 to 10 : 1) to give the title compound (3.5 g, 60%) as a light yellow oil. MS (ESI): mass calcd. for C19H26O4: 318.18, found: 319.4 [M+H]+.

[0630] 5-((8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-5-methylimidazolidine- 2, 4-dione

[0631] To a solution of l-[8-(benzyloxymethyl)-l,4-dioxaspiro[4.5]decan-8-yl]propan-2-one

[0632] (3.5 g, 10.99 mmol) in H2O (20 mL) and MeOH (20 mL) was added (NEL^hCCh (5.28 g, 54.96 mmol) and TMSCN (2.18 g, 21.98 mmol). The reaction was stirred at 90 °C for 16 h under N2. After completion, the reaction was concentrated under reduced pressure. The residue was poured into H2O (50 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4 and filtrated and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 99 : 1 to 10 : 1) to give the title compound (3.8 g, 80%) as a colorless oil. MS (ESI): mass calcd. for C21H28N2O5: 388.20, found: 389.3 [M+H]+. (S)-5-((8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-5-methyl-3-((2-

[0633] (trimethylsilyl)ethoxy) methyl)imidazolidine-2, 4-dione and (R)-5-((8-

[0634] ((benzyIoxy)methyI)-l,4-dioxaspiro[4.5]decan-8-yI)methyI)-5-methyI-3-((2-

[0635] (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione

[0636] To a solution of 5-((8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-5- methylimidazolidine-2, 4-dione (3.8 g, 9.78 mmol) in DCM (38 mL) was added SEM-C1 (1.71 g, 10.27 mmol) and DIPEA (6.32 g, 48.9 mmol). The mixture was stirred at 40 °C for 12 h and concentrated under reduced pressure. The residue was poured into H2O (50 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4 and filtrated and concentrated under reduced pressure. The residue was purified by column chromatography CSiCL. petroleum ether : ethyl acetate = 99 : 1 to 1 : 1) to give the racemate. The product was separated by chiral SFC (column: DAICEL CHIRALCEL OZ 250*50 mm I.D. 10 um; mobile phase: CCh-MeOH; 25% B with isocratic elution) to give (S)-5-((8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-5-methyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione (1.5 g, 28%) from the first eluting peak as a colorless oil.1H NMR (400 MHz, CDCh) 5 ppm 7.33-7.41 (m, 5H), 5.98 (s, 1H), 4.88 (s, 2H), 4.48-4.57 (m, 2H), 3.92 (s, 4H), 3.62 (t, J = 8.4 Hz, 2H), 3.40 (s, 2H), 1.98 (d, J = 15.2 Hz, 1H), 1.81 (d. 7 = 14.8 Hz, 1H), 1.68-1.76 (m, 1H), 1.61-1.67(m, 2H), 1.51-1.57 (m, 1H), 1.41 (s, 6H), 1.34 (d, J = 3.6 Hz, 1H), 0.87-0.99 (m, 2H), 0.00 (s, 9H). (R)-5-((8- ((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-5-methyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione was obtained from the second eluting peak (1.5 g, 28%) as a colorless oil.:H NMR (400 MHz, CDCh) 5 ppm 7.31-7.41 (m, 5H), 5.99 (s, 1H), 4.88 (s, 2H), 4.49-4.60 (m, 2H), 3.90 (s, 4H), 3.62 (t, J = 8.4 Hz, 2H), 3.39 (s, 2H), 1.98 (d, 7 = 15.2 Hz, 1H), 1.81 (d, 7 = 14.8 Hz, 1H), 1.68-1.76 (m, 1H), 1.65 (s, 1H), 1.52- 1.56 (m, 1H), 1.41 (s, 6H), 1.23-1.39 (m, 2H), 0.84-1.00 (m, 2H), 0.00 (s, 9H).

