Spirocycle-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] SPIROCYCLE-CONTAINING DIAMINOMETHYLENE PYRIMIDINE-2,4,6-TRIONE AGONISTS OF PARATHYROID HORMONE 1 AND INCRETIN RECEPTORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application Nos.63 / 752,529, filed January 31, 2025; 63 / 706,474, filed October 11, 2024; and 63 / 638,019, filed April 24, 2024; each of which is incorporated herein by reference in its entirety. BACKGROUND 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. 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. 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. 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-1R is also expressed in the brain, where it is involved in the control of appetite. Furthermore, mice that over express GLP-1R display improved memory and learning. 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. The gastric inhibitory polypeptide receptor (GIPR), also known as the glucose- dependent 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. 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. 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. 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. 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. SUMMARY The present disclosure provides in some embodiments a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: R1is (C1-C6)alkyl optionally substituted with one or more instances of fluoro, carboxy, (C1-C6)carboxyalkoxy, 4- to 7-membered heterocycloalkyl or (C3-C8)cycloalkyl, wherein (C3-C8)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more instances of (C1-C6)alkyl, carboxy, and fluoro, R2is (C1-C6)alkyl optionally substituted with cyano; R3is: a) (C1-C6)alkyl substituted with SO2R3a, (C1-C6)alkoxy, (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl are optionally substituted with one or more instances of (C1-C6)alkyl and fluoro, or b) unsubstituted branched (C1-C6)alkyl; and R3ais (C1-C6)alkyl. The present invention also provides a compound Formula (II): (II) or a pharmaceutically acceptable salt thereof; wherein: R4and R5taken together form a heterocyclic ring having the structure: a) , wherein:R7and R8are independently hydrogen or (C1-C6)alkyl; b) ;c) , wherein:R9is (C1-C6)hydroxyalkyl or (C1-C6)alkoxyalkyl;d) , wherein:Y is absent or CH2, R10is hydrogen or (C1-C6)alkyl; e) , wherein:R11is (C1-C6)alkyl; f) , wherein:R12aand R12bare each independently (C1-C6)alkyl, and R13is hydrogen or (C3-C8)cycloalkyl; or g) , wherein R14and R15are each independently (C1-C6)alkyl; and R6is (C1-C6)alkyl or (C3-C8)cycloalkyl. The present invention also provides a compound Formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein: R16is (C1-C6)alkyl substituted with tetrahydrofuran-2-yl, pyrazolyl optionally substituted with (C1-C6)alkyl, phenyl substituted with (C=O)NH2, or cyclobutyl substituted with pyridyl; R17is (C1-C6)alkyl; and R18is (C1-C6)alkyl. The present invention also provides a compound of Formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein: R19is (C1-C6)fluoroalkyl; R20is (C1-C6)alkyl; and R21is (C1-C3)alkyl. The present invention also provides a compound of Formula (V) (V), or a pharmaceutically acceptable salt thereof, wherein: R22is (C1-C6)alkyl; R23is (C1-C6)alkoxy; or R22and R23taken together with the carbon to which they are attached form 4- to 7-membered heterocycloalkyl; and R24is (C1-C6)alkyl optionally substituted with phenyl or (C3-C8)cycloalkyl; provided that the compound is not: or . 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. 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 a therapeutically effective amount of a compound of compound of the present invention, or a pharmaceutically acceptable salt thereof. In still other aspects, provided herein is a method of: a) reducing of HbA1c; 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. 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. Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. BRIEF DESCRIPTION OF THE FIGURES Figure 1 tabulates exemplary compounds of the invention, and their characterization data and PTH1R activity. DETAILED DESCRIPTION Definitions 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. 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. 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. 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. 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. 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. 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. 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. “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. 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. 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. 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. 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- or14C- enriched carbon are within the scope of this invention. 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. 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.) 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). The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule. 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. 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). 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. 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. “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-C30for straight chains, C3-C30for branched chains), and more preferably 20 or fewer. Alkyl groups may be substituted or unsubstituted. 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. As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen. 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. As used herein, the term “hydroxyalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl. 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. "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. “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. As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen. "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. 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. “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). “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety. 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. 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). 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. 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 C1-6alkyl, C3-6cycloalkyl, 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. 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. 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). 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. 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. 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. 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. As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response. 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. Compounds of the Invention The present disclosure provides in some embodiments a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: R1is (C1-C6)alkyl optionally substituted with one or more instance of fluoro, carboxy, (C1-C6)carboxyalkoxy, 4- to 7-membered heterocycloalkyl or (C3-C8)cycloalkyl, wherein (C3-C8)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more instances of (C1-C6)alkyl, carboxy, and fluoro; R2is (C1-C6)alkyl optionally substituted with cyano; R3is: a) (C1-C6)alkyl substituted with SO2R3a, (C1-C6)alkoxy, (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl are optionally substituted with one or more instances of (C1-C6)alkyl and fluoro, or b) unsubstituted branched (C1-C6)alkyl; and R3ais (C1-C6)alkyl. In some embodiments, the compound has the structure of Formula (Ia) or (Ib): (Ia) (Ib),or a pharmaceutically acceptable salt thereof. In certain embodiments, R1is methyl optionally substituted with (C1-C6)alkyl optionally substituted with one or more instance of fluoro, carboxy, (C1-C6)carboxyalkoxy, 4- to 7-membered heterocycloalkyl or (C3-C8)cycloalkyl, wherein (C3-C8)cycloalkyl and 4- to 7- membered heterocycloalkyl are each optionally substituted with one or more instances of (C1-C6)alkyl, carboxy, and fluoro. In more particular embodiments, R1is (C1-C6)alkyl substituted with 4- to 7-membered heterocycloalkyl, wherein 4- to 7-membered heterocycloalkyl, is optionally substituted with fluoro or (C1-C6)alkyl. In some embodiments, the 4- to 7-membered heterocycloalkyl istetrahydrofuranyl, 1,1-dioxo- -thietanyl, tetrahydropyran-4-yl, 1,4-dioxanyl, 1,1-dioxo-1 -thianyl, azetidinyl, 2-azaspiro[3.3]heptyl pyrrolidinyl, piperidyl, morpholinyl, oxabicyclo[2.1.1]hexyl, oxetanyl, or oxaspiro[3.3]heptanyl, each of which is optionally substituted with carboxy, fluoro or (C1-C6)alkyl. In more particular embodiments, the 4- to 7-membered heterocycloalkyl is tetrahydrofuran-3-yl, 5-methyltetrahydrofuran-3-yl, 1,1-dioxo-1 -3-thietanyl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, 1,4-dioxan-2-yl, 2-methyltetrahydro-4H-pyran-4-yl, 4-fluorotetrahydro-4H-pyran-4-yl, 1,1-dioxo-1 -4-thianyl,2-azetidinyl, 3-fluoro-3-azetidinyl, 2-aza-6-spiro[3.3]heptyl 3-pyrrolidinyl, 4-piperidyl, 2- morpholinyl, 2-oxabicyclo[2.1.1]hex-4-yl, oxetan-2-yl, oxetan-3-yl, 3-fluoro-3-oxetanyl, 3- methyl-3-oxetanyl, 3-ethyl-3-oxetanyl, or 2-oxaspiro[3.3]heptan-6-yl. In certain preferred embodiments, the 4- to 7-membered heterocycloalkyl is tetrahydrofuran-2-yl, tetrahydropyran-4-yl, 2-oxabicyclo[2.1.1]hex-4-yl, oxetan-2-yl, oxetan-3-yl, 3-fluoro-3- oxetanyl, 3-methyl-3-oxetanyl, 3-ethyl-3-oxetanyl, or 2-oxaspiro[3.3]heptan-6-yl. In certain embodiments, the 4- to 7-membered heterocycloalkyl is 3,3-dioxo-3 -thiabicyclo[3.1.0]hex-6-yl, 1,1-dioxo-1 -3-thianyl, 1,1-dioxo-1 -tetrahydro-3H-thien-3-yl,2-methyltetrahydro-4H-pyran-4-yl, 2-methyltetrahydro-4H-pyran-4-yl, 1-[(2,2,6,6-tetramethyl-1,1-dioxo-1 -4-thianyl, 1,1-dioxo-1 -4-thiepanyl, or 1,1-dioxo-1 ,2-thiazinan-5-yl. In other embodiments, R1is methyl substituted with tetrahydrofuran-3-yl, 5-methyltetrahydrofuran-3-yl, 1,1-dioxo-1 -3-thietanyl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, 1,4-dioxan-2-yl, 2-methyltetrahydro-4H-pyran-4-yl, 4-fluorotetrahydro-4H-pyran-4-yl,1,1-dioxo-1 -4-thianyl, 2-azetidinyl, 3-fluoro-3-azetidinyl, 2-aza-6-spiro[3.3]heptyl 3-pyrrolidinyl, 4-piperidyl, 2-morpholinyl, 2-oxabicyclo[2.1.1]hex-4-yl, oxetan-2-yl, oxetan-3- yl, 3-fluoro-3-oxetanyl, 3-methyl-3-oxetanyl, 3-ethyl-3-oxetanyl, or 2-oxaspiro[3.3]heptan-6-yl. In further embodiments, R1 is methyl substituted with 3,3-dioxo-3 -thiabicyclo[3.1.0]hex-6-yl, 1,1-dioxo-1 -3-thianyl, 1,1-dioxo-1 -tetrahydro-3H-thien-3-yl,2-methyltetrahydro-4H-pyran-4-yl, 2-methyltetrahydro-4H-pyran-4-yl, 1-[(2,2,6,6-tetramethyl-1,1-dioxo-1 -4-thianyl, 1,1-dioxo-1 -4-thiepanyl, or 1,1-dioxo-1 ,2-thiazinan-5-yl. In other embodiments, R1is (C1-C6)alkyl substituted with (C3-C8)cycloalkyl, wherein (C3-C8)cycloalkyl is optionally substituted with carboxy, for example cyclopropyl or cyclobutyl substituted with carboxy. In other embodiments, the (C3-C8)cycloalkyl is cyclopropyl, cyclobutyl, or bicyclo[1.1.1]pentane-1- each of which substituted with one or more instances of carboxy and (C1-C6)alkyl. In some embodiments, R1is (C1-C6)alkyl substituted with one or more instances of fluoro or carboxy. In other embodiments, R1is (C1-C6)alkyl substituted with one or more instances of fluoro. In some embodiments, R1is 2,2,2-trifluoroethyl, while in other embodiments, R1is 3,3,3-trifluoropropyl. In some embodiments, R1is methyl. In some embodiments, R2is methyl. In other embodiments, R2is cyanomethyl. In some embodiments, R3is methyl or ethyl substituted with SO2R4(C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl, and fluoro. In more preferred embodiments, R3is methyl substituted with SO2R4, (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl, and fluoro. In some embodiments, R3is (C1-C6)alkyl substituted with phenyl, wherein phenyl is optionally substituted with fluoro, for example R3can be (C1-C6)alkyl substituted, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl. In other embodiments, R3is (C1-C6)alkyl, preferably methyl, substituted with 5- to 6- membered heteroaryl. In some embodiments, the 5- to 6-membered heteroaryl is thiazolyl or pyridyl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl and fluoro. In some embodiments, R3is (C1-C6)alkyl substituted with 2-methyl-1,3-thiazol-4- yl, while in other embodiments, R3is (C1-C6)alkyl substituted with 2-methylpyridin-4-yl or pyridine-2-yl. In other embodiments, R3is (C1-C6)alkyl substituted with (C3-C8)cycloalkyl, wherein (C3-C8)cycloalkyl is optionally substituted with one or more instances of (C1-C6)alkyl and fluoro. In some embodiments, R3is (C1-C6)alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, spiro[2.3]hexyl, bicyclo[2.1.1]hexyl, or bicyclo[3.1.0]hexyl, each of which is optionally substituted with one or more of (C1-C6)alkyl and fluoro. In more particular embodiments, R3is (C1-C6)alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pent-1-yl, bicyclo[2.1.0]pent-5-yl, spiro[2.3]hexyl , bicyclo[2.1.1]hex-1-yl, bicyclo[3.1.0]hex-3-yl, bicyclo[3.1.0]hex-6-yl, 3,3- dimethylcyclobutyl, 3-methylcyclobutyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 2,2- dimethylcyclobutyl, 3-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3- difluorocyclobutyl , 3-fluoro-3-methylcyclobutyl, 3-methylcyclopentyl, 3,3- difluorocyclopentyl, 3-fluorocyclopentyl, 1-fluorocyclopentyl or 3-ethylcyclobutyl. In even more particular embodiments, R3is (C1-C6)alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pent-1-yl, bicyclo[2.1.1]hex-1-yl, 3,3- dimethylcyclobutyl, 3-methylcyclobutyl, 1-methylcyclobutyl, 3,3-difluorocyclopentyl, or 3- ethylcyclobutyl. In still further embodiments, R3is methyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pent-1-yl, bicyclo[2.1.0]pent-5-yl, spiro[2.3]hexyl , bicyclo[2.1.1]hex-1-yl, bicyclo[3.1.0]hex-3-yl, bicyclo[3.1.0]hex-6-yl, 3,3- dimethylcyclobutyl, 3-methylcyclobutyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 2,2- dimethylcyclobutyl, 3-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3- difluorocyclobutyl , 3-fluoro-3-methylcyclobutyl, 3-methylcyclopentyl, 3,3- difluorocyclopentyl, 3-fluorocyclopentyl, 1-fluorocyclopentyl or 3-ethylcyclobutyl. In other embodiments, R3is (C1-C6)alkyl substituted with 4- to 7-membered heterocycloalkyl, preferably tetrahydrofurany-2-yl, or tetrahydropyrany-4-yl. In some embodiments, R3is (C1-C6)alkyl 3,3-dimethylbutyl, 3-methylbutyl, 2- methylbutyl, isopropyl, 3-methylpentyl, 4-methylpentyl, or spiro[2.3]hexan-4-yl. The present invention also provides a compound Formula (II): (II) or a pharmaceutically acceptable salt thereof; wherein: R4and R5taken together form a heterocyclic ring having the structure: a) , wherein:R7and R8are independently hydrogen or (C1-C6)alkyl; b) ;c) , wherein:R9is (C1-C6)hydroxyalkyl or (C1-C6)alkoxyalkyl;d) , wherein:Y is absent or CH2, R10is hydrogen or (C1-C6)alkyl; e) , wherein:R11is (C1-C6)alkyl; f) , wherein:R12aand R12bare each independently (C1-C6)alkyl, and R13is hydrogen or (C3-C8)cycloalkyl; or g) , wherein R14and R15are each independently (C1-C6)alkyl; and R6is (C1-C6)alkyl or (C3-C8)cycloalkyl. In some embodiments, the compound has the the structure of Formula (IIa) or (IIb): (Ia) (Ib), or a pharmaceutically acceptable salt thereof, wherein: if the structure is Formula (IIa), then R4and R5taken together form a heterocyclic ring having the structure:

[0002] if the structure is Formula (IIb), then R4and R5taken together form a heterocyclic ring having the structure:

[0003] In some embodiments, R4and R5taken together form a heterocyclic ring having the structure (a); and R7is hydrogen. In other embodiments, R4and R5taken together form a heterocyclic ring having the structure (a); and R7is methyl. In some embodiments, R4and R5taken together form a heterocyclic ring having the structure (a); and R8is methyl. In other embodiments, R4and R5taken together form a heterocyclic ring having the structure (a); and R8is hydrogen. In some embodiments, R4and R5taken together form a heterocyclic ring having the structure (c); and R9is methoxy. In other embodiments, R4and R5taken together form a heterocyclic ring having the structure (c); and R9is 1-hydroxyethyl. In some embodiments, R4and R5taken together form a heterocyclic ring having the structure (d); and Y is absent. In other embodiments, R4and R5taken together form a heterocyclic ring having the structure (d); and Y is CH2. In some embodiments, R4and R5taken together form a heterocyclic ring having the structure (d); and R10is hydrogen. In other embodiments, R4and R5taken together form a heterocyclic ring having the structure (d); and R10is methyl. In some embodiments, R4and R5taken together form a heterocyclic ring having the structure (e); and R11is methyl. In some embodiments, R4and R5taken together form a heterocyclic ring having the structure (f); and R12aand R12bare each methyl. In some embodiments, R4and R5taken together form a heterocyclic ring having the structure (f); and R13is cyclopropyl. In other embodiments, R4and R5taken together form a heterocyclic ring having the structure (f); and R13is hydrogen. In some embodiments, R4and R5taken together form a heterocyclic ring having the structure (g); and R14is methyl. In some embodiments, R4and R5taken together form a heterocyclic ring having the structure (g); and R15is methyl. In some embodiments, R6is n-butyl. The present invention also provides a compound of Formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein: R16is (C1-C6)alkyl substituted with tetrahydrofuran-2-yl, pyrazolyl optionally substituted with (C1-C6)alkyl, phenyl substituted with (C=O)NH2, or cyclobutyl substituted with pyridyl; R17is (C1-C6)alkyl; and R18is (C1-C6)alkyl. In some embodiments, the compound has the structure of Formula (IIIa) or (IIIb) (IIIa) (IIIb) or a pharmaceutically acceptable salt thereof. In some embodiments, the pyrazolyl is 1-methylpyrazol-4-yl, or pyrazol-4-yl. In some embodiments, R17is methyl. In some embodiments, R18is n-butyl. The present invention also provides a compound of Formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein: R19is (C1-C6)fluoroalkyl; R20is (C1-C6)alkyl; and R21is (C1-C3)alkyl. In some embodiments, the compound has the structure of Formula (IVa) or (IVb): (IVa) (IVb), or a pharamceutically acceptable salt thereof. In some embodiments, R19is 2,2,2-trifluoroethyl. In some embodiments, R20is methyl. In some embodiments, R21is ethyl or propyl. The present invention also provides a compound of Formula (V) (V), or a pharmaceutically acceptable salt thereof, wherein: R22is (C1-C6)alkyl; R23is (C1-C6)alkoxy; or R22and R23taken together with the carbon to which they are attached form 4- to 7-membered heterocycloalkyl; and R24is (C1-C6)alkyl optionally substituted with phenyl or (C3-C8)cycloalkyl; provided that the compound is not: or . In some embodiments, the compound has the structure of Formula (Va) or (Vb) (Va) (Vb), or apharmaceutically acceptable salt thereof. In some embodiments, R22is methyl. In some embodiments, R23is methoxymethyl. In other embodiments, R22and R23taken together form: or . In some embodiments, wherein R24is n-butyl, while in other embodiments, R24is benzyl, and in still other embodiments, R24is (cyclopentyl)methyl. In other embodiments, R24is n-propyl. The present invention also provides a compound having the structure:

[0004]

[0005] or a pharmaceutically acceptable salt thereof Methods of Treatment 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 a therapeutically effective amount of a compound according to the present invention, or a pharmaceutically acceptable salt thereof. 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. Another aspect of the invention provides a method of: a) reducing of HbA1c; 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, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is administered orally to the subject. In certain embodiments, the compound is administered parenterally to the subject. In certain embodiments, the disease is prevented. In other embodiments, the disease is treated. Pharmaceutical Compositions, Routes of Administration, and Dosing 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. 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. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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-1,3,6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable. 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. 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. 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. 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. 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. One may dilute or increase the volume of the therapeutic with an inert material. These diluents could include carbohydrates, especially mannitol, α-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. 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. 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. 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. 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. 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. 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. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. 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. 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, dichlorotetrafluoroethane, 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. 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) (α1- 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. 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. 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. 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. 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. 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. 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 (μm), most preferably 0.5 to 5 μm, for most effective delivery to the deep lung. 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. 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. 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. 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. 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. Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. 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. 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. 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. 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). 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. 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). 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. 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. 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, polyanhydrides, 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.” 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. 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. EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Abbreviations:

[0006] General Scheme 1: General Scheme 2:

[0007] General Scheme 3:

[0008] General Scheme 4:

[0009] Example 1: 5-(diaminomethylene)-1-(2-(6,8-dioxo-2-oxa-5,7-diazaspiro[3.4]octan-5- yl)spiro[3.5]nonan-7-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-trione (1) Synthetic scheme:

[0010] methyl 3-(8,11-dioxadispiro[3.2.47.24]tridecan-2-ylamino)oxetane-3-carboxylate To a solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (1 g, 5.1 mmol) and methyl 3-aminooxetane-3-carboxylate (868.7 mg, 6.62 mmol) in DCM (10 mL) was added AcOH (306 mg, 5.1 mmol). NaBH(OAc)3(3.24 g, 15.3 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 16 h. After completion, the residue was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether : ethyl acetate=1 : 0 to 1 : 1) to give the title compound (1.1 g, 69%) as a yellow solid. MS (ESI): mass calcd. for C16H25NO5: 311.17, found: 312.1 [M+H]+. 3-(8,11-dioxadispiro[3.2.47.24]tridecan-2-ylamino)oxetane-3-carboxamide To a solution of methyl 3-(8,11-dioxadispiro[3.2.47.24]tridecan-2-ylamino)oxetane-3- carboxylate (1.1 g, 3.53 mmol) in NH3 / MeOH (11 mL). The mixture was stirred in a sealed tube at 95 °C for 12 h. The reaction was concentrated under reduced pressure to give the title compound (0.81 g, 78%) as a white solid. MS (ESI): mass calcd. for C15H24N2O4: 296.17, found: 297.1 [M+H]+. 5-(8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)-2-oxa-5,7-diazaspiro[3.4]octane-6,8-dione To a solution of 3-(8,11-dioxadispiro[3.2.47.24]tridecan-2-ylamino)oxetane-3- carboxamide (0.81 g, 2.74 mmol) in ACN (8 mL) was added CDI (888.5 mg, 5.48 mmol) and DIPEA (1.06 g, 8.22 mmol). The reaction was stirred at 90 °C for 16 h. The residue was poured into H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (0.4 g, 45%) as a white solid. MS (ESI): mass calcd. for C16H22N2O5: 322.15, found: 323.2 [M+H]+. 5-(7-oxospiro[3.5]nonan-2-yl)-2-oxa-5,7-diazaspiro[3.4]octane-6,8-dione To a solution of 5-(8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)-2-oxa-5,7- diazaspiro[3.4]octane-6,8-dione (0.4 g, 1.24mmol) in H2O and acetone (4 mL) was added TsOH.H2O (472 mg, 2.48 mmol). The mixture was stirred at 50 °C for 5 h. After completion, the mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). 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 1 : 1) to give the title compound (310 mg, 90%) as a white solid. MS (ESI): mass calcd. for C14H18N2O4: 278.13, found: 279.1 [M+H]+. 5-(7-oxospiro[3.5]nonan-2-yl)-7-(2-trimethylsilylethoxymethyl)-2-oxa-5,7- diazaspiro[3.4]octane-6,8-dione To a solution of 5-(7-oxospiro[3.5]nonan-2-yl)-2-oxa-5,7-diazaspiro[3.4]octane-6,8- dione (310 mg, 1.11 mmol) in DCM (5 mL) was added SEM-Cl (371.4 mg, 2.23 mmol) and DIPEA (575.9 mg, 4.46 mmol). The mixture was stirred at 25 °C for 12 h. The residue was poured into H2O (20 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 20 : 1 to 0 : 1) to give the title compound (310 mg, 68%) as a white solid. MS (ESI): mass calcd. for C20H32N2O5Si: 408.21, found: 431.3 [M+Na]+. 4-[(4-amino-1-methyl-cyclohexyl)methyl]-5-methyl-2-(2-trimethylsilylethoxymethyl)- 1,2,4-triazol-3-one To a mixture of 5-methyl-4-[(1-methyl-4-oxo-cyclohexyl)methyl]-2-(2- trimethylsilylethoxymethyl)-1,2,4-triazol-3-one (2.17 g, 6.14 mmol), NH4OAc (9.46 g, 122.76 mmol) in MeOH (22 mL) was added NaBH(OAc)3(3.25 g, 15.35 mmol) under N2. After stirring at 25 °C for 16 h under N2, the reaction was concentrated under reduced pressure. The residue was poured into H2O (10 mL) and extracted with ethyl acetate (10 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 (0.3 g, 99%) as a yellow oil. MS (ESI): mass calcd. for C20H35N3O4Si: 409.24, found: 410.3 [M+H]+. 1-[2-[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-2-oxa-5,7-diazaspiro[3.4]octan-5- yl]spiro[3.5]nonan-7-yl]-3-propyl-urea A mixture of 5-(7-aminospiro[3.5]nonan-2-yl)-7-(2-trimethylsilylethoxymethyl)-2- oxa-5,7-diazaspiro[3.4]octane-6,8-dione (0.25 g, 610 mol), 1-isocyanatopropane (51.94 mg, 610 mol), TEA (61.8 mg, 610 mol) in DCM (2.5 mL) was degassed and purged with N23 times. The mixture was stirred at 25 °C for 1 h under N2. The residue was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (0.118 g, 39%) as a colorless oil. MS (ESI): mass calcd. for C24H42N4O5Si: 494.29, found: 517.2 [M+Na]+. 1-[2-[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-2-oxa-5,7-diazaspiro[3.4]octan-5- yl]spiro[3.5]nonan-7-yl]-3-propyl-hexahydropyrimidine-2,4,6-trione A mixture of 1-[2-[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-2-oxa-5,7- diazaspiro[3.4]octan-5-yl]spiro[3.5]nonan-7-yl]-3-propyl-urea (98 mg, 198 mol), malonic acid (206 mg, 1.98 mmol) and Ac2O (101 mg, 991 mol) in dioxane (1 mL) was degassed and purged with N23 times. The mixture was stirred at 80 °C for 1 h under N2. The residue was poured into H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (43 mg, 39%) as a colorless oil. MS (ESI): mass calcd. for C27H42N4O7Si: 562.28, found: 585.4 [M+Na]+. 5-(diaminomethylene)-1-[2-[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-2-oxa-5,7- diazaspiro[3.4]octan-5-yl]spiro[3.5]nonan-7-yl]-3-propyl-hexahydropyrimidine-2,4,6- trione A mixture of 1-[2-[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)-2-oxa-5,7- diazaspiro[3.4]octan-5-yl]spiro[3.5]nonan-7-yl]-3-propyl-hexahydropyrimidine-2,4,6-trione (80 mg, 142 mol), cyanamide (59.77 mg, 1.42 mmol), Ni(acac)2 (10.96 mg, 43 mol) in THF (0.8 mL) was degassed and purged with N23 times. The mixture was stirred at 80 °C for 16 h under N2. The residue was poured into H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure the title compound (0.1 g, crude) as a colorless oil. MS (ESI): mass calcd. for C28H44N6O7Si: 604.30, found: 627.3 [M+Na]+. 5-(diaminomethylene)-1-(2-(6,8-dioxo-2-oxa-5,7-diazaspiro[3.4]octan-5- yl)spiro[3.5]nonan-7-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-trione A mixture of 5-(diaminomethylene)-1-[2-[6,8-dioxo-7-(2-trimethylsilylethoxymethyl)- 2-oxa-5,7-diazaspiro[3.4]octan-5-yl]spiro[3.5]nonan-7-yl]-3-propyl-hexahydropyrimidine- 2,4,6-trione (0.1 g, 165 mol) in TFA (1 mL) and H2O (0.2 mL) was degassed and purged with N23 times. The mixture was stirred at 20 °C for 1 h under N2. The mixture was concentrated under reduced pressure. The residue was dissolved into MeOH (1 mL) and adjusted to pH = 8 with K2CO3. The reaction was stirred at 25 °C for 30 min, adjusted to pH = 5 with saturated citric acid and extracted with ethyl acetate (3 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (50 mg, 63%) as a white solid. MS (ESI): mass calcd. for C22H30N6O6: 474.22, found: 475.2 [M+H]+.1H NMR (400 MHz, DMSO- d6) ppm 10.83 (s, 1H), 9.55 (s, 2H), 7.30 (s, 2H), 4.57-4.75 (m, 5H), 4.25 (m, 1H), 3.66-3.75 (t, J = 6.8 Hz, 2H), 2.55-2.62 (m, 1H), 2.40-2.47 (m, 2H), 2.33 (m, 2H), 2.00-2.12 (m, 1H), 1.95 (d, J = 11.6 Hz, 1H), 1.79 (d, J = 11.2 Hz, 1H), 1.28-1.58 (m, 6H), 0.83 (t, J = 7.6 Hz, 3H). Example 2. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-(2-(6,8-dioxo-2-oxa-5,7- diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (2) Synthetic scheme:

