WO2025226892A1 - Spirocycle-containing diaminomethylene pyrimidine-2,4,6-trione agonists of parathyroid hormone 1 and incretin receptors - Google Patents

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

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: R¹ is (C_1-C₆)alkyl optionally substituted with one or more instances of fluoro, carboxy, (C_1-C₆)carboxyalkoxy, 4- to 7-membered heterocycloalkyl or (C_3-C₈)cycloalkyl, wherein (C_3-C₈)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more instances of (C_1-C₆)alkyl, carboxy, and fluoro, R² is (C_1-C₆)alkyl optionally substituted with cyano; R³ is: a) (C_1-C₆)alkyl substituted with SO₂R^3a, (C_1-C₆)alkoxy, (C_3-C₈)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein (C_3-C₈)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl are optionally substituted with one or more instances of (C_1-C₆)alkyl and fluoro, or b) unsubstituted branched (C_1-C₆)alkyl; and R^3a is (C_1-C₆)alkyl. The present invention also provides a compound Formula (II): (II) or a pharmaceutically acceptable salt thereof; wherein: R⁴ and R⁵ taken together form a heterocyclic ring having the structure: a_{) , wherein:} R⁷ and R⁸ are independently hydrogen or (C_1-C₆)alkyl; b_{) ; c) , wherein:} R⁹ is (C_1-C₆)hydroxyalkyl or (C_1-C₆)alkoxyalkyl; _{d) , wherein:} Y is absent or CH₂, R¹⁰ is hydrogen or (C_1-C₆)alkyl; e_{) , wherein:} R¹¹ is (C_1-C₆)alkyl; f_{) , wherein:} R^12a and R^12b are each independently (C_1-C₆)alkyl, and R¹³ is hydrogen or (C_3-C₈)cycloalkyl; or g) , wherein R¹⁴ and R¹⁵ are each independently (C_1-C₆)alkyl; and R⁶ is (C_1-C₆)alkyl or (C_3-C₈)cycloalkyl. The present invention also provides a compound Formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein: R¹⁶ is (C_1-C₆)alkyl substituted with tetrahydrofuran-2-yl, pyrazolyl optionally substituted with (C_1-C₆)alkyl, phenyl substituted with (C=O)NH₂, or cyclobutyl substituted with pyridyl; R¹⁷ is (C_1-C₆)alkyl; and R¹⁸ is (C_1-C₆)alkyl. The present invention also provides a compound of Formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein: R¹⁹ is (C_1-C₆)fluoroalkyl; R²⁰ is (C_1-C₆)alkyl; and R²¹ is (C₁-C₃)alkyl. The present invention also provides a compound of Formula (V) (V), or a pharmaceutically acceptable salt thereof, wherein: R²² is (C_1-C₆)alkyl; R²³ is (C_1-C₆)alkoxy; or R²² and R²³ taken together with the carbon to which they are attached form 4- to 7-membered heterocycloalkyl; and R²⁴ is (C_1-C₆)alkyl optionally substituted with phenyl or (C_3-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 a ¹³C- or ¹⁴C- 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-C₃₀ for straight chains, C₃-C₃₀ for 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 C_1-6 alkyl, C_3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. 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: R¹ is (C_1-C₆)alkyl optionally substituted with one or more instance of fluoro, carboxy, (C_1-C₆)carboxyalkoxy, 4- to 7-membered heterocycloalkyl or (C_3-C₈)cycloalkyl, wherein (C_3- C₈)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more instances of (C_1-C₆)alkyl, carboxy, and fluoro; R² is (C_1-C₆)alkyl optionally substituted with cyano; R³ is: a) (C_1-C₆)alkyl substituted with SO₂R^3a, (C_1-C₆)alkoxy, (C_3-C₈)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein (C_3-C₈)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl are optionally substituted with one or more instances of (C_1-C₆)alkyl and fluoro, or b) unsubstituted branched (C_1-C₆)alkyl; and R^3a is (C_1-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, R¹ is methyl optionally substituted with (C_1-C₆)alkyl optionally substituted with one or more instance of fluoro, carboxy, (C_1-C₆)carboxyalkoxy, 4- to 7-membered heterocycloalkyl or (C_3-C₈)cycloalkyl, wherein (C_3-C₈)cycloalkyl and 4- to 7- membered heterocycloalkyl are each optionally substituted with one or more instances of (C_1- C6)alkyl, carboxy, and fluoro. In more particular embodiments, R¹ is (C_1-C₆)alkyl substituted with 4- to 7-membered heterocycloalkyl, wherein 4- to 7-membered heterocycloalkyl, is optionally substituted with fluoro or (C_1-C₆)alkyl. In some embodiments, the 4- to 7-membered heterocycloalkyl is _{tetrahydrofuranyl, 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. I_{n 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, R¹ is 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, R¹ is (C_1-C₆)alkyl substituted with (C_3-C₈)cycloalkyl, wherein (C_3-C₈)cycloalkyl is optionally substituted with carboxy, for example cyclopropyl or cyclobutyl substituted with carboxy. In other embodiments, the (C_3-C₈)cycloalkyl is cyclopropyl, cyclobutyl, or bicyclo[1.1.1]pentane-1- each of which substituted with one or more instances of carboxy and (C_1-C₆)alkyl. In some embodiments, R¹ is (C_1-C₆)alkyl substituted with one or more instances of fluoro or carboxy. In other embodiments, R¹ is (C_1-C₆)alkyl substituted with one or more instances of fluoro. In some embodiments, R¹ is 2,2,2-trifluoroethyl, while in other embodiments, R¹ is 3,3,3-trifluoropropyl. In some embodiments, R¹ is methyl. In some embodiments, R² is methyl. In other embodiments, R² is cyanomethyl. In some embodiments, R³ is methyl or ethyl substituted with SO₂R⁴ (C_3- 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 (C_1-C₆)alkyl, and fluoro. In more preferred embodiments, R³ is methyl substituted with SO₂R⁴, (C_3-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 (C_1-C₆)alkyl, and fluoro. In some embodiments, R³ is (C_1-C₆)alkyl substituted with phenyl, wherein phenyl is optionally substituted with fluoro, for example R³ can be (C_1-C₆)alkyl substituted, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl. In other embodiments, R³ is (C_1-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 (C_1-C₆)alkyl and fluoro. In some embodiments, R³ is (C_1-C₆)alkyl substituted with 2-methyl-1,3-thiazol-4- yl, while in other embodiments, R³ is (C_1-C₆)alkyl substituted with 2-methylpyridin-4-yl or pyridine-2-yl. In other embodiments, R³ is (C_1-C₆)alkyl substituted with (C_3-C₈)cycloalkyl, wherein (C_3-C₈)cycloalkyl is optionally substituted with one or more instances of (C_1-C₆)alkyl and fluoro. In some embodiments, R³ is (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 (C_1-C₆)alkyl and fluoro. In more particular embodiments, R³ is (C_1-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, R³ is (C_1-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, R³ is 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, R³ is (C_1-C₆)alkyl substituted with 4- to 7-membered heterocycloalkyl, preferably tetrahydrofurany-2-yl, or tetrahydropyrany-4-yl. In some embodiments, R³ is (C_1-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: R⁴ and R⁵ taken together form a heterocyclic ring having the structure: a_{) , wherein:} R⁷ and R⁸ are independently hydrogen or (C_1-C₆)alkyl; b_{) ; c) , wherein:} R⁹ is (C_1-C₆)hydroxyalkyl or (C_1-C₆)alkoxyalkyl; _{d) , wherein:} Y is absent or CH₂, R¹⁰ is hydrogen or (C_1-C₆)alkyl; e_{) , wherein:} R¹¹ is (C_1-C₆)alkyl; f_{) , wherein:} R^12a and R^12b are each independently (C_1-C₆)alkyl, and R¹³ is hydrogen or (C_3-C₈)cycloalkyl; or g) , wherein R¹⁴ and R¹⁵ are each independently (C_1-C₆)alkyl; and R⁶ is (C_1-C₆)alkyl or (C_3-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 R⁴ and R⁵ taken together form a heterocyclic ring having the structure:

if the structure is Formula (IIb), then R⁴ and R⁵ taken together form a heterocyclic ring having the structure:

In some embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (a); and R⁷ is hydrogen. In other embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (a); and R⁷ is methyl. In some embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (a); and R⁸ is methyl. In other embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (a); and R⁸ is hydrogen. In some embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (c); and R⁹ is methoxy. In other embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (c); and R⁹ is 1-hydroxyethyl. In some embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (d); and Y is absent. In other embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (d); and Y is CH₂. In some embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (d); and R¹⁰ is hydrogen. In other embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (d); and R¹⁰ is methyl. In some embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (e); and R¹¹ is methyl. In some embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (f); and R^12a and R^12b are each methyl. In some embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (f); and R¹³ is cyclopropyl. In other embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (f); and R¹³ is hydrogen. In some embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (g); and R¹⁴ is methyl. In some embodiments, R⁴ and R⁵ taken together form a heterocyclic ring having the structure (g); and R¹⁵ is methyl. In some embodiments, R⁶ is n-butyl. The present invention also provides a compound of Formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein: R¹⁶ is (C_1-C₆)alkyl substituted with tetrahydrofuran-2-yl, pyrazolyl optionally substituted with (C_1-C₆)alkyl, phenyl substituted with (C=O)NH₂, or cyclobutyl substituted with pyridyl; R¹⁷ is (C_1-C₆)alkyl; and R¹⁸ is (C_1-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, R¹⁷ is methyl. In some embodiments, R¹⁸ is n-butyl. The present invention also provides a compound of Formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein: R¹⁹ is (C_1-C₆)fluoroalkyl; R²⁰ is (C_1-C₆)alkyl; and R²¹ is (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, R¹⁹ is 2,2,2-trifluoroethyl. In some embodiments, R²⁰ is methyl. In some embodiments, R²¹ is ethyl or propyl. The present invention also provides a compound of Formula (V) (V), or a pharmaceutically acceptable salt thereof, wherein: R²² is (C_1-C₆)alkyl; R²³ is (C_1-C₆)alkoxy; or R²² and R²³ taken together with the carbon to which they are attached form 4- to 7-membered heterocycloalkyl; and R²⁴ is (C_1-C₆)alkyl optionally substituted with phenyl or (C_3-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 a} pharmaceutically acceptable salt thereof. In some embodiments, R²² is methyl. In some embodiments, R²³ is methoxymethyl. In other embodiments, R²² and R²³ taken together form: or . In some embodiments, wherein R²⁴ is n-butyl, while in other embodiments, R²⁴ is benzyl, and in still other embodiments, R²⁴ is (cyclopentyl)methyl. In other embodiments, R²⁴ is n-propyl. The present invention also provides a compound having the structure:

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:

General Scheme 1: General Scheme 2:

General Scheme 3:

General Scheme 4:

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:

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:

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, R_f = 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 K₂CO₃ and 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)

Example 2 (0.01 g) was separated by chiral SFC (column: DAICEL CHIRALPAK IG 2-EtOH (0.1% NH₃H₂ elution) 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)

Example 5 (70 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK AD 2-EtOH (0.1% NH₃H₂ elution) 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:

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 NaHCO₃ and 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 N₂ at 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%NH₃H₂ 11 (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:

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 N₂ 3 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 N₂ and 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)

Example 13 (50 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK ID 2-MeOH (0.1% NH₃H₂ elution) 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)

Example 16 (60 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK 2-IPA (0.1% NH₃H₂ elution) 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:

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

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 NH₃ H₂O (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% NH₃H₂ 20 (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:

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% NH₃H₂ compound (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)

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% NH₃H₂ to 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:

(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

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 NHCl₄ and 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:

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:

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 N₂ and 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 separated _{CO2- 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% NH₃ in 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)

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)

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)

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:

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

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) was _{phase: 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)

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:

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%} NH₃H₂ 91 (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

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:

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)

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)

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)

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)

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]⁺. ¹ H 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:

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 by ¹H 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)

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% NH₃ in 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% NH₃H₂ 105 (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:

(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)

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% NH₃ in 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:

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 separated _{by 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 25 ^oC 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% NH₃ in 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)

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 NaHCO₃ and 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:

(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% NH₃H₂ B 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:

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)

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 a} colorless 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 N₂ at 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 phase _{HPLC (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% NH₃H₂ 120 (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% NH_3.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:

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 N₂ was 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 NaHCO₃ and 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 25^oC 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, R_f = 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:

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:

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

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 of 1,3-dimethyl-1,3-diazadispiro[4.1.6⁷.1⁵]tetradecane-2,4,10-trione (90 mg, 340 μmol), ammonium formate (130 mg, 2.04 mmol), dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (2.7 mg, 3.4 μmol), and acetic acid (19.5 μL, 340 μmol) in MeOH (3.4 mL) was stirred at 50 °C for 17 h. The mixture was cooled down to rt and diluted with DCM and 1 N NaOH. Phases were separated and the aqueous phases was extracted with DCM (3x). The combined organic phase was dried over Na₂SO₄, filtered, and concentrated to provide the crude title compound (90 mg), which was used directly for the next step. MS (ESI): mass calcd. for C₁₄H₂₃N₃O₂: 265.18, found: 266.4 [M+H]⁺. 1-butyl-3-(1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.6⁷.1⁵]tetradecan-10-yl)urea To 10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.6⁷.1⁵]tetradecane-2,4-dione (90 mg, 339 μmol) in DCM (1.7 mL) was added triethylamine (71 μL, 509 μmol) followed by butyl isocyanate (746 μL, 373 μmol) and the reaction was stirred for 30 min. Water was added and the mixture was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude was purified by flash column chromatography (silica, 0-10% MeOH/DCM) to provide the title compound (124 mg, 100%). MS (ESI): mass calcd. for C₁₉H₃₂N₄O₃: 364.25, found: 365.3 [M+H]⁺. 1-butyl-3-(1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.6⁷.1⁵]tetradecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To 1-butyl-3-(1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.6⁷.1⁵]tetradecan-10-yl)urea (124 mg, 340 μmol) in DCM (3.4 mL) was added malonyl chloride (68 μL, 680 μmol) and the mixture was stirred at rt for 1 h. Water was added and the mixture was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude was purified by flash column chromatography (silica, 20-50% EtOAc/heptane) to provide the title compound (72 mg, 49%). MS (ESI): mass calcd. for C22H32N4O5: 432,24 found: 431.3 [M-H]- 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) 1-butyl-3-(1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.6⁷.1⁵]tetradecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (72 mg, 166 μmol), cyanamide (71 mg, 1.66 mmol), and nickel(II) acetylacetonate (12.8 mg, 50 μmol) were dissolved in THF (1.7 mL) and the mixture was heated to 80 °C for 44 h. The reaction was cooled down to rt, filtered through Celite and concentrated. The crude was purified by prep HPLC (CSH-C18, 35-55% MeCN/AmF 10 mM buffer) to provide the title compound (20 mg, 25%) as a white solid. MS (ESI): mass calcd. for C₂₃H₃₄N₆O₅: 474.26, found: 475.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO) 9.53 (s, 2H), 7.28 (s, 2H), 4.54 – 4.90 (m, 1H), 3.67 – 3.76 (m, 2H), 2.93 (s, 1.5H), 2.92 (s, 1.5H), 2.81 (s, 1.5H), 2.81 (s, 1.5H), 2.08 – 2.38 (m, 4H), 1.91 – 2.03 (m, 2H), 1.18 – 1.71 (m, 10H), 0.86 (t, J = 7.3 Hz, 3H) Example 141, Example 142, Example 143, and Example 144 were obtained from the chiral SFC separation of Example 140 (Cellulose tris(3,5-dichlorophenylcarbamate, 22% ( IPA+0.1% NH₄OH )/78% supercritical CO₂. The stereochemistry for these four compounds is arbitrarily assigned. Example 145. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-((3- ethyloxetan-3-yl)methyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (145)

Synthetic scheme: 3-ethyl-3-(iodomethyl)oxetane To triphenylphosphine resin (1.48 mmol/ g) (755 mg, 2.26 mmol) and imidazole (148 mg, 2.15 mmol) in DCM (3.2 mL) at 0 °C was added iodine (282 mg, 1.11 mmol) and the solution was stirred until all the iodine got dissolved. 3-Ethyl-3-oxetanemethanol (100 mg, 861 μmol) in solution in DCM (1.1 mL) was added and the mixture was slowly warmed up to rt and stirred for 18 h. The resin was filtered, rinsed well with EtOAc, and the filtrate was washed with 10% aqueous sodium thiosulfate solution, water, and brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (160 mg, 82%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) ppm 4.36 (d, J = 6.2 Hz, 2H), 4.34 (d, J = 6.2 Hz, 2H), 3.53 (s, 2H), 1.85 (q, J = 7.5 Hz, 2H), 0.85 (t, J = 7.5 Hz, 3H). 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-((3-ethyloxetan-3- yl)methyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (145) The title compound was synthesized following the same sequence of steps as in Example 93 and by using 3-ethyl-3-(iodomethyl)oxetane as starting material instead of 3- (iodomethyl)-3-methyloxetane. The last step was purified by prep HPLC to give the title compound (13.6 mg, 29%) as a white solid. MS (ESI): mass calcd. for C₂₉H₄₂N₆O₆: 570.32, found: 571.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO) ppm 9.53 (s, 2H), 7.48 (s, 2H), 4.73 – 4.58 (m, 1H), 4.55 (dd, J = 13.5, 6.4 Hz, 2H), 4.25 (d, J = 6.3 Hz, 2H), 3.70 (d, J = 7.5 Hz, 2H), 3.47 (d, J = 3.2 Hz, 2H), 2.83 (s, 3H), 2.37 – 2.02 (m, 7H), 1.83 (d, J = 12.6 Hz, 1H), 1.67 – 1.28 (m, 12H), 1.28 – 1.09 (m, 3H), 1.01 (t, J = 7.4 Hz, 3H). Example 146 synthesized in a similar route to the one described in Example 40. 1-butyl-5- (diaminomethylene)-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 was used instead 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 and 1-bromo-2-(methylsulfonyl)ethane was used instead of 2- (bromomethyl)tetrahydrofuran. Example 147 and Example 148 were obtained through the chiral SFC separation of Example 1 (DAICEL CHIRALCEL OD, (250 mm*30 mm, 10 um); mobile phase: CO₂-IPA (0.1% NH₃H₂O)]; gradient: 42% B with isocratic elution). The stereochemistry for these two compounds is arbitrarily assigned. Example 149 and Example 150 were obtained through the chiral SFC separation of Example 131 (column: DAICEL CHIRALPAK IC, (250 mm*30 mm, 10 um); mobile phase: CO₂-IPA (0.1%NH₃H₂O); gradient: 40% B with isocratic elution). The stereochemistry for these two compounds is arbitrarily assigned. Example 151 and Example 152 were obtained through the chiral SFC separation of Example 119 (column: DAICEL CHIRALPAK IC, (250 mm*30 mm, 10 um); mobile phase: CO₂-EtOH (0.1% NH₃H₂O); gradient: 50% B with isocratic elution). The stereochemistry for these two compounds is arbitrarily assigned. Example 153 and Example 154 were obtained through the chiral SFC separation of Example 108 (column: DAICEL CHIRALPAK IC, (250 mm*30 mm, 10 um); mobile phase: CO₂-EtOH (0.1% NH₃H₂O); gradient: 65% B with isocratic elution). The stereochemistry for these two compounds is arbitrarily assigned. Example 155 and Example 156 were prepared through a similar synthetic sequence to Example 108, and separated by chiral SFC separation (column: REGIS(S,S)WHELK-O1, (250 mm*25 mm, 10 um); mobile phase: CO₂-IPA (0.1% NH₃H₂O); gradient: 45% B with isocratic elution). (R)-3-(bromomethyl)tetrahydrofuran was used instead of (S)-3- (bromomethyl)tetrahydrofuran. The stereochemistry for these two compounds is arbitrarily assigned. Example 157, Example 158, Example 159, and Example 160 were prepared through a similar synthetic sequence to Example 89 after SFC separation (column: DAICEL CHIRALPAK IC, (250 mm*30 mm, 10 um); mobile phase: CO₂-EtOH (0.1%NH₃H₂O); gradient: 45% B with isocratic elution). 4-(bromomethyl)-2-methyltetrahydrofuran was used instead of (R)-3- (bromomethyl)tetrahydrofuran. The stereochemistry for these four compounds is arbitrarily assigned. Example 161 was prepared through a similar synthetic sequence to Example 89. (1,1- dioxidothietan-3-yl)methyl 4-methylbenzenesulfonate was used instead of (R)-3- (bromomethyl)tetrahydrofuran. Example 162 and Example 163. 1-butyl-5-(diaminomethylene)-3-((1s,3'S,4S)-5''- methoxy-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 (162) and 1-butyl-5- (diaminomethylene)-3-((1r,3'R,4R)-5''-methoxy-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 (163) Synthetic scheme: 2-(3-bromo-6-methoxy-2-pyridyl)-8,11-dioxadispiro[3.2.4⁷.2⁴]tridecane-2-carbonitrile A mixture of 8,11-dioxadispiro[3.2.4⁷.2⁴]tridecane-2-carbonitrile (1.5 g, 7.24 mmol) in toluene (15 mL) was degassed and purged with N₂3 times. NaHMDS (1 M in THF, 7.96 mL, 7.96 mmol) was added at 0 °C and stirred at 0–25 °C for 30 min. 3-bromo-2-fluoro-6-methoxy- pyridine (1.49 g, 7.24 mmol) was added at 0 °C and stirred at 25 °C for 30 min under N₂. The reaction was quenched with saturated aqueous NH₄Cl (40 mL), diluted with H₂O (50 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 silica gel column chromatography (petroleum ether : ethyl acetate = 10 : 1 to 3 : 1) to give the title compound (2 g, 69.9%) as a white solid. MS (ESI): mass calcd. for C₁₈H₂₁BrN₂O₃: 392.07, found: 393.1/395.1 [M+H]⁺. 2-(3-bromo-6-methoxy-2-pyridyl)-8,11-dioxadispiro[3.2.4⁷.2⁴]tridecane-2-carboxamide To a solution of 2-(3-bromo-6-methoxy-2-pyridyl)-8,11- dioxadispiro[3.2.4⁷.2⁴]tridecane-2-carbonitrile (2 g, 5.09 mmol) in DMSO (20 mL) was added K₂CO₃ (1.41 g, 10.17 mmol) and H₂O₂ (1.73 g, 15.26 mmol, 1.47 mL, 30% purity). The mixture was stirred at 25 °C for 16 h. LC-MS showed 79% of desired compound. The reaction mixture was quenched by saturated aqueous Na₂SO₃ (60 mL), diluted with H₂O (50 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 = 10 : 1 to 3 : 2) to give the title compound (1.71 g, 79.9%) as a white solid. MS (ESI): mass calcd. for C₁₈H₂₃BrN₂O₄: 410.08, found: 411.0/413.0 [M+H]⁺. 5-methoxytrispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''-cyclohexane-4'',2'''- [1,3]dioxolan]-2(1H)-one A mixture of 2-(3-bromo-6-methoxy-2-pyridyl)-8,11-dioxadispiro[3.2.4⁷.2⁴]tridecane- 2-carboxamide (1.61 g, 3.91 mmol), N,N'-dimethylethane-1,2-diamine (517.60 mg, 5.87 mmol), CuI (149.10 mg, 783 mol) and K₃PO₄ (2.49 g, 11.74 mmol) in dioxane (35 mL) was degassed and purged with N₂3 times. The mixture was stirred at 110 °C for 32 h under N₂. 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 = 10 : 1 to 3 : 2) to give the title compound (1.04 g, 62.24%) as a white solid. MS (ESI): mass calcd. for C₁₈H₂₂N₂O₄: 330.16, found: 331.1 [M+H]⁺. 5''-methoxydispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridine]- 2'',4(1''H)-dione A mixture of 5-methoxytrispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''- cyclohexane-4'',2'''-[1,3]dioxolan]-2(1H)-one (900 mg, 2.72 mmol) and TsOH.H₂O (1.04 g, 5.45 mmol) in acetone (5 mL) and H₂O (5 mL) was stirred at 25 °C for 4 h under N₂. The mixture was diluted with H₂O (30 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether : ethyl acetate = 10 : 1 to 3 : 1) to give the title compound (750 mg, 87.5%) as a white solid. MS (ESI): mass calcd. for C16H18N2O3: 286.13, found: 287.0 [M+H]⁺. 4-amino-5''-methoxydispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]- 2''(1''H)-one To a solution of 5''-methoxydispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2- b]pyridine]-2'',4(1''H)-dione (750 mg, 2.62 mmol) in MeOH (10 mL) was added NH₄OAc (4.04 g, 52.39 mmol) and NaBH(OAc)3 (1.67 g, 7.86 mmol). The mixture was stirred at 25 °C for 3 h. The reaction was concentrated under reduced pressure. The residue was diluted with H2O (30 mL) and extracted with DCM : IPA = 3 : 1 (50 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 (750 mg, 94.7%) as a white solid. MS (ESI): mass calcd. for C₁₆H₂₁N₃O₂: 287.16, found: 288.2 [M+H]⁺. 1-butyl-3-(5''-methoxy-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,1'-cyclobutane- 3',3''-pyrrolo[3,2-b]pyridin]-4-yl)urea A mixture of 4-amino-5''-methoxydispiro[cyclohexane-1,1'-cyclobutane-3',3''- pyrrolo[3,2-b]pyridin]-2''(1''H)-one (700 mg, 2.44 mmol), TEA (1.23 g, 12.18 mmol) in DCM (2 mL) was degassed and purged with N₂3 times. 1-isocyanatobutane (289.78 mg, 2.92 mmol) was added and stirred at 25 °C for 30 min under N₂. The reaction was diluted with H₂O (30 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether : ethyl acetate = 10 : 1 to 0 : 1) to give the title compound (600 mg, 58%) as a white solid. MS (ESI): mass calcd. for C₂₁H₃₀N₄O₃: 386.23, found: 387.2 [M+H]⁺. 1-butyl-3-(5''-methoxy-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''-methoxy-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,1'- cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4-yl)urea (500 mg, 1.29 mmol) in AcOH (3.5 mL) was added malonic acid (134.62 mg, 1.29 mmol) and Ac₂O (924.51 mg, 9.06 mmol). The mixture was stirred at 25 °C for 3 h. The reaction was diluted with saturated aqueous NaHCO₃ (40 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 = 10 : 1 to 0 : 1) to give the title compound (300 mg, 48.47%) as a white solid. MS (ESI): mass calcd. for C₂₄H₃₀N₄O₅: 454.22, found: 455.2 [M+H]⁺. 1-butyl-5-(diaminomethylene)-3-(5''-methoxy-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 A mixture of 1-butyl-3-(5''-methoxy-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 (270 mg, 594 mol), cyanamide (249.7 mg, 5.94 mmol) and Ni(acac)₂ (45.78 mg, 178 mol) in THF (3 mL) was degassed and purged with N₂3 times. The mixture was stirred at 80 °C for 16 h under N₂. The mixture 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 reverse phase HPLC to give the title compound (230 mg, 78%) as a white solid. MS (ESI): mass calcd. for C25H32N6O5: 496.24, found: 497.3 [M+H]⁺. 1-butyl-5-(diaminomethylene)-3-((1s,3'S,4S)-5''-methoxy-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 (162) and 1-butyl-5-(diaminomethylene)-3- ((1r,3'R,4R)-5''-methoxy-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 (163) 1-butyl-5-(diaminomethylene)-3-(5''-methoxy-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 (30 mg, 60.4 mol) was separated by chiral SFC (column: ChiralPak IH, (250 mm*30 mm, 10 um; mobile phase: CO2-MeOH (0.1% NH3H2O); gradient: 35% B with isocratic elution) to give 162 (6.0 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C₂₅H₃₂N₆O₅: 496.24, found: 497.3 [M+H]⁺.¹H NMR (400 MHz, DMSO- d₆) ppm 10.14 (s, 1H), 9.54 (s, 2H), 7.35 (s, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 4.48-4.85 (m, 1H), 3.84 (s, 3H), 3.72 (t, J = 7.2 Hz, 2H), 2.27-2.46 (m, 2H), 2.02-2.23 (m, 5H), 1.33-1.49 (m, 6H), 1.24 (qd, J = 7.2, 14.8 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H). And to provide 163 (6.9 mg) from the second eluting peak from chiral SFC as a white solid. MS (ESI): mass calcd. for C₂₅H₃₂N₆O₅: 496.24, found: 497.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) ppm 10.16 (s, 1H), 9.55 (s, 2H), 7.36 (s, 2H), 7.15 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 4.61-4.77 (m, 1H), 3.85 (s, 3H), 3.74 (t, J = 7.2 Hz, 2H), 2.29-2.46 (m, 2H), 2.12-2.25 (m, 4H), 2.01-2.11 (m, 1H), 1.34-1.50 (m, 6H), 1.26 (qd, J = 7.2, 14.8 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). Example 164 and Example 165. 1-((5R,7r,10R)-1-((1H-pyrazol-4-yl)methyl)-3-methyl- 2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3-butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (164) and 1-((5S,7s,10S)-1-((1H- pyrazol-4-yl)methyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3- butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (165) Synthetic scheme:

Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate To a suspension of NaH (3.65 g, 91.34 mmol, 60% purity) in dry THF (120 mL) at 0 °C was added a solution of ethyl 1H-pyrazole-4-carboxylate (8 g, 57.1 mmol) in dry THF (30 mL). The resulting purple suspension was stirred at 25°C for 3 h. A solution of SEM-Cl (11.42 g, 68.5 mmol, 12.12 mL) in dry THF (30 mL) was added dropwise at 0 °C and then warmed to 25°C for 3 h. The reaction was poured into water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (15.29 g, 99%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) ppm 8.50 (s, 1H), 7.92 (s, 1H), 5.44 (s, 2H), 4.22 (s, 2H), 3.52-3.57 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H), 0.80-0.85 (m, 2H), -0.05 (s, 9H). (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol To a solution of ethyl 1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (5 g, 18.49 mmol) in THF (50 mL) was added LiAlH₄ (2.5 M in THF, 11.1 mL) at 0 °C under N₂. The mixture was stirred at 25 °C for 4 h. H₂O (11 mL) was added at 0 °C, followed by aqueous NaOH (15%, 11 mL) and H₂O (11 mL). The mixture was stirred at 25 °C for 1 h. The mixture was filtered through a celite pad and washed with ethyl acetate (20 mL). The filtrate was evaporated in vacuo to give the title compound (3.85 g, 91.2%) as a pale-yellow liquid. ¹H NMR (400 MHz, CDCl₃) ppm 7.58 (s, 1H), 7.56 (s, 1H), 5.41 (s, 2H), 4.62 (s, 2H), 3.57 (t, J = 8.0 Hz, 2H), 0.91 (t, J = 8.0 Hz, 2H), -0.02 (s, 9H). 4-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole To a solution of [1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methanol (1 g, 4.38 mmol) in DCM (10 mL) was added DIPEA (1.41 g, 10.95 mmol) at 25 °C. MsCl (601.9 mg, 5.25 mmol) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 17 h. The reaction was cooled to 0 °C and added DIPEA (1.41 g, 10.95 mmol), followed by MsCl (601.9 mg, 5.25 mmol). After stirring at 25 °C for 4 h, the reaction was quenched with ice-water (5 mL) and extracted with DCM (10 mL x 3). The combined organic layer was washed with brine, dried over anhy-drous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 10 : 1 to 0 : 1) to give the title compound (550 mg, 50.9%) as a yellow oil.¹H NMR (400 MHz, CDCl₃) ppm 7.61 (s, 1H), 7.57 (s, 1H), 5.40 (s, 2H), 4.56 (s, 2H), 3.54-3.59 (m, 2H), 0.88-0.93 (m, 2H), - 0.01 (s, 9H). 3-methyl-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-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 (0.3 g, 1.07 mmol) in DMF (4 mL) was added 2-[[4-(chloromethyl)pyrazol-1- yl]methoxy]ethyl-trimethyl-silane (264.1 mg, 1.07 mmol) and Cs₂CO₃ (1.05 g, 3.21 mmol). The mixture was stirred at 25 °C for 18 h. The reaction was quenched with water (6 mL) and extracted with ethyl acetate (7 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na₂SO₄, filtered and concentrated under vacuum to give the title compound (550 mg, crude) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) ppm 7.62 (s, 1H), 7.51 (s, 1H), 5.39 (s, 2H), 4.54 (s, 2H), 3.94 (s, 4H), 3.44-3.61 (m, 2H), 3.00-3.07 (m, 3H), 2.30-2.38 (m, 2H), 2.15-2.22 (m, 2H), 2.00 (s, 2H), 1.72-1.79 (m, 2H), 1.55-1.60 (m, 4H), 0.85- 0.95 (m, 2H), -0.03 (s, 9H). 2-methyl-4-[[1-(2-trimethylsilylethoxymethyl) pyrazol-4-yl]methyl]-2,4- diazadispiro[4.1.5⁷.1⁵]tridecane-1,3,10-trione To a solution of 2-methyl-4-[[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methyl]- 11,14-dioxa-2,4-diazatrispiro[4.1.2.4¹⁰.2⁷.1⁵]heptadecane-1,3-dione (500 mg, 1.02 mmol) in acetone (4 mL) and H₂O (2 mL) was added TsOH.H₂O (387.67 mg, 2.04 mmol) at 25 °C. The mixture was stirred at 50 °C for 2 h. The reaction was adjusted pH to 7 with saturated NaHCO₃, and extracted with ethyl acetate (6 mL x 3). The 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 = 1 : 0 to 0 : 1) to give the title compound (420 mg, 92.3%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) ppm 7.63 (s, 1H), 7.52 (s, 1H), 5.39 (s, 2H), 4.58 (s, 2H), 3.55 (t, J = 8.4 Hz, 2H), 3.05 (s, 3H), 2.43-2.52 (m, 2H), 2.27-2.39 (m, 8H), 1.99 (t, J = 6.8 Hz, 2H), 0.90 (s, 2H), -0.03 (s, 9H). 10-amino-3-methyl-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)- 1,3-diazadispiro[4.1.5⁷.1⁵]tridecane-2,4-dione A mixture of 2-methyl-4-[[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methyl]-2,4- diazadispiro[4.1.5⁷.1⁵]tridecane-1,3,10-trione (800 mg, 1.79 mmol), NH₄Cl (2.76 g, 35.83 mmol) and sodium triacetoxyborohydride (949.1 mg, 4.48 mmol) in MeOH (8 mL) was degassed and purged with N₂3 times. The mixture was stirred at 25 °C for 1 h under N₂. The reaction was concentrated under reduced pressure. The residue was diluted with H₂O (10 mL), extracted with DCM (15 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 (1.33 g, 80.03%) as a white solid. MS (ESI): mass calcd. for C22H37N5O3Si: 447.27, found: 448.2 [M+H]⁺. 1-butyl-3-[2-methyl-1,3-dioxo-4-[[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methyl]- 2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]urea A mixture of 10-amino-3-methyl-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 4-yl)methyl)-1,3-diazadispiro[4.1.5⁷.1⁵]tridecane-2,4-dione (0.93 g, 2.05 mmol), 1- isocyanatobutane (202.8 mg, 2.05 mmol, 230 L) and TEA (207.00 mg, 2.05 mmol, 285 L) in DCM (9 mL) was degassed and purged with N23 times. The mixture was stirred at 25 °C for 1 h under N₂. The mixture was diluted with H₂O (10 mL), extracted with ethyl acetate (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 = 10 : 1 to 1 : 1) to give the title compound (1.28 g, crude) as a white solid. ¹H NMR (400 MHz, CDCl₃) ppm 7.62 (s, 1H), 7.50 (s, 1H), 5.38 (s, 2H), 4.53 (s, 2H), 3.49-3.59 (m, 3H), 3.15 (t, J = 7.2 Hz, 2H), 3.02 (s, 3H), 2.09-2.39 (m, 5H), 1.71- 2.00 (m, 4H), 1.43-1.52 (m, 3H), 1.32-1.41 (m, 2H), 1.05-1.19 (m, 2H), 0.87-0.96 (m, 5H), - 0.03 (s, 9H). 1-butyl-3-[2-methyl-1,3-dioxo-4-[[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methyl]- 2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-[2-methyl-1,3-dioxo-4-[[1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]methyl]-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl]urea (0.98 g, 1.79 mmol), malonic acid (186.5 mg, 1.79 mmol) in AcOH (9.8 mL) was added Ac₂O (1.28 g, 12.55 mmol). The mixture was stirred at 80 °C for 8 h under N₂. The reaction mixture was diluted with H₂O (10 mL) and extracted with ethyl acetate (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 (700 mg, 63.5%) as a white solid. ¹H NMR (400 MHz, CDCl₃) ppm 7.62 (s, 1H), 7.52 (s, 1H), 5.39 (s, 2H), 4.45-4.62 (m, 3H), 3.84 (s, 2H), 3.50-3.69 (m, 4H), 3.03 (s, 3H), 1.74- 2.71 (m, 11H), 1.22-1.43 (m, 5H), 0.89-0.99 (m, 5H), -0.02 (s, 9H). 1-butyl-5-(diaminomethylene)-3-[2-methyl-1,3-dioxo-4-[[1-(2- trimethylsilylethoxymethyl) pyrazol-4-yl]methyl]-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione A mixture of 1-butyl-3-[2-methyl-1,3-dioxo-4-[[1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]methyl]-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione (520 mg, 845.79 mol), cyanamide (356 mg, 8.46 mmol, 356 L) and Ni(acac)2 (65.19 mg, 253.7 mol) in THF (5.2 mL) was degassed and purged with N₂3 times. The mixture was stirred at 80 °C for 16 h under N₂. The reaction mixture was filtered and diluted with H₂O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic weas washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to give the title compound (318 mg, 57%) as a white solid. ¹H NMR (400 MHz, CDCl₃) ppm 10.19-10.52 (m, 2H), 7.62 (s, 1H), 7.52 (s, 1H), 5.39 (s, 2H), 5.11-5.33 (m, 2H), 4.68-4.82 (m, 1H), 4.43-4.63 (m, 2H), 3.82-3.91 (m, 2H), 3.50-3.61 (m, 2H), 3.03 (s, 3H), 2.14-2.61 (m, 7H), 1.78-1.91 (m, 1H), 1.62 (s, 2H), 1.54 (s, 3H), 1.33-1.44 (m, 3H), 0.86-0.97 (m, 5H), -0.07-0.00 (m, 9H). 1-butyl-5-(diaminomethylene)-3-[2-methyl-1,3-dioxo-4-(1H-pyrazol-4-ylmethyl)-2,4- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione A mixture of 1-butyl-5-(diaminomethylene)-3-[2-methyl-1,3-dioxo-4-[[1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]methyl]-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione (285 mg, 433.9 mol) in TFA (1.5 mL) and DCM (0.3 mL) was stirred at 25 °C for 30 min under N₂. The mixture was concentrated under reduced pressure. The pH was adjusted to around 7 with aqueous NaHCO₃ and the resulting mixture was lyophilized under vacuum. The residue was purified by reverse phase HPLC to give the title compound (130 mg, 55.19%) as a white solid. MS (ESI): mass calcd. for C₂₅H₃₄N₈O₅: 526.27, found: 527.3 [M+H]⁺. 1-((5R,7r,10R)-1-((1H-pyrazol-4-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3-butyl-5-(diaminomethylene)pyrimidine- 2,4,6(1H,3H,5H)-trione (164) and 1-((5S,7s,10S)-1-((1H-pyrazol-4-yl)methyl)-3-methyl- 2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3-butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (165)

1-butyl-5-(diaminomethylene)-3-[2-methyl-1,3-dioxo-4-(1H-pyrazol-4-ylmethyl)-2,4- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione (38 mg) was separated by chiral SFC (column: DAICEL CHIRALCEL OD, (250 mm*30 mm, 10 um); mobile phase: CO₂-EtOH (0.1% NH₃H₂O); gradient: 32% B with isocratic elution) to give 164 (17.2 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C₂₅H₃₄N₈O₅: 526.27, found: 527.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 12.72 (s, 1H), 9.52 (s, 2H), 7.42-7.68 (m, 2H), 7.32 (s, 2H), 4.46-4.69 (m, 3H), 3.72 (t, J = 7.2 Hz, 2H), 2.87 (s, 3H), 2.43 (d, J = 10.8 Hz, 1H), 2.15-2.34 (m, 5H), 2.05-2.12 (m, 1H), 1.82-1.85 (m, 1H), 1.33-1.48 (m, 5H), 1.16-1.31 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H). 165 (14.6 mg) was obtained from the second eluting peak from chiral SFC separation as a white solid. MS (ESI): mass calcd. for C₂₅H₃₄N₈O₅: 526.27, found: 527.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 12.72 (s, 1H), 9.38-9.64 (m, 2H), 7.41-7.71 (m, 2H), 7.31 (s, 2H), 4.45-4.66 (m, 3H), 3.67-3.76 (m, 2H), 2.86 (s, 3H), 2.38-2.43 (m, 1H), 2.16-2.33 (m, 5H), 2.04-2.12 (m, 1H), 1.79-1.87 (m, 1H), 1.33- 1.47 (m, 5H), 1.18-1.29 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H). Example 166 and Example 167 were prepared through a similar synthetic sequence to Example 164 and Example 165.4-(Chloromethyl)-1-methyl-1H-pyrazole was used instead of 4-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, and no SEM deprotection step was necessary. Example 168 and Example 169.1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-1- (3-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (168) and 1-butyl-5-(diaminomethylene)-3- ((5R,7r,10R)-3-methyl-1-(3-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (169) Synthetic scheme: 2-[(3-methyl-1H-pyrazol-4-yl)amino]-8,11-dioxadispiro[3.2.4⁷.2⁴]tridecane-2- carbonitrile To a solution of 8,11-dioxadispiro[3.2.4⁷.2⁴]tridecan-2-one (1 g, 5.10 mmol) in AcOH (1 mL) and MeOH (9 mL) was added dropwise 3-methyl-1H-pyrazol-4-amine (494.9 mg, 5.1 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. TMSCN (505.53 mg, 5.1 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °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 vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (1.03 g, 66.85%) as a colorless oil. MS (ESI): mass calcd. for C₁₆H₂₂N₄O₂: 302.17, found: 303.3 [M+H]⁺. 2-[[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]amino]-8,11- dioxadispiro[3.2.4⁷.2⁴]tridecane-2-carbonitrile To a solution of 2-[(3-methyl-1H-pyrazol-4-yl)amino]-8,11- dioxadispiro[3.2.4⁷.2⁴]tridecane-2-carbonitrile (1.03 g, 3.41 mmol) in DCM (10 mL) was added dropwise DIPEA (1.32 g, 10.22 mmol) at 20 °C. SEM-Cl (567.92 mg, 3.41 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. 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 vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (1.17 g, 79.4%) as a colorless oil. MS (ESI): mass calcd. for C₂₂H₃₆N₄O₃Si: 432.26, found: 433.3 [M+H]⁺. 2-[[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]amino]-8,11- dioxadispiro[3.2.4⁷.2⁴]tridecane-2-carboxamide To a solution of 2-[[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]amino]- 8,11-dioxadispiro[3.2.4⁷.2⁴]tridecane-2-carbonitrile (4.5 g, 10.40mmol) in MeOH (30 mL) was poured into H₂O₂ (1.18 g, 10.4 mmol, 30% purity) and 1 N NaOH (15 mL). The mixture was stirred at 25 °C for 1 h. The residue was quenched with saturated aqueous Na₂SO₃ (50 mL) at 0 °C, diluted with H₂O (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (1.92 g, 40.96%) as a white solid. MS (ESI): mass calcd. for C₂₂H₃₈N₄O₄Si: 450.27, found: 451.3 [M+H]⁺. 4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-11,14-dioxa-2,4- diazatrispiro[4.1.2.4¹⁰.2⁷.1⁵]heptadecane-1,3-dione To a solution of 2-[[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]amino]- 8,11-dioxadispiro[3.2.4⁷.2⁴]tridecane-2-carboxamide (2.93 g, 6.5 mmol) in dimethyl carbonate (30 mL) was added CDI (2.11 g, 13.0 mmol) and NaH (780.14 mg, 19.5 mmol, 60% purity). The mixture was stirred at 50 °C for 4 h, added water (50 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 = 1 : 1 to 0 : 1) to give the title compound (2.5 g, 80.39%) as a white solid.¹H NMR (400 MHz, DMSO-d6) ppm 11.06 (s, 1H), 7.60-8.21 (m, 1H), 5.45 (s, 1H), 5.34 (s, 1H), 3.74-3.84 (m, 4H), 3.49 (d, J = 7.6 Hz, 2H), 2.29 (d, J = 12.0 Hz, 2H), 2.00-2.18 (m, 3H), 1.90-1.99 (m, 2H), 1.76 (s, 2H), 1.44 (s, 2H), 1.30 (s, 2H), 1.01-1.14 (m, 2H), 0.83 (t, J = 8.0 Hz, 2H), -0.04 (s, 9H). 2-methyl-4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-11,14-dioxa-2,4- diazatrispiro[4.1.2.4¹⁰.2⁷.1⁵]heptadecane-1,3-dione To a solution of 4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-11,14- dioxa-2,4-diazatrispiro[4.1.2.4¹⁰.2⁷.1⁵]heptadecane-1,3-dione (2.5 g, 5.25 mmol) in DMF (25 mL) was added K₂CO₃ (1.45 g, 10.5 mmol) and CH₃I (818.9 mg, 5.8 mmol). The mixture was stirred at 20 °C for 12 h. The reaction was poured into H₂O (50 mL) and extracted with ethyl acetate (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 column chromatography (SiO₂, petroleum ether : ethyl acetate = 3 : 1 to 1 : 1) to provide the title compound (2.5 g, 97.1%) as a yellow oil.¹H NMR (400 MHz, DMSO-d₆) ppm 7.62-8.21 (m, 1H), 5.46 (s, 1H), 5.35 (s, 1H), 3.74-3.84 (m, 4H), 3.46-3.55 (m, 2H), 2.92 (d, J = 1.6 Hz, 3H), 2.26-2.36 (m, 2H), 2.01-2.18 (m, 3H), 1.93-2.01 (m, 2H), 1.80 (s, 2H), 1.46 (d, J = 4.8 Hz, 2H), 1.31 (s, 2H), 1.07 (d, J = 1.6 Hz, 2H), 0.83 (t, J = 8.0 Hz, 2H), -0.04 (s, 9H). 1-butyl-5-(diaminomethylene)-3-[2-methyl-4-[3-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]-1,3-dioxo-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan- 10-yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione The title compound was prepared in a similar sequence to steps 5-9 of Example 164, starting from 2-methyl-4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-11,14- dioxa-2,4-diazatrispiro[4.1.2.4¹⁰.2⁷.1⁵]heptadecane-1,3-dione. MS (ESI): mass calcd. for C₃₁H₄₈N₈O₆Si: 656.35, found: 657.3 [M+H]⁺. 1-butyl-5-(diaminomethylene)-3-[2-methyl-4-(3-methyl-1H-pyrazol-4-yl)-1,3-dioxo-2,4- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-[2-methyl-4-[3-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]-1,3-dioxo-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione (300 mg, 456.73 mol) in THF (3 mL) was added TBAF (1 M in THF, 1.37 mL, 1.37 mmol). The mixture was stirred at 60 °C for 1 h. The reaction mixture was added water (10 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. The residue was purified by column chromatography (SiO₂, petroleum ether : ethyl acetate = 1 : 1 to 0 : 1). The residue was purified a second time by reverse phase HPLC to give the title compound (45 mg, 18.71%) as a white solid. MS (ESI): mass calcd. for C₂₅H₃₄N₈O₅: 526.27, found: 527.3 [M+H]⁺. 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-1-(3-methyl-1H-pyrazol-4-yl)- 2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (168) and 1-butyl-5-(diaminomethylene)-3-((5R,7r,10R)-3-methyl-1-(3-methyl-1H- pyrazol-4-yl)-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (169) 1-butyl-5-(diaminomethylene)-3-[2-methyl-4-(3-methyl-1H-pyrazol-4-yl)-1,3-dioxo- 2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione (40 mg, 61 mol) was separated by chiral SFC (column: REGIS (s,s) WHELK-O1, (250 mm*30 mm, 5 um); mobile phase: CO₂-IPA (0.1% NH₃H₂O); gradient: 45% B with isocratic elution) to give 168 (12 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C₂₅H₃₄N₈O₅: 526.27, found: 527.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 12.81 (s, 1H), 9.51 (s, 2H), 7.53-8.01 (m, 1H), 7.30 (s, 2H), 4.46-4.62 (m, 1H), 3.67-3.75 (m, 2H), 2.92 (s, 3H), 2.29-2.34 (m, 2H), 2.12-2.28 (m, 3H), 2.07 (s, 3H), 1.99 (dd, J = 12.8, 5.2 Hz, 2H), 1.34-1.47 (m, 3H), 1.11-1.27 (m, 5H), 0.95 (d, J = 11.2 Hz, 1H), 0.87 (t, J = 7.2 Hz, 3H). 169 (11.6 mg) was obtained from the second eluting peak from chiral SFC separation as a white solid. MS (ESI): mass calcd. for C₂₅H₃₄N₈O₅: 526.27, found: 527.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 12.70-12.90 (m, 1H), 9.51 (s, 2H), 7.47-8.02 (m, 1H), 7.30 (s, 2H), 4.54 (s, 1H), 3.71 (t, J = 7.6 Hz, 2H), 2.92 (s, 3H), 2.32 (d, J = 12.8 Hz, 2H), 2.13-2.27 (m, 3H), 2.07 (s, 3H), 1.99 (dd, J = 12.4, 5.2 Hz, 2H), 1.34-1.47 (m, 3H), 1.12-1.27 (m, 5H), 0.95 (d, J = 11.2 Hz, 1H), 0.87 (t, J = 7.2 Hz, 3H). Example 170 was synthesized in a similar route to the one described in Example 40. 4- (bromomethyl)benzamide was used instead of 2-(bromomethyl)tetrahydrofuran. Example 172 was synthesized in a similar route to the one described in Example 46 starting from cyclobutylmethanamine. Example 173, Example 174, Example 175, and Example 176 were prepared in a similar fashion to Example 46, starting from (3-fluorocyclopentyl)methanamine. The four diastereomers of 1-((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan- 10-yl)-3-((3-fluorocyclopentyl)methyl)urea were separated by sequential SFC separations (column: DAICEL CHIRALPAK IC, (250 mm*30 mm, 10 um); mobile phase: CO₂-IPA; gradient: 50% B with isocratic elution, followed by column: DAICEL CHIRALPAK IG, (250 mm*30 mm, 10 um); mobile phase: CO₂-EtOH (0.1% NH₃H₂O); gradient: 38% B with isocratic elution). The stereochemistry for these four compounds is arbitrarily assigned. Example 177 and Example 178. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3- ((5S,7s,10S)-3-methyl-2,4-dioxo-1-(3,3,3-trifluoropropyl)-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (177) and 1- (cyclopentylmethyl)-5-(diaminomethylene)-3-((5R,7r,10R)-3-methyl-2,4-dioxo-1-(3,3,3- trifluoropropyl)-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)- trione (178) Synthetic scheme:

2-(3,3,3-trifluoropropylamino)-8,11-dioxadispiro[3.2.4⁷.2⁴]tridecane-2-carbonitrile To a solution of 3,3,3-trifluoropropan-1-amine hydrochloride (3.43 g, 22.93 mmol) in DCM (50 mL) was added DIPEA (3.29 g, 25.48 mmol), 8,11-dioxadispiro[3.2.4⁷.2⁴]tridecan- 2-one (5 g, 25.48 mmol) and Na₂SO₄ (1.81 g, 12.74 mmol). The mixture was stirred at 25 °C for 12 h. TMSCN (5.06 g, 50.96 mmol) was added and stirred at 25 °C for 1 h. After completion, the reaction mixture was quenched with H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was dried over 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 (4.04 g 49.8%) as a yellow oil. MS (ESI): mass calcd. for C₁₅H₂₁F₃N₂O₂: 318.16, found: 319.1 [M+H]⁺. 4-(3,3,3-trifluoropropyl)-2,4-diazadispiro[4.1.5⁷.1⁵]tridecane-1,3,10-trione To a solution of 2-(3,3,3-trifluoropropylamino)-8,11-dioxadispiro[3.2.4⁷.2⁴]tridecane- 2-carbonitrile (2 g, 6.28 mmol) in DCM (20 mL) was added N-(oxomethylene)sulfamoyl chloride (978.1 mg, 6.91 mmol) at 0 °C. The solution was stirred at 25 °C for 3 h. The mixture was concentrated under reduced pressure. HCl (1 N, 28.27 mL) was added and stirred at 100 °C for 2 h. After completion, the reaction was triturated with H₂O (10 mL). The solid was collected by filtration and dried under vacuum to give the title compound (1.5 g, 75%) as a white solid. MS (ESI): mass calcd. for C₁₄H₁₇F₃N₂O₃: 318.12, found: 319.1 [M+H]⁺. 2-methyl-4-(3,3,3-trifluoropropyl)-2,4-diazadispiro[4.1.5⁷.1⁵]tridecane-1,3,10-trione To a solution of 4-(3,3,3-trifluoropropyl)-2,4-diazadispiro[4.1.5⁷.1⁵]tridecane-1,3,10- trione (1.5 g, 4.71 mmol) in DMF (15 mL) was added K₂CO₃ (651.32 mg, 4.71 mmol) and MeI (668.9 mg, 4.71 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. After completion, the reaction was quenched with H₂O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over 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 (1.19 g, 75.98%) as a white solid. MS (ESI): mass calcd. for C₁₅H₁₉F₃N₂O₃: 332.13, found: 333.1 [M+H]⁺. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-[2-methyl-1,3-dioxo-4-(3,3,3- trifluoropropyl)-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]hexahydropyrimidine- 2,4,6(1H,3H,5H)-trione