[0637] (S)-5-((l-((benzyloxy)methyl)-4-oxocyclohexyl)methyl)-5-methyl-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidine-2, 4-dione

[0638] To a solution of (S)-5-((8-((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8- yl)methyl)-5-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione (1.3 g, 2.51 mmol) in acetone (14.4 mL) and H2O (7.2 mL) was added TSOH.H2O (476.73 mg, 2.51 mmol). The mixture was stirred at 25 °C for 5 h under N2 and concentrated under reduced pressure. The residue was poured into saturated NaHCCL (30 mL) and extracted with ethyl acetate (75 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 20 : 1 to 3 : 1) to give the title compound (1.57 g, crude) as a colorless oil. MS (ESI): mass calcd. for C25H38N20sSi: 474.25, found: 473.4 [M-H]".

[0639] (S)-5-((4-amino-l-((benzyloxy)methyl)cyclohexyl)methyl)-5-methyl-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidine-2, 4-dione

[0640] To a solution of (S)-5-((l-((benzyloxy)methyl)-4-oxocyclohexyl)methyl)-5-methyl-3-

[0641] ((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione (1.26 g, 2.65 mmol) in MeOH (13 mL) was added NH4CI (4.09 g, 53.09 mmol) and NaBH(OAc)3 (1.13 g, 5.31 mmol). The mixture was stirred at 20 °C for 3 h. The mixture was adjusted to pH = 8 with saturated NaHCCL. diluted with H2O (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (1.53 g, crude) as a colorless oil. MS (ESI): mass calcd. for C2sH4iN3O4Si: 475.29, found: 474.4 [M-H]".

[0642] (S)-l-(4-((benzyloxy)methyl)-4-((4-methyl-2,5-dioxo-l-((2-

[0643] (trimethylsilyl)ethoxy)methyl)imidazolidin-4-yl)methyl)cyclohexyl)-3-butylurea

[0644] The title compound was prepared using an identical method to the urea synthesis in

[0645] Example 1.

[0646] (S)-l-(4-((benzyloxy)methyl)-4-((4-methyl-2,5-dioxo-l-((2-

[0647] (trimethylsilyl)ethoxy)methyl)imidazolidin-4-yl)methyl)cyclohexyl)-3-butylpyrimidine-

[0648] 2,4,6(lH,3H,5H)-trione

[0649] The title compound was prepared using an identical method to the barbiturate synthesis in Example 1.

[0650] (S)-l-(4-((benzyloxy)methyl)-4-((4-methyl-2,5-dioxo-l-((2-

[0651] (trimethylsilyl)ethoxy)methyl)imidazolidin-4-yl)methyl)cyclohexyl)-3-butyl-5-

[0652] (diaminomethylene)pyrimidine-2,4,6(lH,3H,5H)-trione

[0653] The title compound was prepared using an identical method to the diaminomethylene synthesis in Example 1.

[0654] (S)-l-butyl-5-(diaminomethylene)-3-(4-(hydroxymethyl)-4-((4-methyl-2,5- dioxoimidazolidin-4-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione

[0655] To a solution of (S)-5-((4-amino-l-((benzyloxy)methyl)cyclohexyl)methyl)-5-methyl- 3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione (380 mg, 555 pmol) in DCM (1 mL) was added BCE (1 M in DCM, 7.6 mL) dropwise at 0 °C over 3 min under N2. The mixture was stirred at 20 °C for 1.5 h under N2. The reaction was quenched with saturated NaHCCh, diluted with H2O (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC to give the title compound (60 mg, 23 %) as a white solid. MS (ESI): mass calcd. for C21H32N6O6: 464.24, found: 465.4 [M+H]+. l-butyl-5-(diaminomethylene)-3-((lS,4r)-4-(hydroxymethyl)-4-(((S)-4-methyl-2,5- dioxoimidazolidin-4-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (68) and l-butyl-5-(diaminomethylene)-3-((lR,4s)-4-(hydroxymethyl)-4-(((S)-4-methyl-2,5- dioxoimidazolidin-4-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (69)