[0011] 1-(cyclopentylmethyl)-3-(2-(6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2-oxa-5,7- diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)urea To a solution of 5-(7-aminospiro[3.5]nonan-2-yl)-7-(2-trimethylsilylethoxymethyl)-2- oxa-5,7-diazaspiro[3.4]octane-6,8-dione (0.8 g, 1.95 mmol) in DCM (8 mL) was added TEA (395.3 mg, 3.91 mmol) and (4-nitrophenyl) N-(cyclopentylmethyl)carbamate (516 mg, 1.95 mmol). The mixture was stirred at 25 °C for 3 h. After completion, the reaction was quenched with H2O (10 mL) and extracted with DCM (10 mL x 3). 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 = 100 : 1 to 0 : 1) to afford the title compound (0.6 g, 51%) as a yellow solid. MS (ESI): mass calcd. for C27H46N4O5Si: 534.32, found: 535.3 [M+H]+. 1-(cyclopentylmethyl)-3-(2-(6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2-oxa-5,7- diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione A mixture of malonic acid (1.07 g, 10.28 mmol) and Ac2O (525 mg, 5.14 mmol) in dioxane (5.5 mL) was stirred at 80 °C for 0.5 h. 1-(cyclopentylmethyl)-3-[2-[6,8-dioxo-7-(2- trimethylsilylethoxymethyl)-2-oxa-5,7-diazaspiro[3.4]octan-5-yl]spiro[3.5]nonan-7-yl]urea (0.55 g, 1.03 mmol) was added and stirred at 80 °C for 0.5 h. After completion, the mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether : ethyl acetate = 1 : 1, Rf= 0.43) to give the title compound (0.2 g, 29%) as a yellow solid. MS (ESI): mass calcd. for C30H46N4O7Si: 602.31, found: 625.3 [M+Na]+. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-(2-(6,8-dioxo-7-((2- (trimethylsilyl)ethoxy)methyl)-2-oxa-5,7-diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-(cyclopentylmethyl)-3-[2-[6,8-dioxo-7-(2- trimethylsilylethoxymethyl)-2-oxa-5,7-diazaspiro[3.4]octan-5-yl]spiro[3.5]nonan-7- yl]hexahydropyrimidine-2,4,6-trione (0.18 g, 299 mol) in THF (1.8 mL) was added cyanamide (125.5 mg, 2.99 mmol) and Ni(acac)2(23 mg, 89.6 mol). The mixture was stirred at 80 °C for 12 h. The reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether : ethyl acetate = 1 : 1) to give the title compound (0.072 g, 37%) as a yellow oil. MS (ESI): mass calcd. for C31H48N6O7Si: 644.34, found: 667.3 [M+Na]+. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-(2-(6,8-dioxo-2-oxa-5,7- diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione 1- (cyclopentylmethyl)-5-(diaminomethylene)-3-(2-(6,8-dioxo-2-oxa-5,7- diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-[2-[6,8-dioxo-7-(2- trimethylsilylethoxymethyl)-2-oxa-5,7-diazaspiro[3.4]octan-5-yl]spiro[3.5]nonan-7- yl]hexahydropyrimidine-2,4,6-trione (0.072 g, 111.7 mol) in TFA (0.5 mL) was added H2O (0.2 mL). The mixture was stirred at 20 °C for 1 h. The reaction was filtered and concentrated under reduced pressure. The residue was diluted with MeOH (1 mL) and adjusted to pH = 8 with saturated K2CO3and stirred at 25 °C for 1 h. The reaction was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (0.012 g, 21%) as a white solid. MS (ESI): mass calcd. for C25H34N6O6: 514.25, found: 515.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.85 (s, 1H), 9.56 (s, 2H), 7.30 (s, 2H), 4.63-4.71 (m, 5 H), 4.23-4.28 (m, 1H), 3.71-3.73 (d, J = 7.6 Hz, 2H), 2.56-2.61 (m, 1H), 2.47 (s, 2H), 2.27-2.36 (m, 2H), 2.18-2.26 (m, 1H), 2.01-2.09 (m, 1H), 1.93-2.00 (m, 1H), 1.80 (d, J = 12.0 Hz, 1H), 1.52-1.61 (m, 4H), 1.32-1.50 (m, 6H), 1.18-1.27 (m, 2H). Example 3 and Example 4.1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((2S,4s,7S)-2- (6,8-dioxo-2-oxa-5,7-diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (3) and 1-(cyclopentylmethyl)-5-(diaminomethylene)-3- ((2R,4r,7R)-2-(6,8-dioxo-2-oxa-5,7-diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (4)

[0012] Example 2 (0.01 g) was separated by chiral SFC (column: DAICEL CHIRALPAK IG 2-EtOH (0.1% NH3H2elution) to give 3 (3.47 mg) as a white solid from the first eluting peak. MS (ESI): mass calcd. for C25H34N6O6: 514.25, found: 515.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.82 (s, 1H), 9.55 (s, 2 H), 7.32 (s, 2H), 4.62-4.69 (m, 5H), 4.24 (t, J = 8.4 Hz, 1H), 3.71 (d, J = 7.2 Hz, 2H), 2.57 (s, 1H), 2.46 (s, 2H), 2.26-2.35 (m, 2H), 2.17-2.25 (m, 1H), 2.00-2.08 (m, 1H), 1.95 (d, J = 12.4 Hz, 1H), 1.78-1.81 (d, J = 12.0 Hz, 1H), 1.51-1.61 (m, 4H), 1.31-1.48 (m, 6H), 1.18-1.25 (m, 2H). 4 (3.71 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C25H34N6O6: 514.25, found: 515.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.73 (s, 1H), 9.55 (s, 2H), 7.32 (s, 2H), 4.62-4.70 (m, 5H), 4.24 (t, J = 8.8 Hz, 1H), 3.71 (d, J = 7.2 Hz, 2H), 2.50-2.57 (m, 1H), 2.46 (s, 2H), 2.30-2.33 (m, 2H), 2.23-2.25 (m, 1H), 1.99-2.07 (m, 1H), 1.95-2.00 (m, 1H), 1.75-1.82 (m, 1H), 1.53-1.58 (m, 4H), 1.23-1.47 (m, 6H), 1.18-1.25 (m, 2H). The stereochemistry for these two compounds is arbitrarily assigned. Example 5 was prepared using an identical synthetic sequence to Example 1, using benzyl isocyanate instead of propyl isocyanate. Example 6 and Example 7. 1-benzyl-5-(diaminomethylene)-3-((2S,4s,7S)-2-(6,8-dioxo-2- oxa-5,7-diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)- trione (6) and 1-benzyl-5-(diaminomethylene)-3-((2R,4r,7R)-2-(6,8-dioxo-2-oxa-5,7- diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (7)

[0013] Example 5 (70 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK AD 2-EtOH (0.1% NH3H2elution) to give 6 (18.28 mg, 26%) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C26H30N6O6: 522.22, found: 523.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.82 (d, J = 2.0 Hz, 1H), 9.51 (s, 2H), 7.13-7.40 (m, 7H), 4.95 (s, 2H), 4.61-4.72 (m, 5H), 4.24 (t, J = 8.8 Hz, 1H), 2.54-2.61 (m, 1H), 2.35-2.46 (m, 2H), 2.24-2.33 (m, 2H), 1.92-2.08 (m, 2H), 1.75-1.83 (m, 1H), 1.31-1.47 (m, 4H).7 (24.0 mg) was isolated from the second eluting peak as a white solid. MS (ESI): mass calcd. for C26H30N6O6: 522.22, found: 523.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.83 (s, 1H), 9.51 (s, 2H), 7.17-7.38 (m, 7H), 4.95 (s, 2H), 4.60-4.71 (m, 5H), 4.24 (m, 1H), 2.54-2.60 (m, 1H), 2.39-2.47 (m, 2H), 2.25-2.34 (m, 2H), 1.92-2.07 (m, 2H), 1.79 (d, J = 13.2 Hz, 1H), 1.31-1.46 (m, 4H). The stereochemistry for these two compounds is arbitrarily assigned. Example 10. 1-butyl-5-(diaminomethylene)-3-(2-(2,2-dioxido-6,8-dioxo-2-thia-5,7- diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (10) Synthetic scheme:

[0014] 2-thia-5,7-diazaspiro[3.4]octane-6,8-dione To a solution of thietan-3-one (23.85 g, 270.63 mmol) in EtOH (120 mL) and H2O (120 mL) was added KCN (15.86 g, 243.6 mmol) and (NH4)2CO3(52 g, 541.3 mmol). The mixture was stirred at 60 °C for 16 h. The reaction was diluted with H2O (50 mL) and extracted with ethyl acetate (60 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 1 : 1) to give the title compound (8 g, 19%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) ppm 10.74 (s, 1H), 8.81 (s, 1H), 3.40-3.49 (m, 4H). 7-(2-trimethylsilylethoxymethyl)-2-thia-5,7-diazaspiro[3.4]octane-6,8-dione To a suspension of 2-thia-5,7-diazaspiro[3.4]octane-6,8-dione (2.6 g, 16.44 mmol) and DIPEA (6.37 g, 49.31 mmol) in dry DCM (62.4 mL) and DMF (15.6 mL) was added SEM-Cl (2.74 g, 16.44 mmol) dropwise at 0 °C. The resulting solution was allowed to warm up to 25 °C and stirred for 12 h. The reaction solution was cool to 0 °C, diluted with H2O (50 mL) and extracted with DCM (60 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 10 : 1 to 0 : 1) to give the title compound (3.7 g, 78%) as a colorless oil. MS (ESI): mass calcd. for C11H20N2O3SSi: 288.10, found: 286.9 [M-H]-. 5-(8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)-7-(2-trimethylsilylethoxymethyl)-2-thia-5,7- diazaspiro[3.4]octane-6,8-dione To a solution of 7-(2-trimethylsilylethoxymethyl)-2-thia-5,7-diazaspiro[3.4]octane- 6,8-dione (3.45 g, 11.96 mmol) in DMF (18 mL) was added Cs2CO3(7.79 g, 23.92 mmol) and 2-iodo-8,11-dioxadispiro[3.2.47.24]tridecane (3.69 g, 11.96 mmol) at 25 °C. The mixture was stirred at 80 °C for 48 h. The reaction was quenched with H2O (30 mL) and extracted with ethyl acetate (35 mL x 3). The combined organic phase was washed with brine, dried with anhydrous 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 (1.8 g, 32%) as yellow oil. MS (ESI): mass calcd. for C22H36N2O5SSi: 468.21, found: 491.2 [M+Na]+. 5-(8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)-2,2-dioxo-7-(2-trimethylsilylethoxymethyl)- 2thia-5,7-diazaspiro [3.4]octane-6,8-dione To a stirred solution of 5-(8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)-7-(2- trimethylsilylethoxymethyl)-2-thia-5,7-diazaspiro[3.4]octane-6,8-dione (1.8 g, 3.84 mmol) in DCM (27 mL) was added mCPBA (2.34 g, 11.52 mmol, 85% purity) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction was diluted with saturated Na2SO3 (30 mL) and extracted with DCM (35 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 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 (1.12 g, 58%) as a white solid. MS (ESI): mass calcd. for C22H36N2O7SSi: 500.2, found: 523.1 [M+Na]+. 2,2-dioxo-5-(7-oxospiro[3.5]nonan-2-yl)-7-(2-trimethylsilylethoxymethyl)-2thia-5,7- diazaspiro[3.4]octane-6,8-dione To a solution of 5-(8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)-2,2-dioxo-7-(2- trimethylsilylethoxymethyl)-2thia-5,7-diazaspiro[3.4]octane-6,8-dione (1.12 g, 2.24 mmol) in acetone (12 mL) and H2O (2.4 mL) was added TsOH.H2O (851 mg, 4.47 mmol) at 25 °C. The mixture was stirred at 50 °C for 18 h. The reaction was adjusted to pH = 7 with saturated NaHCO3. The precipitate was collected by filtration and was dried under vacuum to give the title compound (880 mg, 86%) as a white solid. MS (ESI): mass calcd. for C20H32N2O6SSi: 456.1, found: 479.2 [M+Na]+. 5-(7-aminospiro[3.5]nonan-2-yl)-2,2-dioxo-7-(2-trimethylsilylethoxymethyl)-2thia- 5,7diazaspiro[3.4]octane-6,8-dione To a solution of 2,2-dioxo-5-(7-oxospiro[3.5]nonan-2-yl)-7-(2- trimethylsilylethoxymethyl)-2thia-5,7-diazaspiro[3.4]octane-6,8-dione (780 mg, 1.71 mmol) in MeOH (15 mL) was added NH4OAc (2.63 g, 34.16 mmol) and NaBH(OAc)3(905 mg, 4.27 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h and concentrated under reduced pressure. The residue was dissolved in H2O (10 mL), adjusted to pH to 7 with saturated NaHCO3and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.2 g, crude) as a pale yellow oil. MS (ESI): mass calcd. for C20H35N3O5SSi: 457.21, found: 458.1 [M+H]+. 1-butyl-3-[2-[2,2,6,8-tetraoxo-7-(2-trimethylsilylethoxymethyl)-2thia-5,7- diazaspiro[3.4]octan-5-yl]spiro[3.5] nonan-7-yl]urea To a solution of 5-(7-aminospiro[3.5]nonan-2-yl)-2,2-dioxo-7-(2- trimethylsilylethoxymethyl)-2thia-5,7-diazaspiro[3.4]octane-6,8-dione (1.2 g, 2.62 mmol) in DCM (12 mL) was added 1-isocyanatobutane (259.9 mg, 2.62 mmol) and TEA (265.3 mg, 2.62 mmol) at 15 °C. The mixture was stirred at 15 °C for 2 h. The reaction was quenched with H2O (8 mL) and extracted with DCM (10 mL x 3). The combined organic phase was washed with brine, dried with anhydrous 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 (780 mg, 53%) as a white solid. MS (ESI): mass calcd. for C25H44N4O6SSi: 556.28, found: 557.4 [M+H]+. 1-butyl-3-[2-[2,2,6,8-tetraoxo-7-(2-trimethylsilylethoxymethyl)-2thia-5,7- diazaspiro[3.4]octan-5-yl]spiro[3.5] nonan-7-yl]hexahydropyrimidine-2,4,6-trione Seven reactions were carried out in parallel. To a solution of 1-butyl-3-[2-[2,2,6,8- tetraoxo-7-(2-trimethylsilylethoxymethyl)-2thia-5,7-diazaspiro[3.4]octan-5- yl]spiro[3.5]nonan-7-yl]urea (60 mg, 107.8 mol) in DCM (1.2 mL) was added propanedioyl dichloride (30.38 mg, 216 mol) at 0 °C. The mixture was stirred at 15 °C for 20 h. The seven reactions were combined for workup together. The reaction solution was concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether : ethyl acetate = 2 : 3) to give the title compound (130 mg, 28%) as a white solid. MS (ESI): mass calcd. for C28H44N4O8SSi: 624.26, found: 647.4 [M+Na]+. 1-butyl-5-(diaminomethylene)-3-[2-[2,2,6,8-tetraoxo-7-(2-trimethylsilylethoxymethyl)- 2thia-5,7-diazaspiro [3.4]octan-5-yl]spiro[3.5]nonan-7-yl]hexahydropyrimidine-2,4,6- trione To a solution of 1-butyl-3-[2-[2,2,6,8-tetraoxo-7-(2-trimethylsilylethoxymethyl)-2thia- 5,7-diazaspiro[3.4]octan-5-yl]spiro[3.5]nonan-7-yl]hexahydropyrimi dine-2,4,6-trione (130 mg, 208 mol) in THF (5 mL) was added cyanamide (87.47 mg, 2.08 mmol) and Ni(acac)2 (16.04 mg, 62 mol) at 25 °C under N2at 25 °C. The mixture was stirred at 80 °C for 15 h. The reaction solution was purified by prep-TLC (petroleum ether : ethyl acetate = 1 : 1) to give the title compound (95 mg, 36%) as a white solid. MS (ESI): mass calcd. for C29H46N6O8SSi: 666.29, found: 689.4 [M+Na]+. 1-butyl-5-(diaminomethylene)-3-(2-(2,2-dioxido-6,8-dioxo-2-thia-5,7- diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (10) A solution of 1-butyl-5-(diaminomethylene)-3-[2-[2,2,6,8-tetraoxo-7-(2- trimethylsilylethoxymethyl)-2thia-5,7-diazaspiro[3.4]octan-5-yl]spiro[3.5]nonan-7- yl]hexahydropyrimidine-2,4,6-trione (10 mg, 15 mol) in TFA (0.2 mL) and H2O (0.1 mL) was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (0.5 mL), and adjusted to pH = 8 with K2CO3. The mixture was stirred at 25 °C for 1 h and concentrated under reduced pressure. The residue was purified by prep- HPLC to give the title compound (4.74 mg, 59%) as a white solid. MS (ESI): mass calcd. for C23H32N6O7S: 536.21, found: 537.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.27 (s, 1H), 9.54 (s, 2H), 7.31 (s, 2H), 4.53-4.64 (m, 5H), 4.09 (quin, J = 8.8 Hz, 1H), 3.73 (t, J = 7.2 Hz, 2H), 2.60-2.64 (m, 1H), 2.35-2.48 (m, 2H), 2.25-2.34 (m, 2H), 1.99-2.08 (m, 1H), 1.78 (t, J = 11.6 Hz, 2H), 1.30-1.49 (m, 6H), 1.18-1.30 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). Example 11 and Example 12. 1-butyl-5-(diaminomethylene)-3-((2R,4r,7R)-2-(2,2- dioxido-6,8-dioxo-2-thia-5,7-diazaspiro[3.4]octan-5-yl)spiro [3.5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (11) and 1-butyl-5-(diaminomethylene)-3-((2S,4s,7S)-2-(2,2- dioxido-6,8-dioxo-2-thia-5,7-diazaspiro[3.4]octan-5-yl)spiro[3.5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (12) 1-butyl-5-(diaminomethylene)-3-[2-(2,2,6,8-tetraoxo-2thia-5,7-diazaspiro[3.4]octan- 5-yl)spiro[3.5]nonan-7-yl]hexahydropyrimidine -2,4,6-trione (30 mg) was separated by chiral 2-MeOH (0.1%NH3H211 (11.79 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C23H32N6O7S: 536.21, found: 537.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.28 (s, 1H), 9.55 (s, 2H), 7.30 (s, 2H), 4.47-4.71 (m, 5H), 4.10 (quin, J = 8.8 Hz, 1H), 3.70-3.81 (m, 2H), 2.60-2.66 (m, 1H), 2.30-2.49 (m, 4H), 2.00-2.08 (m, 1H), 1.79 (t, J = 11.6 Hz, 2H), 1.32-1.51 (m, 6H), 1.24-1.29 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).12 (13.37 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C23H32N6O7S: 536.21, found: 537.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): ppm 11.25 (s, 1H), 9.55 (s, 2H), 7.30 (s, 2H), 4.48-4.71 (m, 5H), 4.10 (quin, J = 8.8 Hz, 1H), 3.74 (t, J = 7.2 Hz, 2H), 2.63 (t, J = 10.0 Hz, 1H), 2.20-2.49 (m, 4H), 1.99-2.08 (m, 1H), 1.78 (t, J = 11.6 Hz, 2H), 1.31-1.51 (m, 6H), 1.23-1.28 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). The stereochemistry for these two compounds is arbitrarily assigned. Example 13. (R)-1-butyl-5-(diaminomethylene)-3-(2-(5-(methoxymethyl)-5-methyl-2,4- dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (13) Synthetic scheme:

[0015] 5-(methoxymethyl)-5-methylimidazolidine-2,4-dione To a solution of NaCN (3.06 g, 62.5 mmol) and (NH4)2CO3 (27.26 g, 283.8 mmol) in H2O (100 mL) was added 1-methoxypropan-2-one (5 g, 56.8 mmol) dropwise under N2. The mixture was stirred at 60 °C for 8 h. After completion, the reaction was concentrated under reduced pressure. The residue was triturated with H2O (20 mL) and filtered. The filter cake was dried under vacuum to give the title compound (3 g, 33%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 10.01-10.98 (m, 1H), 7.87 (s, 1H), 3.43 (d, J = 9.6 Hz, 1H), 3.26 (s, 1H), 3.24 (s, 3H), 1.16 (s, 3H). 5-(methoxymethyl)-5-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4- dione To a solution of 5-(methoxymethyl)-5-methylimidazolidine-2,4-dione (2.7 g, 17.07 mmol) in DCM (24 mL) and DMF (6 mL) was added DIPEA (4.41 g, 34.14 mmol) and SEM- Cl (2.85 g, 17.1 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 16 h. After completion, the mixture 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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 5 : 1 to 3 : 1) to give the title compound (3.2 g, 65%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) ppm 8.32 (s, 1H), 4.71 (s, 2H), 3.43-3.54 (m, 3H), 3.31 (d, J = 9.6 Hz, 1H), 3.23 (s, 3H), 1.20 (s, 3H), 0.78-0.89 (m, 2H), -0.03 (s, 9H). 1-(8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)-5-(methoxymethyl)-5-methyl-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidine-2,4-dione To a mixture of 5-(methoxymethyl)-5-methyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (1.8 g, 6.24 mmol) and 2-iodo-8,11- dioxadispiro[3.2.47.24]tridecane (1.92 g, 6.24 mmol) in DMF (9 mL) was added Cs2CO3 (4.07 g, 12.48 mmol) and stirred at 80 °C for 48 h. After completion, the mixture 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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 4 : 1) to give the title compound (1.5 g, 51%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) ppm 4.73 (s, 2H), 3.81-3.90 (m, 5H), 3.43-3.52 (m, 4H), 3.17 (s, 3H), 2.52- 2.58 (m, 1H), 2.42-2.48 (m, 1H), 1.93-2.04 (m, 2H), 1.57-1.68 (m, 4H), 1.49-1.55 (m, 2H), 1.42-1.48 (m, 3H), 1.18 (s, 3H), 0.80-0.87 (m, 2H), -0.03 (s, 9H). (R)-5-(methoxymethyl)-5-methyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidine-2,4-dione and (S)-5-(methoxymethyl)-5- methyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine- 2,4-dione To a solution of 1-(8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)-5-(methoxymethyl)-5- methyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (1.5 g, 3.2 mmol) in acetone (10 mL) and H2O (5 mL) was added TsOH.H2O (1.22 g, 6.4 mmol). The mixture was stirred at 50 °C for 3 h. After completion, the mixture was poured into saturated NaHCO3 (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The mixture was separated by chiral SFC (column: DAICEL CHIRALCEL OX (250mm * 2- (R)-5-(methoxymethyl)-5-methyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-((2-(trimethylsilyl)ethoxy) methyl)imidazolidine-2,4-dione (0.6 g, 44%) from the first eluting peak as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 4.69-4.79 (m, 2H), 3.90-4.04 (m, 1H), 3.41-3.56 (m, 4H), 3.13-3.22 (m, 3H), 2.56-2.75 (m, 2H), 2.26 (t, J = 6.0 Hz, 2H), 2.10-2.23 (m, 4H), 1.81-1.96 (m, 4H), 1.12-1.27 (m, 3H), 0.84 (t, J = 8.0 Hz, 2H), -0.03 (s, 9H). (S)-5-(methoxymethyl)-5- methyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4- dione (0.6 g, 44%) was obtained from the second eluting peak as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 4.69-4.79 (m, 2H), 3.91-4.03 (m, 1H), 3.43-3.56 (m, 4H), 3.11-3.23 (m, 3H), 2.55-2.76 (m, 2H), 2.26 (t, J = 6.4 Hz, 2H), 2.09-2.23 (m, 4H), 1.82-1.94 (m, 4H), 1.13-1.25 (m, 3H), 0.84 (t, J = 8.0 Hz, 2H), -0.03 (s, 9H). The stereochemistry for these two compounds is arbitrarily assigned. (5R)-1-(7-aminospiro[3.5]nonan-2-yl)-5-(methoxymethyl)-5-methyl-3-(2- trimethylsilylethoxymethyl) imidazolidine-2,4-dione A mixture of (5R)-5-(methoxymethyl)-5-methyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione (0.5 g, 1.18 mmol), ammonium acetate (1.82 g, 23.55 mmol), NaBH(OAc)3(623.94 mg, 2.94 mmol) in MeOH (5 mL) was degassed and purged with N23 times. The mixture was stirred at 25 °C for 16 h under N2. After completion, the mixture 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 Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.62 g, crude) as a yellow oil. MS (ESI): mass calcd. C21H39N3O4Si: 425.27, found: m / z (ESI, +ve ion) = 426.2 [M+H]+. 1-butyl-3-[2-[(5R)-5-(methoxymethyl)-5-methyl-2,4-dioxo-3-(2- trimethylsilylethoxymethyl)imidazolidin-1-yl]spiro[3.5]nonan-7-yl]urea A mixture of (5R)-1-(7-aminospiro[3.5]nonan-2-yl)-5-(methoxymethyl)-5-methyl-3- (2-trimethylsilylethoxymethyl)imidazolidine-2,4-dione (0.62 g, 1.46 mmol), 1- isocyanatobutane (144.4 mg, 1.46 mmol) and TEA (147.4 mg, 1.46 mmol) in DCM (6.2 mL) was degassed and purged with N23 times. The mixture was stirred at 25 °C for 1 h under N2. The residue was poured into H2O (10 mL) and extracted with DCM (10 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 1 : 1) to give the title compound (0.4 g, 52%) as a yellow oil. MS (ESI): mass calcd. C26H48N4O5Si: 524.34, found: m / z (ESI, +ve ion) = 547.4 [M+Na]+. 1-butyl-3-[2-[(5R)-5-(methoxymethyl)-5-methyl-2,4-dioxo-3-(2- trimethylsilylethoxymethyl)imidazolidin-1-yl]spiro[3.5]nonan-7- yl]hexahydropyrimidine-2,4,6-trione A mixture of 1-butyl-3-[2-[(5R)-5-(methoxymethyl)-5-methyl-2,4-dioxo-3-(2- trimethylsilylethoxymethyl)imidazolidin-1-yl]spiro[3.5]nonan-7-yl]urea (0.3 g, 571.7 mol), malonic acid (59.5 mg, 572 mol), Ac2O (408.5 mg, 4.0 mmol) in AcOH (3 mL) was degassed and purged with N23 times. The mixture was stirred at 80 °C for 1 h under N2. The residue was poured into H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to afford the title compound (0.2 g, 59%) as a colorless oil. MS (ESI): mass calcd. C29H48N4O7Si: 592.33, found: m / z (ESI, +ve ion) = 615[M+Na]+. (R)-1-butyl-5-(diaminomethylene)-3-(2-(5-(methoxymethyl)-5-methyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione A mixture of 1-butyl-3-[2-[(5R)-5-(methoxymethyl)-5-methyl-2,4-dioxo-3-(2- trimethylsilylethoxymethyl)imidazolidin-1-yl]spiro[3.5]nonan-7-yl]hexahydropyrimidine- 2,4,6-trione (0.18 g, 303.6 mol), cyanamide (127.65 mg, 3.04 mmol) and Ni(acac)2 (23.4 mg, 91 mol) in THF (1.8 mL) was degassed and purged with N23 times. The mixture was stirred at 80 °C for 16 h under N2. The residue was poured into H2O (10 mL) and extracted with ethyl acetate (10 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 (0.14 g, 72%) as a colorless oil. MS (ESI): mass calcd. C30H50N6O7Si: 634.35, found: 657.5 [M+Na]+. (R)-1-butyl-5-(diaminomethylene)-3-(2-(5-(methoxymethyl)-5-methyl-2,4- dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (13) A mixture of 1-butyl-5-(diaminomethylene)-3-[2-[(5R)-5-(methoxymethyl)-5-methyl- 2,4-dioxo-3-(2-trimethylsilylethoxymethyl)imidazolidin-1-yl]spiro[3.5]nonan-7- yl]hexahydropyrimidine-2,4,6-trione (0.14 g, 221 mol) in TFA (1.5 mL) and H2O (0.3 mL) was degassed and purged with N23 times. The mixture was stirred at 20 °C for 1 h under N2and concentrated under reduced pressure. The residue was diluted with MeOH (1 mL), adjusted to pH = 8 with K2CO3, and stirred at 25 °C for 30 min. The mixture was adjusted to pH = 5 with saturated citric acid and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (34 mg, 31%) as a white solid. MS (ESI): mass calcd. C24H36N6O6: 504.27, found: 505.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.63 (s, 1H) ,9.54 (s, 2H), 7.32 (s, 2H), 4.54-4.67 (m, 1H), 3.70-3.76 (m, 2H), 3.35-3.53 (m, 3H), 3.21 (m, 3H), 2.52-2.65 (m, 1H), 2.23-2.46 (m, 3H), 2.02-2.16 (m, 1H), 1.69-1.97 (m, 3H), 1.21-1.52 (m, 8H), 1.11-1.20 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H). Example 14 and Example 15. 1-butyl-5-(diaminomethylene)-3-((2R,4r,7R)-2-((R)-5- (methoxymethyl)-5-methyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (14) and 1-butyl-5-(diaminomethylene)-3-((2S,4r,7S)-2-((S)-5- (methoxymethyl)-5-methyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (15)

[0016] Example 13 (50 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK ID 2-MeOH (0.1% NH3H2elution) to give 14 (7.68 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. C24H36N6O6: 504.27, found: 505.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.56- 10.74 (m, 1H), 9.54 ( s, 2H), 7.26-7.37 (m, 2H), 4.54-4.70 (m, 1H), 3.68-3.83 (m, 3H), 3.36- 3.45 (m, 2H), 3.22 (s, 3H), 2.57 (t, J = 10.0 Hz, 1H), 2.34-2.42 (m, 2H), 2.23-2.32 (m, 1H), 2.04-2.12 (m, 1H), 1.75-1.93 (m, 3H), 1.32-1.49 (m, 5H), 1.22-1.29 (m, 3H), 1.13 (s, 3H), 0.88 (t, J = 7.6 Hz, 3H). 15 (4.74 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. C24H36N6O6: 504.27, found: 505.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.63 (s, 1H), 9.54 (s, 2H), 7.31 (s, 2H), 4.62 (t, J = 11.6 Hz, 1H), 3.70-3.80 (m, 3H), 3.36-3.45 (m, 2H), 3.19 (s, 3H), 2.24-2.47 (m, 3H), 2.06-2.14 (m, 1 H), 1.71-1.94 (m, 3H), 1.20-1.51 (m, 9H), 1.15 (s, 3H), 0.87 (t, J = 7.6 Hz, 3H). The stereochemistry for these two compounds is arbitrarily assigned. Example 16 was prepared though an identical route to Example 13 starting from (S)-5- (methoxymethyl)-5-methyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione. Example 17 and Example 18. 1-butyl-5-(diaminomethylene)-3-((2S,4r,7S)-2-((S)-5- (methoxymethyl)-5-methyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione^17) and 1-butyl-5-(diaminomethylene)-3-((2R,4r,7R)-2-((R)-5- (methoxymethyl)-5-methyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nona-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (18)