The title compound was prepared following steps 6-9 of Example 164. (4-nitrophenyl) N- (cyclopentylmethyl)carbamate was used instead of butyl isocyanate. MS (ESI): mass calcd. for C26H35F3N6O5: 568.26, found: 569.3 [M+H]⁺. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1-(3,3,3- trifluoropropyl)-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)- trione (177) and 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5R,7r,10R)-3-methyl- 2,4-dioxo-1-(3,3,3-trifluoropropyl)-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (178) 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-[2-methyl-1,3-dioxo-4-(3,3,3- trifluoropropyl)-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]hexahydropyrimidine- 2,4,6(1H,3H,5H)-trione (45 mg) was separated by SFC (column: DAICEL CHIRALCEL OJ, (250 mm*30 mm, 10 um); mobile phase: CO₂-MeOH (0.1% NH₃H₂O); gradient: 25% B with isocratic elution) to give 177 (15.2 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C₂₆H₃₅F₃N₆O₅: 568.26, found: 569.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) ppm 9.55 (s, 2H), 7.30 (s, 2H), 4.60-4.68 (m, 1H), 3.71 (d, J = 7.2 Hz, 2H), 3.53-3.63 (m, 2H), 2.85 (s, 3H), 2.68-2.80 (m, 2H), 2.36-2.46 (m, 2H), 2.14-2.29 (m, 6H), 1.78 (d, J = 12.0 Hz, 1H), 1.51-1.61 (m, 4H), 1.36-1.49 (m, 5H), 1.18-1.29 (m, 3H).178 (8.53 mg) was obtained from the second eluting peak from chiral SFC separation as a white solid. MS (ESI): mass calcd. for C₂₆H₃₅F₃N₆O₅: 568.26, found: 569.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.54 (s, 2H), 7.30 (s, 2H), 4.58-4.70 (m, 1H), 3.71 (d, J = 7.6 Hz, 2H), 3.53-3.64 (m, 2H), 2.85 (s, 3H), 2.69-2.80 (m, 2H), 2.36-2.46 (m, 2H), 2.14-2.29 (m, 6H), 1.75-1.81 (m, 1H), 1.50- 1.61 (m, 4H), 1.37-1.49 (m, 5H), 1.17-1.29 (m, 3H). Example 179 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)-3-methylcyclopentane. Example 180 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 4- (chloromethyl)-2-methylthiazole. Example 181 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-2- methylpropane. Example 182 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-2- methylbutane. Example 183 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 (bromomethyl)benzene. Example 184 and Example 185. 1-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)methyl)-5- (diaminomethylene)-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 (184) & 1- (((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)methyl)-5-(diaminomethylene)-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 (185) Synthetic scheme: bicyclo[3.1.0]hexan-3-ylmethanol A 50 mL three neck flask was degassed and purged with N₂3 times. LiAlH₄ (2.5 M in THF, 2.85 mL) was added to the flask. A solution of bicyclo[3.1.0]hexane-3-carboxylic acid (300 mg, 2.38 mmol) in THF (3 mL) was added dropwise at –30 °C under N₂. The mixture was stirred at –30 °C for 5 min, raised to 20 °C and stirred for 3 h. The mixture was quenched with water (0.3 mL), 15% of aqueous NaOH (0.3 mL) and H2O (0.9 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (270 mg, crude) as colorless oil, which was used directly in the next step without further purification. 1-(3-bicyclo[3.1.0]hexanylmethyl)-5-[bis(ethylsulfanyl)methylene]-3-[2-methyl-4- (oxetan-3-ylmethyl)-1,3-dioxo-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 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(1H,3H,5H)- trione (90 mg, 163.4 mol) and 3-bicyclo[3.1.0]hexanylmethanol (36.66 mg, 326.9 mol) in toluene (1 mL) was added PPh₃ (64.3 mg, 245 mol) and DIAD (62.79 mg, 310.5 mol) at 20 °C. The solution was stirred at 40 °C for 16 h. The reaction was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound (34 mg, 32%) as a yellow solid. MS (ESI): mass calcd. for C₃₂H₄₄N₄O₆S₂: 644.27, found: 645.3 [M+H]⁺. 1-(3-bicyclo[3.1.0]hexanylmethyl)-5-(diaminomethylene)-3-[2-methyl-4-(oxetan-3- ylmethyl)-1,3-dioxo-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]hexahydropyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 1-(3-bicyclo[3.1.0]hexanylmethyl)-5-[bis(ethylsulfanyl)methylene]-3- [2-methyl-4-(oxetan-3-ylmethyl)-1,3-dioxo-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione (34 mg, 52.73 mol) in THF (0.5 mL) was added NH₃.H₂O (443.5 mg, 3.16 mmol, 487.34 L, 25% purity). The mixture was stirred at 40 °C for 144 h. The reaction was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to provide the title compound (5.59 mg, 19%) as a white solid. MS (ESI): mass calcd. for C28H38N6O6: 554.29, found: 555.3 [M+H]⁺. 1-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)methyl)-5-(diaminomethylene)-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 (184) & 1-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3- yl)methyl)-5-(diaminomethylene)-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 (185) 1-(3-bicyclo[3.1.0]hexanylmethyl)-5-(diaminomethylene)-3-[2-methyl-4-(oxetan-3- ylmethyl)-1,3-dioxo-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]hexahydropyrimidine- 2,4,6(1H,3H,5H)-trione (45 mg, 81.1 mol) was separated by chiral SFC (column: DAICEL CHIRALPAK IC, (250 mm*30 mm, 10 um); mobile phase: CO₂-EtOH: CAN = 1: 1 (0.1% NH₃H₂O); gradient: 50% B with isocratic elution) to give 184 (20.2 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C₂₈H₃₈N₆O₆: 554.29, found: 555.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.53 (s, 2H), 7.32 (s, 2H), 4.63 (dd, J = 7.6, 6.0 Hz, 3H), 4.42 (q, J = 6.4 Hz, 2H), 3.66 (d, J = 7.2 Hz, 2H), 3.57 (d, J = 8.0 Hz, 2H), 3.35 (s, 1H), 3.27-3.31 (m, 1H), 2.82 (s, 3H), 2.45 (s, 1H), 2.31-2.39 (m, 1H), 2.21-2.30 (m, 2H), 2.10-2.18 (m, 3H), 1.81-1.96 (m, 3H), 1.39 (dd, J = 13.2, 3.4 Hz, 5H), 1.17-1.28 (m, 3H), 0.51 (td, J = 8.4, 4.6 Hz, 1H), 0.12-0.25 (m, 1H).185 (20.2 mg) was obtained from the second eluting peak from chiral SFC separation as a white solid. MS (ESI): mass calcd. for C₂₈H₃₈N₆O₆: 554.29, found: 555.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.52 (s, 2H), 7.33 (s, 2H), 4.63 (dd, J = 7.6, 6.0 Hz, 3H), 4.36-4.47 (m, 2H), 3.73 (d, J = 7.0 Hz, 2H), 3.66 (d, J = 7.2 Hz, 2H), 2.82 (s, 3H), 2.45 (s, 1H), 2.35 (s, 1H), 2.20-2.28 (m, 2H), 2.11-2.17 (m, 3H), 1.79-1.90 (m, 2H), 1.65 (dd, J = 12.0, 7.2 Hz, 2H), 1.46 (t, J = 10.2 Hz, 2H), 1.39 (d, J = 9.8 Hz, 3H), 1.21- 1.27 (m, 2H), 1.15-1.20 (m, 2H), 0.16-0.28 (m, 1H), 0.02-0.13 (m, 1H). Example 186 and Example 187 were prepared though a similar synthetic sequence to Example 184. Trans (2-methylcyclopropyl)methanol was used instead of bicyclo[3.1.0]hexan- 3-ylmethanol. Trans-5-(diaminomethylene)-1-((5S,7r,10S)-3-methyl-1-(oxetan-3-ylmethyl)- 2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3-((2- methylcyclopropyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione was separated by chiral SFC (column: DAICEL CHIRALCEL OD, (250 mm*30 mm, 10 um); mobile phase: CO₂-MeOH (0.1% NH₃H₂O); gradient: 20%-40% B over 15.0 min). The stereochemistry for these two compounds is arbitrarily assigned. Example 188 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 3- (bromomethyl)-1,1-difluorocyclobutane. Example 189. 5-(diaminomethylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4- dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3-(spiro[2.3]hexan-5- ylmethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (189) Synthetic scheme: Spiro[2.3]hexan-5-ylmethyl 4-methylbenzenesulfonate To a solution of spiro[2.3]hexan-5-ylmethanol (70 mg, 624.06 mol) in DCM (1 mL) was added pyridine (148.1 mg, 1.87 mmol) and 4-methylbenzenesulfonyl chloride (178.5 mg, 936 mol) at 0 °C. The mixture was stirred at 20 °C for 12 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18, (100 mm*25 mm, 10 um); mobile phase: H₂O (10 mM NH₄HCO₃)-ACN; gradient: 35-75% B over 8.0 min) to give the title compound (0.15 g, 90%) as a colorless oil. MS (ESI): mass calcd. for C₁₄H₁₈O₃S: 266.10, found: 267.0 [M+H]⁺. 5-(diaminomethylene)-1-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3-(spiro[2.3]hexan-5-ylmethyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (189) Example 189 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 spiro[2.3]hexan-5-ylmethyl 4-methylbenzenesulfonate. MS (ESI): mass calcd. for C₂₈H₃₈N₆O₆: 554.29, found: 555.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.57-4.69 (m, 3H), 4.38-4.46 (m, 2H), 3.93 (d, J = 7.2 Hz, 2H), 3.66 (d, J = 7.2 Hz, 2H), 3.33-3.36 (m, 1H), 2.82 (s, 3H), 2.63-2.73 (m, 1H), 2.22-2.46 (m, 4H), 2.09-2.18 (m, 3H), 1.96-2.02 (m, 2H), 1.81-1.94 (m, 3H), 1.33-1.47 (m, 3H), 1.19-1.27 (m, 1H), 0.35 (s, 4H). Example 190 and Example 191 were synthesized in a similar route to the one described in Example 189, 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 (3-fluoro-3-methylcyclobutyl)methanol. The diastereomers were separated by chiral SFC. Example 192 and Example 193 were synthesized in a similar route to the one described in Example 189, 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 (3-methylcyclobutyl)methanol. The diastereomers were separated by chiral SFC. Example 194 and Example 195 were synthesized in a similar route to the one described in Example 189, 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 (3-fluorocyclobutyl)methanol. The diastereomers were separated by chiral SFC (column: DAICEL CHIRALPAK IK (250 mm*25 mm, 10 um); mobile phase: CO₂-MeOH (0.1% NH₃H₂O); gradient: 50% B with isocratic elution). Example 196 and Example 197 were synthesized in a similar route to the one described in Example 189, 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 (2,2-difluorocyclobutyl)methanol. The diastereomers were separated by chiral SFC. column: DAICEL CHIRALPAK IK, (250 mm*25 mm, 10 um); mobile phase: CO2-EtOH (0.1% NH3H2O); gradient: 50% B with isocratic elution) Example 198, Example 199, Example 200, and Example 201 were synthesized in a similar route to the one described in Example 189, 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-fluorocyclobutyl)methanol. (2- fluorocyclobutyl)methyl 4-methylbenzenesulfonate was separated by chiral SFC into 4 stereoisomers before the alkylation step. Example 202 and Example 203. 1-(cyclopropylmethyl)-5-(diaminomethylene)-3- ((5R,7r,10R)-3-methyl-2,4-dioxo-1-(((R)-tetrahydrofuran-3-yl)methyl)-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (202) and 1- (cyclopropylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1-(((R)- tetrahydrofuran-3-yl)methyl)-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (203) Synthetic scheme: (4-nitrophenyl) N-(cyclopropylmethyl)carbamate To a solution of cyclopropylmethanamine (200 mg, 2.81 mmol) in DCM (2 mL) was added pyridine (444.9 mg, 5.62 mmol), DMAP (343.6 mg, 2.81 mmol) and (4-nitrophenyl) chloroformate (566.8 mg, 2.81 mmol). The mixture was stirred at 25 °C for 10 min. The crude reaction solution was used in the next step directly. 2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.5⁷.1⁵]tridecane- 1,3,10-trione To a solution of 2-methyl-2,4-diazadispiro[4.1.5⁷.1⁵]tridecane-1,3,10-trione (1.5 g, 6.35 mmol) in DMF (7.5 mL) was added Cs₂CO₃ (6.21 g, 19.05 mmol) and (3S)-3- (bromomethyl)tetrahydrofuran (1.26 g, 7.62 mmol). The mixture was stirred at 50 °C for 48 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to give the title compound (1.44 g, 70.8%) as a yellow oil. MS (ESI): mass calcd. for C₁₇H₂₄N₂O₄: 320.17, found: 321.1 [M+H]⁺. 10-amino-2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4- diazadispiro[4.1.5⁷.1⁵]tridecane-1,3-dione To a solution of 2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4- diazadispiro[4.1.5⁷.1⁵]tridecane-1,3,10- trione (1.39 g, 4.34 mmol) in MeOH (25 mL) was added NH4OAc (6.69 g, 86.77 mmol) at 25 °C. NaBH(OAc)3 (2.30 g, 10.85 mmol) was added at 25 °C and the reaction was stirred at 25 °C for 12 h. The reaction was concentrated under reduced pressure. The residue was dissolved in water (10 mL), adjusted pH to 8 with saturated aqueous NaHCO₃ and extracted with DCM/i-PrOH (3/1) (15 mL x 3). The combined organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated under vacuum to give the title compound (1.5 g, crude) as a pale oil, which was used in the next step directly without purification. MS (ESI): mass calcd. for C₁₇H₂₇N₃O₃: 321.21, found: 322.2 [M+H]⁺. 1-(cyclopropylmethyl)-3-[2-methyl-1,3-dioxo-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl]urea To a solution of 10-amino-2-methyl-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4- diazadispiro[4.1.5⁷.1⁵]tridecane-1,3-dione (600 mg, 1.87 mmol) and TEA (377.8 mg, 3.73 mmol) in DCM (7 mL) was added (4-nitrophenyl) N-(cyclopropylmethyl)carbamate (441 mg, 1.87 mmol) (THF solution) at 20 °C. The mixture was stirred at 20 °C for 1 h. The mixture was quenched with water (10 mL) and extracted with DCM (15 mL x3). 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 (480 mg, 61.4% yield) as pale oil. MS (ESI): mass calcd. for C₂₂H₃₄N₄O₄: 418.26, found: 419.1 [M+H]⁺. 1-(cyclopropylmethyl)-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(1H,3H,5H)-trione A solution of malonic acid (106.91 mg, 1.03 mmol) in AcOH (4.3 mL) was added Ac₂O (4.3 mL) and stirred at 80 °C for 30 min. A solution of 1-(cyclopropylmethyl)-3-[2-methyl- 1,3-dioxo-4-[[(3R)-tetrahydrofuran-3-yl]methyl]-2,4-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl]urea (430 mg, 1.03 mmol) in dioxane (8.6 mL) was added and the resulting mixture was stirred at 80 °C for 30 min. The reaction was quenched with water (15 mL) and extracted with DCM (20 mL x 3). The combined organic phase was 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 (350 mg, 70%) as a yellow oil. MS (ESI): mass calcd. for C₂₅H₃₄N₄O₆: 486.25, found: 487.3 [M+H]⁺. 1-(cyclopropylmethyl)-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(1H,3H,5H)-trione To a solution of 1-(cyclopropylmethyl)-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(1H,3H,5H)-trione (120 mg, 247 mol) in THF (2.5 mL) was added cyanamide (103.7 mg, 2.47 mmol) and Ni(acac)₂ (19.01 mg, 74 mol) under N₂. The mixture was stirred at 80 °C for 20 h. After completion, the reaction was filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound (34.1 mg, 26.2%) as a white solid. MS (ESI): mass calcd. for C₂₆H₃₆N₆O₆: 528.27, found: 529.2 [M+H]⁺. 1-(cyclopropylmethyl)-5-(diaminomethylene)-3-((5R,7r,10R)-3-methyl-2,4-dioxo-1- (((R)-tetrahydrofuran-3-yl)methyl)-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (202) and 1-(cyclopropylmethyl)-5-(diaminomethylene)-3- ((5S,7s,10S)-3-methyl-2,4-dioxo-1-(((R)-tetrahydrofuran-3-yl)methyl)-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (203) (R)-1-(cyclopropylmethyl)-5-(diaminomethylene)-3-(3-methyl-2,4-dioxo-1- ((tetrahydrofuran-3-yl)methyl)-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (30 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm,10 um); mobile phase: CO₂-EtOH (0.1% NH₃H₂O); 50% B, isocratic elution) to give 202 (11.46 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C₂₆H₃₆N₆O₆: 528.27, found: 529.3 [M+H]⁺.¹H NMR (400 MHz, DMSO- d₆) ppm 9.54 (s, 2H), 7.32 (s, 2H), 4.56-4.72 (m, 1H), 3.79 (d, J = 8.4Hz, 1H), 3.60-3.70 (m, 4H), 3.49 (dd, J = 8.4, 5.6 Hz, 1H), 3.33-3.36 (m, 2H), 2.84 (s, 3H), 2.62-2.77 (m, 1H), 2.16- 2.46 (m, 7H), 1.88-2.02 (m, 1H), 1.74-1.84 (m, 1H), 1.63 (dd, J = 13.6, 6.0 Hz, 1H), 1.35-1.51 (m, 3H), 1.18-1.31 (m, 1H), 1.03-1.16 (m, 1H), 0.34-0.41 (m, 2H), 0.23-0.32 (m, 2H). 203 (14.1 mg) was obtained from the second eluting peak from chiral SFC separation as a white solid. MS (ESI): mass calcd. for C₂₆H₃₆N₆O₆: 528.27, found: 529.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.54 (s, 2H), 7.32 (s, 2H), 4.35-4.48 (m, 1H), 3.79 (d, J = 8.4Hz, 1H), 3.58-3.69 (m, 4H), 3.50 (dd, J = 8.4, 5.6 Hz, 1H), 3.36-3.43 (m, 1H), 3.24-3.30 (m, 1H),2.84 (s, 3H), 2.65-2.76 (m, 1H), 2.15-2.46 (m, 7H), 1.88-2.02 (m, 1H), 1.72-1.85 (m, 1H), 1.56-1.70 (m, 1H), 1.35-1.49 (m, 3H), 1.19-1.31 (m, 1H), 1.00-1.17 (m, 1H), 0.34-0.45 (m, 2H), 0.23- 0.32 (m, 2H). Example 204 and Example 205 were synthesized in a similar route to the one described in Example 46. (1-fluorocyclopentyl)methanamine 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. The stereoisomers were separated by chiral SFC (column: DAICEL CHIRALCEL OJ, (250 mm*30 mm, 10 um); mobile phase: CO₂-MeOH (0.1% NH₃H₂O); gradient: 45% B with isocratic elution). Example 206 was synthesized in a similar route to the one described in Example 189, 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 trans 3-(2- methylcyclopropyl)propan-1-ol. Example 207 and Example 208. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3- ((5R,8r,11R)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.2.5⁸.2⁵]pentadecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (207) and 1- (cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,8s,11S)-3-methyl-1-(oxetan-3- ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.2.5⁸.2⁵]pentadecan-11-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (208) Synthetic scheme: 12,15-dioxa-1,3-diazatrispiro[4.2.2.4¹¹.2⁸.2⁵]nonadecane-2,4-dione To a solution of 1,4-dioxadispiro[4.2.5⁸.2⁵]pentadecan-11-one (500 mg, 2.23 mmol) in MeOH (17 mL) and H₂O (17 mL) was added (NH₄)₂CO₃ (856.8 mg, 8.92 mmol). The mixture was degassed and purged with N₂3 times. TMSCN (442.3 mg, 4.46 mmol) was added at 20 °C and stirred at 90 °C for 5 h under N₂. After completion, the reaction mixture was cooled to 25 °C. The reaction was concentrated under reduced pressure. The residual aqueous phase was filtered to give a white solid. The solid was washed with H₂O (10 mL x 3) and dried under vacuum to give the title compound (530 mg, 80.77%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) ppm 10.53 (s, 1H), 8.43 (s, 1H), 3.83 (s, 4H), 1.78-1.65 (m, 2H), 1.59-1.43 (m, 8H), 1.42-1.31 (m, 6H). 3-methyl-12,15-dioxa-1,3-diazatrispiro[4.2.2.4¹¹.2⁸.2⁵]nonadecane-2,4-dione To a solution of 12,15-dioxa-1,3-diazatrispiro[4.2.2.4¹¹.2⁸.2⁵]nonadecane-2,4-dione (250 mg, 849.3 mol), MeI (120.55 mg, 849.3 mol) in DMF (2.5 mL) was added Cs2CO3 (442.77 mg, 1.36 mmol). The mixture was stirred at 0 °C for 1 h under N₂. After completion, the reaction was quenched with water (10 mL). The residual aqueous phase was filtered to give a white solid. The solid was washed with H₂O (10 mL x 3) and dried under vacuum to give the title compound (137 mg, 52.3%) as a white solid. MS (ESI): mass calcd. for C₁₆H₂₄N₂O₄: 308.17, found: 309.2 [M+H]⁺. 3-methyl-1,3-diazadispiro[4.2.5⁸.2⁵]pentadecane-2,4,11-trione To a solution of 3-methyl-12,15-dioxa-1,3-diazatrispiro[4.2.2.4¹¹.2⁸.2⁵]nonadecane- 2,4-dione (137 mg, 444.3 mol) in THF (2 mL) was poured into aqueous HCl (1 N, 1.37 mL). The mixture was stirred at 60 °C for 1 h. After completion, the mixture was adjusted to pH 9 with aqueous Na₂CO₃ and diluted with ethyl acetate (30 mL). The organic layer was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound (110 mg, 93.7%) as a white solid. MS (ESI): mass calcd. for C14H20N2O3: 264.15, found: 265.3 [M+H]⁺. 3-methyl-1-(oxetan-3-ylmethyl)-1,3-diazadispiro[4.2.5⁸.2⁵]pentadecane-2,4,11-trione A mixture of 3-methyl-1,3-diazadispiro[4.2.5⁸.2⁵]pentadecane-2,4,11-trione (110 mg, 416 mol), 3-(iodomethyl)oxetane (90.64 mg, 457.8 mol), Cs2CO3 (271.2 mg, 832.3 mol) in DMF (1.5 mL) was degassed and purged with N23 times. The mixture was stirred at 40 °C for 16 h under N₂. After completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (30 mL). 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 = 1 : 0 to 0 : 1) to the title compound (100 mg, 71.9%) as a white solid. MS (ESI): mass calcd. C₁₈H₂₆N₂O₄: 334.19, found: 335.2 [M+H]⁺. 11-amino-3-methyl-1-(oxetan-3-ylmethyl)-1,3-diazadispiro[4.2.5⁸.2⁵]pentadecane-2,4- dione A solution of 3-methyl-1-(oxetan-3-ylmethyl)-1,3-diazadispiro[4.2.5⁸.2⁵]pentadecane- 2,4,11-trione (100 mg, 299 mol) in NH₃/MeOH (7 M, 1.0 mL) was stirred at 25 °C for 3 h. To the mixture was added Raney-Ni (5.12 mg, 59.8 mol) in one portion at 25 °C under Ar. The mixture was degassed and purged with H₂ three times and stirred under H₂ (15 psi) at 25 °C for 13 h. After completion, the mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (100 mg, 99.7%) as a colorless oil. MS (ESI): mass calcd. C₁₈H₂₉N₃O₃: 335.22, found: 336.3 [M+H]⁺. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(3-methyl-1-(oxetan-3-ylmethyl)-2,4- dioxo-1,3-diazadispiro[4.2.5⁸.2⁵]pentadecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

The title compound was synthesized in a similar route to the one described in Example 46. Cyclobutylmethanamine was used instead of (2-fluorophenyl)methanamine, and a racemic mixture of 11-amino-3-methyl-1-(oxetan-3-ylmethyl)-1,3-diazadispiro[4.2.5⁸.2⁵]pentadecane- 2,4-dione was used in the urea synthesis. MS (ESI): mass calcd. C₂₈H₄₀N₆O₆: 556.30, found: 557.3 [M+H]⁺. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5R,8r,11R)-3-methyl-1-(oxetan-3- ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.2.5⁸.2⁵]pentadecan-11-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (207) and 1-(cyclobutylmethyl)-5-(diaminomethylene)-3- ((5S,8s,11S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.2.5⁸.2⁵]pentadecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (208) 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(3-methyl-1-(oxetan-3-ylmethyl)-2,4- dioxo-1,3-diazadispiro[4.2.5⁸.2⁵]pentadecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (82 mg) was separated by chiral SFC (column: ChiralPak IH, 250 mm*30 mm, 10 um; mobile phase: CO₂-MeOH(0.1% NH₃H₂O); 35% B, isocratic elution) to give 207 (29.7 mg) from the first eluting peak 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), 7.32 (s, 2H), 4.67 (s, 1H), 4.58 (dd, J = 7.6, 6.0 Hz, 2H), 4.40 (t, J = 6.0 Hz, 2H), 3.82 (d, J = 7.2 Hz, 2H), 3.52 (d, J = 7.2 Hz, 2H), 3.17-3.25 (m, 1H), 2.81 (s, 3H), 2.54-2.61 (m, 1H), 2.37-2.46 (m, 1H), 2.25 (d, J = 12.8 Hz, 1H), 2.03 (d, J = 12.8 Hz, 1H), 1.83-1.98 (m, 4H), 1.59-1.82 (m, 7H), 1.42.1.54 (m, 2H), 1.25-1.39 (m, 4H), 1.18 (d, J = 12.4 Hz, 1H), 0.86-0.97 (m, 1H). 208 (30 mg) was obtained from the second eluting peak from chiral SFC separation 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), 4.67 (s, 1H), 4.58 (dd, J = 7.6, 6.0 Hz, 2H), 4.40 (t, J = 6.0 Hz, 2H), 3.82 (d, J = 7.2 Hz, 2H), 3.52 (d, J = 7.2 Hz, 2H), 3.17-3.25 (m, 1H), 2.81 (s, 3H), 2.54-2.61 (m, 1H), 2.36-2.47 (m, 1H), 2.25 (d, J = 12.8 Hz, 1H), 2.03 (d, J = 12.8 Hz, 1H), 1.82-1.98 (m, 4H), 1.59-1.81 (m, 7H), 1.42-1.53 (m, 2H), 1.25-1.38 (m, 4H), 1.14-1.24 (m, 1H), 0.86-0.97 (m, 1H). Example 209. 1-((5S,7s,10S)-1-(azetidin-3-ylmethyl)-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 (209) Synthetic scheme: tert-butyl 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)methyl)azetidine-1-carboxylate