[0656] (S)-l-butyl-5-(diaminomethylene)-3-(4-(hydroxymethyl)-4-((4-methyl-2,5- dioxoimidazolidin-4-yl)methyl)cyclohexyl)pyrimidine-2,4,6(lH,3H,5H)-trione (60 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10 um); mobile phase: CCL-EtOH; 43% B with isocratic elution) to give 68 (18.01 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C21H32N6O6: 464.24, found: 465.2 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 5 ppm 10.61 (s, 1H), 9.57 (s, 2H), 7.74 (s, 1H), 7.32 (s, 2H), 4.54-4.65 (m, 1H), 4.51 (t. 7 = 5.6 Hz, 1H), 3.76 (t. 7 = 7.2 Hz, 2H), 3.25-3.29 (m, 1H), 3.13- 3.16 (m, 1H), 2.55 (s, 2H), 1.95 (d, J = 15.2 Hz, 1H), 1.79 (d, J = 15.2 Hz, 1H), 1.64 (d, J = 13.6 Hz, 1H), 1.47 (quin, 7 = 7.2 Hz, 2H), 1.37-1.42 (m, 1H), 1.15-1.37 (m, 9H), 0.89 (t. 7 = 7.2 Hz, 3H). 69(19.73 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C21H32N6O6: 464.24, found: 465.2 [M+H]+. ’H NMR (400 MHz, DMSO- d6) 5 ppm 10.59 (s, 1H), 9.55 (s, 2H), 7.77 (s, 1H), 7.32 (s, 2H), 4.53-4.68 (m, 1H), 4.47 (t, J = 5.2 Hz, 1H), 3.74 (t, J = 7.2 Hz, 2H), 3.55-3.59 (m, 1H), 3.39-3.43 (m, 1H), 2.31-2.47 (m, 2H), 1.61-1.74 (m, 3H), 1.34-1.53 (m, 4H), 1.18-1.31 (m, 7H), 1.02-1.15 (m, 1H), 0.88 (t, 7 = 7.2 Hz, 3H).

[0657] Example 70 was prepared using an identical method to Example 68 starting from (R)-5-((8- ((benzyloxy)methyl)-l,4-dioxaspiro[4.5]decan-8-yl)methyl)-5-methyl-3-((2-

[0658] (trimethylsilyl)ethoxy)methyl)imidazolidine-2, 4-dione and separated by SFC as the first eluting peak. Example 71 was obtained from the second eluting peak from SFC separation.

[0659] Example 72. l-butyl-5-(diaminomethylene)-3-((2R,4R)-2-methyl-l-((l-methyl-2-oxo-l,2- dihydropyridin-4-yl)methyl)piperidin-4-yl)pyrimidine-2,4,6(lH,3H,5H)-trione (72) tert-butyl (2R,4R)-4-(3-butylureido)-2-methyl-l-piperidinecarboxylate

[0660] To a 100 mL round bottom flask equipped with a magnetic stir bar was added tert -butyl (2R,4R)-4-amino-2-methyl-l -piperidinecarboxylate (1 g, 4.67 mmol), triethylamine (0.7 mL, 5.13 mmol) and dichloromethane (47 mL) under an atmosphere of N2. The flask was cooled to 0 °C. 1-isocyanatobutane (0.51 g, 5.13 mmol) was added dropwise by syringe over 10 min. The reaction was allowed to warm to 22 °C over 1 h. The reaction was concentrated under reduced pressure, and the crude residue was purified by flash chromatography over silica gel (24 g column, gradient 0-10% MeOH in DCM,) to provide the title compound (1.46 g, 98%) as a colorless oil. MS (ESI): mass calcd. for C16H31N3O3: 313.24, found: 214.3 [M-Boc+H]+tert-butyl (2R,4R)-4-(l-butyl-2,4,6-trioxo-3-pyrimidinyl)-2-methyl-l- piperidinecarboxylate