[0017] Example 16 (60 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK 2-IPA (0.1% NH3H2elution) to give 17 (10 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. C24H36N6O6: 504.27, found: 505.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.61- 10.68 (m, 1H), 9.54 (s, 2H), 7.33 (s, 2H), 4.62 (t, J = 12.0 Hz, 1H), 3.74-3.89 (m, 3H), 3.45 (s, 2H), 3.25 (s, 3H), 2.42-2.52 (m, 2H), 2.29-2.37 (m, 1H), 2.12-2.20 (m, 1H), 1.80-2.00 (m, 3H), 1.28-1.54 (m, 9H), 1.21 (s, 3H), 0.94 (t, J = 7.2 Hz, 3H). 18 (8 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. C24H36N6O6: 504.27, found: 505.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.63 (s, 1H), 9.48-9.61 (m, 2H), 7.33 (s, 2H), 4.55-4.67 (m, 1H), 3.70-3.79 (m, 3H), 3.37-3.45 (m, 2H), 3.23 (s, 3H), 2.55-2.60 (m, 2H), 2.35-2.42 (m, 2H), 2.23-2.31 (m, 1H), 2.04-2.12 (m, 1H), 1.86-1.94 (m, 1H), 1.75-1.83 (m, 1H), 1.22-1.47 (m, 8H), 1.14 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 19. 5-(diaminomethylene)-1-ethyl-3-(3-methyl-2,4-dioxo-1-(2,2,2- trifluoroethyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)- trione (19) Synthetic scheme:

[0018] 11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione To a mixture of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (80 g, 407.7 mmol) in MeOH (800 mL) and H2O (800 mL) was added TMSCN (80.88 g, 815.3 mmol) and (NH4)2CO3(156.68 g, 1.63 mol) in one portion at 25 °C under N2. The mixture was stirred at 90 °C for 12 h. After completion, the mixture was concentrated under reduced pressure and filtered. The filter cake was washed with H2O (500 mL x 3) and dried under vacuum to give the title compound (76.8 g, 71%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 10.52 (s, 1H), 8.39 (s, 1H), 3.82 (s, 4H), 2.27 (d, J = 13.2 Hz, 2H), 1.95 (d, J = 13.2 Hz, 2H), 1.56-1.78 (m, 4H), 1.46 ( d, J = 4.0 Hz, 4H). 2-methyl-11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione To a mixture of 11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione (76.8 g, 288.4 mmol) in DMF (800 mL) was added MeI (45 g, 317.3 mmol) and K2CO3(43.85 g, 317.3 mmol) in one portion at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. After completion, the residue was poured into water (1 L) and extracted with ethyl acetate (1 L x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether : ethyl acetate = 20 : 1 to 0 : 1) to afford the title compound (40 g, 50%) as a white solid.1H NMR (400 MHz, DMSO-d6) (ppm) 8.65 (s, 1H), 3.83 (s, 4H), 2.79 (s, 3H), 2.21-2.34 (m, 2H), 1.91-2.05 (m, 2H), 1.74 (d, J = 5.2 Hz, 2H), 1.60-1.69 (m, 2H), 1.40- 1.50 (m, 4H). 3-methyl-1-(2,2,2-trifluoroethyl)-11,14-dioxa-1,3- diazatrispiro[4.1.2.410.27.15]heptadecane-2,4-dione To a solution of 2-methyl-11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane- 1,3-dione (40 g, 142.7 mmol) in DMF (400 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (66.24 g, 285.4 mmol) and Cs2CO3(69.74 g, 214 mmol). The mixture was heated to 25 °C for 12 h. After completion, the mixture was poured into water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether : ethyl acetate = 10 : 1 to 0 : 1) to afford the title compound (36.8 g, 71%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 4.24-4.34 (m, 2H), 3.84 (s, 4H), 2.88 (s, 3H), 2.26 (s, 4H), 1.88 (s, 2H), 1.62-1.69 (m, 2H), 1.45-1.51 (m, 4H). 3-methyl-1-(2,2,2-trifluoroethyl)-1,3-diazadispiro[4.1.57.15]tridecane-2,4,10-trione To a solution of 2-methyl-4-(2,2,2-trifluoroethyl)-11,14-dioxa-2,4- diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione (36.8 g, 101.56 mmol) in acetone (400 mL) and H2O (200 mL) was added TsOH.H2O (38.64 g, 203.1 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was poured into water (500 mL), and then extracted with ethyl acetate (500 mL x2). The organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether : ethyl acetate = 10 : 1 to 0 : 1) to give the title compound (29 g, 90%) as a white solid.1H NMR (400 MHz, DMSO-d6) (ppm) 4.35 (q, J = 9.6 Hz, 2H), 2.90 (s, 3H), 2.36-2.47 (m, 4H), 2.19-2.27 (m, 4H), 2.12-2.19 (m, 2H), 1.88-1.96 (m, 2H). 10-amino-3-methyl-1-(2,2,2-trifluoroethyl)-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione To a solution of 2-methyl-4-(2,2,2-trifluoroethyl)-2,4-diazadispiro[4.1.57.15]tridecane- 1,3,10-trione (5 g, 15.71 mmol) in MeOH (50 mL) was added NH3 / MeOH (7 M, 22.44 mL) at 25 °C for 1 h. Raney-Ni (1.35 g, 15.71 mmol) was added under N2. The suspension was degassed and purged with H23 times. The mixture was stirred under H2(15 Psi) at 25 °C for 15 h. After completion, the reaction was filtered over a pad of Celite and concentrated under reduced pressure to afford the title compound (5 g) as a green oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C14H20F3N3O2: 319.15, found: 320.1 [M+H]+. 1-(4-methoxybenzyl)-3-(3-methyl-2,4-dioxo-1-(2,2,2-trifluoroethyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)urea To a solution of 10-amino-2-methyl-4-(2,2,2-trifluoroethyl)-2,4- diazadispiro[4.1.57.15]tridecane-1,3-dione (9.1 g, 28.5 mmol) in DCM (90 mL) was added 1- (isocyanatomethyl)-4-methoxy-benzene (4.65 g, 28.5 mmol) and TEA (2.88 g, 28.5 mmol). The mixture was stirred at 25 °C for 1 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 80 : 1 to 0 : 1) to give the title compound (7.5 g, 55%) as a white solid. MS (ESI): mass calcd. for C23H29F3N4O4: 482.21, found: 483.3 [M+H]+. 1-(4-methoxybenzyl)-3-(3-methyl-2,4-dioxo-1-(2,2,2-trifluoroethyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-[(4-methoxyphenyl)methyl]-3-[2-methyl-1,3-dioxo-4-(2,2,2- trifluoroethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10-yl]urea (7.5 g, 15.54 mmol) in DCM (75 mL) was added malonyl dichloride (3.28 g, 23.31 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h. An additional aliquot of malonyl dichloride (1096 mg, 7.77 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 4 h. After completion, the mixture was poured into water (100 mL) and extracted with DCM (100 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 50 : 1 to 0 : 1) to give the title compound (5.5 g, 64%) as a white solid. MS (ESI): mass calcd. for C26H29F3N4O6: 550.20, found: 551.1[M+H]+. 5-(bis(ethylthio)methylene)-1-(4-methoxybenzyl)-3-(3-methyl-2,4-dioxo-1-(2,2,2- trifluoroethyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)- trione To a solution of 1-[(4-methoxyphenyl)methyl]-3-[2-methyl-1,3-dioxo-4-(2,2,2- trifluoroethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (5 g, 9.08 mmol) in DMSO (50 mL) was added TEA (36.35 g, 359.2 mmol) and CS2(63.15 g, 829.4 mmol). After addition, the mixture was stirred at 25 °C for 1 h. Bromoethane (73 g, 669.9 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. After addition, the mixture was poured into water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 80 : 1 to 0 : 1) to give the title compound (5 g, 81%) as a yellow solid. MS (ESI): mass calcd. for C31H37F3N4O6S2: 682.21, found: 683.3 [M+H]+. 5-(bis(ethylthio)methylene)-1-(3-methyl-2,4-dioxo-1-(2,2,2-trifluoroethyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 5-[bis(ethylsulfanyl)methylene]-1-[(4-methoxyphenyl)methyl]-3-[2- methyl-1,3-dioxo-4-(2,2,2-trifluoroethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione (4.5 g, 6.59 mmol) in TFA (22.5 mL) was added methanesulfonic acid (22.5 mL). The mixture was stirred at 70 °C for 0.5 h. After completion, the pH was adjusted to around 7 by progressively adding saturated NaHCO3. The aqueous phase was extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (2.8 g, 76%) as a yellow solid. MS (ESI): mass calcd. for C23H29F3N4O5S2: 562.15, found: 563.2 [M+H]+. 5-[bis(ethylsulfanyl)methylene]-1-ethyl-3-[2-methyl-1,3-dioxo-4-(2,2,2-trifluoroethyl)- 2,4-diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione

[0019] To a solution of 5-[bis(ethylsulfanyl)methylene]-1-[2-methyl-1,3-dioxo-4-(2,2,2- trifluoroethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (300 mg, 533 mol) in DMF (3 mL) was added K2CO3(147.39 mg, 1.07 mmol) and bromoethane (87.15 mg, 800 mol). The mixture was stirred at 20 °C for 16 h. The reaction was added ethyl acetate (30 mL) and washed with brine (20 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 3 : 1 to 1 : 1) to give the title compound (266 mg, 85%) as a yellow solid. MS (ESI): mass calcd. for C25H33F3N4O5S2: 590.18, found: 591.3 [M+H]+. 5-(diaminomethylene)-1-ethyl-3-(3-methyl-2,4-dioxo-1-(2,2,2-trifluoroethyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (19) To a solution of 5-[bis(ethylsulfanyl)methylene]-1-ethyl-3-[2-methyl-1,3-dioxo-4- (2,2,2-trifluoroethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6- trione (266 mg, 450.33 mol) in THF (2.6 mL) was added NH3H2O (2.6 mL). The mixture was stirred at 30 °C for 72 h and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (100 mg, 44%) as a white solid. MS (ESI): mass calcd. for C21H27F3N6O5: 500.20, found: 501.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.32 (s, 2H), 4.64 (s, 1H), 4.19-4.38 (m, 2H), 3.78 (q, J = 6.8 Hz, 2H), 2.88 (s, 3H), 2.15-2.46 (m, 7H), 1.86 (d, J = 11.6 Hz, 1H), 1.39 (t, J = 11.6 Hz, 3H), 1.24 (dt, J = 3.2, 13.2 Hz, 1H), 1.04 (t, J = 7.2 Hz, 3H). Example 20 and Example 21 were obtained from chiral SFC separation of Example 19 2-MeOH (0.1% NH3H220 (34.76 mg) from the first eluting peak and 21 (34.78 mg) from the second eluting peak. Example 22 was prepared in a similar route to Example 19, using propyl bromide instead of ethyl bromide. Example 23 and Example 24. were obtained from chiral SFC separation from Example 22 in a similar fashion to Example 20 and Example 21. Example 25. 5-(diaminomethylene)-1-(3-fluorobenzyl)-3-(3-methyl-2,4-dioxo-1-(2,2,2- trifluoroethyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)- trione (25) Synthetic scheme:

[0020] 1-(3-fluorobenzyl)-3-(3-methyl-2,4-dioxo-1-(2,2,2-trifluoroethyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)urea The title compound was prepared in a similar fashion to the urea synthesis in Example 19 using 1-fluoro-3-(isocyanatomethyl)benzene instead of 4-methoxybenzyl isocyanate. 1-(3-fluorobenzyl)-3-(3-methyl-2,4-dioxo-1-(2,2,2-trifluoroethyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione The title compound was prepared in a similar fashion to the barbiturate synthesis in Example 19. 5-(diaminomethylene)-1-(3-fluorobenzyl)-3-(3-methyl-2,4-dioxo-1-(2,2,2-trifluoroethyl)- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (25) The title compound was prepared in a similar fashion to the diaminomethylene synthesis in Example 1. MS (ESI): mass calcd. for C26H28F4N6O5: 580.21, found: 581.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.48 (s, 2H), 7.28-7.41 (m, 3H), 6.96-7.11 (m, 3H), 4.95 (s, 2H), 4.55-4.75 (m, 1H), 4.15-4.41 (m, 2H), 2.88 (s, 3H), 2.12-2.45 (m, 7H), 1.85 (d, J = 11.2 Hz, 1H), 1.34-1.48 (m, 3H), 1.17-1.32 (m, 1H). Example 26 and Example 27. were obtained through chiral SFC separation of Example 25 to provide 26 as the first eluting peak and 27 as the second eluting peak. The stereochemistry for these two compounds is arbitrarily assigned. Example 28 was synthesized in a similar procedure to the one described in Example 25. 4- nitrophenyl ((2-methylpyridin-4-yl)methyl)carbamate was used instead of 1-fluoro-3- (isocyanatomethyl)benzene. Example 29 and Example 30 were obtained from the chiral SFC separation of Example 28. The stereochemistry for these two compounds is arbitrarily assigned. Example 31 was synthesized in a similar procedure to the one described in Example 25. Isopropyl isocyanate was used instead of 1-fluoro-3-(isocyanatomethyl)benzene. Example 32 and Example 33 were obtained from the chiral SFC separation of Example 31. The stereochemistry for these two compounds is arbitrarily assigned. Example 34 was synthesized in a similar procedure to the one described in Example 25. 4- nitrophenyl (cyclopentylmethyl)carbamate was used instead of 1-fluoro-3- (isocyanatomethyl)benzene. Example 35 and Example 36 were obtained from the chiral SFC separation of Example 34. The stereochemistry for these two compounds is arbitrarily assigned. Example 37 was synthesized in a similar procedure to the one described in Example 25. (isocyanatomethyl)cyclopropane was used instead of 1-fluoro-3-(isocyanatomethyl)benzene. Example 38 and Example 39 were obtained from the chiral SFC separation of Example 37. The stereochemistry for these two compounds is arbitrarily assigned. Example 40 and Example 41.1-butyl-5-(diaminomethylene)-3-((5S,7r,10S)-3-methyl-2,4- dioxo-1-(((S)-tetrahydrofuran-2-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (40) 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)- 3-methyl-2,4-dioxo-1-(((R)-tetrahydrofuran-2-yl)methyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (41) Synthetic scheme: 11,14-Dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione To a mixture of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (15 g, 76.4 mmol) in MeOH (150 mL) and H2O (150 mL) was added TMSCN (15.17 g, 152.9 mmol) and (NH4)2CO3(29.38 g, 305.7 mmol) in one portion at 25 °C under N2. After heating at 90 °C for 12 h, the reaction was concentrated under reduced pressure to remove MeOH. The precipitate was collected by filtration, washed with H2O (3 x 100 mL) and dried under vacuum to provide the title compound (13.65 g, 67.1%) as a white solid, which was used directly in the next step without further purification.1H NMR (400 MHz, DMSO-d6) ppm 8.38 (s, 1H), 3.83 (s, 4H), 2.27 (d, J = 13.6 Hz, 2H), 1.95 (d, J = 13.6 Hz, 2H), 1.68-1.77 (m, 2H), 1.63 (t, J = 6.4 Hz, 2H), 1.43- 1.48 (m, 4H). 2-Methyl-11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione To a mixture of 11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione (6 g, 22.5 mmol) in DMF (50 mL) was added MeI (3.52 g, 24.8 mmol) and K2CO3(3.43 g, 24.8 mmol) in one portion at 0 °C under N2. The reaction was stirred at 25 °C for 12 h. After completion, the crude residue was poured into water (20 mL) and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layer was washed with brine (3 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 20 : 1 to 0 : 1) to afford the title compound (5.99 g, 94.8%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 8.65 (s, 1H), 3.83 (s, 4H), 2.79 (s, 3H), 2.27 (d, J = 12.8 Hz, 2H), 1.97 (d, J = 13.6 Hz, 2H), 1.75 (m, 1.71-1.79, 2H), 1.64 (t, J = 6.4 Hz, 2H), 1.43-1.48 (m, 4H). 2-Methyl-2,4-diazadispiro[4.1.57.15]tridecane-1,3,10-trione To a mixture of 2-methyl-11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane- 1,3-dione (5.99 g, 21.4 mmol) in acetone (40 mL) and H2O (20 mL) was added TsOH.H2O (8.13 g, 42.7 mmol) in one portion at 25 °C under N2. After stirring for 12 h, the mixture was poured into water (50 mL). The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 10 : 1 to 0 : 1) to afford the title compound (3.19 g, 63.2%) as a white solid. 10-Amino-2-methyl-2,4-diazadispiro[4.1.57.15]tridecane-1,3-dione To a mixture of 2-methyl-2,4-diazadispiro[4.1.57.15]tridecane-1,3,10-trione (3.19 g, 13.5 mmol) in MeOH (30 mL) was added ammonia (7 M in MeOH, 19.29 mL) at 25 °C. After stirring for 1 h, 10% Pd / C (502.9 mg) was added in one portion. The reaction was stirred at 25 °C for 3 h under H2(15 Psi). Then it was filtered though a Celite pad and the filtrate was concentrated under reduced pressure to provide the title compound (3 g) as a white solid, which was used in the next step without further purification. 1-Butyl-3-(3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)urea To a mixture of 10-amino-2-methyl-2,4-diazadispiro[4.1.57.15]tridecane-1,3-dione (3 g, 12.6 mmol) in DCM (30 mL) was added 1-isocyanatobutane (1.25 g, 12.6 mmol), followed by addition of TEA (1.28 g, 12.6 mmol) at 25 °C under N2. After stirring for 30 min, H2O (20 mL) was added and the reaction was extracted with DCM (3 x 15 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 5 : 1 to 0 : 1) to provide the title compound (2.7 g, 6%) as a white solid. MS (ESI): mass calcd. for C17H28N4O3: 336.22, found: 337.2 [M+H]+. 1-Butyl-3-(3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6-trione To a mixture of 1-butyl-3-(2-methyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10- yl)urea (2.6 g, 7.7 mmol) and malonic acid (804.2 mg, 7.3 mmol) in AcOH (25 mL) was added Ac2O (5.52 g, 54.1 mmol) in one portion at 25 °C under N2. After heating at 80 °C for 4 h, the reaction was poured into water (30 mL) and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 20 : 1 to 1 : 1) to provide the title compound (2.3 g, 73.6%) as a yellow oil. MS (ESI): mass calcd. for C20H28N4O5: 404.21, found: 405.2 [M+H]+. 1-Butyl-5-(diaminomethylene)-3-(2-methyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan- 10-yl)hexahydropyrimidine-2,4,6-trione To a mixture of 1-butyl-3-(2-methyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10- yl)hexahydropyrimidine-2,4,6-trione (2.3 g, 5.7 mmol) and cyanamide (2.39 g, 56.9 mmol) in THF (25 mL) was added Ni(acac)2(438.3 mg, 1.7 mmol) at 25 °C under N2. After heating at 80 °C for 12 h, the reaction was filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the crude residue was purified by reverse phase HPLC to provide the title compound (0.45 g, 17.7%) as a white solid. MS (ESI): mass calcd. for C21H30N6O5: 446.23, found: 447.2 [M+H]+. 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione 1-Butyl-5-(diaminomethylene)-3-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (0.23 g, 0.52 mmol) mobile phase: CO2-MeOH (0.1% NH3H2compound (0.064 g, 27.8%, second-eluting peak) as a white solid. MS (ESI): mass calcd. for C21H30N6O5: 446.23, found: 447.2 [M+H]+. 1-butyl-5-(diaminomethylene)-3-[2-methyl-1,3-dioxo-4-(tetrahydrofuran-2-ylmethyl)- 2,4-diazadispiro[4.1.57.15] tridecan-10-yl]hexahydropyrimidine-2,4,6-trione To a solution of 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (200 mg, 447.9 mol) in DMF (2 mL) was added Cs2CO3(437.83 mg, 1.34 mmol) and 2- (bromomethyl)tetrahydrofuran (88.71 mg, 537.5 mol) at 25 °C. The mixture was stirred at 50 °C for 16 h. The reaction was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (10 mg, 50%) as a white solid. MS (ESI): mass calcd. for C26H38N6O6: 530.29, found: 531.4 [M+H]+. 1-butyl-5-(diaminomethylene)-3-((5S,7r,10S)-3-methyl-2,4-dioxo-1-(((S)- tetrahydrofuran-2-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (40) and 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl- 2,4-dioxo-1-(((R)-tetrahydrofuran-2-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (41)

[0021] 1-butyl-5-(diaminomethylene)-3-[2-methyl-1,3-dioxo-4-(tetrahydrofuran-2-ylmethyl)- 2,4-diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (10 mg) was phase: CO2-IPA (0.1% NH3H2to give 40 (1.77 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C26H38N6O6: 530.29, found: 531.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.53 (s, 2H), 7.34 (s, 2H), 4.56-4.69 (m, 1H), 4.05-4.15 (m, 1H), 3.63-3.80 (m, 3H), 3.51 (dd, J = 3.6, 14.8 Hz, 1H), 3.25 (d, J = 8.0 Hz, 2H), 2.84 (s, 3H), 2.40-2.45 (m, 2H), 2.18-2.30 (m, 3H), 2.13 (d, J = 12.4 Hz, 1H), 1.91-2.02 (m, 1H), 1.77-1.89 (m, 3H), 1.53-1.63 (m, 1H), 1.35-1.49 (m, 5H), 1.19-1.30 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H). 41 (2.32 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C26H38N6O6: 530.29, found: 531.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.35 (s, 2H), 4.56-4.72 (m, 1H), 4.12 (qd, J = 3.6, 7.2 Hz, 1H), 3.61-3.82 (m, 3H), 3.50 (dd, J = 3.6, 15.2, Hz, 1H), 3.26-3.29 (m, 2H), 2.85 (s, 3H), 2.44 (d, J = 12.6 Hz, 2H), 2.19-2.31 (m, 3H), 2.13 (d, J = 12.8 Hz, 1H), 1.91-2.02 (m, 1H), 1.77-1.91 (m, 3H), 1.54-1.64 (m, 1H), 1.35-1.50 (m, 5H), 1.22-1.31 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H). The stereochemistry for these two compounds is arbitrarily assigned. Example 42. 5-(diaminomethylene)-1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4-fluorobenzyl)pyrimidine-2,4,6(1H,3H,5H)- trione (42) Synthetic scheme:

[0022] (5S,7s,10S)-10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione and (5R,7r,10R)-10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione 10-amino-2,4-dimethyl-2,4-diazadispiro[4.1.57.15]tridecane-1,3-dione was prepared using a similar synthetic sequence to the corresponding amine 10-amino-3-methyl-1-(2,2,2- trifluoroethyl)-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione in Example 19, using iodomethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate. 10-amino-2,4- dimethyl-2,4-diazadispiro[4.1.57.15]tridecane-1,3-dione (8.5 g) was separated by chiral SFC -EtOH (0.1% NH3H2(5S,7s,10S)-10-amino-1,3-dimethyl- 1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione (3.8 g) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C13H21N3O2: 251.16, found: 252.0 [M+H]+. (5R,7r,10R)-10- amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione (3.8 g) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C13H21N3O2: 251.16, found: 251.9 [M+H]+. 1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4- fluorobenzyl)urea To a solution of (5S,7s,10S)-10-amino-1,3-dimethyl-1,3- diazadispiro[4.1.57.15]tridecane-2,4-dione (100 mg, 397.9 mol) in DCM (1.5 mL) was added TEA (40.26 mg, 397.9 mol) and 1-fluoro-4-(isocyanatomethyl)benzene (66.15 mg, 437.7 mol). The mixture was stirred at 20 °C for 1 h under N2. The reaction was quenched with H2O (20 mL) and extracted with DCM (25 mL x 2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, DCM : MeOH = 10 : 1) to give the title compound (80 mg, 48%) as a colorless oil. MS (ESI): mass calcd. for C21H27N4O3F: 402.21, found: 403.1 [M+H]+. 1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4- fluorobenzyl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of Ac2O (0.3 mL) in AcOH (0.3 mL) was added malonic acid (15.5 mg, 149 mol). The mixture was stirred at 20 °C for 0.5 h.1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4-fluorobenzyl)urea (60 mg, 149 mol) was added to the mixture. After heating at 80 °C for 1 h, the reaction was quenched with H2O (15 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with H2O, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether : ethyl acetate = 1 : 1) to give the title compound (40 mg, 52%) as a colorless oil. MS (ESI): mass calcd. for C24H27N4O5F: 470.20, found: 471.2 [M+H]+. 5-(diaminomethylene)-1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4-fluorobenzyl)pyrimidine-2,4,6(1H,3H,5H)- trione

[0023] To a solution of 1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4-fluorobenzyl)pyrimidine-2,4,6(1H,3H,5H)-trione (40 mg, 85 mol) in THF (1.5 mL) was added cyanamide (107.22 mg, 2.55 mmol) and Ni(acac)2 (21.84 mg, 85 mol). The mixture was stirred at 80 °C for 16 h under N2. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC to give the title compound (15.8 mg, 36%) as a white solid. MS (ESI): mass calcd. for C25H29N6O5F: 512.22, found: 513.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.49 (s, 2H), 7.35 (s, 2H), 7.30 (dd, J = 5.6, 8.4 Hz, 2H), 7.12 (t, J = 8.8 Hz, 2H), 4.92 (s, 2H), 4.56-4.75 (m, 1H), 2.95 (s, 3H), 2.84 (s, 3H), 2.40-2.44 (m, 2H), 2.20-2.32(m, 3H), 2.05-2.19 (m, 2H), 1.76-1.88 (m,Example 43 was synthesized in a similar route to the one described in Example 42. (2- isocyanatoethyl)benzene was used instead of 1-fluoro-4-(isocyanatomethyl)benzene, and a racemic mixture of 10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione was used in the urea synthesis. Example 44 and Example 45 were obtained from the chiral SFC separation of Example 43. The stereochemistry for these two compounds is arbitrarily assigned. Example 46. 5-(diaminomethylene)-1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(2-fluorobenzyl)pyrimidine-2,4,6(1H,3H,5H)- trione (46) Synthetic scheme: (4-nitrophenyl) N-[(2-fluorophenyl)methyl]carbamate To a solution of (2-fluorophenyl)methanamine (80 mg, 639 mol) in DCM (1.6 mL) was added pyridine (101.1 mg, 1.28 mmol), DMAP (78.10 mg, 639.3 mol) and (4- nitrophenyl) chloroformate (128.85 mg, 639.3 mol). The mixture was stirred at 25 °C for 1 h and concentrated under reduced pressure to obtain the title compound (176 mg, crude) as a white liquid, which was used directly in the next step. 1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(2- fluorobenzyl)urea To a solution of (4-nitrophenyl) N-[(2-fluorophenyl)methyl]carbamate (175.54 mg, 604.8 mol) in DCM (1 mL) was added TEA (61.2 mg, 605 mol) and (5S,7s,10S)-10-amino- 1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione (76 mg, 302 mol) was added. The mixture was stirred at 25 °C for 12 h. The reaction was quenched with H2O (10 mL) and extracted with DCM (20 mL x 3). The combined organic layer was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with saturated Na2CO3, saturated NHCl4and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether : ethyl acetate = 0 : 1) to give the title compound (90 mg, 74%) as a white solid. MS (ESI): mass calcd. for C21H27N4O3F: 402.21, found: 403.3 [M+H]+. 1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(2- fluorobenzyl)pyrimidine-2,4,6(1H,3H,5H)-trione The title compound was obtained in a similar fashion to 1-((5S,7s,10S)-1,3-dimethyl- 2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4-fluorobenzyl)pyrimidine- 2,4,6(1H,3H,5H)-trione in Example 42. 5-(diaminomethylene)-1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(2-fluorobenzyl)pyrimidine-2,4,6(1H,3H,5H)- trione (46) The title compound was obtained in a similar fashion to final step of Example 42 as a white solid. MS (ESI): mass calcd. for C25H29N6O5F: 512.22, found: 513.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.47 (s, 2H), 7.36 (s, 2H), 7.24-7.31 (m, 1H), 7.08-7.20 (m, 2H), 6.99-7.06 (m, 1H), 5.00 (s, 2H), 4.55-4.73 (m, 1H), 2.94 (s, 3H), 2.83 (s, 3H), 2.27-2.45 (m, 3H), 2.20-2.26 (m, 2H), 2.05-2.19 (m, 2H), 1.82 (d, J = 10.8 Hz, 1H), 1.37-1.51 (m, 3H), 1.20- 1.33 (m, 1H). Example 47 was synthesized in a similar route to the one described in Example 46. (S)- (tetrahydrofuran-2-yl)methanamine was used instead of (2-fluorophenyl)methanamine. Example 48 and Example 49 were synthesized in a similar route to the one described in Example 46.2-cyclopentylethan-1-amine was used instead of (2-fluorophenyl)methanamine, and a racemic mixture of 10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4- dione was used in the urea synthesis. The final compounds were separated by chiral SFC. The stereochemistry for these two compounds is arbitrarily assigned. Example 50 was synthesized in a similar route to the one described in Example 46. 3,3- dimethylbutan-1-amine was used instead of (2-fluorophenyl)methanamine, and a racemic mixture of 10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione was used in the urea synthesis. Example 51 and Example 52 were obtained from the chiral SFC separation of Example 50. The stereochemistry for these two compounds is arbitrarily assigned. Example 53 was synthesized in a similar route to the one described in Example 46. Cyclohexylmethanamine was used instead of (2-fluorophenyl)methanamine, and a racemic mixture of 10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione was used in the urea synthesis. Example 54 and Example 55 were obtained from the chiral SFC separation of Example 53. The stereochemistry for these two compounds is arbitrarily assigned. Example 56 was synthesized in a similar route to the one described in Example 46. Cyclopropylmethanamine was used instead of (2-fluorophenyl)methanamine, and a racemic mixture of 10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione was used in the urea synthesis. Example 8 and Example 9 were obtained from the chiral SFC separation of Example 56 using similar conditions to those reported for Example 26 and Example 27. The stereochemistry for these two compounds is arbitrarily assigned. Example 57 was synthesized in a similar route to the one described in Example 42. Benzyl isocyante was used instead of 1-fluoro-4-(isocyanatomethyl)benzene, and a racemic mixture of 10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione was used in the urea synthesis. Example 58 and Example 59 were obtained from the chiral SFC separation of Example 57. The stereochemistry for these two compounds is arbitrarily assigned. Example 60. 1-(bicyclo[1.1.1]pentan-1-ylmethyl)-5-(diaminomethylene)-3-(3-methyl-2,4- dioxo-1-(2,2,2-trifluoroethyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (60) Synthetic scheme:

[0024] bicyclo[1.1.1]pentane-1-carboxamide To a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (1 g, 8.92 mmol) in DCM (10 mL) was added SOCl2(1.91 g, 16.05 mmol). The mixture was stirred at 45 °C for 16 h under N2. NH3.H2O (89.2 mmol, 13.74 mL, 25% in water) was added to the above mixture at 0 °C. The mixture was stirred at 0 °C for 1 h under N2 and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (940 mg, 94.8%) as a white solid, which was used directly in next step.1H NMR (400 MHz, DMSO-d6) ppm 7.16 (s, 1H), 6.84 (s, 1H), 2.37 (s, 1H), 1.91 (s, 6H). 1-bicyclo[1.1.1]pentanylmethanamine To a solution of bicyclo[1.1.1]pentane-1-carboxamide (940 mg, 8.46 mmol) in THF (9.4 mL) was added BH3.THF (1 M, 25.37 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 4 h. To the mixture was added MeOH (9.4 mL) dropwise and the reaction was stirred at 0 °C for 30 min. HCl (1 N, 25.38 mL) was added and stirred for 30 min. The mixture was concentrated under reduced pressure to give the title compound (1.8 g, crude) as a white solid, which was used in the next step directly.1H NMR (400 MHz, DMSO-d6) ppm 8.01 (s, 2H), 2.79-2.84 (m, 2H), 1.90 (s, 1H), 1.73-1.80 (m, 6H). 4-nitrophenyl (bicyclo[1.1.1]pentan-1-ylmethyl)carbamate The title compound was obtained from a similar sequence to (4-nitrophenyl) N-[(2- fluorophenyl)methyl]carbamate in Example 43. 1-bicyclo[1.1.1]pentanylmethanamine was used in place of (2-fluorophenyl)methanamine 1-(bicyclo[1.1.1]pentan-1-ylmethyl)-3-(3-methyl-2,4-dioxo-1-(2,2,2-trifluoroethyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)urea The title compound was obtained from a similar procedure to 1-((5S,7s,10S)-1,3- dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(2-fluorobenzyl)urea in Example 43.4-nitrophenyl (bicyclo[1.1.1]pentan-1-ylmethyl)carbamate was used in place of (4-nitrophenyl) N-[(2-fluorophenyl)methyl]carbamate. 1-(bicyclo[1.1.1]pentan-1-ylmethyl)-3-(3-methyl-2,4-dioxo-1-(2,2,2-trifluoroethyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione The title compound was obtained from a similar procedure to 1-((5S,7s,10S)-1,3- dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(2-fluorobenzyl)pyrimidine- 2,4,6(1H,3H,5H)-trione in Example 43. 1-(bicyclo[1.1.1]pentan-1-ylmethyl)-5-(diaminomethylene)-3-(3-methyl-2,4-dioxo-1- (2,2,2-trifluoroethyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (60) The tile compound was obtained from a similar procedure to the final step of Example 43 as a white solid. MS (ESI): mass calcd. for C25H31F3N6O5: 552.23, found: 553.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.53 (s, 2H), 7.30 (s, 2H), 4.55-4.75 (m, 1H), 4.19-4.41 (m, 2H), 3.82 (s, 2H), 2.88 (s, 3H), 2.45 (s, 1H), 2.37 (s, 1H), 2.33 (s, 1H), 2.26-2.31 (m, 3H), 2.17-2.26 (m, 2H), 1.86 (d, J = 12.4 Hz, 1H), 1.60 (s, 6H), 1.32-1.45 (m, 3H), 1.20-1.31 (m, 1H). Example 61 and Example 62 were obtained from the chiral SFC separation of Example 44 using similar conditions to those reported for Example 26 and Example 27. Example 63. 5-(diaminomethylene)-1-((3,3-dimethylcyclobutyl)methyl)-3-((5R,7r,10R)- 3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (63) Synthetic scheme:

[0025] 3-methyl-1-(oxetan-3-ylmethyl)-1,3-diazadispiro[4.1.57.15]tridecane-2,4,10-trione To a solution of 2-methyl-2,4-diazadispiro[4.1.57.15]tridecane-1,3,10-trione (50 g, 211.63 mmol) in DMF (500 mL) was added 3-(iodomethyl)oxetane (46.09 g, 232.8 mmol) and Cs2CO3 (137.9 g, 423.3 mmol). The mixture was stirred at 40 °C for 12 h under N2. The mixture was poured into water (2 L) and extracted with ethyl acetate (1 L x 2). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 5 : 1 to 0 : 1) to give the title compound (44 g, 68%) as a white solid. MS (ESI): mass calcd. for C16H22N2O4: 306.16, found: 307.1 [M+H]+. 10-amino-3-methyl-1-(oxetan-3-ylmethyl)-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione Three reactions were carried out in parallel. To a solution of 2-methyl-4-(oxetan-3- ylmethyl)-2,4-diazadispiro[4.1.57.15]tridecane-1,3,10-trione (22 g, 71.81 mmol) in NH3 / MeOH (200 mL) was added Raney-Ni (6.15 g, 71.81 mmol) under N2. The suspension was degassed and purged with H23 times. The mixture was stirred under H2(15 psi) at 25 °C for 12 h. The three parallel reactions were combined and worked-up together. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the title compound (65 g, crude) as a green oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C16H25N3O3: 307.19, found: 308.1 [M+H]+. 1-(3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)urea To a solution of 10-amino-2-methyl-4-(oxetan-3-ylmethyl)-2,4- diazadispiro[4.1.57.15]tridecane-1,3-dione (41 g, 133.4 mmol) in DCM (440 mL) was added TEA (44.54 g, 440.16 mmol) and isocyanato(trimethyl)silane (33.81 g, 293.44 mmol). The mixture was stirred at 30 °C for 12 h under N2and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, ethyl acetate : methanol = 50 : 1to 10 : 1) to give the title compound (45 g, 96%) as a white solid. MS (ESI): mass calcd. for C17H26N4O4: 350.20, found: 351.1 [M+H]+. 1-(3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of [2-methyl-4-(oxetan-3-ylmethyl)-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl]urea (30 g, 85.61 mmol) in EtOH (300 mL) was added diethyl propanedioate (17.83 g, 111.3 mmol) and EtONa (43.7 g, 128.42 mmol, 20% purity). The mixture was stirred at 85 °C for 12 h. After cooled to room temperature, the mixture was poured into water (1 L), adjusted the pH = 4 using citric acid (1 M) and extracted with ethyl acetate (1 L x 2). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether (50 mL) to give the title compound (30 g) as a white solid, which was used in the next step without further purification. MS (ESI): mass calcd. for C20H26N4O6: 418.19, found: 419.2 [M+H]+. 5-(bis(ethylthio)methylene)-1-(3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-[2-methyl-4-(oxetan-3-ylmethyl)-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (60 g, 0.14 mol) in DMSO (600 mL) was added TEA (84.5 g, 0.84 mol) and CS2(31.9 g, 0.42 mol). After stirring at 25 °C for 1 h, bromoethane (90.68 g, 0.84 mol) was added. After stirring at 25 °C for 6 h, the reaction was poured into water (2 L) and extracted with ethyl acetate (2 L x 2). 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 = 5 : 1 to 0 : 1) to give the title compound (32 g, 41%) as a yellow solid. MS (ESI): mass calcd. for C25H34N4O6S2: 550.19, found: 551.3 [M+H]+. 5-(bis(ethylthio)methylene)-1-((5R,7r,10R)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 5- (bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione 5-[bis(ethylsulfanyl)methylene]-1-[2-methyl-4-(oxetan-3-ylmethyl)-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (32 g) was separatedCO2- to give 5-[bis(ethylsulfanyl)methylene]-1-[2-methyl-4-(oxetan-3-ylmethyl)-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione (14.19 g) from the first eluting peak as a yellow solid. MS (ESI): mass calcd. for C25H34N4O6S2: 550.19, found: 551.2 [M+H]+. 5- [bis(ethylsulfanyl)methylene]-1-[2-methyl-4-(oxetan-3-ylmethyl)-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (16.71 g) was obtained from the second eluting peak as a yellow solid. MS (ESI): mass calcd. for C25H34N4O6S2: 550.19, found: 551.2 [M+H]+. 5-(bis(ethylthio)methylene)-1-((3,3-dimethylcyclobutyl)methyl)-3-((5R,7r,10R)-3- methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a mixture of 5-(bis(ethylthio)methylene)-1-((5R,7r,10R)-3-methyl-1-(oxetan-3- ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)- trione (70 mg, 127.1 mol) in DMF (0.7 mL) was added 3-(bromomethyl)-1,1-dimethyl- cyclobutane (27.01 mg, 152.5 mol) and K2CO3(35.14 mg, 254.2 mol). The mixture was stirred at 25 °C for 12 h. After completion, the mixture was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (80 mg), which was used directly in the next step without further purification. MS (ESI): mass calcd. for C32H46N4O6S2: 646.29, found: 647.3 [M+H]+. 5-(diaminomethylene)-1-((3,3-dimethylcyclobutyl)methyl)-3-((5R,7r,10R)-3-methyl-1- (oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (63) To a mixture of 5-(bis(ethylthio)methylene)-1-((3,3-dimethylcyclobutyl)methyl)-3- ((5R,7r,10R)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan- 10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (80 mg, 123.7 mol) in NH4OH (25% NH3in water) (1 mL) was added THF (0.5 mL). The mixture was stirred at 40 °C for 36 h and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (38.2 mg, 55%) as a white solid. MS (ESI): mass calcd. for C28H40N6O6: 556.30, found: 557.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.53 (s, 2H), 7.30 (s, 2H), 4.57-4.69 (m, 3H), 4.39-4.45 (m, 2H), 3.80 (d, J = 7.2 Hz, 2H), 3.66 (d, J = 7.2 Hz, 2H), 3.35 (s, 1H), 2.82 (s, 3H), 2.43-2.48 (m, 2H), 2.32-2.39 (m, 1H), 2.21-2.29 (m, 2H), 2.11-2.19 (m, 3H), 1.84 (d, J = 10.4 Hz, 1H), 1.65-1.72 (m, 2H), 1.52-1.59 (m, 2H), 1.34-1.46 (m, 3H), 1.20-1.27 (m, 1H), 1.06 (s, 3H), 1.02 (s, 3H). Example 64 was synthesized in a similar route to the one described in Example 63. 5- (bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione was used instead of 5-(bis(ethylthio)methylene)-1-((5R,7r,10R)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione. Example 65 was synthesized in a similar route to the one described in Example 46. Cyclobutylmethanamine was used instead of (2-fluorophenyl)methanamine for the first step, and 10-amino-3-methyl-1-(oxetan-3-ylmethyl)-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione was used instead of (5S,7s,10S)-10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane- 2,4-dione for the second step. Example 66 and Example 67 were obtained from the chiral SFC separation of Example 65 using similar conditions to those reported for Example 26 and Example 27. Example 68 was synthesized in a similar route to the one described in Example 46. Cyclopropylmethanamine was used instead of (2-fluorophenyl)methanamine for the first step, and 10-amino-3-methyl-1-(oxetan-3-ylmethyl)-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione was used instead of (5S,7s,10S)-10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane- 2,4-dione for the second step. Example 69 and Example 70 were obtained from the chiral SFC separation of Example 68 using similar conditions to those reported for Example 26 and Example 27. Example 71 was synthesized in a similar route to the one described in Example 46. Cyclopentylmethanamine was used instead of (2-fluorophenyl)methanamine for the first step, and 10-amino-3-methyl-1-(oxetan-3-ylmethyl)-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione was used instead of (5S,7s,10S)-10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane- 2,4-dione for the second step. Example 72 and Example 73 were obtained from the chiral SFC separation of Example 71 using similar conditions to those reported for Example 26 and Example 27. Example 74 was synthesized in a similar route to the one described in Example 63, using 5- (bis(ethylthio)methylene)-1-((5R,7r,10R)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 1- (bromomethyl)-1-methylcyclobutane. Example 75 was synthesized in a similar route to the one described in Example 63, using 5- (bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 1- (bromomethyl)-1-methylcyclobutane. Example 76 was synthesized in a similar route to the one described in Example 63, using 5- (bis(ethylthio)methylene)-1-((5R,7r,10R)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 1- bromopentane. Example 77 was synthesized in a similar route to the one described in Example 63, using 5- (bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 1- bromopentane. Example 78 was synthesized in a similar route to the one described in Example 63, using 5- (bis(ethylthio)methylene)-1-((5R,7r,10R)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 2- bromoethyl)cyclopropane. Example 79 was synthesized in a similar route to the one described in Example 63, using 5- (bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 2- bromoethyl)cyclopropane. Example 80 was synthesized in a similar route to the one described in Example 63, using 5- (bis(ethylthio)methylene)-1-((5R,7r,10R)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 1-bromo-3- methylbutane. Example 81 was synthesized in a similar route to the one described in Example 63, using 5- (bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 1-bromo-3- methylbutane. Example 82 was synthesized in a similar route to the one described in Example 63, using 5- (bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 2-bromoethyl- 1-methylsulfone. Example 83: 5-(diaminomethylene)-1-(2-ethoxyethyl)-3-((5S,7s,10S)-3-methyl-1-(oxetan- 3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (83) Synthetic scheme: 2-Ethoxyethyl 4-methylbenzenesulfonate To a solution of 2-ethoxyethanol (215 μL, 2.22 mmol) in DCM (3.2 mL) was added triethylamine (619 μL, 4.44 mmol) followed by p-toluenesulfonyl chloride (518 mg, 2.66 mmol) and the solution was stirred at rt for 16 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution and diluted with DCM. The layer was separated, and the aqueous layer was extracted with DCM (3x). The combined organic layer was washed with water, dried over Na2SO4, filtered, and concentrated to give the title compound (300 mg), which was used directly in the next step.1H NMR (400 MHz, CDCl3) 7.78 – 7.83 (m, 2H), 7.32 – 7.36 (m, 2H), 4.15 (dd, J = 5.4, 4.3 Hz, 2H), 3.61 (dd, J = 5.5, 4.2 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 2.44 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H). 5-(bis(ethylthio)methylene)-1-(2-ethoxyethyl)-3-((5S,7s,10S)-3-methyl-1-(oxetan-3- ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 5-(bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3- ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-((1- methylcyclobutyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (50 mg, 91 μmol) in DMF (2.0 mL) was added 2-ethoxyethyl 4-methylbenzenesulfonate (111 mg, 454 μmol) followed by potassium carbonate (62.7 mg, 454 μmol) and the suspension was stirred at rt for 16 h. The reaction was quenched with the addition of water (5 mL) and diluted with EtOAc. The layer was separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated to provide the title compound (56 mg, 99%), which was used directly for the next step. MS (ESI): mass calcd. for C29H42N4O7S2: 622.25, found: 623.3 [M+H]+. 3-{(5S,7S,10S)-3-methyl-1-[(3-oxetanyl)methyl]-2,4-dioxo-1,3-diaza-10- dispiro[4.1.5.1]tridecyl}-5-diaminomethylene-1-(2-ethoxyethyl)-2,4,6(1H,3H,5H)- pyrimidinetrione (83)

[0026] To a solution of 5-(bis(ethylthio)methylene)-1-(2-ethoxyethyl)-3-((5S,7s,10S)-3- methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (56 mg, 89.9 μmol) in THF (450 μL) was added ammonium hydroxide (28%, 125 μL, 899 μmol) and the reaction was stirred at 45 °C for 60 h. The reaction was quenched with the addition of water (5 mL) and diluted with EtOAc. The layer was separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (C18, 50% MeCN / 10 mM AmF buffer) to provide the title compound (7.0 mg, 14%) as a white solid. MS (ESI): mass calcd. for C25H36N6O7: 532.26, found: 533.2 [M+H]+.1H NMR (400 MHz, DMSO) 9.51 (s, 2H), 7.35 (s, 2H), 4.58 – 4.67 (m, 3H), 4.42 (dd, J = 11.0, 6.1 Hz, 2H), 3.91 (t, J = 6.2 Hz, 2H), 3.66 (d, J = 7.3 Hz, 2H), 3.38 – 3.47 (m, 4H), 3.25 – 3.32 (m, 1H), 2.82 (s, 3H), 2.19 – 2.42 (m, 4H), 2.06 – 2.19 (m, 3H), 1.84 (d, J = 11.3 Hz, 1H), 1.31 – 1.48 (m, 3H), 1.23 (t, J = 11.8 Hz, 1H), 1.06 (t, J = 7.0 Hz, 3H). Example 84: 1-{(5S,7S,10S)-3-methyl-1-[(3-oxetanyl)methyl]-2,4-dioxo-1,3-diaza-10- dispiro[4.1.5.1]tridecyl}-5-diaminomethylene-3-[(3,3-difluorocyclopentyl)methyl]- 2,4,6(1H,3H,5H)-pyrimidinetrione (84)

[0027] Synthetic scheme: (3,3-difluorocyclopentyl)methyl 4-methylbenzenesulfonate To a solution of (3,3-difluorocyclopentyl)methanol (210 mg, 1.54 mmol) in DCM (6 mL) at 0 °C was added 4-dimethylaminopyridine (212 mg, 1.7 mmol) followed by p- toluenesulfonyl chloride (300 mg, 1.54 mmol). The mixture was stirred for 10 min and warmed to ambient temperature and stirred for another 16 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (5 mL) and diluted with DCM. The layer was separated, and the aqueous layer was extracted with DCM (3x). The combined organic layer was washed with water, dried over Na2SO4, filtered, and concentrated and used as such in the next step. 1,1-difluoro-3-(iodomethyl)cyclopentane To a solution of (3,3-difluorocyclopentyl)methyl 4-methylbenzenesulfonate (440 mg, 1.52 mmol) in acetone (6 mL) was added sodium iodide (769 mg, 5.11 mmol) and the reaction was heated to 60 °C and stirred for 16 h. The reaction was filtered and concentrated to give the title compound (200 mg), which was used directly in the next step.1H NMR (400 MHz, CDCl3) 3.22 (d, J = 6.6 Hz, 2H), 2.20 – 2.46 (m, 3H), 1.98 – 2.15 (m, 2H), 1.74 – 1.91 (m, 1H), 1.47 – 1.55 (m, 1H). 5-(bis(ethylthio)methylene)-1-((3,3-difluorocyclopentyl)methyl)-3-((5S,7s,10S)-3-methyl- 1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 5-(bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3- ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)- trione (50 mg, 90.8 μmol) in DMF (2.0 mL) at rt was added 1,1-difluoro-3- (iodomethyl)cyclopentane (78.2 mg, 318 μmol) followed by potassium carbonate (62.7 mg, 454 μmol) and the suspension was stirred for 16 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (5 mL) and diluted with EtOAc. The layer was separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to provide the crude title compound (60 mg), which was used directly for the next step. 1-{(5S,7S,10S)-3-methyl-1-[(3-oxetanyl)methyl]-2,4-dioxo-1,3-diaza-10- dispiro[4.1.5.1]tridecyl}-5-diaminomethylene-3-[(3,3-difluorocyclopentyl)methyl]- 2,4,6(1H,3H,5H)-pyrimidinetrione (84)

[0028] To a solution of 5-(bis(ethylthio)methylene)-1-((3,3-difluorocyclopentyl)methyl)-3- ((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan- 10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (60 mg, 89.7 μmol) in THF (449 μL) was added ammonium hydroxide ( 28%, 125 μL, 897 μmol) and the reaction was stirred at 45 °C for 60 h. The reaction was quenched with water (5 mL), diluted with EtOAc, and extracted with EtOAc (3x). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (C18, 50% MeCN / 10 mM AmF buffer) to provide the title compound (20.0 mg, 37%) as a white solid. MS (ESI): mass calcd. for C27H36F2N6O6: 578.27, found: 579.2 [M+H]+.1H NMR (400 MHz, DMSO) 9.52 (s, 2H), 7.33 (s, 2H), 4.66 – 4.70 (m, 1H), 4.63 (dd, J = 7.8, 6.2 Hz, 2H), 4.42 (dd, J = 11.0, 6.2 Hz, 2H), 3.77 – 3.82 (m, 2H), 3.66 (d, J = 7.3 Hz, 2H), 3.25 – 3.33 (m, 1H), 2.82 (s, 3H), 2.19 – 2.47 (m, 5H), 2.08 – 2.19 (m, 5H), 1.71 – 2.08 (m, 4H), 1.34 – 1.54 (m, 4H), 1.23 (t, J = 12.2 Hz, 1H) Example 85 was synthesized following the same sequence of steps as in Example 83 by using 3-methyl-1-pentanol as starting material instead of 2-ethoxyethanol. Example 86 was synthesized following the same sequence of steps as in Example 83 by using (3-ethylcyclobutyl)methanol (as a mixture of cis / trans isomers) as starting material instead of 2-ethoxyethanol. Example 87 was synthesized following the same sequence of steps as in Example 83 by using (spiro[2.3]hexan-4-yl)methanol as starting material instead of 2-ethoxyethanol. Example 88 was synthesized in a similar route to the one described in Example 63, using 5- (bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 1-bromo-4- methylpentane. Example 89. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7r,10S)-3-methyl-2,4- dioxo-1-(((S)-tetrahydrofuran-3-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (89) Synthetic scheme:

[0029] 4-nitrophenyl (cyclopentylmethyl)carbamate To a solution of cyclopentylmethanamine (4 g, 40.33 mmol) in DCM (80 mL) was added DMAP (4.93 g, 40.33 mmol), pyridine (80.67 mmol, 6.51 mL) and (4-nitrophenyl) chloroformate (8.13 g, 40.33 mmol). The mixture was stirred at 25 °C for 10 min. After completion, the title compound (10.66 g, crude) was used in the next step without further purification. MS (ESI): mass calcd. for C13H16N2O4: 264.11, found: 265.0 [M+H]+. 1-(cyclopentylmethyl)-3-(3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)urea To a solution of 10-amino-2-methyl-2,4-diazadispiro[4.1.57.15]tridecane-1,3-dione (9.57 g, 40.34 mmol) in DCM (200 mL) was added TEA (8.16 g, 80.67 mmol) and 4- nitrophenyl (cyclopentylmethyl)carbamate (10.66 g, 40.34 mmol). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was poured into water (200 mL) and extracted with DCM (200 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 50 : 1 to 0 : 1) to give the title compound (9.6 g, 66%) as a white solid. MS (ESI): mass calcd. for C19H30N4O3: 362.23, found: 363.3 [M+H]+. 1-(cyclopentylmethyl)-3-(3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-(cyclopentylmethyl)-3-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl)urea (9.6 g, 26.48 mmol) in AcOH (100 mL) was added malonic acid (5.51 g, 52.97 mmol) and Ac2O (18.93 g, 185.4 mmol). The mixture was stirred at 80 °C for 3 h. After completion, the mixture was poured into water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 80 : 1 to 0 : 1) to give the title compound (6.3 g, 55.3%) as a white solid. MS (ESI): mass calcd. for C22H30N4O5: 430.22, found: 431.2 [M+H]+. 5-(bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-(3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0030] To a solution of 1-(cyclopentylmethyl)-3-(3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (6.3 g, 14.63 mmol) in DMSO (63 mL) was added TEA (45.91 g, 453.66 mmol) and CS2(80.22 g, 1054 mmol). After addition, the mixture was stirred at 25 °C for 1 h. Bromoethane (75.93 g, 697 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. The mixture was poured into water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (4.4 g, 63.5%) as a yellow solid. MS (ESI): mass calcd. for C27H38N4O5S2: 562.23, found: 563.3 [M+H]+. 5-(bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 5- (bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-((5R,7r,10R)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione 5-(bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-(3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (4.4 g) wasphase: CO2- -(bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan- 10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (1.1 g) from the first eluting peak as a yellow solid. MS (ESI): mass calcd. for C27H38N4O5S2: 562.23, found: 563.3 [M+H]+. 5- (bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-((5R,7r,10R)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (1.1 g) was obtained from the second eluting peak as a yellow solid. MS (ESI): mass calcd. for C27H38N4O5S2: 562.23, found: 563.3 [M+H]+. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a mixture of 5-[bis(ethylsulfanyl)methylene]-1-(cyclopentylmethyl)-3-(2-methyl- 1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (0.1 g, 177.7 mol) in THF (1 mL) was added NH3.H2O (2 mL). The mixture was stirred at 40 °C for 24 h. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether : ethyl acetate = 0 : 1) to give the title compound (70 mg, 83%) as a white solid. MS (ESI): mass calcd. for C23H32N6O5: 472.24, found: 473.2 [M+H]+. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7r,10S)-3-methyl-2,4-dioxo-1-(((S)- tetrahydrofuran-3-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (89)

[0031] To a mixture of 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-(2-methyl-1,3-dioxo- 2,4-diazadispiro[4.1.57.15]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (0.1 g, 211.6 mol) and (3R)-3-(bromomethyl)tetrahydrofuran (41.91 mg, 254 mol) in DMF (1 mL) was added Cs2CO3(137.90 mg, 423.3 mol). The mixture was stirred at 50 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (14.89 mg, 13%) as a white solid. MS (ESI): mass calcd. for C28H40N6O6: 556.30, found: 557.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.56-4.74 (m, 1H), 3.75-3.82 (m, 1H), 3.61-3.72 (m, 4H), 3.49 (dd, J = 3.6, 8.8 Hz, 1H), 3.33-3.38 (m, 2H), 2.84 (s, 3H), 2.68-2.75 (m, 1H), 2.33-2.47 (m, 2H), 2.14-2.31 (m, 6H), 1.92-2.01 (m, 1H), 1.79 (d, J = 11.2 Hz, 1H), 1.51-1.67 (m, 5H), 1.35-1.49 (m, 5H), 1.18-1.29 (m, 3H). Example 90 was synthesized in a similar route to the one described in Example 89. (3S)-3- (bromomethyl)tetrahydrofuran was used instead of (3R)-3-(bromomethyl)tetrahydrofuran. Example 91 and Example 92.1-((5S,7s,10S)-1-((2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-3- methyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(cyclopentylmethyl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (91) and 1-((5R,7r,10R)-1-((2- oxabicyclo[2.1.1]hexan-4-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(cyclopentylmethyl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (92) Synthetic scheme:

[0032] 2-oxabicyclo[2.1.1]hexan-4-ylmethyl methanesulfonate To a solution of 2-oxabicyclo[2.1.1]hexan-4-ylmethanol (200 mg, 1.75 mmol) in DCM (2 mL) was added pyridine (207.9 mg, 2.63 mmol) and DMAP (21.41 mg, 175.2 mol), followed by addition of methylsulfonyl methanesulfonate (335.8 mg, 1.93 mmol) in DCM (2 mL). The mixture was stirred at 20 °C for 3 h. The mixture was diluted with DCM (20 mL), washed with HCl (0.1M, 20 mL), saturated NaHCO3(20 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (280 mg, 83%) as a white solid.1H NMR (400 MHz, CDCl3) ppm 4.60 (s, 1H), 4.51 (s, 2H), 3.69 (s, 2H), 3.05 (s, 3H), 1.82-1.89 (m, 2H), 1.63-1.67 (m, 2H). 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-[2-methyl-4-(2-oxabicyclo[2.1.1]hexan-4- ylmethyl)-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine- 2,4,6-trione To a solution of 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-(2-methyl-1,3-dioxo- 2,4-diazadispiro[4.1.57.15]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (145 mg, 306.9 mol) in DMF (2.9 mL) was added Cs2CO3(98.31 mg, 301.7 mol). The mixture was stirred at 20 °C for 10 min, 2-oxabicyclo[2.1.1]hexan-4-ylmethyl methanesulfonate (116 mg, 603.4 mol) was added. After stirring at 40 °C for 16 h, the reaction was added DMF (2 mL) and filtered. The filtrate was purified by prep-HPLC to give the title compound (48.7 mg, 28%) as a white solid. MS (ESI): mass calcd. for C29H40N6O6: 568.30, found: 569.5 [M+H]+. 1-((5S,7s,10S)-1-((2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(cyclopentylmethyl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (91) and 1-((5R,7r,10R)-1-((2- oxabicyclo[2.1.1]hexan-4-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(cyclopentylmethyl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (92) 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-[2-methyl-4-(2- oxabicyclo[2.1.1]hexan-4-ylmethyl)-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione (45 mg) was separated by chiral SFC (column:REGIS(S,S)WHELK- 2-MeOH (0.1%NH3H291 (10.59 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C29H40N6O6: 568.30, found: 569.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.30 (s, 2H), 4.63-4.65 (m, 1H), 4.41 (s, 1H), 3.63- 3.78 (m, 4H), 3.50 (s, 2H), 2.84 (s, 3H), 2.14-2.40 (m, 6H), 2.05-2.14 (m, 2H), 1.80-1.89 (m, 1H), 1.68-1.80 (m, 2H), 1.55 (dd, J = 6.8, 11.6 Hz, 4H), 1.37-1.50 (m, 7H), 1.16-1.28 (m, 3H). 92 (5.14 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C29H40N6O6: 568.30, found: 569.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.62-4.65 (m, 1H), 4.41 (s, 1H), 3.64-3.77 (m, 4H), 3.50 (s, 2H), 2.84 (s, 3H), 2.15-2.39 (m, 6H), 2.04-2.15 (m, 2H), 1.85 (d, J = 11.6 Hz, 1H), 1.69-1.79 (m, 2H), 1.55 (dd, J = 6.8, 11.6 Hz, 4H), 1.35-1.48 (m, 7H), 1.15-1.28 (m, 3H). Example 93. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-1-((3- methyloxetan-3-yl)methyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (93) Synthetic scheme: 5-(bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-1-((3- methyloxetan-3-yl)methyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0033] 3-(Iodomethyl)-3-methyloxetane (37.7 mg, 178 μmol) was dissolved in DMF (444 μL) and 5-(bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-2,4-dioxo- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (50 mg, 88.9 μmol) was added followed by cesium carbonate (59.1 mg, 178 μmol). The suspension was stirred at 45 °C for 2.5 h then the mixture was cooled down to rt, diluted with EtOAc and washed with water (3x). The organic phase was dried over MgSO4, filtered, and concentrated to provide the crude title compound as a yellow oil which was used directly in the next step. MS (ESI): mass calcd. for C32H46N4O6S2: 646.29, found: 647.3 [M+H]+. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-1-((3- methyloxetan-3-yl)methyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (93) To 5-(bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-1-((3- methyloxetan-3-yl)methyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (55.5 mg, 85.8 μmol) in THF (429 μL) was added ammonium hydroxide (28%, 96.6 μL, 2.48 mmol) and the solution was stirred at 45 °C for 48 h. The reaction was then diluted with EtOAc and washed with water (2x). The organic phase was dried over MgSO4, filtered, and concentrated. The crude was purified by prep HPLC to give the title compound (14.4 mg, 30%) as a white solid. MS (ESI): mass calcd. for C28H40N6O6: 556.30, found: 557.4 [M+H]+.1H NMR (400 MHz, dmso) 9.52 (s, 2H), 7.38 (s, 2H), 4.57 – 4.62 (m, 3H), 4.13 (dd, J = 6.0, 2.7 Hz, 2H), 3.68 (d, J = 7.5 Hz, 2H), 3.47 (d, J = 2.0 Hz, 2H), 2.81 (s, 3H), 2.05 – 2.33 (m, 7H), 1.84 (d, J = 12.8 Hz, 1H), 1.32 – 1.61 (m, 10H), 1.24 (s, 3H), 1.14 – 1.21 (m, 2H). Example 94 was synthesized in a similar route to the one described in Example 93. (3S)- 3- fluoro-3-(iodomethyl)oxetane was used instead of 3-(iodomethyl)-3-methyloxetane. Example 95. 1-(((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)methyl)cyclopropane-1-carboxylic acid (95) Synthetic scheme:

[0034] Ethyl 1-(((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)methyl)cyclopropane-1-carboxylate The title compound was synthesized following the same sequence of steps as in Example 94 using ethyl 1-(hydroxymethyl)cyclopropanecarboxylate as starting material instead of 3-ethyl-3-oxetanemethanol. 1-(((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)methyl)cyclopropane-1-carboxylic acid (95) To ethyl 1-(((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan- 1-yl)methyl)cyclopropane-1-carboxylate (158 mg, 264 μmol) in THF (2.6 mL) was added 1 N aqueous lithium hydroxide solution (2.6 mL, 2.64 mmol). The mixture was stirred at rt for 20 h. 10% aqueous citric acid solution was added, and the reaction was extracted 3 times with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude was purified by prep HPLC to provide the title compound (31.8 mg, 21%) as a white solid. MS (ESI): mass calcd. for C28H38N6O7: 570.28, found: 571.3 [M+H]+.1H NMR (400 MHz, DMSO) 9.52 (s, 2H), 7.50 (bs, 2H), 4.54 – 4.73 (m, 1H), 3.90 (d, J = 15.4 Hz, 1H), 3.64 – 3.83 (m, 3H), 2.82 (s, 3H), 1.95 – 2.38 (m, 8H), 0.96 – 1.66 (m, 18H). Example 96. 3-((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)propanoic acid (96)

[0035] Synthetic scheme Tert-butyl 3-((5S,7s,10S)-10-(5-(bis(ethylthio)methylene)-3-(cyclopentylmethyl)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)propanoate 5-(Bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-2,4- dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (60 mg, 107 μmol) was dissolved in anhydrous DMSO (2.1 mL) and tert-butyl acrylate (80 μL, 540 μmol) was added followed by cesium carbonate (142 mg, 426 μmol). The reaction was stirred at rt for 1 h, diluted with EtOAc and washed with water (2x). The organic phase was dried over MgSO4, filtered, and concentrated to provide the crude title compound as an orange oil which was directly used in the next step. MS (ESI): mass calcd. for C34H50N4O7S2: 690.31, found: 691.2 [M+H]+. 3-((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)propanoic acid (96)

[0036] To tert-butyl 3-((5S,7s,10S)-10-(5-(bis(ethylthio)methylene)-3-(cyclopentylmethyl)- 2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)propanoate (68 mg, 98.4 μmol) in DCM (2.0 mL) was added TFA (680 μL) and the solution was stirred at rt for 30 min. The reaction was concentrated, and the residue was dissolved in THF (1.4 mL). Ammonium hydroxide (30% in water, 115 μL, 2.95 mmol) was added and the solution was stirred at 45 °C for 18 h. The reaction was diluted with DCM, acidified with 1 N HCl (10 mL). The aqueous phase was extracted with DCM (3x). The combined organic phase was dried over MgSO4, filtered, and concentrated. The crude was purified by prep HPLC to give the title compound (18 mg, 34%) as a white solid. MS (ESI): mass calcd. for C26H36N6O7: 544.26, found: 545.3 [M+H]+.1H NMR (400 MHz, DMSO) 9.51 (s, 2H), 7.45 (s, 2H), 4.62 (br s, 1H), 3.68 (d, J = 7.3 Hz, 2H), 3.51 – 3.55 (m, 2H), 2.81 (s, 3H), 2.60 (t, J = 7.2 Hz, 2H), 2.26 – 2.45 (m, 4H), 2.08 – 2.23 (m, 5H), 1.84 (d, J = 11.1 Hz, 1H), 1.48 – 1.59 (m, 4H), 1.31 – 1.46 (m, 5H), 1.14 – 1.26 (m, 3H). Example 97. 2-((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)acetic acid (97)

[0037] Synthetic scheme Tert-butyl 2-((5S,7s,10S)-10-(5-(bis(ethylthio)methylene)-3-(cyclopentylmethyl)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)acetate Tert-butyl bromoacetate (52.5 μL, 355 μmol) was dissolved in anhydrous DMSO (1.8 mL) and 5-(bis(ethylthio)methylene)-1-(cyclopentylmethyl)-3-((5S,7s,10S)-3-methyl-2,4- dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (50 mg, 88.9 μmol) was added followed by cesium carbonate (59.1 mg, 178 μmol). The suspension was stirred at rt for 1 h and more tert-butyl bromoacetate (52.5 μL, 355 μmol) was added. The suspension was stirred for another 2 h at rt. The reaction was diluted with EtOAc and washed with water (2x). The organic phase was dried over MgSO4, filtered, and concentrated to provide the title crude compound as an orange oil which was used directly in the next step. Tert-butyl 2-((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)acetate To tert-butyl 2-((5S,7s,10S)-10-(5-(bis(ethylthio)methylene)-3-(cyclopentylmethyl)- 2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)acetate (58.1 mg, 85.8 μmol) in THF (429 μL) was added ammonium hydroxide (28% in water, 96.6 μL) and the solution was stirred at 45 °C for 48 h. The reaction was diluted with EtOAc and washed with water (2x). The organic phase was dried over MgSO4, filtered, and concentrated to provide the title compound as an orange oil which was used directly in the next step. 2-((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)acetic acid (97)

[0038] To tert-butyl 2-((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan- 1-yl)acetate (48 mg, 70.9 μmol) in DCM (500 μL) was added TFA (250 μL) and the solution was stirred at rt for 30 min. The mixture was diluted with toluene (0.5 mL) and concentrated. The crude was purified by prep HPLC to give the title compound (18.6 mg, 49%) as a white solid. MS (ESI): mass calcd. for C25H34N6O7: 530.25, found: 531.3 [M+H]+.1H NMR (400 MHz, DMSO) 9.49 (s, 2H), 7.68 (s, 2H), 4.59 (br s, 1H), 3.83 – 3.95 (m, 2H), 3.68 (d, J = 7.3 Hz, 2H), 2.83 (s, 3H), 2.04 – 2.42 (m, 10H), 1.73 (d, J = 10.9 Hz, 1H), 1.30 – 1.58 (m, 8H), 1.15 – 1.23 (m, 3H). Example 98. 2-(2-((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)ethoxy)acetic acid (98) Synthetic scheme:

[0039] tert-butyl 2-(2-((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)ethoxy)acetate The title compound was synthesized following the same sequence of steps as Example 147 and by using tert-butyl 2-(2-hydroxyethoxy)acetate as starting material instead of 3-ethyl- 3-oxetanemethanol. 2-(2-((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)ethoxy)acetic acid (98) Tert-butyl 2-(2-((5S,7s,10S)-10-(3-(cyclopentylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan- 1-yl)ethoxy)acetate (29.7 mg, 47 μmol) was dissolved in DCM (236 μL) and trifluoroacetic acid (100 μL, 1.31 mmol) was added. The solution was stirred at rt for 1 h and was concentrated. The crude was purified by reverse phase chromatography (C18, 30-50% MeCN / 10 mM AmF buffer) to provide the title compound (11.3 mg, 40%) as a white solid. MS (ESI): mass calcd. for C27H38N6O8: 574.28, found: 575.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 9.49 (s, 2H), 7.70 (s, 2H), 4.61 (s, 1H), 3.89 (s, 2H), 3.62 – 3.69 (m, 4H), 3.50 – 3.54 (m, 2H), 2.82 (s, 3H), 2.07 – 2.34 (m, 8H), 1.85 (d, J = 11.1 Hz, 1H), 1.49 – 1.58 (m, 4H), 1.31 – 1.45 (m, 5H), 1.15 – 1.25 (m, 3H). Example 99 was synthesized in a similar route to the one described in Example 98. tert-butyl 4-hydroxybutanoate as starting material instead of tert-butyl 2-(2-hydroxyethoxy)acetate. Example 100 was synthesized in a similar route to the one described in Example 93. 2- (Iodomethyl)oxetane as starting material instead of 3-(iodomethyl)-3-methyloxetane. Example 101 and Example 102 were synthesized in a similar route to the one described in Example 147. Methyl 3-(hydroxymethyl)cyclobutanecarboxylate was used as a starting material instead of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate. The final two compounds were separated using chiral SFC (cellulose tris(3-chloro-methylphenylcarbamate, (60% MeCN:EtOH (1:1) + 0.1% NH4OH) / 40% supercritical CO2) to 101 as the first eluting peak and 102 as the second eluting peak. The cis / trans stereochemistry of the cyclobutane is tentatively assigned by1H NMR. Example 103 1-((5S,7s,10S)-1-((2-oxaspiro[3.3]heptan-6-yl)methyl)-3-methyl-2,4-dioxo- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(cyclopentylmethyl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (103) Synthetic scheme: 2-oxaspiro[3.3]heptan-6-ylmethanol To a solution of ethyl 2-oxaspiro[3.3]heptane-6-carboxylate (500 mg, 2.94 mmol) in anhydrous THF (4.4 mL) at 0 °C was slowly added lithium aluminum hydride 2 M in THF (1.6 mL, 3.23 mmol) and the solution was stirred at rt for 2 h. Sodium sulfate decahydrate was added to quench the reaction at 0 °C. The reaction was filtered and concentrated to provide the title compound (200 mg, 53%).1H NMR (400 MHz, CDCl3) 4.70 (s, 2H), 4.61 (s, 2H), 3.53 (d, J = 5.9 Hz, 2H), 2.23 – 2.36 (m, 3H), 1.94 – 2.00 (m, 2H) 1-((5S,7s,10S)-1-((2-oxaspiro[3.3]heptan-6-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(cyclopentylmethyl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (103) The title compound was synthesized following the same sequence of steps as Example 147 and by using 2-oxaspiro[3.3]heptan-6-ylmethanol as starting material instead of 3-ethyl- 3-oxetanemethanol. The last step was purified by reverse phase chromatography (C18, 35- 55% MeCN / 10 mM AmF buffer) to afford the title compound (9.6 mg, 53%) as a white solid. MS (ESI): mass calcd. for C30H42N6O6: 582.32, found: 583.3 [M+H]+.1H NMR (400 MHz, DMSO) 9.52 (s, 2H), 7.32 (s, 2H), 4.62 (s, 1H), 4.54 (s, 2H), 4.46 (s, 2H), 3.69 (d, J = 7.4 Hz, 2H), 3.22 – 3.31 (m, 1H), 2.81 (s, 3H), 2.39 – 2.46 (m, 2H), 2.15 – 2.39 (m, 7H), 2.06 – 2.14 (m, 3H), 1.89 – 1.97 (m, 2H), 1.77 (d, J = 11.1 Hz, 1H), 1.48 – 1.60 (m, 4H), 1.33 – 1.47 (m, 5H), 1.14 – 1.25 (m, 3H). Example 104. 1-(1-bicyclo[2.1.1]hexanylmethyl)-5-(diaminomethylene)-3-(2,4-dimethyl- 1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (104)

[0040] Synthetic scheme: bicyclo[2.1.1]hexan-1-ylmethanol To a solution of bicyclo[2.1.1]hexane-1-carboxylic acid (0.2 g, 1.59 mmol) in THF (2 mL) was added LAH (2.5 M, 761 L) dropwise at 0 °C under N2. The mixture was stirred at 20 °C for 2 h. After completion, the reaction was quenched with H2O (0.1 mL) and 15% NaOH (0.1 mL), and H2O (0.3 mL). The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the title compound, which was used in the next step directly without further purification. 1-bicyclo[2.1.1]hexanylmethyl 4-methylbenzenesulfonate To a solution of 1-bicyclo[2.1.1]hexanylmethanol (0.17 g, 1.52 mmol) in DCM (2 mL) was added pyridine (392 mg, 4.96 mmol) and TsCl (346.7 mg, 1.82 mmol) in one portion at 0 °C under N2. The mixture was stirred at 20 °C for 16 h. After completion, the mixture was poured into water (5 mL) and extracted with DCM (10 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether : ethyl acetate = 5 : 1) to give the title compound (0.3 g, 74%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) ppm 7.78 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.13 (s, 2H), 2.42 (s, 3H), 2.37 (d, J = 1.2 Hz, 1H), 1.54-1.62 (m, 2H), 1.33-1.44 (m, 4H), 0.85-0.93 (m, 2H). (2,4-dimethyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10-yl)urea To a solution of 10-amino-2,4-dimethyl-2,4-diazadispiro[4.1.57.15]tridecane-1,3-dione (1.9 g, 7.56 mmol) in H2O (20 mL) was added potassium cyanate (1.84 g, 22.68 mmol) at 20 °C under N2. The mixture was stirred at 85 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 5 : 1 to 0 : 1) to give the title compound (1.3 g, 58%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 5.91 (d, J = 7.2 Hz, 1H), 5.43 (s, 2H), 3.28 (s, 1H), 2.94 (s, 3H), 2.82 (s, 3H), 2.05-2.25 (m, 5H), 1.56-1.76 (m, 3H), 1.31-1.47 (m, 2H), 0.99-1.19 (m, 2H). 1-(2,4-dimethyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10- yl)hexahydropyrimidine-2,4,6-trione To a solution of malonic acid (2.83 g, 27.18 mmol) in dioxane (8 mL) was added Ac2O (1.39 g, 13.6 mmol) at 20 °C under N2. The mixture was stirred at 80 °C for 0.5 h. (2,4- dimethyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10-yl)urea (0.8 g, 2.72 mmol) was added and stirred at 80 °C for 1 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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 3: 1 to 1: 2) to give the title compound (0.6 g, 61%) as a yellow solid.1H NMR (400 MHz, DMSO- d6) ppm 11.21 (s, 1H), 4.31-4.48 (m, 1H), 3.57 (s, 2H), 2.94 (s, 3H), 2.83 (s, 3H), 2.36-2.45 (m, 1H), 2.06-2.30(m, 6H), 1.76-1.87 (m, 1H), 1.36-1.53 (m, 3H), 1.20-1.33 (m, 1H). 1-(2,4-dimethyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10-yl)-5-(1,3-dithian-2- ylidene)hexahydropyrimidine-2,4,6-trione To a solution of 1-(2,4-dimethyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10- yl)hexahydropyrimidine-2,4,6-trione (0.3 g, 827.9 mol) in DMSO (3 mL) was added TEA (418.85 mg, 4.14 mmol) and CS2(189.1 mg, 2.48 mmol) and the reaction was stirred at 20 °C for 1 h. 1,3-dibromopropane (501.4 mg, 2.48 mmol) was added at 0 °C and stirring was continued at 20 °C for 1.5 h. After completion, the mixture was poured into water (20 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with ethyl acetate (5 mL) at 20 °C for 10 min. The mixture was filtered, and the filter cake was dried under reduced pressure to give the title compound (0.22 g, 56%) as a yellow solid. MS (ESI): mass calcd. for C21H26N4O5S2: 478.13, found: 479.0 [M+H]+. 1-(1-bicyclo[2.1.1]hexanylmethyl)-3-(2,4-dimethyl-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl)-5-(1,3-dithian-2-ylidene)hexahydropyrimidine- 2,4,6-trione To a mixture of 1-(2,4-dimethyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10-yl)- 5-(1,3-dithian-2-ylidene)hexahydropyrimidine-2,4,6-trione (0.22 g, 460 mol) and 1- bicyclo[2.1.1]hexanylmethyl 4-methylbenzenesulfonate (244.88 mg, 919 mol) in DMF (2 mL) was added K2CO3(76.24 mg, 552 mol) and KI (7.63 mg, 46 mol). The mixture was stirred at 40 °C for 16 h. After completion, the mixture was poured into water (5 mL) and extracted with DCM (5 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with ethyl acetate (2 mL) at 20 °C for 30 min. The mixture was filtered, and the filter cake was dried under reduced pressure to give the title compound (0.18 g, 68%) as a yellow solid. MS (ESI): mass calcd. for C28H36N4O5S2: 572.21, found: 573.1 [M+H]+. 1-(1-bicyclo[2.1.1]hexanylmethyl)-5-(diaminomethylene)-3-(2,4-dimethyl-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (104) A solution of 1-(1-bicyclo[2.1.1]hexanylmethyl)-3-(2,4-dimethyl-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl)-5-(1,3-dithian-2-ylidene)hexahydropyrimidine-2,4,6- trione (50 mg, 87.3 mol) in THF (0.5 mL) was added NH4OH (0.5 mL, 25% NH3in water) and stirred at 30 °C for 48 h. After completion, the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (8.91 mg, 22%) as a white solid. MS (ESI): mass calcd. for C25H34N6O5: 498.26, found: 499.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.55 (s, 2H), 7.29 (s, 2H), 4.56-4.73 (m, 1H), 3.96 (s, 2H), 2.94 (s, 3H), 2.83 (s, 3H), 2.05-2.45 (m, 8H), 1.82 (d, J = 11.2 Hz, 1H), 1.52-1.61 (m, 2H), 1.33-1.50 (m, 5H), 1.18-1.32 (m, 3H), 0.84-0.97 (m, 2H). Example 105 and Example 106 was obtained from Example 104 (160 mg) by chiral SFC 2-MeOH (0.1% NH3H2105 (28.1 mg) from the first eluting peak as a white solid and 106 (30.01 mg) from the second eluting peak as a white solid. The stereochemistry for these two compounds is arbitrarily assigned. Example 107. 5-(diaminomethylene)-1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(pyridin-2-ylmethyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (107) Synthetic Scheme: 4-nitrophenyl ((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)carbamate To a solution of (5S,7s,10S)-10-amino-1,3-dimethyl-1,3- diazadispiro[4.1.57.15]tridecane-2,4-dione (150 mg, 597 mol) in DCM (1.5 mL) was added pyridine (94.4 mg, 1.19 mmol) and DMAP (72.9 mg, 597 mol) at 20 °C. (4-nitrophenyl) chloroformate (120.3 mg, 597 mol) in DCM (1.5 mL) was added dropwise at –20 °C. The resulting mixture was stirred at –20 °C for 1 h. The reaction was concentrated under reduced pressure and the crude title compound (248 mg, crude) was used in the next step without further purification. MS (ESI): mass calcd. for C20H24O6N4: 416.17, found: 417.2 [M+H]+. 1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3- (pyridin-2-ylmethyl)urea To a solution of 4-nitrophenyl ((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)carbamate (245.7 mg, 590 mol, crude) in DCM (2 mL) was added TEA (108.54 mg, 1.07 mmol) and 2-pyridylmethanamine (58 mg, 536.34 mol) at –20 °C. The mixture was stirred at 20 °C for 16 h. The residue was diluted with H2O (15 mL) and extracted with ethyl acetate (25 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 prep-TLC (SiO2, DCM : MeOH = 10 : 1) to give the title compound (60 mg, 26%) as a white solid. MS (ESI): mass calcd. for C20H27N5O3: 385.21, found: 386.2 [M+H]+. 5-(diaminomethylene)-1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(pyridin-2-ylmethyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (107) Example 107 was prepared from 1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(pyridin-2-ylmethyl)urea according to the last two reactions of Example 43. MS (ESI): mass calcd. for C24H29N7O5: 495.22, found: 496.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.49 (s, 2H), 8.44 (d, J = 4.4 Hz, 1H), 7.71 (dt, J = 1.6, 7.6 Hz, 1H), 7.34 (s, 2H), 7.22 (dd, J = 4.8, 6.8 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 5.00-5.10 (m, 2H), 4.58-4.73 (m, 1H), 2.93 (s, 3H), 2.82 (s, 3H), 2.28-2.43 (m, 3H), 2.24 (dd, J = 8.0, 13.2 Hz, 2H), 2.04-2.18 (m, 2H), 1.81 (d, J = 10.8 Hz, 1H), 1.41 (t, J = 11.8 Hz, 3H), 1.20-1.32 (m, 1H). Example 108. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-[2-methyl-1,3-dioxo-4- [[(3R)-tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione (108) Synthetic scheme:

[0041] (4-nitrophenyl) N-(cyclobutylmethyl)carbamate To a solution of cyclobutylmethanamine (500 mg, 5.87 mmol) in DCM (10 mL) was added pyridine (929 mg, 11.74 mmol), DMAP (717 mg, 5.87 mmol) and (4-nitrophenyl) carbonochloridate (1.18 g, 5.87 mmol). The mixture was stirred at 20 °C for 15 min. The reaction was concentrated under reduced pressure and the crude title compound (1.47 g, crude) was used in the next step without further purification as a yellow oil. MS (ESI): mass calcd. for C12H14N2O4: 250.10, found: 251.1 [M+H]+. 1-(cyclobutylmethyl)-3-(2-methyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10- yl)urea To a solution of 10-amino-2-methyl-2,4-diazadispiro[4.1.57.15]tridecane-1,3-dione (1.32 g, 5.58 mmol) in DCM (10 mL) was added TEA (1.13 g, 11.16 mmol) and (4-nitrophenyl) N-(cyclobutylmethyl)carbamate (1.47 g, 5.58 mmol). The mixture was stirred at 20 °C for 16 h. The reaction was quenched with H2O (15 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with ethyl acetate (6 mL), filtered, and dried under reduced pressure to give the title compound (1.21 g, 50%) as a white solid. MS (ESI): mass calcd. for C18H28N4O3: 348.22, found: 349.0 [M+H]+. 1-(cyclobutylmethyl)-3-(2-methyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10- yl)hexahydropyrimidine-2,4,6-trione To a solution of 1-(cyclobutylmethyl)-3-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl)urea (630 mg, 1.81 mmol) in AcOH (6.3 mL) was added malonic acid (376.3 mg, 3.62 mmol) and Ac2O (1.29 g, 12.66 mmol). The mixture was stirred at 80 °C for 1 h. The reaction was quenched with H2O (35 mL) and extracted with ethyl acetate (40 mL x 3). 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 = 99 : 1 to 70 : 30) to give the title compound (1.11 g) as a yellow solid. MS (ESI): mass calcd. for C21H28N4O5: 416.21, found: 417.2 [M+H]+. 1-(cyclobutylmethyl)-5-(1,3-dithian-2-ylidene)-3-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione To a solution of 1-(cyclobutylmethyl)-3-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (490 mg, 1.18 mmol) in DMSO (5 mL) was added TEA (595.3 mg, 5.88 mmol) and CS2(268.75 mg, 3.53 mmol) and the reaction was stirred at 20 °C for 3 h. 1,3-dibromopropane (712.6 mg, 3.53 mmol) was added. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated NH4Cl (15 mL), diluted with H2O (5 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with MTBE : ethyl acetate = 2 : 1 (10 mL) to give the title compound (630 mg, 88%) as an orange solid. MS (ESI): mass calcd. for C25H32N4O5S2: 532.18, found: 533.3 [M+H]+. 1-(cyclobutylmethyl)-5-(1,3-dithian-2-ylidene)-3-[2-methyl-1,3-dioxo-4-[[(3R)- tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione To a solution of 1-(cyclobutylmethyl)-5-(1,3-dithian-2-ylidene)-3-(2-methyl-1,3- dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (400 mg, 751 mol) in DMF (5 mL) was added (3S)-3-(bromomethyl)tetrahydrofuran (247.9 mg, 1.5 mmol) and Cs2CO3(489.3 mg, 1.5 mmol). The mixture was stirred at 50 °C for 16 h. The reaction was quenched with H2O (20 mL) and extracted with ethyl acetate (25 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 prep-HPLC to give the title compound (130 mg, 26%) as a white solid. MS (ESI): mass calcd. for C30H40N4O6S2: 616.24, found: 617.3 [M+H]+. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-[2-methyl-1,3-dioxo-4-[[(3R)- tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione (108)

[0042] To a solution of 1-(cyclobutylmethyl)-5-(1,3-dithian-2-ylidene)-3-[2-methyl-1,3- dioxo-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione (90 mg, 145.9 mol) in THF (1.5 mL) was added NH4OH (1.46 mmol, 225 L, 25% NH3in water). The mixture was stirred at 30 °C for 16 h. The reaction was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (20 mg, 25%) as a white solid. MS (ESI): mass calcd. for C27H38N6O6: 542.29, found: 543.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.34 (s, 2H), 4.54-4.72 (m, 1H), 3.75-3.86 (m, 3H), 3.61-3.72 (m, 2H), 3.50 (td, J = 4.8, 9.2 Hz, 1H), 3.37- 3.44 (m, 1H), 3.33-3.36 (m, 1H), 3.263.32 (m, 1H), 2.85 (s, 3H), 2.66-2.75 (m, 1H), 2.54-2.60 (m, 1H), 2.42-2.49 (m, 1H), 2.24-2.40 (m, 3H), 2.16-2.23 (m, 3H), 1.94-2.03 (m, 1H), 1.85-1.93 (m, 2H), 1.78-1.83 (m, 1H), 1.73-1.77 (m, 2H), 1.59-1.72 (m, 2H), 1.34-1.50 (m, 3H), 1.19-1.30 (m, 1H). Example 109. 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1-((1- (pyridin-2-yl)cyclobutyl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (109) Synthetic scheme:

[0043] 1-butyl-5-(1,3-dithian-2-ylidene)-3-(3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-(2-methyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10- yl)hexahydropyrimidine-2,4,6-trione (5.0 g, 12.3 mmol) in DMSO (50 mL) was added TEA (6.2 g, 61.8 mmol) and CS2(2.8 g, 37.0 mmol) at 25 °C for 1 h. 1,3-dibromopropane (7.4 g, 37.0 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. After completion, the reaction was triturated with ice water (100 mL) at 25 °C for 30 min. The reaction was filtered. The filter cake was washed with H2O (100 mL) and dried under reduced pressure. The crude product was triturated with MTBE (100 mL) at 25 °C for 30 min to give the title compound (20 g, 77%) as a white solid. MS (ESI): mass calcd. for C24H32N4O5S2: 520.18, found: 521.3 [M+H]+. 1-butyl-5-(1,3-dithian-2-ylidene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione 1-butyl-5-(1,3-dithian-2-ylidene)-3-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (20 g) was separatedby prep-SFC (column: ChiralPak IH, 250x 2-with isocratic elution) to give the title compound (12.9 g) from the second eluting peak as a white solid. MS (ESI): mass calcd. for C24H32N4O5S2: 520.18, found: 521.2 [M+H]+. 1-(pyridin-2-yl)cyclobutane-1-carbonitrile To a solution of cyclobutanecarbonitrile (2.0 g, 24.6 mmol) and 2-fluoropyridine (2.3 g, 24.6 mmol) in toluene (36 mL) was added NaHMDS (1.0 M, 27.1 mL) at 0 °C. The mixture was stirred at 25 °C for 20 h. The reaction was quenched with saturated NH4Cl (40 mL) and extracted with DCM (40 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 20 : 1) to give the title compound (3.2 g, 74%) as a white solid. MS (ESI): mass calcd. for C10H10N2: 158.08, found: 159.5 [M+H]+. 1-(pyridin-2-yl)cyclobutane-1-carboxylic acid To a solution of 1-(2-pyridyl)cyclobutanecarbonitrile (2.0 g, 12.6 mmol) in H2O (2 mL) was added AcOH (2.1 g, 34.9 mmol) and H2SO4(3.6 g, 37.5 mmol). The reaction was stirred at 90 °C for 16 h and cooled down. The reaction was poured into water (5.0 mL), adjusted to pH = 4.5-5 with 10% NaOH and extracted with DCM (100 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether (10 mL) at 25oC for 5 min to give the title compound (1.5 g, 66%) as a white solid. MS (ESI): mass calcd. for C10H11NO2: 177.08, found: 178.5 [M+H]+. (1-(pyridin-2-yl)cyclobutyl)methanol To a solution of 1-(2-pyridyl)cyclobutanecarboxylic acid (900 mg, 5 mmol) and TEA (565 mg, 5.5 mmol) in THF (18 mL) was added dropwise isobutyl chloroformate (763 mg, 5.5 mmol) at –10 °C. After addition, the mixture was stirred at this temperature for 1 h. The reaction was filtered. The filtrate was added to a solution of NaBH4(576.4 mg, 15.2 mmol) in H2O (2.2 mL) and THF (9.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated NH4Cl (20 mL) and extracted with ethyl acetate (20 mL× 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 3 : 1) to give the title compound (466 mg, 48%) as a white solid. MS (ESI): mass calcd. for C10H13NO: 163.10, found: 164.5 [M+H]+. [1-(2-pyridyl)cyclobutyl]methyl methanesulfonate To a solution of [1-(2-pyridyl)cyclobutyl]methanol (700 mg, 4.2 mmol) in THF (7 mL) was added methylsulfonyl methanesulfonate (1.1 g, 6.4 mmol) and TEA (1.0 g, 10.7 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction was diluted with H2O (10 mL) and extracted with DCM (10 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 3 : 1) to provide the title compound (871 mg, 71%) as a yellow oil. MS (ESI): mass calcd. for C11H15NO3S: 241.08, found: 242.3 [M+H]+. 2-(1-(iodomethyl)cyclobutyl)pyridine To a solution of [1-(2-pyridyl)cyclobutyl]methyl methanesulfonate (640 mg, 2.6 mmol) in acetone (3.2 mL) was added NaI (2.3 g, 15.9 mmol). The mixture was stirred at 60 °C for 16 h and cooled to 20 °C. The reaction was diluted with water (5 mL) and extracted with DCM (5 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate=1 : 0 to 10 : 1) to give the title compound (680 mg, 79%) as a colorless oil. MS (ESI): mass calcd. for C10H12IN: 273.00, found: 274.3 [M+H]+. 1-butyl-5-(1,3-dithian-2-ylidene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1-((1-(pyridin-2- yl)cyclobutyl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 2-[1-(iodomethyl)cyclobutyl]pyridine (150 mg, 549 mol) and 1-butyl- 5-(1,3-dithian-2-ylidene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (190.6 mg, 366 mol) in DMF (1.5 mL) was added Cs2CO3(238.6 mg, 732 mol). The mixture was stirred at 40 °C for 24 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (40 mg, 13%) as a white solid. MS (ESI): mass calcd. for C34H43N5O5S2: 665.27, found: 666.3 [M+H]+. 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1-((1-(pyridin-2- yl)cyclobutyl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (109) To a solution of 1-butyl-5-(1,3-dithian-2-ylidene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo- 1-((1-(pyridin-2-yl)cyclobutyl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (40 mg, 60 mol) in THF (0.5 mL) was added NH4OH (1.8 mmol, 278 L, 25% NH3in water). The mixture was stirred at 30 °C for 24 h and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (9.3 mg, 26%) as a white solid. MS (ESI): mass calcd. for C31H41N7O5: 591.32, found: 592.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 8.49-8.60 (m, 1H), 7.72 (dt, J = 1.6, 7.6 Hz, 1H), 7.26-7.33 (m, 3H), 7.20 (dd, J = 5.2, 7.2 Hz, 1H), 4.44-4.59 (m, 1H), 3.67-3.80 (m, 4H), 2.83 (s, 3H), 2.50-2.51 (m, 2H), 2.36-2.43 (m, 2H), 2.28 (d, J = 12.4 Hz, 1H), 2.05-2.16 (m, 2H), 1.94-2.03 (m, 1H), 1.81 (d, J = 12.8 Hz, 1H), 1.64-1.75 (m, 2H), 1.40-1.53 (m, 3H), 1.18-1.32 (m, 6H), 0.98–1.16 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). Example 110. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(3-methyl-2,4-dioxo-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (110)

[0044] Synthetic scheme: 3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-11,14-dioxa-1,3- diazatrispiro[4.1.2.410.27.15]heptadecane-2,4-dione To a solution of 2-methyl-11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane- 1,3-dione (3 g, 10.7 mmol,) and 4-(iodomethyl)tetrahydropyran (4.84 g, 21.4 mmol) in DMF (15 mL) was added Cs2CO3(6.97 g, 21.4 mmol). The solution was stirred at 80 °C for 16 h. After completion, the suspension was filtered through silica gel and washed with ethyl acetate (90 mL × 3). The organic phase was washed with saturated NaHCO3 (60 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 30 : 1 to 4 : 1) to give the title compound (2.5 g, 62%) as a yellow solid. MS (ESI): mass calcd. for C20H30N2O5: 378.22, found: 379.2 [M+H]+. 3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecane- 2,4,10-trione To a solution of 2-methyl-4-(tetrahydropyran-4-ylmethyl)-11,14-dioxa-2,4- diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione (2.5 g, 6.6 mmol) in acetone (25 mL) and H2O (12.5 mL) was added TsOH.H2O (2.51 g, 13.2 mmol). The solution was stirred at 30 °C for 16 h. After completion, the mixture was adjusted to pH = 9 with saturated NaHCO3and extracted with DCM (80 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.2 g, crude) as a yellow solid. MS (ESI): mass calcd. for C18H26N2O4: 334.19, found: 335.1 [M+H]+. 10-amino-3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3- diazadispiro[4.1.57.15]tridecane-2,4-dione A solution of 2-methyl-4-(tetrahydropyran-4-ylmethyl)-2,4- diazadispiro[4.1.57.15]tridecane-1,3,10-trione (1.9 g, 5.68 mmol) in NH3 / MeOH (7 M, 16.23 mL) was stirred at 20 °C for 1 h under N2. Raney-Ni (243.4 mg) was added and the reaction was stirred at 20 °C for 16 h under H2 (15 psi). After completion, the mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (1.9 g, crude) as a white solid. MS (ESI): mass calcd. for C18H29N3O3: 335.22, found: 336.5 [M+H]+1-(3-methyl-2,4-dioxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)urea To a solution of 10-amino-2-methyl-4-(tetrahydropyran-4-ylmethyl)-2,4- diazadispiro[4.1.57.15]tridecane-1,3-dione (1.14 g, 3.4 mmol) in H2O (12 mL) was added potassium cyanate (275.7 mg, 3.4 mmol). The reaction was stirred at 50 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (60 mL), MeOH (6 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Ethyl acetate : MeOH = 100 : 0 to 30 : 1) to give the title compound (1.2 g, 93%) as a white solid. MS (ESI): mass calcd. for C19H30N4O4: 378.23, found: 379.3 [M+H]+. 1-(3-methyl-2,4-dioxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of [2-methyl-1,3-dioxo-4-(tetrahydropyran-4-ylmethyl)-2,4- diazadispiro[4.1.57.15]tridecan-10-yl]urea (1.2 g, 3.17 mmol) in HOAc (12 mL) was added acetic anhydride (2.27 g, 22.2 mmol) and malonic acid (660 mg, 6.34 mmol). The solution was stirred at 80 °C for 2 h. After completion, the reaction was poured into water (100 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 20 : 1 to 1 : 1) to give the title compound (830 mg, 59%) as a white solid. MS (ESI): mass calcd. for C22H30N4O6: 446.22, found: 447.2 [M+H]+. 5-(1,3-dithian-2-ylidene)-1-(3-methyl-2,4-dioxo-1-((tetrahydro-2H-pyran-4-yl)methyl)- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-[2-methyl-1,3-dioxo-4-(tetrahydropyran-4-ylmethyl)-2,4- diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (560 mg, 1.25 mmol) in DMSO (10 mL) was added TEA (507.7 mg, 5.02 mmol) and CS2(286.5 mg, 3.76 mmol). The reaction was stirred at 40 °C for 2 h. 1,3-dibromopropane (506.4 mg, 2.51 mmol) was added and the reaction was stirred at 20 °C for 1 h. After completion, the reaction was partitioned between saturated NH4Cl (10 mL) and ethyl acetate (20 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 41 : 59) to give the title compound (204 mg, 29%) as a yellow solid. MS (ESI): mass calcd. for C26H34N4O6S2: 562.19, found: 563.3 [M+H]+. 1-(cyclobutylmethyl)-5-(1,3-dithian-2-ylidene)-3-(3-methyl-2,4-dioxo-1-((tetrahydro-2H- pyran-4-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 5-(1,3-dithian-2-ylidene)-1-[2-methyl-1,3-dioxo-4-(tetrahydropyran- 4-ylmethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (170 mg, 302 μmol) in DMF (6 mL) was added K2CO3(209 mg, 1.51 mmol) and iodomethylcyclobutane (119 mg, 604 μmol). The reaction was stirred at 20 °C for 16 h. After completion, the reaction was partitioned between saturated NH4Cl (5 mL) and ethyl acetate (8 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 1) to give the title compound (90 mg, 47%) as a yellow solid. MS (ESI): mass calcd. for C31H42N4O6S2: 630.25, found: 631.3 [M+H]+. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(3-methyl-2,4-dioxo-1-((tetrahydro-2H- pyran-4-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (110) To a solution of 1-(cyclobutylmethyl)-5-(1,3-dithian-2-ylidene)-3-[2-methyl-1,3- dioxo-4-(tetrahydropyran-4-ylmethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione (80 mg, 127 μmol) in THF (4 mL) was added NH3.H2O (4 mL). The reaction was stirred at 30 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was purified by prep-HPLC (mobile phase:H2O (10 mM NH4HCO3)- -65% B over 8.0 min).to give the title compound(5.0 mg, 7.1%) as a white solid. MS (ESI): mass calcd. for C28H40N6O6: 556.30, found: 557.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.64 (s, 1H), 3.79- 3.92 (m, 4H), 3.20-3.31 (m, 4H), 2.84 (s, 3H), 2.54-2.60 (m, 1H), 2.34 (d, J = 3.6 Hz, 1H), 2.27 (d, J = 13.2 Hz, 2H), 2.13-2.20 (m, 3H), 2.05 (s, 1H), 1.64-1.94 (m, 8H), 1.59 (d, J = 11.6 Hz, 2H), 1.41 (t, J = 12.0 Hz, 3H), 1.19-1.29 (m, 3H). Example 111. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5R,7r,10R)-3-methyl-2,4- dioxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (111) Synthetic scheme:

[0045] (5R,7r,10R)-10-amino-3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3 diazadispiro[4.1.57.15]tridecane-2,4-dione and (5S,7s,10S)-10-amino-3-methyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1,3 diazadispiro[4.1.57.15]tridecane-2,4-dione 10-amino-2-methyl-4-(tetrahydropyran-4-ylmethyl)-2,4-diazadispiro [4.1.57.15]tridecane-1,3-dione (1 g) was separated by chiral SFC (column: DAICEL 2-EtOH (0.1% NH3H2B with isocratic elution) to give (5R,7r,10R)-10-amino-3-methyl-1-((tetrahydro-2H-pyran-4- yl)methyl)-1,3 diazadispiro[4.1.57.15]tridecane-2,4-dione (480 mg) from the first eluting peak as a green solid. MS (ESI): mass calcd. for C18H29N3O3: 335.22, found: 336.4 [M+H]+. (5S,7s,10S)-10-amino-3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3 diazadispiro[4.1.57.15]tridecane-2,4-dione (480 mg) was obtained from the second eluting peak as a green solid. MS (ESI): mass calcd. for C18H29N3O3: 335.22, found: 336.4 [M+H]+. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5R,7r,10R)-3-methyl-2,4-dioxo-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (111) The title compound was prepared in a similar fashion to Example 110 starting from (5R,7r,10R)-10-amino-3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3 diazadispiro[4.1.57.15]tridecane-2,4-dione. MS (ESI): mass calcd. for C28H40N6O: 556.30, found: 557.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.53 (s, 2H), 7.30 (s, 2H), 4.57- 4.70 (m, 1H), 3.77-3.89 (m, 4H), 3.19-3.29 (m, 4H), 2.84 (s, 3H), 2.53-2.60 (m, 1H), 2.31-2.40 (m, 1H), 2.27 (d, J = 13.2 Hz, 2H), 2.12-2.21(m, 3H), 1.98-2.11 (m, 1H), 1.66-1.93 (m, 8H), 1.58 (d, J = 11.6 Hz, 2H), 1.34-1.48 (m, 3H), 1.16-1.29 (m, 3H). Example 112 was prepared in a similar fashion to Example 110 starting from (5S,7s,10S)-10- amino-3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3 diazadispiro[4.1.57.15]tridecane- 2,4-dione. Example 113. was prepared though a similar synthetic sequence to Example 110. 4- nitrophenyl ((tetrahydro-2H-pyran-4-yl)methyl)carbamate was used instead of 4-nitrophenyl (cyclobutylmethyl)carbamate, and 10-amino-3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)- 1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione was used instead of (5R,7r,10R)-10-amino-3- methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,3 diazadispiro[4.1.57.15]tridecane-2,4-dione. Example 114 and Example 115 were obtained though the chiral SFC separation of Example 113 using similar conditions to those reported for Example 26 and Example 27. Example 116. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-(3-ethyl-1-(oxetan-3- ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (116) Synthetic scheme:

[0046] 3-((2-(Trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.57.15]tridecane-2,4,10-trione To a solution of 1,3-diazadispiro[4.1.57.15]tridecane-2,4,10-trione (5 g, 22.5 mmol) in DMA (50 mL) was added K2CO3(6.22 g, 45 mmol) and SEM-Cl (5.63 g, 33.8 mmol). After stirring at 25 °C for 3 h, the reaction was diluted with H2O (150 mL) and extracted with EtOAc (3 x 70 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 0 to 1 : 2) to provide the title compound (1.33 g, 16.8%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) ppm 5.12-5.99 (m, 1H), 4.91-4.95 (m, 2H), 3.60-3.67 (m, 2H), 2.72 (d, J = 14.4 Hz, 1H), 2.57 (q, J = 13.6 Hz, 1H), 2.15-2.41 (m, 8H), 1.96-2.05 (m, 2H), 0.88-1.02 (m, 2H), 0.01 (s, 9H). 4-(oxetan-3-ylmethyl)-2-(2-trimethylsilylethoxymethyl)-2,4- diazadispiro[4.1.57.15]tridecane-1,3,10-trione To a solution of 3-(iodomethyl)oxetane (2.60 g, 13.11 mmol) and 2-(2- trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecane-1,3,10-trione (4.2 g, 11.91 mmol) in DMF (40 mL) was added Cs2CO3 (5.82 g,17.87 mmol). The mixture was stirred at 40 °C for 12 h. After completion, the mixture was poured into water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 20 : 1 to 1 : 1) to give the title compound (3.5 g, 70%) as a yellow solid. MS (ESI): mass calcd. for C21H34O5N2Si: 422.22, found: 423.2 [M+H]+. 10-amino-4-(oxetan-3-ylmethyl)-2-(2-trimethylsilylethoxymethyl)-2,4- diazadispiro[4.1.57.15]tridecane-1,3-dione To a solution of 4-(oxetan-3-ylmethyl)-2-(2-trimethylsilylethoxymethyl)-2,4- diazadispiro[4.1.57.15]tridecane-1,3,10-trione (3.5 g, 8.28 mmol) in NH3 / MeOH (40 mL) was stirred at 25 °C for 2 h. Raney Ni (709.6 mg, 8.28 mmol) was added under N2. The mixture was stirred under H2(15 psi) at 25 °C for 14 h. After completion, the mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (2.98 g, 85%) as a green solid. MS (ESI): mass calcd. for C21H37O4N3Si: 423.26, found: 424.1 [M+H]+. 1-(cyclopentylmethyl)-3-[4-(oxetan-3-ylmethyl)-1,3-dioxo-2-(2- trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10-yl]urea To a solution of 10-amino-4-(oxetan-3-ylmethyl)-2-(2-trimethylsilylethoxymethyl)- 2,4-diazadispiro[4.1.57.15]tridecane-1,3-dione (1.4 g, 3.3 mmol) in DCM (14 mL) was added TEA (669 mg, 6.6 mmol) and (4-nitrophenyl) N-(cyclopentylmethyl)carbamate (873.4 mg, 3.3 mmol). The mixture was stirred at 25 °C for 1 h. After completion, the mixture was poured into H2O (30 mL) and AcOH (20 mL). The aqueous phase was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether : ethyl acetate = 50 : 1 to 0 : 1) to afford the title compound (1.2 g, 66%) as a white solid. MS (ESI): mass calcd. for C28H48N4O5Si: 548.34, found: 549.4 [M+H]+. 1-(cyclopentylmethyl)-3-[4-(oxetan-3-ylmethyl)-1,3-dioxo-2-(2- trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione To a mixture of malonic acid (75.9 mg, 729 mol) in Ac2O (4 mL) and AcOH (4 mL) at 80 °C for 0.5 h. Then to the mixture was added 1-(cyclopentylmethyl)-3-[4-(oxetan-3- ylmethyl)-1,3-dioxo-2-(2-trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]urea (0.4 g, 729 mol) in dioxane (8 mL) and the reaction was stirred for 1.5 h. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated NaHCO3, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether : ethyl acetate = 50 : 1 to 0 : 1) to afford the title compound (0.24 g, 53%) as a white solid. MS (ESI): mass calcd. for C31H48N4O7Si: 616.33, found: 617.3 [M+H]+. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-[4-(oxetan-3-ylmethyl)-1,3-dioxo-2-(2- trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione To a mixture of 1-(cyclopentylmethyl)-3-[4-(oxetan-3-ylmethyl)-1,3-dioxo-2-(2- trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine- 2,4,6-trione (0.21 g, 341 mol) and cyanamide (143.1 mg, 3.4 mmol) in THF (2 mL) was added Ni(acac)2(26.2 mg, 102 mol) under N2. The reaction was stirred at 80 °C for 24 h. After completion, the mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether : ethyl acetate = 50 : 1 to 0 : 1) to afford the title compound (0.15 g, 67%) as a white solid. MS (ESI): mass calcd. for C32H50N6O7Si: 658.35, found: 659.4 [M+H]+. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-[4-(oxetan-3-ylmethyl)-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione To a mixture of 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-[4-(oxetan-3- ylmethyl)-1,3-dioxo-2-(2-trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione (0.15 g, 228 mol) in THF (2 mL) was added TBAF (1 M, 911 L). The reaction was stirred at 75 °C for 36 h. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether : ethyl acetate = 0 : 1) to give the title compound (35 mg, 29%) as a white solid. MS (ESI): mass calcd. for C26H36N6O6: 528.27, found: 529.3 [M+H]+. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-(3-ethyl-1-(oxetan-3-ylmethyl)-2,4-dioxo- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (116)

[0047] To a mixture of 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-[4-(oxetan-3- ylmethyl)-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6- trione (30 mg, 57 mol) in DMF (0.3 mL) was added iodoethane (9.74 mg, 62 mol) and K2CO3(8.63 mg, 62 mol). The reaction was stirred at 20 °C for 6 h. After completion, the reaction was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (20 mg, 63%) as a white solid. MS (ESI): mass calcd. for C28H40N6O6: 556.30, found: 557.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.55 (s, 2H), 7.31 (s, 2H), 4.58-4.69 (m, 3H), 4.38-4.45 (m, 2H), 3.68 (dd, J = 8.4, 16.0 Hz, 4H), 3.35-3.40 (m, 2H), 3.27-3.32 (m, 1H), 2.45 (s, 1H), 2.11-2.38 (m, 7H), 1.84 (d, J = 12.0 Hz, 1H), 1.50-1.60 (m, 4H), 1.34-1.49 (m, 5H), 1.17-1.27 (m, 3H), 1.05 (t, J = 7.2 Hz, 3H). Example 117 and Example 118 were obtained though the chiral SFC separation of Example 116 using similar conditions to those reported for Example 26 and Example 27. Example 119 was prepared in a similar fashion to Example 116. Cyanomethyl 4- methylbenzenesulfonate was used instead of iodoethane. Example 120 and Example 121. 2-((5R,7r,10R)-10-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-1-(2-methoxyethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-3-yl)acetonitrile (120) and 2-((5S,7s,10S)-10-(3-butyl-5- (diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-1-(2-methoxyethyl)-2,4- dioxo-1,3-diazadispiro[4.1.57.15]tridecan-3-yl)acetonitrile (121) Synthetic scheme: 1-butyl-5-(diaminomethylene)-3-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione The title compound was prepared in a similar synthetic sequence to Example 116, but with no alkylation of the hydantoin with 3-(iodomethyl)oxetane. 1-Butyl-5-(diaminomethylene)-3-[4-(2-methoxyethyl)-1,3-dioxo-2-(2- trimethylsilylethoxy methyl)-2,4-diazadispiro[4.1.57.15]tridecan-10- yl]hexahydropyrimidine-2,4,6-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (see Example 302 for synthesis, 500 mg, 0.89 mmol) in DMF (5 mL) was added K2CO3(369 mg, 2.67 mmol) and 1-iodo-2-methoxy-ethane (397 mg, 2.13 mmol). The reaction was heated at 80 °C for 12 h under N2. After completion, the reaction was quenched with H2O (20 mL) and extracted with DCM : isopropanol = 3 : 1 (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (H2O(10 mM NH4HCO3)- -70%) to give the title compound (80 mg, 14%) as acolorless oil. MS (ESI): mass calcd. for C29H48N6O7Si: 620.34, found: 643.4 [M+Na]+. 1-Butyl-5-(diaminomethylene)-3-[4-(2-methoxyethyl)-1,3-dioxo-2,4- diazadispiro[4.1.57.15] tridecan-10-yl]hexahydropyrimidine-2,4,6-trione A solution of 1-butyl-5-(diaminomethylene)-3-[4-(2-methoxyethyl)-1,3-dioxo-2-(2- trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine- 2,4,6-trione (80 mg, 0.13 mmol) in TFA (0.5 mL) and H2O (0.1 mL) was stirred for 2 h under N2at 25 °C. K2CO3(17.8 mg, 0.13 mmol) and MeOH (0.5 mL) were added under N2. After stirring for 1 h, the reaction was adjusted to pH = 6 with citric acid. The aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep- TLC (SiO2, petroleum ether : ethyl acetate = 0 : 1) to give the title compound (40 mg, 63%) as a colorless oil. MS (ESI): mass calcd. for C23H34N6O6: 490.25, found: 491.3 [M+H]+. 2-(10-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-1-(2- methoxyethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-3-yl)acetonitrile To a solution of 1-butyl-5-(diaminomethylene)-3-[4-(2-methoxyethyl)-1,3-dioxo-2,4- diazadispiro[4.1.57.15]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (20 mg, 0.041 mmol) in DMSO (0.5 mL) was added K2CO3(11.3 mg, 0.082 mmol) and cyanomethyl 4- methylbenzenesulfonate (8.6 mg, 0.041 mmol). After stirring at 25 °C for 4 h under N2, the reaction mixture was filtered and concentrated. The residue was purified by reverse phaseHPLC (H2O (10mM NH4HCO3)- -60%) to give the title compound (2.3 mg,11%) as a white solid. MS (ESI): mass calcd. for C25H35N7O6: 529.26, found: 530.3 [M+H]+. 2-((5R,7r,10R)-10-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin- 1(2H)-yl)-1-(2-methoxyethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-3- yl)acetonitrile (120) and 2-((5S,7s,10S)-10-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-1-(2-methoxyethyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-3-yl)acetonitrile (121) 2-[10-[3-butyl-5-(diaminomethylene)-2,4,6-trioxo-hexahydropyrimidin-1-yl]-S4-(2- methoxyethyl)-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tridecan-2-yl]acetonitrile (60 mg) was phase: CO2-IPA (0.1% NH3H2120 (17.57 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C25H35N7O6: 529.26, found: 530.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.30 (s, 2H), 4.58-4.71 (m, 1H), 4.53 (s, 2H), 3.73 (t, J = 7.2 Hz, 2H), 3.52-3.58 (m, 4H), 3.28 (s, 3H), 2.37-2.43 (m, 1H), 2.24-2.35 (m, 5H), 2.18 (d, J = 12.8 Hz, 1H), 1.83 (d, J = 11.6 Hz, 1H), 1.37-1.49 (m, 5H), 1.21-1.30 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H). 121 (19.37 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C25H35N7O6: 529.26, found: 530.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.30 (s, 2H), 4.58-4.69 (m, 1H), 4.53 (s, 2H), 3.73 (t, J = 7.2 Hz, 2H), 3.49-3.59 (m, 4H), 3.28 (s, 3H), 2.38-2.42 (m, 1H), 2.24-2.35 (m, 5H), 2.18 (d, J = 13.2 Hz, 1H), 1.83 (d, J = 12.4 Hz, 1H), 1.36-1.49 (m, 5H), 1.20-1.30 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H). Example 122. (R)-1-butyl-3-(4-cyclopropyl-1,3-dimethyl-2-oxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-5-(diaminomethylene)pyrimidine- 2,4,6(1H,3H,5H)-trione (122) 2,4-dimethyl-11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione To a solution of 2,4-dimethyl-11,14-dioxa-2,4- diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione (4 g, 13.6 mmol) in THF (70 mL) was added bromo(cyclopropyl)magnesium (1 M, 27.18 mL) dropwise at 0 °C over 3 min under N2. After addition, the mixture was stirred at 20 °C for 1.5 h under N2. The reaction was quenched with saturated NH4Cl (20 mL), diluted with H2O (10 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with ethyl acetate (10 mL) to give the title compound (4.8 g, crude) as a white solid. MS (ESI): mass calcd. for C18H28N2O4: 336.20, found: 337.0 [M+H]+. 1-cyclopropyl-2,4-dimethyl-2,4-diazadispiro[4.1.57.15]tridecane-3,10-dione To a solution of 1-cyclopropyl-1-hydroxy-2,4-dimethyl-11,14-dioxa-2,4- diazatrispiro[4.1.2.410.27.15]heptadecan-3-one (1.9 g, 5.65 mmol) in DCM (20 mL) was added TFA (3.22 g, 28.24 mmol) and triethylsilane (3.28 g, 28.24 mmol). The mixture was stirred at 20 °C for 1 h and concentrated under reduced pressure. The residue was dissolved in H2O (3 mL) and acetone (15 mL), and added TsOH.H2O (2.15 g, 11.3 mmol). The mixture was stirred at 25 °C for 3 h under N2, adjusted to pH = 9 with saturated NaHCO3(20 mL) and extracted with ethyl acetate (20 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 (2.1 g, crude) as a colorless oil. MS (ESI): mass calcd. for C16H24N2O2: 276.18, found: 277.2 [M+H]+. (R)-4-cyclopropyl-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,10-dione and (S)- 4-cyclopropyl-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,10-dione 1-cyclopropyl-2,4-dimethyl-2,4-diazadispiro[4.1.57.15]tridecane-3,10-dione (2.1 g) was separated by chiral SFC (column: DAICEL CHIRALPAK AY-H (250mm^30mm, 10 2-EtOH (0.1% NH3.H2-4- cyclopropyl-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,10-dione (870 mg) from the first eluting peak as a yellow oil. MS (ESI): mass calcd. for C16H24N2O2: 276.18, found: 277.2 [M+H]+. (S)-4-cyclopropyl-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,10-dione (885 mg) was obtained from the second eluting peak as a white solid. MS (ESI): mass calcd. for C16H24N2O2: 276.18, found: 277.2 [M+H]+. The stereochemistry for these two compounds is arbitrarily assigned. (R)-10-amino-4-cyclopropyl-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecan-2-one A solution of (R)-4-cyclopropyl-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane- 2,10-dione (770 mg, 2.79 mmol) in NH3 / MeOH (7 M, 7.96 mL) was stirred at 20 °C for 1 h. The mixture was added Raney-Ni (477.4 mg) in one portion at 20 °C under H2(15 Psi) and stirred at 20 °C for 15 h under H2(15 Psi). The mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (750 mg, crude) as a colorless oil. MS (ESI): mass calcd. for C16H27N3O: 277.22, found: 278.2 [M+H]+. (R)-1-butyl-3-(4-cyclopropyl-1,3-dimethyl-2-oxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)urea To a solution of (R)-10-amino-4-cyclopropyl-1,3-dimethyl-1,3- diazadispiro[4.1.57.15]tridecan-2-one (750 mg, 2.7 mmol) in DCM (8 mL) was added TEA (547.2 mg, 5.41 mmol) and 1-isocyanatobutane (294.8 mg, 2.97 mmol). The mixture was stirred at 20 °C for 1 h. The reaction was quenched with H2O (25 mL) and extracted with DCM (30 mL x 2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane : methanol = 10 : 1) to provide the title compound (1 g, 93%) as a colorless oil. MS (ESI): mass calcd. for C21H36N4O2: 376.28, found: 377.4 [M+H]+. (R)-1-butyl-3-(4-cyclopropyl-1,3-dimethyl-2-oxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of Ac2O (1.3 mL) in AcOH (1.3 mL) was added malonic acid (69 mg, 664 mol). The mixture was stirred at 20 °C for 0.5 h. (R)-1-butyl-3-(4-cyclopropyl-1,3-dimethyl- 2-oxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)urea (250 mg, 664 mol) was added to the mixture. The reaction was stirred at 80 °C for 1 h, quenched with H2O (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with H2O, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 99 : 1 to 40 : 60) to give the title compound (170 mg, 52%) as a colorless oil. MS (ESI): mass calcd. for C24H36N4O4: 444.27, found: 445.2 [M+H]+. (R)-1-butyl-3-(4-cyclopropyl-1,3-dimethyl-2-oxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (122) To a solution of (R)-1-butyl-3-(4-cyclopropyl-1,3-dimethyl-2-oxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (45 mg, 101 mol) in THF (1 mL) was added cyanamide (127.7 mg, 3.04 mmol) and Ni(acac)2 (26 mg, 101 mol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC to give the title compound (18.3 mg, 37%) as a white solid. MS (ESI): mass calcd. for C25H38N6O4: 486.30, found: 487.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.30 (s, 2H), 4.65 (t, J = 10.0 Hz, 1H), 3.74 (t, J = 7.2 Hz, 2H), 3.40 (dd, J = 2.4, 6.8 Hz, 1H), 2.65 (dd, J = 11.6, 16.0 Hz, 6H), 2.28-2.46 (m, 2H), 1.98 (t, J = 14.4 Hz, 1H), 1.51-1.68 (m, 3H), 1.41- 1.50 (m, 3H), 1.31-1.39 (m, 3H), 1.19-1.30 (m, 3H), 1.13-1.18 (m, 1H), 1.00-1.12 (m, 1H), 0.88 (t, J = 7.2 Hz, 3H), 0.46-0.59 (m, 1H), 0.26-0.43 (m, 2H), 0.03-0.19 (m, 1H). Example 123 and Example 124 were obtained though the chiral SFC separation of Example 122 using similar conditions to those reported for Example 26 and Example 27. The stereochemistry for these two compounds is arbitrarily assigned. Example 125 was prepared in a similar fashion to Example 122. (R)-4-cyclopropyl-1,3- dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,10-dione was used instead of (S)-4- cyclopropyl-1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,10-dione. The stereochemistry for this compound is arbitrarily assigned. Example 126 and Example 127 were obtained though the chiral SFC separation of Example 122 using similar conditions to those reported for Example 26 and Example 27. The stereochemistry for these two compounds is arbitrarily assigned. Example 128. 1-butyl-5-(diaminomethylene)-3-(2,4-dioxo-3- azadispiro[5.1.58.16]tetradecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (128) Synthetic scheme:

[0048] Ethyl 2-(8,11-dioxadispiro[3.2.47.24]tridecan-2-ylidene)acetate A suspension of NaH (1.53 g, 38.2 mmol, 60% in mineral oil) in THF (30 mL) under N2was cooled down to 0 °C. Ethyl 2-diethoxyphosphorylacetate (9.71 g, 43.3 mmol) was added dropwise with vigorous stirring. After stirring at 0 °C for 30 min, 8,11- dioxadispiro[3.2.47.24]tridecan-2-one (5 g, 25.5 mmol) in THF (20 mL) was added dropwise. The reaction was stirred at 25 °C for 16 h under N2, poured into saturated aqueous NH4Cl (50 mL) and stirred for 2 min. The aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 10 : 1) to give the title compound (5.49 g, 81%) as a white solid. MS (ESI): mass calcd. for C15H22O4: 266.15, found: 267.0 [M+H]+. dimethyl 2-(2-(2-ethoxy-2-oxoethyl)-8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)malonate To a solution of ethyl 2-(8,11-dioxadispiro[3.2.47.24]tridecan-2-ylidene)acetate (10 g, 37.55 mmol) in DMA (100 mL) was added dimethyl propanedioate (17.36 g, 131.4 mmol) and Cs2CO3(61.17 g, 187.7 mmol). The mixture was stirred at 70 °C for 16 h under N2. After completion, the reaction was quenched with H2O (200 mL) and extracted with ethyl acetate (250 mL x 2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 4 : 6) to give the title compound (11 g, 74%) MS (ESI): mass calcd. for C20H30O8: 398.19, found: 399.3 [M+H]+. ethyl 2-(2-(2-methoxy-2-oxoethyl)-8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)acetate To a solution of dimethyl 2-[2-(2-ethoxy-2-oxo-ethyl)-8,11- dioxadispiro[3.2.47.24]tridecan-2-yl]propanedioate (9.4 g, 23.6 mmol) in DMSO (5 mL) and H2O (0.5 mL) was added NaCl (2.76 g, 47.2 mmol). The solution was stirred at 145 °C for 12 h. NaCl (2.76 g, 47.2 mmol) was added and stirred at 145 °C for 12 h. After the completion, the reaction was partitioned between ethyl acetate (100 mL) and brine (50 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 10 : 1) to give the title compound (2.43 g, 30%) as a colorless oil.1H NMR (400 MHz, CDCl3) ppm 4.11 (q, J = 7.2 Hz, 2H), 3.91 (s, 4H), 3.65 (s, 3H), 2.67 (d, J = 10.0 Hz, 4H), 1.89 (s, 4H), 1.64 (d, J = 6.4 Hz, 4H), 1.52-1.59 (m, 4H), 1.24 (t, J = 7.2 Hz, 3H). 2,2'-(8,11-dioxadispiro[3.2.47.24]tridecane-2,2-diyl)diacetic acid To a solution of methyl 2-[2-(2-ethoxy-2-oxo-ethyl)-8,11- dioxadispiro[3.2.47.24]tridecan-2-yl]acetate (2 g, 5.88 mmol) in H2O (20 mL) and MeOH (20 mL) was added NaOH (705 mg, 17.63 mmol). The mixture was stirred at 20 °C for 24 h and concentrated under reduced pressure. The residue was adjusted to pH = 7 with citric acid. The mixture was filtered, and the filter cake was dried under vacuum to provide the title compound (1.74 g, 99%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 12.03 (s, 2H), 3.82 (s, 4H), 2.55 (s, 4H), 1.79 (s, 4H), 1.56 (dd, J = 3.6, 7.2 Hz, 4H), 1.40-1.47 (m, 4H). 13-(4-methoxybenzyl)-1,4-dioxa-13-azatrispiro[4.2.1.510.18.25]octadecane-12,14-dione A solution of 2-[2-(carboxymethyl)-8,11-dioxadispiro[3.2.47.24]tridecan-2-yl]acetic acid (500 mg, 1.68 mmol) and DCC (380.4 mg, 1.84 mmol) in DMF (5 mL) was stirred at 20 °C for 1.5 h. A solution of PMBNH2(241.4 mg, 1.76 mmol) in DMF (5 mL) was added and the mixture was stirred for 18 h at 20 °C. The precipitate was separated by filtration. The filtrate was concentrated under reduced pressure. NaOAc (412.4 mg, 5.03 mmol) and Ac2O (10 mL) were added to the residue. The resulting mixture was heated at 100 °C for 2 h. After completion, the reaction was partitioned between H2O (5 mL) and ethyl acetate (10 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 7 : 3) to provide the title compound (460 mg, 69%) as a white solid. MS (ESI): mass calcd. for C23H29O5N: 399.20, found: 400.3 [M+H]+. 3-(4-methoxybenzyl)-3-azadispiro[5.1.58.16]tetradecane-2,4,11-trione To a solution of 13-[(4-methoxyphenyl)methyl]-1,4-dioxa-13- azatrispiro[4.2.1.510.18.25]octadecane-12,14-dione (460 mg, 1.15 mmol) in acetone (5 mL) was added TsOH.H2O (438 mg, 2.3 mmol) and H2O (1 mL). The mixture was stirred at 20 °C for 6 h. After completion, the reaction mixture was partitioned between H2O (10 mL) and ethyl acetate (20 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 65 : 35) to give the title compound (255 mg, 62%) as a white solid. MS (ESI): mass calcd. for C21H25O4N: 355.18, found: 356.2 [M+H]+. 11-amino-3-(4-methoxybenzyl)-3-azadispiro[5.1.58.16]tetradecane-2,4-dione To a solution of 11-[(4-methoxyphenyl)methyl]-11-azadispiro[5.1.58.16]tetradecane- 3,10,12-trione (200 mg, 563 μmol) in MeOH (4 mL) was added NH4OAc (867.5 mg, 11.25 mmol) and NaBH(OAc)3(238.5 mg, 1.13 mmol). After stirring at 20 °C for 1 h, the reaction was concentrated under reduced pressure to give the title compound (200 mg, crude) as a white solid. MS (ESI): mass calcd. for C21H28N2O3: 356.21, found: 357.1 [M+H]+. 1-butyl-5-(diaminomethylene)-3-(3-(4-methoxybenzyl)-2,4-dioxo-3- azadispiro[5.1.58.16]tetradecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione The title compound was prepared using the last three synthetic steps from Example 122. 1-butyl-5-(diaminomethylene)-3-(2,4-dioxo-3-azadispiro[5.1.58.16]tetradecan-11- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (128) To a solution of 1-butyl-5-(diaminomethylene)-3-[11-[(4-methoxyphenyl)methyl]- 10,12-dioxo-11-azadispiro[5.1.58.16]tetradecan-3-yl]hexahydropyrimidine-2,4,6-trione (50 mg, 88.4 μmol) in TFA (1 mL) was added methanesulfonic acid (1 mL). The reaction was stirred at 70 °C for 50 h and was purified by prep-HPLC to provide the title compound (9 mg, 23%) as a white solid. MS (ESI): mass calcd. for C22H31O5N5: 445.23, found: 446.1 [M+H]+.1H NMR (400 MHz, DMSO-d6): ppm 10.72 (s, 1H), 9.53 (s, 2H), 7.29 (s, 2H), 4.67-4.47 (m, 1H), 3.72 (t, J = 7.2 Hz, 2H), 2.60 (s, 4H), 2.26-2.41 (m, 2H), 1.69-1.79 (m, 4H), 1.64 (s, 2H), 1.44 (t, J = 7.2 Hz, 2H), 1.19- 1.38 (m, 6H), 0.87 (t, J = 7.2 Hz, 3H). Example 129 was prepared in a similar fashion to Example 128. Methylamine instead of (4- methoxyphenyl)methanamine. No deprotection sequence was needed. Example 130. 1-butyl-5-(diaminomethylene)-3-(2-methyl-3-oxo-2- azadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (130) Synthetic scheme: Ethyl 2-[2-(nitromethyl)-8,11-dioxadispiro[3.2.47.24]tridecan-2-yl]acetate To a solution of ethyl 2-(8,11-dioxadispiro[3.2.47.24]tridecan-2-ylidene)acetate (5.4 g, 20.3 mmol) in THF (54 mL) was added nitromethane (6.3 g, 103 mmol) and TBAF (1 M, 31.4 mL). The reaction was heated at 70 °C for 5 h. The reaction was then cooled to 25 °C, poured into water (80 mL) and stirred vigorously for 2 min. The aqueous phase was extracted with EtOAc (80 mL x 2). The combined organic phase was washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 3 : 1) to give the title compound (5.3 g, 79%) as a yellow oil. MS (ESI): mass calcd. for C16H25NO6: 327.17, found: 328.3 [M+H]+. Ethyl 2-[2-(aminomethyl)-8,11-dioxadispiro[3.2.47.24]tridecan-2-yl]acetate To a solution of ethyl 2-[2-(nitromethyl)-8,11-dioxadispiro[3.2.47.24]tridecan-2- yl]acetate (4.75 g, 14.5 mmol) in EtOH (35.7 mL) and H2O (11.8 mL) was added Fe (3.89 g, 69.7 mmol) and NH4Cl (3.73 g, 69.7 mmol). The mixture was heated to 80 °C for 5 h and cooled to room temperature. The mixture was filtered over Celite and the filtrate was concentrated under reduced pressure. The residue was diluted with H2O (20 mL), adjusted to pH = 10 with saturated aqueous NaHCO3and extracted with DCM (60 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 (3.69 g) as a yellow solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C16H27NO4: 297.19, found: 298.0 [M+H]+. 11,14-Dioxa-3-azatrispiro[4.1.2.410.27.15]heptadecan-2-one A mixture of ethyl 2-[2-(aminomethyl)-8,11-dioxadispiro[3.2.47.24]tridecan-2- yl]acetate (3.69 g, 12.4 mmol) and NaOH (0.55 g, 13.7 mmol) in H2O (36.9 mL) was stirred at 25 °C for 5 h. The reaction was filtered and the solid was dried under vacuum to give the title compound (2.7 g) as a white solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C14H21NO3: 251.15, found: 252.3 [M+H]+. 3-methyl-11,14-dioxa-3-azatrispiro[4.1.2.410.27.15]heptadecan-2-one A mixture of 11,14-dioxa-3-azatrispiro[4.1.2.410.27.15]heptadecan-2-one (820 mg, 3.26 mmol), MeI (694.7 mg, 4.89 mmol), Cs2CO3(1.06 g, 3.26 mmol) in DMF (8.2 mL) was stirred at 25 °C for 16 h. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 2 : 1) to give the title compound (250 mg, 29%) as a white solid.1H NMR (400 MHz, CDCl3) ppm 3.82 (s, 4H), 3.34 (s, 2H), 2.67 (s, 3H), 2.33 (s, 2H), 1.76-1.89 (m, 4H), 1.40-1.59 (m, 8H). 3-methyl-3-azadispiro[4.1.57.15]tridecane-2,10-dione To a solution of 3-methyl-11,14-dioxa-3-azatrispiro[4.1.2.410.27.15]heptadecan-2-one (130 mg, 490 mol) in acetone (0.6 mL) was added 4-methylbenzenesulfonic acid hydrate (186.4 mg, 980 mol) and H2O (0.3 mL). The mixture was stirred at 25oC for 5 h under N2. After completion, the reaction was quenched with saturated NaHCO3(10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep- TLC (SiO2, petroleum ether : ethyl acetate = 0 : 1, Rf= 0.21) to give the title compound (75 mg, 69%) as a white solid. MS (ESI): mass calcd. for C13H19O2N: 221.14, found: 222.2 [M+H]+. 10-amino-3-methyl-3-azadispiro[4.1.57.15]tridecan-2-one To a solution of 3-methyl-3-azadispiro[4.1.57.15]tridecane-2,10-dione (70 mg, 316 mol) in MeOH (1 mL) was added NH4OAc (487.7 mg, 6.33 mmol) and NaBH(OAc)3(134.1 mg, 632.6 mol). The reaction was stirred at 25 °C for 3 h and concentrated under reduced pressure. The residue was poured into H2O (5 mL) and extracted with ethyl acetate (5 mL x 2). The organic phase was dried and concentrated under reduced pressure to give the title compound (70 mg, 99%) as a colorless oil. MS (ESI): mass calcd. for C13H22ON2: 222.17, found: 223.0 [M+H]+. 1-butyl-5-(diaminomethylene)-3-(2-methyl-3-oxo-2-azadispiro[4.1.57.15]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (130) The title compound was prepared according to the last three steps of Example 122 starting from 10-amino-3-methyl-3-azadispiro[4.1.57.15]tridecan-2-one. MS (ESI): mass calcd. for C22H33N5O4: 431.25, found: 432.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.29 (s, 2H), 4.53-4.67 (m, 1H), 3.66-3.77 (m, 2H), 3.36 (d, J = 2.8 Hz, 2H), 2.68 (s, 3H), 2.25-2.43 (m, 4H), 1.76-1.94 (m, 4H), 1.70 (d, J = 8.8 Hz, 2H), 1.17-1.53 (m, 8H), 0.87 (t, J = 7.2 Hz, 3H). Example 131. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-(2,4-dimethyl-3-oxo-1,4- diazadispiro[4.1.57.15]tridec-1-en-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (131) Synthetic scheme:

[0049] 2,4-dimethyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadecan-3-one To a solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (1.76 g, 8.95 mmol) and 2- amino-N-methyl-propanamide hydrochloride (1.24 g, 8.95 mmol) in MeOH (15 mL) was added TEA (905 mg, 8.95 mmol). The mixture was stirred at 80 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane : methanol = 1 : 0 to 99 : 1) to give the title compound (1.83 g, 73%) as a white solid. MS (ESI): mass calcd. for C15H24N2O3: 280.18, found: 281.2 [M+H]+. 2,4-dimethyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadec-1-en-3-one To a solution of 2,4-dimethyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadecan- 3-one (1.78 g, 6.35 mmol) in DCE (20 mL) was added MnO2(11.04 g, 127 mmol). The reaction was stirred at 80 °C for 16 h. After completion, the reaction mixture was diluted with DCM (30 mL), filtered through a pad of silica gel and washed with DCM (40 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane : methanol = 1 : 0 to 98.5 : 1.5) to give the title compound (830 mg, 47%) as a colorless oil. MS (ESI): mass calcd. for C15H22N2O3: 278.16, found: 279.2 [M+H]+. 2,4-dimethyl-1,4-diazadispiro[4.1.57.15]tridec-1-ene-3,10-dione To a solution of 2,4-dimethyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadec-1- en-3-one (830 mg, 2.98 mmol) in acetone (6 mL) and H2O (3 mL) was added TsOH.H2O (567.21 mg, 2.98 mmol). The mixture was stirred at 25 °C for 4 h. After completion, the reaction mixture was adjusted to pH = 9 with aqueous NaHCO3. The reaction mixture was extracted with DCM : IPA (10 : 1, 40 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane : methanol = 1 : 0 to 97 : 3) to give the title compound (540 mg, 77%) as white solid. MS (ESI): mass calcd. for C13H18N2O2: 234.14, found: 235.2 [M+H]+. 10-amino-2,4-dimethyl-1,4-diazadispiro[4.1.57.15]tridec-1-en-3-one A solution of 2,4-dimethyl-1,4-diazadispiro[4.1.57.15]tridec-1-ene-3,10-dione (490 mg, 2.09 mmol) in NH3 / MeOH (5.95 mL) was stirred at 20 °C for 1 h. Raney-Ni (35.84 mg, 418.28 mol) was added in one portion at 20 °C under H2(15 Psi). After stirring for 15 h, the reaction was filtered through a Celite pad and washed with MeOH (20 mL). The filtrate was concentrated to give the title compound (487 mg, 99%) as a light green solid. MS (ESI): mass calcd. for C13H21N3O: 235.17, found: 236.0 [M+H]+. 1-(cyclopentylmethyl)-3-(2,4-dimethyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en-10- yl)urea To a solution of (4-nitrophenyl) N-(cyclopentylmethyl)carbamate (541.3 mg, 2.05 mmol) in DCM (6 mL) was added TEA (414.52 mg, 4.1 mmol) and 10-amino-2,4-dimethyl- 1,4-diazadispiro[4.1.57.15]tridec-1-en-3-one (482 mg, 2.05 mmol). The mixture was stirred at 20 °C for 4 h. After completion, the reaction was partitioned between ethyl acetate (50 mL) and saturated NH4Cl (50 mL). The organic phase was separated, washed with saturated NH4Cl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane : methanol = 1 : 0 to 97 : 3) to give the title compound (490 mg, 66%) as a white solid. MS (ESI): mass calcd. for C20H32N4O2: 360.25, found: 361.3 [M+H]+. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-(2,4-dimethyl-3-oxo-1,4- diazadispiro[4.1.57.15]tridec-1-en-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (131) The title compound was prepared according to the last two steps of Example 122. MS (ESI): mass calcd. for C24H34N6O4: 470.26, found: 471.3 [M+H]+.1H NMR (400 MHz, DMSO- d6) ppm 9.55 (s, 2H), 7.30 (s, 2H), 4.61-4.76 (m, 1H), 3.71 (d, J = 7.2 Hz, 2H), 2.96 (s, 3H), 2.40-2.44 (m, 1H), 2.35 (d, J = 12.8 Hz, 3H), 2.17-2.26 (m, 1H), 2.09-2.12 (m, 1H), 2.07 (s, 3H), 1.89-2.02 (m, 1H), 1.80 (d, J = 12.4 Hz, 1H), 1.50-1.63 (m, 5H), 1.36-1.50 (m, 6H), 1.16- 1.27 (m, 2H). Example 132.1-butyl-5-(diaminomethylene)-3-(5''-oxo-5'',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[3,4-b]pyridin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (132) Synthetic scheme:

[0050] 8,11-dioxadispiro[3.2.47.24]tridecan-2-ol To a solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (40 g, 203.83 mmol) in THF (400 mL) was added LiAlH4(2.5 M, 97.84 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h under N2. After completion, the mixture was quenched with H2O (10 mL) at 0 °C, 15% NaOH (10 mL) at 0 °C and stirred at 0 °C for 30 min. The mixture was diluted with H2O (25 mL), ethyl acetate (200 mL), and filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 : 1 to 1 : 100) to give the title compound (32 g, 79%) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) ppm 4.23-4.30 (m, 1H), 3.86-3.97 (m, 4H), 2.20- 2.32 (m, 2H), 2.08 (s, 1H), 1.60-1.68 (m, 4H), 1.52-1.59 (m, 6H). 8,11-dioxadispiro[3.2.47.24]tridecan-2-yl methanesulfonate To a solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-ol (32 g, 161.41 mmol) in DCM (320 mL) was added TEA (65.33 g, 645.62 mmol) and MsCl (36.98 g, 322.81 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h under N2. After completion, the mixture was poured into ice-water (100 mL), extracted with DCM (100 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 : 1 to 1 : 100) to give the title compound (23.6 g, 52.9%) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) ppm 4.96-5.03 (m, 1H), 3.92 (s, 4H), 2.97 (s, 3H), 2.34-2.43 (m, 2H), 2.01-2.09 (m, 2H), 1.66-1.71 (m, 2H), 1.62-1.69 (m, 2H), 1.54-1.61 (m, 4H). 8,11-dioxadispiro[3.2.47.24]tridecane-2-carbonitrile To a solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-yl methanesulfonate (23.6 g, 85.4 mmol) in DMSO (240 mL) was added 18-crown-6 (22.57 g, 85.4 mmol), NaI (12.80 g, 85.4 mmol) and KCN (8.34 g, 128.1 mmol). The mixture was stirred at 80 °C for 12 h under N2. After completion, the reaction was diluted with H2O (250 mL), and extracted with ethyl acetate (250 mL x 3). 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 = 100 : 1 to 1 : 100) to give the title compound (5.67 g, 32%) as a colorless oil.1H NMR (400 MHz, CDCl3) ppm 3.92 (s, 4H), 2.98-3.07 (m, 1H), 2.12-2.26 (m, 4H), 1.72-1.77 (m, 2H), 1.63-1.69 (m, 2H), 1.53-1.60 (m, 4H). 2-(3-bromopyridin-2-yl)-8,11-dioxadispiro[3.2.47.24]tridecane-2-carbonitrile A mixture of 8,11-dioxadispiro[3.2.47.24]tridecane-2-carbonitrile (8.4 g, 40.53 mmol) in toluene (85 mL) was degassed and purged with N2 for 3 times. NaHMDS (1 M, 44.58 mL) was added to the mixture dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. 3- bromo-2-fluoro-pyridine (7.13 g, 40.53 mmol) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 30 min under N2. After completion, the reaction was quenched with saturated NH4Cl (50 mL) at 0 °C, diluted with H2O (50 mL) and extracted with ethyl acetate (80 mL x 3). 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 = 9 : 1 to 7 : 3) to give the title compound (9.5 g, 88%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 8.58-8.65 (m, 1H), 8.17-8.24 (m, 1H), 7.33-7.46 (m, 1H), 3.81-3.86 (m, 4H), 2.65-2.82 (m, 4H), 1.82-1.94 (m, 2H), 1.58-1.65 (m, 2H), 1.40-1.44 (m, 4H). 2-(3-bromopyridin-2-yl)-8,11-dioxadispiro[3.2.47.24]tridecane-2-carboxamide To a solution of 2-(3-bromopyridin-2-yl)-8,11-dioxadispiro[3.2.47.24] tridecane-2- carbonitrile (10.5 g, 28.9 mmol) in DMSO (100 mL) was added K2CO3 (7.99 g, 57.8 mmol), then H2O2(9.83 g, 86.7 mmol, 8.33 mL, 30% w / w in water) was added at 0 °C under N2. The mixture was stirred at 20 °C for 48 h. After completion, the mixture was quenched with saturated Na2SO3(30 mL) , diluted with H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 5 : 1 to 1 : 1) to give the title compound (9.7 g, 88%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 8.55-8.58 (m, 1H), 8.00-8.03 (m, 1H), 7.22- 7.26 (m, 1H), 6.90 (s, 1H), 6.22 (s, 1H), 3.79-3.82 (m, 4H), 2.52 (s, 4H), 1.60-1.76 (m, 2H), 1.44-1.53 (m, 2H), 1.34-1.42 (m, 2H), 1.25-1.34 (m, 2H). 2-(3-bromopyridin-2-yl)-8,11-dioxadispiro[3.2.47.24]tridecan-2-amine To a solution of 2-(3-bromopyridin-2-yl)-8,11-dioxadispiro[3.2.47.24] tridecane-2- carboxamide (10.4 g, 27.28 mmol) in n-BuOH (100 mL) was added NaOH (2.18 g, 54.56 mmol) and NaClO (40.17 mL, 68.2 mmol, 10.5% purity). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was poured into saturated NH4Cl (100 mL), extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 4 : 1 to 1 : 1) to give the title compound (8 g, 83%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) ppm 8.46-8.49 (m, 1H), 8.00- 8.03 (m, 1H), 7.17-7.21 (m, 1H), 3.81-3.84 (m, 4H), 2.57 (d, J = 12.8 Hz, 2H), 2.18 (s, 2H), 1.95-2.04 (m, 2H), 1.79-1.91 (m, 2H), 1.47-1.57 (m, 2H), 1.37-1.45 (m, 2H), 1.25-1.35 (m, 2H). tert-butyl N-[2-(3-bromo-2-pyridyl)-8,11-dioxadispiro[3.2.47.24]tridecan-2-yl]carbamate To a solution of 2-(3-bromo-2-pyridyl)-8,11-dioxadispiro[3.2.47.24]tridecan-2-amine (1.4 g, 3.96 mmol) in DCM (15 mL) was added Boc2O (1.04 g, 4.76 mmol) and TEA (1.00 g, 9.91 mmol). The mixture was stirred at 25 °C for 16 h. The reaction was diluted with H2O (30 mL) and extracted with ethyl acetate (30 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 = 95 : 5 to 80 : 20) to give the title compound (1.4 g, 75%) as a white solid. MS (ESI): mass calcd. for C21H29N2BrO4: 452.13, found: 453.2 / 455.2 [M+H]+. 2-(2-amino-8,11-dioxadispiro [3.2.47.24] tridecan-2-yl) pyridine-3-carbonitrile A mixture of tert-butyl N-[2-(3-bromo-2-pyridyl)-8,11-dioxadispiro[3.2.47.24]tridecan- 2-yl] carbamate (1.4 g, 3.09 mmol), Zn(CN)2(802 mg, 6.83 mmol), Pd(PPh3)4(535.25 mg, 463.2 mol) in DMF (2 mL) was degassed and purged with N23 times. The mixture was stirred at 120 °C for 16 h under N2, cooled down, poured into water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 0 : 1 to ethyl acetate: methanol = 0 : 1) to give the title compound (300 mg, 32%) as a white solid. MS (ESI): mass calcd. for C17H21N3O2: 299.16, found: 300.1 [M+H]+. trispiro[pyrrolo[3,4-b]pyridine-7,1'-cyclobutane-3',1''-cyclohexane-4'',2'''- [1,3]dioxolan]-5(6H)-one To a solution of 2-(2-amino-8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)pyridine-3- carbonitrile (300 mg, 1.0 mmol) in DMSO (2 mL) was added NaOH (4 M, 6 mL). The mixture was stirred at 100 °C for 16 h. The reaction was adjusted to pH = 7 by 1 N HCl, diluted with H2O (20 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. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 30 : 70 to ethyl acetate: methanol = 50 : 50) to give the title compound (200 mg, 65%) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) ppm 8.73 (dd, J = 1.6, 4.8 Hz, 1H), 7.98 (dd, J = 1.6, 7.6 Hz, 1H), 7.30 (dd, J = 4.8, 7.6 Hz, 1H), 6.49 (s, 1H), 3.90 (s, 4H), 2.65 (d, J = 14.0 Hz, 2H), 2.19 (d, J = 13.6 Hz, 2H), 1.94-2.07 (m, 2H), 1.72-1.84 (m, 2H), 1.56-1.64 (m, 4H). dispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[3,4-b]pyridine]-4,5''(6''H)-dione To a solution of trispiro[pyrrolo[3,4-b]pyridine-7,1'-cyclobutane-3',1''-cyclohexane- 4'',2'''-[1,3]dioxolan]-5(6H)-one (200 mg, 665.9 mol) in H2O (1 mL), acetone (1 mL) was added followed by TsOH.H2O (253.3 mg, 1.33 mmol). The mixture was stirred at 25 °C for 16 h. The reaction was diluted with H2O (20 mL) and extracted with ethyl acetate (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 (140 mg, 82%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 9.31 (s, 1H), 8.81 (dd, J = 1.6, 6.4 Hz, 1H), 7.99 (dd, J = 1.2, 7.6 Hz, 1H), 7.49 (dd, J = 5.2, 7.6 Hz, 1H), 2.44 (d, J = 13.2 Hz, 4H), 2.28-2.37 (m, 2H), 2.22 (d, J = 12.8 Hz, 2H), 1.69-1.71 (m, 2H), 1.57 (s, 2H). 4-aminodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[3,4-b]pyridin]-5''(6''H)-one To a solution of dispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[3,4-b]pyridine]- 4,5''(6''H)-dione (130 mg, 507 mol) in MeOH (13 mL) was added NH4OAc (977.44 mg, 12.68 mmol) and NaBH(OAc)3(430 mg, 2.03 mmol). The mixture was stirred at 20 °C for 4 h. The reaction was concentrated under reduced pressure, diluted with saturated NaHCO3(20 mL) and extracted with (DCM : IPA = 3 : 1) (30 mL x 5). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (100 mg, crude) as a white solid. MS (ESI): mass calcd. for C15H19N3O: 257.15, found: 258.1 [M+H]+. 1-butyl-3-(5''-oxo-5'',6''-dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[3,4- b]pyridin]-4-yl)urea A mixture of 4-aminodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[3,4- b]pyridin]-5''(6''H)-one (100 mg, 388.6 mol), 1-isocyanatobutane (46.2 mg, 466 mol), TEA (157.3 mg, 1.55 mmol) in DCM (6 mL) was degassed and purged with N23 times. The mixture was stirred at 25 °C for 20 min under N2. The reaction was diluted with H2O (20 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. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 20 : 80 to ethyl acetate : methanol = 1 : 1) to give the title compound (80 mg, 56%) as a white solid.1H NMR (400 MHz, CDCl3) ppm 8.72 (d, J = 4.8 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.30 (dd, J = 5.0, 7.6 Hz, 1H), 6.84 (s, 1H), 3.49-3.51 (m, 1H), 3.09 (t, J = 6.4 Hz, 2H), 2.53-2.66 (m, 2H), 2.21-2.38 (m, 1H), 2.17 (d, J = 13.2 Hz, 2H), 1.74-1.93 (m, 4H), 1.47-1.68 (m, 4H), 1.37-1.45 (m, 2H), 1.24-1.33 (m, 2H), 0.70-0.91 (m, 4H). 1-butyl-3-(5''-oxo-5'',6''-dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[3,4- b]pyridin]-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-(5''-oxo-5'',6''-dihydrodispiro[cyclohexane-1,1'-cyclobutane- 3',7''-pyrrolo[3,4-b]pyridin]-4-yl)urea (75 mg, 210 mol), malonic acid (24.08 mg, 231 mol) in AcOH (2 mL) was added Ac2O (150 mg, 1.47 mmol). The mixture was stirred at 70 °C for 7 h. The reaction mixture was adjusted to pH = 7 by saturated NaHCO3, diluted with H2O (20 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. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 70 to 0 / 1) to give the title compound (45 mg, 45%) as a white solid.1H NMR (400 MHz, CDCl3) ppm 8.80 (dd, J = 1.6, 4.8 Hz, 1H), 7.96-8.15 (m, 1H), 7.34-7.46 (m, 1H), 6.74-6.91 (m, 1H), 4.59-4.73 (m, 1H), 3.80-3.87 (m, 2H), 3.64 (s, 2H), 2.79 (d, J = 13.2 Hz, 1H), 2.57-2.73 (m, 2H), 2.30- 2.50 (m, 3H), 2.25 (d, J = 12.4 Hz, 1H), 1.96 (dd, J = 2.8, 13.6 Hz, 1H), 1.49-1.64 (m, 5H), 1.25-1.38 (m, 3H), 0.94 (t, J = 7.2 Hz, 3H). 1-butyl-5-(diaminomethylene)-3-(5''-oxo-5'',6''-dihydrodispiro[cyclohexane-1,1'- cyclobutane-3',7''-pyrrolo[3,4-b]pyridin]-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (132) A mixture of 1-butyl-3-(5''-oxo-5'',6''-dihydrodispiro[cyclohexane-1,1'-cyclobutane- 3',7''-pyrrolo[3,4-b]pyridin]-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (35 mg, 82.5 mol), cyanamide (34.7 mg, 825 mol), bis[(Z)-1-methyl-3-oxo-but-1-enoxy]nickel (10.59 mg, 41 mol) in THF (2 mL) was degassed and purged with N23 times. The mixture was stirred at 80 °C for 16 h under N2. The reaction was diluted with H2O (20 mL) and extracted with DCM (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (18 mg, 47%) as a white solid. MS (ESI): mass calcd. for C24H30N6O4: 466.23, found: 467.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.55 (s, 2H), 9.30 (s, 1H), 8.82 (dd, J = 1.2, 4.8 Hz, 1H), 7.99 (dd, J = 1.2, 7.6 Hz, 1H), 7.49 (dd, J = 4.8, 7.6 Hz, 1H), 7.34 (s, 2H), 4.55-4.72 (m, 1H), 3.74 (t, J = 7.2 Hz, 2H), 2.63 (d, J = 11.6 Hz, 1H), 2.28-2.48 (m, 6H), 2.23 (d, J = 12.8 Hz, 1H), 1.22-1.50 (m, 8H), 0.88 (t, J = 7.2 Hz, 3H). Example 133 and Example 134 were obtained though the chiral SFC separation of Example 132 using similar conditions to those reported for Example 26 and Example 27. The stereochemistry for these two compounds is arbitrarily assigned. Example 135. 1-butyl-5-(diaminomethylene)-3-(5''-(1-hydroxyethyl)-2''-oxo-1'',2''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (135) Synthetic scheme: 5-bromotrispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''-cyclohexane-4'',2'''- [1,3]dioxolan]-2(1H)-one To a solution of trispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''-cyclohexane- 4'',2'''-[1,3]dioxolan]-2(1H)-one (8.5 g, 28.3 mmol) in DCM (100 mL) was added NBS (6.04 g, 39 mmol). The reaction was stirred at 40 °C for 12 h. More NBS (5.04 g, 28.3 mmol) was added and the reaction was stirred at 40 °C for 24 h. The mixture was poured into saturated Na2SO3(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. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 : 1 to 7 : 3) to give the title compound (7.3 g, 68%) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 10.58 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 3.85 (s, 4H), 2.09-2.23 (m, 4H), 1.77-1.95 (m, 4H), 1.43-1.66 (m, 4H). 5-(1-ethoxyvinyl)trispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''-cyclohexane- 4'',2'''-[1,3]dioxolan]-2(1H)-one To a solution of 5-bromotrispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''- cyclohexane-4'',2'''-[1,3]dioxolan]-2(1H)-one (8 g, 21.1 mmol) and tributyl(1- ethoxyvinyl)stannane (9.14 g, 25.3 mmol) in dioxane (70 mL) was added Pd(PPh3)2Cl2(1.48 g, 2.1 mmol) under N2. The mixture was stirred at 110 °C for 12 h. The reaction was quenched with saturated KF (100 mL) and extracted with ethyl acetate (100 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 = 100 : 1 to 8 : 1) to give the title compound (6.5 g, 83%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 10.56 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 5.33 (s, 1H), 4.33 (s, 1H), 3.90-4.01 (m, 2H), 3.87 (s, 4H), 2.19-2.26 (m, 2H), 2.11- 2.17 (m, 2H), 2.02 (s, 2H), 1.82 (s, 2H), 1.49-1.64 (m, 4H), 1.37 (t, J = 6.4 Hz, 3H). 5-acetyltrispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''-cyclohexane-4'',2'''- [1,3]dioxolan]-2(1H)-one A solution of 5-(1-ethoxyvinyl)trispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''- cyclohexane-4'',2'''-[1,3]dioxolan]-2(1H)-one (6 g, 16.2 mmol) in HCl (1 N, 323.94 mL) was stirred at 25 °C for 3 h. The reaction was poured into saturated NaHCO3(100 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.7 g, 67%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) ppm 10.89 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 3.86 (s, 4H), 2.63 (s, 3H), 2.15-2.28 (m, 4H), 2.05 (s, 2H), 1.82 (d, J = 6.0 Hz, 2H), 1.47-1.63 (m, 4H). 5-(1-hydroxyethyl)trispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''-cyclohexane- 4'',2'''-[1,3]dioxolan]-2(1H)-one To a solution of 5-acetyltrispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''- cyclohexane-4'',2'''-[1,3]dioxolan]-2(1H)-one (3.66 g, 10.7 mmol) in MeOH (50 mL) was added NaBH4(404.4 mg, 10.7 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. The reaction was poured into saturated NH4Cl (100 mL) and extracted with ethyl acetate (100 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 (3.7 g, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 10.38 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.23 (d, J = 4.4 Hz, 1H), 4.71-4.74 (m, 1H), 3.86 (s, 4H), 2.16-2.20 (m, 2H), 2.11- 2.13 (m, 2H), 1.95 (s, 2H), 1.85 (s, 2H), 1.47-1.63 (m, 4H), 1.38 (d, J = 6.4 Hz, 3H). 5''-(1-hydroxyethyl)dispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridine]- 2'',4(1''H)-dione To a solution of 5-(1-hydroxyethyl)trispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane- 3',1''-cyclohexane-4'',2'''-[1,3]dioxolan]-2(1H)-one (3.7 g, 10.74 mmol) in acetone (30 mL) and H2O (15 mL) was added TsOH.H2O (4.09 g, 21.5 mmol). The mixture was stirred at 25 °C for 2 h. The reaction was poured into saturated NaHCO3(100 mL) and extracted with ethyl acetate (100 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 (3.1 g, 96%) as a white solid. MS (ESI): mass calcd. C17H20N2O3: 300.15, found: 301.1 [M+H]+. 5''-(1-((tert-butyldiphenylsilyl)oxy)ethyl)dispiro[cyclohexane-1,1'-cyclobutane-3',3''- pyrrolo[3,2-b]pyridine]-2'',4(1''H)-dione To a solution of 5''-(1-hydroxyethyl)dispiro[cyclohexane-1,1'-cyclobutane-3',3''- pyrrolo[3,2-b]pyridine]-2'',4(1''H)-dione (3.1 g, 10.3 mmol) and imidazole (5.62 g, 82.6 mmol) in DCM (50 mL) was added tert-butyl-chloro-diphenyl-silane (17.0 g, 61.9 mmol). The mixture was stirred at 25 °C for 1 h. The reaction was poured into water (100 mL) and extracted with ethyl acetate (100 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 = 100 : 1 to 1 : 1) to give the title compound (4.34 g, 78%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 10.46 (s, 1H), 7.66 (d, J = 6.4 Hz, 2H), 7.38-7.53 (m, 6H), 7.27-7.35 (m, 3H), 7.15 (d, J = 8.0 Hz, 1H), 4.92 (d, J = 5.6 Hz, 1H), 2.32 (d, J = 5.2 Hz, 1H), 2.19-2.23 (m, 6H), 2.05-2.16 (m, 5H), 1.39 (d, J = 5.6 Hz, 3H), 1.01 (s, 9H). 4-amino-5''-(1-((tert-butyldiphenylsilyl)oxy)ethyl)dispiro[cyclohexane-1,1'-cyclobutane- 3',3''-pyrrolo[3,2-b]pyridin]-2''(1''H)-one To a solution of 5''-(1-((tert-butyldiphenylsilyl)oxy)ethyl)dispiro[cyclohexane-1,1'- cyclobutane-3',3''-pyrrolo[3,2-b]pyridine]-2'',4(1''H)-dione (4.34 g, 8.06 mmol) and NH4OAc (15.52 g, 201.4 mmol) in MeOH (100 mL) was added NaBH(OAc)3(4.27 g, 20.1 mmol). The mixture was stirred at 25 °C for 1 h. The reaction was poured into water (50 mL) and extracted with DCM : i-PrOH = 3 : 1 (100 mL x 2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.9 g, crude) as a white solid. MS (ESI): mass calcd. C33H41N3O2Si: 539.30, found: 540.3 [M+H]+. 1-butyl-3-(5''-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-2''-oxo-1'',2''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4-yl)urea To a solution of 4-amino-5''-(1-((tert-butyldiphenylsilyl)oxy) ethyl)dispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-2''(1''H)-one (3.9 g, 7.2 mmol) and TEA (1.46 g, 14.5 mmol) in DCM (40 mL) was added 1-isocyanatobutane (787.86 mg, 8.0 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. The mixture was poured into saturated NH4Cl (100 mL) and extracted with DCM (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 : 1 to 7 : 3) to give the title compound (4.3 g, 93%) as a white solid. MS (ESI): mass calcd. C38H50N4O3Si: 638.37, found: 639.4 [M+H]+. 1-butyl-3-(5''-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-2''-oxo-1'',2''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-(5''-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-2''-oxo-1'',2''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4-yl)urea (1 g, 1.57 mmol) in Ac2O (5 mL) and AcOH (5 mL) was added propanedioyl dichloride (179.2 mg, 1.72 mmol). The mixture was stirred at 80 °C for 0.5 h. The reaction was poured into water (100 mL) and extracted with ethyl acetate (100 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 : 1) to give the title compound (0.32 g, crude) as a yellow oil. MS (ESI): mass calcd. C41H50N4O5Si: 706.36, found: 707.3 [M+H]+. 1-butyl-3-(5''-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-2''-oxo-1'',2''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4-yl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-(5''-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-2''-oxo-1'',2''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (0.32 g, 452.7 mol) and cyanamide (380.6 mg, 9.05 mmol) in THF (3 mL) was added Ni(acac)2 (34.9 mg, 136 mol). The mixture was stirred at 80 °C for 12 h. The reaction was poured into water (50 mL) and extracted with ethyl acetate (50 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 = 5 : 1 to 1 : 1) to give the title compound (0.26 g, 77%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 10.38 (s, 1H), 9.56 (s, 2H), 7.65 (d, J = 5.2 Hz, 2H), 7.36-7.51 (m, 6H), 7.19-7.34 (m, 5H), 7.11 (t, J = 8.0 Hz, 1H), 4.90 (d, J = 5.6 Hz, 1H), 4.65 (s, 1H), 3.65-3.83 (m, 2H), 2.28-2.44 (m, 3H), 2.01-2.27 (m, 4H), 1.90-1.97 (m, 1H), 1.39-1.52 (m, 3H), 1.20-1.38 (m, 8H), 0.99 (s, 9H), 0.77-0.91 (m, 3H). 1-butyl-5-(diaminomethylene)-3-(5''-(1-hydroxyethyl)-2''-oxo-1'',2''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (135) To a solution of 1-butyl-3-(5''-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-2''-oxo-1'',2''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4-yl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (0.26 g, 347.14 mol) in THF (3 mL) was added TBAF (1 M, 2.2 mL). The mixture was stirred at 25 °C for 12 h. The mixture was poured into saturated NH4Cl (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 100 : 1 to 1 : 1) give the title compound (0.17 g, 71.8%) as a white solid. MS (ESI): mass calcd. C26H34N6O5: 510.26, found: 511.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.37 (s, 1H), 9.55 (s, 2H), 7.25-7.30 (m, 3H), 7.10 (d, J = 7.6 Hz, 1H), 5.23 (d, J = 4.8 Hz, 1H), 4.59-4.77 (m, 2H), 3.73 (t, J = 7.2 Hz, 2H), 2.30-2.48 (m, 3H), 2.11-2.29 (m, 4H), 2.02-2.10 (m, 1H), 1.37-1.44 (m, 9H), 1.20-1.30 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). Example 136, Example 137, Example 138, and Example 139 were obtained from the chiral SFC separation of Example 135. The stereochemistry for these four compounds is arbitrarily assigned. Example 140. 1-butyl-5-diaminomethylene-3-(1,3-dimethyl-2,4-dioxo-1,3-diaza-10- dispiro[4.1.6.1]tetradecyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (140) Synthetic scheme

[0051] 1,3-dimethyl-1,3-diazadispiro[4.1.67.15]tetradecane-2,4,10-trione A solution of 1,3-dimethyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4,10-trione (150 mg, 599 μmol) in DCM (6.0 mL) was cooled to –40 °C and boron trifluoride diethyl etherate (148 μL, 1.2 mmol) was added followed by (trimethylsilyl)diazomethane solution 2M in hexanes (599 μL, 1.2 mmol). The mixture was stirred at –40 °C for 2 h, warmed to rt, quenched with water, and extracted with DCM (3x). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography (silica, 20-80% EtOAc / heptane) to provide the title compound (90.0 mg, 57%). MS (ESI): mass calcd. for C14H20N2O3: 264.15, found: 265.3 [M+H]+. 10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.67.15]tetradecane-2,4-dione A solution...

Claims

CLAIMS We claim:

1. A compound according to Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: R1is (C1-C6)alkyl optionally substituted with one or more instance of fluoro, carboxy, (C1-C6)carboxyalkoxy, 4- to 7-membered heterocycloalkyl or (C3-C8)cycloalkyl, wherein (C3- C8)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more instances of (C1-C6)alkyl, carboxy, and fluoro; R2is (C1-C6)alkyl optionally substituted with cyano; R3is: a) (C1-C6)alkyl substituted with SO2R3a, (C1-C6)alkoxy, (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl are optionally substituted with one or more instances of (C1-C6)alkyl and fluoro, or b) unsubstituted branched (C1-C6)alkyl; and R3ais (C1-C6)alkyl.

2. The compound of claim 1, having the structure of Formula (Ia) or (Ib): (Ia) (Ib),or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R1is methyl optionally substituted with one or more instance of fluoro, carboxy, (C1-C6)carboxyalkoxy, 4- to 7-membered heterocycloalkyl or (C3-C8)cycloalkyl, wherein (C3-C8)cycloalkyl and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more instances of (C1-C6)alkyl, carboxy, and fluoro.

4. The compound of any one of claims 1 to 3, wherein R1is (C1-C6)alkyl substituted with 4- to 7-membered heterocycloalkyl, wherein 4- to 7-membered heterocycloalkyl, is optionally substituted with fluoro or (C1-C6)alkyl.

5. The compound of claim 4, wherein the 4- to 7-membered heterocycloalkyl istetrahydrofuranyl, 1,1-dioxo- -thietanyl, tetrahydropyran-4-yl, 1,4-dioxanyl, 1,1-dioxo-1 -thianyl, azetidinyl, 2-azaspiro[3.3]heptyl pyrrolidinyl, oxopiperidinyl, piperidyl, morpholinyl, oxabicyclo[2.1.1]hexyl, oxetanyl, or oxaspiro[3.3]heptanyl, each of which is optionally substituted with carboxy, fluoro or (C1-C6)alkyl.

6. The compound of claim 4 or 5, wherein the 4- to 7-membered heterocycloalkyl istetrahydrofuran-3-yl, 5-methyltetrahydrofuran-3-yl, 1,1-dioxo-1 -3-thietanyl,tetrahydrofuran-2-yl, tetrahydropyran-4-yl, 1,4-dioxan-2-yl, 2-methyltetrahydro-4H-pyran-4-yl, 4-fluorotetrahydro-4H-pyran-4-yl, 1,1-dioxo-1 -4-thianyl, 2-azetidinyl, 3-fluoro-3-azetidinyl, 2-aza-6-spiro[3.3]heptyl 3-pyrrolidinyl, 4-piperidyl, 2-morpholinyl, 2- oxabicyclo[2.1.1]hex-4-yl, oxetan-2-yl, oxetan-3-yl, 3-fluoro-3-oxetanyl, 3-methyl-3- oxetanyl, 3-ethyl-3-oxetanyl, or 2-oxaspiro[3.3]heptan-6-yl.

7. The compound of claim 4, wherein the 4- to 7-membered heterocycloalkyl is 3,3-dioxo-3 -thiabicyclo[3.1.0]hex-6-yl, 1,1-dioxo-1 -3-thianyl, 1,1-dioxo-1 -tetrahydro-3H-thien-3-yl, 2-methyltetrahydro-4H-pyran-4-yl, 2-methyltetrahydro-4H-pyran-4-yl, 1-[(2,2,6,6-tetramethyl-1,1-dioxo-1 -4-thianyl, 1,1-dioxo-1 -4-thiepanyl, or 1,1-dioxo-1 ,2-thiazinan-5-yl.

8. The compound of any one of claims 4 to 7, wherein R1is methyl substituted withtetrahydrofuran-3-yl, 5-methyltetrahydrofuran-3-yl, 1,1-dioxo-1 -3-thietanyl,tetrahydrofuran-2-yl, tetrahydropyran-4-yl, 1,4-dioxan-2-yl, 2-methyltetrahydro-4H-pyran-4-yl, 4-fluorotetrahydro-4H-pyran-4-yl, 1,1-dioxo-1 -4-thianyl, 2-azetidinyl, 3-fluoro-3-azetidinyl, 2-aza-6-spiro[3.3]heptyl 3-pyrrolidinyl, 4-piperidyl, 2-morpholinyl, 2-oxabicyclo[2.1.1]hex-4-yl, oxetan-2-yl, oxetan-3-yl, 3-fluoro-3-oxetanyl, 3-methyl-3- oxetanyl, 3-ethyl-3-oxetanyl, or 2-oxaspiro[3.3]heptan-6-yl.

9. The compound of any one of claims 4 to 8, wherein R1is methyl substituted with 3,3-dioxo-3 -thiabicyclo[3.1.0]hex-6-yl, 1,1-dioxo-1 -3-thianyl, 1,1-dioxo-1 -tetrahydro-3H-thien-3-yl, 2-methyltetrahydro-4H-pyran-4-yl, 2-methyltetrahydro-4H-pyran-4-yl, 1-[(2,2,6,6-tetramethyl-1,1-dioxo-1 -4-thianyl, 1,1-dioxo-1 -4-thiepanyl, or 1,1-dioxo-1 ,2-thiazinan-5-yl.

10. The compound of any one of claims 1 to 3, wherein R1is (C1-C6)alkyl substituted with (C3-C8)cycloalkyl, wherein (C3-C8)cycloalkyl is optionally substituted with carboxy.

11. The compound of claim 10, wherein the (C3-C8)cycloalkyl is cyclopropyl, cyclobutyl, or bicyclo[1.1.1]pentane-1- each of which substituted with one or more instances of carboxy and (C1-C6)alkyl.

12. The compound of claim 1 or 2, wherein R1is (C1-C6)alkyl substituted with one or more instances of fluoro or carboxy.

13. The compound of claim 12, wherein R1is a trifluoro(C1-C6)alkyl.

14. The compound of claim 13, wherein R1is 2,2,2-trifluoroethyl.

15. The compound of claim 13, wherein R1is 3,3,3-trifluoropropyl.

16. The compound of any one of claims 1 or 2, wherein R1is methyl.

17. The compound of any one of claims 1 to 14, wherein R2is methyl.

18. The compound of any one of claims 1 to 10, wherein R2is cyanomethyl.

19. The compound of any one of claims 1 to 16, wherein R3is methyl or ethyl substituted with SO2R4(C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6- membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl, and fluoro.

20. The compound of any one of claims 1 to 19, wherein R3is methyl substituted with SO2R4, (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl, and fluoro.

21. The compound of any one of claims 1 to 18, wherein R3is (C1-C6)alkyl substituted with phenyl, wherein phenyl is optionally substituted with fluoro.

22. The compound of claim 21, wherein R3is (C1-C6)alkyl substituted, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl.

23. The compound of any one of claims 1 to 21, wherein R3is (C1-C6)alkyl substituted with 5- to 6-membered heteroaryl.

24. The compound of claim 23, wherein the 5- to 6-membered heteroaryl is thiazolyl or pyridyl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl and fluoro.

25. The compound of claim 24, wherein R3is (C1-C6)alkyl substituted with 2-methyl-1,3- thiazol-4-yl.

26. The compound of claim 23, wherein R3is (C1-C6)alkyl substituted with 2- methylpyridin-4-yl or pyridine-2-yl.

27. The compound of any one of claims 1 to 18, wherein R3is (C1-C6)alkyl substituted with (C3-C8)cycloalkyl, wherein (C3-C8)cycloalkyl is optionally substituted with one or more (C1-C6)alkyl.

28. The compound of claim 27, wherein R3is (C1-C6)alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, spiro[2.3]hexyl , bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl and fluoro.

29. The compound of claim 28, wherein R3is (C1-C6)alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pent-1-yl, bicyclo[2.1.0]pent-5-yl, spiro[2.3]hexyl , bicyclo[2.1.1]hex-1-yl, bicyclo[3.1.0]hex-3-yl, bicyclo[3.1.0]hex-6-yl, 3,3- dimethylcyclobutyl, 3-methylcyclobutyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 2,2- dimethylcyclobutyl, 3-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3- difluorocyclobutyl , 3-fluoro-3-methylcyclobutyl, 3-methylcyclopentyl, 3,3- difluorocyclopentyl, 3-fluorocyclopentyl, 1-fluorocyclopentyl or 3-ethylcyclobutyl.

30. The compound of claim 20, wherein R3is methyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pent-1-yl, bicyclo[2.1.0]pent-5-yl, spiro[2.3]hexyl , bicyclo[2.1.1]hex-1-yl, bicyclo[3.1.0]hex-3-yl, bicyclo[3.1.0]hex-6-yl, 3,3- dimethylcyclobutyl, 3-methylcyclobutyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 2,2- dimethylcyclobutyl, 3-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3- difluorocyclobutyl , 3-fluoro-3-methylcyclobutyl, 3-methylcyclopentyl, 3,3- difluorocyclopentyl, 3-fluorocyclopentyl, 1-fluorocyclopentyl or 3-ethylcyclobutyl.

31. The compound of any one of claims 1 to 18, wherein R3is (C1-C6)alkyl substituted with 4- to 7-membered heterocycloalkyl.

32. The compound of claim 31, wherein R3is (C1-C6)alkyl substituted with tetrahydrofurany-2-yl, or tetrahydropyrany-4-yl.

33. The compound of claim 18, wherein R3is 3,3-dimethylbutyl, 3-methylbutyl, 2- methylbutyl, isopropyl, 3-methylpentyl, 4-methylpentyl, or spiro[2.3]hexan-4-yl.

34. A compound according to Formula (II): (II) or a pharmaceutically acceptable salt thereof;wherein: R4and R5taken together form a heterocyclic ring having the structure: a) , wherein:R7and R8are independently hydrogen or (C1-C6)alkyl; b) ;c) , wherein:R9is (C1-C6)hydroxyalkyl or (C1-C6)alkoxyalkyl; d) , wherein:Y is absent or CH2, R10is hydrogen or (C1-C6)alkyl; e) , wherein:R11is (C1-C6)alkyl; f) , wherein:R12aand R12bare each independently (C1-C6)alkyl, and R13is hydrogen or (C3-C8)cycloalkyl; org) , wherein R14and R15are each independently (C1-C6)alkyl; and R6is (C1-C6)alkyl or (C3-C8)cycloalkyl.

35. The compound of claim 34, having the structure of Formula (IIa) or (IIb): (Ia) (Ib), or a pharmaceutically acceptable salt thereof, wherein: if the structure is Formula (IIa), then R4and R5taken together form a heterocyclic ring having the structure: a) ,b) ,c) ,d) ,e) ,f) org) ; and if the structure is Formula (IIb), then R4and R5taken together form a heterocyclic ring having the structure: a) ,b) ,c) ,d) ,e) ,f) or , org) .

36. The compound of claim 34 or 35, wherein R4and R5taken together form a heterocyclic ring having the structure (a); and R7is hydrogen.

37. The compound of claim 34 or 35, wherein R4and R5taken together form a heterocyclic ring having the structure (a); and R7is methyl.

38. The compound of any one of claims 34 to 37, wherein R4and R5taken together form a heterocyclic ring having the structure (a); and R8is methyl.

39. The compound of any one of claims 34 to 37, wherein R4and R5taken together form a heterocyclic ring having the structure (a); and R8is hydrogen.

40. The compound of claim 34 or 35, wherein R4and R5taken together form a heterocyclic ring having the structure (c); and R9is methoxy.

41. The compound of claim 34 or 35, wherein R4and R5taken together form a heterocyclic ring having the structure (c); and R9is 1-hydroxyethyl.

42. The compound of claim 34 or 35, wherein R4and R5taken together form a heterocyclic ring having the structure (d); and Y is absent.

43. The compound of claim 34 or 35, wherein R4and R5taken together form a heterocyclic ring having the structure (d); and Y is CH2.

44. The compound of any one of claims 34, 35, 42 and 43, wherein R4and R5taken together form a heterocyclic ring having the structure (d); and R10is hydrogen.

45. The compound of any one of claims 34, 35, 42 and 43, wherein R4and R5taken together form a heterocyclic ring having the structure (d); and R10is methyl.

46. The compound of claim 34 or 35, wherein R4and R5taken together form a heterocyclic ring having the structure (e); and R11is methyl.

47. The compound of claim 34 or 35, wherein R4and R5taken together form a heterocyclic ring having the structure (f); and R12aand R12bare each methyl.

48. The compound of any one of claims 34, 35, and 47, wherein R4and R5taken together form a heterocyclic ring having the structure (f); and R13is cyclopropyl.

49. The compound of any one of claims 34, 35, 42 and 43, wherein R4and R5taken together form a heterocyclic ring having the structure (f); and R13is hydrogen.

50. The compound of claim 34 or 35, wherein R4and R5taken together form a heterocyclic ring having the structure (g); and R14is methyl.

51. The compound of any one of claims 34, 35, and 50, wherein R4and R5taken together form a heterocyclic ring having the structure (g); and R15is methyl.

52. The compound of any one of claims 34 to 51, wherein R6is n-butyl.

53. A compound according to Formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein: R16is (C1-C6)alkyl substituted with tetrahydrofuran-2-yl, pyrazolyl optionally substituted with (C1-C6)alkyl, phenyl substituted with (C=O)NH2, or cyclobutyl substituted with pyridyl; R17is (C1-C6)alkyl; andR18is (C1-C6)alkyl.

54. The compound of claim 53, having the structure of Formula (IIIa) or (IIIb) (IIIa) (IIIb) or a pharmaceutically acceptable salt thereof.

55. The compound of claim 53 or 54, wherein the pyrazolyl is 1-methylpyrazol-4-yl, or pyrazol-4-yl.

56. The compound of any one of claims 53 to 54, wherein R17is methyl.

57. The compound of any one of claims 53 to 56, wherein R18is n-butyl.

58. A compound according to Formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein: R19is (C1-C6)fluoroalkyl; R20is (C1-C6)alkyl; and R21is (C1-C3)alkyl.

59. The compound of claim 58 having the structure of Formula (IVa) or (IVb): (IVa) (IVb), or a pharamceutically acceptable salt thereof.

60. The compound of claim 58 or 59, wherein R19is 2,2,2-trifluoroethyl.

61. The compound of any one of claims 58 to 60, wherein R20is methyl.

62. The compound of any one of claims 58 to 61, wherein R21is ethyl or propyl.

63. A compound according to Formula (V) (V), or a pharmaceutically acceptable salt thereof, wherein: R22is (C1-C6)alkyl; R23is (C1-C6)alkoxy; or R22and R23taken together with the carbon to which they are attached form 4- to 7-membered heterocycloalkyl; and R24is (C1-C6)alkyl optionally substituted with phenyl or (C3-C8)cycloalkyl; provided that the compound is not:or .

64. The compound of claim 63, wherein the compound has the structure of Formula (Va) or (Vb) (Va) (Vb).

65. The compound of claim 63 or 64, wherein R22is methyl.

66. The compound of any one of claims 63 to 65, wherein R23is methoxymethyl.

67. The compound of any one of claims 63 or 64, wherein R22and R23taken together form: or .

68. The compound of any one of claims 63 to 67, wherein R24is butyl.

69. The compound of any one of claims 63 to 67, wherein R24is benzyl.

70. The compound of any one of claims 63 to 67, wherein R24is (cyclopentyl)methyl.

71. The compound of any one of claims 62 to 67, wherein R24is n-propyl.

72. A compound having the structure:

73. A pharmaceutical composition, comprising a compound of any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

74. 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 amount of a compound of any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof.

75. 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 any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof.

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