To a solution of 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 (732 mg, 1.55 mmol) and tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (1.86 g, 7.44 mmol) in DMF (7 mL) was added Cs₂CO₃ (4.04 g, 12.4 mmol) and NaI (232.2 mg, 1.55 mmol) at 20 °C. The solution was stirred at 50 °C for 32 h. After completion, the mixture was diluted with H₂O (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine, dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound (210 mg, 21.1%) as a white solid. MS (ESI): mass calcd. for C₃₂H₄₇N₇O₇:641.35, found: 642.4 [M+H]⁺. 1-((5S,7s,10S)-1-(azetidin-3-ylmethyl)-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 (209) To a solution of tert-butyl 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)methyl)azetidine-1-carboxylate (8 mg, 12 mol) in DCM (0.5 mL) was added TFA (0.1 mL) at 20 °C. The solution was stirred at 20 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give 209 (2.52 mg, 33.62%) as a white solid. MS (ESI): mass calcd. for C₂₇H₃₉N₇O₅: 541.30, found: 542.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.51 (s, 2H), 8.43 (s, 1H), 7.70 (s, 2H), 4.65 (s, 1H), 3.56-3.92 (m, 8H), 2.99-3.17 (m, 2H), 2.83 (s, 3H), 2.06-2.47 (m, 7H), 1.88 (d, J = 11.6 Hz, 1H), 1.14-1.64 (m, 12H). Example 210 and 211. (1R,3s)-3-(2-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5- (diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclobutane-1-carboxylic acid (210) and (1S,3r)-3-(2-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclobutane-1-carboxylic acid (211) Synthetic scheme:

tert-butyl 3-(2-(benzyloxy)-2-oxoethylidene)cyclobutanecarboxylate To a solution of NaH (516.97 mg, 12.93 mmol) in THF (20 mL) was added dropwise a solution of benzyl 2-diethoxyphosphorylacetate (3.70 g, 12.93 mmol) in THF (8 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and stirred at 20 °C for 1 h. The reaction was cooled to 0 °C. A solution of tert-butyl 3-oxocyclobutanecarboxylate (2 g, 11.75 mmol) in (8 mL) was added dropwise at 0 °C and stirred at 20 °C for 2 h. The reaction was quenched with saturated aqueous NH₄Cl (30 mL) and extracted with ethyl acetate (20 mL x 4). 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 9 : 1) to give the title compound (2 g, 56.3%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) ppm 7.26-7.44 (m, 5H), 5.74 (t, J = 4.0 Hz, 1H), 5.11 (s, 2H), 2.90-3.32 (m, 5H), 1.41 (s, 9H). 2-(3-(tert-butoxycarbonyl)cyclobutyl)acetic acid To a solution of tert-butyl 3-(2-benzyloxy-2-oxo-ethylidene)cyclobutanecarboxylate (1 g, 3.31 mmol) in EtOH (16.6 mL) was added 10% w/w Pd/C (333.3 mg) under N₂. The mixture was degassed and purged with H23 times. The mixture was stirred under H2 (15 psi) at 20 °C for 6 h. The reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (567 mg, 80%) as a colorless oil. MS (ESI): mass calcd. for C₁₁H₁₈O₄: 214.1, found: 213.5 [M-H]-. tert-butyl 3-(2-hydroxyethyl)cyclobutanecarboxylate To a solution of 2-(3-tert-butoxycarbonylcyclobutyl)acetic acid (380 mg, 1.77 mmol) in THF (4 mL) was slowly added dropwise BH₃.THF (1 M in THF, 3.55 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min and at 20 °C for 12 h. The reaction was quenched with MeOH (5 mL). The resulting mixture was 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 (286 mg, 80.5%) as a colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) ppm 3.56-3.65 (m, 2H), 2.85-3.05 (m, 1H), 2.25-2.53 (m, 3H), 1.83-1.95 (m, 2H), 1.63-1.77 (m, 2H), 1.41-1.49 (m, 9H). tert-butyl 3-(2-bromoethyl)cyclobutanecarboxylate A solution of tert-butyl 3-(2-hydroxyethyl)cyclobutanecarboxylate (240 mg, 1.2 mmol) in DCM (2.4 mL) was cooled to 0 °C. PPh₃ (408.61 mg, 1.56 mmol) and CBr₄ (516.6 mg, 1.56 mmol) were added and stirred at 20 °C for 14 h. The reaction was diluted with DCM (20 mL) and washed with H₂O (10 mL x 3). 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 = 1 : 0 to 19 : 1) to give the title compound (206 mg, 65.3%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) ppm 3.32 (t, J = 4.0 Hz, 2H), 2.91 (m, 1H), 2.86-2.93 (m, 3H), 2.29-2.36 (m, 2H), 1.83-1.94 (m, 2H), 1.45 (s, 9H). tert-butyl 3-(2-((5S,7s,10S)-10-(5-(bis(ethylthio)methylene)-3-(cyclobutylmethyl)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclobutane-1-carboxylate To a solution of 5-(bis(ethylthio)methylene)-1-(cyclobutylmethyl)-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, 364.49 mol) and tert-butyl 3-(2-bromoethyl)cyclobutanecarboxylate (95.92 mg, 364.49 mol) in DMSO (1 mL) was added Cs₂CO₃ (237.51 mg, 728.97 mol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H₂O (30 mL) and extracted with ethyl acetate (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 prep-TLC (SiO₂, petroleum ether : ethyl acetate = 1 : 1) to give the title compound (80 mg, 23.26%) as a yellow solid. MS (ESI): mass calcd. for C₃₇H₅₄N₄O₇S₂: 730.34, found: 731.5 [M+H]⁺. tert-butyl 3-(2-((5S,7s,10S)-10-(5-(bis(ethylthio)methylene)-3-(cyclobutylmethyl)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclobutane-1-carboxylate To a solution of tert-butyl 3-(2-((5S,7s,10S)-10-(5-(bis(ethylthio)methylene)-3- (cyclobutylmethyl)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclobutane-1-carboxylate (90 mg, 123 mol) in THF (3 mL) was added NH₃.H₂O (1.09 g, 7.79 mmol). The mixture was stirred at 50 °C for 16 h. The reaction was concentrated under reduced pressure to give the title compound (78 mg, crude) as a yellow solid. MS (ESI): mass calcd. for C33H48N6O7: 640.36, found: 585.4 [M- 56+H]⁺. 3-(2-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclobutane-1-carboxylic acid

To a solution of tert-butyl 3-(2-((5S,7s,10S)-10-(5-(bis(ethylthio)methylene)-3- (cyclobutylmethyl)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclobutane-1-carboxylate (63 mg, 98.3 mol) in DCM (0.9 mL) was added TFA (460.5 mg, 4.04 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction 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 reverse phase HPLC to give the title compound (40 mg, 68.9%) as a yellow solid. MS (ESI): mass calcd. for C₂₉H₄₀N₆O₇: 584.3, found: 585.3 [M+H]⁺. (1R,3s)-3-(2-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclobutane-1-carboxylic acid (210) and (1S,3r)-3-(2-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclobutane-1-carboxylic acid (211) 3-(2-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan- 1-yl)ethyl)cyclobutane-1-carboxylic acid (40 mg) was separated by chiral SFC (column: DAICEL CHIRALCEL OJ, (250 mm*30 mm, 10 um); mobile phase: CO2-MeOH (0.1% NH3H2O); gradient: 25% B with isocratic elution) to give 210 (16.6 mg) from the first eluting peak as white solid. MS (ESI): mass calcd. for C₂₉H₄₀N₆O₇: 584.3, found: 585.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.53 (s, 2H), 7.35 (s, 2H), 4.57-4.70 (m, 1H), 3.81 (d, 2H), 3.21-3.27 (m, 3H), 2.86-2.95 (m, 1H), 2.83 (s, 3H), 2.53-2.59 (m, 1H), 2.33-2.47 (m, 2H), 2.20- 2.23 (m, 5H), 2.13-2.20 (m, 3H), 1.84-1.93 (m, 2H), 1.66-1.80 (m, 9H), 1.34-1.50 (m, 3H), 1.18-1.30 (m, 1H).211 (5.74 mg) was obtained from the second eluting peak from chiral SFC separation as a white solid. MS (ESI): mass calcd. for C₂₉H₄₀N₆O₇: 584.3, found: 585.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) ppm 9.52 (s, 2H), 7.51 (s, 2H), 4.55-4.71 (m, 1H), 3.81 (d, J = 7.2 Hz, 2H), 3.22-3.26 (m, 3H), 2.88-3.02 (m, 2H), 2.83 (s, 3H), 2.31-2.44 (m, 3H), 2.21-2.29 (m, 4H), 2.13-2.19 (m, 3H), 1.67-1.90 (m, 10H), 1.32-1.50 (m, 3H), 1.19-1.29 (m, 2H). Example 212 and Example 213. (1R,2S)-2-(2-((5S,7r,10S)-10-(3-(cyclobutylmethyl)-5- (diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclopropane-1-carboxylic acid (212) and (1S,2R)-2-(2-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclopropane-1-carboxylic acid (213) Synthetic scheme:

ethyl trans-2-(2-((5S,7r,10S)-10-(5-(bis(ethylthio)methylene)-3-(cyclobutylmethyl)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclopropane-1-carboxylate To a solution of 5-(bis(ethylthio)methylene)-1-(cyclobutylmethyl)-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 (0.2 g, 364 mol) in DMSO (5 mL) was added Cs₂CO₃ (237.51 mg, 729 mol) and ethyl trans-2-(2-bromoethyl)cyclopropanecarboxylate (80.58 mg, 364 mol). The mixture was stirred at 25 °C for 2 h. The residue was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by prep-TLC (SiO₂, petroleum ether : ethyl acetate = 1 : 1) to give the title compound (113 mg, 45%) as a yellow solid. MS (ESI): mass calcd. for C₃₄H₄₈N₄O₇S₂: 688.30, found: 689.4 [M+H]⁺. ethyl trans-2-(2-((5S,7r,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclopropane-1-carboxylate To a solution of ethyl trans-2-(2-((5S,7r,10S)-10-(5-(bis(ethylthio)methylene)-3- (cyclobutylmethyl)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclopropane-1-carboxylate (110.00 mg, 159.68 mol) in THF (2 mL) was added NH3.H2O (1.82 g, 12.98 mmol, 2 mL, 25% purity). The mixture was stirred at 40 °C for 192 h. LC-MS showed the reactant was consumed completely. The reaction mixture was concentrated under vacuum to give the title compound (95 mg, crude) as a yellow solid. MS (ESI): mass calcd. for C₃₀H₄₂N₆O₇: 598.31, found: 599.4 [M+H]⁺. trans-2-(2-((5S,7r,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclopropane-1-carboxylic acid

To a solution of ethyl trans-2-(2-((5S,7r,10S)-10-(3-(cyclobutylmethyl)-5- (diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclopropane-1-carboxylate (30 mg, 50.1 mol) in THF (0.5 mL), H₂O (0.2 mL) and MeOH (0.5 mL) was added LiOH.H₂O (4.21 mg, 100.2 mol). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC to give the title compound (5 mg, 17.4%) as a white solid. MS (ESI): mass calcd. for C₂₈H₃₈N₆O₇: 570.28, found: 571.3 [M+H]⁺. (1R,2S)-2-(2-((5S,7r,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclopropane-1-carboxylic acid (212) and (1S,2R)-2-(2-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)ethyl)cyclopropane-1-carboxylic acid (213) Trans-2-(2-((5S,7r,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan- 1-yl)ethyl)cyclopropane-1-carboxylic acid was separated by chiral SFC (column: DAICEL CHIRALPAK IC, (250 mm*30 mm, 10 um); mobile phase: CO₂-EtOH (0.1% NH₃H₂O); gradient: 50% B with isocratic elution) to give 212 (13.8 mg) from the first eluting peak as a white solid. MS (ESI): mass calcd. for C₂₈H₃₈N₆O₇: 570.28, found: 571.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.53 (s, 2H), 7.35 (s, 2H), 4.59-4.70 (m, 1H), 3.81 (d, J = 7.2 Hz, 2H), 2.83 (s, 3H), 2.57 (d, J = 7.2 Hz, 4H), 2.11-2.42 (m, 6H), 1.67-1.95 (m, 8H), 1.53-1.65 (m, 1H), 1.18-1.50 (m, 6H), 0.91-0.99 (m, 1H), 0.69-0.77 (m, 1H). 213 (13.4 mg) was obtained from the second eluting peak from chiral SFC separation as a white solid. MS (ESI): mass calcd. for C₂₈H₃₈N₆O₇: 570.28, found: 571.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.52 (s, 2H), 7.38 (s, 2H), 4.63 (s, 1H), 3.81 (d, J = 7.2 Hz, 2H), 2.83 (s, 3H), 2.53-2.63 (m, 4H), 2.11-2.47 (m, 7H), 1.61-1.94 (m, 8H), 1.34-1.52 (m, 3H), 1.15-1.31 (m, 3H), 0.90-0.98 (m, 1H), 0.66-0.77 (m, 1H). Example 214 was synthesized in a similar route to the one described in Example 212, using methyl 1-(bromomethyl)cyclopropanecarboxylate instead of trans-2-(2- bromoethyl)cyclopropanecarboxylate. Example 215 was synthesized in a similar route to the one described in Example 91, using (2- methyltetrahydropyran-4-yl) methanol instead of 2-oxabicyclo[2.1.1]hexan-4-ylmethanol and 1-(cyclobutylmethyl)-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 instead 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. Example 216 was synthesized in a similar route to the one described in Example 91, using 4- (hydroxymethyl)tetrahydro-2H-thiopyran 1,1-dioxide instead of 2-oxabicyclo[2.1.1]hexan-4- ylmethanol and 1-(cyclobutylmethyl)-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 instead 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. Example 217. 3-butyl-5-diaminomethylene-1-(2,4-dioxo-1,3-diaza-11- dispiro[5.1.5.1]tetradecyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (217) Synthetic scheme Ethyl (R)-2-(2-((tert-butylsulfinyl)amino)-8,11-dioxadispiro[3.2.4⁷.2⁴]tridecan-2- yl)acetate To a –78 °C solution of lithium diisopropylamide (8.1 mL, 16.1 mmol) in THF (27.6 mL) was added ethyl acetate (1.5 mL, 15.4 mmol) dropwise. After stirring for 20 min, a solution of chlorotitanium triisopropoxide (7.7 mL, 30.7 mmol) in THF (9.2 mL) was added dropwise. After 1 h, (R)-N-(8,11-dioxadispiro[3.2.4⁷.2⁴]tridecan-2-ylidene)-2-methylpropane- 2-sulfinamide (2.3 g, 7.68 mmol) in THF (10.0 mL) was added dropwise. The reaction was stirred at –78 °C for 2.5 h, and then quenched with NH₄Cl (10 mL) and warmed to rt. The mixture was filtered through Celite and the cake was washed with EtOAc. Phases were separated and the organic phase was dried over Na₂SO₄, filtered and concentrated. The crude was purified by column chromatography (silica, 0-100% EtOAc/heptanes) to afford the title compound (1.77 g, 59%) as an oil. MS (ESI): mass calcd. for C₁₉H₃₃NO₅S: 387.12, found: 388.4 [M+H]⁺. Ethyl 2-(2-amino-8,11-dioxadispiro[3.2.4⁷.2⁴]tridecan-2-yl)acetate hydrochloride Ethyl (R)-2-(2-((tert-butylsulfinyl)amino)-8,11-dioxadispiro[3.2.4⁷.2⁴]tridecan-2- yl)acetate (1.7 g, 4.39 mmol) in dioxane (10 mL) was poured into a solution of hydrochloric acid 4 N in dioxane (10 mL, 40 mmol) and the mixture was stirred at rt for 4 h. The mixture was concentrated to dryness to give the crude title compound which was carried forward as is for next step. ¹H NMR (400 MHz, DMSO-d₆) ppm 8.20 (br s, 3H), 4.12 (q, J = 7.1 Hz, 2H), 3.82 (s, 4H), 2.87 (s, 2H), 2.11 – 2.00 (m, 4H), 1.72 – 1.65 (m, 2H), 1.61 – 1.56 (m, 2H), 1.48 – 1.41 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H) 3-(2,4-dimethoxybenzyl)-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecane-2,4,11-trione

To a solution of ethyl 2-(2-amino-8,11-dioxadispiro[3.2.4⁷.2⁴]tridecan-2-yl)acetate (65.0 mg, 229 μmol) in MeCN (1.0 mL) was added cesium carbonate (299 mg, 918 μmol) followed by 2,4-dimethoxybenzyl isocyanate (52.3 μL, 298 μmol). The mixture was stirred at rt for 30 min, resulting in almost full conversion to intermediate (benzylated-urea) based on LCMS. The mixture was then heated and stirred at 60 °C for 1 h and after complete conversion, aqueous HCl 1 N (1.5 mL) was added and the mixture was stirred at 60 °C for 1 h. The mixture was cooled down to rt and water was added and then extracted with EtOAc (2 x). The combined organic phase was dried over Na₂SO₄, filtered and concentrated. The crude material was purified by column chromatography (silica, 0-100% EtOAc/heptanes) to provide the title compound (55 mg, 62%). MS (ESI): mass calcd. for C₂₁H₂₆N₂O₅: 386.18, found: 387.4 [M+H]⁺. 11-amino-3-(2,4-dimethoxybenzyl)-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecane-2,4-dione A solution of 3-(2,4-dimethoxybenzyl)-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecane-2,4,11- trione (45.0 mg, 116 μmol) in ammonia 7 M in MeOH (499 μL, 3.49 mmol) was stirred at rt for 2 h. MeOH (4.0 mL) and palladium on carbon 10% (12.4 mg, 116 μmol) were added and the suspension was purged with hydrogen. The mixture was stirred under a hydrogen balloon at rt for 2 h. The reaction was filtered and concentrated to afford the title compound which was carried forward as crude material. MS (ESI): mass calcd. for C₂₁H₂₉N₃O₄: 387.22, found: 388.4 [M+H]⁺. 1-butyl-3-(3-(2,4-dimethoxybenzyl)-2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11- yl)urea

To 11-amino-3-(2,4-dimethoxybenzyl)-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecane-2,4- dione (45.0 mg, 116 μmol) in DCM (1.0 mL) was added butyl isocyanate (13.3 μL, 116 μmol). The reaction was stirred at rt for 30 min. The reaction mixture was diluted with DCM and the organic phase was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated to provide the title compound (29 mg, 51 %) as a white solid which was used as such in the next step. MS (ESI): mass calcd. for C₂₆H₃₈N₄O₅: 486.28, found: 487.5 [M+H]⁺. 1-butyl-3-(2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)urea To 1-butyl-3-(3-(2,4-dimethoxybenzyl)-2,4-dioxo-1,3- diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)urea (26.3 mg, 54.1 μmol) in TFA (1.0 mL) was added trifluoromethanesulfonic acid (14.4 μL, 162 μmol) and the solution was stirred at rt for 4 h. The reaction was diluted with DCM and the organic phase was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The crude was purified by column chromatography (silica, 0-10% MeOH/DCM) to provide the title compound (13.2 mg, 73%) as a light yellow solid. MS (ESI): mass calcd. for C₁₇H₂₈N₄O₃: 336.22, found: 337.4 [M+H]⁺. 1-butyl-3-(2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione A solution of 1-butyl-3-(2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)urea (13.2 mg, 39.2 μmol) and malonic acid (4.7 mg, 45.1 μmol) in AcOH (388 μL) was added anhydride (14.8 μL, 157 μmol). The solution was stirred at 90 °C for 4 h. The reaction was cooled down to rt and quenched with saturated aqueous Na₂CO₃. DCM was added and the aqueous layer was slowly acidified to pH 1 using HCl (6 N). Phases were separated and the aqueous phase was extracted with DCM. The combined organic phase was dried over Na₂SO₄, filtered, and concentrated to afford the title compound as a white crude solid which was used as such for the next step. MS (ESI): mass calcd. for C₂₀H₂₈N₄O₅: 404.21, found: 405.4 [M+H]⁺. 3-butyl-5-diaminomethylene-1-(2,4-dioxo-1,3-diaza-11-dispiro[5.1.5.1]tetradecyl)- 2,4,6(1H,3H,5H)-pyrimidinetrione (217) To 1-butyl-3-(2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (5.0 mg, 12.4 μmol) in THF (500 μL) was added cyanamide (3.2 mg, 74.2 μmol) and nickel(II) acetylacetonate (640 μg, 2.47 μmol) and the mixture was stirred at 90 °C for 4 h. The reaction was concentrated, and the crude was purified by reverse phase HPLC (C18, 0-100% MeCN/10 mM AmF buffer) to provide the title compound (1.4 mg, 26 %) as a white solid. MS (ESI): mass calcd. for C₂₁H₃₀N₆O₅: 446.23, found: 447.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.06 (s, 1H), 9.53 (s, 2H), 8.46 (s, 1H), 8.02 (s, 1H), 7.42 (s, 2H), 4.63 – 4.54 (m, 1H), 3.76 – 3.69 (m, 2H), 2.58 (d, J = 4.8 Hz, 2H), 2.54 (s, 2H), 2.34 – 2.26 (m, 2H), 2.01 – 1.71 (m, 6H), 1.49 – 1.39 (m, 2H), 1.38 – 1.20 (m, 6H), 0.87 (t, J = 7.3 Hz, 3H). Example 218 and Example 219. 1-butyl-5-(diaminomethylene)-3-((6R,8r,11R)-3-methyl- 2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (218) and 1-butyl-5-(diaminomethylene)-3-((6S,8s,11S)-3-methyl-2,4-dioxo-1,3- diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (219) Synthetic scheme 13-methyl-1,4-dioxa-11,13-diazatrispiro[4.2.1.5¹⁰.1⁸.2⁵]octadecane-12,14-dione To a solution of ethyl 2-(2-amino-8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)acetate (500 mg, 1.76 mmol) in THF (12.5 mL) was added N-methyl-1H-imidazole-1-carboxamide (265 mg, 2.12 mmol) followed by triethylamine (738 μL, 5.29 mmol) and the solution was stirred at 60 °C for 1 h. Then cesium carbonate (1.76 g, 5.29 mmol) was added along with MeCN (12.5 mL), and the mixture was stirred at 60 °C for 17 h. The solution was cooled down and extracted with DCM (3 x). The combined organic phase was washed with NaHCO3, brine, dried over Na₂SO₄, filtered, and concentrated to provide the crude title compound (400 mg, 77%) as a light yellow solid. MS (ESI): mass calcd. for C₁₅H₂₂N₂O₄: 294.16, found: 295.4 [M+H]⁺. 3-methyl-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecane-2,4,11-trione In a vial was dissolved 13-methyl-1,4-dioxa-11,13- diazatrispiro[4.2.1.5¹⁰.1⁸.2⁵]octadecane-12,14-dione (400 mg, 1.36 mmol) in THF (8.0 mL) to which HCl 1N (1.2 mL, 1.17 mmol) was added and the reaction was stirred for 3 h at 50 °C. The reaction was cooled down and extracted with DCM (3x). The combined organic phase was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated to provide the crude title compound (291 mg, 99%) as a light-yellow solid which was carried forward to the next step. MS (ESI): mass calcd. for C13H18N2O3: 250.13, found: 251.4 [M+H]⁺. 11-amino-3-methyl-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecane-2,4-dione In a vial was dissolved 3-methyl-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecane-2,4,11-trione (291 mg, 1.16 mmol) in ammonia 7 M in MeOH (2.5 mL, 17.5 mmol) and the solution was stirred at rt for 4 h. MeOH (6.0 mL) was added followed by palladium on carbon 10% (248 mg, 116 μmol). The suspension was purged with hydrogen and the mixture was stirred under a hydrogen balloon at rt for 17 h. The reaction was filtered over Celite and concentrated to afford the crude title compound (259 mg, 89%) as a light yellow solid which was carried forward for the next step. MS (ESI): mass calcd. for C₁₃H₂₁N₃O₂: 251.16, found: 252.4 [M+H]⁺. 1-butyl-3-(3-methyl-2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)urea To 11-amino-3-methyl-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecane-2,4-dione (259 mg, 1.03 mmol) in DCM (4.4 mL) was added butyl isocyanate (134 μL, 1.19 mmol) dropwise. The reaction was stirred at rt for 1 h and was concentrated on a silica gel. The crude was purified by flash column chromatography (silica, 0-10% MeOH/DCM) to provide the title compound (160 mg, 44%) as a white solid. MS (ESI): mass calcd. for C₁₈H₃₀N₄O₃: 350.23, found: 351.5 [M+H]⁺. 1-butyl-3-(3-methyl-2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione In a vial were dissolved 1-butyl-3-(3-methyl-2,4-dioxo-1,3- diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)urea (160 mg, 457 μmol) and malonic acid (57.6 mg, 548 μmol) in AcOH (3.0 mL) to which acetic anhydride (95.9 μL, 1.00 mmol) was added when the temperature reached 60 °C. The solution was stirred at 90 °C for 4 h and quenched with water (2 mL) and heating continued for 30 min (to quench excess of Ac₂O). The reaction was cooled down and extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford the crude title compound (180 mg, 94%) as a thick gum residue that partially solidified. MS (ESI): mass calcd. for C21H30N4O5: 418.22, found: 419.4 [M+H]⁺. 1-butyl-5-(diaminomethylene)-3-((6R,8r,11R)-3-methyl-2,4-dioxo-1,3- diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (218) and 1- butyl-5-(diaminomethylene)-3-((6S,8s,11S)-3-methyl-2,4-dioxo-1,3- diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (219) To 1-butyl-3-(3-methyl-2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (180 mg, 430 μmol) in THF (17.4 mL) was added cyanamide (110 mg, 2.58 mmol) and nickel(II) acetylacetonate (22.1 mg, 86 μmol), and the mixture was stirred at 90 °C for 18 h. The reaction was concentrated, and the crude was purified by reverse phase chromatography (C18, 0-100% MeCN/10 mM AmB buffer) to provide a white solid (66.0 mg, 33 %) as a racemate. The racemic mixture was subjected to chiral separation (Phenomenex, i-Amylose, 70% Hexanes, 30% Ethanol/methanol +0.1% NH₄OH as a modifier), and the first peak to elute gave 218 (17.0 mg, 9%) as a white solid. MS (ESI): mass calcd. for C₂₂H₃₂N₆O₅: 460.24, found: 461.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 9.53 (s, 2H), 8.31 (s, 1H), 7.38 (s, 2H), 4.65 – 4.53 (m, 1H), 3.77 – 3.67 (m, 2H), 2.95 (s, 3H), 2.72 (d, J = 2.0 Hz, 2H), 2.36 – 2.23 (m, 2H), 2.02 – 1.70 (m, 6H), 1.49 – 1.39 (m, 2H), 1.36 – 1.19 (m, 6H), 0.87 (t, J = 7.3 Hz, 3H). The second peak to elute gave 219 (17.7 mg, 9%) as a white solid. MS (ESI): mass calcd. for C₂₂H₃₂N₆O₅: 460.24, found: 461.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 9.53 (s, 2H), 8.31 (s, 1H), 7.41 (s, 2H), 4.65 – 4.52 (m, 1H), 3.76 – 3.68 (m, 2H), 2.95 (s, 3H), 2.72 (d, J = 1.9 Hz, 2H), 2.37 – 2.23 (m, 2H), 2.02 – 1.70 (m, 6H), 1.48 – 1.38 (m, 2H), 1.37 – 1.19 (m, 6H), 0.87 (t, J = 7.3 Hz, 3H). Stereochemistry is arbitraily assigned. Example 220: 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (220) Synthetic scheme:

11,13-dimethyl-1,4-dioxa-11,13-diazatrispiro[4.2.1.5¹⁰.1⁸.2⁵]octadecane-12,14-dione In a vial was dissolved 13-methyl-1,4-dioxa-11,13- diazatrispiro[4.2.1.5¹⁰.1⁸.2⁵]octadecane-12,14-dione (540 mg, 1.83 mmol) in DMF (27 mL) to which iodomethane (461 L, 7.34 mmol) and cesium carbonate (1.83 g, 5.50 mmol) were added. The mixture was heated to 60 °C for 17 h. The reaction was quenched with water and extracted with AcOEt (2x). The combined organic phase was washed with aq. LiCl 5%, water, and brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by column chromatography (silica, 0-100% AcOEt in heptanes) to give the title compound (373 mg, 66%) as a white solid. MS (ESI): mass calcd. for C₁₆H₂₄N₂O₄: 308.17, found: 309.3 [M+H]⁺. 1,3-dimethyl-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecane-2,4,11-trione In a vial was dissolved 11,13-dimethyl-1,4-dioxa-11,13- diazatrispiro[4.2.1.5¹⁰.1⁸.2⁵]octadecane-12,14-dione (284 mg, 919 mol) in THF (5.0 mL) and HCl 1 N (1.0 mL, 919 mol) was added. The mixture was heated to 60 °C for 1 h. The reaction was quenched with 1 mL of ammonia in MeOH (2 M) and extracted with DCM (3 x). The combined organics phase was dried over Na₂SO₄, filtered, and concentrated to provide the crude title compound (243 mg, 100%) as a white solid which was directly used in the next step. MS (ESI): mass calcd. for C14H20N2O3: 264.15, found: 265.4 [M+H]⁺. 11-amino-1,3-dimethyl-1,3-diazadispiro[5.1.5^8.1⁶]tetradecane-2,4-dione In a flask was dissolved 1,3-dimethyl-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecane-2,4,11- trione (243 mg, 919 mol) in ammonia 7 M in MeOH (2.5 mL, 17.5 mmol) and the solution was stirred at rt for 4 h. To the solution was added MeOH (5.0 mL) followed by palladium on carbon 10% (248 mg, 116 mol). The reaction was stirred under a hydrogen balloon for 17 h. The reaction was filtered over Celite and the filtrate was concentrated to afford the title compound (309 mg, 100%) as a light yellow solid which was directly used in the next step. MS (ESI): mass calcd. for C₁₄H₂₃N₃O₂: 265.18, found: 266.4 [M+H]⁺. 1-(cyclobutylmethyl)-3-(1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11- yl)urea In a vial and to 11-amino-1,3-dimethyl-1,3-diazadispiro[5.1.5^8.1⁶]tetradecane-2,4- dione (309 mg, 1.16 mmol) in DCM (2.0 mL) was added 4-nitrophenyl (cyclobutylmethyl)carbamate (297 mg, 1.19 mmol) followed by triethylamine (326 L, 2.33 mmol) and the mixture was stirred at rt for 1 h. The solution was extracted with DCM (3x). The combined organic phase was washed with saturated aq. K₂CO₃ (2x), NaHCO₃ (1x), and brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by column chromatography (silica, 0-100% AcOEt/ heptanes) to give the title compound (280 mg, 64%) as a white solid. MS (ESI): mass calcd. for C₂₀H₃₂N₄O₃: 376.25, found: 377.4 [M+H]⁺. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(1,3-dimethyl-2,4-dioxo-1,3- diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (220) The title compound (220) was synthesized from 1-(cyclobutylmethyl)-3-(1,3-dimethyl- 2,4-dioxo-1,3-diazadispiro[5.1.5⁸.1⁶]tetradecan-11-yl)urea in similar procedures as described in Example 218. MS (ESI): mass calcd. for C27H36N6O6: 486.26 found: 487.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 9.53 (s, 2H), 7.31 (s, 2H), 4.66 – 4.55 (m, 1H), 3.80 (d, J = 7.0 Hz, 2H), 3.33 – 3.31 (m, 1H), 3.03 (s, 3H), 2.98 (s, 3H), 2.86 (s, 2H), 2.59 – 2.52 (m, 1H), 2.37 – 2.16 (m, 4H), 1.97 – 1.63 (m, 9H), 1.36 (t, J = 11.7 Hz, 4H). Example 221 and Example 222. 1-butyl-5-(diaminomethylene)-3-((5R,7r,10R)-1,3- dimethyl-2-oxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)- trione (221) and 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-1,3-dimethyl-2-oxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (222) Synthetic scheme:

1,3-dimethyl-11,14-dioxa-1,3-diazatrispiro[4.1.2.4¹⁰.2⁷.1⁵]heptadecan-2-one To a solution of sodium borohydride (450 mg, 11.4 mmol) in THF (3.5 mL) at 0 °C was added boron trifluoride diethyl etherate (1.5 mL, 12.1 mmol) dropwise. The mixture was stirred at 0 °C for 15 min then a solution of 1,3-dimethyl-11,14-dioxa-1,3- diazatrispiro[4.1.2.4^10.2⁷.1⁵]heptadecane-2,4-dione (500 mg, 1.7 mmol) in THF (2.0 mL) was added. The mixture was slowly warmed up to rt and stirred for 17 h. MeOH (5 mL) was slowly added at 0 °C and the solution was stirred at rt for 1 h. Solvent was removed and to the residue was added water which was extracted with EtOAc (2x). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by column chromatography (silica, 5-100% of a solution mix of 20% MeOH/EtOAc in DCM) to provide the title compound (367 mg, 77%). ¹H NMR (400 MHz, DMSO-d₆) ppm 3.83 (s, 4H), 3.34 (s, 2H), 2.66 (s, 3H), 2.61 (s, 3H), 2.22 – 2.16 (m, 2H), 1.83 – 1.77 (m, 2H), 1.63 – 1.42 (m, 8H). 1,3-dimethyl-1,3-diazadispiro[4.1.5⁷.1⁵]tridecane-2,10-dione To 1,3-dimethyl-11,14-dioxa-1,3-diazatrispiro[4.1.2.4¹⁰.2⁷.1⁵]heptadecan-2-one (500 mg, 1.78 mmol) in acetone (4.0 mL) and water (2.0 mL) was added p-toluenesulfonic acid monohydrate (172 mg, 892 μmol) and the mixture was heated at 50 °C for 17 h. The reaction was cooled down to rt and diluted with EtOAc, washed with 50% aqueous K₂CO₃ solution and brine dried over MgSO₄, filtered, and concentrated to give the crude title compound (421 mg, 100 %) as a colorless solid which was used without further purification in the next step. 10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-2-one To a solution of 1,3-dimethyl-1,3-diazadispiro[4.1.5⁷.1⁵]tridecane-2,10-dione (300 mg, 1.27 mmol) in MeOH (750 μL) was added ammonia 7 M in MeOH (3.7 mL, 25.9 mmol), followed by palladium on carbon 10% (135 mg, 1.27 mmol). The reaction was submitted to 3 cycles of vacuum/ hydrogen purges and stirred under hydrogen for 72 h. The reaction mixture was purged with nitrogen, filtered through Celite and concentrated to give the title compound, which was used as such in the next step. MS (ESI): mass calcd. for C₁₃H₂₃N₃O: 237.18, found: 238.3 [M+H]⁺. 1-butyl-3-(1,3-dimethyl-2-oxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)urea To 10-amino-1,3-dimethyl-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-2-one (300 mg, 1.26 mmol) in DCM (2.3 mL) was added triethylamine (705 μL, 5.06 mmol) at rt and the reaction was stirred for 5 min when butyl isocyanate (726 μL, 6.32 mmol) was added and the reaction was stirred for 17 h. The mixture was concentrated onto silica gel and the crude was purified by column chromatography (silica, 0-20% MeOH/DCM) to provide the title compound (250 mg, 59%). MS (ESI): mass calcd. for C₁₈H₃₂N₄O₂: 336.25, found: 337.3 [M+H]⁺. 1-butyl-3-(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 1-butyl-3-(1,3-dimethyl-2-oxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl)urea (125 mg, 372 μmol) in AcOH (1.1 mL) was added malonic acid (78.1 mg, 743 μmol). The reaction was heated to 60 °C and acetic anhydride (281 μL, 2.97 mmol) was added. The reaction was sealed and stirred at 90 °C for 1 h. The mixture was cooled down to rt, neutralized with saturated aqueous NaHCO3 solution and extracted with DCM (3x). The combined organic phase was dried over Na₂SO₄, filtered, and concentrated to give the crude title compound which was used as such in the next step. MS (ESI): mass calcd. for C₂₁H₃₂N₄O₄: 404.24, found: 405.4 [M+H]⁺. 1-butyl-5-(diaminomethylene)-3-(1,3-dimethyl-2-oxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan- 10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To 1-butyl-3-(1,3-dimethyl-2-oxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (40 mg, 99 μmol) in THF (594 μL) was added cyanamide (42.0 mg, 989 μmol) and nickel(II) acetylacetonate (7.6 mg, 30 μmol) and the mixture was stirred at 85 °C for 17 h. The reaction was concentrated, and the crude was purified by reverse phase HPLC (C18, 0-100% MeCN/10 mM AmF buffer) to provide the title compound (8.5 mg, 19%). MS (ESI): mass calcd. for C₂₂H₃₄N₆O₄: 446.26, found: 447.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) ppm 9.52 (br.s, 2H), 7.30 (br.s, 2H), 4.67 – 4.54 (m, 1H), 3.74 – 3.67 (m, 2H), 3.34 (br.s, 2H), 2.65 (s, 3H), 2.59 (s, 3H), 2.39 – 2.26 (m, 2H), 2.18 (dd, J = 12.6, 6.8 Hz, 2H), 1.90 – 1.84 (m, 1H), 1.78 – 1.60 (m, 3H), 1.50 – 1.30 (m, 6H), 1.28 – 1.18 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). 1-butyl-5-(diaminomethylene)-3-((5R,7r,10R)-1,3-dimethyl-2-oxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (221) and 1- butyl-5-(diaminomethylene)-3-((5S,7s,10S)-1,3-dimethyl-2-oxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (222) 1-butyl-5-(diaminomethylene)-3-(1,3-dimethyl-2-oxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione was submitted for chiral SFC separation (Cellulose tris(3,5-dichlorophenylcarbamate, 35% ( IPA + 0.1% NH4OH ) / 65% supercritical CO₂). The first peak to elute was collected to provide the title compound 221 as a white solid. mass calcd. for C₂₂H₃₄N₆O₄: 446.26, found: 447.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.53 (s, 2H), 7.41 (s, 2H), 4.67 – 4.55 (m, 1H), 3.76 – 3.70 (m, 2H), 3.35 (s, 2H), 2.67 (s, 3H), 2.61 (s, 3H), 2.44 – 2.26 (m, 2H), 2.20 (dd, J = 12.6, 6.3 Hz, 2H), 1.88 (dd, J = 12.7, 2.8 Hz, 1H), 1.80 – 1.61 (m, 3H), 1.52 – 1.31 (m, 6H), 1.25 (dq, J = 14.6, 7.3 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). The second peak to elute was collected to provide the title 222. mass calcd. for C₂₂H₃₄N₆O₄: 446.26, found: 447.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.53 (s, 2H), 7.43 (s, 2H), 4.61 (s, 1H), 3.77 – 3.68 (m, 2H), 3.35 (s, 2H), 2.67 (s, 3H), 2.61 (s, 3H), 2.45 – 2.26 (m, 2H), 2.20 (dd, J = 12.5, 6.3 Hz, 2H), 1.93 – 1.85 (m, 1H), 1.80 – 1.63 (m, 3H), 1.49 – 1.31 (m, 6H), 1.31 – 1.18 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 223. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-((3- fluoroazetidin-3-yl)methyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (223) Synthetic scheme: Tert-butyl 3-fluoro-3-(iodomethyl)azetidine-1-carboxylate To a suspension of triphenylphosphine resin (1.9 g, 7.25 mmol) and imidazole (151 mg, 2.19 mmol) in DCM (13.6 mL) at 0 °C was added iodine (482 mg, 1.9 mmol) and the solution was stirred until all the iodine was dissolved. Tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine- 1-carboxylate (300 mg, 1.46 mmol) in DCM (1.8 mL) was added, and the mixture was slowly warmed up to rt and stirred for 2 h. The resin was filtered and rinsed well with EtOAc. The filtrate was washed with 10 % aqueous sodium thiosulfate solution (1x 30 mL) and once with water (30 mL). The organic phase was dried over MgSO₄, filtered, and concentrated to provide the title compound (450 mg, 98%) as a yellow oil, which was used in the next step without further purification. 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)methyl)-3-fluoroazetidine-1-carboxylate To tert-butyl 3-fluoro-3-(iodomethyl)azetidine-1-carboxylate (112 mg, 355 μmol) in anhydrous DMSO (889 μL) was added 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 (100 mg, 178 μmol) followed by cesium carbonate (118 mg, 355 μmol). The suspension was stirred at rt for 1 h, diluted with EtOAc (10 mL), and washed with water (2 x 5 mL). The organic phase was dried over MgSO₄, filtered, and concentrated to provide the crude title compound (180 mg, 135%) as an orange oil. MS (ESI): mass calcd. for C₃₆H₅₂FN₅O₇S₂: 749.33, found: 650.3 [M-Boc+H]⁺. Tert-butyl 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)methyl)-3-fluoroazetidine-1-carboxylate

To a vial containing 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)methyl)-3-fluoroazetidine-1-carboxylate (25 mg, 33.3 μmol) in THF (167 μL) was added ammonium hydroxide 28% in water (83.3 μL, 2.14 mmol). The vial was sealed and stirred at 45 °C for 42 h. The reaction was diluted with EtOAc (5 mL) and washed with water (2 x 2 mL). The organic phase was dried over MgSO₄, filtered, and concentrated to provide the title compound as a yellow oil, which was directly used in the next step. MS (ESI): mass calcd. for C32H46FN7O7: 659.34, found: 560.3 [M-Boc+H]⁺. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-((3-fluoroazetidin-3- yl)methyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (223) To tert-butyl 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)methyl)-3-fluoroazetidine-1-carboxylate (22.0 mg, 33 μmol) in DCM (500 μL) was added trifluoroacetic acid (301 μL, 3.93 mmol), and the solution was stirred at rt for 1 h. The reaction was diluted with toluene (100 μL) and concentrated. The residue was purified by reverse phase HPLC (C18, 25-45% MeCN/AmF 10 mM buffer) to provide the title compound (14 mg, 69%) as a colorless powder. MS (ESI): mass calcd. for C27H38FN7O5: 559.29, found: 560.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.51 (s, 2H), 7.43 (s, 2H), 4.61 (s, 1H), 3.97 – 3.79 (m, 2H), 3.69 (br, m, 4H), 3.59 (br, m, 2H), 2.85 (s, 3H), 2.43 (d, J = 13.3 Hz, 1H), 2.32 – 2.17 (m, 6H), 2.10 (d, J = 13.0 Hz, 1H), 1.80 (d, J = 11.0 Hz, 1H), 1.59 – 1.49 (m, 4H), 1.47 – 1.40 (m, 2H), 1.39 – 1.29 (m, 3H), 1.24 – 1.15 (m, 3H). Example 224 was prepared in a similar sequence to Example 184, using 1- methylcyclopropanemethanol instead of bicyclo[3.1.0]hexan-3-ylmethanol. Example 225 was prepared in a similar sequence to Example 184, using (bicyclo[3.1.0]hexan- 6-yl)methanol instead of bicyclo[3.1.0]hexan-3-ylmethanol. Example 226. 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-((3-fluoro- 1-methylazetidin-3-yl)methyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (226) Synthetic scheme

To 1-(cyclopentylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-((3-fluoroazetidin- 3-yl)methyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (223) (80 mg, 119 μmol) in MeOH (1.2 mL) was added formaldehyde (80 μL, 1.05 mmol) followed by sodium triacetoxyborohydride (51.9 mg, 238 μmol) and the suspension was stirred at rt for 45 min. The reaction was quenched with 1 N NaOH (100 μL), diluted with EtOAc (15 mL), and washed with water (2 x 10 mL). The organic phase was dried over MgSO₄, filtered, and concentrated. The crude was purified by reverse column HPLC (C18, 25-45% MeCN/AmF 10 mM buffer) to provide the title compound (15 mg, 22%) as a white powder. MS (ESI): mass calcd. for C28H39FN8O6: 573.31, found: 574.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) 9.52 (s, 2H), 8.20 (s, 1H), 7.38 (s, 2H), 4.61 (s, 1H), 3.93 – 3.75 (m, 2H), 3.68 (d, J = 7.4 Hz, 2H), 3.53 (dd, J = 14.4, 9.3 Hz, 2H), 3.06 (dd, J = 22.1, 8.2 Hz, 2H), 2.84 (s, 3H), 2.52 (s, 1H), 2.43 (d, J = 12.6 Hz, 1H), 2.36 – 2.25 (m, 6H), 2.24 – 2.14 (m, 3H), 2.10 (d, J = 12.7 Hz, 1H), 1.79 (d, J = 11.6 Hz, 1H), 1.59 – 1.49 (m, 4H), 1.47 – 1.40 (m, 2H), 1.39 – 1.29 (m, 3H), 1.25 – 1.15 (m, 3H). Example 227. 5-(diaminomethylene)-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- methylcyclopentyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (227) Synthetic scheme:

1-(iodomethyl)-1-methylcyclopentane To a solution of triphenylphosphine (1.39 g, 5.25 mmol) and imidazole (361 mg, 5.25 mmol) in DCM (12.5 mL) at 0 °C was added iodine (1.34 mg, 5.25 mmol) and the solution was stirred until all the iodine was dissolved. (1-Methylcyclopentyl)methanol (500 mg, 4.38 mmol) in solution in DCM (2.1 mL) was added, and the reaction was refluxed at 50 °C for 16 h. The reaction mixture was filtered through a pad of silica and concentrated. The residue was diluted with diethyl ether (10 mL), filtered through a pad of silica, and concentrated. The residue was again diluted with pentane (10 mL), filtered through a pad of silica, and concentrated. The residue was quenched with 10% aqueous Na₂S₂O₃ solution (5 mL) and diluted with DCM (5 mL). The layers were separated and the aqueous layer was extracted with DCM (5 mL x 3). The combined organic layer was washed with water (5 mL), dried over Na₂SO₄, and concentrated to yield the title compound (357 mg, 36%), which was used directly in the next step. ¹H NMR (400 MHz, CDCl₃) ppm 3.27 (s, 2H), 1.73 – 1.64 (m, 4H), 1.64 – 1.52 (m, 2H), 1.52 – 1.44 (m, 2H), 1.11 (s, 3H). 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-methylcyclopentyl)methyl)pyrimidine- 2,4,6(1H,3H,5H)-trione

To a solution 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 (100 mg, 182 μmol) and 1-(iodomethyl)-1-methylcyclopentane (153 mg, 681 μmol) in DMF (2 mL), potassium carbonate (201 mg, 1.45 mmol) was added at ambient temperature. The reaction was heated to 45 °C and stirred for 24 h. Another aliquot of 1-(iodomethyl)-1- methylcyclopentane (153 mg, 681 μmol) was added and the reaction was stirred for another 60 h. The reaction was quenched with water (5 mL) and diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layer was washed with water (5 mL) and brine (5 mL), dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 0-100% EtOAc/heptanes) to get the title compound (54.6 mg, 46%). MS (ESI): mass calcd. for C₃₂H₄₆N₄O₆S₂: 646.29, found: 647.4 [M+H]⁺. 5-(diaminomethylene)-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-methylcyclopentyl)methyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (227) To a vial containing 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- methylcyclopentyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (54.7 mg, 85 μmol) in THF (423 μL) was added ammonium hydroxide 28% in water (235 μL, 1.69 mmol). The vial was sealed and stirred at 45 °C for 40 h. The reaction was quenched with water (5 mL) and diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layer was washed with water (5 mL) and brine (5 mL), dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by reverse- phase HPLC (C-18, 50% MeCN in 10 mM AmF) to provide the title compound (12 mg, 25%) 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), 7.33 (s, 2H), 4.72 – 4.64 (m, 1H), 4.63 (dd, J = 7.8, 6.2 Hz, 2H), 4.42 (td, J = 6.2, 3.6 Hz, 2H), 3.81 (s, 2H), 3.66 (d, J = 7.4 Hz, 2H), 3.30 – 3.24 (m, 1H), 2.82 (s, 3H), 2.42 – 2.10 (m, 7H), 1.85 (d, J = 10.8 Hz, 1H), 1.62 – 1.32 (m, 9H), 1.29 – 1.12 (m, 3H), 0.85 (s, 3H). Example 228 and Example 229 were synthesized following the same sequence of steps for Example 227 using (spiro[2.3]hexan-4-yl)methanol as starting material instead of (R)- pyrrolidin-3-ylmethanol. The racemic mixture was subjected to chiral separation (ChiralPak IC SFC, 30% MeOH + 0.1% NH₄OH, 70% supercritical CO₂) to separate the two diastereomers. The stereochemistry for these two compounds is arbitrarily assigned. Example 230 was synthesized following the same sequence of steps for Example 227. 2- (bromomethyl)-1,4-dioxane as starting material instead of 2- (iodomethyl)cyclopropanecarbonitrile Example 231 and Example 232 were synthesized following a simlar sequnce to that described for Example 221, using (R)-3-methyl-1-((tetrahydrofuran-3-yl)methyl)-11,14-dioxa-1,3- diazatrispiro[4.1.2.4¹⁰.2⁷.1⁵]heptadecane-2,4-dione as starting material instead of 1,3- dimethyl-11,14-dioxa-1,3-diazatrispiro[4.1.2.4^10.2⁷.1⁵]heptadecane-2,4-dione and 4- nitrophenyl (cyclobutylmethyl)carbamate instead of isocyanatobutane. The diastereomers were separated by SFC (ChiralPak IC SFC, 50% MeOH + 0.1% NH₄OH, 50% supercritical CO₂). Example 233 was synthesized following the same sequence of steps for Example 227, using (2-methylcyclobutyl)methanol as starting material instead of 1-methylcyclopropanemethanol. Example 234, Example 235, and Example 236 were obtained from the chiral SFC separation (column: DAICEL CHIRALPAK IC, (250 mm*30 mm, 10 um); mobile phase: CO₂-IPA (0.1% NH₃H₂O); gradient: 50% B with isocratic elution) of Example 233. Example 237 was synthesized following the same sequence of steps for Example 227, using (2-methylcyclobutyl)methanol as starting material instead of 1-methylcyclopropanemethanol. Example 238 and Example 239 were obtained from the chiral SFC separation (column: DAICEL CHIRALPAK IK, (250 mm*25 mm, 10 um); mobile phase: CO₂-MeOH (0.1% NH₃H₂O); gradient: 55% B with isocratic elution) of Example 237. Example 240 was obtained using a similar procedure to the one described in Example 95, using methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate and 5- (bis(ethylthio)methylene)-1-(cyclobutylmethyl)-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 as starting materials. Example 241. 1-(bicyclo[2.1.0]pentan-5-ylmethyl)-5-(diaminomethylene)-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 (241) Synthetic scheme

(5S,7s,10S)-10-isocyanato-3-methyl-1-(oxetan-3-ylmethyl)-1,3- diazadispiro[4.1.5⁷.1⁵]tridecane-2,4-dione To a solution of 10-amino-3-methyl-1-(oxetan-3-ylmethyl)-1,3- diazadispiro[4.1.5⁷.1⁵]tridecane-2,4-dione (200 mg, 651 μmol) in DCM (1.3 mL) and saturated. NaHCO₃ (1.3 mL) was added triphosgene (63.7 mg, 215 μmol) at 0 °C. The biphasic reaction was stirred at rt for 1 h. The layers were separated, and the aqueous phase was extracted with DCM (5 mL x 3). The combined organic layer was washed with water (5 mL), dried over Na₂SO₄, filtered, and concentrated to provide the title compound (215 mg, 99%) as a colorless sticky solid, which was directly used in the next step. 1-(bicyclo[2.1.0]pentan-5-ylmethyl)-3-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4- dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)urea A solution of (5S,7s,10S)-10-isocyanato-3-methyl-1-(oxetan-3-ylmethyl)-1,3- diazadispiro[4.1.5⁷.1⁵]tridecane-2,4-dione (215 mg, 645 μmol) and {bicyclo[2.1.0]pentan-5- yl}methanamine (59.4 mg, 580 μmol) in DCM (6.5 mL) was stirred at rt for 4 h. The crude mixture was concentrated to provide the title compound (275 mg, 99 %), which was directly used in the next step. MS (ESI): mass calcd. for C₂₃H₃₄N₄O₄: 430.26 found: 431.4 [M+H]⁺. 1-(bicyclo[2.1.0]pentan-5-ylmethyl)-5-(diaminomethylene)-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 (241) The title compound (241) was synthesized from 1-(bicyclo[2.1.0]pentan-5-ylmethyl)- 3-((5S,7s,10S)-3-methyl-1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan- 10-yl)urea in similar procedures as described in steps 5-6 of Example 221. MS (ESI): mass calcd. for C₂₇H₃₆N₆O₆: 540.27 found: 541.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.53 (s, 2H), 7.37 (s, 2H), 4.73 – 4.65 (m, 1H), 4.63 (dd, J = 7.8, 6.2 Hz, 2H), 4.42 (dd, J = 11.4, 6.1 Hz, 2H), 3.67 (d, J = 7.0 Hz, 2H), 3.54 (d, J = 7.0 Hz, 2H), 3.31 – 3.25 (m, 1H), 2.82 (s, 3H), 2.40 – 2.10 (m, 7H), 2.05 – 1.96 (m, 2H), 1.85 (d, J = 12.3 Hz, 1H), 1.54 (s, 2H), 1.47 – 1.35 (m, 3H), 1.35 – 1.25 (m, 3H), 1.25 – 1.18 (m, 1H). Example 242. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(1-((4-fluorotetrahydro-2H- pyran-4-yl)methyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (242)

Synthetic scheme: 1-(cyclobutylmethyl)urea Cyclobutylmethylamine hydrochloride (14.2 g, 114 mmol) and potassium cyanate (14.4 g, 168 mmol) were dissolved in water (114 mL) and heated to 90 °C for 1 h. The mixture was filtered hot, then cooled with an ice bath. The resulting precipitate was collected by filtration to yield the title compound (9.46 g, 65%) as white crystals. MS (ESI): mass calcd. for C₆H₁₂N₂O: 128.09, found: 129.5 [M+H]⁺. 1-(cyclobutylmethyl)pyrimidine-2,4,6(1H,3H,5H)-trione Sodium (7.27 g, 111 mmol) (35% dispersion in paraffin) was first dissolved in toluene (300 mL) and triturated (2-3 hours) until most paraffin was dissolved. Then, three washes were performed with heptanes to remove paraffin oils/waxes, leaving behind a fine sodium powder. A suspension of sodium in heptane was slowly added to 50 mL EtOH at 0 °C. A mixture of 1- (cyclobutylmethyl)urea (9.46 g, 73.8 mmol), diethyl malonate (11.4 mL, 73.8 mmol) and the freshly prepared sodium ethoxide solution (111 mmol) in ethanol (208 mL) was heated to 80 °C and stirred for 18 h. The reaction was cooled to rt and the solvent was evaporated with stream of air. The residue was taken in water and washed with Et₂O. The aqueous layer was then acidified with aqueous HCl 6 N. It was extracted with DCM (5x). The combined DCM layer was dried with Na₂SO₄, filtered, and evaporated to afford the title compound (13.9 g, 96 %) as a slight orange solid. MS (ESI): mass calcd. for C₉H₁₂N₂O₃: 196.08, found: 197.2 [M+H]⁺. 5-(bis(ethylthio)methylene)-1-(cyclobutylmethyl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-(cyclobutylmethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (13.9 g, 70.8 mmol) in DMSO (50.0 mL) was added Et₃N (21.9 mL, 156 mmol) and carbon disulfide (6.46 mL, 106 mmol). After stirring at rt for 2 h, iodoethane (13.8 mL, 170 mmol) was added and the mixture was stirred at rt for 22 h. The reaction was quenched by slowly pouring over aqueous 1 N HCl, then extracted with EtOAc (3x). The combined organic layer was washed with brine (2x), dried with Na₂SO₄, filtered, and evaporated. The product was concentrated over silica and purified by column chromatography (silica, 0-20% EtOAc in a 60:40 mixture of heptanes:DCM) to afford the title compound (9.75 g, 42%) as an orange solid. MS (ESI): mass calcd. for C14H20N2O3S2: 328.09, found: 329.2 [M+H]⁺. 2,2-dimethoxyspiro[3.5]nonan-7-ol To 7-hydroxyspiro[3.5]nonan-2-one (500 mg, 3.08 mmol) dissolved in MeOH (15.4 mL) was added p-toluenesulfonic acid monohydrate (29.7 mg, 154 mol) and the mixture was stirred at 45 °C for 1 h. The reaction was quenched with sat. aq. NaHCO₃ and extracted with DCM (3x). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated to afford the title compound (617 mg, 100%). ¹H NMR (400 MHz, CDCl₃) ppm 3.66 – 3.57 (m, 1H), 3.13 (s, 6H), 1.89 (d, J = 5.8 Hz, 4H), 1.81 – 1.67 (m, 4H), 1.44 – 1.24 (m, 4H). 5-(bis(ethylthio)methylene)-1-(cyclobutylmethyl)-3-(2,2-dimethoxyspiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To 2,2-dimethoxyspiro[3.5]nonan-7-ol (617 mg, 3.08 mmol), triphenylphosphine (1.63 g, 6.16 mmol), and DIAD (1.24 mL, 6.16 mmol) dissolved in THF (30.8 mL) at 0 °C was added 5-(bis(ethylthio)methylene)-1-(cyclobutylmethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (1.01 g, 3.08 mmol). The reaction was stirred at rt for 1 h and quenched with a few drops of water. The mixture was extracted with EtOAc (3x). The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 5-40% EtOAc/heptanes) to yield the title compound (820 mg, 52%). MS (ESI): mass calcd. for C₂₅H₃₈N₂O₅S₂: 510.22, found: 511.4 [M+H]⁺. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(2,2-dimethoxyspiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To 5-(bis(ethylthio)methylene)-1-(cyclobutylmethyl)-3-(2,2- dimethoxyspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (820 mg, 1.61 mmol) in THF (5.4 mL) was added ammonium hydroxide, 28% (4.5 mL, 32.1 mmol) and the mixture was stirred at 45 °C for 48 h. Water was added and the solution was extracted with EtOAc (3x). The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to yield the title compound (675 mg, 100%). MS (ESI): mass calcd. for C₂₁H₃₂N₄O₅: 420.24, found: 419.3 [M-H]-. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(2-oxospiro[3.5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione To 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(2,2-dimethoxyspiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (675 mg, 1.61 mmol) dissolved in acetone (4.0 mL) and water (4.0 mL) was added p-toluenesulfonic acid monohydrate (31 mg, 161 mol) and the reaction was stirred for 17 h at 50 °C. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM (3x). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude was purified by column chromatography (silica, 10-80% EtOAc/heptanes) to yield the title compound (436 mg, 73%). MS (ESI): mass calcd. for C₁₉H₂₆N₄O₄: 374.20, found: 375.3 [M+H]⁺. 7-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)- yl)-2-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)spiro[3.5]nonane-2- carbonitrile To 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(2-oxospiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (80.1 mol) and (4-fluorotetrahydro-2H-pyran-4- yl)methanamine hydrochloride (16.8 mg, 96.1 mol) dissolved in MeOH (267 L) was added triethylamine (22.4 L, 160 mol) followed by acetic acid (22.9 L, 401 mol) and the mixture was stirred for 20 min. Trimethylsilyl cyanide (20.5 L, 160 mol) was added and the reaction was stirred at rt for 17 h. The reaction was quenched with saturated aqueous NaHCO₃ and extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to afford the title compound (40.0 mg, 97%). MS (ESI): mass calcd. for C₂₆H₃₇FN₆O₄: 516.29, found: 517.4 [M+H]⁺. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-(1-((4-fluorotetrahydro-2H-pyran-4- yl)methyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (242) To 7-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin- 1(2H)-yl)-2-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)spiro[3.5]nonane-2- carbonitrile (55.4 mg, 107 mol) dissolved in DCM (3.6 mL) was added pyridine (26.3 L, 322 mol) followed by triphosgene (21.4 mg, 70.8 mol), and the mixture was stirred for 30 min at rt. 1 N HCl aq. was added, and the solution was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to afford a carbamic chloride intermediate, which was used directly. MS (ESI): mass calcd. for C₂₇H₃₆ClFN₆O₅: 578.24, found: 579.3 [M+H]⁺. The carbamic chloride intermediate was dissolved in DCM (3.6 mL), methylamine (10 M in ethanol, 215 L, 2.15 mmol), and 4- dimethylaminopyridine (13.4 mg, 107 mol) were added. The reaction was stirred at rt for 18 h and then quenched with 1 N HCl. The mixture was extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to afford a methyl-urea intermediate. MS (ESI): mass calcd. for C₂₈H₄₀FN₇O₅: 573.31, found: 574.5 [M+H]⁺. The methyl-urea intermediate was dissolved in MeOH (1.0 mL) and HCl (6 N in water, 345 L, 2.07 mmol) was added. The reaction was stirred at 70 °C for 18 h, quenched with saturated aqueous NaHCO3, and extracted with DCM (3x). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase column chromatography (C18 silica, 0-100% MeCN/10 mM AmF) to afford the title compound (1.4 mg, 2.4%). MS (ESI): mass calcd. for C₂₈H₃₉FN₆O₆: 574.29, found: 575.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.50 (s, 2H), 7.73 – 7.34 (m, 2H), 4.62 (s, 1H), 3.79 (d, J = 7.0 Hz, 2H), 3.76 – 3.58 (m, 4H), 3.58 – 3.48 (m, 2H), 2.84 (s, 3H), 2.43 – 2.33 (m, 3H), 2.14 (dd, J = 36.7, 13.4 Hz, 2H), 1.92 – 1.60 (m, 9H), 1.41 – 1.13 (m, 9H). Example 243 and 244: (1R,3s)-3-(((5S,7S,10S)-10-(5-(diaminomethylene)-3-(((1s,3R)-3- methylcyclobutyl)methyl)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4- dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)methyl)cyclobutane-1-carboxylic acid (243) and (1S,3r)-3-(((5S,7S,10S)-10-(5-(diaminomethylene)-3-(((1s,3R)-3- methylcyclobutyl)methyl)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4- dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)methyl)cyclobutane-1-carboxylic acid (244) Synthetic scheme:

(5R,7r,10R)-10-hydroxy-3-methyl-1,3-diazadispiro[4.1.5⁷.1⁵]tridecane-2,4-dione and (5S,7s,10S)-10-hydroxy-3-methyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione To a suspension of 3-methyl-1,3-diazadispiro[4.1.5⁷.1⁵]tridecane-2,4,10-trione (8.43 g, 35.7 mmol) in DCM (270 mL) and methanol (27 mL, 668 mmol) was added NaBH₄ (1.41 g, 35.7 mmol) at 0 °C. The reaction was stirred at room temperature for 2.3 h. The resulting mixture was quenched with saturated aqueous NH₄Cl (200 mL) at 0 °C and stirred vigorously at room temperature for 30 min. Water (100 mL) was added, followed by 4:1 mixture of CHCl₃/IPA (250 mL). After the layers were separated, the aqueous layer was extracted with 4:1 mixture of CHCl₃/IPA (150 mL x 3) and the combined organic layer was dried over Na₂SO₄ and concentrated. To the residue was added MeOH (20 mL) and CHCl₃ (15 mL), warming up by a heat gun into a solution. To the solution was added n-heptanes (250 mL) and sonicated to precipitate white particles. The solid was collected by filtration with Büchner funnel, washed with n-heptanes, and concentrated to afford a racemic mixture of alcohol (6.17 g, 73%) as a white solid. The product was purified by chiral SFC (Column Lux i-Amylose-3, 21.2x250mm, 5 m, isocratic 30% MeOH + 0.1% NH₄OH / 70% CO₂, 40 °C, 50 mg/mL) to afford (5R,7r,10R)-10-hydroxy-3-methyl-1,3-diazadispiro[4.1.5⁷.1⁵]tridecane-2,4-dione as the second peak to elute (2.12 g, 25%, 97.6% ee) as a white solid. MS (ESI): mass calcd. for C₁₂H₁₈N₂O₃: 238.13, found: 239.2 [M+H]⁺. Also obtained was (5S,7s,10S)-10-hydroxy-3- methyl-1,3-diazadispiro[4.1.57.15]tridecane-2,4-dione as the first peak to elute (2.19 g, 26%, 99.9% ee). MS (ESI): mass calcd. for C₃₁H₄₄N₄O₆S₂: 238.13, found: 239.2 [M+H]⁺. 5-(bis(ethylthio)methylene)-1-(((1s,3s)-3-methylcyclobutyl)methyl)pyrimidine- 2,4,6(1H,3H,5H)-trione The title compound was synthesized following steps 1-3 as reported in Example 242, using 1-(3-methylcyclobutyl)methanamine hydrochloride instead of cyclobutylmethanamine _{hydrochloride. The racemic mixture was subjected to chiral SFC separation (Lux Amylose 2,} 25% EtOH:ACN (1:1) + 0.1% TFA/75% supercritical CO₂). The first eluting peak was collected and determined to have cis relative stereochemistry. MS (ESI): mass calcd. for C₁₅H₂₂N₂O₃S₂: 342.11, found: 343.3 [M+H]⁺. 5-(bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3-(((1s,3R)-3-ethylcyclobutyl)methyl)pyrimidine- 2,4,6(1H,3H,5H)-trione The title compound was synthesized following step 5 of Example 242 and using 5- (bis(ethylthio)methylene)-1-(((1s,3s)-3-methylcyclobutyl)methyl)pyrimidine- 2,4,6(1H,3H,5H)-trione and (5R,7r,10R)-10-hydroxy-3-methyl-1,3- diazadispiro[4.1.5⁷.1⁵]tridecane-2,4-dione. MS (ESI): mass calcd. for C₂₇H₃₈N₄O₅S₂: 562.23, found: 563.8 [M+H]⁺. (1R,3s)-3-(((5S,7S,10S)-10-(5-(diaminomethylene)-3-(((1s,3R)-3- methylcyclobutyl)methyl)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4- dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)methyl)cyclobutane-1-carboxylic acid (243) and (1S,3r)-3-(((5S,7S,10S)-10-(5-(diaminomethylene)-3-(((1s,3R)-3- methylcyclobutyl)methyl)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4- dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)methyl)cyclobutane-1-carboxylic acid (244)

The title compounds were synthesized following the same procedure as described in Example 95, starting from 5-(bis(ethylthio)methylene)-1-((5S,7s,10S)-3-methyl-2,4-dioxo- 1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3-(((1s,3R)-3-ethylcyclobutyl)methyl)pyrimidine- 2,4,6(1H,3H,5H)-trione and methyl 3-(iodomethyl)cyclobutane-1-carboxylate.The racemic mixture was subjected to chiral separation (Phenomenex, Lux Cellulose-2; 50% ACN/EtOH (1:1) + 0.1% NH₄OH 50% supercritical CO₂). The first peak to elute gave the title compound (243). MS (ESI): mass calcd. for C₂₉H₄₀N₆O₇: 584.30, found: 585.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.51 (s, 2H), 7.35 (s, 2H), 4.56 (br, 1H), 3.73 (d, J = 6.6 Hz, 2H), 3.43 (d, J = 7.4 Hz, 2H), 2.98 (br, 1H), 2.81 (s, 3H), 2.69 (br, 1H), 2.27 – 2.08 (m, 6H), 2.04 – 1.91 (m, 4H), 1.51 – 1.15 (m, 12H), 0.94 (d, J = 6.2 Hz, 3H). The second peak to elute gave the title compound (244). MS (ESI): mass calcd. for C₂₉H₄₀N₆O₇: 584.30, found: 585.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.52 (s, 2H), 7.29 (s, 2H), 4.62 (s, 1H), 3.73 (d, J = 7.0 Hz, 2H), 3.36 – 3.33 (m, 2H), 2.91 – 2.84 (m, 1H), 2.81 (s, 3H), 2.44 – 2.33 (m, 1H), 2.27 – 2.17 (m, 4H), 2.17 – 2.10 (m, 3H), 2.05 – 1.95 (m, 3H), 1.94 – 1.77 (m, 2H), 1.50 – 1.14 (m, 10H), 0.94 (d, J = 6.2 Hz, 3H). Example 245 and Example 246 were synthesized in a similar fashion to Example 243 and Example 244, using 5-(bis(ethylthio)methylene)-1-(((1r,3r)-3- methylcyclobutyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione instead of 5- (bis(ethylthio)methylene)-1-(((1s,3s)-3-methylcyclobutyl)methyl)pyrimidine- 2,4,6(1H,3H,5H)-trione. Example 247. 1-((5S,7s,10S)-1-(((R)-azetidin-2-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3-(cyclobutylmethyl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (247) Synthetic scheme:

(R)-tert-butyl 2-((((4-nitrophenyl)sulfonyl)oxy)methyl)azetidine-1-carboxylate To tert-butyl (R)-2-(hydroxymethyl)azetidine-1-carboxylate (120 mg, 641 μmol) in DCM (3.0 mL) were added pyridine (104 μL, 1.28 mmol) and 4-nitrobenzenesulfonyl chloride (220 mg, 961 μmol). The solution was stirred at rt for 19 h. The mixture was poured in DCM, washed with 5% aqueous KHSO₄ solution, then water, dried over Na₂SO₄, filtered, and concentrated. The product was purified by oclumn chromatography (silica, 5-100% EtOAc/heptane) to provide the title compound (168 mg, 70%) as a white solid. ¹H NMR (400 MHz, CDCl₃) ppm 8.44 – 8.36 (m, 2H), 8.16 – 8.08 (m, 2H), 4.45 – 4.31 (m, 2H), 4.23 (dd, J = 10.2, 2.5 Hz, 1H), 3.81 (dd, J = 15.6, 8.6 Hz, 1H), 3.75 – 3.64 (m, 1H), 2.33 – 2.22 (m, 1H), 2.22 – 2.10 (m, 1H), 1.37 (s, 9H). tert-butyl (R)-2-(((5S,7s,10S)-10-(3-(cyclobutylmethyl)-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)azetidine-1-carboxylate

The title compound was synthesized following the same sequence of steps as in Example 223, using (R)-tert-butyl 2-((((4-nitrophenyl)sulfonyl)oxy)methyl)azetidine-1- carboxylate and 5-(bis(ethylthio)methylene)-1-(cyclobutylmethyl)-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 as starting materials. MS (ESI): mass calcd. for C₃₁H₄₅N₇O₇: 627.34, found: 528.5 [M-Boc+H]⁺. 1-((5S,7s,10S)-1-(((R)-azetidin-2-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)-3-(cyclobutylmethyl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (247) A solution of 5% trifluoroacetic acid in HFIP (1.1 mL, 746 μmol) was added to tert- butyl (R)-2-(((5S,7s,10S)-10-(3-(cyclobutylmethyl)-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)azetidine-1-carboxylate (46.8 mg, 74.6 μmol) and the mixture was stirred at rt for 60 min. 5 mL of toluene was added, and the mixture was concentrated. The product was purified by reverse phase HPLC (C-18, 25-70% MeCN in 10 mM AmF) to provide the title compound (16.6 mg, 43%) as a beige solid. MS (ESI): mass calcd. for C₂₆H₃₇N₇O₅: 527.29, found: 528.4 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d₆) ppm 9.51 (s, 2H), 8.25 (s, 1H), 7.42 (s, 2H), 4.69 – 4.53 (m, 1H), 4.27 – 4.16 (m, 1H), 3.79 (d, J = 7.1 Hz, 2H), 3.59 – 3.47 (m, 4H), 2.82 (s, 3H), 2.42 – 2.00 (m, 9H), 1.94 – 1.78 (m, 3H), 1.78 – 1.58 (m, 4H), 1.44 – 1.26 (m, 3H), 1.22 (t, J = 13.6 Hz, 1H). Example 248 was synthesized following the same sequence of steps for Example 247, using tert-butyl (S)-2-(hydroxymethyl)azetidine-1-carboxylate as starting material instead of tert- butyl (R)-2-(hydroxymethyl)azetidine-1-carboxylate. Example 249 was synthesized following the same sequence of steps for Example 247, using (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate as starting material instead of tert- butyl (R)-2-(hydroxymethyl)azetidine-1-carboxylate. Example 250 was synthesized following the same sequence of steps for Example 247, using (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate as starting material instead of tert- butyl (R)-2-(hydroxymethyl)azetidine-1-carboxylate. Example 251 was synthesized following the same sequence of steps for Example 247, using (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate as starting material instead of tert- butyl (R)-2-(hydroxymethyl)azetidine-1-carboxylate. Example 252 was synthesized following the same sequence of steps for Example 247, using (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate as starting material instead of tert- butyl (R)-2-(hydroxymethyl)azetidine-1-carboxylate. Example 253 was synthesized following a similar sequence of steps for Example 247, using tert-butyl 4-(iodomethyl)piperidine-1-carboxylate as starting materiel instead of ((R)-tert-butyl 2-((((4-nitrophenyl)sulfonyl)oxy)methyl)azetidine-1-carboxylate in the alkylation step. Example 254 was synthesized following a similar sequence of steps for Example 247, using tert-butyl 6-(iodomethyl)-2-azaspiro[3.3]heptane-2-carboxylate as starting materiel instead of ((R)-tert-butyl 2-((((4-nitrophenyl)sulfonyl)oxy)methyl)azetidine-1-carboxylate in the alkylation step. Example 255. (1R,3s)-3-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)- 2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)cyclobutane-1-carboxylic acid (255)

Synthetic scheme: Methyl (1R,3s)-3-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)cyclobutane-1-carboxylate The title compound was prepared using the same procedures as described in Example 242, using cis-methyl 3-aminocyclobutanecarboxylate hydrochloride as starting material instead of (4-fluorotetrahydro-2H-pyran-4-yl)methanamine hydrochloride. MS (ESI): mass calcd. for C₂₈H₃₈N₆O₇: 570.28, found: 571.6 [M+H]⁺. (1R,3s)-3-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-1-yl)cyclobutane-1-carboxylic acid (255)

To lithium hydroxide monohydrate (37.1 mg, 876 μmol) in THF (876 μL) and water (45 μL) was added methyl (1R,3s)-3-((5S,7s,10S)-10-(3-(cyclobutylmethyl)-5- (diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-1-yl)cyclobutane-1-carboxylate (50 mg, 87.6 μmol) and the solution was stirred at 50 °C for 3 h. The mixture was acidified with 1 N HCl (2 mL) and extracted with DCM (2 mL x 3). The combined organic phase was dried over MgSO₄, filtered, and concentrated. The crude was purified by reverse phase HPLC (CSH-C18, 30-50% MeCN/AmF 10 mM buffer) to provide the title compound (8.5 mg, 17%) as a white solid. MS (ESI): mass calcd. for C₂₇H₃₆N₆O₇: 556.26, found: 555.3 [M-H]-. ¹H NMR (400 MHz, DMSO- d₆) ppm 9.51 (s, 2H), 7.39 (s, 2H), 4.62 (br, 1H), 3.94 – 3.83 (m, 1H), 3.79 (d, J = 7.0 Hz, 2H), 3.02 – 2.90 (m, 3H), 2.81 – 2.72 (m, 4H), 2.58 – 2.51 (m, 1H), 2.43 – 2.28 (m, 4H), 2.28 – 2.18 (m, 2H), 2.14 – 2.03 (m, 3H), 1.95 – 1.81 (m, 3H), 1.79 – 1.64 (m, 4H), 1.47 – 1.30 (m, 3H), 1.27 – 1.15 (m, 1H). Example 256 was prepared in a similar sequence to the one described in Example 255, using trans-methyl 3-aminocyclobutanecarboxylate hydrochloride as starting materiel instead of cis- methyl 3-aminocyclobutanecarboxylate hydrochloride Example 257 and Example 258 were synthesized following the same sequence of steps for Example 247, using trans tert-butyl 2-(hydroxymethyl)cyclobutane-1-carboxylate as starting material instead of tert-butyl (R)-2-(hydroxymethyl)azetidine-1-carboxylate. The diastereomers were separated by chiral HPLC (ChiralPak IB, 10% MeOH, 10% EtOH, 80% hexanes + 0.1 formic acid)). Example 259 and Example 260 were synthesized following the same sequence of steps for Example 247, using tert-butyl 3-(hydroxymethyl)cyclobutane-1-carboxylate as starting material instead of tert-butyl (R)-2-(hydroxymethyl)azetidine-1-carboxylate. The diastereomers were separated by chiral SFC (column: DAICEL CHIRALPAK IK^ (250mm*25mm, 10um); mobile phase: CO₂-EtOH (0.1%NH₃H₂O); gradient: 45% B with isocratic elution). Example 261 and Example 262 were synthesized following the same sequence of steps for Example 247, using tert-butyl 3-(hydroxymethyl)-1-methylcyclobutane-1-carboxylate as starting material instead of tert-butyl (R)-2-(hydroxymethyl)azetidine-1-carboxylate. The diastereomers were separated by chiral SFC (column: (s,s) WHELK-O1, (250mm*30mm, 5um); mobile phase: Heptane-IPA:ACN = 4 : 1 (0.1% TFA); gradient: 20% B with isocratic elution). Example 263 and Example 264.1-(cyclobutylmethyl)-5-(diaminomethylene)-3- ((5S,7r,10S)-3-methyl-2,4-dioxo-1-(((S)-6-oxopiperidin-2-yl)methyl)-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (263) and 1- (cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7r,10S)-3-methyl-2,4-dioxo-1-(((R)-6- oxopiperidin-2-yl)methyl)-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (264) Synthetic scheme:

(6-oxo-2-piperidyl)methyl 4-methylbenzenesulfonate To a solution of 6-(hydroxymethyl)piperidin-2-one (450 mg, 3.48 mmol) in DCM (25 mL) was added DIPEA (900.6 mg, 6.97 mmol), DMAP (42.6 mg, 348 mol), and 4- methylbenzenesulfonyl chloride (1.1 g, 5.75 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h. The residue was poured into water (20 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether : ethyl acetate = 3 : 1 to 0 : 1) to give the title compound (524 mg, 49%) as a white solid. MS (ESI): mass calcd. for C₁₃H₁₇NO₄S: 283.09, found: 284.2 [M+H]⁺. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1-((6- oxopiperidin-2-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-(cyclobutylmethyl)-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 (100 mg, 218 mol) and (6-oxo-2-piperidyl)methyl 4-methylbenzenesulfonate (123.6 mg, 436.2 mol) in DMF (0.5 mL) was added Cs₂CO₃ (213.2 mg, 654 mol) and NaI (326 g, 2.2 mol). The mixture was stirred at 80 °C for 12 h. The reaction was poured into water (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine, dried with Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by prep-TLC (SiO2, ethyl acetate : methanol = 20 : 1) and by prep-HPLC to give the title compound (25 mg, 20%) as a white solid. MS (ESI): mass calcd. for C₂₈H₃₉N₇O₆: 569.30, found: 570.3 [M+H]⁺. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7r,10S)-3-methyl-2,4-dioxo-1-(((S)-6- oxopiperidin-2-yl)methyl)-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (263) and 1-(cyclobutylmethyl)-5-(diaminomethylene)-3- ((5S,7r,10S)-3-methyl-2,4-dioxo-1-(((R)-6-oxopiperidin-2-yl)methyl)-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (264) 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4-dioxo-1-((6- oxopiperidin-2-yl)methyl)-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (27 mg) was separated by chiral SFC (column: ChiralPak IH, (250 mm*30 mm, 10 um); mobile phase: CO₂-MeOH; gradient: 50% of B with isocratic elution) to give the title compound 263 (7.02 mg) as a white solid from the first eluting peak from the chiral SFC separation. MS (ESI): mass calcd. for C₂₈H₃₉N₇O₆: 569.30, found: 570.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 9.53 (s, 2H), 7.59 (s, 1H), 7.31 (s, 2H), 4.63 (s, 1H), 3.81 (d, J = 7.2 Hz, 2H), 3.73 (d, J = 6.4 Hz, 1H), 3.33-3.42 (m, 2H), 2.83 (s, 3H), 2.53-2.61 (m, 2H), 2.19-2.32 (m, 3H), 2.09-2.19 (m, 5H), 1.84-1.93 (m, 3H), 1.78-1.83 (m, 2H), 1.56- 1.78 (m, 5H), 1.32-1.47 (m, 4H), 1.17-1.28 (m, 1H). The title compound 264 (11.5 mg) was obtained from the second eluting peak from chiral SFC separation a white solid. MS (ESI): mass calcd. for C28H39N7O6: 569.30, found: 570.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6) ppm 9.53 (s, 2H), 7.58 (s, 1H), 7.32 (s, 2H), 4.62 (s, 1H), 3.81 (d, J = 7.2 Hz, 2H), 3.68-3.78 (m, 1H), 3.35-3.44 (m, 1H), 3.25-3.30 (m, 1H), 2.84 (s, 3H), 2.53-2.60 (m, 2H), 2.24-2.39 (m, 3H), 2.13 (s, 5H), 1.84-1.91 (m, 3H), 1.78-1.83 (m, 2H), 1.66-1.77 (m, 4H), 1.55-1.66 (m, 1H), 1.31-1.49 (m, 4H), 1.17-1.27 (m, 1H). The stereochemistry for these two compounds is arbitrarily assigned. Example 265.1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-1- (((2R,4R)-2-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (265)

Synthetic scheme: 4-(hydroxymethyl)-2-methyltetrahydro-2H-thiopyran 1,1-dioxide To a solution of 2-methyl-1,1-dioxo-thiane-4-carboxylic acid (900 mg, 4.68 mmol) in THF (9 mL) was added BH₃-THF (1 M in THF, 5.15 mL, 5.15 mmol) at 0 °C under N₂. The mixture was stirred at 0-20 °C for 12 h. The resulting mixture was stirred at room temperature for 3 h before slowly quenching with H₂O (10 mL) and extracting with ethyl acetate (50 mL × 3). The combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether : ethyl acetate = 10 : 1 to 1 : 1) to give the title compound (850 mg, crude) as a colorless oil.¹H NMR (400 MHz, DMSO-d₆) ppm 4.62- 4.67 (m, 1H), 3.24 (t, J = 5.6 Hz, 2H), 3.10-3.20 (m, 2H), 3.06-3.09 (m, 1H), 1.91-2.02 (m, 2H), 1.73 (dddt, J = 15.2, 9.2, 6.0, 3.2 Hz, 1H), 1.46-1.58 (m, 1H), 1.24-1.32 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H). (2-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate To a solution of (2-methyl-1,1-dioxo-thian-4-yl) methanol (850 mg, 4.77 mmol) in DCM (9 mL) was added pyridine (1.13 g, 14.3 mmol) and DMAP (58.3 mg, 477 mol). 4- methylbenzenesulfonyl chloride (1.36 g, 7.15 mmol) was added and the reaction was stirred at 0-20 °C for 12 h under N₂. After completion, the reaction mixture was quenched with H₂O (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layer was dried over Na₂SO₄, filtered and concentration under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether : ethyl acetate = 10 : 1 to 1 : 1) to give the title compound (1.72 g, crude) as a colorless oil.¹H NMR (400 MHz, DMSO-d₆) ppm 7.76- 7.83 (m, 2H), 7.49 (d, J = 8.4 Hz, 2H), 3.91 (dd, J = 6.0, 2.4 Hz, 2H), 3.03-3.21 (m, 3H), 2.43 (s, 3H), 2.00-2.11 (m, 1H), 1.81-1.95 (m, 2H), 1.55 (qd, J = 13.2, 4.2 Hz, 1H), 1.24-1.39 (m, 1H), 1.09 (d, J = 6.8 Hz, 3H). ((2R,4R)-2-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl) methyl 4- methylbenzenesulfonate, ((2S,4R)-2-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl) methyl 4-methylbenzenesulfonate, ((2R,4S)-2-methyl-1,1-dioxidotetrahydro-2H- thiopyran-4-yl) methyl 4-methylbenzenesulfonate and ((2S,4S)-2-methyl-1,1- dioxidotetrahydro-2H-thiopyran-4-yl) methyl 4-methylbenzenesulfonate (2-methyl-1,1-dioxo-thian-4-yl)methyl 4-methylbenzenesulfonate (1.72 g, 5.17 mmol) was separated by chiral SFC (DAICEL CHIRALPAK AY-H, (250 mm*30 mm, 10 um); mobile phase: CO₂-EtOH; gradient: 47% of B with isocratic elution) to give [(2R,4R)-2-methyl-1,1- dioxo-thian-4-yl]methyl 4-methylbenzenesulfonate (540 mg) as a colorless oil..¹H NMR (400 MHz, DMSO-d6) ppm 7.79 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 3.91 (dd, J = 6.0, 2.0 Hz, 2H), 3.02-3.23 (m, 3H), 2.43 (s, 3H), 1.98-2.11 (m, 1H), 1.80-1.95 (m, 2H), 1.48- 1.62 (m, 1H), 1.25-1.37 (m, 1H), 1.09 (d, J = 6.8 Hz, 3H). [(2S,4R)-2-methyl-1,1-dioxo- thian-4-yl]methyl 4-methylbenzenesulfonate (80 mg) was obtained from the chiral SFC separation as a colorless oil.¹H NMR (400 MHz, DMSO-d₆) ppm 7.81 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.05 (d, J = 6.8 Hz, 2H), 3.03-3.16 (m, 2H), 2.88-3.00 (m, 1H), 2.43 (s, 3H), 2.04-2.13 (m, 1H), 1.65-1.97 (m, 4H), 1.19 (d, J = 7.2 Hz, 3H). [(2R,4S)-2-methyl- 1,1-dioxo-thian-4-yl]methyl 4-methylbenzenesulfonate (80 mg) was obtained from the chiral SFC separation as a colorless oil.¹H NMR (400 MHz, DMSO-d₆) ppm 7.81 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.05 (d, J = 6.8 Hz, 2H), 3.03-3.16 (m, 2H), 2.88-3.00 (m, 1H), 2.43 (s, 3H), 2.04-2.13 (m, 1H), 1.65-1.97 (m, 4H), 1.19 (d, J = 7.2 Hz, 3H). [(2S,4S)-2- methyl-1,1-dioxo-thian-4-yl]methyl 4-methylbenzenesulfonate (566 mg) was obtained from the chiral SFC separation as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) ppm 7.81 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.05 (d, J = 6.8 Hz, 2H), 3.01-3.18 (m, 2H), 2.86- 3.00 (m, 1H), 2.43 (s, 3H), 2.03-2.15 (m, 1H), 1.64-1.97 (m, 4H), 1.19 (d, J = 7.2 Hz, 3H). The stereochemistry for these four compounds is arbitrarily assigned. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-1-(((2R,4R)-2- methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (265) To a solution of 1-(cyclobutylmethyl)-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 (30 mg, 65 mol) in DMF (0.2 mL) was added Cs2CO3 (64 mg, 196 mol) and NaI (98 g, 0.64 mol). A solution of [(2R,4R)-2-methyl-1,1-dioxo-thian-4-yl]methyl 4- methylbenzenesulfonate (17.4 mg, 52 mol) in DMF (0.2 mL) was added to the mixture and the reaction was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (3 mg, 4.7%) as a white solid. MS (ESI): mass calcd. C₂₉H₄₂N₆O₇S: 618.28, found: 619.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.56-4.69 (m, 1H), 3.81 (d, J = 7.2 Hz, 2H), 3.05-3.26 (m, 5H), 2.84 (s, 3H), 2.54-2.58 (m, 1H), 2.44 (s, 1H), 2.34-2.40 (m, 1H), 2.12-2.29 (m, 6H), 1.94-2.04 (m, 2H), 1.81-1.91 (m, 3H), 1.67-1.78 (m, 4H), 1.59 (dd, J = 13.2, 2.0 Hz, 1H), 1.33-1.45 (m, 4H), 1.22-1.26 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H). Example 266 was synthesized following the final step of Example 265, using [(2S,4R)-2- methyl-1,1-dioxo-thian-4-yl]methyl 4-methylbenzenesulfonate as starting material instead of [(2R,4R)-2-methyl-1,1-dioxo-thian-4-yl]methyl 4-methylbenzenesulfonate. Example 267 was synthesized following the final step of Example 265, using [(2R,4S)-2- methyl-1,1-dioxo-thian-4-yl]methyl 4-methylbenzenesulfonate as starting material instead of [(2R,4R)-2-methyl-1,1-dioxo-thian-4-yl]methyl 4-methylbenzenesulfonate. Example 268 was synthesized following the final step of Example 265, using [(2S,4S)-2- methyl-1,1-dioxo-thian-4-yl]methyl 4-methylbenzenesulfonate as starting material instead of [(2R,4R)-2-methyl-1,1-dioxo-thian-4-yl]methyl 4-methylbenzenesulfonate. Example 269 and Example 270.1-(cyclobutylmethyl)-5-(diaminomethylene)-3- ((5S,7s,10S)-1-(((2R,4R)-2-ethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-3- methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)- trione (269) and 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-(((2S,4S)- 2-ethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (270) Synthetic scheme:

(cis)-4-((benzyloxy)methyl)-2-ethyltetrahydro-2H-thiopyran 1,1-dioxide To a solution of 4-(benzyloxymethyl)thiane 1,1-dioxide (500 mg, 1.97 mmol) in THF (10 mL) was added dropwise LDA (2 M, 1.08 mL) at – 78 °C over 2 min under N₂ atmosphere. After addition, the mixture was stirred at this temperature for 2 min, and EtI (337 mg, 2.16 mmol) in THF (10 mL) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 2 h under N2. The reaction was quenched with saturated aqueous NH₄Cl (3 mL) and extracted with EtOAc (20 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 0 : 1) to provide the title compound (250 mg, 45%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) ppm 7.24-7.39 (m, 5H), 4.44-4.49 (m, 2H), 3.30 (d, J = 6.0 Hz, 2H), 2.94-3.19 (m, 3H), 1.81-2.11 (m, 4H), 1.58 (qd, J = 13.2, 3.2 Hz, 1H), 1.25-1.43 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H). (cis)-2-ethyl-4-(hydroxymethyl)tetrahydro-2H-thiopyran 1,1-dioxide To a solution of (cis)-4-(benzyloxymethyl)-2-ethyl-thiane 1,1-dioxide (250 mg, 885 mol) in MeOH (10 mL) was added Pd/C (471 mg, 443 mol, 10% purity) under N₂. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 16 h. The reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to provide the title compound (130 mg, 76%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) ppm 4.66 (s, 1H), 3.25 (d, J = 6.0 Hz, 2H), 2.93-3.16 (m, 3H), 1.82-2.09 (m, 3H), 1.70 (dtt, J = 15.2, 6.0, 3.2 Hz, 1H), 1.43-1.58 (m, 1H), 1.17-1.41 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H). ((cis)-2-ethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl 4- methylbenzenesulfonate To a solution of [(cis)-2-ethyl-1,1-dioxo-thian-4-yl]methanol (130 mg, 676 mol) in DCM (5 mL) was added 4-methylbenzenesulfonyl chloride (193 mg, 1.01 mmol), DMAP (41.3 mg, 338 mol) and TEA (205 mg, 2.03 mmol). The mixture was stirred at 20 °C for 16 h. The reaction was diluted with H₂O (20 mL), 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. The residue was purified by column chromatography (SiO₂, hexanes : ethyl acetate = 100 : 1 to 1 : 1) to provide the title compound (160 mg, 68%) as a white solid.¹H NMR (400 MHz, CDCl₃) ppm 7.79 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 3.86-3.90 (m, 2H), 3.08 (dt, J = 14.4, 3.6 Hz, 1H), 2.91 (td, J = 14.0, 3.4 Hz, 1H), 2.74 (ddt, J = 12.4, 8.4, 4.0 Hz, 1H), 2.48 (s, 3H), 2.03-2.20 (m, 3H), 1.98 (dddd, J = 12.0, 9.0, 6.0, 3.2 Hz, 1H), 1.73-1.86 (m, 1H), 1.41-1.53 (m, 2H), 1.05 (t, J = 7.6 Hz, 3H). 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-(((cis)-2-ethyl-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-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-(cyclobutylmethyl)-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 (50 mg, 109 mol) and [cis-ethyl-1,1-dioxo-thian-4-yl]methyl 4- methylbenzenesulfonate (45.3 mg, 131 mol) in DMSO (1 mL) was added Cs₂CO₃ (355 mg, 1.09 mmol) and KI (54.3 mg, 327 mol). The mixture was stirred at 60 °C for 12 h. The reaction was filtered and concentrated under reduced pressure. The crude product was purified by prep HPLC to provide the title compound (60 mg, 85%) as a white solid. MS (ESI): mass calcd. for C₃₀H₄₄N₆O₇S: 632.30, found: 633.3 [M+H]⁺. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-(((2R,4R)-2-ethyl-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (269) and 1- (cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-(((2S,4S)-2-ethyl-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (270) 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-(([cis-2-ethyl-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)]methyl)-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) was separated by chiral SFC (column: Chiral-Cellulose-2-30-Phenomenex-Cellulose-2, (250 mm*30 mm, 10 um); mobile phase: CO2-MeOH : ACN = 7 : 3 (0.1% NH3H2O); gradient: 60% of B with isocratic elution) to give the title compound 269 (24 mg) as a white solid from the first eluting peak from chiral SFC separation. MS (ESI): mass calcd. for C₃₀H₄₄N₆O₇S: 632.30, found: 633.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.64 (s, 1H), 3.82 (d, J = 7.2 Hz, 2H), 3.01-3.30 (m, 5H), 2.85 (s, 3H), 2.57 (d, J = 7.6 Hz, 1H), 2.14-2.41 (m, 8H), 1.99-2.10 (m, 2H), 1.82-1.94 (m, 4H), 1.67-1.80 (m, 4H), 1.52- 1.66 (m, 1H), 1.31-1.48 (m, 5H), 1.24 (s, 1H), 1.00 (t, J = 7.6 Hz, 3H). The title compound 270 (20 mg) was obtained from the second eluting peak from chiral SFC separation as a white solid. MS (ESI): mass calcd. for C₃₀H₄₄N₆O₇S: 632.30, found: 633.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.64 (s, 1H), 3.82 (d, J = 7.2 Hz, 2H), 3.01-3.30 (m, 5H), 2.85 (s, 3H), 2.57 (d, J = 7.6 Hz, 1H), 2.14-2.41 (m, 8H), 1.99- 2.10 (m, 2H), 1.82-1.94 (m, 4H), 1.67-1.80 (m, 4H), 1.52-1.66 (m, 1H), 1.31-1.48 (m, 5H), 1.24 (s, 1H), 1.00 (t, J = 7.6 Hz, 3H). Example 271 and Example 272 were synthesized in a similar route to the one described in Example 91, using 6-(hydroxymethyl)-3-thiabicyclo[3.1.0]hexane 3,3-dioxide and 1- (cyclobutylmethyl)-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 instead 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. The diastereomers were separated by reverse phase HPLC. The stereochemistry for these two diastereomers is arbitrarily assigned. Example 273 and Example 274 were synthesized in a similar route to the one described in Example 91, using 3-(hydroxymethyl) tetrahydro-2H-thiopyran 1,1-dioxide and 1- (cyclobutylmethyl)-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 instead 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. The diastereomers were separated by chiral SFC. The stereochemistry for these two diastereomers is arbitrarily assigned. Example 275 and Example 276 was synthesized in a similar route to the one described in Example 91, using (1,1-dioxothiolan-3-yl)methanol and 1-(cyclobutylmethyl)-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 instead 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. The diastereomers were separated by chiral SFC. The stereochemistry for these two diastereomers is arbitrarily assigned. Example 277, Example 278, Example 279, and Example 280 were synthesized in a similar route to the one described in Example 91, using (2-methyltetrahydro-2H-pyran-4- yl)methanol and 1-(cyclobutylmethyl)-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. The diastereomers were separated by chiral SFC (column: DAICEL CHIRALPAK IC, (250mm*30mm, 10um); mobile phase: CO₂-EtOH (0.1% NH₃H₂O); gradient: 45% of B with isocratic elution). The stereochemistry for these diastereomers is arbitrarily assigned. Example 281 was synthesized in a similar route to the one described in Example 91, using 4-(2-bromoethyl)tetrahydro-2H-thiopyran 1,1-dioxide and 1-(cyclobutylmethyl)-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. Example 282. 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4- dioxo-1-((2,2,6,6-tetramethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione Synthetic scheme:

4-((benzyloxy)methyl)tetrahydro-2H-thiopyran To a solution of tetrahydrothiopyran-4-ylmethanol (4.6 g, 34.79 mmol) in DMF (50 mL) was added NaH (1.81 g, 45.23 mmol, 60% purity) at 0 °C under N₂. After addition, the mixture was stirred at this temperature for 30 min, and then BnBr (7.74 g, 45.23 mmol, 5.37 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) at 0 °C, followed by dilution with H₂O (20 mL) and extraction with EtOAc (40 mL). The combined organic phase was washed with brine (20 mL), 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 (5 g, 64.6%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) ppm 7.29-7.40 (m, 5H), 4.50 (s, 2H), 3.30 (d, J = 6.4 Hz, 2H), 2.59-2.74 (m, 4H), 2.10 (d, J = 13.6 Hz, 2H), 1.67-1.81 (m, 1H), 1.39-1.43 (m, 2H). 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide To a solution of 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran (5.0 g, 22.48 mmol) in DCM (200 mL) was added mCPBA (10.68 g, 49.48 mmol, 85% purity). The mixture was stirred at 20 °C for 2 h under N₂. The reaction mixture was quenched with saturated aqueous Na₂S₂SO₃ (200 mL) at 0 °C, concentrated under reduced pressure, and extracted with DCM (500 mL). The combined organic phase was washed with brine (500 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, hexanes: ethyl acetate = 100: 1 to 10: 1) to give the title compound (4.4 g, 61.5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) ppm 7.26-7.37 (m, 5H), 4.46 (s, 2H), 3.32 (d, J = 6.4 Hz, 2H), 3.02-3.15 (m, 4H), 2.03 (d, J = 13.2 Hz, 2H), 1.68-1.90 (m, 1H), 1.62-1.65 (m, 2H) 4-((benzyloxy)methyl)-2,2,6,6-tetramethyltetrahydro-2H-thiopyran 1,1-dioxide To a solution of 4-((benzyloxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (1 g, 3.93 mmol) in THF (10 mL) was added LDA (2 M, 9.83 mL) at –70 °C dropwise over 1 h. Iodomethane (2.79 g, 19.66 mmol, 1.22 mL) was added to the reaction at -70 °C and the mixture was stirred at -70 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was poured into H₂O (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 3). Then combined organic phase was washed with brine (100 mL), dried with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (0.75 g, 61.5%) as a white solid.¹H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.40 (m, 5H), 4.51 (s, 2H), 3.29 (d, J = 6.4 Hz, 2H), 2.17- 2.31 (m, 1H), 1.73-1.88 (m, 4H), 1.53 (s, 6H), 1.39 (s, 6H). 4-(hydroxymethyl)-2,2,6,6-tetramethyltetrahydro-2H-thiopyran 1,1-dioxide To a solution of 4-((benzyloxy)methyl)-2,2,6,6-tetramethyltetrahydro-2H-thiopyran 1,1-dioxide (0.75 g, 2.42 mmol) in MeOH (10 mL) was added Pd/C (257 mg, 242 mol, 10% w/w) under Ar. The suspension was degassed and purged with H₂3 times. The mixture was stirred under H₂ (15 Psi) at 25 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (0.4 g, 75.5%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) ppm 3.47-3.54 (m, 3H), 2.07-2.19 (m, 1H), 1.74-1.87 (m, 4H), 1.55 (s, 6H), 1.41 (s, 6H). Example 282 was synthesized in a similar route to the one described in Example 91, using 4-(hydroxymethyl)-2,2,6,6-tetramethyltetrahydro-2H-thiopyran 1,1-dioxide and 1- (cyclobutylmethyl)-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 instead 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. Example 283 and Example 284.1-(cyclobutylmethyl)-5-(diaminomethylene)-3- ((5S,7s,10S)-1-(((R)-1,1-dioxidothiepan-4-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (283) and 1- (cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7r,10S)-1-(((S)-1,1-dioxidothiepan-4- yl)methyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (284)

Synthetic scheme:

Ethyl 5-hydroxythiepane-4-carboxylate To a solution of ethyl 5-oxothiepane-4-carboxylate (4 g, 19.78 mmol) in EtOH (40 mL) was added NaBH₄ (748 mg, 19.78 mmol) at 0 °C under N₂. The mixture was warmed to 25 °C for 2 h. After completion, the mixture was poured into saturated aqueous NH₄Cl (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (3.5 g, 86.6%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) ppm 4.37 (t, J = 4.0 Hz, 1H), 4.14-4.22 (m, 2H), 2.70-3.00 (m, 5H), 2.51-2.61 (m, 1H), 2.25-2.36 (m, 2H), 2.04-2.15 (m, 1H), 1.88-1.99 (m, 1H), 1.25-1.32 (m, 3H). Ethyl 5-((methylsulfonyl)oxy)thiepane-4-carboxylate To a solution of ethyl 5-hydroxythiepane-4-carboxylate (3.5 g, 17.13 mmol) in DCM (35 mL) was added TEA (5.2 g, 51.4 mmol, 7.15 mL) and MsCl (3.93 g, 34.27 mmol, 2.65 mL) at 0 °C under N₂. The mixture was warmed to 25 °C for 1 h. After completion, the mixture was poured into saturated aqueous NaHCO₃ (20 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (4.6 g, crude) as a colorless oil, which was used in the next step directly. Ethyl 2,3,6,7-tetrahydrothiepine-4-carboxylate To a mixture of ethyl 5-((methylsulfonyl)oxy)thiepane-4-carboxylate (4.6 g, 16.29 mmol) in THF (50 mL) was added DBU (2.98 g, 19.55 mmol, 2.95 mL). The reaction was allowed to proceed at 25 °C for 6 h. After completion, the mixture was poured into saturated aqueous NH₄Cl (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (20 mL), 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 97: 3) to give the title compound (2.1 g, 69.2%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) ppm 7.18 (t, J = 6.4 Hz, 1H), 4.14- 4.25 (m, 2H), 2.97-3.05 (m, 2H), 2.74-2.83 (m, 2H), 2.61-2.70 (m, 4H), 1.27-1.33 (m, 3H) Ethyl 2,3,6,7-tetrahydrothiepine-4-carboxylate 1,1-dioxide To a solution of ethyl 2,3,6,7-tetrahydrothiepine-4-carboxylate (2.1 g, 11.27 mmol) in DCM (30 mL) was added m-CPBA (4.58 g, 22.55 mmol, 85% purity) at 0 °C under N₂. The reaction was allowed to warm to 25 °C over 2 h. The mixture was added to saturated aqueous Na₂SO₃ (30 mL) and extracted with DCM (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether: Ethyl acetate = 10: 1 to 4: 1) to give the title compound (1.5 g, 61%) as a white solid.¹H NMR (400 MHz, CDCl₃) ppm 7.27-7.31 (m, 1H), 4.20-4.28 (m, 2H), 2.98- 3.04 (m, 4H), 2.90-2.98 (m, 2H), 2.66-2.77 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H) Ethyl thiepane-4-carboxylate 1,1-dioxide To a solution of ethyl 2,3,6,7-tetrahydrothiepine-4-carboxylate 1,1-dioxide (1 g, 4.58 mmol) in MeOH (20 mL) was added Pd/C (242.2 mg, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H₂3 times. The mixture was stirred under H₂ (15 psi) at 25 °C for 0.5 h. After completion, the reaction mixture was filtered, then concentrated under reduced pressure to yield the title compound (1 g, 99%) as a colorless oil. ¹H NMR (400 MHz, CDCl3) ppm 4.12-4.21 (m, 2H), 3.27-3.37 (m, 1H), 3.07-3.21 (m, 3H), 2.72-2.82 (m, 1H), 2.29-2.40 (m, 1H), 2.05-2.27 (m, 3H), 1.88-2.02 (m, 2H), 1.27 (t, J = 6.8 Hz, 3H) 4-(hydroxymethyl)thiepane 1,1-dioxide To a solution of ethyl thiepane-4-carboxylate 1,1-dioxide (1 g, 4.54 mmol) in THF (10 mL) was added DIBAL-H (1 M, 9.08 mL) at –70 °C under N₂. The mixture was stirred at 25 °C for 4 h. After completion, saturated aqueous NH₄Cl (20 mL) was added at 0 °C and the mixture was extracted with ethyl acetate (20 mL x 5). The combined organic phase was washed with brine (40 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound (0.5 g, 61.8%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) ppm 3.44-3.58 (m, 2H), 3.08-3.30 (m, 4H), 2.07-2.24 (m, 2H), 1.84-2.02 (m, 3H), 1.69-1.81 (m, 1H), 1.40-1.53 (m, 1H) Example 283 and Example 284 were synthesized in a similar route to the one described in Example 91, using 4-(hydroxymethyl)thiepane 1,1-dioxide and 1-(cyclobutylmethyl)-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 instead 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. The diastereomers were separated by chiral SFC (column: DAICEL CHIRALPAK IK (250mm*25mm,10 - IPA:ACN=4:1 (0.1% NH₃H₂ . The stereochemistry for the diastereomers is arbitrarily assigned. Example 285 and Example 286.1-(cyclobutylmethyl)-5-(diaminomethylene)-3- ((5S,7r,10S)-3-methyl-1-(((S)-2-methyl-1,1-dioxido-1,2-thiazinan-5-yl)methyl)-2,4-dioxo- 1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (285) and 1- (cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-1-(((R)-2-methyl-1,1- dioxido-1,2-thiazinan-5-yl)methyl)-2,4-dioxo-1,3-diazadispiro[4.1.5⁷.1⁵]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (286)

Synthetic scheme: Methyl 2-(cyanomethyl)acrylate To a solution of methyl 2-(bromomethyl)prop-2-enoate (23 g, 128.48 mmol) in CH₃CN (400 mL) was added dropwise TBAF (1 M, 128.48 mL) at 25 °C over 5 min under N₂. After addition, the mixture was stirred at this temperature for 10 min, and then TMSCN (15.30 g, 154.18 mmol, 19.29 mL) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 2 h under N₂. After the reaction, under a stream of N₂, H₂O (400 mL) was slowly added dropwise to the reaction at 25 °C for 10 min. The mixture was basified at 0 °C with 2 N NaOH to pH = 12-14 and extracted with EtOAc (300 mL x 3). The combined organic phase was washed with brine (200 mL), dried by Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give the title compound (13.2 g, 80.5%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) ppm 6.47 (s, 1H), 6.09 (s, 1H), 3.82 (s, 3H), 3.42 (s, 2H) Methyl 3-(benzylthio)-2-(cyanomethyl)propanoate To a solution of methyl 2-(cyanomethyl)acrylate (6 g, 47.95 mmol) in THF (80 mL) was added TEA (14.56 g, 143.86 mmol, 20 mL) dropwise at 25 °C over 10 min. After addition, the mixture was stirred at this temperature for 10 min, and BnSH (7.15 g, 57.54 mmol, 6.76 mL) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 2 h under N₂. NaClO (20 mL) was slowly added dropwise to the reaction solution at 0 °C for 20 min. The reaction was poured into water (100 mL) and extracted with EtOAc (40 mL x 3). Then the combined organic phase was washed with brine (130 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give the title compound (11.1 g, 88%) as a colorless oil. MS (ESI): mass calcd. for C₁₃H₁₅NO₂S: 249.08, found: 250.0 [M+H]⁺. 4-amino-2-((benzylthio)methyl)butan-1-ol To a solution of methyl 3-(benzylthio)-2-(cyanomethyl)propanoate (11 g, 44.12 mmol) in THF (100 mL) was added dropwise LiAlH₄ (2.5 M in THF, 52.94 mL) at 0 °C over 30 min under N₂. After addition, the resulting mixture was stirred at 0 °C for 2 h under N₂. After completion, Na₂SO₄ decahydrate (17.5 g) was added to the reaction solution in 5 portions at 0 over 30 min. The mixture was filtered over Celite, the filtrate was collected, and the solution was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound (3.5 g, 33.4% yield) as a yellow oil. MS (ESI): mass calcd. for C₁₂H₁₉NOS: 225.12, found: 226.0 [M+H]⁺. 4-(benzylthio)-3-(((tert-butyldiphenylsilyl)oxy)methyl)butan-1-amine To a solution of 4-amino-2-((benzylthio)methyl)butan-1-ol (1 g, 4.44 mmol) and imidazole (362.52 mg, 5.33 mmol) in DCM (10 mL) was added dropwise TBDPSCl (1.34 g, 4.88 mmol, 1.25 mL) at 25 °C over 5 min under N₂. After addition, the resulting mixture was stirred at 25 °C for 2 h under N₂. The reaction was poured into water (30 mL) and extracted with DCM (15 mL x 2). Then the combined phase was washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to provide the title compound (1.4 g, 67.4%) as a yellow oil. MS (ESI): mass calcd. for C28H37NOSSi: 463.24, found: 464.6 [M+H]⁺. 4-amino-2-(((tert-butyldiphenylsilyl)oxy)methyl)butane-1-sulfonyl chloride To a solution of 4-(benzylthio)-3-(((tert-butyldiphenylsilyl)oxy)methyl)butan-1-amine (0.2 g, 431 mol) in AcOH (2 mL) and H₂O (0.4 mL) was added NCS (172.77 mg, 1.29 mmol) at 25 °C over 5 min under N₂. After addition, the resulting mixture was stirred at 25 °C for 1 h under N₂. The solution was concentrated under reduced pressure to give the title compound (0.2 g, crude) as a yellow solid, which was used without further purification. 5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2-thiazinane 1,1-dioxide To a solution of 4-amino-2-(((tert-butyldiphenylsilyl)oxy)methyl)butane-1-sulfonyl chloride (0.2 g, 454.47 mol) in DCM (2 mL) was added TEA (138 mg, 1.36 mmol, 190 L) at 25 °C over 5 min under N₂. After addition, the resulting mixture was stirred at 25°C for 2 h under N₂. The solution was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give the title compound (0.1 g, 52.3%) as a white solid. MS (ESI): mass calcd. for C₂₁H₂₉NO₃SSi: 403.16, found: 404.0 [M+H]⁺. 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methyl-1,2-thiazinane 1,1-dioxide To a solution of 5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2-thiazinane 1,1-dioxide (100 mg, 247.76 mol) and K₂CO₃ (102.7 mg, 743 mol) in DMF (1 mL) was added MeI (42.2 mg, 297 mol, 18.5 L) dropwise at 25 °C under N₂. After addition, the resulting mixture was stirred at 20 °C for 16 h under N₂. The reaction mixture was poured into water (20 mL) and extracted with DCM (10 mL x 2). Then the organic combined phase was washed with brine (5 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (78 mg, 71.6%) as a yellow oil. MS (ESI): mass calcd. for C₂₂H₃₁NO₃SSi: 417.18, found: 418.2 [M+H]⁺. 5-(hydroxymethyl)-2-methyl-1,2-thiazinane 1,1-dioxide To a solution of 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methyl-1,2-thiazinane 1,1- dioxide (78 mg, 187 mol) in THF (1 mL) was added TBAF (1 M, 280 L) dropwise at 25 °C under N₂. After addition, the resulting mixture was stirred at 25 °C for 12 h under N₂. The solution was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give the title compound (25 mg, 67.2%) as a colorless oil.¹H NMR (400 MHz, DMSO-d₆) ppm 4.74 (t, J = 5.6 Hz, 1H), 3.35-3.40 (m, 1H), 3.26-3.32 (m, 2H), 3.16-3.24 (m, 1H), 3.10 (dd, J = 13.6, 3.2 Hz, 1H), 2.81 (dd, J = 13.6, 12.4 Hz, 1H), 2.69 (s, 3H), 2.09-2.23 (m, 1H), 1.45-1.53 (m, 2H) Example 285 and Example 286 were synthesized in a similar route to the one described in Example 91, using 5-(hydroxymethyl)-2-methyl-1,2-thiazinane 1,1-dioxide and 1-(cyclobutylmethyl)-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. The diastereomers were separated by chiral SFC (column: Chiral-OJ-30-DAICEL CHIRALCEL OJ(250mm*30mm,10 um);mobile phase: [CO₂-EtOH:ACN=4:1 (0.1% NH₃H₂O)]; B%:30%, isocratic elution mode). The stereochemistry for these two compounds is arbitrarily assigned. Example 287.1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-((2,2- dioxido-2-thiaspiro[3.3]heptan-6-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (115) Synthetic scheme: (2,2-dioxo-2thiaspiro[3.3]heptan-6-yl)methanol To a solution of 2,2-dioxo-2thiaspiro[3.3]heptane-6-carboxylic acid (0.5 g, 2.63 mmol) in THF (5 mL) was added LiAlH₄ (2.5 M, 789 L) at 0 °C. The mixture was stirred at 0 °C for 2 h under N2. The reaction was quenched with H2O (0.01 mL) and 15% aqueous NaOH (0.01 mL). H₂O (0.03 mL) was added, and the reaction was allowed to stir at room temperature for 1 h. The reaction was filtered and concentrated under reduced pressure to give the title compound (0.56 g, crude) as a white solid.¹H NMR (400 MHz, DMSO-d₆) ppm 4.55 (t, J = 5.2 Hz, 1H), 4.21 (s, 2H), 4.09 (s, 2H), 2.5 (m, 1H), 2.18-2.35 (m, 4H), 2.01-2.08 (m, 2H) 1-(cyclobutylmethyl)-5-(diaminomethylene)-3-((5S,7s,10S)-1-((2,2-dioxido-2- thiaspiro[3.3]heptan-6-yl)methyl)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5⁷.1⁵]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (115) The title compound was prepared in a similar fashion to the one described in Example 91, using (2,2-dioxo-2thiaspiro[3.3]heptan-6-yl)methanol instead of 2- oxabicyclo[2.1.1]hexan-4-ylmethanol. PTH1R Assay Assays were performed using Expi293F Inducible cells (Invitrogen) stably expressing hPTH1R via a pcZeo TetO DNA plasmid. Cell lines were maintained in suspension in Expi293 Expression Medium (ThermoFisher Scientific) supplemented with 10 μg/mL Blasticidin and 10 μg/mL Zeocin and incubated at 37°C, 8% CO2, with shaking. To induce receptor expression, hPTH1R cells were incubated in induction medium (Expi293 Expression Medium with 4 μg/mL Doxycycline (Millipore Sigma), 5 mM sodium butyrate (Millipore Sigma) and 100 ng/mL Pertussis toxin (Millipore Sigma)) for 24 hours at 32°C, 5% CO2, with shaking. Assay-ready aliquots were prepared by harvesting cells 24-hour post-induction. Cells were pelleted at 4°C, resuspended in Expi293 Expression medium + 10% DMSO, aliquoted, and kept frozen at -80°C until ready for use. For the assay, concentration-response curves of test and reference compounds were added to 384-well plates using an Apricot liquid handler (SPT Labtech) and backfilled with DMSO to a final concentration of 0.3%. cAMP was measured using the cisbio cAMP Gs dynamic HTRF kit (PerkinElmer) according to manufacturer instructions. Aliquots of frozen hPTH1R cells were quickly thawed and washed with phosphate-buffered saline (Sigma- Aldrich) to remove media and DMSO. The cells were resuspended in kit-supplied Stimulation Buffer at 0.2 x 10⁶ cells/mL.10 μl of the hPTH1R cell dilution were added to each well of the assay plate and incubated with the compounds for 1 hour in a 37°C, 0% CO2 incubator. Following this incubation, the cells were lysed and accumulated cAMP was detected through the addition of kit-supplied lysis buffer containing d2-reagent and Eu- cryptate antibody. The HTRF signal was quantified using a BMG PHERAstar FSX plate reader optimized for HTRF assays. The HTRF ratio was determined by dividing the signal output at 665 nm by that at 620 nm. Data were normalized to the signal produced by 1 μM PTH(1-34) (100% activation) and vehicle (0% activation). A complete listing of the compounds, characterization data, and PTH1R assay data for the exemplary compounds is set forth in the table in Figure 1. GCGR Assays were performed using Expi293F Inducible cells (Invitrogen) stably expressing hGCGR via a pcZeo TetO DNA plasmid. Cell lines were maintained in suspension in Expi293 Expression Medium (ThermoFisher Scientific) supplemented with 10 μg/mL Blasticidin and 10 μg/mL Zeocin and incubated at 37°C, 8% CO2, with shaking. To induce receptor expression, hGCGR cells were incubated in induction medium (Expi293 Expression Medium with 4 μg/mL Doxycycline (Millipore Sigma), 5 mM sodium butyrate (Millipore Sigma) and 100 ng/mL Pertussis toxin (Millipore Sigma) for 24 hours at 32°C, 5% CO2, with shaking. Assay-ready aliquots were prepared by harvesting cells 24-hour post-induction. Cells were pelleted at 4°C, resuspended in Expi293 Expression medium + 10% DMSO, aliquoted, and kept frozen at -80°C until ready for use. For the assay, concentration-response curves of test and reference compounds were added to 384-well plates using an Apricot liquid handler (SPT Labtech) and backfilled with DMSO to a final concentration of 0.3%. cAMP was measured using the cisbio cAMP Gs dynamic HTRF kit (PerkinElmer) according to manufacturer instructions. Aliquots of frozen hGCGR cells were quickly thawed and washed with phosphate-buffered saline (Sigma- Aldrich) to remove media and DMSO. The cells were resuspended in kit-supplied Stimulation Buffer at 60,000 cells/mL.10 μl of the hGCGR cell dilution were added to each well of the assay plate and incubated with the compounds for 1 hour in a 37°C, 0% CO2 incubator. Following this incubation, the cells were lysed and accumulated cAMP was detected through the addition of kit-supplied lysis buffer containing d2-reagent and Eu- cryptate antibody. The HTRF signal was quantified using a BMG PHERAstar FSX plate reader optimized for HTRF assays. The HTRF ratio was determined by dividing the signal output at 665 nm by that at 620 nm. Data were normalized to the signal produced by 3 nM Glucagon (100% activation) and vehicle (0% activation). Results of the assay are provided in Table 1 below: Table 1. GCGR Assay Data



GCGR pEC₅₀ >7: +++; pEC₅₀ between 6 and 7: ++; and pEC₅₀ <6: +. GIPR Cell-based functional activation of GIPR was measured using the CisBio cAMP Gs dynamic kit (PerkinElmer). Prior to the day of the assay, Expi293F Inducible cells (Invitrogen) stably overexpressing the human GIP receptor under a Tet repressor system were induced with 4 μg/mL doxycycline, 5 mM sodium butyrate, and 100 ng/mL Pertussis toxin at 37°C. After 20 hours of induction, cells were harvested, aliquoted, and cryopreserved. Concentration response curves of test and reference compounds were acoustically dispensed to a 384-well assay plate using an Echo 650 (Beckman Coulter). On the day of the assay, cells are rapidly thawed and resuspended in 1X Cisbio stimulation buffer and plated at 2,500 cells/well, 10 μL/well into the assay plate containing compounds. Following a 1-hour incubation at 37°C and 0% CO2, the reaction was terminated by addition of the Cisbio kit- supplied lysis buffer containing d2-reagent and Eu-cryptate antibody. Following a 1-hour incubation at room temperature in the dark, HTRF-FRET values were measured using the BMG ClarioStar Plus plate reader according to manufacturer instructions. Data were normalized to the signal produced by 3 nM GIP1-42 peptide (100% activation) and vehicle (0% activation). Results of the GIPR Assay are provided in Table 2. Table 2: GIPR Assay +++ +++ ++ ++ ++ ++ ++ +++ ++ +++ ++

GIPR pEC₅₀ >7: +++; pEC₅₀ between 6 and 7: ++; and pEC₅₀ <6: +. GLP1R Cell-based functional activation of GLP1R was measured using the CisBio cAMP Gs dynamic kit (PerkinElmer). Prior to the day of the assay, Expi293F Inducible cells (Invitrogen) stably overexpressing the human GLP1 receptor under a Tet repressor system were induced with 4 μg/mL doxycycline, 5 mM sodium butyrate, and 100 ng/mL Pertussis toxin at 37°C. After 20 hours of induction, cells were harvested, aliquoted, and cryopreserved. Concentration response curves of test and reference compounds were acoustically dispensed to a 384-well assay plate using an Echo 650 (Beckman Coulter). On the day of the assay, cells are rapidly thawed and resuspended in 1X Cisbio stimulation buffer and plated at 2,000 cells/well, 10 μL/well into the assay plate containing compounds. Following a 1-hour incubation at 37°C and 0% CO₂, the reaction was terminated by addition of the Cisbio kit-supplied lysis buffer containing d2-reagent and Eu-cryptate antibody. Following a 1-hour incubation at room temperature in the dark, HTRF-FRET values were measured using the BMG ClarioStar Plus plate reader according to manufacturer instructions. Data were normalized to the signal produced by 10 nM Danuglipron (100% activation) and vehicle (0% activation). Results: For GLP-1R, Examples 16, 41, 66, 103, 112, pEC₅₀ are ++; the remaining compounds are + (pEC₅₀ >7: +++; pEC₅₀ between 6 and 7: ++; and pEC₅₀ <6:+). Additional results of the GIPR Assay are provided in Table 3. Table 3: GLP1R Assay INCORPORATION BY REFERENCE All of the U.S. patents and U.S. and PCT patent application publications cited herein are hereby incorporated by reference. EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

CLAIMS We claim: 1. A compound according to Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: R¹ is (C_1-C₆)alkyl optionally substituted with one or more instance of fluoro, carboxy, (C_1-C₆)carboxyalkoxy, 4- to 7-membered heterocycloalkyl or (C_3-C₈)cycloalkyl, wherein (C3- C8)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more instances of (C_1-C₆)alkyl, carboxy, and fluoro; R² is (C_1-C₆)alkyl optionally substituted with cyano; R³ is: a) (C_1-C₆)alkyl substituted with SO₂R^3a, (C_1-C₆)alkoxy, (C_3-C₈)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein (C_3-C₈)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl are optionally substituted with one or more instances of (C_1-C₆)alkyl and fluoro, or b) unsubstituted branched (C_1-C₆)alkyl; and R^3a is (C_1-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 R¹ is methyl optionally substituted with one or more instance of fluoro, carboxy, (C_1-C₆)carboxyalkoxy, 4- to 7-membered heterocycloalkyl or (C_3-C₈)cycloalkyl, wherein (C_3-C₈)cycloalkyl and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more instances of (C_1-C₆)alkyl, carboxy, and fluoro.

4. The compound of any one of claims 1 to 3, wherein R¹ is (C_1-C₆)alkyl substituted with 4- to 7-membered heterocycloalkyl, wherein 4- to 7-membered heterocycloalkyl, is optionally substituted with fluoro or (C_1-C₆)alkyl.

5. The compound of claim 4, wherein the 4- to 7-membered heterocycloalkyl is _{tetrahydrofuranyl, 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 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.

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 R¹ is 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.

9. The compound of any one of claims 4 to 8, wherein 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.

10. The compound of any one of claims 1 to 3, wherein R¹ is (C_1-C₆)alkyl substituted with (C_3-C₈)cycloalkyl, wherein (C_3-C₈)cycloalkyl is optionally substituted with carboxy.

11. The compound of claim 10, wherein the (C_3-C₈)cycloalkyl is cyclopropyl, cyclobutyl, or bicyclo[1.1.1]pentane-1- each of which substituted with one or more instances of carboxy and (C_1-C₆)alkyl.

12. The compound of claim 1 or 2, wherein R¹ is (C_1-C₆)alkyl substituted with one or more instances of fluoro or carboxy.

13. The compound of claim 12, wherein R¹ is a trifluoro(C₁-C₆)alkyl.

14. The compound of claim 13, wherein R¹ is 2,2,2-trifluoroethyl.

15. The compound of claim 13, wherein R¹ is 3,3,3-trifluoropropyl.

16. The compound of any one of claims 1 or 2, wherein R¹ is methyl.

17. The compound of any one of claims 1 to 14, wherein R² is methyl.

18. The compound of any one of claims 1 to 10, wherein R² is cyanomethyl.

19. The compound of any one of claims 1 to 16, wherein R³ is methyl or ethyl substituted with SO₂R⁴ (C_3-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 (C_1-C₆)alkyl, and fluoro.

20. The compound of any one of claims 1 to 19, wherein R³ is methyl substituted with SO₂R⁴, (C_3-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 (C_1-C₆)alkyl, and fluoro.

21. The compound of any one of claims 1 to 18, wherein R³ is (C_1-C₆)alkyl substituted with phenyl, wherein phenyl is optionally substituted with fluoro.

22. The compound of claim 21, wherein R³ is (C_1-C₆)alkyl substituted, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl.

23. The compound of any one of claims 1 to 21, wherein R³ is (C_1-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 (C_1-C₆)alkyl and fluoro.

25. The compound of claim 24, wherein R³ is (C₁-C₆)alkyl substituted with 2-methyl-1,3- thiazol-4-yl.

26. The compound of claim 23, wherein R³ is (C_1-C₆)alkyl substituted with 2- methylpyridin-4-yl or pyridine-2-yl.

27. The compound of any one of claims 1 to 18, wherein R³ is (C_1-C₆)alkyl substituted with (C_3-C₈)cycloalkyl, wherein (C_3-C₈)cycloalkyl is optionally substituted with one or more (C_1-C₆)alkyl.

28. The compound of claim 27, wherein R³ is (C_1-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 (C_1-C₆)alkyl and fluoro.

29. The compound of claim 28, wherein R³ is (C_1-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 R³ is 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 R³ is (C_1-C₆)alkyl substituted with 4- to 7-membered heterocycloalkyl.

32. The compound of claim 31, wherein R³ is (C_1-C₆)alkyl substituted with tetrahydrofurany-2-yl, or tetrahydropyrany-4-yl.

33. The compound of claim 18, wherein R³ is 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: R⁴ and R⁵ taken together form a heterocyclic ring having the structure: a_{) , wherein:} R⁷ and R⁸ are independently hydrogen or (C_1-C₆)alkyl; b_{) ; c) , wherein:} R⁹ is (C_1-C₆)hydroxyalkyl or (C_1-C₆)alkoxyalkyl; d_{) , wherein:} Y is absent or CH₂, R¹⁰ is hydrogen or (C_1-C₆)alkyl; e_{) , wherein:} R¹¹ is (C_1-C₆)alkyl; f_{) , wherein:} R^12a and R^12b are each independently (C_1-C₆)alkyl, and R¹³ is hydrogen or (C_3-C₈)cycloalkyl; or g) , wherein R¹⁴ and R¹⁵ are each independently (C_1-C₆)alkyl; and R⁶ is (C_1-C₆)alkyl or (C_3-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 R⁴ and R⁵ taken together form a heterocyclic ring having the structure: a_{) , b) , c) , d) , e) , f) or} g) ; and if the structure is Formula (IIb), then R⁴ and R⁵ taken together form a heterocyclic ring having the structure: a_{) , b) , c) , d) , e) , f) or , or} g) .

36. The compound of claim 34 or 35, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (a); and R⁷ is hydrogen.

37. The compound of claim 34 or 35, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (a); and R⁷ is methyl.

38. The compound of any one of claims 34 to 37, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (a); and R⁸ is methyl.

39. The compound of any one of claims 34 to 37, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (a); and R⁸ is hydrogen.

40. The compound of claim 34 or 35, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (c); and R⁹ is methoxy.

41. The compound of claim 34 or 35, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (c); and R⁹ is 1-hydroxyethyl.

42. The compound of claim 34 or 35, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (d); and Y is absent.

43. The compound of claim 34 or 35, wherein R⁴ and R⁵ taken 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 R⁴ and R⁵ taken together form a heterocyclic ring having the structure (d); and R¹⁰ is hydrogen.

45. The compound of any one of claims 34, 35, 42 and 43, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (d); and R¹⁰ is methyl.

46. The compound of claim 34 or 35, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (e); and R¹¹ is methyl.

47. The compound of claim 34 or 35, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (f); and R^12a and R^12b are each methyl.

48. The compound of any one of claims 34, 35, and 47, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (f); and R¹³ is cyclopropyl.

49. The compound of any one of claims 34, 35, 42 and 43, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (f); and R¹³ is hydrogen.

50. The compound of claim 34 or 35, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (g); and R¹⁴ is methyl.

51. The compound of any one of claims 34, 35, and 50, wherein R⁴ and R⁵ taken together form a heterocyclic ring having the structure (g); and R¹⁵ is methyl.

52. The compound of any one of claims 34 to 51, wherein R⁶ is n-butyl.

53. A compound according to Formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein: R¹⁶ is (C_1-C₆)alkyl substituted with tetrahydrofuran-2-yl, pyrazolyl optionally substituted with (C_1-C₆)alkyl, phenyl substituted with (C=O)NH₂, or cyclobutyl substituted with pyridyl; R¹⁷ is (C_1-C₆)alkyl; and R¹⁸ is (C_1-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 R¹⁷ is methyl.

57. The compound of any one of claims 53 to 56, wherein R¹⁸ is n-butyl.

58. A compound according to Formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein: R¹⁹ is (C_1-C₆)fluoroalkyl; R²⁰ is (C_1-C₆)alkyl; and R²¹ is (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 R¹⁹ is 2,2,2-trifluoroethyl.

61. The compound of any one of claims 58 to 60, wherein R²⁰ is methyl.

62. The compound of any one of claims 58 to 61, wherein R²¹ is ethyl or propyl.

63. A compound according to Formula (V) (V), or a pharmaceutically acceptable salt thereof, wherein: R²² is (C_1-C₆)alkyl; R²³ is (C_1-C₆)alkoxy; or R²² and R²³ taken together with the carbon to which they are attached form 4- to 7-membered heterocycloalkyl; and R²⁴ is (C_1-C₆)alkyl optionally substituted with phenyl or (C_3-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 R²² is methyl.

66. The compound of any one of claims 63 to 65, wherein R²³ is methoxymethyl.

67. The compound of any one of claims 63 or 64, wherein R²² and R²³ taken together form: or .

68. The compound of any one of claims 63 to 67, wherein R²⁴ is butyl.

69. The compound of any one of claims 63 to 67, wherein R²⁴ is benzyl.

70. The compound of any one of claims 63 to 67, wherein R²⁴ is (cyclopentyl)methyl.

71. The compound of any one of claims 62 to 67, wherein R²⁴ is 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.