[0661] To a 200 mL round bottom flask equipped with a magnetic stir bar was added tert -butyl (2R,4R)-4-(3-butylureido)-2-methyl-l -piperidinecarboxylate (1.39 g, 4.43 mmol) and DCM (45 mL) under N2. The reaction was cooled to 0 °C and malonyl dichloride (0.65 mL, 6.65 mmol) was added dropwise by syringe over 5 min. The reaction was allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous NaHCCL (50 mL) and the organics were collected. The aqueous phase was extracted with DCM (2 x 20 mL). The combined organic layer was dried over Na2SC>4, concentrated under reduced pressure, and purified by column chromatography over silica gel (24 g, 0-10% MeOH in DCM) to provide the title compound as a light yellow foam (173 mg, 10%). MS (ESI): mass calcd. for C19H31N3O5: 381.23, found: 282.3 [M-Boc+H]+tert-butyl (2R)-4-(l-butyl-5-diaminomethylene-2,4,6-trioxo-3-pyrimidinyl)-2-methyl-l- piperidinecarboxylate

[0662] To a 20 mL reaction vial equipped with a magnetic stir bar and a pressure septum was added tert-butyl (2R)-4-(l-butyl-2,4,6-trioxo-3-pyrimidinyl)-2-methyl-l- piperidinecarboxylate (173 mg, 0.45 mmol), cyanamide (191 mg, 4.54 mmol), Ni(acac)2 (24 mg, 0.09 mmol), and THF (4.5 mL). The vial was purged with N2, sealed, and heated at 80 °C for 16 h. Precipitate was observed. The reaction was filtered through a syringe filter and concentrated under reduced pressure. The residue was then purified by chromatography over silica gel (4 g column, gradient 0-5% MeOH in DCM) to provide the title compound as a colorless foam (80 mg, 42%). MS (ESI): mass calcd. for C20H33N5O5: 423.25, found: 323.3 [M-Boc+H]+l-butyl-5-(diaminomethylene)-3-((2R,4R)-2-methyl-l-((l-methyl-2-oxo-l,2- dihydropyridin-4-yl)methyl)piperidin-4-yl)pyrimidine-2,4,6(lH,3H,5H)-trione (72)

[0663] To a 50 mL RBF equipped with a magnetic stir bar and a rubber septum was added tertbutyl (2R,4R)-4-( 1 -butyl-5 -diaminomethylene-2,4,6-trioxo-3 -pyrimidinyl)-2-methyl- 1 - piperidinecarboxylate (90 mg, 0.21 mmol) and 4 N HC1 in 1-4-dioxane (1 mL). The reaction was stirre...

Claims

CLAIMSWe claim:

1. A compound according to formula (I),or a pharmaceutically acceptable salt thereof, wherein:R1is selected from:5-oxo-l,4-dihydro-l,2,4-triazol-4-yl, optionally substituted with one or more instances of (Ci-Ce)alkyl, and2-oxo-4-pyridyl, optionally substituted with one or more instances of (Ci-Ce)alkyl;R2is (Ci-C6)alkyl,R3is alkyl optionally substituted with (C3-Cs)cycloalkyl;R4is hydrogen;R5is (Ci-Ce)alkyl or (Ci-Ce)alkoxy alkyl, or R4and R5taken together with the carbon atom to which they are attached form a 5- to 7-membered heterocycloalkyl;R6is hydrogen or alkyl; andR7and R8are each alkyl; or R7and R8are taken together with the carbon atom to which they are attached form 4- to 7-membered heterocycloalkyl; provided that the compound is not:

2. The compound of claim 1, wherein the compound has the structure of formula (la) or (lb):or a pharmacemtucally acceptable salt thereof.The compound of claim 1 or 2, wherein4. The compound of claim 3, wherein R4and R5taken together with the carbon atom to which they are attached form5. The compound of claim 3, wherein R4is hydrogen and R5is methyl.

6. The compound of claim 3 wherein R4is hydrogen and R5is ethoxymethyl.

7. The compound of claim 1 or 2, wherein8. The compound of claim 7, wherein R6is hydrogen.

9. The compound of claim 7, wherein R6is methyl.

10. The compound of any one of claims 7-9, wherein R7and R8are each methyl.

11. The compound of any one of claims 7-9, wherein R7and R8taken together with the carbon atom to which they are attached form:

12. The compound of any one of claims 1 to 11, wherein R2is methyl.

13. The compound of any one of claims 1 to 12, wherein R3is n-butyl.

14. A compound according to Formula (II):or a pharmaceutically acceptable salt thereof, wherein:R9is selected from:2-oxo-l,3-dihydro-l,3,4-triaza-3-indenyl,2.5-dioxo-l-imidazolidinyl optionally substituted with one or more is (Ci-Ce)alkyl, and2.6-dioxo-l,3,4,5-tetrahydro-4-pyrimidinyl;R10is (Ci-Ce)alkyl;R11and R12taken together with the carbon atom to which they are attached form 4- to 7-membered heterocycloalkyl;R13is (Ci-C6)alkyl; andR14is (Ci-Ce)alkyl optionally substituted with cycloalkyl, provided that the compound is not:

15. The compound of claim 14, wherein the compound has the structure of Formula (Ila):or a pharmaceutically acceptable salt thereof.

16. The compound of claim 14 or 15, wherein R11and R12taken together with the carbon atom to which they are attached form:

17. The compound of claim 14 or 15, wherein R13is methyl.

18. The compound of any one of claims 14 to 17, wherein R10is n-butyl.

19. A compound according to Formula (III):or a pharmaceutically acceptable salt thereof, wherein:R16is hydroxy or cyano;R17is (Ci-C6)alkyl; andR18and R19taken together with the carbon atom to which they are attached form (C3- Cs)cycloalkyl.

20. The compound of claim 19, wherein the compound has the structure of Formula (Illa) or (Illb):(Illb), or a pharmaceutically acceptable salt thereof.

21. The compound of claim 19 or 20, wherein R17is n-butyl.

22. The compound of any one of claims 19 to 21, wherein R18and R19taken together with the carbon atom to which they are attached form cyclobutyl.

23. A compound according to Formula (IV):(IV), or a pharmaceuticall acceptable salt thereof, wherein:R20is:R21is (Ci-Ce)hydroxyalkyl;R22is (Ci-C6) alkyl;R23is (Ci-C6) alkyl; andR24is (C3-Cs)cycloalkyl.

24. The compound of claim 23, wherein the compound has a structure of Formula (IVa) or (IVb):or a pharmaceutically acceptable salt thereof.

25. The compound of claim 23 or 24, wherein R21is hydroxymethyl.

26. The compound of any one of claims 23 to 25, wherein R22is n-butyl.

27. The compound of any one of claims 23 to 26, wherein R23is methyl.

28. The compound of any one of claims 23 to 27, wherein R24is cyclopropyl.

29. A compound according to Formula (V):(V), or a pharmaceutically acceptable salt thereof, whereinR25is (Ci-Ce)hydroxyalkyl;R26is (C1-C3) alkyl; andR27and R28taken together with the carbon atom to which they are attached form (C3- Csjcycloalkyl.

30. The compound of claim 29, wherein the compound has the structure of Formula (Va) or (Vb):or a pharmaceutically acceptable salt thereof.

31. The compound of claim 29 or 30, wherein R25is hydroxymethyl.

32. The compound of any one of claims 29 to 31, wherein R26is n-propyl.

33. The compound of any one of claims 29 to 32, wherein R27and R28taken together with the carbon atom to which they are attached form cyclobutyl.

34. A compound having a structure selected from the following table:or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition, comprising a compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

36. A method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof.

37. A method of: a) reducing of HbAlc; b) treating or preventing type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin dependent diabetes, and / or obesity; c) reducing body weight and / or food intake, and / or inducing satiety; and / ord) treating or preventing Alzheimer’s disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and / or cardiovascular diseases; comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof.