COMPOUNDS, COMPOSITIONS AND METHODS OF USE TO TREAT HYPOPARATHYROIDISM AND OSTEOPOROSIS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application Nos. 63/418,754, filed October 24, 2022; 63/464,457, filed May 5, 2023; and 63/532,181, filed August 11, 2023; 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. 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. SUMMARY One aspect of the invention provides compounds, compositions, and methods useful for preventing or treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis. Accordingly, provided herein in some embodiments is a compound having the structure of Formula (Ia) or (Ib): (Ia); or (Ib); or a pharmaceutically acceptable salt thereof; wherein: Z is O or S; Y represents: , , , , or ; X is N or CR ² ; L is -(C ₁ -C ₆ )alkylenyl-; B represents (C3-C8)cycloalkyl, (C6-C10)aryl, 4-7 membered heterocycloalkyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C ₁ -C ₆ )alkyl; R ¹ is hydrogen, -CO ₂ R ^a -CONR ^a R ^b , -SO ₂ R ^a , -SONR ^a R ^b , -SO ₂ NR ^a R ^b , -NR ^a R ^b , 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, , or –O-(4- to 7-membered heterocycloalkyl); wherein (C1- C ₆ )alkyl, (C _3- C ₈ )cycloalkyl, (C _1- C ₆ )alkoxy, 4- to 7-membered heterocycloalkyl and –O-(4- to 7-membered heterocycloalkyl) are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C1- C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, hydroxy(C ₃ -C ₈ )cycloalkyl, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )alkoxy, (C _1- C ₆ )hydroxyalkyl, , (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, and benzyl; or when Y represents –L-B-, R ¹ taken together with the atom to which it is attached forms a 4- to 7- membered heterocycloalkyl ring, provided that if Y is or , then R ¹ is not hydrogen; R ^1a , R ^1b , and R ^1c are independently for each occurrence hydrogen, (C _1- C ₆ )alkyl, or (C ₃ -C ₈ )cycloalkyl; or R ^1a and R ^1b taken together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl; R ² is hydrogen, fluoro, chloro, cyano, hydroxyl, NH ₂ , NHCO(C ₁ -C ₆ )alkyl, NHR ^a , (C _1- C ₆ )alkoxy, -CONR ^a R ^b or (C _1- C ₆ )alkyl, wherein (C _1- C ₆ )alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NR ^a R ^b ; or R ¹ and R ² taken together with the atom to which they are attached form a 4- to 9- membered heterocycloalkyl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, wherein the (C1-C6)alkyl is further optionally substituted with (C _3- C ₈ )cycloalkyl, 4- to 7-membered heterocylcylalkyl, hydroxy, halo, (C _1- C6)alkoxy, cyano, carboxy, -CONR ^a R ^b , and -SO2R ^a ; R ³ is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C _1- C ₆ )alkoxy, (C _3- C ₈ )cycloalkyl, aryl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; R ^a and R ^b are independently for each occurrence hydrogen, (C1-C6)alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C _1- C ₆ )alkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R ^a and R ^b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R ^5a , R ^5b , R ^6a , and R ^6b are independently hydrogen or (C1-C6)alkyl; R ^A is hydrogen or (C1-C6)alkyl; n, m, and p are independently 0 or 1; and q is 0, 1, or 2; provided that the sum of p and q equals 0, 1, or 2. In some embodiments, provided herein is a compound having the structure of Formula (Ia) or (Ib): (Ia); or (Ib); or a pharmaceutically acceptable salt thereof; wherein: Y represents: , , , , or ; X is N or CR ² ; L is -(C ₁ -C ₆ )alkylenyl-; B represents (C3-C8)cycloalkyl, (C6-C10)aryl, 4-7 membered heterocycloalkyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C ₁ -C ₆ )alkyl; R ¹ is hydrogen, -CO2R ^a -CONR ^a R ^b , -SO2R ^a , -SONR ^a R ^b , -SO2NR ^a R ^b , -NR ^a R ^b , 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, , or –O-(4- to 7-membered heterocycloalkyl); wherein (C1- C ₆ )alkyl, (C _3- C ₈ )cycloalkyl, (C _1- C ₆ )alkoxy, 4- to 7-membered heterocycloalkyl and –O-(4- to 7-membered heterocycloalkyl) are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C _1- C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, hydroxy(C ₃ -C ₈ )cycloalkyl, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )alkoxy, (C _1- C ₆ )hydroxyalkyl, , (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, and benzyl; or when Y represents –L-B-, R ¹ taken together with the atom to which it is attached forms a 4- to 7- membered heterocycloalkyl ring, provided that if Y is or , then R ¹ is not hydrogen; R ^1a , R ^1b , and R ^1c are independently for each occurrence hydrogen, (C1-C6)alkyl, or (C ₃ -C ₈ )cycloalkyl; or R ^1a and R ^1b taken together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl; R ² is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHR ^a , (C1- C ₆ )alkoxy, -CONR ^a R ^b or (C _1- C ₆ )alkyl, wherein (C _1- C ₆ )alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C _1- C ₆ )alkoxy, and NR ^a R ^b ; or R ¹ and R ² taken together with the atom to which they are attached form a 4- to 9- membered heterocycloalkyl optionally substituted with one or more substituents independently selected from (C ₁ -C ₆ )alkyl, wherein the (C ₁ -C ₆ )alkyl is further optionally substituted with (C3-C8)cycloalkyl, 4- to 7-membered heterocylcylalkyl, hydroxy, (C1- C6)alkoxy, cyano, carboxy, -CONR ^a R ^b , and -SO2R ^a ; R ³ is (C _1- C ₆ )alkyl or (C _3- C ₈ )cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, (C3- C8)cycloalkyl, aryl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; R ^a and R ^b are independently for each occurrence hydrogen, (C _1- C ₆ )alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C _1- C ₆ )alkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C _1- C ₆ )alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R ^a and R ^b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R ^5a , R ^5b , R ^6a , and R ^6b are independently hydrogen or (C _1- C ₆ )alkyl; n, m, and p are independently 0 or 1; and q is 0, 1, or 2; provided that the sum of p and q equals 0, 1, or 2. In other embodiments, provided herein is a compound according to Formula (Ia) and (Ib): (Ia); or (Ib); or a pharmaceutically acceptable salt thereof; wherein: Y represents: , , , , or ; X is N or CR ² ; L is -(C ₁ -C ₆ )alkylenyl-; B represents (C ₃ -C ₈ )cycloalkyl, (C ₆ -C ₁₀ )aryl, 4-7 membered heterocycloalkyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R ¹ is hydrogen, -CO ₂ R ^a -CONR ^a R ^b , -SO ₂ R ^a , -SONR ^a R ^b , -SO ₂ NR ^a R ^b , -NR ^a R ^b , 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, or ; wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, and ; or when Y represents –L-B-, R ¹ taken together with the atom to which it is attached forms a 4- to 7-membered heterocycloalkyl ring, provided that if Y is or , then R ¹ is not hydrogen; R ^1a , R ^1b , and R ^1c are independently for each occurrence hydrogen or (C _1- C ₆ )alkyl; or R ^1a and R ^1b taken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R ² is hydrogen, fluoro, chloro, cyano, hydroxyl, NH ₂ , NHCO(C ₁ -C ₆ )alkyl, NHR ^a , (C _1- C6)alkoxy, -CONR ^a R ^b or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NR ^a R ^b ; or R ¹ and R ² taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R ³ is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, (C3- C ₈ )cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; R ^a and R ^b are independently for each occurrence hydrogen, (C1-C6)alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C1-C6)alkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R ^a and R ^b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; n, m, and p are independently 0 or 1; and q is 0, 1, or 2; provided that the sum of p and q equals 0, 1, or 2. In other embodiments, provided herein is a compound according to Formula (IIa) or (IIb): (IIa); or (IIb); or a pharmaceutically acceptable salt thereof; wherein: Y represents: , , , , or ; X is N or CR ² ; L is -(C1-C6)alkylenyl-; B represents (C ₃ -C ₈ )cycloalkyl, (C ₆ -C ₁₀ )aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C ₁ -C ₆ )alkyl; R ¹ is hydrogen, -CO2R ^a -CONR ^a R ^b , -SO2R ^a , -SONR ^a R ^b , -SO2NR ^a R ^b , -NR ^a R, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, or ; wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7- membered heterocycloalkyl 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C _1- C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C _1- C ₆ )haloalkyl, and (C _1- C ₆ )alkoxy, (C _1- C ₆ )hydroxyalkyl, and ; or when Y represents –L-B-, R ¹ taken together with the atom to which it is attached forms a 4- to 7-membered heterocycloalkyl ring, provided that if Y is , , or (C ₁ -C ₆ )alkylene, then R ¹ is not hydrogen; R ^1a , R ^1b , and R ^1c are independently for each occurrence hydrogen or (C1-C6)alkyl; or R ^1a and R ^1b taken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R ² is hydrogen, fluoro, chloro, , -CONR ^a R ^b or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1- C ₆ )alkoxy, or R ¹ and R ² taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl ; R ³ is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C _1- C ₆ )alkoxy, (C _3- C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; R ^a and R ^b are independently for each occurrence hydrogen,(C1-C6)alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C _1- C ₆ )alkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or R ^a and R ^b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; n, m, and p are independently 0 or 1; q is 0, 1, or 2; provided that the sum of p and q equals 0, 1, or 2; Z is S or O; R ⁴ is H, -C(O)NH2, (C1-C6)alkyl, or -N(R ^4a )2; and R ^4a is independently for each occurrence hydrogen or (C _1- C ₆ )alkyl. In still other embodiments, provided herein is a compound according to Formula (IIIa), (IIIb), (IIIc), or (IIId): (IIIa); (IIIb); (IIIc); or (IIId); or a pharmaceutically acceptable salt thereof; wherein: Y-R ¹ represents: , , , , , or -(C1-C6)alkylene-R ¹ ; X is N or CR ² ; L is -(C ₁ -C ₆ )alkylenyl-; B represents (C ₃ -C ₈ )cycloalkyl, (C ₆ -C ₁₀ )aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R ¹ is hydrogen, -CO2R ^a -CONR ^a R ^b , -SO2R ^a , -SONR ^a R ^b , -SO2NR ^a R ^b , -NR ^a R, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C _1- C ₆ )alkyl, (C _3- C ₈ )cycloalkyl, (C _1- C ₆ )alkoxy, or ; wherein (C _1- C ₆ )alkyl, (C _3- C ₈ )cycloalkyl, (C _1- C ₆ )alkoxy, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7- membered heterocycloalkyl 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, and ; or when Y represents –L-B-, R ¹ taken together with the atom to which it is attached forms a 4- to 7-membered heterocycloalkyl ring, provided that if Y is , , or (C ₁ -C ₆ )alkylene, then R ¹ is not hydrogen; R ^1a , R ^1b , and R ^1c are independently for each occurrence hydrogen or (C1-C6)alkyl; or R ^1a and R ^1b taken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R ² is hydrogen, fluoro, chloro, -CONR ^a R ^b or (C _1- C ₆ )alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1- C ₆ )alkoxy, or R ¹ and R ² taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R ³ is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, (C3- C ₈ )cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; R ^a and R ^b are independently for each occurrence hydrogen,(C1-C6)alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C1-C6)alkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C _1- C ₆ )alkoxy, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or R ^a and R ^b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; n, m, and p are independently 0 or 1; q is 0, 1, or 2; provided that the sum of p and q equals 0, 1, or 2; R ⁴ is H or N(R ^4a ) ₂ ; and R ^4a is independently for each occurrence hydrogen or (C1-C6)alkyl. Other aspects of the disclosure provide a pharmaceutical composition comprising a compound of formula (Ia)-(IIId), 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 an effective amount of a compound of compound of formula (Ia)-(IIId), 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 1 to 105 of the invention, and their characterization data and biological activity. Figure 2 tabulates exemplary compounds 106 to 191, and their characterization data and biological activity. Figure 3 tabulates exemplary compounds 192 to 295, and their characterization data and biological activity. Figure 4 tabulates exemplary compounds 296 to 362, and their characterization data and biological 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 ¹³ C- or ¹⁴ C- 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., C ₁ -C ₃₀ for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl goups 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 “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 -(CH ₂ )-, ethylene -(CH ₂ CH ₂ )-, n-propylene - (CH ₂ CH ₂ CH ₂ )-, isopropylene -(CH ₂ CH(CH ₃ ))-, 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. As used herein, the term “halocycloalkyl” refers to an cycloalkyl group as hereinbefore defined substituted with at least one halogen. "Cycloheteroalkyl" refers to an 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 and pyrimidine, 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. 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, -CF ₃ , -CN, and the like. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. 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 ascompared 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 radiolabelled pharmaceutical agent, for example, a radiolabelled 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 In some embodiments, provided is a compound of Formula (Ia) or (Ib): (Ia); or (Ib); or a pharmaceutically acceptable salt thereof; wherein: Z is O or S; Y represents: , , , , or ; X is N or CR ² ; L is -(C1-C6)alkylenyl-; B represents (C3-C8)cycloalkyl, (C6-C10)aryl, 4-7 membered heterocycloalkyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C ₁ -C ₆ )alkyl; R ¹ is hydrogen, -CO2R ^a -CONR ^a R ^b , -SO2R ^a , -SONR ^a R ^b , -SO2NR ^a R ^b , -NR ^a R ^b , 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C _1- C ₆ )alkyl, (C _3- C ₈ )cycloalkyl, (C _1- C ₆ )alkoxy, , or –O-(4- to 7-membered heterocycloalkyl); wherein (C _1- C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, 4- to 7-membered heterocycloalkyl and –O-(4- to 7-membered heterocycloalkyl) are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C1- C6)alkyl, (C3-C8)cycloalkyl, hydroxy(C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, , (C3-C8)cycloalkyl(C1-C6)alkyl, and benzyl; or when Y represents –L-B-, R ¹ taken together with the atom to which it is attached forms a 4- to 7- membered heterocycloalkyl ring, provided that if Y is or , then R ¹ is not hydrogen; R ^1a , R ^1b , and R ^1c are independently for each occurrence hydrogen, (C1-C6)alkyl, or (C ₃ -C ₈ )cycloalkyl; or R ^1a and R ^1b taken together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl; R ² is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHR ^a , (C1- C6)alkoxy, -CONR ^a R ^b or (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C _1- C ₆ )alkoxy, and NR ^a R ^b ; or R ¹ and R ² taken together with the atom to which they are attached form a 4- to 9- membered heterocycloalkyl optionally substituted with one or more substituents independently selected from (C ₁ -C ₆ )alkyl, wherein the (C ₁ -C ₆ )alkyl is further optionally substituted with (C _3- C ₈ )cycloalkyl, 4- to 7-membered heterocylcylalkyl, hydroxy, halo, (C _1- C6)alkoxy, cyano, carboxy, -CONR ^a R ^b , and -SO2R ^a ; R ³ is (C _1- C ₆ )alkyl or (C _3- C ₈ )cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C _1- C ₆ )alkoxy, (C _3- C8)cycloalkyl, aryl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; R ^a and R ^b are independently for each occurrence hydrogen, (C1-C6)alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C _1- C ₆ )alkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C _1- C ₆ )alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R ^a and R ^b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R ^5a , R ^5b , R ^6a , and R ^6b are independently hydrogen or (C _1- C ₆ )alkyl; R ^A is hydrogen or (C _1- C ₆ )alkyl; n, m, and p are independently 0 or 1; and q is 0, 1, or 2; provided that the sum of p and q equals 0, 1, or 2. In some embodiments, provided is a compound of Formula (Ia) or (Ib): (Ia); or (Ib); or a pharmaceutically acceptable salt thereof; wherein: Y represents: , , , , or ; X is N or CR ² ; L is -(C ₁ -C ₆ )alkylenyl-; B represents (C3-C8)cycloalkyl, (C6-C10)aryl, 4-7 membered heterocycloalkyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C ₁ -C ₆ )alkyl; R ¹ is hydrogen, -CO ₂ R ^a -CONR ^a R ^b , -SO ₂ R ^a , -SONR ^a R ^b , -SO ₂ NR ^a R ^b , -NR ^a R ^b , 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, , or –O-(4- to 7-membered heterocycloalkyl); wherein (C1- C ₆ )alkyl, (C _3- C ₈ )cycloalkyl, (C _1- C ₆ )alkoxy, 4- to 7-membered heterocycloalkyl and –O-(4- to 7-membered heterocycloalkyl) are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C1- C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, hydroxy(C ₃ -C ₈ )cycloalkyl, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )alkoxy, (C _1- C ₆ )hydroxyalkyl, , (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, and benzyl; or when Y represents –L-B-, R ¹ taken together with the atom to which it is attached forms a 4- to 7- membered heterocycloalkyl ring, provided that if Y is or , then R ¹ is not hydrogen; R ^1a , R ^1b , and R ^1c are independently for each occurrence hydrogen, (C _1- C ₆ )alkyl, or (C3-C8)cycloalkyl; or R ^1a and R ^1b taken together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl; R ² is hydrogen, fluoro, chloro, cyano, hydroxyl, NH ₂ , NHCO(C ₁ -C ₆ )alkyl, NHR ^a , (C _1- C ₆ )alkoxy, -CONR ^a R ^b or (C _1- C ₆ )alkyl, wherein (C _1- C ₆ )alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NR ^a R ^b ; or R ¹ and R ² taken together with the atom to which they are attached form a 4- to 9- membered heterocycloalkyl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, wherein the (C1-C6)alkyl is further optionally substituted with (C3-C8)cycloalkyl, 4- to 7-membered heterocylcylalkyl, hydroxy, (C1- C ₆ )alkoxy, cyano, carboxy, -CONR ^a R ^b , and -SO ₂ R ^a ; R ³ is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C _1- C ₆ )alkoxy, (C _3- C8)cycloalkyl, aryl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; R ^a and R ^b are independently for each occurrence hydrogen, (C1-C6)alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C _1- C ₆ )alkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R ^a and R ^b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R ^5a , R ^5b , R ^6a , and R ^6b are independently hydrogen or (C1-C6)alkyl; n, m, and p are independently 0 or 1; and q is 0, 1, or 2; provided that the sum of p and q equals 0, 1, or 2. In further embodiments, provided is a compound of Formula (Ia) or (Ib): (Ia); or (Ib); or a pharmaceutically acceptable salt thereof; wherein: Y represents: , , , , or ; X is N or CR ² ; L is -(C1-C6)alkylenyl-; B represents (C ₃ -C ₈ )cycloalkyl, (C ₆ -C ₁₀ )aryl, 4-7 membered heterocycloalkyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R ¹ is hydrogen, -CO ₂ R ^a -CONR ^a R ^b , -SO ₂ R ^a , -SONR ^a R ^b , -SO ₂ NR ^a R ^b , -NR ^a R ^b , 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C _1- C ₆ )alkyl, (C _3- C ₈ )cycloalkyl, (C _1- C ₆ )alkoxy, or ; wherein (C _1- C ₆ )alkyl, (C _3- C ₈ )cycloalkyl, (C _1- C ₆ )alkoxy, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy, (C1- C6)hydroxyalkyl, and ; or when Y represents –L-B-, R ¹ taken together with the atom to which it is attached forms a 4- to 7-membered heterocycloalkyl ring, provided that if Y is or , then R ¹ is not hydrogen; R ^1a , R ^1b , and R ^1c are independently for each occurrence hydrogen or (C _1- C ₆ )alkyl; or R ^1a and R ^1b taken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R ² is hydrogen, fluoro, chloro, cyano, hydroxyl, NH ₂ , NHCO(C ₁ -C ₆ )alkyl, NHR ^a , (C _1- C ₆ )alkoxy, -CONR ^a R ^b or (C _1- C ₆ )alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NR ^a R ^b ; or R ¹ and R ² taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R ³ is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, (C3- C ₈ )cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; R ^a and R ^b are independently for each occurrence hydrogen, (C _1- C ₆ )alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C1-C6)alkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C _1- C ₆ )alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R ^a and R ^b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; n, m, and p are independently 0 or 1; and q is 0, 1, or 2; provided that the sum of p and q equals 0, 1, or 2. In particular embodiments, Y represents: . In other embodiments, Y represents: . In other embodiments, Y represents: . In some embodiments, R ¹ is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R ^1d , R ^1e , and R ^1f are independently for each occurrence selected from hydrogen, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl and (C1-C6)alkoxy, wherein (C1-C6)alkyl is further optionally substituted with (C ₃ -C ₈ )cycloalkyl or phenyl; or R ^1d and R ^1e taken together with the carbon to which they are attached form a (C ₃ -C ₈ )cycloalkyl or a 3- to 7-membered heterocycloalkyl each of which is optionally substituted with hydroxy. In some embodiments, R ¹ is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R ^1d , R ^1e , and R ^1f are independently for each occurrence selected from hydrogen, (C1- C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; or R ^1d and R ^1e taken together with the carbon to which they are attached form a (C ₃ -C ₈ )cycloalkyl or a 3- to 7-membered heterocycloalkyl. In some embodimeents, R ¹ is , and: R ^a and R ^b are each hydrogen, or R ^a is hydrogen; and R ^b is methyl. In some embodiments, R ¹ is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R ^1d , R ^1e , and R ^1f are independently for each occurrence selected from hydrogen, (C _1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl and (C1-C6)alkoxy, wherein (C1-C6)alkyl is further optionally substituted with (C3-C8)cycloalkyl or phenyl; or R ^1d and R ^1e taken together with the carbon to which they are attached form a (C ₃ -C ₈ )cycloalkyl or a 3- to 7-membered heterocycloalkyl each of which is optionally substituted with hydroxy. In some embodiments, R ¹ is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R ^1d , R ^1e , and R ^1f are independently for each occurrence selected from hydrogen, (C1- C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; or R ^1d and R ^1e taken together with the carbon to which they are attached form a (C ₃ -C ₈ )cycloalkyl or a 3- to 7-membered heterocycloalkyl. In some embodiments, R ¹ is, , and R ^1d and R ^1e taken together with the carbon to which they are attached R ^1d and R ^1e taken together with the carbon to which they are attached form morpholine, cyclobutane, oxetane, azetidine, or cyclohexane. In certain preferred embodiments, R ^1d and R ^1e are each methyl. In some preferred embodiments, R ^1f is hydrogen. In other preferred embodiments, R ^1f is (C _1- C ₆ )alkyl, preferably methyl or ethyl. In other embodiments, R ^1f is (C _1- C ₆ )fluoroalkyl, preferably 2,2,2-trifluorethyl. In some embodiments, R ¹ is ; and R ^1a is cyclopropyl, 2-propyl, ethyl, or methyl. In some embodiments, R ¹ is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . In some embodiments, R ¹ is: , , , , , , , , , or . In certain embodiments, Y is , , , , , , , , , , , , , , , , , , , or . In some embodiments, X is N, while in other embodiments X is CR ² . In certain embodiments where X is CR ² , R ² is hydrogen, while in other embodiments R ² is fluoro. In particularly preferred embodiments, R ² is hydrogen. In some embodiments, R ² is (C _1- C ₆ )alkyl optionally substituted with (C _1- C ₆ )alkoxy, preferably methyl or methoxymethyl. In certain embodiments, R ¹ is or , and R ² is –CH ₃ or -CH ₂ -OCH ₃ . In some embodiments, R ¹ and R ² taken together with the atom to which they are attached form R ¹ and R ² taken together with the atom to which they are attached form a 4- to 9-membered heterocycloalkyl, wherein the 4- to 9-membered heterocycloalkyl is optionally substituted with one or more independently selected instances of (C _1- C ₆ )alkyl, wherein the (C1-C6)alkyl is further optionally substituted with one or more substitutents independently selected from (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocyloalkyl, hydroxy, halo, (C _1- C ₆ )alkoxy, cyano, carboxy, -CONR ^a R ^b , and -SO ₂ R ^a . In some embodiments, wherein R ¹ and R ² taken together with the atom to which they are attached form: , , , or ; wherein R ^1g and R ^1h are each independently hydrogen or (C1-C6)alkyl, wherein the (C1- C ₆ )alkyl is optionally substituted with one or more substitutents independently selected from (C _3- C ₈ )cycloalkyl, 4- to 7-membered heterocylcylalkyl, hydroxy, halo, (C _1- C ₆ )alkoxy, cyano, carboxy, -CONR ^a R ^b , and -SO2R ^a . In some embodiments, R ^1h is ethyl, methyl, ethyl, isopropyl, or t-butyl, each of which is optionally substituted with hydroxy, methoxy, cyclopropyl, oxetanyl, tetrahydrofuranyl, phenyl, cyano, carboxy, hydroxy, -CONR ^a R ^b , -SO2R ^a , or one to three fluorine atoms. In some embodiments, R ^1h is trifluoromethyl. In some embodiments, R ^1g hydrogen, methyl, or ethyl, wherein methyl or ethyl is optionally substituted with cyano. In some embodiments, R ^a is methyl. In some embodiments, R ^b is methyl. In further embodiments, R ^a and R ^b are each methyl. In certain preferred embodiments, R ^1g is methyl or hydrogen. In more particular embodiments, R ¹ and R ² taken together with the atom to which they are attached form: , , , , , , , , , , or . In some embodiments, R ¹ and R ² taken together with the atom to which they are attached form: . In other embodiments, R ¹ and R ² taken together with the atom to which they are attached form: . In some embodiments, n is 1, while in other embodiments n is 0. In some embodiments, m is 1 while in other embodiments m is 0. In some embodiments, p is 1, while in other embodiments p is 0. In certain preferred embodiments, p is 0; and q is 2. In other preferred embodiments, n, m, p, and q are each 1. In still other preferred embodiments, n, m, p, and q are each 0. In some embodiments, B represents 4- to 7-membered hetercycloalkyl. In other particular embodiments, B represents cyclohexyl or cyclopentyl, while in other embodiments B represents phenyl, tolyl, or pyridyl. More particularly, in certain preferred embodiments, B represents: , , , , , , , , , , , or . In some embodiments, L represents methylene, ethylene, or n-butylene. In some preferred embodiments, R ^5a , R ^5b , R ^6a , and R ^6b are each hydrogen. In other embodiments, R ^5a , R ^5b , R ^6a , and R ^6b are each methyl, and in still other embodiments, R ^5a is methyl and R ^5b , R ^6a , and R ^6b are each hydrogen. In some embodiments, Z is O. In some embodiments, R ^A is hydrogen, while in other embodiments, R ^A is methyl. In some preferred embodiments, the compound has the structure of Formula (Ic): (Ic), or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from (C _1- C ₆ )alkyl, 4- to 7-membered heterocycloalkyl, 5- to 6- membered heteroaryl, NR ^a R ^b , and ; wherein (C1-C6)alkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C _1- C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C _1- C ₆ )haloalkyl, and (C1-C6)alkoxy; and R ^1a is hydrogen or (C _1- C ₆ )alkyl; In other preferred embodiments, the compound has the structure of Formula (Id): (Id), or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from -CO2R ^a -CONR ^a R ^b , -SO2R ^a , -SONR ^a R ^b , -SO2NR ^a R ^b , -NR ^a R ^b , (C3- C ₈ )cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and ; wherein 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C1- C ₆ )hydroxyalkyl, R ^1a is hydrogen or (C1-C6)alkyl, and R ² is selected from hydrogen, cyano, hydroxyl, NH ₂ , NHCOCH ₃ , NHR ^a , (C _1- C6)alkoxy, -CONR ^a R ^b or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NR ^a R ^b . In other preferred embodiments, the compound has the structure of Formula (Ie): NH ₂ H ₂ N O O N A N R ₃ O (Ie), or a pharmaceutically acceptable salt thereof, wherein A represents a 4- to 7- membered heterocycloalkyl. In certain preferred embodiments, R ³ is methyl, n-propyl, n-butyl, , , , , or , and more preferably, n-butyl. In certain embodiments, the compound is represented by Formula Ia. In other embodiments, the compound is represented by Formula Ib. In some embodiments, the compound has the structure: , , , , , , , H ₂ N NH ₂ O O N N O N O ^NH2 , ,H ₂ N NH ₂ O O N N O N H ₂ N O , ,

, , , , , , , ,

, , , , , , , , , , , , , , , , , NH ₂ H ₂ N O O N N O N O ^NH2 , H ₂ N NH ₂ O O N N O O N NH ₂ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , H ₂ N NH ₂ H ₂ N NH ₂ O O O O O O N N N N O _N ^NH O _N ^NH O , O , H ₂ N NH ₂ H ₂ N NH ₂ O O O O O O N N N N O _N ^NH O _N ^NH O , O , H H ₂ N NH _{2 2} N NH ₂ O O O O O _O ^O N N N N O _N ^NH O _N ^NH O , O , H ₂ N NH ₂ H ₂ N NH ₂ O O O O O ^O _O ^O N N N N O _N ^NH O _N ^NH O , O , H ₂ N NH ₂ O O O N N O _N ^NH O , , ; , , , NH ₂ H ₂ N O H O O N N _N ^NH O O , O , O NH ₂ NH ₂ O H ₂ N O H ₂ N O H O N _NH O N N _N ^NH O N N H O O O O , , NH ₂ NH O ₂ H ₂ N O H ₂ N O O N _NH O N _{O N} ^NH N N H N O O O O , O , NH ₂ NH ₂ OH ₂ N O O H ₂ N O N O ^NH N _N ^O _N N N N _H O O O O , , NH ₂ NH ₂ OH ₂ N O H ₂ N O O H ^{NH O} _N N ^O N N _N N N _H O O O O , , , , NH NH _{2 2} H H 2N O O ₂ N O O O N _N ^NH2 _O ^NH N _N ² N N O O , , NH ₂ NH ₂ H ₂ N O O H ₂ N O O N NH O ^H N _N ^O N _N O N O N O O O , , NH ₂ H ₂ N O H O O N N ^NH N O O , ^O , NH ₂ O H ₂ N O N NH O N N H O O , , NH ₂ O O H ₂ N O N _NH O N N H O O , , NH ₂ H ₂ N O H O O N N N NH O O , , NH ₂ NH ₂ H ₂ N O O H ₂ N O O NH N O N O N N ^N O N H ^N H O O O , , NH ₂ NH ₂ H O HN O O 2N ^H O _{2 N} N O N O N N N N N O O ^O O H , , NH ₂ NH ₂ H N O HN O O 2 ^H O _{2 N} N O N O N N N N ^N O O ^O O _H , , NH ₂ H O 2N ^H N O O N N N CF ₃ O O , NH ₂ NH ₂ H ₂ N O O H ₂ N O ^H N O N CF ₃ O N O N N ^N NH O N O _H O ^O , , NH ₂ NH ₂ O H ₂ N O O H ₂ N N O N O N O N N N N O N O H O O , , NH ₂ NH ₂ H N O O O O 2 H ₂ N NH N O N O N N N N O O N O , , NH ₂ NH ₂ N H ₂ N O H O O 2N N O N O N N NH N N O O O O , , NH ₂ H ₂ N O O NH O N N O N . , or ; or a pharmaceutically acceptable salt thereof. In yet other embodiments, the compound has the structure: , , , , , , ,

H ₂ N NH ₂ O O N N O N O ^NH2 , ,H ₂ N NH ₂ O O N N O N H ₂ N O , , , , , ,

, , , , , , , , , , , , , , , , , , , , , NH ₂ H ₂ N O O N N O N O ^NH2 , H ₂ N NH ₂ O O N N O O N NH ₂ , , , , ,

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , H ₂ N NH ₂ H ₂ N NH ₂ O O O O N N N N O O H ₂ N NH ₂ O O O N NH ₂ N N N NH N NH N N O , , , H ₂ N NH ₂ H ₂ N NH ₂ O O O O N N N N O O H ₂ N N O O ^H H N H ₂ N N _N O O N O _N ^{N O} , ^NH2 , or ^H , or a pharmcaeutically acceptable salt thereof. In still other embodiments, the compound has the structure: , , , NH ₂ N H ₂ N O NH N O N O N H O , , NH ₂ O H ₂ N O NH N O N H N O O , , , , , , , , , , , , , , , , , , , , , , , , NH ₂ O H ₂ N O N O N N N O O , , , , , , , , , , NH ₂ O H ₂ N O N O N N N O O , , , , , , , , , , , , , , , , , , , , HO NH ₂ O H ₂ N O N O N N N O O , , O NH ₂ O H ₂ N O N O N NH N O O , , , , , , MeO NH ₂ O H ₂ N O N O N N N O O , , , , , , , , , , , , , , , , , , , , NH ₂ NH ₂ O O H2N O H ₂ N NH H N O O N O N N N O N N _CN O O O , , , , , , , , , , , , NH ₂ NH ₂ COOH H ₂ ^N _O N O H ₂ N O NH N N O N O N H NH N O N O O O , , HO NH ₂ O H ₂ N O N O N NH N O O , or a pharmaceutically acceptable salt thereof. In some embodiments, a compound has the structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

, , or a pharmaceutically acceptable salt thereof. In some embodiments, provided is a compound of Formula (IIa) or (IIb): R ^{4 R} 4 Z _Z N O _O ^{N 3} N ^N N ^N R _Y R ³ _Y O (IIa); or O (IIb); or a pharmaceutically acceptable salt thereof; wherein: Y represents: n p m ^{X 1 q} _R , n X ^R1 , n X ^R1 , R ¹ , or ; X is N or CR ² ; L is -(C1-C6)alkylenyl-; B represents (C ₃ -C ₈ )cycloalkyl, (C ₆ -C ₁₀ )aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R ¹ is hydrogen, -CO2R ^a -CONR ^a R ^b , -SO2R ^a , -SONR ^a R ^b , -SO2NR ^a R ^b , -NR ^a R, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C _1- C ₆ )alkyl, (C _3- C ₈ )cycloalkyl, (C _1- C ₆ )alkoxy, or ; wherein (C _1- C ₆ )alkyl, (C _3- C ₈ )cycloalkyl, (C _1- C ₆ )alkoxy, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7- membered heterocycloalkyl 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C _1- C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C _1- C ₆ )haloalkyl, and (C _1- C ₆ )alkoxy, (C _1- C ₆ )hydroxyalkyl, and ; or when Y represents –L-B-, R ¹ taken together with the atom to which it is attached forms a 4- to 7-membered heterocycloalkyl ring, provided that if Y is , , or (C ₁ -C ₆ )alkylene, then R ¹ is not hydrogen; R ^1a , R ^1b , and R ^1c are independently for each occurrence hydrogen or (C _1- C ₆ )alkyl; or R ^1a and R ^1b taken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R ² is hydrogen, fluoro, chloro, -CONR ^a R ^b or (C _1- C ₆ )alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1- C6)alkoxy; or R ¹ and R ² taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R ³ is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, (C3- C ₈ )cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; R ^a and R ^b are independently for each occurrence hydrogen,(C1-C6)alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C _1- C ₆ )alkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R ^a and R ^b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; n, m, and p are independently 0 or 1; q is 0, 1, or 2; provided that the sum of p and q equals 0, 1, or 2; Z is S or O; R ⁴ is H, -C(O)NH2, (C1-C6)alkyl, -NHSO2Me, or -N(R ^4a )2; and R ^4a is independently for each occurrence hydrogen or (C _1- C ₆ )alkyl. In certain embodiments, Y represents: or . In some embodiments, R ¹ is: , while in other embodiments R ¹ is . In some embodiments, R ¹ is: hydrogen, , , , , , , , , , , , , or , , , , , , , , , , , , , , or ; and R ^1d , R ^1e , and R ^1f are independently for each occurrence selected from hydrogen, (C1- C ₆ )alkyl, (C _1- C ₆ )haloalkyl, and (C _1- C ₆ )alkoxy; or R ^1d and R ^1e taken together with the carbon to which they are attached form a (C ₃ -C ₈ )cycloalkyl or a 3- to 7-membered heterocycloalkyl. In certain embodiments, R ¹ is, ; and R ^1d and R ^1e taken together with the carbon to which they are attached form morpholine, cyclobutane, oxetane, or cyclohexane. In certain particular embodiments, R ^1d and R ^1e are each methyl. In certain particular embodiments, R ^1f is hydrogen, while in others, R ^1f is (C _1- C ₆ )alkyl, more particularly, R ^1f is methyl or ethyl. In other embodiments, R ^1f is (C1-C6)fluoroalkyl, such as R ^1f is 2,2,2-trifluorethyl. In certain particular embodiments, Y is , , , , , , , , , , , , , , , , , , , or . In some embodiments, X is N. In other embodiments, X is CR ² . In certain preferred embodiments, R ² is hydrogen. In other embodiments, R ² is fluoro. In still other embodiments, R ² is (C1-C6)alkyl optionally substituted with (C1- C6)alkoxy, preferably methyl or methoxymethyl. In certain embodiments,R ¹ is or , and R ² is methyl or methoxymethyl. In certain embodiments, R ¹ and R ² taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl. More particularly, in some embodiments, R ¹ and R ² taken together with the atom to which they are attached form: , , , or . In certain embodiments R ³ is: methyl, , , , , , , or . In certain preferred embodiments, R ³ is . In particular embodiments, Z is O. In other particular embodiments, Z is S. In particular embodiments, R ⁴ is H, -C(O)NH2, or NH2. In certain preferred embodiments, R ⁴ is H or NH _2. In certain embodiments, a compound of formula (IIa) or (IIb) has the structure: , , , , , , NH ₂ O O S NH ₂ N N N N O , _, , , , ; , , , , , , , , , , , , , , , , , , , H ₂ ^N _O ^O O S NH N N N O N O , , , or ; or a pharmaceutically acceptable salt thereof. In other embodiments, the compound has the structure: , , , , , , NH ₂ O O S NH ₂ N N N N O , _, , , , ; , or , or a pharmaceutically acceptable salt thereof. In still further embodiments, the compound has the structure: , , , , , , , , , , or ; Other aspects of the disclosure provide a compound according to Formula (IIIa), (IIIb), (IIIc), or (IIId): (IIIa); (IIIb); (IIIc); or (IIId); or a pharmaceutically acceptable salt thereof; wherein: Y-R ¹ represents: , , , , , or -(C ₁ -C ₆ )alkylene-R ¹ ; X is N or CR ² ; L is -(C1-C6)alkylenyl-; B represents (C ₃ -C ₈ )cycloalkyl, (C ₆ -C ₁₀ )aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C ₁ -C ₆ )alkyl; R ¹ is hydrogen, -CO2R ^a -CONR ^a R ^b , -SO2R ^a , -SONR ^a R ^b , -SO2NR ^a R ^b , -NR ^a R, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, or ; wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7- membered heterocycloalkyl 5- to 6-membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C _1- C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C _1- C ₆ )haloalkyl, and (C _1- C ₆ )alkoxy, (C _1- C ₆ )hydroxyalkyl, and ; or when Y represents –L-B-, R ¹ taken together with the atom to which it is attached forms a 4- to 7-membered heterocycloalkyl ring, provided that if Y is , , or (C1-C6)alkylene, then R ¹ is not hydrogen; R ^1a , R ^1b , and R ^1c are independently for each occurrence hydrogen or (C _1- C ₆ )alkyl; or R ^1a and R ^1b taken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R ² is hydrogen, fluoro, chloro, -CONR ^a R ^b or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C _1- C6)alkoxy, or R ¹ and R ² taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R ³ is (C _1- C ₆ )alkyl or (C _3- C ₈ )cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C _1- C ₆ )alkoxy, (C _3- C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; R ^a and R ^b are independently for each occurrence hydrogen,(C _1- C ₆ )alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C _1- C ₆ )alkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or R ^a and R ^b taken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; n, m, and p are independently 0 or 1; q is 0, 1, or 2; provided that the sum of p and q equals 0, 1, or 2; R ⁴ is H or N(R ^4a )2; and R ^4a is independently for each occurrence hydrogen or (C _1- C ₆ )alkyl. In certain embodiments, R ¹ is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , or . In other embodiments, R ¹ is or , and R ² is –CH ₃ or -CH ₂ -OCH ₃ . In still other embodiments, R ¹ is: , while in more particular embodiments R ¹ is: or . In some embodiments, Y is , , , , , , , , , , , , , , , , , , , or . In certain embodiments, R ³ is: methyl, , , , , , or , preferably . In certain preferred embodiments, R ⁴ is H or NH2. In certain embodiments, a compound of formula (IIIa), (IIb), (IIIc), or (IIId) has the structure: , , , , or ; or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds are atropisomers. Additionally, unless otherwise stated, 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 ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. For example, in the case of variable R ¹ , the (C1-C4)alkyl or the -O-(C1-C4)alkyl can be suitably deuterated (e.g., -CD3, or -OCD3, respectively). Any compound of the invention can also be radiolabed for the preparation of a radiopharmaceutical agent. 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 an effective amount of a compound of formula (Ia)–(IIId), 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 of formula (Ia)–(IIId), or a pharmaceutically acceptable salt thereof, either alone or in admixture with a pharmaceutically excipient. Another aspect of the invention includes compounds of formula (Ia) –(IIId), 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 formula (Ia)-(IIId) 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. 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 of Formula (Ia)-(IIId), 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. The following general reaction schemes were used to prepare pyrimidinedione cores and are described in further detail in the experimentals:

Abbreviations: ACN Acetonitrile Ac2O Acetic anhydride AcOH Acetic acid CBr ₄ Carbon tetrabromide CbzCl Benzyl chloroformate CDI 1,1'-Carbonyldiimidazole Cs2CO3 Cesium carbonate CDCl3 Deuterated chloroform DCM Dichloromethane DEAD Diethyl azodicarboxylate DIPEA N,N-diisopropylethylamine DMBNH2 2,4-Dimethoxybenzylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide EA Ethyl acetate h Hour H ₂ Hydrogen _HATU ^{Hexafluorophosphate azabenzotriazole tetramethyl uronium} HF Hydrogen fluoride K2CO3 Potassium carbonate KCN Potassium cyanide KOCN Potassium cyanate LDA Lithium diisopropylamide LiAlH ₄ Lithium aluminum hydride LiOH Lithium hydroxide MeI Methyl iodide MeOH Methanol MsCl Mesyl chloride N2 nitrogen NaBH ₄ Sodium borohydride NaBH ₃ CN Sodium cyanoborohydride NaBH(OAc)3 Sodium triacetoxyborohydride NaHCO3 Sodium bicarbonate NaHSO ₃ Sodium bisulfite Na ₂ SO ₄ Sodium sulfate n-Bu3P Tri-n-butylphosphine NaH Sodium hydride NH ₄ Cl Ammonium chloride NH4HCO3 Ammonium bicarbonate NH2OH.HCl Hydroxylamine hydrochloride Pd/C Palladium on carbon PE Petroleum ether PMBNH2 4-Methoxybenzylamine POCl ₃ Phosphorus oxychloride PPh ₃ Triphenylphosphine rt Room temperature SEMCl 2-(Trimethylsilyl)ethoxymethyl chloride TBAF Tetrabutylammonium fluoride TBDPSCl tert-Butyl(chloro)diphenylsilane TEA triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TMAD Tetramethylazodicarboxamide TosMIC Toluenesulfonylmethyl isocyanide TsOH p-Toluenesulfonic acid Examples 1, 15, 19, 22, 27, 28, and 34 were synthesized in similar procedures as described in Example 4 below. Example 2 was an intermediate in the synthesis of Example 3. Example 3 was synthesized in similar procedures as described in Example 4, with Boc as the protecting group. Example 4: 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)- yl)-2-azaspiro[3.5]nonane-2-carboxamide (4) Synthetic scheme: 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)-yl)-2- azaspiro[3.5]nonane-2-carboxamide To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7-yl)py rimidine- 2,4,6(1H,3H,5H)-trione (Example 17, 330 mg, 0.94 mmol) in water (4 mL) and MeOH (4 mL) was added potassium cyanate (383.02 mg, 4.72 mmol). After heating at 70 °C for 5 h, the resulting mixture was extracted with DCM/MeOH. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reverse phase HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5μm; mobile phase A: Water (10 mmol/L NH4HCO3), mobile phase B: ACN; gradient: 17% B to 42% B) to afford the title compound 4 (143.3 mg, 38.38%) as a white solid. MS (ESI): mass calcd. for C18H28N6O4: 392.22, found: 393.25 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 9.54 (s, 2H), 7.31 (s, 2H), 5.78 (s, 2H), 4.61-4.67 (m, 1H), 3.73 (t, J = 7.4 Hz, 2H), 3.53 (s, 2H), 3.40 (s, 2H), 2.27-2.37 (m, 2H), 1.82-1.87 (m, 2H), 1.40-1.50 (m, 6H), 1.25 (dq, J = 14.8, 7.4 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). Example 6 was synthesized in similar procedures as described for Example 104, below, without chiral separation. Example 14 was synthesized from Example 18 in similar procedures as described in Example 4. Examples 11 and 16 were synthesized in similar procedures as described in Example 14. Example 36 was synthesized from Example 37 in similar procedures as described in Example 4. Example 7: 5-(2-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyr imidin-1(2H)- yl)ethyl)picolinamide Synthetic scheme: Methyl 5-(cyanomethyl)picolinate To a stirred mixture of methyl 5-bromopyridine-2-carboxylate (2 g, 9.26 mmol) and 2- (trimethylsilyl)acetonitrile (3.14 g, 27.77 mmol) in DMF (5 mL, 64.608 mmol) was added Pd2(dba)3 (1.70 g, 1.85 mmol), XantPhos (2.14 g, 3.70 mmol) and zinc fluoride (574.24 mg, 5.56 mmol) in portions. After heating for 2 h at 90 °C under N ₂ , the reaction was diluted with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford the title compound (863 mg, 52.91%) as a white solid. MS (ESI): mass calcd. for C ₉ H ₈ N ₂ O ₂ : 176.06, found: 177.10 [M+H] ⁺ . Methyl 5-(2-aminoethyl)picolinate To a stirred mixture of methyl 5-(cyanomethyl)picolinate (683 mg, 3.88 mmol) in MeOH (8 mL, 197.59 mmol) was added con. HCl (0.2 mL) and Pd(OH) ₂ (0.2 g). After stirring for 2 h at room temperature under H ₂ , the reaction was basified to pH = 8 with NaHCO3 (aq.), diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (680 mg, 97.98%) as a white solid, which was used in the next step without further purification. MS (ESI): mass calcd. for C9H12N2O2: 180.09, found: 181.15 [M +H] ⁺ . 5-(2-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyr imidin-1(2H)- yl)ethyl)picolinamide The title compound 7 was synthesized in similar procedures as described in Example 17, steps 2, 5-7. MS (ESI): mass calcd. for C17H22N6O4: 374.17, found: 375.15 [M +H] ⁺ . ¹ H NMR (300 MHz; DMSO-d6) δ 9.48 (s, 2H), 8.39 (d, J = 1.3 Hz, 1H), 8.05 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.76 (dd, J = 8.0, 2.0 Hz, 1H), 7.55 (s, 1H), 7.34 (d, J = 0.6 Hz, 2H), 4.05 (t, J = 7.1 Hz, 2H), 3.70 (t, J = 7.2 Hz, 2H), 2.93 (t, J = 7.1 Hz, 2H), 1.31-1.41 (m, 2H), 1.11-1.23 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). Example 10 was synthesized from methyl 3-(cyanomethyl)bicyclo[1.1.1]pentane-1- carboxylate (prepared from methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate) in similar procedures as described in Example 7. Example 9 was synthesized from 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[3,4-b]pyridine in similar procedures as described in Example 7. Example 8: 1-Butyl-5-(diaminomethylene)-3-(4-(5,5-dimethyl-2,4-dioxoimi dazolidin-1- yl)butyl)pyrimidine-2,4,6(1H,3H,5H)-trione Synthetic scheme: 5,5-Dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidi ne-2,4-dione To a stirred solution of 5,5-dimethylimidazolidine-2,4-dione (5 g, 39.023 mmol) in anhydrous DCM (20 mL) was added DIPEA (15.13 g, 117.07 mmol) and SEMCl (7.81 g, 46.83 mmol) at 0 °C. After stirring for 1 h at the same temperature, the reaction was continued stirring for 24 h at room temperature. After completion, the reaction was quenched with water (60 mL) and extracted with DCM (3 x 60 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the title compound (5.4 g, 45.39%). MS (negative mode): mass calcd. for C ₁₁ H ₂₂ N ₂ O ₃ Si: 258.14, found: 257.05 [M-H]-. 2-(4-(5,5-Dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)me thyl)imidazolidin-1- yl)butyl)isoindoline-1,3-dione To a solution of 5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidi ne-2,4- dione (1.5 g, 5.81 mmol) and cesium carbonate (3.79 g, 11.61 mmol) in dimethylformamide (40 mL) was added N-(4-bromobutyl)phthalimide (1.97 g, 6.97 mmol). After heating at 60 °C under N2 overnight, the reaction was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-50% PE in EA) to afford the title compound (2.5 g, 93.7%) as a colorless oil. MS (ESI): mass calcd. for C ₂₃ H ₃₃ N ₃ O ₅ Si: 459.22, found: 482.15 [M+Na] ⁺ . 1-(4-Aminobutyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)m ethyl)imidazolidine-2,4- dione To a solution of 2-(4-(5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)butyl)isoind oline-1,3-dione (2.4 g, 5.22 mmol) in EtOH (50 mL) was added hydrazine hydrate (1.31 g, 26.11 mmol). The reaction was heated at 50 °C for 3 h under N ₂ , quenched with water (50 mL) and extracted with DCM/MeOH (6/1). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-10% DCM/MeOH) to afford the title compound (1.6 g, 92.99%) as a white solid. MS (ESI): mass calcd. for C15H31N3O3Si: 329.21, found: 330.15 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(4-(5,5-dimethyl-2,4-dioxoimi dazolidin-1- yl)butyl)pyrimidine-2,4,6(1H,3H,5H)-trione O NH ₂ O NH ₂ H ₂ N O ^N H ₂ N O ^N N O _NH O N O Si O N O N N O O 8 A solution of 1-butyl-5-(diaminomethylene)-3-(4-(5,5-dimethyl-2,4-dioxo-3- ((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)butyl)pyrimi dine-2,4,6(1H,3H,5H)-trione (synthesized follow procedure of Example 17 from the above previous step product, 80 mg, 0.15 mmol) in TFA (1.5 mL) and DCM (4.5 mL) was stirred at rt for 1 h. After concentration, the crude residue was added 2 N NH3 in MeOH (5 mL) and stirred for 1 h. The reaction was concentrated and purified by silica gel column chromatography (0-10% DCM in MeOH) followed by reverse phase HPLC purification (26% to 45% (v/v) ACN and H2O with 0.05% NH4HCO3) to afford the title compound 8 (15 mg, 24.71%) as a white solid. MS (ESI): mass calcd. for C ₁₈ H ₂₈ N ₆ O ₅ : 408.21, found: 409.20 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 10.74 (s, 1H), 9.53 (s, 2H), 7.34 (s, 2H), 3.76 (t, J = 7.8 Hz, 4H), 3.17 (t, J = 6.4 Hz, 2H), 1.47 (dt, J = 15.5, 7.3 Hz, 6H), 1.20-1.29 (m, 8H), 0.87 (t, J = 7.3 Hz, 3H). Example 12: 1-(2-Acetyl-2-azaspiro[3.5]nonan-7-yl)-3-butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (12) Synthetic scheme: 1-(2-Acetyl-2-azaspiro[3.5]nonan-7-yl)-3-butyl-5-(diaminomet hylene)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (80 mg, 0.229 mmol) in DCM (4 mL) was added TEA (69 mg, 0.69mmol) and Ac ₂ O (47 mg, 0.46 mmol) at 0 °C under N ₂ . After stirring at room temperature for 2 h, the reaction was quenched with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by reverse phase HPLC (25% to 45% (v/v) ACN and H2O with 0.05% NH4HCO3) to afford the title compound 12 (19.4 mg, 21.61%) as a white solid. MS (ESI): mass calcd. for C19H29N5O4: 391.22, found: 392.25 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 9.53 (s, 2H), 7.32 (s, 2H), 4.62-4.68 (m, 1H), 3.83 (s, 1H), 3.71-3.75 (m, 3H), 3.53 (s, 1H), 3.44 (s, 1H), 2.27-2.37 (m, 2H), 1.88 (d, J = 13.0 Hz, 2H), 1.74 (d, J = 6.8 Hz, 3H), 1.46 (ddd, J = 20.3, 12.8, 6.8 Hz, 6H), 1.25 (dq, J = 14.9, 7.4 Hz, 2H), 0.88 (d, J = 14.6 Hz, 3H). Examples 5 and 20 were synthesized in similar procedures as described in Example 12. Example 13: 1-Butyl-5-(diaminomethylene)-3-(2-(methylsulfonyl)-2-azaspir o[3.5]nonan- 7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (13) Synthetic scheme: 1-Butyl-5-(diaminomethylene)-3-(2-(methylsulfonyl)-2-azaspir o[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (80 mg, 0.23 mmol) in DCM (4 mL) was added TEA (69 mg, 0.69 mmol) and MsCl (39 mg, 0.34 mmol) in DCM (0.1 mL) at 0 °C under N ₂ . After stirring at room temperature for 3 h, the reaction was quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by reverse phase HPLC (25% to 45% (v/v) ACN and H ₂ O with 0.05% NH4HCO3) to afford the title compound 13 (20.5 mg, 20.89%) as a white solid. MS (ESI): mass calcd. for C18H29N5O5S: 427.19, found: 428.25 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO- d6) δ 9.54 (s, 2H), 7.33 (s, 2H), 4.65 (t, J = 11.7 Hz, 1H), 3.74 (t, J = 7.3 Hz, 2H), 3.65 (s, 2H), 3.53 (s, 2H), 3.01 (s, 3H), 2.32 (q, J = 12.0 Hz, 2H), 1.95 (d, J = 13.0 Hz, 2H), 1.42-1.51 (m, 6H), 1.26 (dq, J = 14.8, 7.4 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). Example 26 was synthesized in similar procedures as described in Example 13, using dimethylcarbamic chloride. Example 30 was synthesized in similar procedures as described in Example 13. Example 24 (was synthesized from Example 18 in similar procedures as described in Example 13. Example 17: 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7-yl)py rimidine- 2,4,6(1H,3H,5H)-trione (17) Synthetic scheme: tert-Butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate To a solution of tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (1.0 g, 4.18 mmol) in 7 N NH ₃ in MeOH (40 mL) was added Pd/C (10%, 0.2 g). The reaction mixture was stirred for 16 h under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure to afford the title compound (1.0 g, 99.57%) which was used in the next step without further purification. MS (ESI): mass calcd. for C13H24N2O2: 240.18 found: 241.15 [M+H] ⁺ . tert-Butyl 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate To a solution of tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (1 g, 4.16 mmol) in ClCH ₂ CH ₂ Cl (20 mL) was added butyl isocyanate (0.45 g, 4.58 mmol). After stirring at room temperature overnight, the reaction was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the title compound (1.2 g, 84.96%). MS (ESI): mass calcd. for C18H33N3O3: 339.25 found: 340.20 [M+H] ⁺ . 1-Butyl-3-(2-azaspiro[3.5]nonan-7-yl)urea To a solution of tert-butyl 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate (1.2 g, 3.54 mmol) in ethyl acetate (8 mL) was added 2 N HCl (in EA, 8 mL). After stirring at room temperature for 3 h, the resulting mixture was concentrated to afford a crude title compound (900 mg, 106%) as a yellow solid. MS (ESI): mass calcd. for C ₁₃ H ₂₅ N ₃ O: 239.20 found: 240.20 [M+H] ⁺ . The crude product was used in the next step directly without further purification. Benzyl 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate To a solution of 1-butyl-3-(2-azaspiro[3.5]nonan-7-yl)urea (0.9 g, 3.76 mmol) in DCM (15 mL) was added CbzCl (0.77 g, 4.51 mmol) and TEA (1.14 g, 11.28 mmol). After stirring for 16 h at rt, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 10/1) to afford the title compound (1 g, 71.21%) as a yellow solid. MS (ESI): mass calcd. for C21H31N3O3: 373.24 found: 374.25 [M+H] ⁺ . Benzyl 7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azasp iro[3.5]nonane-2- carboxylate To a solution of benzyl 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate (1 g, 2.68 mmol) in acetic acid (15 mL) was added acetic anhydride (0.96 g, 9.37 mmol) and malonic acid (0.36 g, 3.48 mmol). After heating at 80 °C for 4 h, the reaction was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the title compound (0.7 g, 59.21%). MS (ESI): mass calcd. for C ₂₄ H ₃₁ N ₃ O ₅ : 441.23 found: 442.20 [M+H] ⁺ . Benzyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydrop yrimidin-1(2H)-yl)-2- azaspiro[3.5]nonane-2-carboxylate To a solution of benzyl 7-(3-butyl-2,4,6-trioxo-1,3-diazinan-1-yl)-2- azaspiro[3.5]nonane-2-carboxylate (0.7 g, 1.585 mmol) in DMSO (10 mL) was added carbon disulfide (1.21 g, 15.85 mmol) and TEA (2.41 g, 23.78 mmol). After stirring at room temperature for 1 h, 1,3-dibromopropane (3.20 g, 15.85 mmol) was added. After completion, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the title compound (600 mg, 67.86%). MS (ESI): mass calcd. for C28H35N3O5S2: 558.20 found: 559.20 [M+H] ⁺ . Benzyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)-yl)-2- azaspiro[3.5]nonane-2-carboxylate To a solution of benzyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2- carboxylate (600 mg, 1.08 mmol) in methanol (15 mL) was added 7 N NH3 (in methanol, 2.5 mL). The reaction was heated for 1 h at 100 °C, cooled down and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH = 10:1) to afford the title compound (280 mg, 53.82%). MS (ESI): mass calcd. for C ₂₅ H ₃₃ N ₅ O ₅ : 483.25 found: 484.20 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7-yl)py rimidine- 2,4,6(1H,3H,5H)-trione To a solution of benzyl 7-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2- carboxylate (280 mg, 0.58 mmol) in methanol (20 mL) was added Pd/C (10%, 50 mg). The reaction was stirred for 16 h under a hydrogen atmosphere (balloon). Then it was filtered through a pad of Celite and concentrated under reduced pressure to afford the title compound 17 (90 mg, 44.48%). MS (ESI): mass calcd. for C ₁₇ H ₂₇ N ₅ O ₃ : 349.21 found: 350.2 [M+H] ⁺ . ¹ H NMR (400 MHz; CD ₃ OD) δ 4.74-4.83 (m, 1 H), 3.90 (s, 2 H), 3.82 (dd, J = 8.5, 6.6 Hz, 2 H), 3.75 (s, 2 H), 2.37-2.49 (m, 2 H), 2.11-2.15 (m, 2 H), 1.49-1.67 (m, 6 H), 1.33 (tt, J = 13.2, 6.6 Hz, 2 H), 0.94 (t, J = 7.3 Hz, 3 H). Examples 23 and 33 were synthesized in similar procedures as described in Example 17. Example 18: 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4- ((methylamino)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-t rione (18) Synthetic scheme:

tert-Butyl ((1s,4s)-4-((methylamino)methyl)cyclohexyl)carbamate To a solution of tert-butyl N-[(1s,4s)-4-formylcyclohexyl]carbamate (950 mg, 4.18 mmol) in THF (25 mL) was added titanium(IV) isopropoxide (2850 mg, 10.03 mmol). After stirring at rt overnight, MeOH (25 mL) was added, and the mixture was cooled to 0 °C. NaBH ₄ (790 mg, 20.90 mmol) was added, and the reaction was stirred at rt for 3 h. The reaction was quenched with NH4Cl (aq.) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (650 mg, 64.17%) as a light-yellow solid. Benzyl (((1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl)(m ethyl)carbamate To a solution of tert-Butyl ((1s,4s)-4-((methylamino)methyl)cyclohexyl)carbamate (630 mg, 2.599 mmol) in toluene (15 mL) was added K ₂ CO ₃ (718.50 mg, 5.2 mmol) and benzyl chloroformate (886 mg, 5.2 mmol). The reaction was heated at 80 °C under N2 for 3 h. After cooling down to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-50% ethyl acetate/petroleum ether) to afford the title compound (560 mg, 57.22%) as a light-yellow oil. MS (ESI): mass calcd. for C ₂₁ H ₃₂ N ₂ O ₄ : 376.24, found: 377.15 [M+H] ⁺ . Benzyl (((1s,4s)-4-aminocyclohexyl)methyl)(methyl)carbamate A solution of benzyl (((1s,4s)-4-((tert- butoxycarbonyl)amino)cyclohexyl)methyl)(methyl)carbamate (550 mg, 1.46 mmol) in 2 N HCl in EA (4 mL) and EA (4 mL) was stirred at rt for 2 h. The resulting mixture was concentrated to afford a crude title compound (400 mg, 99.07%) as a yellow semi-solid. MS (ESI): mass calcd. for C ₁₆ H ₂₄ N ₂ O ₂ : 276.18, found: 277.05 [M+H] ⁺ . The crude product was used in the next step without further purification. Benzyl (((1s,4s)-4-(3-butylureido)cyclohexyl)methyl)(methyl)carbama te To a solution of benzyl (((1s,4s)-4-aminocyclohexyl)methyl)(methyl)carbamate (560 mg, 2.03 mmol) in ClCH ₂ CH ₂ Cl (15 mL) was added TEA (410 mg, 4.05 mmol) and butyl isocyanate (220 mg, 2.23 mmol). After stirring at room temperature for 3 h, the resulting mixture was concentrated and purified by silica gel column chromatography (0-10% MeOH/DCM) to afford the title compound as a light-yellow oil. MS (ESI): mass calcd. for C21H33N3O3: 375.25, found: 376.25 [M+H] ⁺ . Benzyl (((1s,4s)-4-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)- yl)cyclohexyl)methyl)(methyl)carbamate To a solution of benzyl (((1s,4s)-4-(3-butylureido)cyclohexyl)methyl)(methyl)carbama te (470 mg, 1.25 mmol) in Ac ₂ O (3 mL) and AcOH (4.5 mL) was added malonic acid (143 mg, 1.38 mmol). The resulting mixture was stirred at 80 °C for 4 h and concentrated. The crude residue was purified by silica gel column chromatography to afford the title compound (330 mg, 59.44%) as a yellow solid. MS (ESI): mass calcd. for C ₂₄ H ₃₃ N ₃ O ₅ : 443.24, found: 444.25 [M+H] ⁺ . Benzyl (((1s,4s)-4-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxot etrahydropyrimidin- 1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate To a solution of benzyl (((1s,4s)-4-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)- yl)cyclohexyl)methyl)(methyl)carbamate (300 mg, 0.68 mmol) in DMSO (8 mL) was added TEA (273, 2.70 mmol) followed by carbon disulfide (154 mg, 2.03 mmol). After stirring at room temperature for 3 h, 1,3-dibromopropane was added (163 mg, 0.81 mmol). The reaction was stirred at room temperature for 1 h and quenched with water. The resulting mixture was extracted with EA. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to afford the title compound (250 mg, 66.03%) as a yellow viscous oil. MS (ESI): mass calcd. for C ₂₈ H ₃₇ N ₃ O ₅ S ₂ : 559.22, found: 560.20 [M+H] ⁺ . Benzyl (((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrah ydropyrimidin- 1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate A solution of benzyl (((1s,4s)-4-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)methyl)(methyl )carbamate (270 mg, 0.48 mmol) in 2 N NH ₃ in MeOH (5 mL) was stirred at 100 °C for 2 h. After cooling down to room temperature, the reaction was quenched with water (10 mL) and extracted with DCM/MeOH (6:1). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to afford the title compound (200 mg, 85.39%) as a light-yellow solid. MS (ESI): mass calcd. for C25H35N5O5: 485.26, found: 486.25 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4- ((methylamino)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-t rione To a solution of benzyl (((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)methyl)(methyl )carbamate (200 mg, 0.41 mmol) in DCM (3 mL) was added 40% HBr in AcOH (1 mL) at 0 °C. After stirring at room temperature for 2 h, the reaction was neutralized to pH = 7 with NaHCO3 (aq.) and extracted with DCM/MeOH (6:1). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound 18 (100 mg, 69%). MS (ESI): mass calcd. for C17H29N5O3: 351.23, found: 352.25 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 9.55 (s, 2H), 7.33 (s, 2H), 4.70-4.61 (m, 1H), 3.73 (t, J = 7.4 Hz, 2H), 2.26-2.42 (m, 6H), 1.71-1.85 (m, 2H), 1.20-1.50 (m, 8H), 0.97-0.86 (m, 5H). Example 44 was synthesized from Example 18 in similar procedures as described in Example 39. Example 25: 1-Butyl-5-(diaminomethylene)-3-(2-(oxetan-3-yl)-2-azaspiro[3 .5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (25) Synthetic scheme: 1-Butyl-5-(diaminomethylene)-3-(2-(oxetan-3-yl)-2-azaspiro[3 .5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a stirred solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (45 mg, 0.13 mmol) in MeOH (2 mL) were added 3- oxetanone (19 mg, 0.26 mmol) and AcOH (15 mg, 0.26 mmol). After stirring for 0.5 h at rt, sodium cyanoborohydride (16 mg, 0.26 mmol) was added to the reaction. The resulting mixture was stirred for 5 h at room temperature. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse phase HPLC (mobile phase A: water (10 mmol/L NH4HCO3), mobile Phase B: ACN; 26% B to 42% B) to afford the title compound 25 (12.1 mg, 20.58%) as a white solid. MS (ESI): mass calcd. for C ₂₀ H ₃₁ N ₅ O ₄ : 405.24, found: 406.15 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 9.54 (s, 2H), 7.31 (s, 2H), 4.64 (t, J = 12.0 Hz, 1H), 4.56 (t, J = 6.5 Hz, 2H), 4.33-4.40 (m, 2H), 3.69-3.78 (m, 3H), 2.89-3.12 (m, 4H), 2.33 (q, J = 12.5 Hz, 2H), 1.93- 1.96 (m, 2H), 1.39-1.49 (m, 6H), 1.26 (dq, J = 14.9, 7.4 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). Examples 46 and 53 were synthesized in similar procedures as described in Example 25. Example 56 and 57 were synthesized in similar procedures from butyl-5- (diaminomethylene)-3-(2-(methylamino)spiro[3.5]nonan-7-yl)py rimidine-2,4,6(1H,3H,5H)- trione (see Example 51 for procedure) as described in Example 25. Example 60 and 61 were synthesized from 1-butyl-5-(diaminomethylene)-3-(piperidin-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared in similar procedures as in Example 18) in similar procedures as described in Example 25. Example 63 was synthesized in similar procedure as Example 25 from 3-amino-5-butyl-7-(2- azaspiro[3.5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H, 7H)-dione (see Example 66 for the procedure). Example 71 was synthesized from the same staring material as Example 60 and tert-butyl 3- oxopyrrolidine-1-carboxylate in the similar procedure as described in Example 25, followed by TFA deprotection of the Boc group and then the same procedure as described in Example 4. Example 72 was synthesized in similar procedures as in Example 71, except last step followed the same procedure as in Example 12. Example 37: 1-(1-(Azetidin-3-yl)piperidin-4-yl)-3-butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (37) Synthetic scheme: tert-Butyl 3-(4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyr imidin-1(2H)- yl)piperidin-1-yl)azetidine-1-carboxylate A solution of 1-butyl-5-(diaminomethylene)-3-(piperidin-4-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (prepared from benzyl 4-aminopiperidine-1-carboxylate in similar procedures as described in Example 18, 200 mg, 0.65 mmol) in MeOH (5 mL) was added tert-butyl 3-oxoazetidine-1-carboxylate (553 mg, 3.23 mmol) and AcOH (116 mg, 1.94 mmol) at room temperature. After stirring for 1 h, NaBH3CN (121 mg, 1.938 mmol) was added at 0 °C. The resulting mixture was stirred for an additional 1 h at room temperature. The reaction was quenched with water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0- 20% MeOH/DCM) to afford the title compound (200 mg, 66.47%) as a white solid. MS (ESI): mass calcd. for C ₂₂ H ₃₆ N ₆ O ₅ : 464.27, found: 465.30 [M+H] ⁺ . 1-(1-(Azetidin-3-yl)piperidin-4-yl)-3-butyl-5-(diaminomethyl ene)pyrimidine- 2,4,6(1H,3H,5H)-trione A solution of tert-butyl 3-(4-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)azetidine- 1-carboxylate (196 mg, 0.42 mmol) in TFA (2 mL) and DCM (6 mL) was stirred at rt for 1.5 h. The mixture was concentrated under reduced pressure and purified by reverse phase HPLC to afford the title compound 37 (160 mg, 73.01%) as a white solid. MS (ESI): mass calcd. for C17H28N6O3: 364.22, found: 365.25 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 9.54 (s, 2H), 7.34 (s, 2H), 4.67 (t, J = 11.9 Hz, 1H), 3.70-3.80 (m, 2H), 3.34-3.62 (m, 4H), 2.98 (dt, J = 12.1, 6.1 Hz, 1H), 2.78 (d, J = 10.9 Hz, 2H), 2.59-2.50 (m, 2H), 1.78 (t, J = 11.0 Hz, 2H), 1.37-1.55 (m, 4H), 1.25 (dq, J = 14.8, 7.4 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). Example 39: 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)- yl)-2-azaspiro[3.5]nonane-2-sulfonamide (39) Synthetic scheme: H ₂ N NH ₂ H ₂ N NH ₂ H ₂ N NH ₂ O O O O Cl O O O S N N _CbzHN ^O N N Pd/C,H ₂ N N O Et N, THF O NH ₃ , rt N O MeOH\DCM, rt O S ^N NH ₂ p ^{le 17} O _{NH S} E ^xam O Cbz O Benzyl ((7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyri midin-1(2H)-yl)-2- azaspiro[3.5]nonan-2-yl)sulfonyl)carbamate To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7-yl)py rimidine- 2,4,6(1H,3H,5H)-trione (80 mg, 0.23 mmol) in THF (3 mL) was added Et ₃ N (46 mg, 0.46 mmol) and benzyl N-(chlorosulfonyl)carbamate (57 mg, 0.23 mmol). After stirring for 3 h at room temperature, the reaction was quenched with water (10 mL) and extracted with DCM/MeOH (6:1). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-20% DCM/MeOH) to afford the title compound (90 mg, 69.87%) as a light-yellow solid. MS (ESI): mass calcd. for C ₂₅ H ₃₄ N ₆ O ₇ S: 562.22, found: 563.25 [M+H] ⁺ . 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)-yl)-2- azaspiro[3.5]nonane-2-sulfonamide To a solution of benzyl ((7-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonan-2-y l)sulfonyl)carbamate (90 mg, 0.16 mmol) in MeOH (1 mL) and DCM (4 mL) was added Pd/C (30 mL) under N ₂ . Then the reaction was stirred at room temperature for 1 h under a H2 atmosphere. The resulting mixture was filtered and rinsed with MeOH. The filtrate was concentrated under reduced pressure and purified by reverse phase HPLC (mobile phase A: water (10 mmol/L NH4HCO3), mobile phase B: ACN; 27% B to 57% B) to afford the title compound 39 (22.3 mg, 32.50%) as a white solid. MS (ESI): mass calcd. for C17H28N6O5S: 428.18, found: 429.20 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 9.53 (s, 2H), 7.31 (s, 2H), 6.88 (s, 2H), 4.63 (t, J = 11.2 Hz, 1H), 3.73 (t, J = 7.4 Hz, 2H), 3.49 (s, 2H), 3.39 (s, 2H), 2.30 (q, J = 12.8 Hz, 2H), 1.91 ( br d, J = 12.9 Hz, 2H), 1.38-1.51 (m, 6H), 1.25 (dq, J = 14.9, 7.4 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). Example 40:.1-Butyl-5-(diaminomethylene)-3-(2-(S-methylsulfonimidoyl )-2- azaspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (40) Synthetic scheme: 1-Butyl-3-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonimid oyl)-2-azaspiro[3.5]nonan- 7-yl)-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)-3-meth yl-1H- imidazol-3-ium trifluoromethanesulfonate (78 mg, 0.29 mmol) triflate) in CH3CN (3 mL) was added triethylamine (29 mg, 0.29 mmol) and 1-butyl-5-(diaminomethylene)-3-(2- azaspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (50 mg, 0.14 mmol) under a N ₂ atmosphere at 0 °C. After stirring at rt for 3 h, the reaction was quenched with water (10 mL) and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (60 mg, 77.54%). The crude product was used in the next step directly without further purification. MS (ESI): mass calcd. for C24H44N6O4SSi: 540.29, found: 541.20 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-(S-methylsulfonimidoyl)-2- azaspiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonimid oyl)-2- azaspiro[3.5]nonan-7-yl)-5-(diaminomethylene)pyrimidine-2,4, 6(1H,3H,5H)-trione (60 mg, 0.11 mmol) in THF (2 mL) was added Et ₃ N ^. 3HF (0.5 mL) at 0 °C. After stirring at rt for 2 h, the reaction was quenched with water (10 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by reverse phase HPLC (mobile phase A: water (0.1% FA), mobile phase B: ACN; 16% B to 40% B) to afford the title compound 40 (22.5 mg, 46.57%) as a white solid. MS (ESI): mass calcd. for C18H30N6O4S: 426.20, found: 427.20 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 9.53 (s, 2H), 7.32 (s, 2H), 4.65 (t, J = 11.8 Hz, 1H), 3.73 (t, J = 7.4 Hz, 2H), 3.58-3.62 (m, 2H), 3.49 (q, J = 7.0 Hz, 2H), 3.00 (s, 3H), 2.32 (q, J = 12.0 Hz, 2H), 1.92 (br d, J = 13.0 Hz, 2H), 1.35-1.54 (m, 6H), 1.25 (dq, J = 14.9, 7.4 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). Examples 41 and 42: 1-Butyl-5-(diaminomethylene)-3-(((1s,4s)-4-(5-methyl-4H-1,2, 4-tri azol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trion e (41) & 1-Butyl-5-(diami nomethylene)-3-(((1r,4r)-4-(5-methyl-4H-1,2,4-triazol-3-yl)c yclohexyl)methyl)pyrimidin e-2,4,6(1H,3H,5H)-trione (42) Synthetic scheme:

Methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate A solution of 4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (3.0 g, 16.11 mmol) in tetrahydrofuran (50 mL) was cooled to -78 °C. Borane-methyl sulfide complex (2.09 mL, 20.94 mmol) was added and the reaction was warmed to room temperature. After stirred for 1 h at room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (2.4 g, 86.5%) as a yellow oil. MS (ESI): mass calcd. for C ₉ H ₁₆ O ₃ : 172.11, found: 173.20 [M+H] ⁺ . Methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbox ylate To a solution of methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate (2.4 g, 13.94 mmol) in DCM (50 mL) was added TBSCl (2.52 g, 16.72 mmol) and imidazole (1.90 g, 27.87 mmol). After stirring for 2 h at room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-20% EA/PE) to afford the title compound (3.0 g, 75.14%) as a yellow oil. MS (ESI): mass calcd. for C ₁₅ H ₃₀ O ₃ Si: 286.20, found: 287.20 [M+H] ⁺ . 4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboh ydrazide To a solution of methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1- carboxylate (2.0 g, 6.98 mmol) in ethyl alcohol (20 mL) was added hydrazine (1.12 g, 34.91 mmol). The mixture was heated at 100 °C for 4 h. After cooling down to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-50% EA in PE) to afford the title compound (1.6 g, 80.0%) as a yellow oil. MS (ESI): mass calcd. for C ₁₄ H ₃₀ N ₂ O ₂ Si: 286.21, found: 287.20 [M+H] ⁺ . 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-met hyl-4H-1,2,4-triazole To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboh ydrazide (1.8 g, 6.28 mmol) in n-butanol (20 mL) was added acetimidamide hydrochloride (0.59 g, 6.28 mmol) and K2CO3 (0.52 g, 3.77 mmol). The mixture was heated for 16 h at 120 °C. After cooling down to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-50% EA in PE) to afford the title compound (1.5 g, 77.13%) as a yellow solid. MS (ESI): mass calcd. For C ₁₆ H ₃₁ N ₃ Osi: 309.22, found: 310.20 [M+H] ⁺ . 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-met hyl-4-((2- (trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole A solution of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-met hyl-4H- 1,2,4-triazole (1.5 g, 4.85 mmol) in THF (20 mL) was cooled to 0 °C. Sodium hydride (0.39 g, 9.69 mmol, 60%) was added. After stirring at 0 °C for 0.5 h, [2- (chloromethoxy)ethyl]trimethylsilane (1.21 g, 7.27 mmol) was added. After stirring for another 2 h at room temperature, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-50% EA in PE) to afford the title compound (1.3 g, 61.0%) as a yellow solid. MS (ESI): mass calcd. for C ₂₂ H ₄₅ N ₃ O ₂ Si ₂ : 439.31, found: 440.30 [M+H] ⁺ . (4-(5-Methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-t riazol-3- yl)cyclohexyl)methanol To a solution of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-met hyl-4-((2- (trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole (1.1 g, 2.50 mmol) in THF (20 mL) was added TBAF (0.72 g, 2.75 mmol). After heating for 2 h at 50 °C, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-50% EA in PE) to afford the title compound (615 mg, 75.53%) as a yellow solid. MS (ESI): mass calcd. For C16H31N3O2Si: 325.22, found: 326.20 [M+H] ⁺ . 1-Butyl-5-(1,3-dithian-2-ylidene)-3-((4-(5-methyl-4-((2-(tri methylsilyl)ethoxy)methyl)- 4H-1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H, 3H,5H)-trione To a solution of (4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-t riazol-3- yl)cyclohexyl)methanol (400 mg, 1.23 mmol) in DCM (10 mL) was added 1-butyl-5-(1,3- dithian-2-ylidene)-1,3-diazinane-2,4,6-trione (369 mg, 1.23 mmol) and PPh3 (322 mg, 1.23 mmol). The reaction was cooled to 0 °C and diethyl azodicarboxylate (214 mg, 1.23 mmol) was added under N2. After warming to rt and stirring for 3 h, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel chromatography (0-50% EA/PE) to afford the title compound (486 mg, 65.06%) as a yellow solid. MS (ESI): mass calcd. for C ₂₈ H ₄₅ N ₅ O ₄ S ₂ Si: 607.27, found: 608.25 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((4-(5-methyl-4-((2-(trimethy lsilyl)ethoxy)methyl)-4H- 1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H, 5H)-trione To a solution of 1-butyl-5-(1,3-dithian-2-ylidene)-3-((4-(5-methyl-4-((2- (trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohe xyl)methyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (486 mg, 0.82 mmol) in methanol (10 mL) was added 7 N NH3 in MeOH (2 mL). The reaction was heated for 1 h at 100 °C. After cooling down to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0- 10% MeOH in DCM) to afford the title compound (203 mg, 46.48%) as a yellow solid. MS (ESI): mass calcd. for C25H43N7O4Si: 533.31, found: 534.40 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(((1s,4s)-4-(5-methyl-4H-1,2, 4-triazol-3- yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (41) & 1-Butyl-5- (diaminomethylene)-3-(((1r,4r)-4-(5-methyl-4H-1,2,4-triazol- 3- yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (42) To a solution of 1-butyl-5-(diaminomethylene)-3-((4-(5-methyl-4-((2- (trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohe xyl)methyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (30 mg, 0.056 mmol) in DCM (3 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for 4 h, the reaction was concentrated to dryness under reduced pressure to provide a crude product, which was purified by reverse phase HPLC (26- 45% (v/v) ACN and H ₂ O with 0.05% NH ₄ HCO ₃ ) to afford the title compound 41 (3.8 mg, 16.73%) as a white solid. MS (ESI): mass calcd. for C19H29N7O3: 403.23 found: 404.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.53 (s, 2H), 7.33 (s, 2H), 3.65-3.81 (m, 4H), 2.71-2.88 (m, 1H), 2.18–2.34 (m, 3H), 1.91-2.07 (m, 3 H), 1.81-1.90 (m, 1H), 1.54-1.68 (m, 2H), 1.21-1.54 (m, 7H), 0.88 (t, J = 7.2 Hz, 3H) and the title compound 42 (2.0 mg, 8.80%) as a white solid. MS (ESI): mass calcd. for C19H29N7O3: 403.23 found: 404.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 13.13 (s, 1H), 9.54 (s, 2H), 7.35 (s, 2H), 3.77 (t, J = 7.3 Hz, 2H), 3.68 (d, J = 6.7 Hz, 2H), 2.51-2.63 (m, 1H), 2.15-2.30 (m, 3H), 1.93 (d, J = 13.0 Hz, 2H), 1.65 (d, J = 12.9 Hz, 3H), 1.38-1.56 (m, 2H), 1.17-1.38 (m, 4H), 0.99- 1.17 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 38 was synthesized from (3-methyl-4-(5-methyl-4-((2- (trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)phenyl) methanol in similar procedures as described in Example 41. Example 43 was synthesized from (2-oxaspiro[3.5]nonan-7-yl)methanol in similar procedures as described in Example 41, steps 7 and 8. Example 51 and 52: 1-((2S,4s,7S)-7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxote trahyd ropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (51) & 1-((2R,4r,7R)-7-(3-buty l-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H) -yl)spiro[3.5]nonan-2-yl) -1-methylurea (52) Synthetic scheme:

N-benzyl-N-methyl-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-amine To a stirred solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one (1.4 g, 7.13 mmol) in methanol (15 mL) was added N-methylbenzylamine (1.73 g, 14.27 mmol) at rt. After stirring for 2 h, NaBH ₃ CN (0.9 g, 14.27 mmol) was added. After stirring for another 16 h at rt, the reaction was quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was further purified by silica gel column chromatography (PE/EA = 3:1) to afford the title compound (1.4 g, 65.11%) as a colorless oil. MS (ESI): mass calcd. for C19H27NO2: 301.20, found: 302.20 [M+H] ⁺ . 2-(Benzyl(methyl)amino)spiro[3.5]nonan-7-one To a solution of N-benzyl-N-methyl-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-amine (1.68 g, 5.57 mmol) in tetrahydrofuran (10 mL) was added 4 N HCl (5 mL). After heated at 60 °C for 5 h, the reaction was neutralized to pH = 7 with saturated NaHCO3 solution. The aqueous layer was extracted with EA (3 x 50 mL). The combined organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA = 3:1) to afford the title compound (1.0 g, 69.71%) as a white solid. MS (ESI): mass calcd. for C17H23NO: 257.18, found: 258.20 [M+H] ⁺ . 2-(Benzyl(methyl)amino)spiro[3.5]nonan-7-ol A solution of 2-(benzyl(methyl)amino)spiro[3.5]nonan-7-one (800 mg, 3.11 mmol) in methanol (10 mL) was added NaBH ₄ (176 mg, 4.66 mmol) in portions at 0 °C. After stirring at rt for 2 h, the reaction was quenched with water (10 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH = 15:1) to afford the title compound (600 mg, 74.42%) as a colorless oil. MS (ESI): mass calcd. for C17H25NO: 259.19, found: 260.30 [M+H] ⁺ . 2-(Methylamino)spiro[3.5]nonan-7-ol To a solution of 2-(benzyl(methyl)amino)spiro[3.5]nonan-7-ol (300 mg, 1.16 mmol) in methanol (10 mL) was added Pd/C (50 mg). The reaction was stirred for 2 h under a hydrogen atmosphere (balloon). The reaction mixture was then filtered through a pad of Celite and concentrated under reduced pressure to afford the title compound (0.2 g, 99%) as a white solid. MS (ESI): mass calcd. for C10H19NO: 169.15 m/z, found: 170.20 [M+H] ⁺ . Benzyl (7-hydroxyspiro[3.5]nonan-2-yl)(methyl)carbamate A solution of 2-(methylamino)spiro[3.5]nonan-7-ol (200 mg, 1.18 mmol) in DCM (10 mL) was treated with TEA (357 mg, 3.54 mmol) for 10 min at rt, followed by addition of CbzCl (221 mg, 1.30 mmol) dropwise at 0 °C. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was further purified by silica gel column chromatography (PE/EA = 2:1) to afford the title compound (0.3 g, 83.8%) as a white solid. MS (ESI): mass calcd. For C ₁₈ H ₂₅ NO ₃ : 303.18 m/z, found: 304.20 [M+H]+. Benzyl (7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydro pyrimidin-1(2I)- yl)spiro[3.5]nonan-2-yl)(methyl)carbamate To a solution of benzyl (7-hydroxyspiro[3.5]nonan-2-yl)(methyl)carbamate (0.29 g, 0.96 mmol) in toluene (6 mL) was added 1-butyl-5-(1,3-dithian-2-ylidene)pyrimidine- 2,4,6(1H,3H,5H)-trione (see Example 80, 288 mg, 0.96 mmol) and TMAD (330 mg, 1.92 mmol). Then tributyl phosphine (388 mg, 1.92 mmol) was added to the mixture at 0 °C under a nitrogen atmosphere. The resulting mixture was heated for 16 h at 100 °C under nitrogen. After cooling down to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (PE/EA = 2:1) to afford the title compound (120 mg, 21.35%) as a yellow solid. MS (ESI): mass calcd. for C30H39N3O5S2: 585.23, found: 586.20 [M+H] ⁺ . Benzyl (7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrim idin-1(2H)- yl)spiro[3.5]nonan-2-yl)(methyl)carbamate A solution of benzyl (7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(met hyl)carbamate (120 mg, 0.20 mmol) in methanol (5 mL) was added 7 N NH3 in methanol (0.7 mL). The resulting mixture was heated at 100 °C for 1 h and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE/EA = 1:1) to afford the title compound (90 mg, 88.23%) as a white solid. MS (ESI): mass calcd. for C ₂₇ H ₃₇ N ₅ O ₅ : 511.28, found: 512.30 [M+H] ^+: . Butyl-5-(diaminomethylene)-3-(2-(methylamino)spiro[3.5]nonan -7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of benzyl (7-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(met hyl)carbamate (90 mg, 0.17 mmol) in methanol was added Pd/C (30 mg). The reaction mixture was stirred for 0.5 h under a hydrogen atmosphere (balloon). The reaction mixture was then filtered through a pad of Celite and concentrated under reduced pressure to afford the title compound (60 mg, 90.9%) as a white solid. MS (ESI): mass calcd. for C ₁₉ H ₃₁ N ₅ O ₃ : 377.24, found: 378.05 [M+H] ⁺ . 1-((2S,4s,7S)-7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxote trahydropyrimidin-1(2H)- yl)spiro[3.5]nonan-2-yl)-1-methylurea (51) & 1-((2R,4r,7R)-7-(3-Butyl-5- (diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl) spiro[3.5]nonan-2-yl)-1- methylurea (52) To a solution of butyl-5-(diaminomethylene)-3-(2-(methylamino)spiro[3.5]nonan -7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (135 mg, 0.36 mmol) in DCM (5 mL) at room temperature was added TEA (182 mg, 1.80 mmol), followed by isocyanatotrimethylsilane (124 mg, 1.08 mmol). After stirring for 2 h at room temperature, the reaction was quenched by water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a crude product, which was directly purified by silica gel column chromatography (DCM/MeOH = 8:1). The resulting purified product was purified by chiral HPLC to afford the title compound 51 (25 mg) as a white solid (MS (ESI): mass calcd. for C20H32N6O4: 420.25, found: 421.20 [M+H] ⁺ ); ¹ H NMR (300 MHz; CD3OD) δ 4.73 (tt, J = 12.2, 3.5 Hz, 1H), 4.55 (quintet, J = 8.7 Hz, 1H), 3.84 (t, J = 7.5 Hz, 2H), 2.86 (s, 3H), 2.50 (dqd, J = 24.4, 12.3, 3.4 Hz, 2H), 2.30 (ddd, J = 11.3, 8.3, 2.9 Hz, 1H), 1.83-1.97 (m, 4H), 1.69 (dq, J = 13.0, 2.7 Hz, 1H), 1.28-1.59 (m, 8H), 0.95 (t, J = 7.3 Hz, 3H) and title compound 52 (25 mg) as a white solid (MS (ESI): mass calcd. for C20H32N6O4: 420.25, found: 421.20 [M+H] ⁺ ; ¹ H NMR (300 MHz; CD ₃ OD) δ 4.73 (tt, J = 12.2, 3.5 Hz, 1H), 4.55 (quintet, J = 8.7 Hz, 1H), 3.84 (t, J = 7.5 Hz, 2H), 2.86 (s, 3H), 2.50 (dqd, J = 24.4, 12.3, 3.4 Hz, 2H), 2.30 (ddd, J = 11.3, 8.3, 2.9 Hz, 1H), 1.83-1.97 (m, 4H), 1.69 (dq, J = 13.0, 2.7 Hz, 1H), 1.28-1.59 (m, 8H), 0.95 (t, J = 7.3 Hz, 3H). The stereochemistry is arbitrarily assigned. Example 21 was the product before the chiral separation in the above synthesis. Example 29 was synthesized from tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2- carboxylate in similar procedures as described in Example 51, steps 6-9. TFA was used to deprotect the Boc group instead of Pd in step 8. Examples 45 and 54 were synthesized from respective isomers of tert-butyl 6- (hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate in similar procedures as described in Example 29. Example 97 was synthesized in similar procedures as Example 45, with the last two steps being a Buchwald coupling with 3-chloro-5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H- 1,2,4-triazole and deprotection of the SEM group. Examples 65, 68, and 73 were synthesized in similar procedures as Example 21. Examples 92 and 93 (were synthesized in similar procedures as described in Example 51 and 52. Example 55: 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)- yl)-2-methylspiro[3.5]nonane-2-carboxamide (55) Synthetic scheme: Methyl 7-oxospiro[3.5]nonane-2-carboxylate To a solution of 7-oxospiro[3.5]nonane-2-carboxylic acid (3 g, 16.46 mmol) in acetone (30 mL) was added potassium carbonate (6.88 g, 49.39 mmol), MeI (11.68 g, 82.32 mmol) at rt. After stirring overnight, the reaction was quenched with water and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (0-100% EA/PE) to afford the title compound (2.2 g, 68.09%) as a yellow solid. MS (ESI): mass calcd. for C ₁₁ H ₁₆ O ₃ : 196.14, found: 197.15 [M+H] ⁺ . Methyl 7-hydroxyspiro[3.5]nonane-2-carboxylate To a solution of methyl 7-oxospiro[3.5]nonane-2-carboxylate (2.1 g, 10.70 mmol) in MeOH (20 mL) was added NaBH ₄ (2.02 g, 53.51 mmol) at 0 °C. After stirring for 2 h at the same temperature, the reaction was quenched by water and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (0-100% EA/PE) to afford the title compound (1.5 g, 70.7%) as a yellow solid. MS (ESI): mass calcd. for C11H18O3: 198.13, found: 181.10 [M-OH] ⁺ . Methyl 7-[(tert-butyldiphenylsilyl)oxy]spiro[3.5]nonane-2-carboxyla te To a solution of methyl 7-hydroxyspiro[3.5]nonane-2-carboxylate (500 mg, 2.52 mmol) in dimethylformamide (10 mL) was added imidazole (515.07 mg, 7.57 mmol), and TBDPSCl (1.04 g, 3.78 mmol) at 0 °C. The mixture was allowed to warm to rt and stirred for 2 h. The reaction was quenched with water and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (0-100% EA/PE) to afford the title compound (1 g, 90.81%) as a yellow solid. MS (ESI): mass calcd. for C27H36O3Si: 436.24, found: 437.30 [M+H] ⁺ . Methyl 7-[(tert-butyldiphenylsilyl)oxy]-2-methylspiro[3.5]nonane-2- carboxylate To a solution of methyl 7-[(tert-butyldiphenylsilyl)oxy]spiro[3.5]nonane-2- carboxylate (50 mg, 0.12 mmol) in THF (2 mL) was added dropwise LDA (0.07 mL, 0.14 mmol) at -78 °C under a N ₂ atmosphere. The reaction mixture was stirred at the same temperature for 30 min. Then a solution of MeI (48.76 mg, 0.35 mmol) in 1 mL THF was added dropwise and the reaction was stirred for another 60 min. The reaction was quenched with water/sat. NH4Cl (5 mL) and extracted with ether/EtOAc (2 x 15 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated to yield a crude product, which was purified by silica gel chromatography (PE:EA = 10:1) mixture to afford the title compound (400 mg, 77.51%) as a yellow solid. MS (ESI): mass calcd. for C ₂₈ H ₃₈ O ₃ Si: 450.26, found: 451.30 [M+H] ⁺ . Methyl 7-hydroxy-2-methylspiro[3.5]nonane-2-carboxylate To a solution of methyl 7-[(tert-butyldiphenylsilyl)oxy]-2-methylspiro[3.5]nonane-2- carboxylate (380 mg, 0.84 mmol) in tetrahydrofuran (3 mL) was added triethylamine trihydrofluoride (3 mL) at 0 °C. The reaction was allowed to warm to rt and heated for 2 h at 70 °C. The reaction was quenched by water and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (0-100% EA/PE) to afford the title compound (100 mg, 55.87%) as a yellow solid. Methyl 7-[3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxo-1,3-diazin an-1-yl]-2- methylspiro[3.5]nonane-2-carboxylate To a solution of methyl 7-hydroxy-2-methylspiro[3.5]nonane-2-carboxylate (80 mg, 0.38 mmol) in toluene (3 mL) was added 1-butyl-5-(1,3-dithian-2-ylidene)-1,3-diazinane- 2,4,6-trione (113.20 mg, 0.38 mmol), TMAD (194.66 mg, 1.131 mmol), n-Bu3P (228.73 mg, 1.13 mmol) at rt. The resulting mixture was heated for 2.5 h at 100 °C. The reaction was quenched with water and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (0-100% EA/PE) to afford the title compound (30 mg, 16.09%) as a yellow solid. MS (ESI): mass calcd. for C24H34N2O5S2: 494.19, found: 495.15 [M+H] ⁺ . Methyl 7-[3-butyl-5-(diaminomethylidene)-2,4,6-trioxo-1,3-diazinan- 1-yl]-2- methylspiro[3.5]nonane-2-carboxylate To a solution of methyl 7-[3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxo-1,3- diazinan-1-yl]-2-methylspiro[3.5]nonane-2-carboxylate (50 mg, 0.10 mmol) was added 7 N ammonia in methanol (6 mL) at rt. After heating at 100 °C for 1 h, the reaction was quenched by water and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (0-100% EA/PE) to afford the title compound (30 mg, 70.58%) as a yellow solid. MS (ESI): mass calcd. for C21H32N4O5: 420.14, found: 421.30 [M+H] ⁺ . 7-[3-Butyl-5-(diaminomethylidene)-2,4,6-trioxo-1,3-diazinan- 1-yl]-2- methylspiro[3.5]nonane-2-carboxylic acid To a solution of methyl 7-[3-butyl-5-(diaminomethylidene)-2,4,6-trioxo-1,3-diazinan- 1-yl]-2-methylspiro[3.5]nonane-2-carboxylate (30 mg, 0.071 mmol) in water (1 mL), THF (3 mL), and MeOH (1 mL) was added LiOH (17.09 mg, 0.71 mmol) at rt. After heating at 65 °C for 3 h, the reaction was quenched with water and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (0-100% EA/PE) to afford the title compound (20 mg, 68.97%) as a white solid. MS (ESI): mass calcd. for C ₂₀ H ₃₀ N ₄ O ₅ : 406.22, found: 407.10 [M+H] ⁺ . 7-[3-Butyl-5-(diaminomethylidene)-2,4,6-trioxo-1,3-diazinan- 1-yl]-2- methylspiro[3.5]nonane-2-carboxamide To a solution of 7-[3-butyl-5-(diaminomethylidene)-2,4,6-trioxo-1,3-diazinan- 1-yl]-2- methylspiro[3.5]nonane-2-carboxylic acid (15 mg, 0.037 mmol) in DMF (2 mL) was added NH4Cl (5.92 mg, 0.11 mmol), HATU (21.05 mg, 0.055 mmol), DIPEA (9.54 mg, 0.074 mmol) at rt. After stirring for rt at 3 h, the reaction was quenched with water and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (0-100% EA/PE) to afford an impure product. The impure product was further purified by reverse phase HPLC (mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; 17% B to 42% B) to afford the title compound 55 (3.1 mg, 20.69%) as a white solid. MS (ESI): mass calcd. for C ₂₀ H ₃₁ N ₅ O ₄ : 405.24, found: 406.05 [M+H] ⁺ . ¹ H NMR (300 MHz; DMSO-d6) δ 9.54 (s, 2H), 7.31 (s, 2H), 7.08 (s, 1H), 6.71 (s, 1H), 4.57 (t, J = 11.5 Hz, 1H), 3.73 (t, J = 7.3 Hz, 2H), 2.13-2.40 (m, 4H) 1.35-1.79 (m, 6H), 1.15-1.34 (m, 9H), 0.87 (t, J = 7.2 Hz, 3H). Example 64 was synthesized in similar procedures as described in Example 55. Example 58: 1-(1-(1H-Pyrazole-4-carbonyl)piperidin-4-yl)-3-butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (58) Synthetic scheme: 1-Butyl-5-(diaminomethylene)-3-(1-(1-((2-(trimethylsilyl)eth oxy)methyl)-1H-pyrazole-4- carbonyl)piperidin-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(piperidin-4-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (prepared from benzyl 4-aminopiperidine-1-carboxylate in similar procedures as described in Example 18, 58 mg, 0.19 mmol) in DMF (2 mL) was added DIPEA (49 mg, 0.38 mmol) and HATU (107 mg, 0.28 mmol). After stirring at room temperature overnight, the reaction was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to afford the title compound (70 mg, 69.93%) as a yellow oil. MS (ESI): mass calcd. for C24H39N7O5Si: 533.28, found: 534.25[M+H] ⁺ . 1-(1-(1H-Pyrazole-4-carbonyl)piperidin-4-yl)-3-butyl-5-(diam inomethylene)pyrimidine- 2,4,6(1H,3H,5H)-trione A solution of 1-butyl-5-(diaminomethylene)-3-(1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonyl)piperi din-4-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (60 mg, 0.11 mmol) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at rt for 2 h. The mixture was neutralized to pH = 7 with NaHCO3 solution. The resulting mixture was extracted with DCM/MeOH. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. To this crude residue was added NH3 ^. H2O (3 mL). After stirring at rt for 1 h, the resulting mixture was extracted with DCM/MeOH. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by reverse phase HPLC (17% to 42% (v/v) ACN and water with 0.05% NH4HCO3) to afford the title compound 58 (5.1 mg, 11.24%) as a white solid. MS (ESI): mass calcd. for C18H25N7O4: 403.20, found: 404.30 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 13.18 (s, 1H), 9.52 (s, 2H), 8.07 (s, 1H), 7.70 (s, 1H), 7.33 (s, 2H), 4.97 (t, J = 11.5 Hz, 1H), 4.04-4.59 (br m, 2H), 3.74 (t, J = 7.3 Hz, 2H), 2.37-2.47 (m, 2H), 1.53-1.60 (m, 2H), 1.46 (dt, J = 14.7, 7.4 Hz, 2H), 1.30-1.21 (m, 4H), 0.88 (t, J = 7.3 Hz, 3H). Example 62: 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4 -dioxoimidazo lidin-1-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trio ne (62) Synthetic scheme: tert-Butyl ((1s,4s)-4-(bromomethyl)cyclohexyl)carbamate To a solution of tert-butyl ((1s,4s)-4-(hydroxymethyl)cyclohexyl)carbamate (1.5 g, 6.54 mmol) in DCM (50 mL) was added carbon tetrabromide (2.39 g, 7.20 mmol) at 0 °C, followed by triphenylphosphine (2.06 g, 7.85 mmol) slowly. The mixture was warmed to room temperature and stirred for 4 h. The reaction was quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-20% PE/EA) to afford the title compound (1.2 g, 62.78%) as a white solid. MS (ESI): mass calcd. for C ₁₂ H ₂₂ BrNO ₂ : 291.08, found: 236.15 [M- ^t Bu+H] ⁺ . tert-Butyl ((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)carbamate To a solution of tert-butyl ((1s,4s)-4-(bromomethyl)cyclohexyl)carbamate (1.2 g, 4.11 mmol) in N,N-dimethylformamide (20 mL) was added Cs ₂ CO ₃ (2.01 g, 6.16 mmol) and 5,5- dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2 ,4-dione (1.06 g, 4.11 mmol). The reaction was heated for 4 h at 50 °C. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-50% EA/PE) to afford the title compound (812 mg, 42.10%) as a yellow oil. MS (ESI): mass calcd. for C23H43N3O5Si: 469.30, found: 492.30 [M+Na] ⁺ . 1-(((1s,4s)-4-Aminocyclohexyl)methyl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione A solution of tert-butyl ((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)carbamate (812 mg, 1.73 mmol) in formic acid (10 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated and then basified to pH = 9. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (501 mg, 78.41%) as a yellow oil. MS(ESI): mass calcd. for C18H35N3O3Si: 369.24, found: 370.20 [M+H] ⁺ . 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)urea To a solution of 1-(((1s,4s)-4-aminocyclohexyl)methyl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (501 mg, 1.36 mmol) in 1,2- dichloroethane (10 mL) was added TEA (411.53 mg, 4.07 mmol) and 1-isocyanatobutane (268 mg, 2.71 mmol). After stirring 2 h at room temperature, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-100% EA/PE) to afford the title compound (482 mg, 75.86%) as a yellow solid. MS (ESI): mass calcd. for C23H44N4O4Si: 468.31, found: 469.35 [M+H] ⁺ . 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)urea (486 mg, 1.04 mmol) in DCM (10 mL) was added malonyl dichloride (438 mg, 3.11 mmol). After stirring for 5 h at room temperature, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-100% EA/PE) to afford the title compound (381 mg, 68.46%) as a yellow solid. 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-5-(1,3-dithian-2- ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (380 mg, 0.71 mmol) in DMSO (10 mL) was added carbon disulfide (538 mg, 7.08 mmol) and TEA (1074 mg, 10.62 mmol). After stirring for 3 h at room temperature, the reaction was cooled to 0 °C then added 1,3-dibromopropane (1429 mg, 7.08 mmol). After stirring for another 2 h, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-70% EA/PE) to afford the title compound (201 mg, 43.48%) as a yellow solid. MS (ESI): mass calcd. for C ₃₀ H ₄₈ N ₄ O ₆ S ₂ Si: 652.28, found: 653.30 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4 -dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-5-(1,3-dithian-2- ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (201 mg, 0.31 mmol) in methanol (5 mL) was added ammonia (7 N solution in methanol, 2 mL). After stirring for 1 h at 100 °C, the reaction was cooled down to room temperature and concentrated. The residue obtained was purified by silica gel column chromatography (0-100% EA/PE) to afford the title compound (115 mg, 64.54%) as a yellow solid. MS (ESI): mass calcd. for C27H46N6O6Si: 578.32, found: 579.35 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4 -dioxoimidazolidin-1- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4 -dioxo- 3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl )cyclohexyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (120 mg, 0.21 mmol) in DCM (4 mL) was added TFA (1 mL). After stirring at room temperature for 4 h, the reaction was concentrated to dryness under reduced pressure then dissolved in ammonia (2 N solution in methanol, 2 mL). After stirring at room temperature for 2 h, the reaction was concentrated to dryness to provide a crude product, which was purified by reverse phase HPLC (mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; 26% B to 45% B) to afford the title compound 62 (17.4 mg, 18.68%) as a white solid. MS (ESI): mass calcd. for C21H32N6O5: 448.24 found: 449.20 [M+H] ⁺ . ¹ H NMR (300 MHz; DMSO-d6) δ 10.78 (s, 1H), 9.56 (s, 2H), 7.32 (s, 2H), 4.67 (t, J = 11.7 Hz, 1H), 3.75 (t, J = 7.2 Hz, 2H), 3.29-3.35 (m, 2H), 2.50-2.63 (m, 2H), 2.01 (t, J = 6.1 Hz, 1H), 1.71 (d, J = 12.9 Hz, 2H), 1.45 (q, J = 6.9 Hz, 4H), 1.23-1.30 (m, 10H), 0.88 (t, J = 7.3 Hz, 3H). Examples 31, 32 and 67 were synthesized in similar procedures as described in Example 62. Example 35 was synthesized from tert-butyl (4-(3,5,5-trimethyl-2,4-dioxoimidazolidin-1- yl)phenethyl)carbamate (prepared through CuI-mediated coupling of 3,5,5- trimethylimidazolidine-2,4-dione and tert-butyl (4-bromophenethyl)carbamate) in similar procedures as described in Example 62. Example 66: 7-(3-Amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]py rimidin-5(4H )-yl)-2-azaspiro[3.5]nonane-2-carboxamide (66) Synthetic scheme: tert-Butyl 7-(N-(butylcarbamoyl)-2-cyanoacetamido)-2-azaspiro[3.5]nonan e-2- carboxylate (minor) and tert-Butyl 7-(3-butyl-3-(2-cyanoacetyl)ureido)-2- azaspiro[3.5]nonane-2-carboxylate (major) To a stirred solution of tert-butyl 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate (see Example 17 for procedure, 790 mg, 2.78 mmol) in acetic anhydride (10 mL) was added cyanoacetic acid (284 mg, 3.34 mmol). After heating at 60 °C for 3 h, the reaction was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (40% to 50% EA in PE) to afford the title compound tert-butyl 7-(N- (butylcarbamoyl)-2-cyanoacetamido)-2-azaspiro[3.5]nonane-2-c arboxylate (200 mg, 17.69%, minor isomer). MS (ESI): mass calcd. for C21H34N4O4: 406.26 m/z, found: 407.30 [M+H] ⁺ ; and the title compound tert-butyl 7-(3-butyl-3-(2-cyanoacetyl)ureido)-2-azaspiro[3.5]nonane- 2-carboxylate (700 mg, 61.92%, major isomer). MS (ESI): mass calcd. for C ₂₁ H ₃₄ N ₄ O ₄ : 406.26, found: 407.30 [M+H] ⁺ . tert-Butyl 7-(4-amino-3-butyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)- 2- azaspiro[3.5]nonane-2-carboxylate To a stirred solution of tert-butyl 7-(N-(butylcarbamoyl)-2-cyanoacetamido)-2- azaspiro[3.5]nonane-2-carboxylate (minor isomer from above, 180 mg, 0.44 mmol) in ethyl alcohol (5 mL) was added sodium ethoxide (9 mg, 0.13 mmol) in EtOH dropwise. After heating at 70 °C for 1 h, the reaction was quenched with water (5 mL) and extracted with DCM (20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (0-10% MeOH in DCM) to afford the title compound (0.1 g, 55.86%). MS (ESI): mass calcd. for C ₂₁ H ₃₄ N ₄ O ₄ : 406.26, found: 407.20 [M+H] ⁺ . tert-Butyl 7-{7-butyl-3-cyano-4,6-dioxo-[1,2]thiazolo[3,4-d]pyrimidin-5 -yl}-2- azaspiro[3.5]nonane-2-carboxylate To a stirred solution of 4,5-dichloro-5H-1,2,3-dithiazol-3-ium chloride (85 mg, 0.49 mmol) in DCM (5 mL) was added tert-butyl 7-(4-amino-3-butyl-2,6-dioxopyrimidin-1-yl)-2- azaspiro[3.5]nonane-2-carboxylate (100 mg, 0.24 mmol) followed by pyridine (89 mg, 1.13 mmol) at room temperature. After stirring overnight, the reaction was quenched with water (5 mL) and extracted with DCM (15 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography (30-35% EA in PE) to afford the title compound (55 mg, 47.21%) as a yellow oil. MS (ESI): mass calcd. for C23H31N5O4S: 473.21, found: 496.25 [M+Na] ⁺ . tert-Butyl 7-(7-butyl-3-{[(4-methoxyphenyl)methyl]amino}-4,6-dioxo-[1,2 ]thiazolo[3,4- d]pyrimidin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate A solution of tert-butyl 7-{7-butyl-3-cyano-4,6-dioxo-[1,2]thiazolo[3,4-d]pyrimidin-5 -yl}- 2-azaspiro[3.5]nonane-2-carboxylate (55 mg, 0.12 mmol) and (4- methoxyphenyl)methanamine (159 mg, 1.16 mmol) in dimethylformamide (3 mL) was heated for 1 h at 90 °C. The crude residue was purified by silica gel column chromatography, eluted with PE/EA (30%) to afford the title compound (40 mg, 59.70%) as a white solid. MS (ESI): mass calcd. for C ₃₀ H ₄₁ N ₅ O ₅ S: 583.28 m/z, found: 584.35 [M+H] ⁺ . 3-Amino-5-{2-azaspiro[3.5]nonan-7-yl}-7-butyl-[1,2]thiazolo[ 3,4-d]pyrimidine-4,6-dione A solution of tert-butyl 7-(7-butyl-3-{[(4-methoxyphenyl)methyl]amino}-4,6-dioxo- [1,2]thiazolo[3,4-d]pyrimidin-5-yl)-2-azaspiro[3.5]nonane-2- carboxylate (40 mg, 0.069 mmol) in trifluoroacetic acid (2.7 mL) and water (0.3 mL) was stirred overnight at room temperature. The reaction was concentrated, and the crude residue was purified by reversed phase HPLC to afford the title compound (25 mg, 99%) as a colorless oil. MS (ESI): mass calcd. for C ₁₇ H ₂₅ N ₅ O ₂ S: 363.17 m/z, found: 364.20 [M+H] ⁺ . 7-(3-Amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]py rimidin-5(4H)-yl)-2- azaspiro[3.5]nonane-2-carboxamide To a solution of 3-amino-5-{2-azaspiro[3.5]nonan-7-yl}-7-butyl-[1,2]thiazolo[ 3,4- d]pyrimidine-4,6-dione (15 mg, 0.041 mmol) in DCM (2 mL) and triethylamine (13.78 mg, 0.13 mmol) was added isocyanatotrimethylsilane (10.46 mg, 0.090 mmol). After stirring at rt for 1 h, the reaction was quenched with water (3 mL) and extracted with DCM (5 mL). The combined organic layer was purified by reverse phase HPLC (mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; 17% B to 42% B in 9 min, 42% B) to afford the title compound 66 (3 mg, 17.76%) as a white solid. MS (ESI): mass calcd. for C18H26N6O3S: 406.18, found: 407.15 [M+H] ⁺ . ¹ H NMR (300 MHz; DMSO-d6) δ 8.11 (t, J = 1.0 Hz, 2H), 5.79 (s, 2H), 4.60 (t, J = 11.3 Hz, 1H), 3.88 (t, J = 6.6 Hz, 2H), 3.54 (s, 4H), 2.33 (dd, J = 25.2, 11.7 Hz, 2H), 1.87 (d, J = 11.0 Hz, 2H), 1.47-1.59 (m, 6H), 1.28 (td, J = 14.1, 6.9 Hz, 2H), 0.88 (t, J = 7.2 Hz, 3H). Example 59 was synthesized in similar procedures as described in Example 66 from the major isomer in first step. Examples 69, 70 and 76 (mixed with 30% of 70) were synthesized in similar procedures as described in Example 66, starting from cis and trans mixture of 1-((4- aminocyclohexyl)methyl)-3,5,5-trimethylimidazolidine-2,4-dio ne and obtained through chiral separation. Example 74: 1-(2-(3-(Aminomethyl)oxetan-3-yl)-2-azaspiro[3.5]nonan-7-yl) -3-butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (74) Synthetic scheme: 3-(7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyr imidin-1(2H)-yl)-2- azaspiro[3.5]nonan-2-yl)oxetane-3-carbonitrile To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (70 mg, 0.2 mmol) in acetic acid (3 mL) was added 3- oxetanone (144 mg, 2.0 mmol) and trimethylsilyl cyanide (298 mg, 3.0 mmol). After heating at 80 °C for 6 h, the reaction was cooled down, quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (DCM/MeOH = 10:1) to afford the title compound (40 mg, 46.38%). MS (ESI): mass calcd. for C ₂₁ H ₃₀ N ₆ O ₄ : 430.23 found: 431.20 [M+H] ⁺ . 1-(2-(3-(Aminomethyl)oxetan-3-yl)-2-azaspiro[3.5]nonan-7-yl) -3-butyl-5- (diaminomethylene) pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyr imidin- 1(2H)-yl)-2-azaspiro[3.5]nonan-2-yl)oxetane-3-carbonitrile (20 mg, 0.046 mmol) in tetrahydrofuran (3 mL) was added LiAlH4 (9 mg, 0.23 mmol). After stirring at 0 °C for 0.5 h, the reaction was quenched with saturated Na2SO4 (aq., 0.1 mL). MeOH (5 mL) was added, and the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude product, which was purified by reverse phase HPLC (mobile phase A: water (0.1% FA), mobile Phase B: ACN; 10% B to 19% B) to afford the title compound 74 (0.8 mg, 3.78%) as a light-yellow solid. MS (ESI): mass calcd. for C ₂₁ H ₃₄ N ₆ O ₄ : 434.26 found: 435.20[M+H] ⁺ . ¹ H NMR (300 MHz; DMSO-d6) δ 9.37-9.65 (m, 2H), 8.13-8.67 (m, 2H), 7.53-8.00 (m, 2H), 4.54-4.69 (m, 3H), 4.29 (s, 2H), 3.66-3.98 (m, 2H), 2.77-3.20 (m, 4H), 2.28-2.43 (m, 2H), 1.99 (t, J = 3.9 Hz, 2H), 1.23-1.42 (m, 10H), 0.87 (t, J = 7.2 Hz, 3H). Example 75: 1-(2-(Aminomethyl)-2-(methoxymethyl)spiro[3.5]nonan-7-yl)-3- butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (75) Synthetic scheme: O ^t BuOK, TosMIC O _LDA, O Br ^O LiAlH O O CN O ₄ O O EtOH, DME, rt O THF, -78 - -40 °C _O ^CN THF, rt O NH ₂ O CbzCl, TEA O _{2N HCl, THF} O ^O HO O NaBH ₄ , MeOH DCM, rt O ^{HN HN} _Cbz ^HN _{Cbz Cbz} S S O O NH S NH N _{2 S} O H ^Cbz _{H N} O HN ^Cbz O N ₂ O N O N TMAD, n-Bu ₃ P _N ^NH ₃ ^{(in MeOH)} N toluene, 110 °C O O O O NH ₂ H ₂ N O NH ₂ 40% HBr (in AcOH) O N DCM, 0°C-rt N O O 8,11-Dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile To a solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one (1.0 g, 5.1 mmol) in DME (10 mL) and t-BuOH (10 mL) was added TosMIC (2.09 g, 10.7 mmol). The resulting mixture was stirred at rt for 10 min and t-BuOK (2.52 g, 22.42 mmol) was added in portions at 0 °C. After stirring at rt overnight, the reaction was quenched with ice water and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (PE/EA = 10:1) to afford the title compound (400 mg, 37.87%) as a yellow solid. 2-(Methoxymethyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile To a solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (400 mg, 1.93 mmol) in THF (10 mL) was added 2 M LDA (in THF, 1.9 mL, 3.86 mmol) at -78 °C under a N ₂ atmosphere. After stirring at -78 °C to -40 °C for 0.5 h, bromo(methoxy)methane (482 mg, 3.86 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C to - 40 °C for 3 h. The reaction was quenched with NH ₄ Cl (aq., 30 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (PE/EA = 10:1) to afford the title compound (330 mg, 68.04%) as a yellow oil. (2-(Methoxymethyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)methanamine To a solution of 2-(methoxymethyl)-8,11-dioxadispiro[3.2.47.24]tridecane-2-ca rbonitrile (390 mg, 1.55 mmol) in THF (8 mL) was added LiAlH4 (117 mg, 3.10 mmol) at 0 °C under a N ₂ atmosphere. After stirring at room temperature for 4 h, the reaction was quenched with saturated Na ₂ SO ₄ (aq., 1 mL) and extracted with EA (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude (2- (methoxymethyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)methanamine (380 mg, 95.9%) as a yellow oil, which was used in the next step without further purification. Benzyl ((2-(methoxymethyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)methyl)carbamate To a solution of (2-(methoxymethyl)-8,11-dioxadispiro[3.2.47.24]tridecan-2- yl)methanamine (400 mg, 1.57 mmol) in DCM (8 mL) was added TEA (475 mg, 4.7 mmol) and CbzCl (320 mg, 1.88 mmol) at 0 °C under a N ₂ atmosphere. After stirring at room temperature for 3 h, the reaction was quenched with water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to afford the title compound (430 mg, 70.48%) as a light-yellow oil. MS (ESI): mass calcd. for C22H31NO5: 389.22, found: 412.30 [M+Na] ⁺ . Benzyl ((2-(methoxymethyl)-7-oxospiro[3.5]nonan-2-yl)methyl)carbama te A solution of benzyl ((2-(methoxymethyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2- yl)methyl)carbamate (440 mg, 1.13 mmol) in 2 N HCl (3 mL) and THF (3 mL) was heated at 60 °C for 2 h. The reaction was neutralized to pH = 7 with NaHCO ₃ solution and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography to afford the title compound (350 mg, 89.69%) as a light- yellow oil. MS (ESI): mass calcd. for C ₂₀ H ₂₇ NO ₄ : 345.19, found: 368.20 [M+Na] ⁺ . Benzyl ((7-hydroxy-2-(methoxymethyl)spiro[3.5]nonan-2-yl)methyl)car bamate To a solution of benzyl ((2-(methoxymethyl)-7-oxospiro[3.5]nonan-2-yl)methyl)carbama te (340 mg, 0.98 mmol) in MeOH (5 mL) was added NaBH4 (56 mg, 1.48 mmol) at 0 °C. After stirring for 2 h at rt, the reaction was quenched with ice water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (PE/EA = 5:1) to afford the title compound (300 mg, 87.72%) as a light-yellow oil. MS (ESI): mass calcd. for C ₂₀ H ₂₉ NO ₄ : 347.21, found: 370.15 [M+Na] ⁺ . Benzyl ((7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydr opyrimidin-1(2H)-yl)- 2-(methoxymethyl)spiro[3.5]nonan-2-yl)methyl)carbamate To a solution of benzyl ((7-hydroxy-2-(methoxymethyl)spiro[3.5]nonan-2- yl)methyl)carbamate (130 mg, 0.37 mmol) in toluene (3 mL) was added 1-butyl-5-(1,3- dithian-2-ylidene)-1,3-diazinane-2,4,6-trione (112.39 mg, 0.37 mmol), TMAD (193.27 mg, 1.12 mmol), and n-Bu3P (227.10 mg, 1.12 mmol) at rt. After heating overnight at 100 °C, the reaction was quenched with water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to afford the title compound (50 mg, 19.62%) as a light-yellow solid. MS (ESI): mass calcd. for C ₃₂ H ₄₃ N ₃ O ₆ S ₂ : 629.26, found: 652.10 [M+Na] ⁺ . Benzyl ((7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyri midin-1(2H)-yl)-2- (methoxymethyl)spiro[3.5]nonan-2-yl)methyl)carbamate A solution of benzyl ((7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-2-(methoxymethyl)spiro[3 .5]nonan-2- yl)methyl)carbamate (50 mg, 0.079 mmol) in MeOH (2 mL) was added 7 N NH ₃ in MeOH (2 mL). After heating at 110 °C for 2 h, the reaction was quenched with water (10 mL) and extracted with DCM/MeOH (6:1). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel chromatography to afford the title compound (40 mg, 86.86%) as a light-yellow solid. MS (ESI): mass calcd. for C29H41N5O6: 555.31, found: 556.30 [M+H] ⁺ . 1-(2-(Aminomethyl)-2-(methoxymethyl)spiro[3.5]nonan-7-yl)-3- butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of benzyl ((7-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-2-(methoxymethyl)spiro[3 .5]nonan-2- yl)methyl)carbamate (40 mg, 0.072 mmol) in DCM (1.5 mL) was added 40% HBr (in AcOH, 0.5 mL) at 0 °C. After stirring at room temperature for 2 h, the reaction was purified by reverse phase HPLC to afford the title compound 75 (TFA salt, 7.5 mg, 17.79%) as a light grey solid. MS (ESI): mass calcd. for C ₂₁ H ₃₅ N ₅ O ₄ : 421.27, found: 422.25 [M+H] ⁺ . ¹ H NMR (400 MHz; CD3OD) δ 4.72 (t, J = 9.0 Hz, 1H), 3.84 (t, J = 7.5 Hz, 2H), 3.52 (s, 2H), 3.39 (s, 3H), 3.10 (s, 2H), 2.44-2.55 (m, 2H), 1.80-1.90 (m, 4H), 1.68-1.76 (m, 2H), 1.41-1.58 (m, 6H), 1.34 (dq, J = 15.2, 7.6 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). Example 78: 1-Butyl-5-(diaminomethylene)-3-(2-(5,5-dimethyl-2,4-dioxoimi dazolidin-1- yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (78) Synthetic scheme: O O O ^H O O O ^H ₂ ^N _{N O} HOAc, 100 °C NH NH , Pd/ O N ₃ C, H ₂ O O MeOH, rt O O O O O ^N O O O O NH NH C HN C N Cl Cl O N N H ₂ N N _O H HN N N O O ClCH ₂ CH ₂ Cl, rt O DCM, rt O NH S ₂ H ₂ N O O 1) S C S S O O NH TEA, DMSO NH ^NH ₃ ^{(in MeOH)} O N N O _N N N O Br B N O 2) r O O Ethyl 2-((8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)amino)-2-methy lpropanoate To a stirred solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (0.5 g, 2.55 mmol) in DCM (5 mL) was added ethyl 2-amino-2-methylpropanoate (0.43 g, 3.32 mmol) and AcOH (0.1 mL) at rt. After stirring for 1 h, NaBH(OAc) ₃ (1.08 g, 5.10 mmol) was added to the reaction and the reaction was stirred for 16 h. The reaction was quenched by addition of NaHCO3/H2O (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE/EA = 2:1) to afford the title compound (0.2 g, 37.0%) as a colorless oil. MS (ESI): mass calcd. for C17H29NO4: 311.20, found: 312.30 [M+H] ⁺ . 5,5-Dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)imidazolidine-2,4- dione To a stirred solution of ethyl 2-((8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)amino)-2- methylpropanoate (0.2 g, 0.64 mmol) in AcOH (3 mL) was added KOCN (0.26 g, 3.21 mmol) at rt. The reaction mixture was heated at 100 °C for 16 h. After completion, the reaction was cooled down and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM/MeOH = 10:1) to afford the title compound (150 mg, 88.2%) as a yellow solid. MS (ESI): mass calcd. for C ₁₄ H ₂₀ N ₂ O ₃ : 264.15, found:265.15 [M+H] ⁺ . 1-(7-Aminospiro[3.5]nonan-2-yl)-5,5-dimethylimidazolidine-2, 4-dione To a solution of 5,5-dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)imidazolidine-2,4- dione (180 mg, 0.68 mmol) in 7 N NH3 in methanol (5 mL) was added Pd/C (50 mg). The reaction was stirred for 0.5 h under a hydrogen atmosphere (balloon). The reaction was filtered through a pad of Celite and concentrated under reduced pressure to afford the title compound (0.15 g, 83.3%) as a yellow oil. MS (ESI): mass calcd. for C14H23N3O2: 265.18, found: 266.30 [M+H] ⁺ . 1-Butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[ 3.5]nonan-7-yl)urea To a solution of 1-(7-aminospiro[3.5]nonan-2-yl)-5,5-dimethylimidazolidine-2, 4-dione (0.15 g, 0.56 mmol) in ClCH ₂ CH ₂ Cl (3 mL) was added butyl isocyanate (83 mg, 0.84 mmol). After stirring at room temperature overnight, the resulting mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the title compound (0.12 g, 59.1%) as a yellow solid. MS (ESI): mass calcd. for C ₁₉ H ₃₂ N ₄ O ₃ : 364.25, found: 365.20 [M+H] ⁺ . 1-Butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[ 3.5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[ 3.5]nonan- 7-yl)urea (120 mg, 0.33 mmol) in DCM (3 mL) was added propanedioyl dichloride (93 mg, 0.66 mmol) at 0 °C. After stirring at rt for 4 h, the reaction mixture was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM/MeOH = 10:1) to afford the title compound (55 mg, 38.7%) as a yellow oil. MS (ESI): mass calcd. for C22H32N4O5: 432.24, found: 433.35 [M+H] ⁺ . 1-Butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[ 3.5]nonan-7-yl)-5-(1,3- dithian-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[ 3.5]nonan- 7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (50 mg, 0.12 mmol) in DMSO (2 mL) was added carbon disulfide (26 mg, 0.35 mmol) and TEA (46 mg, 0.460 mmol) at rt. After stirring for 1 h at rt, 1,3-dibromopropane (46 mg, 0.23 mmol) was added. The resulting mixture was stirred for 2.5 h. After completion, the reaction was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM/MeOH = 10:1) to afford the title compound (45 mg, 71.4%) as a yellow solid. MS (ESI): mass calcd. for C26H36N4O5S2: 548.21, found: 549.15 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-(5,5-dimethyl-2,4-dioxoimi dazolidin-1- yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1- yl)spiro[3.5]nonan-7-yl)-5-(1,3-dithian-2-ylidene)pyrimidine -2,4,6(1H,3H,5H)-trione (40 mg, 0.07 mmol) in methanol (3 mL) was added 7 N NH3 in methanol (0.4 mL). After heating at 100 °C for 1 h, the reaction was concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC to afford the title compound 78 (2.4 mg, 6.8%) as a white solid. MS (ESI): mass calcd. for C23H34N6O5: 474.26, found: 475.20 [M+H] ⁺ . ¹ H NMR (300 MHz; DMSO-d6) δ 10.67 (s, 1H), 9.54 (s, 2H), 7.30 (d, J = 0.9 Hz, 2H), 4.58-4.65 (m, 1H), 3.70-3.85 (m, 3H), 2.57 (t, J = 10.1 Hz, 1H), 2.21-2.44 (m, 2H), 2.08-2.15 (m, 1H), 1.75-1.93 (m, 4H), 1.33-1.49 (m, 6H), 1.19-1.33 (m, 8H), 0.88 (d, J = 14.5 Hz, 3H). Example 79:. (R)-1-Butyl-5-(diaminomethylene)-3-(2-(3-hydroxypyrrolidin-1 -yl)spiro[3. 5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (79) Synthetic scheme: 8,11-Dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-ol To a solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one (1.0 g, 5.1 mmol) in methanol (20 mL) was added NaBH ₄ (289 mg, 7.64 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-50% EA/PE) to afford the title compound (812 mg, 80.37%) as a yellow oil. MS (ESI): mass calcd. for C11H18O3: 198.13, found: 199.20 [M+H] ⁺ . 2-(Benzyloxy)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane A solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-ol (780 mg, 3.93 mmol) in tetrahydrofuran (20 mL) was cooled to 0 °C. NaH (60% in mineral oil, 236.03 mg, 5.90 mmol) was added. After stirring for 0.5 h at 0 °C, benzyl bromide (807 mg, 4.72 mmol) was added. After stirring for 2 h at room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-50% EA/PE) to afford the title compound (821 mg, 72.36%) as a yellow solid. MS (ESI): mass calcd. for C18H24O3: 288.17, found: 289.25 [M+H] ⁺ . Methyl 2-(benzyloxy)spiro[3.5]nonan-7-one To a solution of 2-(benzyloxy)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane (821 mg, 2.85 mmol) in tetrahydrofuran (5 mL) was added 4 N HCl (10 mL). The reaction was heated at 70 °C for 3 h. After cooling down to room temperature, the reaction was concentrated, basified to pH = 10, and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-50% EA/PE) to afford the title compound (527 mg, 75.76%) as a yellow solid. MS (ESI): mass calcd. for C16H20O2: 244.15, found: 245.10 [M+H] ⁺ . 2-(Benzyloxy)spiro[3.5]nonan-7-ol A solution of 2-(benzyloxy)spiro[3.5]nonan-7-one (500 mg, 2.05 mmol) in methanol (10 mL) was cooled to 0 °C and NaBH ₄ (116 mg, 3.07 mmol) was added. After stirring for 1 h at room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-50% EA/PE) to afford the title compound (345 mg, 68.44%) as a yellow solid. MS (ESI): mass calcd. for C16H22O2: 246.16, found: 247.10 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-oxospiro[3.5]nonan-7-yl)py rimidine- 2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(2-hydroxyspiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (synthesized from 2-(benzyloxy)spiro[3.5]nonan-7-ol following Example 51, 10 mg, 0.027 mmol) in DCM (1 mL) was added Dess-Martin (23 mg, 0.054 mmol). After stirring for 2 h at room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-50% EA/PE) to afford the title compound Int B (72 mg, 80.44%) as a yellow solid. MS(ESI): mass calcd. for C ₁₈ H ₂₆ N ₄ O ₄ : 362.20, found: 363.10 [M+H] ⁺ . (R)-1-Butyl-5-(diaminomethylene)-3-(2-(3-hydroxypyrrolidin-1 -yl)spiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(2-oxospiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (50 mg, 0.14 mmol) in MeOH (2 mL) was added (3R)- pyrrolidin-3-ol (18 mg, 0.21 mmol) and AcOH (8.28 mg, 0.138 mmol). The reaction was stirred for 0.5 h and NaBH3CN (17.34 mg, 0.28 mmol) was added. After stirring at room temperature for 2 h, the reaction was concentrated to dryness under reduced pressure to provide a crude product, which was purified by reverse phase HPLC (26% to 45% (v/v) ACN and H2O with 0.05% NH4HCO3) to afford the title compound 79 (15.3 mg, 24.32%) as a white solid. MS (ESI): mass calcd. for C ₂₂ H ₃₅ N ₅ O ₄ : 433.27 found: 434.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 2H), 7.31 (s, 2H), 4.80 (s, 1H), 4.54-4.68 (m, 1H), 4.21 (d, J = 1.4 Hz, 1H), 3.74 (t, J = 7.4 Hz, 2H), 2.95 (s, 1H), 2.64-2.75 (m, 1H), 2.55-2.61 (m, 1H), 2.23-2.49 (m, 3H), 1.89-2.07 (m, 2H), 1.70-1.85 (m, 2H), 1.52-1.69 (m, 4H), 1.16 -1.51 (m, 8H), 0.88 (t, J = 7.3 Hz, 3H). Examples 94, 95, 96 were synthesized from Int B in similar procedures as described in Example 79. Example 80: 1-(2-(4H-1,2,4-Triazol-3-yl)-2-azaspiro[3.5]nonan-7-yl)-3-bu tyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione Synthetic scheme: O O O 1) S C S ^{HN NH} I ^H N _N HN NH TEA, DMSO O O K ₂ CO ₃ , O O O O 2) Br Br S S DMF, rt S S S O S N S NH N ^O S ₂ O O H ₂ N O H NaBH ₄ DEAD, PPh ₃ O _N N Boc ^NH ₃ ^{(in MeOH) O N Boc} _{HO N Boc} O N N Boc MeOH, rt DCM, rt N 100 °C N O O H N NH ₂ NH NH _{2 2} H ₂ N O H ₂ N O H ₂ N O T _FA/DCM ^{CuI, K} N 2 ^CO ₃ ^N H O N N _N 1, TFA, DCM, rt ^N O N N _N O N NH t ^olue N N 2, NH ₃ in MeOH, rt N N N ^{ne 100 °C} O _SEM O H O 5-(1,3-Dithian-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of pyrimidine-2,4,6(1H,3H,5H)-trione (4 g, 31.22 mmol) in DMSO (60 mL) was added carbon disulfide (7.13 g, 93.66 mmol) and TEA (15.76 g, 156.10 mmol). After stirring for 1 h at room temperature, the reaction was cooled down to 0 °C and 1,3- dibromopropane (18.90 g, 93.66 mmol) was added. After stirring another 3 h at room temperature, ice water (500 mL) was added and the precipitate was collected to give the title compound (5.33 g, 70.0%) as a white solid. MS (ESI): mass calcd. for C ₈ H ₈ N ₂ O ₃ S ₂ : 244.00, found: 245.15 [M+H] ⁺ . 1-Butyl-5-(1,3-dithian-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)- trione To a solution of 5-(1,3-dithian-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (2.0 g, 8.18 mmol) in DMF (30 mL) was added butyl iodide (1.51 g, 8.18 mmol) and K2CO3 (2.26 g, 16.37 mmol) at rt. After heating for 3 h at 50 °C, the reaction was quenched with water and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford a crude product which was purified by silica gel column chromatography (0-100% PE/EA) to provide the title compound (1.4 g, 56.92%) as a yellow solid. MS (ESI): mass calcd. for C ₁₂ H ₁₆ N ₂ O ₃ S ₂ : 300.06, found: 301.20 [M+H] ⁺ . tert-Butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate To a solution of tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (1.0 g, 4.18 mmol) in methanol (15 mL) was added NaBH4 (317 mg, 8.36 mmol) at 0 °C. After stirring for 3 h at 0 °C, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (PE/EA=2:1) to afford the title compound (0.8 g, 79.33%). MS (ESI): mass calcd. for C ₁₃ H ₂₃ NO ₃ : 241.17, found: 242.25 [M+H] ⁺ . tert-Butyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydrop yrimidin-1(2H)- yl)-2-azaspiro[3.5]nonane-2-carboxylate To a solution of tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (600 mg, 2.49 mmol) in DCM (10 mL) was added 1-butyl-5-(1,3-dithian-2-ylidene)-1,3-diazinane-2,4,6- trione (597 mg, 1.99 mmol) and triphenylphosphine (978 mg, 3.73 mmol), followed by addition of DEAD (649 mg, 3.73 mmol) under a N2 atmosphere. After stirring at room temperature for 2 h, the reaction mixture was quenched with water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE/EA=2:1) to afford the title compound (800 mg, 61.44%). MS (ESI): mass calcd. for C ₂₅ H ₃₇ N ₃ O ₅ S ₂ : 523.22, found: 524.20 [M+H] ⁺ . tert-Butyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)-yl)- 2-azaspiro[3.5]nonane-2-carboxylate To a solution of tert-butyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2- carboxylate (200 mg, 0.38 mmol) in methanol (8 mL) was added 7 N NH ₃ (in methanol, 1.2 mL). The resulting mixture was heated for 1 h at 100 °C. After cooling down, the reaction was concentrated under reduced pressure and purified by silica gel column chromatography (DCM/MeOH = 10:1) to afford the title compound (600 mg, 87.37%). MS (ESI): mass calcd. for C ₂₂ H ₃₅ N ₅ O ₅ : 449.26, found: 450.20 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7-yl)py rimidine- 2,4,6(1H,3H,5H)-trione To a solution of tert-butyl 7-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2- carboxylate (600 mg, 1.34 mmol) in DCM (20 mL) was added trifluoroacetic acid (5 mL). After stirring at room temperature for 1 h, the reaction was concentrated under reduced pressure and then quenched by NaHCO ₃ (aq.). The resulting crude was further purified by reverse phase HPLC to afford the title compound (Example 17, 420 mg, 90.35%). MS (ESI): mass calcd. for C17H27N5O3: 349.21, found: 350.30 [M+H] ⁺ . This is a different synthetic route to make Example 17. 1-Butyl-5-(diaminomethylene)-3-(2-(4-((2-(trimethylsilyl)eth oxy)methyl)-4H-1,2,4- triazol-3-yl)-2-azaspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H, 3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (100 mg, 0.286 mmol) in toluene (3 mL) was added 3- bromo-4-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4-triazole (87 mg, 0.32 mmol), CuI (11 mg, 0.057 mmol), potassium carbonate (119.52 mg, 0.86 mmol) and (1R,2R)-N ¹ ,N ² - dimethylcyclohexane-1,2-diamine (16 mg, 0.11 mmol). The reaction was heated at 100 °C for 3 h under N ₂ . After completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was further purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the title compound (30 mg, 19.17%). MS (ESI): mass calcd. for C25H42N8O4Si: 546.31, found: 547.30 [M+H] ⁺ . 1-(2-(4H-1,2,4-triazol-3-yl)-2-azaspiro[3.5]nonan-7-yl)-3-bu tyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(2-(4-((2- (trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-2-azas piro[3.5]nonan-7-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (30 mg, 0.055 mmol) in DCM (2 mL) was added TFA (0.5 mL). After stirring at room temperature for 1 h, the reaction was concentrated under reduced pressure and ammonia (2 mL) was added. After stirring at room temperature for another hour, the mixture was concentrated to dryness to provide a crude product, which was purified by reverse phase HPLC (mobile phase A: water (10 mmol/L NH4HCO3), mobile phase B: ACN; 25% B to 45% B) to afford the title compound 80 (3.2 mg, 14.00%) as a white solid. MS (ESI): mass calcd. for C19H28N8O3: 416.23, found: 417.20 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 12.52 (s, 1H), 9.54 (s, 2H), 7.42 (s, 1H), 7.33 (s, 2H), 4.62-4.69 (m, 1H), 3.74 (t, J = 7.2 Hz, 2H), 3.68 (s, 2H), 3.58 (s, 2H), 2.35 (dd, J = 24.9, 12.1 Hz, 2H), 1.99 (dd, J = 18.2, 10.4 Hz, 2H), 1.42-1.58 (m, 4H), 1.23-1.34 (m, 4H), 0.88 (t, J = 7.3 Hz, 3H). Examples 47, 48, 49, and 50 were synthesized in similar procedures as described for the synthesis of Example 17 in Example 80, followed by similar procedure as described for the synthesis of Example 4 and then chiral separation to obtain the 4 stereoisomers. The stereochemistry of each isomer is arbitrarily assigned. Example 81 and 82: 1-((2R,4r,7R)-7-(3-Amino-7-butyl-4,6-dioxo-6,7-dihydroisothi azolo[ 3,4-d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (81) & 1-((2S,4s,7S)-7-(3- Amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimid in-5(4H)-yl)spiro[3.5]non an-2-yl)-1-methylurea (82) Synthetic scheme:

tert-Butyl (8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)(methyl)carbamate To a solution of N-benzyl-N-methyl-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-amine (see Example 51 for synthesis, 300 mg, 0.995 mmol) and di-tert-butyl dicarbonate (434.43 mg, 1.99 mmol) in methanol (5 mL) was added Pd/C (10%, 55 mg) under a nitrogen atmosphere. Then the reaction was stirred for 3 h at rt under a hydrogen atmosphere (balloon). The reaction was filtered through a pad of Celite and concentrated under reduced pressure to afford the crude title compound (280 mg, 93.33%), which was used in the next step without further purification. MS (ESI): mass calcd. for C17H29NO4: 311.21, found: 312.25 [M+H] ⁺ . tert-Butyl methyl(7-oxospiro[3.5]nonan-2-yl)carbamate A solutionof tert-butyl (8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)(methyl)carbamate (420 mg, 1.35 mmol) and TsOH (464.48 mg, 2.7 mmol) in acetone (3 mL) and water (1.5 mL) was stirred for 2 h at rt. After completion, the reaction was quenched with water (3 mL) and extracted with EA (10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE:EA = 2:1) to afford the title compound. MS (ESI): mass calcd. for C ₁₅ H ₂₅ NO ₃ : 267.18, found: 212.25 [M-tBu+H] ⁺ . tert-Butyl (7-hydroxyspiro[3.5]nonan-2-yl)(methyl)carbamate To a stirred solution of tert-butyl methyl(7-oxospiro[3.5]nonan-2-yl)carbamate (150 mg, 0.56 mmol) in methanol (3 mL) was added NaBH4 (42.45 mg, 1.12 mmol) in portions at 0 °C. After stirring at rt for 2 h, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (30-35% EA in PE) to afford the title compound (125 mg, 82.71%). MS (ESI): mass calcd. for C ₁₅ H ₂₇ NO ₃ : 267.20 m/z, found: 214.25 [M- ^t Bu+H] ⁺ . tert-Butyl (7-(3-butyl-4-chloro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)- yl)spiro[3.5]nonan-2-yl)(methyl)carbamate A solution of tert-butyl (7-hydroxyspiro[3.5]nonan-2-yl)(methyl)carbamate (270 mg, 1.0 mmol) in DCM (5 mL) was treated with 1-butyl-6-chloro-3H-pyrimidine-2,4-dione (203 mg, 1.0 mmol) and triphenylphosphine (394.34 mg, 1.5 mmol), followed by addition of DEAD (261.83 mg, 1.5 mmol) dropwise at 0 °C under N ₂ . After stirring for 16 h at rt, the reaction was quenched with water (5 mL) and extracted with DCM (15 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (15-25% EA in PE) to afford the title compound (130 mg, 28.57%). MS (ESI): mass calcd. for C23H36ClN3O4: 453.24, found: 476.30 [M+Na] ⁺ . tert-Butyl (7-(4-amino-3-butyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)- yl)spiro[3.5]nonan-2-yl)(methyl)carbamate A solution of tert-butyl (7-(3-butyl-4-chloro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)- yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (150 mg, 0.33 mmol) and ammonium hydroxide (578 mg, 16.5 mmol) in CH3CN (3 mL) was heated overnight at 80 °C. After completion, the reaction was quenched with water (2 mL) and extracted with ethyl acetate (15 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was further purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the title compound (80 mg, 55.72%). MS (ESI): mass calcd. for C ₂₃ H ₃₈ N ₄ O ₄ : 434.29, found: 435.35 [M+H] ⁺ . tert-Butyl (7-(7-butyl-3-cyano-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]p yrimidin-5(4H)- yl)spiro[3.5]nonan-2-yl)(methyl)carbamate A solution of 4-chloro-5H-1,2,3-dithiazolium chloride (76 mg, 0.37 mmol) in DCM (3 mL) was treated with tert-butyl (7-(4-amino-3-butyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)- yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (80 mg, 0.18 mmol) and pyridine (66 mg, 0.85 mmol) for 5 min at rt. After stirring for 16 h, the reaction was quenched with water (5 mL) and extracted with DCM (10 mL). The combined organic layer was washed with brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the title compound (50 mg, 54.14%) as a yellow oil. MS (ESI): mass calcd. for C ₂₅ H ₃₅ N ₅ O ₄ S: 501.24, found: 524.30 [M+Na] ⁺ . tert-Butyl (7-(7-butyl-3-((4-methoxybenzyl)amino)-4,6-dioxo-6,7-dihydro isothiazolo[3,4- d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate A solution of tert-butyl (7-(7-butyl-3-cyano-4,6-dioxo-6,7-dihydroisothiazolo[3,4- d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (50 mg, 0.100 mmol) and (4- methoxyphenyl)methanamine (136 mg, 1.000 mmol) in DMF (3 mL) was heated for 1 h at 90 °C. After completion, the reaction was quenched with water (2 mL) and extracted with DCM (5 mL x 3). The combined organic layer was washed with brine (2 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (30-35% EA in PE) to afford the title compound (50 mg, 82.0%). MS (ESI): mass calcd. for C32H45N5O5S: 611.31, found: 612.40 [M+H] ⁺ . 3-Amino-7-butyl-5-(2-(methylamino)spiro[3.5]nonan-7-yl)isoth iazolo[3,4-d]pyrimidine- 4,6(5H,7H)-dione A solution of tert-butyl (7-(7-butyl-3-((4-methoxybenzyl)amino)-4,6-dioxo-6,7- dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)spiro[3.5]nonan- 2-yl)(methyl)carbamate (50 mg, 0.082 mmol) and TFA (2.7 mL, 36.35 mmol) in H ₂ O (0.3 mL, 16.65 mmol) was heated at 50 °C overnight. The residue was purified by reversed phase HPLC (10-50% ACN in water, with TFA as a modifier) to afford the title compound (30 mg, 93.76%) as an oil. MS (ESI): mass calcd. for C ₁₉ H ₂₉ N ₅ O ₂ S: 391.20, found: 392.30[M+H] ⁺ . 1-((2R,4r,7R)-7-(3-Amino-7-butyl-4,6-dioxo-6,7-dihydroisothi azolo[3,4-d]pyrimidin- 5(4H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (81) & 1-((2S,4s,7S)-7-(3-Amino-7-butyl- 4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)sp iro[3.5]nonan-2-yl)-1- methylurea (82) A solution of 3-amino-7-butyl-5-[2-(methylamino)spiro[3.5]nonan-7-yl]- [1,2]thiazolo[3,4-d]pyrimidine-4,6-dione (30 mg, 0.077 mmol) in DCM (3 mL) was treated with TEA (26 mg, 0.25 mmol) followed by the addition of isocyanatotrimethylsilane (19.42 mg, 0.17 mmol) dropwise at rt. After stirring for 1 h, the reaction was quenched with water (2 mL) and extracted with ethyl acetate (10 mL). The combined organic layer was washed with brine (3 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by chiral HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: MtBE(0.5% 2M NH ₃ -MeOH), mobile phase B: EtOH; Flow rate: 20 mL/min; 15% B to 15% B in 16 min) to afford the title compound 81 (2.3 mg, 6.89%, RT1: 11.03 min) as a white solid. MS (ESI): mass calcd. for C ₂₀ H ₃₀ N ₆ O ₃ S: 434.21, found: 435.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d6) δ 8.14 (s, 2H), 5.79 (s, 2H), 4.36-4.69 (m, 2H), 3.89 (t, J = 7.5 Hz, 2H), 2.73 (s, 3H), 2.23-2.48 (m, 2H), 2.08 (t, J = 9.7 Hz, 1H), 1.50-1.93 (m, 6H), 1.17-1.48 (m, 7H), 0.90 (t, J = 7.3 Hz, 3H) and title compound 82 (2.7 mg, 8.10%, RT2: 15.096 min) as a white solid. MS (ESI): mass calcd. for C ₂₀ H ₃₀ N ₆ O ₃ S: 434.21, found: 435.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 2H), 5.79 (s, 2H), 4.36-4.69 (m, 2H), 3.89 (t, J = 7.5 Hz, 2H), 2.73 (s, 3H), 2.23-2.48 (m, 2H), 2.08 (t, J = 9.7 Hz, 1H), 1.50-1.93 (m, 6H), 1.17-1.48 (m, 7H), 0.90 (t, J = 7.3 Hz, 3H). Examples 104 and 105 made in similar procedures as described in Examples 81 and 82, starting from 1-(7-hydroxyspiro[3.5]nonan-2-yl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (made from 5,5-dimethyl-1-(7- oxospiro[3.5]nonan-2-yl)imidazolidine-2,4-dione in Example 78). Tributylphosphoranylidene)acetonitrile was used as the reagent for Mistunobu coupling. Example 83: 3-(7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyr imidin- 1(2H)-yl)-2-azaspiro[3.5]nonan-2-yl)oxetane-3-carboxamide (83) Synthetic scheme: 3-(7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyr imidin-1(2H)-yl)-2- azaspiro[3.5]nonan-2-yl)oxetane-3-carboxamide To a solution of 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyr imidin- 1(2H)-yl)-2-azaspiro[3.5]nonan-2-yl)oxetane-3-carbonitrile (30 mg, 0.070 mmol) in DMSO (3 mL) was added K ₂ CO ₃ (29 mg, 0.210 mmol). The mixture was stirred until homogenous and then was cooled to 0 °C.30% hydrogen peroxide (0.6 mL) was added. After stirring at 0 °C for 30 min and then 3 h at room temperature, the mixture was concentrated to dryness under reduced pressure to provide a crude product, which was purified by reverse phase HPLC (25% to 45% (v/v) ACN and H ₂ O with 0.05% NH ₄ HCO ₃ ) to afford the title compound 83 (9.4 mg, 30.07%) as a white solid. MS (ESI): mass calcd. for C21H32N6O5: 448.24, found: 449.20 [M+H] ⁺ . ¹ H NMR (300 MHz; DMSO-d6) δ 9.54 (d, J = 0.8 Hz, 2H), 7.31 (s, 2H), 7.20 (br d, J = 18.3 Hz, 2H), 4.64-4.71 (m, 3H), 4.51 (d, J = 6.6 Hz, 2H), 3.73 (t, J = 7.1 Hz, 2H), 3.16 (s, 2H), 3.06 (s, 2H), 2.27-2.37 (m, 2H), 2.04 (d, J = 12.2 Hz, 2H), 1.35-1.50 (m, 4H), 1.19-1.31 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H). Example 84 was prepared in similar procedures from 1-butyl-5-(diaminomethylene)-3- (piperidin-4-ylmethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared according to Example 51) as described in Example 83. Example 85: 3-Amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazo lidin-1- yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H) -dione Synthetic scheme: Ethyl (1r,4r)-4-(benzyloxy)cyclohexane-1-carboxylate A solution of ethyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (4 g, 23.23 mmol), DIPEA (7.50 g, 58.07 mmol) and BnBr (4.37 g, 25.55 mmol) was heated at 130 °C for 16 h. After cooling down to room temperature, the reaction was quenched with 2 N HCl (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-20% PE/EA) to afford the title compound (4 g, 52.06%) as a colorless oil. MS (ESI): mass calcd. for C ₁₆ H ₂₂ O ₃ : 262.16, found: 263.15[M+H] ⁺ . ((1r,4r)-4-(Benzyloxy)cyclohexyl)methanol To a solution of ethyl (1r,4r)-4-(benzyloxy)cyclohexane-1-carboxylate (4.7 g, 17.92 mmol) in THF (40 mL) was added LiAlH ₄ (1.70 g, 44.79 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was heated at 60 °C for 3 h. After cooling down to room temperature, the reaction was quenched with saturated Na2SO4 aqueous solution at 0 °C, dried with Na ₂ SO ₄ , filtered and concentrated. The residue obtained was purified by silica gel column chromatography (0-30% PE/EA) to afford the title compound (2.9 g, 73.48%) as a colorless oil. ((((1r,4r)-4-(Bromomethyl)cyclohexyl)oxy)methyl)benzene To a solution of ((1r,4r)-4-(benzyloxy)cyclohexyl)methanol (950 mg, 4.31 mmol) in DCM (10 mL) was added CBr ₄ (1573 mg, 4.74 mmol) in DCM (2 mL) at 0 °C under a nitrogen atmosphere, followed by addition of PPh3 (1131.02 mg, 4.31 mmol) in DCM (2 mL) dropwise at 0 °C. After stirring for 3 h at rt, the reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (0-10% PE/EA) to afford the title compound (800 mg, 65.51%) as a colorless oil. 1-(((1r,4r)-4-(Benzyloxy)cyclohexyl)methyl)-5,5-dimethyl-3-( (2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione A solution of ((((1r,4r)-4-(bromomethyl)cyclohexyl)oxy)methyl)benzene (0.78 g, 2.75 mmol), 5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidi ne-2,4-dione (0.71 g, 2.75 mmol) and Cs ₂ CO ₃ (1.35 g, 4.13 mmol) in DMF (15 mL) was heated at 50 °C for 12 h. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate. The organic layer was concentrated to afford the title compound (0.8 g, 63.05%) as a light-yellow oil. MS (ESI): mass calcd. for C ₂₅ H ₄₀ N ₂ O ₄ Si: 460.28, found: 483.30 [M+Na] ⁺ . 1-(((1r,4r)-4-Hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione To a solution of 1-(((1r,4r)-4-(benzyloxy)cyclohexyl)methyl)-5,5-dimethyl-3-( (2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (0.8 g, 1.74 mmol) in MeOH (10 mL) was added Pd/C (10%, 0.1 g) under a N ₂ atmosphere. The reaction was then stirred for 1 h under a hydrogen atmosphere (balloon). The reaction was filtered through a pad of Celite and concentrated under reduced pressure to afford the title compound Int A (0.5 g, 77.70%) as a colorless oil. MS (ESI): mass calcd. for C ₁₈ H ₃₄ N ₂ O ₄ Si: 370.23, found: 393.3 [M+Na] ⁺ . 1-Butyl-6-chloro-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2 - (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)pyrimidine- 2,4(1H,3H)-dione To a solution of 1-butyl-6-chloropyrimidine-2,4(1H,3H)-dione (300 mg, 1.48 mmol) in DCM (5 mL) was added 1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione IntA (548 mg, 1.48 mmol) and triphenylphosphine (581 mg, 2.22 mmol), followed by addition of DEAD (261.83 mg, 1.50 mmol) dropwise at 0 °C under N ₂ . After stirring overnight at rt, the reaction was quenched with water (10 mL) and extracted with DCM (15 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE:EA = 3:1) to afford the title compound (107 mg, 13.0%). MS (ESI): mass calcd. for C26H43ClN4O5Si: 554.27, found: 555.35 [M+H] ⁺ . 3-Amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazo lidin-1 yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H) -dione The title compound 85 was synthesized from 1-butyl-6-chloro-3-((1s,4s)-4-((5,5- dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imida zolidin-1- yl)methyl)cyclohexyl)pyrimidine-2,4(1H,3H)-dione in similar procedures as described in Example 81. MS (ESI): mass calcd. for C21H30N6O4S: 462.20, found: 463.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.13 (s, 2H), 4.42-4.81 (m, 1H), 3.91 (t, J = 7.4 Hz, 2H), 2.55-2.85 (m, 3H), 1.95-2.10 (m, 2H), 1.75 (d, J = 13.5 Hz, 2H), 1.41-1.67 (m, 6H), 1.20-1.32 m, 8H), 0.90 (t, J = 7.3 Hz, 3H). Example 90 was synthesized in similar procedures as described in Example 85. Example 99 was synthesized in similar procedures as described in Example 85, with DMBNH2 replacing PMBNH2. Example 101 was synthesized in similar procedures as described in Example 85, with MeNH ₂ replacing PMBNH ₂ . Example 102 was synthesized in similar procedures as described in Example 85, with isopropylamine replacing PMBNH2. Example 86: 1-((1s,4s)-4-((2-Aminoethyl)(oxetan-3-yl)amino)cyclohexyl)-3 -butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione Synthetic scheme:

tert-Butyl (2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotet rahydropyrimidin- 1(2H)-yl)cyclohexyl)amino)ethyl)carbamate To a solution of 1-((1s,4s)-4-aminocyclohexyl)-3-butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared in similar procedures as described in Example 18, 140 mg, 0.43 mmol) in MeOH (3 mL) was added tert-butyl N-(2- oxoethyl)carbamate (83 mg, 0.52 mmol) and AcOH AcOH (78 mg, 1.299 mmol). After stirring for 30 min, 1-boraneyl-2-methyl-1λ4-pyridine (138 mg, 1.3 mmol) was added in portions at 0 °C. The resulting mixture was stirred at rt overnight. The reaction was quenched with ice water and extracted with DCM/MeOH (6:1). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to afford the title compound (90 mg, 44.56%). MS (ESI): mass calcd. for C ₂₂ H ₃₈ N ₆ O ₅ : 466.29, found: 467.25[M+H] ⁺ . Tert-Butyl (2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)(oxetan-3-yl)a mino)ethyl)carbamate To a solution of tert-butyl (2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)amino)ethyl)ca rbamate (70 mg, 0.15 mmol) in DMF (3 mL) was added Cs2CO3 (98 mg, 0.30 mmol) and 3-bromooxetane (103 mg, 0.75 mmol). After heating at 50 °C overnight, the reaction was quenched with water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography to afford the title compound (30 mg, 38.26%) as a yellow solid. MS (ESI): mass calcd. for C ₂₅ H ₄₂ N ₆ O ₆ : 522.32, found: 523.25 [M+H] ⁺ . 1-((1s,4s)-4-((2-Aminoethyl)(oxetan-3-yl)amino)cyclohexyl)-3 -butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione A solution of tert-butyl (2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)(oxetan-3-yl)a mino)ethyl)carbamate (30 mg, 0.057 mmol) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at rt for 1 h. The resulting mixture was concentrated and purified by reverse phase HPLC (20% to 50% (v/v) ACN and H ₂ O with 0.05% NH ₄ HCO ₃ ) to afford the title compound 86 (2.1 mg, 8.26%) as a yellow solid. MS (ESI): mass calcd. for C20H30N6O4: 422.26, found: 423.20 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d ₆ ) δ 9.08 (s, 2H), 8.95 (s, 2H), 5.06 (s, 2H), 4.64 (t, J = 11.3 Hz, 1H), 4.01 (td, J = 10.5, 5.0 Hz, 2H), 3.65-3.80 (m, 5H), 2.50-2.71 (m, 7H), 1.77 (d, J = 13.5 Hz, 2H), 1.35-1.49 (m, 4H), 1.24 (td, J = 15.5, 7.5 Hz, 4H), 0.88 (t, J = 7.3 Hz, 3H). Example 77 was synthesized in similar procedures as described in Example 86. Example 87: 5-Butyl-7-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1- yl)methyl)cyclohexyl)-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidi ne-4,6(5H)-dione (87) Synthetic scheme: O O O SEMCl,K ₂ CO ₃ LiOH, Me HN O _SEM N ^O OH SEM N OH N DMF N _H ^N H 2 _{NH2 2} O, THF ^N _NH2 SEM ^O N _HO NH ₂ O O N _N ^N SEM HATU, DIEA _SEM ^CDI N ^N N NH O N _H DMF _NH2 DMF O DEAD, PPh ₃ SEM N NH O N O N O O N N N N TFA/DCM O _N ^N SEM O _N ^NH NH ₃ O O Ethyl 3-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-c arboxylate To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (3 g, 19.34 mmol) in DMF (80 mL) was added K ₂ CO ₃ (4.01 g, 29.0 mmol) and SEMCl (3.87 g, 23.20 mmol). After stirring overnight at rt, the reaction was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (PE:EA = 3:1) to afford the title compound as a yellow oil. MS (ESI): mass calcd. for C12H23N3O3Si: 285.15, found: 286.10 [M+H] ⁺ . 3-Amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-c arboxylic acid To a solution of ethyl 3-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxylate (600 mg, 2.10 mmol) in MeOH (5 mL) and H2O (1 mL) was added LiOH (503 mg, 21.02 mmol). The resulting mixture was stirred at rt overnight. The reaction was acidified to pH = 6 with 2 N HCl, diluted with water (20 mL) and extracted with DCM/MeOH (6:1). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude title compound (450 mg, 83.18%) which was used in the next step without further purification. 3-Amino-N-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyra zole-4-carboxamide To a solution of 3-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-c arboxylic acid (450 mg, 1.748 mmol) and butylamine (153 mg, 2.1 mmol) in DMF (7 mL) was added DIPEA (451 mg, 3.5 mmol) and HATU (997.26 mg, 2.62 mmol). After stirring at room temperature overnight, the reaction was quenched with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (PE:EA = 2:1) to afford the title compound (400 mg, 73.21%) as a yellow oil. MS (ESI): mass calcd. for C ₁₄ H ₂₈ N ₄ O ₂ Si: 312.20, found: 313.15[M+H] ⁺ . 5-Butyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-dihydro-4H- pyrazolo[3,4-d]pyrimidine- 4,6(5H)-dione To a solution of 3-amino-N-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyra zole-4- carboxamide (200 mg, 0.64 mmol) in DMF (5 mL) was added DIPEA (248 mg, 1.92 mmol) and CDI (622 mg, 3.84 mmol). After heating at 70 °C for 5 h, the reaction was cooled down, quenched with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (PE:EA = 2:1) to afford the title compound (150 mg, 69.24%) as a white solid. MS (ESI): mass calcd. for C ₁₅ H ₂₆ N ₄ O ₃ Si: 338.18, found: 339.25[M+H] ⁺ . 5-Butyl-7-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2,7-dihydro-4H-pyrazolo[3,4-d ]pyrimidine-4,6(5H)-dione SEM N O N O N N O _N ^N SEM O To a solution of 5-butyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrazolo[3,4 - d]pyrimidine-4,6-dione (125 mg, 0.37 mmol) and 1-(((1r,4r)-4-hydroxycyclohexyl)methyl)- 5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidi ne-2,4-dione (IntA in Example 85, 136 mg, 0.37 mmol) in DCM (5 mL) was added PPh3 (193 mg, 0.74 mmol) and DEAD (128 mg, 0.74 mmol) at 0 °C under a N ₂ atmosphere. After stirring for 3 h at rt, the reaction was quenched with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (PE:EA = 2:1) to afford the title compound as a light-yellow oil. MS (ESI): mass calcd. for C33H58N6O6Si2: 690.40, found: 691.35 [M+H] ⁺ . 5-Butyl-7-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1- yl)methyl)cyclohexyl)-2,7- dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione A solution of 5-butyl-7-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2,7-dihydro-4H-pyrazolo[3,4-d ]pyrimidine-4,6(5H)-dione (80 mg, 0.12 mmol) in TFA (1 mL) and DCM (3 mL) was stirred at rt for 1 h. The reaction was neutralized to pH = 7 with NaHCO3 solution and extracted with DCM/MeOH. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was added NH ₃ in MeOH (3 mL) and stirred at rt for 1 h. The resulting mixture was concentrated and purified by reverse phase HPLC (22-52% (v/€ACN in and H2O with 0.05% NH4HCO3) to afford the title compound 87 (8.8 mg, 17.63%) as a white solid. MS (ESI): mass calcd. for C ₂₁ H ₃₀ N ₆ O ₄ : 430.23, found: 431.15 [M+H] ⁺ . ¹ H NMR (400 MHz; DMSO-d6) δ 13.54 (br, 1H), 10.82 (br, 1H), 8.46 (s, 1H), 4.63 (t, J = 12.0 Hz, 1H), 3.84 (dd, J = 7.4, 7.2 Hz, 2H), 3.37 (d, J = 7.6 Hz, 2H), 2.66-2.77 (m, 2H), 2.07 (br s, 1H), 1.77 (br d, J = 13.1 Hz, 2H), 1.40-1.58 (m, 6H), 1.23-1.36 (m, 8H), 0.89 (d, J = 14.7 Hz, 3H). Example 88 was synthesized in similar procedures as described in Example 87. Example 89: 7-Butyl-5-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidin -1- yl)methyl)cyclohexyl)-1,7-dihydro-4H-pyrazolo[3,4-d]pyrimidi ne-4,6(5H)-dione (89) Synthetic scheme: 1-Butyl-6-chloro-2,4-dioxo-3-((1s,4s)-4-((3,5,5-trimethyl-2, 4-dioxoimidazolidin-1- yl)methyl)cyclohexyl)-1,2,3,4-tetrahydropyrimidine-5-carbald ehyde To a solution of 1-butyl-3-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidin -1- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (see Example 62 for procedure, 600 mg, 1.43 mmol) in POCl ₃ (10 mL ) was added DMF (2 mL) at 0 °C. The resulting mixture was heated for 3 h at 100 °C. After cooling down, the reaction was concentrated, quenched with ice water, and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated to yield a crude product, which was purified by silica gel column chromatography (0-15% DCM/MeOH) to afford the title compound (100 mg, 15.0%) as a yellow oil. MS (ESI): mass calcd. for C22H31ClN4O5: 466.20, found: 489.10 [M+Na] ⁺ . 7-Butyl-5-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidin -1-yl)methyl)cyclohexyl)-1,7- dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione To a solution of 1-butyl-6-chloro-2,4-dioxo-3-((1s,4s)-4-((3,5,5-trimethyl-2, 4- dioxoimidazolidin-1-yl)methyl)cyclohexyl)-1,2,3,4-tetrahydro pyrimidine-5-carbaldehyde (150 mg, 0.32 mmol) in MeOH (8 mL ) was added hydrazine hydrochloride (44 mg, 0.64 mmol) at rt, followed by addition of TEA (163 mg, 1.605 mmol) at 0 °C. After heating at 70 °C for 1.5 h, the reaction was quenched with water (20 mL) and extracted with DCM/MeOH (5:1, 3 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue obtained was purified by reverse phase HPLC (17% to 42% (v/v) CH ₃ CN and H ₂ O with 10 mmol/L NH ₄ HCO ₃ ) to afford the title compound 89 (8.7 mg, 6.51%) as a white solid. MS (ESI): mass calcd. for C22H32N6O4: 444.25, found: 445.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 13.43 (br s, 1H), 8.45 (s, 1H), 4.74 (s, 1H), 3.92 (t, J = 7.4 Hz, 2H), 3.39 (d, J = 7.6 Hz, 2H), 2.87 (s, 3H), 2.57-2.75 (m, 2H), 2.04-2.14 (m, 1H), 1.69-1.80 (m, 2H), 1.59-1.69 (m, 2H), 1.42-1.58 (m, 2H), 1.21- 1.38 (m, 10H), 0.92 (t, J = 7.3 Hz, 3H). Example 98.5-Amino-1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimid azolidin-1- yl)methyl)cyclohexyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dion e (98) Synthetic scheme:

1-Butyl-6-methylpyrimidine-2,4(1H,3H)-dione To a solution of butylurea (6.91 g, 59.471 mmol) in pyridine (50 mL) was added 4- methyleneoxetan-2-one (5 g, 59.47 mmol) at 0 °C under a nitrogen atmosphere. After stirring at rt overnight, most of the solvent was evaporated. The resulting solid was collected by filtration, washed with ether, and dried under vacuum to give N-(butylcarbamoyl)-3- oxobutanamide. AcOH (60 mL) was added to it, and the resulting mixture was heated at 115 °C for 2 h under a nitrogen atmosphere. The reaction was cooled down and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (0-100% PE/EA) to afford the title compound (1.2 g, 64.30%) as a yellow oil. MS (ESI): mass calcd. for C9H14N2O2: 182.11, found: 183.20 [M+H] ⁺ . 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-6- methylpyrimidine-2,4(1H,3H)-dione To a solution of 1-butyl-6-methylpyrimidine-2,4(1H,3H)-dione (250 mg, 1.37 mmol) in DCM (5 mL) was added 1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3- ((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (IntA in Example 85, 510 mg, 1.38 mmol), PPh3 (719 mg, 2.74 mmol) at rt, followed by addition of DEAD (477 mg, 2.74 mmol) under N ₂ . After stirring at rt for 2.5 h, the reaction was quenched with water (50 mL) and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield a crude product, which was purified by silica gel column chromatography (0-100% PE/EA) to afford the title compound (400 mg, 54.52%) as a yellow solid. MS (ESI): mass calcd. for C27H46N4O5Si: 534.32, found: 535.30 [M+H] ⁺ . 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-5-(hydroxymethyl)- 6-methylpyrimidine-2,4(1H,3H)-dione To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-6-methylpyrimidine- 2,4(1H,3H)-dione (360 mg, 0.67 mmol) in AcOH (10 mL) was added HCHO (80 mg, 2.692 mmol). The reaction mixture was heated at 100 °C for 6 h. The reaction was concentrated under reduced pressure to afford a crude product, which was suspended in a 1% aqueous of NaOH (10 mL), DMF (10 mL) and heated at reflux for 1 h. The reaction mixture was acidified to pH = 5 with 10% HCl and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over Na2SO4, and concentrated to yield a crude product, which was directly purified by silica gel column chromatography to afford the title compound (120 mg, 31.56%) as a yellow solid. MS (ESI): mass calcd. for C28H48N4O6Si: 564.33, found: 565.15 [M+H] ⁺ . 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-6-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carbaldehyde To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-5-(hydroxymethyl)-6- methylpyrimidine-2,4(1H,3H)-dione (110 mg, 0.195 mmol) in DCM (3 mL) was added Dess- Martin reagent (165 mg, 0.390 mmol). After stirring for 3 h at rt, the reaction was quenched by water (5 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford a crude product (0.1 g, 90.9%) as a yellow oil, which was directly used in the nex€tep. (E)-1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-6-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carbaldehyde oxime To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-6-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (100 mg, 0.18 mmol) in MeOH (3 mL)/H2O (3 mL) was added NH ₂ OH ^. HCl (245 mg, 3.56 mmol). After stirring for 0.5 h at rt, the reaction was quenched with water (5 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford a crude title compound (0.1 g, 98.5%) as a yellow oil, which was used directly in next step. 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-6-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carbonitrile A stirred €ution of (E)-1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-6-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carbaldehyde oxime (90 mg, 0.156 mmol) in Ac2O (4 mL) was heated at 90 °C for 3 h. After completion, the reaction was quenched with water (2 mL) and extracted with CH ₂ Cl ₂ (10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound (60 mg, 68.97%) as a yellow oil. MS (ESI): mass calcd. for C ₂₈ H ₄₅ N ₅ O ₅ Si: 559.32, found: 560.35 [M+H] ⁺ . 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-6-((E)-2- (dimethylamino)vinyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carbonitrile A solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-6-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carbonitrile (60 mg, 0.11 mmol) and 1,1-dimethoxy-N,N- dimethylmethanamine (64 mmol, 0.54 mmol) in DMF (3 mL) was heated for 2 h at 80 °C. After cooling down to rt, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (30 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound (50 mg, 75.76%) as a yellow oil, which was used directly in next step. 5-Amino-1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)pyrido[4,3- d]pyrimidine-2,4(1H,3H)-dione A solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-6-((E)-2- (dimethylamino)vinyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carbonitrile (50 mg, 0.081 mmol) in NH4OH (1 mL) and DMF (4 mL) was heated overnight at 100 °C. The reaction mixture was quenched with water (3 mL) and extracted with ethyl acetate (10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography using (0-10% MeOH in DCM) to afford the title compound (30 mg, 62.89%) as a yellow oil. MS (ESI): mass calcd. for C ₂₉ H ₄₆ N ₆ O ₅ Si: 586.33, found: 587.35 [M+H] ⁺ . 5-Amino-1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazo lidin-1- yl)methyl)cyclohexyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dion e A solution of 5-amino-1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)pyrido[4,3-d]pyrimidine- 2,4(1H,3H)-dione (25 mg, 0.043 mmol) and TFA (0.6 mL) in DCM (1.8 mL) was stirred for 1 h at rt and concentrated under reduced pressure. To the above mixture was added 7 N NH ₃ in MeOH (1 mL). The resulting mixture was stirred for additional 30 min. The residue was purified by reversed phase HPLC (ACN in TFA aqueous solution, 10-50% ACN in water with TFA as a modifier) to afford the title compound 98 (8.8 mg, 45.08%) as a white solid. MS (ESI): mass calcd. for C23H32N6O4: 456.25, found 457.10 [M+H] ⁺ . ¹ H NMR (300 MHz, Acetonitrile-d3) δ 8.13 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 4.91-5.10 (m, 1H), 4.29 (t, J = 7.4 Hz, 2H), 3.63 (d, J = 8.0 Hz, 2H), 2.80 (q, J = 12.1 Hz, 2H), 2.33 (br s, 1H), 1.99 (br d, J = 13.5 Hz, 2H), 1.73-1.89 (m, 4H), 1.52-1.70 (m, 10H), 1.13 (t, J = 7.3 Hz, 3H). Example 100: 1-Butyl-5-(diaminomethylene)-3-(2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (100) Synthetic scheme: 1-Butyl-5-(diaminomethylene)-3-(2,4-dioxo-1,3-diazadispiro[4 .1.5 ⁷ .1 ⁵ ]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of IntB (50 mg, 0.138 mmol) in EtOH (2 mL) was added NaHSO3 (5.74 mg, 0.055 mmol), KCN (17.97 mg, 0.28 mmol) and (NH ₄ ) ₂ CO ₃ (106 mg, 1.10 mmol). The reaction was heated at 130 °C for 24 h. The mixture was concentrated to dryness under reduced pressure to provide a crude product, which was purified by reverse phase HPLC (26% to 45% (v/v) ACN and H ₂ O with 0.05% NH ₄ HCO ₃ ) to afford the title compound 100 (10.8 mg, 18.06%) as a white solid. MS (ESI): mass calcd. for C20H28N6O5: 432.21, found: 433.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.42-10.58 (m, 1H), 9.55 (s, 2H), 8.40 (s, 1H), 7.31 (s, 2H), 4.55-4.70 (m, 1H), 3.73 (t, J = 7.4 Hz, 2H), 2.13-2.37 (m, 5H), 1.97 (t, J = 12.9 Hz, 2H), 1.87 (d, J = 12.5 Hz, 1H), 1.32-1.51 (m, 5H), 1.17-1.31 (m, 3H), 0.88 (t, J = 7.3 Hz, 3H). Example 103: 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1- yl)methyl)cyclohexyl)imidazo[1,2-a][1,3,5]triazine-2,4(1H,3H )-dione (103) Synthetic scheme: 1-Butylimidazo[1,2-a][1,3,5]triazine-2,4(1H,3H)-dione To a solution of 1H-imidazo[1,2-a][1,3,5]triazine-2,4-dione (1 g, 6.57 mmol) in DMSO (50 mL) was added NaH (657.35 mg, 16.44 mmol, 60% in mineral oil) at 0°C. The mixture was stirred at 0 °C for 30 min, and 1-iodobutane (1.21 g, 6.57 mmol, 746.77 uL) was added at 25°C. After stirring for 2 h, the reaction was poured into saturated NH ₄ Cl (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EA = 5:1 to 3:1) to provide the title compound (0.26 g, 19%) as a white solid. MS (ESI): mass calcd. for C ₉ H ₁₂ N ₄ O ₂ : 208.10, found: 209.2 [M+H] ⁺ . 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimeth ylsilyl)ethoxy)methyl) imidazolidin-1-yl)methyl)cyclohexyl)imidazo[1,2-a][1,3,5]tri azine-2,4(1H,3H)-dione To a mixture of 1-butylimidazo[1,2-a][1,3,5]triazine-2,4(1H,3H)-dione (0.2 g, 0.960 mmol) and 1-[(4-hydroxycyclohexyl)methyl]-5,5-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione (IntA in Example 85, 355.93 mg, 0.96 mmol) in toluene (2 mL) was added 2-(tributyl-λ5-phosphanylidene)acetonitrile (811.40 mg, 3.36 mmol) in one portion at 25 °C under Ar. The reaction was heated at 100°C for 12 h. After completion, the mixture was poured into H2O (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA = 1:1) to provide the title compound (0.17 g, 19%) as a white solid. MS (ESI): mass calcd. for C27H44N6O5Si: 560.31, found: 561.3 [M+H] ⁺ . 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1- yl)methyl)cyclohexyl)imidazo [1,2-a][1,3,5]triazine-2,4(1H,3H)-dione To a mixture of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)imidazo[1,2- a][1,3,5]triazine-2,4(1H,3H)-dione (0.17 g, 0.30 mmol) in DCM (2 mL) and H ₂ O (0.2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 0.5 h, poured into aq. NaHCO3 (5 mL) and extracted with DCM (2 x 5 mL). The combined organic layer was washed with brine (5 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (25-55% ACN in water (NH4HCO3)) to provide the title compound 103 (5.5 mg, 4.21%) as a white solid. MS (ESI): mass calcd. for C ₂₁ H ₃₀ N ₆ O ₄ : 430.23, found: 431.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1 H), 7.46 (d, J = 1.6 Hz, 1 H), 7.01 (d, J = 1.6 Hz, 1 H), 4.51-4.64 (m, 1H), 3.95 (t, J = 7.2 Hz, 2 H), 2.53-2.61 (m, 2H), 1.99-2.09 (m, 1 H), 1.62-1.78 (m, 5H), 1.46-1.53 (m, 4H), 1.28-1.39 (m, 9H), 0.87-0.94 (m, 3H). Examples 106 was synthesized in similar procedures as described in Example 81 and Example 82, without chiral separation. Example 108 and Example 109 were synthesized in similar procedures as described in Example 104 and Example 105. Stereochemistry is arbitrarily assigned. Example 110.1-(7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydr opyrimidin- 1(2H)-yl)spiro[3.5]nonan-2-yl)-1-cyclopropylurea (110) Synthetic scheme: N-Cyclopropyl-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-amine To a solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one (500 mg, 2.55 mmol) in MeOH (5 mL) was added cyclopropanamine (290.9 mg, 5.1 mmol) and AcOH (306 mg, 5.1 mmol) at 25 °C. After 1 h, the reaction was added NaBH3CN (400.3 mg, 6.4 mmol) and heated at 60 °C for 12 h. After completion, the reaction was concentrated under reduced pressure. The residue was diluted with H ₂ O (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (6.8 g, crude) as a yellow oil, which was used directly in the next step without further purification. ¹ H NMR (400 MHz, CDCl3) δ ppm 5.57 (br s, 1H), 3.93 (s, 4H), 3.47-3.58 (m, 1H), 2.21-2.32 (m, 2H), 1.78-1.86 (m, 2H), 1.65-1.75 (m, 4H), 1.55-1.65 (m, 4H), 0.68-0.76 (m, 2H), 0.61-0.68 (m, 2H). Benzyl cyclopropyl(8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)carbamate To a solution of N-cyclopropyl-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-amine (1.7 g, 7.16 mmol) in DCM (20 mL) was added CbzCl (1.23 g, 7.23 mmol) and TEA (1.45 g, 14.33 mmol) at 25 °C. After stirring for 1 h, the reaction was diluted with H ₂ O (60 mL) and extracted with DCM (3 x 40 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 = 100 : 0 to 0 : 100) to provide the title compound (6.2 g, 58.3%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.16-7.26 (m, 5H), 5.02 (s, 2H), 3.92-4.01 (m, 1H), 3.83 (s, 4H), 2.36-2.42 (m, 1H), 1.95-2.08 (m, 4H), 1.54-1.58 (m, 2H), 1.47-1.53 (m, 6H), 0.65-0.73 (m, 2H), 0.48-0.56 (m, 2H). Benzyl cyclopropyl(7-oxospiro[3.5]nonan-2-yl)carbamate To a solution of benzyl cyclopropyl(8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2- yl)carbamate (3.1 g, 8.35 mmol) in acetone (30 mL) and H ₂ O (15 mL) was added TsOH.H ₂ O (3.17 g, 16.69 mmol) at 25 °C. After stirring for 2 h, the reaction was diluted with H ₂ O (30 mL) and extracted with EtOAc (3 x 20 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 = 100 : 0 to 0 : 100) to provide the title compound (5.5 g, crude) as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C20H25NO3: 327.18, found: 328.1 [M+H] ⁺ . Benzyl (7-aminospiro[3.5]nonan-2-yl)(cyclopropyl)carbamate To a mixture of benzyl cyclopropyl(7-oxospiro[3.5]nonan-2-yl)carbamate (5.5 g, 16.8 mmol) and NH ₄ OAc (25.9 g, 0.34 mmol) in MeOH (60 mL) was added NaBH(OAc) ₃ (8.9 g, 42 mmol) in one portion at 25 °C under N ₂ . After heating at 50 °C for 12 h, the reaction was concentrated under reduced pressure. The residue was adjusted to pH = 8 by saturated NaHCO ₃ . The mixture was diluted with H ₂ O (40 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to provide the title compound (6 g, crude) as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C ₂ H ₂₈ N ₂ O ₂ : 328.22, found: 329.3 [M+H] ⁺ . Benzyl (7-(3-butylureido)spiro[3.5]nonan-2-yl)(cyclopropyl)carbamat e To a solution of benzyl (7-aminospiro[3.5]nonan-2-yl)(cyclopropyl)carbamate (6 g, 18.3 mmol) in DCM (60 mL) was added 1-isocyanatobutane (2.72 g, 27.4 mmol) and TEA (3.7 g, 36.5 mmol) at 25 °C. After stirring for 1 h, the reaction was quenched with H2O and extracted with DCM 60 mL (3 x 20 mL). The combined organic layer was washed with brine 30 mL (2 x 15 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 0 to 0 : 100) to provide the title compound (4.1 g, 52.5%) as a white solid. MS (ESI): mass calcd. for C ₂₅ H ₃₇ N ₃ O ₃ : 427.28, found: 428.4 [M+H] ⁺ . Benzyl (7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3 .5]nonan-2- yl)(cyclopropyl)carbamate To a solution of benzyl (7-(3-butylureido)spiro[3.5]nonan-2- yl)(cyclopropyl)carbamate (1.2 g, 2.8 mmol) in AcOH (12 mL) was added malonic acid (292.1 mg, 2.8 mmol) and Ac ₂ O (2.01 g, 19.7 mmol) at 25 °C. After heating at 80 °C under N2 for 12 h, the reaction was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 0 to 0 : 100) to provide the title compound (1.3 g, 93.5%) as a yellow solid. MS (ESI): mass calcd. for C28H37N3O5: 495.27, found: 496.4 [M+H] ⁺ . 1-Butyl-3-(2-(cyclopropylamino)spiro[3.5]nonan-7-yl)pyrimidi ne-2,4,6(1H,3H,5H)- trione To a solution of benzyl (7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)- yl)spiro[3.5]nonan-2-yl)(cyclopropyl)carbamate (1.3 g, 2.62 mmol) in MeOH (20 mL) was added 5% Pd/C (300 mg, 0.14 mmol) under N2. The suspension was degassed and purged with H2 three times. The reaction was stirred under H2 (15 Psi) at 20 °C for 48 h. After completion, the reaction was filtered through a Celite pad and washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to provide the title compound (1.25 g, crude) as a white solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C ₂₄ H ₃₁ N ₃ O ₃ : 361.24, found: 362.2 [M+H] ⁺ . 1-(7-(3-Butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro [3.5]nonan-2-yl)-1- cyclopropylurea A solution of 1-butyl-3-(2-(cyclopropylamino)spiro[3.5]nonan-7-yl)pyrimidi ne- 2,4,6(1H,3H,5H)-trione (1.2 g, 3.3 mmol) in DCM (15 mL) was treated with TEA (1.68 g, 16.6 mmol) followed by the addition of isocyanato(trimethyl)silane (1.53 g, 13.3 mmol) dropwise at 15 °C. After stirring for 16 h, the reaction was concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC [H2O (10 mM NH4HCO3)- ACN]; gradient 10% to 40% B) to provide the title compound (300 mg, 22.3%) as a red solid. MS (ESI): mass calcd. for C ₂₁ H ₃₂ N ₄ O ₄ : 404.24, found: 405.3 [M+H] ⁺ . 1-(7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyr imidin-1(2H)- yl)spiro[3.5]nonan-2-yl)-1-cyclopropylurea (110) To a solution of 1-(7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)- yl)spiro[3.5]nonan-2-yl)-1-cyclopropylurea (80 mg, 0.2 mmol) in THF (0.1 mL) was added bis[(Z)-1-methyl-3-oxo-but-1-enoxy]nickel (25.4 mg, 0.099 mmol) and cyanamide (24.9 mg, 0.59 mmol) at 15 °C. After heating at 85 °C for 12 h, the reaction was diluted with H2O (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (mobile phase: [H2O (10 mM NH4HCO3)- ACN]; gradient 25% to 55% B) to provide the title compound (racemic, 4.2 mg, 4.6%) as a white solid. MS (ESI): mass calcd. for C ₂₂ H ₃₄ N ₆ O ₄ : 446.26, found: 447.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.29 (s, 2H), 5.78 (s, 2H), 4.52-4.70 (m, 1H), 4.03-4.21 (m, 1H), 3.67-3.80 (m, 2H), 2.29-2.42 (m, 2H), 2.10-2.18 (m, 1H), 1.92-2.05 (m, 2H), 1.84-1.92 (m, 1H), 1.74-1.83 (m, 1H), 1.55-1.66 (m, 1H), 1.40-1.49 (m, 2H), 1.19-1.38 (m, 6H), 0.88 (t, J = 7.2 Hz, 3H), 0.70-0.84 (m, 2H), 0.52-0.60 (m, 2H). Example 169 was synthesized in similar procedures as described in Example 110. Example 175 was synthesized in similar procedures as described in Example 110, with Boc as the protecting group instead of Cbz. Example 111.7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidi n-1- yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazol o[3,4-d]pyrimidine-3- carboxamide (111) Synthetic scheme: 7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-4,6-dioxo-4,5,6,7- tetrahydroisothiazolo[3,4-d]pyrimidine-3-carboxamide O NH S ₂ N O O N N O _N ^N SEM O To a solution of 7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-4,6-dioxo-4,5,6,7- tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbonitrile (an intermediate from Example 85 synthesis, 100 mg, 0.17 mmol) was added K2CO3 (27.51 mg, 0.2 mmol) and 30% H2O2 (94 mg, 0.83 mmol) in DMSO (1 mL). The reaction was stirred at 25 °C for 1 h under N ₂ . After completion, the reaction was quenched with water (1 mL). The aqueous layer was extracted with DCM (3 x 2 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by prep-TLC (SiO ₂ , petroleum ether : EtOAc = 3 : 1) to provide the title compound (90 mg, 87.4%) as a yellow oil. MS (ESI): mass calcd. for C28H44N6O6SSi 620.28, found: 643.2 [M+Na] ⁺ . 7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1- yl)methyl)cyclohexyl)-4,6- dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbo xamide To a solution of 7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-4,6-dioxo-4,5,6,7- tetrahydroisothiazolo[3,4-d]pyrimidine-3-carboxamide (90 mg, 0.14 mmol) in TFA (0.5 mL) was added H2O (0.1 mL). After stirring at 25 °C for 1 h, the reaction was concentrated under reduced pressure and added MeOH (5 mL) and K2CO3 (100 mg). After stirring for 10 min, the reaction was concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (mobile phase: [water (NH ₄ HCO ₃ )-ACN]; 30% to 60% B) to provide the title compound (3.6 mg, 5.1%) as a white solid. MS (ESI): mass calcd. for C22H30N6O5S: 490.20, found: 491.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 10.41 (s, 1H), 7.63 (s, 1H), 6.14 (s, 1H), 4.82-4.94 (m, 1H), 4.20 (t, J = 7.6 Hz, 2H), 3.47 (d, J = 8.0 Hz, 2H), 2.72-2.76 (m, 2H), 2.20 (br s, 1H), 1.84 (br d, J = 12.8 Hz, 2H), 1.63-1.79 (m, 5H), 1.38-1.49 (m, 9H), 0.99 (t, J = 7.2 Hz, 3H). Example 112. N-(7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin -1- yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazol o[3,4-d]pyrimidin-3- yl)methanesulfonamide Synthetic scheme: 7-Butyl-3-((2,4-dimethoxybenzyl)amino)-5-((1s,4s)-4-((5,5-di methyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)isothiazolo[3,4- d]pyrimidine-4,6(5H,7H)-dione To a solution of 7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)-4,6-dioxo-4,5,6,7- tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbonitrile (an intermediate from Example 85 synthesis, 1.35 g, 2.2 mmol) in DMA (20 mL) was added (2,4- dimethoxyphenyl)methanamine (3.74 g, 22.4 mmol). After heating at 90 °C for 3 h, the reaction was diluted with H ₂ O (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 1 to 2 : 1) to provide the title compound (1.2 g, 72%) as a yellow solid. ¹ H NMR (400 MHz, CDCl3) δ ppm 7.90 (t, J = 6.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.43-6.49 (m, 2H), 4.94 (s, 2H), 4.71-4.83 (m, 1H), 4.32 (d, J = 6.0 Hz, 2 H), 3.98-4.05 (m, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.59-3.65 (m, 2H), 3.46 (d, J = 7.6 Hz, 2H), 2.70 (dq, J = 12.8, 3.2 Hz, 2H), 2.23 (br s, 1H), 1.79 (br d, J = 13.6 Hz, 2H), 1.63-1.77 (m, 6H), 1.45 (s, 6H), 1.34-1.42 (m, 2H), 0.90-0.97 (m, 5H), 0.00 (s, 9H). 3-Amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazo lidin-1- yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H) -dione A solution of 7-butyl-3-((2,4-dimethoxybenzyl)amino)-5-((1s,4s)-4-((5,5-di methyl- 2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1 - yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H) -dione in TFA (20 mL) and H2O (4 mL) was stirred at 20 °C for 1 h. The crude residue was diluted with H2O (15 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to provide the title compound (0.66 g, 83.9%) as a white solid, which was used directly in the next step without further purification. N-(7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin -1-yl)methyl)cyclohexyl)- 4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidin-3-yl )methanesulfonamide To a solution of 3-amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazo lidin- 1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7 H)-dione (0.1 g, 0.22 mmol) in DCM (2 mL) was added TEA (218.8 mg, 2.2 mmol) and MsCl (123.8 mg, 1.1 mmol) at 0 °C. After stirring at 25 °C for 2 h, the reaction was diluted with NH ₄ Cl (5 mL) and extracted with DCM (3 x 3 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (water (NH ₄ HCO ₃ )-ACN) to provide the title compound (9.8 mg, 7%) as a white solid. MS (ESI): mass calcd. for C ₂₂ H ₃₂ N ₆ O ₆ S ₂ : 540.18, found: 540.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (s, 1H), 4.57-4.71 (m, 1H), 3.88-3.92 (d, J = 7.2 Hz, 2H), 3.52-3.54 (s, 3H), 2.56-2.70 (m, 1H), 2.02 (br s, 1H), 1.71-1.81 (m, 2H), 1.51-1.62 (m, 4H), 1.43 (s, 6 H), 1.24 - 1.37 (m, 5H), 0.89 (t, J = 7.2 Hz, 3H). Example 113.3-Amino-7-butyl-5-(2-(3-ethyl-5,5-dimethyl-2,4-dioxoimid azolidin-1- yl)spiro[3.5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H, 7H)-dione (113) Synthetic scheme: 5,5-Dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione To a solution of 5,5-dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)imidazolidine-2,4- dione (see Example 78 for synthesis, 10 g, 37.8 mmol) in DCM (100 mL) was added DIPEA (19.6 g, 151.3 mmol) and SEM-Cl (12.6 g, 75.7 mmol) at 0 °C. After stirring at 25 °C for 12 h, the reaction was quenched with saturated NH ₄ Cl (55 mL) and extracted with DCM (2 x 100 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 = 10 : 1 to 5 : 1) to provide the title compound (10 g, 667%) as a yellow oil. MS (ESI): mass calcd. for C20H34N2O4Si: 394.23, found: 393.4 [M- H]-. 1-(7-Hydroxyspiro[3.5]nonan-2-yl)-5,5-dimethyl-3-((2-(trimet hylsilyl)ethoxy)methyl) imidazolidine-2,4-dione (INT 3) To a solution of 5,5-dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione (10 g, 25.3 mmol) in MeOH (100 mL) was added NaBH ₄ (527.3 mg, 13.9 mmol) in several portions at 0 °C. After stirring 25 °C for 1 h, the reaction was quenched with H2O (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was 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 1 : 1) to provide the title compound (5.3 g, 52.7%) as a white solid. MS (ESI): mass calcd. for C20H36N2O4Si: 396.24, found: 419.2 [M+Na] ⁺ . 1-Butyl-6-chloropyrimidine-2,4(1H,3H)-dione To a mixture of 6-chloro-1H-pyrimidine-2,4-dione (5 g, 34.1 mmol) and 1-iodobutane (6.91 g, 37.5 mmol) in DMSO (25 mL) was added K ₂ CO ₃ (2.36 g, 17.1 mmol) in one portion at 25 °C under N2. After stirring at 25 °C for 12 h, the combined mixture was poured into water (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under redued pressure. The crude residue was triturated with petroleum ether (20 mL) and stirred for 5 min. The precipitate was collected by filtration, washed by petroleum ether (3 x 20 mL) and dried under vacuum to provide the title compound (4.5 g, 22.2 mmol, 65.1%) as a white solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C ₈ H ₁₁ ClN ₂ O ₂ : 202.05, found: 203.2 [M+H] ⁺ . 1-Butyl-6-chloro-3-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimeth ylsilyl)ethoxy)methyl) imidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4(1H,3H) -dione To a solution of 1-butyl-6-chloropyrimidine-2,4(1H,3H)-dione (1.04 g, 5.14 mmol) in toluene (10 mL) was added 1-(7-hydroxyspiro[3.5]nonan-2-yl)-5,5-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione (INT 3, 1.7 g, 4.3 mmol). The reaction was heated to 120 °C, and 2-(tributyl-λ ⁵ -phosphanylidene)acetonitrile (3.62 g, 15.00 mmol) was added dropwise. After stirring at 120 °C for 12 h under N ₂ , the reaction was quenched with H2O (20 mL) and extracted with EtOAc (2 x 20 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 1 : 1) to provide the title compound (1.4 g, 24%) as a colorless oil. MS (ESI): mass calcd. for C28H45ClN4O5Si: 580.28, found: 581.3 [M+H] ⁺ . 6-Amino-1-butyl-3-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethy lsilyl)ethoxy)methyl) imidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4(1H,3H) -dione To a solution of 1-butyl-6-chloro-3-(2-(5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine- 2,4(1H,3H)-dione (0.56 g, 0.96 mmol) in CH3CN (6 mL) was added NH3.H2O (6 mL). The reaction was heated to 90 °C for 12 h in a sealed tube. The reaction was diluted with H ₂ O (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.5 g, 92.4%) as a white solid, which was used in the next step directly without further purification. MS (ESI): mass calcd. for C28H47N5O5Si: 561.33, found: 562.3 [M+H] ⁺ . 7-Butyl-5-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)e thoxy)methyl)imidazolidin-1- yl)spiro[3.5]nonan-7-yl)-4,6-dioxo-4,5,6,7-tetrahydroisothia zolo[3,4-d]pyrimidine-3- carbonitrile To a solution of 6-amino-1-butyl-3-(2-(5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine- 2,4(1H,3H)-dione (1.36 g, 2.4 mmol) in DCM (15 mL) was added 4,5-dichlorodithiazol-2- ium chloride (1.01 g, 4.8 mmol). After cooling to 0 °C, pyridine (0.88 g, 11.14 mmol) was added and the reaction was stirred at 20 °C for 2 h. The reaction was diluted with H2O (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 10 : 1 to 1 : 1) to provide the title compound (756.9 mg, 42.3%) as a colorless oil. MS (ESI): mass calcd. for C ₃₀ H ₄₄ N ₆ O ₅ SSi: 628.29, found: 651.3 [M+Na] ⁺ . 7-Butyl-3-((2,4-dimethoxybenzyl)amino)-5-(2-(5,5-dimethyl-2, 4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[3.5]no nan-7-yl)isothiazolo[3,4- d]pyrimidine-4,6(5H,7H)-dione To a solution of (2,4-dimethoxyphenyl)methanamine (971.8 mg, 5.8 mmol) in DMA (10 mL) was added 7-butyl-5-[2-[5,5-dimethyl-2,4-dioxo-3-(2- trimethylsilylethoxymethyl)imidazolidin-1-yl]spiro[3.5]nonan -7-yl]-4,6-dioxo- isothiazolo[3,4-d]pyrimidine-3-carbonitrile (731 mg, 1.2 mmol). The reaction was stirred at 50 °C for 2 h and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 3 : 1 to 1 : 1) to provide the title compound (303 mg, 33.9%) as a colorless oil. MS (ESI): mass calcd. for C ₃₈ H ₅₆ N ₆ O ₇ SSi: 768.37, found: 769.3 [M+H] ⁺ . 3-Amino-7-butyl-5-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-y l)spiro[3.5]nonan-7- yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione A solution of 7-butyl-3-((2,4-dimethoxybenzyl)amino)-5-(2-(5,5-dimethyl-2, 4-dioxo- 3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[ 3.5]nonan-7-yl)isothiazolo[3,4- d]pyrimidine-4,6(5H,7H)-dione (205 mg, 0.27 mmol) in TFA (2.5 mL) and H2O (0.5 mL) was stirred at 20 °C for 2 h. The reaction was concentrated under reduced pressure and the crude residue was dissolved into MeOH (5 mL). K ₂ CO ₃ (20 mg) was added. The mixture was stirred at 25 °C for 1 h, filtered, washed with MeOH (5 mL) and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (Waters Xbridge BEH C18 100*30mm*10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; 40% to 70% B) to provide the title compound (15 mg, 11.5%) as a white solid. MS (ESI): mass calcd. for C ₂₃ H ₃₂ N ₆ O ₄ S: 488.22, found: 489.3 [M+H] ⁺ . 3-Amino-7-butyl-5-(2-(3-ethyl-5,5-dimethyl-2,4-dioxoimidazol idin-1-yl)spiro[3.5]nonan- 7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (113) To a solution of 3-amino-7-butyl-5-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1- yl)spiro[3.5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H, 7H)-dione (20 mg, 0.04 mmol) in DMF (2 mL) was added EtI (6.38 mg, 0.04 mmol) and K ₂ CO ₃ (4.53 mg, 0.03 mmol). After stirring at 20 °C for 2 h, the reaction was filtered to remove the insoluble solid. The filtrate was purified by reverse phase HPLC (Waters Xbridge BEH C18100*30mm*10 um; mobile phase: [water ( NH ₄ HCO ₃ )-ACN]; 40% to 70%B) to provide the title compound (113) as a white solid. MS (ESI): mass calcd. for C ₂₅ H ₃₆ N ₆ O ₄ S: 516.25, found: 517.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.09-8.14 (br s, 2H), 4.55-4.62 (m, 1H), 3.83-4.97 (m, 3H), 3.39-3.51 (m, 2H), 2.57-2.63 (m, 2H), 2.36-2.45 (m, 2H), 2.10-2.20 (m, 1H), 1.86-2.00 (m, 2H), 1.78-1.85 (m, 1H), 1.52-1.64 (m, 2H), 1.34-1.49 (m, 4H), 1.28-1.34 (m, 2H), 1.26 (d, J = 6.0 Hz, 6H), 1.08 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H). Example 144 was synthesized following the last step of Example 113 (with heating at 90 °C for 12 h) from Example 62. Example 114 and Example 115 were synthesized in the same route as Example 6 and with chiral separation. Stereochemistry is arbitrarily assigned. Example 116.1-Butyl-5-(diaminomethylene)-3-(4-((3,5,5-trimethyl-2,4- dioxoimidazolidin-1-yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H, 5H)-trione (116) Synthetic scheme: 3,5,5-Trimethylimidazolidine-2,4-dione To a solution of 5,5-dimethylimidazolidine-2,4-dione (5 g, 39 mmol) in EtOH (50 mL) was added MeI (11.08 g, 78.1 mmol) and NaOH (1.56 g, 39 mmol). After heating at 60 °C for 12 h, the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, which was purified by silica gel column chromatography (EtOAc : MeOH = 100 : 0 to 10 : 1) to provide the title compound (1.6 g, 28.8%) as a yellow solid. MS (ESI): mass calcd. for C ₆ H ₁₀ N ₂ O ₂ : 142.07, found: 143.3 [M+H] ⁺ . 1-(4-Bromobenzyl)-3,5,5-trimethylimidazolidine-2,4-dione To a solution of 1-bromo-4-(bromomethyl)benzene (1.58 g, 6.33 mmol) and 3,5,5- trimethylimidazolidine-2,4-dione (900 mg, 6.33 mmol) in THF (20 mL) was added NaH (253.2 mg, 6.33 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 h, quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 0 to 10 : 1) to provide the title compound (1.4 g, 71%) as a colorless oil. MS (ESI): mass calcd. for C ₁₃ H ₁₅ BrN ₂ O ₂ : 310.03, found: 311.1 [M+H] ⁺ . Ethyl 2-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-6-yl)-3,3,3 -trifluoro-2- hydroxypropanoate To a solution of 1-[(4-bromophenyl)methyl]-3,5,5-trimethyl-imidazolidine-2,4- dione (0.5 g, 1.61 mmol) in EtOH (10 mL) and H ₂ O (2 mL) was added NaN ₃ (313.4 mg, 4.8 mmol), CuSO ₄ (256.5 mg, 1.6 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (137.1 mg, 0.96 mmol). The reaction was stirred at 80 °C for 3 h, quenched with saturated Na ₂ CO ₃ (5 mL), diluted with H ₂ O (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to provide the title compound (0.35 g, 88.1%) as a colorless oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C ₁₃ H ₁₅ N ₅ O ₂ : 273.12, found: 274.2 [M+H] ⁺ . 1-(4-Aminobenzyl)-3,5,5-trimethylimidazolidine-2,4-dione To a solution of 1-[(4-azidophenyl)methyl]-3,5,5-trimethyl-imidazolidine-2,4- dione (0.8 g, 2.93 mmol) in THF (10 mL) and H ₂ O (2 mL) was added PPh ₃ (767.8 mg, 2.93 mmol). After stirring at 25 °C for 2 h, the reaction was concentrated under reduced pressure. The crude residue was purified by prep-TLC (SiO2, petroleum ether : EtOAc = 2 : 1) to provide the title compound (0.3 g, 41.4%) as a white solid. MS (ESI): mass calcd. for C ₁₃ H ₁₇ N ₃ O ₂ : 247.13, found: 248.3 [M+H] ⁺ . 1-Butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)me thyl)phenyl)urea To a solution of 1-[(4-aminophenyl)methyl]-3,5,5-trimethyl-imidazolidine-2,4- dione (0.3 g, 1.2 mmol) in DCM (3 mL) was added n-BuNCO (120.1 mg, 1.2 mmol) and TEA (368.3 mg, 3.64 mmol). The reaction was stirred at 25 °C for 1 h, filtered and concentrated under reduced pressure. The crude residue was purified by prep-TLC (SiO2, petroleum ether : EtOAc = 2 : 1) to provide the title compound (0.2 g, 47.6%) as a white solid. MS (ESI): mass calcd. for C ₁₈ H ₂₆ N ₄ O ₃ : 346.20, found: 347.3 [M+H] ⁺ . 1-Butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1yl)met hyl)phenyl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-[4-[(3,5,5-trimethyl-2,4-dioxo-imidazolidin-1- yl)methyl]phenyl]urea (0.3 g, 0.87 mmol) in DCM (5 mL) was added malonyl dichloride (3.66 g, 26 mmol). The reaction was stirred at 25 °C for 1 h, filtered and concentrated under reduced pressure. The crude residue was purified by prep-TLC (SiO ₂ , petroleum ether : EtOAc = 0 : 1) to provide the title compound (0.4 g) as a white solid. MS (ESI): mass calcd. for C ₂₁ H ₂₆ N ₄ O ₅ : 414.19, found: 415.2 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(4-((3,5,5-trimethyl-2,4-diox oimidazolidin-1- yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione (116) H ₂ N NH ₂ O O O N N O _N ^N O To a solution of 1-butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidin- 1yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione (0.2 g, 0.48 mmol) in THF (1 mL) was added cyanamide (608.6 mg, 14.5 mmol) and bis[(Z)-1-methyl-3-oxo-but-1- enoxy]nickel (124 mg, 0.48 mmol). After heating at 85 °C for 16 h, the residue was diluted with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (mobile phase: [water (NH ₄ HCO ₃ )-ACN]; 15% to 45% B) to provide the title compound (0.04 g, 18.2%) as a white solid. MS (ESI): mass calcd. for C22H28N6O5: 456.21, found: 457.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.44 (s, 2H), 7.34-7.40 (m, 4H), 7.14 (d, J = 8.0 Hz, 2 H), 4.54 (s, 2 H), 3.77 (t, J = 7.2 Hz, 2 H), 2.92 (s, 3 H), 1.46-1.52 (m, 2 H), 1.26-1.30 (m, 8 H), 0.88 (t, J = 7.2 Hz, 3 H). Example 117 and Example 120.3-Amino-7-butyl-5-((5S,7s,10S)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)isothiazolo[3,4-d]pyri midine-4,6(5H,7H)-dione (117) and 3-Amino-7-butyl-5-((5R,7r,10R)-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)isothiazolo[3,4-d]pyri midine-4,6(5H,7H)-dione (120) Synthetic scheme:

^HO O CN N SEM CN S ^O HN O O O S SEM DMBNH N ₂ N NH N N DM ^o CMBP, tolue A, 90 C, 4h N ne, o N N Bu O 1 O n- 00 C, 12 h n-Bu O H NH NHDMB ₂ O O O O S S SEM TFA/H ₂ O N NH N N N N N N N N O O n-Bu O H n-Bu O H NH ₂ NH ₂ O O O O S S SFC separation N NH N NH N N N N _O ^N N O O H O H 1-Butyl-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimid ine-2,4(1H,3H)-dione To a solution of 1-butyl-6-chloropyrimidine-2,4(1H,3H)-dione (See Example 113 for synthesis, 2 g, 2.87 mmol) in DCM (20 mL) was added DIPEA (3.83 g, 29.6 mmol) and SEM-Cl (3.95 g, 23.7 mmol) at 0 °C under N ₂ . After stirring at 25 °C for 12 h, the reaction was quenched with saturated NH ₄ Cl (20 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with HCl (1 N, 2 x 10 mL) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under redued pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 0 to 20 : 1) to provide the title compound (2.99 g, 85.98%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ ppm 5.91 (s, 1H), 5.37 (s, 2H), 4.01-4.07 (m, 2H), 3.64-3.71 (m, 2H), 1.62-1.73 (m, 3H), 1.34-1.43 (m, 2H), 0.96-0.99 (m, 4H), 0.00 (s, 9H). 6-Amino-1-butyl-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidi ne-2,4(1H,3H)-dione To a solution of 1-butyl-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimid ine- 2,4(1H,3H)-dione (5 g, 15 mmol) in CH3CN (25 mL) was added NH3.H2O (25 mL). After heating at 80 °C for 12 h, the reaction was quenched with saturated NH ₄ Cl (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with HCl (1 N, 2 x 30 mL) and brine (60 mL), dried with anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 1 to 1 : 100) to provide the title compound (4.5 g, 93.5%) as a colorless oil. MS (ESI): mass calcd. for C14H27N3O3Si: 313.38, found: 314.3 [M+H] ⁺ . 7-Butyl-4,6-dioxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6 ,7-tetrahydroisothiazolo[3,4- d]pyrimidine-3-carbonitrile To a solution of 4,5-dichlorodithiazol-2-ium chloride (2.99 g, 14.4 mmol) in DCM (50 mL) was added 6-amino-1-butyl-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidi ne- 2,4(1H,3H)-dione (4.5 g, 14.4 mmol), followed by the addition of pyridine (5.22 g, 66 mmol) at 25 °C. The reaction was stirred at 25 °C for 3 h. After completion, the reaction was quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 1 to 20 : 1) to provide the title compound (1.5 g, 27.5%) as a brown oil. ¹ H NMR (400 MHz, CDCl3) δ ppm 5.47-5.49 (m, 2H), 4.18-4.24 (m, 2H), 3.69-3.75 (m, 2H), 1.71-1.81 (m, 2H), 1.36-1.48 (m, 2H), 0.96-1.02 (m, 5H), 0.015 (s, 9H). 7-Butyl-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimi dine-3-carbonitrile (INT A) A mixture of 7-butyl-4,6-dioxo-5-(2-trimethylsilylethoxymethyl)isothiazol o[3,4- d]pyrimidine-3-carbonitrile (1.5 g, 3.94 mmol), TFA (5 mL) and H2O (1 mL) was stirred at 25 °C for 12 h under N2. After completion, the reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to provide the title compound (INTA, 600 mg, 55.7%) as a brown oil, which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.15-4.20 (m, 2H), 1.71-1.79 (m, 2H), 1.37- 1.46 (m, 2H), 0.96-1.01 (m, 3H). 1,3-Diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4,10-trione To a solution of 11,14-dioxa-2,4-diazatrispiro[4.1.2.4 ¹⁰ .2 ⁷ .1 ⁵ ]heptadecane-1,3-dione (See Example 130 for synthesis, 20 g, 75.1 mmol) in acetone (400 mL) was added HCl (1 M, 225.3 mL). After heating at 70 °C for 2 h, the reaction was filtered. The solid was washed with H2O (3 x 50 mL) and dried under vacuum to provide the title compound (13.9 g, 83.3%) as a white solid, which was used in the next step without further purification. MS (ESI): mass calcd. for C ₁₁ H ₁₄ N ₂ O ₃ : 222.10, found: 223.2 [M+H] ⁺ . 3-((2-(Trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4,10-trione To a solution of 1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4,10-trione (5 g, 22.5 mmol) in DMA (50 mL) was added K ₂ CO ₃ (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 H ₂ O (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. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 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). 10-Hydroxy-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadis piro[4.1.5 ⁷ .1 ⁵ ]tridecane- 2,4-dione (INT B) To a solution of 2-(2-trimethylsilylethoxymethyl)-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-1,3,10-trione (1.7 g, 4.82 mmol) in MeOH (15 mL) was added NaBH ₄ (91.23 mg, 2.41 mmol) at 0 °C. After stirring at 25 °C for 2 h, the reaction was quenched with H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to provide the title compound (INTB, 900 mg, 52.6%) as a white solid, which was used in the next step without further purification. MS (ESI): mass calcd. for C17H30N2O4Si: 354.20, found: 377.2 [M+Na] ⁺ . 7-Butyl-5-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1, 3-diazadispiro[4.1.5 ⁷ .1 ⁵ ] tridecan-10-yl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4- d]pyrimidine-3-carbonitrile To a mixture of 7-butyl-4,6-dioxo-isothiazolo[3,4-d]pyrimidine-3-carbonitril e (INTA, 430 mg, 1.72 mmol) and 10-hydroxy-2-(2-trimethylsilylethoxymethyl)-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-1,3-dione (INTB, 609.1 mg, 1.72 mmol) in toluene (2 mL) was added 2-(tributyl-λ5-phosphanylidene)acetonitrile (1.45 g, 6.0 mmol) at 20 °C. The reaction was heated at 120 °C for 12 h under Ar. After cooling down, the reaction was poured into H ₂ O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (280 mg, 27.8%) as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C ₂₇ H ₃₈ N ₆ O ₅ SSi 586.24, found: 609.2 [M+Na] ⁺ . 7-Butyl-3-((2,4-dimethoxybenzyl)amino)-5-(2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)isothiazolo[3,4- d]pyrimidine-4,6(5H,7H)-dione To a mixture of 7-butyl-5-[1,3-dioxo-2-(2-trimethylsilylethoxy methyl)-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl]-4,6-dioxo-isothiazolo[3,4-d]pyrimidin e-3-carbonitrile (230 mg, 0.39 mmol) in DMA (1 mL) was added (2,4-dimethoxyphenyl)methanamine (655.4 mg, 3.9 mmol) in one portion at 25 °C under N2. After heating at 90 °C for 3 h, the reaction was cooled down and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 1 : 0 to 0 : 1) to provide the title compound (240 mg, 84.2%) as a white solid. MS (ESI): mass calcd. for C ₃₅ H ₅₀ N ₆ O ₇ SSi: 726.32, found: 727.3 [M+H] ⁺ . 3-Amino-7-butyl-5-(2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)isothiazolo[3,4- d]pyrimidine-4,6(5H,7H)-dione To a solution of 7-butyl-3-((2,4-dimethoxybenzyl)amino)-5-(2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)isothiazolo[3,4- d]pyrimidine-4,6(5H,7H)-dione (274.2 mg, 0.39 mmol) in TFA (0.5 mL) and H ₂ O (0.1 mL). The reaction was stirred at 25 °C for 1 h and concentrated under reduced pressure. The crude residue was diluted with MeOH (2 mL) and added K2CO3 until pH = 8-9. After stirring for 1 h, the mixture was acidified by citric acid monohydrate to pH = 5-6 and extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase HPLC (mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient 25% to 55% B) to provide the title compound (110 mg, 64%) as a white solid. MS (ESI): mass calcd. for C20H26N6O4S: 446.17, found: 447.2 [M+H] ⁺ . 3-Amino-7-butyl-5-((5S,7s,10S)-2,4-dioxo-1,3-diazadispiro[4. 1.5 ⁷ .1 ⁵ ]tridecan-10- yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (117) and 3-Amino-7-butyl-5- ((5R,7r,10R)-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)isothiazolo[3,4- d]pyrimidine-4,6(5H,7H)-dione (120) 3-Amino-7-butyl-5-(2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10- yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (110 mg, 0.25 mmol) was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30mm, 10 um); mobile phase: [CO2-IPA (0.1% NH3H2O)]; 47% isocratic) to provide the title compound (117) (25.5 mg, 14.8%, the later-eluting peak) as a white solid. MS (ESI): mass calcd. for C20H26N6O4S: 446.17, found: 447.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.52 (s, 1H), 8.39 (s, 1H), 8.13 ( br s, 2 H), 4.47-4.64 (m, 1H), 3.88 (t, J = 8.0 Hz, 2H), 2.16-2.39 (m, 5H), 1.85- 2.01 (m, 3H), 1.52-1.61 (m, 2H), 1.39-1.48 (m, 3H), 1.22-1.30 (m, 3H), 0.89 (t, J = 7.2 Hz, 3H) and the title compound (120) (29.3 mg, 17%, the early-eluting peak) as a white solid. MS (ESI): mass calcd. for C20H26N6O4S: 446.17, found: 447.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 8.40 (s, 1H), 8.15 (br s, 2H), 4.48 - 4.68 (m, 1H), 3.89 (t, J = 7.2 Hz, 2H), 2.16-2.40 (m, 5 H), 1.85-2.04 (m, 3H), 1.52-1.60 (m, 2H), 1.36-1.49 (m, 3H), 1.21-1.32 (m, 3 H), 0.90 (t, J = 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 119.3-Amino-7-butyl-5-((1r,4r)-4-((5,5-dimethyl-2,4-dioxoimi dazolidin-1- yl)methyl)-4-fluorocyclohexyl)isothiazolo[3,4-d]pyrimidine-4 ,6(5H,7H)-dione (119) Synthetic scheme: 2,7,10-Trioxadispiro[2.2.4 ⁶ .2 ³ ]dodecane To a mixture of 1,4-dioxaspiro[4.5]decan-8-one (19.8 g, 127 mmol) in DMSO (200 mL) was added trimethylsulfoxonium iodide (41.85 g, 190 mmol) and t-BuOK (21.34 g, 190 mmol) at 25 ℃ under N ₂ . After heating at 50 ℃ for 3 h, the reaction was poured into water (100 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 5 : 1 to 2 : 1) to afford the title compound (12.19 g, 56.5%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.99 (t, J = 3.2 Hz, 4H), 2.69 (s, 2H), 1.89-1.93 (m, 4H), 1.75-1.80 (m, 2H), 1.55-1.60 (m, 2H). (8-Fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methanol To a mixture of 2,7,10-trioxadispiro[2.2.4 ⁶ .2 ³ ]dodecane (12.19 g, 71.6 mmol) in DCM (100 mL) was added dropwise a cooled mixture of pyridine hydrofluoride (15.21 g, 107.4 mmol, 70%) in DCM (100 mL) at –10 °C under N2. After stirring at 25° C for 12 h, the reaction was poured into saturated NaHCO3 (100 mL). The aqueous phase was extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 5 : 1 to 2 : 1) to afford the title compound (3.56 g, 26.1%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.92-3.99 (m, 4H), 3.60 (d, J = 10.0 Hz, 2H), 1.98-2.10 (m, 2H), 1.82-1.91 (m, 3H), 1.62-1.72 (m, 3H). 8-Fluoro-1,4-dioxaspiro[4.5]decane-8-carbaldehyde To a mixture of (8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methanol (3.56 g, 18.7 mmol) in DCM (50 mL) was added DMP (9.53 g, 22.5 mmol) in one portion at 0 °C under N2. After stirring for 4 h, water was added and the aqueous phase was extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 3 : 1 to 1 : 1) to afford the title compound (2.6 g, 73.8%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ ppm 9.74 (d, J = 5.6 Hz, 1H), 3.93 - 3.99 (m, 4H), 1.89-2.08 (m, 5H), 1.71-1.79 (m, 3H). Ethyl 2-[(8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methylamino]-2-me thyl-propanoate O O OEt O NH F To a mixture of 8-fluoro-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (1.94 g, 10.3 mmol) in toluene (20 mL) was added ethyl 2-amino-2-methyl-propanoate hydrochloride (2.25 g, 13.4 mmol) and the reaction was equipped with a Dean-Stark trap. The reaction was heated to 130 °C for 6 h under N2. After cooling down, NaBH(OAc)3 (4.37 g, 20.6 mmol) was added in one portion at 25 °C. After stirring for 12 h, the reaction was poured into saturated NaHCO3 (20 mL). The aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 5 : 1 to 2 : 1) to afford the title compound (1.18 g, 37.7%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.15 (q, J = 6.8 Hz, 2H), 3.93-3.99 (m, 4H), 2.60 (d, J = 19.6 Hz, 2H), 1.98-2.08 (m, 2H), 1.83-1.92 (m, 2H), 1.59-1.76 (m, 4H), 1.25- 1.30 (m, 9H). 1-[(8-Fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methyl]-5,5-dimet hyl-imidazolidine-2,4- dione To a mixture of ethyl 2-[(8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methylamino]-2- methyl-propanoate (1 g, 3.3 mmol) in AcOH (10 mL) was added potassium isocyanate (1.34 g, 16.5 mmol) in one portion at 25 °C under N ₂ . After heating at 100 °C for 12 h, the reaction was quenched with addition of NaHCO ₃ and extracted with EtOAc (3 x 10 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 1 : 1) to provide the title compound (0.24 g, 28.4%) as a white solid. 1-[(1-Fluoro-4-oxo-cyclohexyl)methyl]-5,5-dimethyl-imidazoli dine-2,4-dione To a mixture of 1-[(8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methyl]-5,5-dimet hyl- imidazolidine-2,4-dione (0.62 g, 2.06 mmol) in acetone (4 mL) and H ₂ O (2 mL) was added TsOH.H ₂ O (785.4 mg, 4.1 mmol) in one portion at 25 °C under N ₂ . After stirring for 12 h, the reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with brine (3 x 5 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 5 : 1 to 1 : 1) to afford the title compound (0.27 g, 51%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.65 (s, 1H), 3.60 (d, J = 25.2 Hz, 2H), 2.58-2.70 (m, 2H), 2.35-2.43 (m, 2H), 2.18-2.31 (m, 2H), 1.92-2.14 (m, 2 H), 1.49 (s, 6 H). 1-[(1-Fluoro-4-hydroxy-cyclohexyl)methyl]-5,5-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione To a mixture of 1-[(1-fluoro-4-oxo-cyclohexyl)methyl]-5,5-dimethyl-imidazoli dine- 2,4-dione (0.51 g, 1.99 mmol) in DCM (5 mL) was added DIPEA (1.03 g, 7.96 mmol) in one portion at 25 °C under N ₂ . SEM-Cl (663.6 mg, 3.98 mmol) was added at 0 °C under N ₂ . After stirring at 25 °C for 12 h, the reaction was quenched aq. NH4Cl (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was washed with brine (3 x 5 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to provide a crude residue, which was purified by silica gel column chromatography (petroleum ether : EtOAc = 10 : 1 to 1 : 1) to afford the title compound (0.73 g, 94.6%) as a yellow oil. 1-[(1-Fluoro-4-hydroxy-cyclohexyl)methyl]-5,5-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione To a mixture of 1-[(1-fluoro-4-oxo-cyclohexyl)methyl]-5,5-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione (0.75 g, 1.94 mmol) in MeOH (5 mL) was added NaBH ₄ (44 mg, 1.16 mmol) in one portion at 0 °C under N ₂ . After stirring at 25 °C for 1 h, the reaction was poured into water (10 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine (3 x 10 mL), dried with anhydrous Na ₂ SO ₄ , 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 afford the title compound (0.3 g, 60%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.95 (s, 2H), 3.69-3.76 (m, 1H), 3.62 (t, J = 8.0 Hz, 2H), 3.47 (d, J = 25.2 Hz, 2H), 1.88-1.98 (m, 4H), 1.56-1.65 (m, 4H), 1.45 (s, 6H), 0.92-0.99 (m, 2H), 0.00 (s, 9H). 7-Butyl-3-((2,4-dimethoxybenzyl)amino)-5-((1r,4r)-4-((5,5-di methyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4- fluorocyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dio ne To a mixture of 1-[(1-fluoro-4-hydroxy-cyclohexyl)methyl]-5,5-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione (0.19 g, 0.48 mmol) and 7-butyl-3-((2,4- dimethoxybenzyl)amino)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H )-dione (see Example 117 for synthesis, 171.6 mg, 0.48 mmol) in DCM (2 mL) was added PPh3 (376.7 mg, 1.44 mmol) under N ₂ . The reaction was cooled down to 0 °C and DEAD (250.1 mg, 1.44 mmol) was added under N ₂ . After heating at 40 °C for 12 h, the reaction was poured into H ₂ O (10 mL). The aqueous phase was extracted with DCM (3 x 10 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 5 : 1) to afford the title compound (147 mg, 48.1%) as a white solid. MS (ESI): mass calcd. for C36H53FN6O7SSi: 760.34, found: 761.3 [M+H] ⁺ . 3-Amino-7-butyl-5-((1r,4r)-4-((5,5-dimethyl-2,4-dioxoimidazo lidin-1-yl)methyl)-4- fluorocyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dio ne (119) To a mixture of 7-butyl-3-((2,4-dimethoxybenzyl)amino)-5-((1r,4r)-4-((5,5- dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imida zolidin-1-yl)methyl)-4- fluorocyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dio ne (0.147 g, 230.2 mmol) was added TFA (2.5 mL) and H2O (0.5 mL) at 25 °C under N2. After stirring for 3 h, the reaction was quenched with citric acid, and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (column: Waters Xbridge BEH C18100*30mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; 30% to 60%B) to provide the title compound (0.017 g, 15.4%) as a white solid. MS (ESI): mass calcd. for C21H29FN6O4S: 480.20, found: 481.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl3) δ ppm 8.78 (s, 1H), 6.87 ( br s, 1H), 4.81-4.93 (m, 1H), 4.04 (t, J = 7.6 Hz, 2H), 3.68-3.84 (m, 2H), 2.78- 2.94 (m, 2H), 2.01-2.07 (m, 2H), 1.75-1.89 (m, 2H), 1.64-1.72 (m, 4H), 1.47 (s, 6H), 1.36- 1.43 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). Only one isomer is isolated from the reaction sequence and stereochemistry is arbitrarily assigned. Example 122 and Example 123 were synthesized from Example 100 by chiral SFC separation. (column: DAICEL CHIRALPAK AD (250mm*30mm,10 um); mobile phase: [CO2-IPA]; isocratic 33% B). Stereochemistry is arbitrarily assigned. Example 124 and 125 were synthesized from Example 78 by chiral SFC separation (column: DAICEL CHIRALPAK IE(50*250mm, 10 um); mobile phase: [CO ₂ -EtOH]; isocratic 50% B). Stereochemistry is arbitrarily assigned. Example 130.1-Butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4 -dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione Synthetic scheme: 11,14-Dioxa-2,4-diazatrispiro[4.1.2.4 ¹⁰ .2 ⁷ .1 ⁵ ]heptadecane-1,3-dione To a mixture of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one (15 g, 76.4 mmol) in MeOH (150 mL) and H ₂ O (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 H ₂ O (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. ¹ H NMR (400 MHz, DMSO-d6) δ 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[4.1.2.4 ¹⁰ .2 ⁷ .1 ⁵ ]heptadecane-1,3-dione To a mixture of 11,14-dioxa-2,4-diazatrispiro[4.1.2.4 ¹⁰ .2 ⁷ .1 ⁵ ]heptadecane-1,3-dione (6 g, 22.5 mmol) in DMF (50 mL) was added MeI (3.52 g, 24.8 mmol) and K ₂ CO ₃ (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 Na ₂ SO ₄ , 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 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[4.1.5 ⁷ .1 ⁵ ]tridecane-1,3,10-trione To a mixture of 2-methyl-11,14-dioxa-2,4-diazatrispiro[4.1.2.4 ¹⁰ .2 ⁷ .1 ⁵ ]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 N ₂ . 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[4.1.5 ⁷ .1 ⁵ ]tridecane-1,3-dione To a mixture of 2-methyl-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]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 through a Celite pad and the filtrate was concentrated under reduced pressure to provide the title compound (3 g, 93.6%) 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[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)urea O N HN HN N O n-Bu O H To a mixture of 10-amino-2-methyl-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]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 N ₂ . After stirring for 30 min, H ₂ O (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, 63.5%) 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[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6-trione To a mixture of 1-butyl-3-(2-methyl-1,3-dioxo-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]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 Na ₂ SO ₄ , 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 C ₂₀ H ₂₈ N ₄ O ₅ : 404.21, found: 405.2 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-methyl-1,3-dioxo-2,4-diaza dispiro[4.1.5 ⁷ .1 ⁵ ]tridecan- 10-yl)hexahydropyrimidine-2,4,6-trione (Example 107) To a mixture of 1-butyl-3-(2-methyl-1,3-dioxo-2,4-diazadispiro[4.1.57.15]tri decan- 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 bis[(Z)-1-methyl-3-oxo-but-1-enoxy]nickel (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 (column: Waters Xbridge Prep OBD C18150*40mm*10 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient 30% to 60% B) to provide the title compound (0.45 g, 17.7%) as a white solid. MS (ESI): mass calcd. for C ₂₁ H ₃₀ N ₆ O ₅ : 446.23, found: 447.2 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-methyl-1,3-dioxo-2,4-diaza dispiro[4.1.5 ⁷ .1 ⁵ ]tridecan- 10-yl)hexahydropyrimidine-2,4,6-trione 1-Butyl-5-(diaminomethylene)-3-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (0.23 g, 0.52 mmol) was separated by chiral SFC (column: DAICEL CHIRALCEL OD (250mm*30mm,10 um); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; 40% B, isocratic elution) to provide the title compound (130) (0.064 g, 27.8%, later-eluting peak) as a white solid. MS (ESI): mass calcd. for C21H30N6O5: 446.23, found: 447.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.53 (s, 2H), 8.67 (s, 1H), 7.31 (s, 2H), 4.52-4.68 (m, 1H), 3.68-3.76 (t, J = 7.2 Hz, 2H), 2.80 (s, 3H), 2.14- 2.31 (m, 5H), 1.98 (t, J = 12.8 Hz, 2H), 1.83-1.91 (m, 1H), 1.32-1.50 (m, 5H), 1.20-1.29, (m, 3H), 0.87 (t, J = 7.2 Hz, 3H). Example 129 was synthesized in the same procedures as described in Example 130 and is the early eluting peak from chiral separation. Examples 148 and 149 were synthesized in similar procedures as described in Example 130, using 2,2,2-trifluoroethyl trifluoromethanesulfonate in step 2. Stereochemistry is arbitrarily assigned. Examples 150, 151, and 152 were synthesized in similar procedures as described in Example 130. Stereochemistry is arbitrarily assigned. Examples 165, 172, and 174 were synthesized in similar procedures as described in Example 129 and 130, with di-methylation at the second step through using NaH and heating to 60 °C. Stereochemistry of 172 and 174 is arbitrarily assigned. Example 133. N-(7-Butyl-4,6-dioxo-5-((1s,4s)-4-((3,5,5-trimethyl-2,4-diox oimidazolidin- 1-yl)methyl)cyclohexyl)-4,5,6,7-tetrahydroisothiazolo[3,4-d] pyrimidin-3-yl)acetamide (133) Synthetic scheme: 3-Amino-7-butyl-5-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimid azolidin-1- yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H) -dione (Example 121) NH ₂ S N O O N N O _N ^N O To a solution of 3-amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazo lidin- 1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7 H)-dione (Example 85, 0.15 g, 0.32 mmol) in DMF (1 mL) was added MeI (46 mg, 0.32 mmol) and K2CO3 (53.8 mg, 0.39 mmol). After stirring at 25 °C for 12 h, the reaction was quenched with saturated NaHCO ₃ (3 mL), extracted with DCM (3 x 2 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-TLC (SiO ₂ , petroleum ether : EtOAc = 1 : 1) to provide the title compound (20 mg, 12.9%) as a white oil. MS (ESI): mass calcd. for C ₂₂ H ₃₂ N ₆ O ₄ S: 476.22, found: 477.2 [M+H] ⁺ . N-(7-Butyl-4,6-dioxo-5-((1s,4s)-4-((3,5,5-trimethyl-2,4-diox oimidazolidin-1- yl)methyl)cyclohexyl)-4,5,6,7-tetrahydroisothiazolo[3,4-d]py rimidin-3-yl)acetamide (133) To a solution of 3-amino-7-butyl-5-((1s,4s)-4-((3,5,5-trimethyl-2,4- dioxoimidazolidin-1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]p yrimidine-4,6(5H,7H)-dione (20 mg, 0.042 mmol), TEA (8.49 mg, 0.084 mmol) and DMAP (1.03 mg, 8.4 μmol) in DCM (1 mL) was added acetyl chloride (4.94 mg, 0.063 mmol) at 0 °C. The reaction was stirred at 25 °C for 30 min under N ₂ . After completion, the mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (mobile phase: [water (NH4HCO3)-ACN]) to provide the title compound (2.6 mg, 12%) as a white solid. MS (ESI): mass calcd. for C ₂₄ H ₃₄ N ₆ O ₅ S: 518.23, found: 519.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 11.19-11.93 (m, 1 H), 4.64-4.77 (m, 1H), 3.99 (t, J = 7.2 Hz, 2H), 3.41 (d, J = 7.6 Hz, 2H), 2.87 (s, 3H), 2.58-2.66 (m, 2H), 2.41 (s , 3H), 2.01-2.07 (m, 1H), 1.78 ( br d, J = 13.6 Hz, 2H), 1.60-1.67 (m, 2H), 1.46-1.55 (m, 2H), 1.38-1.43 (m, 2H), 1.32 (s, 6 H), 1.19-1.31 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). Example 134 and Example 135.3-Amino-7-butyl-5-((5R,7r,10R)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H )-dione (134) and 3-Amino-7-butyl-5-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H )-dione (135) Synthetic scheme: 3-Amino-7-butyl-5-((5R,7r,10R)-3-methyl-2,4-dioxo-1,3-diazad ispiro[4.1.5 ⁷ .1 ⁵ ]tridecan- 10-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (134) and 3-Amino-7-butyl-5- ((5S,7s,10S)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)isothiazolo[3,4- d]pyrimidine- 4,6(5H,7H)-dione (135) To a solution of 3-amino-7-butyl-5-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)isothiazolo[3,4-d]pyrimidine-4,6-dione (See Example 117 for synthesis, 154.7 mg, 0.34 mmol) in DMF (2 mL) was added MeI (47.7 mg, 0.34 mmol) and K2CO3 (55.7 mg, 0.4 mmol). The reaction was stirred at 25 °C for 2 h and then purified by reverse phase HPLC (column: Phenomenex Luna C18200*40mm*10 um; mobile phase: [water (FA)-ACN]; gradient 30% to 60%B). The resulting material was separated by chiral SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10 um); mobile phase: [CO ₂ -i-PrOH (0.1% NH ₃ H ₂ O)]; isocratic 40% B) to provide the title compound (134) (2.3 mg, 1.5%, later-eluting peak) as a white solid. MS (ESI): mass calcd. for C ₂₁ H ₂₈ N ₆ O ₄ S: 460.19, found: 461.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (s, 1H), 8.13 (s, 2H), 4.51-4.60 (m, 1H), 3.88 (t, J = 7.2 Hz, 2H), 2.80 (s, 3H), 2.17-2.38 (m, 6H), 2.00 (t, J = 12.4 Hz, 2H), 1.52-1.65 (m, 2 H), 1.40-1.53 (m, 3H), 1.23-1.31 (m, 3H), 0.89 (t, J = 7.2 Hz, 3H). And to provide the title compound (135) (1.5 mg, 0.97%, early eluting peak) as a white solid. MS (ESI): mass calcd. for C21H28N6O4S: 460.19, found: 461.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (s, 1H), 8.12 (s, 2H), 4.47-4.65 (m, 1 H), 3.88 (t, J = 7.6 Hz, 2H), 2.80 (s, 3H), 2.18-2.39 (m, 6H), 2.00 (t, J = 12.0 Hz, 2H), 1.49-1.70 (m, 2H), 1.40-153 (m, 3H), 1.25-1.33 (m, 3H), 0.89 (t, J = 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 131 was synthesized in similar procedures as Example 134, using ethyl iodide for the alkylation. Example 118 was synthesized from the racemates of Example 104 in a similar procedure of the alkylation with MeI and K2CO3 as in Example 134. Example 126 and Example 127 were synthesized from Example 78 in a similar procedure of the alkylation with MeI and K2CO3 as in Example 134, followed by chiral SFC separation (column: Daicel ChiralPak IG (250*30mm, 10 um); mobile phase: [heptane-EtOH]; isocratic 50% B). Stereochemistry is arbitrarily assigned. Example 128 was synthesized from the racemates of Example 104 in a similar procedure of the alkylation with CF ₃ CH ₂ OTf and K ₂ CO ₃ as in Example 134. Example 132 was synthesized from Example 85 in a similar procedure of the alkylation with CF3CH2OTf and K2CO3 as in Example 134. Example 138 and 139.1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl -2,4- dioxoimidazolidin-1-yl)methyl)-4-methylcyclohexyl)pyrimidine -2,4,6(1H,3H,5H)-trione (138) and 1-butyl-5-(diaminomethylene)-3-((1r,4r)-4-((5,5-dimethyl-2,4 - dioxoimidazolidin-1-yl)methyl)-4-methylcyclohexyl)pyrimidine -2,4,6(1H,3H,5H)-trione (139) Synthetic scheme: Step 1: 8-Methyl-1,4-dioxaspiro[4.5]decane-8-carbaldehyde To a solution of DMSO (9.69 g, 124 mmol) in DCM (80 mL) was added oxalyl dichloride (10.49 g, 82.7 mmol) dropwise at –70 °C. After 1 h, (8-methyl-1,4- dioxaspiro[4.5]decan-8-yl)methanol (7.7 g, 41.3 mmol) in DCM (30 mL) was added and reaction was stirred at –70 °C for another 30 min, before TEA (25.1 g, 248.1 mmol) was added. After 2 h at the same temperature, the reaction was quenched with saturated NH4Cl (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (8.61 g, crude) as a yellow oil, which was used in the next step directly without further purification. Ethyl 2-methyl-2-(((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl) amino)propanoate To a solution of crude 8-methyl-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (8.61 g, 46.7 mmol) and ethyl 2-amino-2-methyl-propanoate hydrochloride (9.40 g, 56.1 mmol) in DCM (100 mL) was added AcOH (2.81 g, 46.7 mmol). After stirring at 20 °C for 30 min, NaBH(OAc)3 (19.81 g, 93.5 mmol) was added. The reaction was stirred at 20 °C for 12 h, poured into ice-water (100 mL), and adjusted to pH = 8 using Na2CO3. The mixture was extracted with DCM (2 x 200 mL). The organic layer was dried, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 10 : 1 to 0 : 1) to provide the title compound (6 g, 42.9%) as a white solid. MS (ESI): mass calcd. for C ₁₆ H ₂₉ NO ₄ : 299.21, found: 300.2 [M+H] ⁺ . 5,5-Dimethyl-1-((1-methyl-4-oxocyclohexyl)methyl)imidazolidi ne-2,4-dione To a solution of ethyl 2-methyl-2-(((8-methyl-1,4-dioxaspiro[4.5]decan-8- yl)methyl)amino)propanoate (6 g, 20 mmol) in AcOH (25 mL) was added potassium isocyanate (8.13 g, 3.95 mL). After heating at 100 °C for 12 h, the reaction was poured into ice-water (100 mL), adjusted to pH = 8 using aqueous Na2CO3, and extracted with EtOAc (2 x 200 mL). The organic layer was dried, filtered and concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 20 : 1 to 0 : 1) to provide the title compound (5 g, 98.9%) as a yellow oil. MS (ESI): mass calcd. for C13H20N2O3: 252.15, found: 253.2 [M+H] ⁺ . 5,5-Dimethyl-1-((1-methyl-4-oxocyclohexyl)methyl)-3-((2-(tri methylsilyl)ethoxy)methyl) imidazolidine-2,4-dione To a solution of 5,5-dimethyl-1-((1-methyl-4-oxocyclohexyl)methyl) imidazolidine- 2,4-dione (5 g, 19.8 mmol) in DCM (60 mL) was added SEM-Cl (6.61 g, 39.6 mmol) and DIPEA (12.81 g, 99.1 mmol). After stirring at 20 °C for 12 h, the reaction was quenched with saturated NH4Cl (60 mL) and extracted with DCM (3 x 60 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 10 : 1 to 0 : 1) to provide the title compound (5.5 g, 72.6%) as a yellow oil. MS (ESI): mass calcd. for C19H24N2O3Si: 382.23, found: 405.2 [M+Na] ⁺ . 1-((4-Amino-1-methylcyclohexyl)methyl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidine-2,4-dione To a solution of 5,5-dimethyl-1-((1-methyl-4-oxocyclohexyl)methyl)-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (5.5 g, 14.4 mmol) in MeOH (100 mL) was added NH ₃ /MeOH (7 M, 20.5 mL) and Raney-Ni (2.22 g, 25.9 mmol) under N ₂ . The suspension was degassed under vacuum and purged with H2 several times and stirred under H2 (15 psi) at 20 °C for 1 h. After filtering through a Celite pad, the filtrate was concentrated under reduced pressure to provide the title compound (5.5 g) as a yellow oil, which was used in the next step directly without further purification. MS (ESI): mass calcd. for C19H37N3O3Si: 383.26, found: 384.3 [M+H] ⁺ . 1-Butyl-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl) ethoxy)methyl)imidazolidin- 1-yl)methyl)-4-methylcyclohexyl)urea To a solution of 1-[(4-amino-1-methyl-cyclohexyl)methyl]-5,5-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione (5.5 g, 14.3 mmol) in DCM (50 mL) was added 1-isocyanatobutane (1.42 g, 14.3 mmol). After stirring at 20 °C for 2 h, the reaction was concentrated under reduced pressure to provide the title compound (6.9 g) as a yellow oil, which was used in the next step directly without further purification. MS (ESI): mass calcd. for C26H46N4O4Si: 482.33, found: 505.3 [M+Na] ⁺ . 1-Butyl-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl) ethoxy)methyl)imidazolidin- 1-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-t rione To a solution of 1-butyl-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)urea (6.9 g, 14.3 mmol) in AcOH (70 mL) was added Ac2O (10.21 g, 100 mmol) and malonic acid (1.49 g, 14.3 mmol). After heating at 80 °C for 6 h, the reaction was quenched with H2O (100 mL) and extracted with EtOAc (3 x 100 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 = 10 : 1 to 0 : 1) to provide the title compound (5.7 g, 72.4%) as a yellow oil. MS (ESI): mass calcd. for C ₂₇ H ₄₆ N ₄ O ₆ Si: 550.32, found: 573.3 [M+Na] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4-dioxo-3 -((2- (trimethylsilyl)ethoxy) methyl)imidazolidin-1-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (5.7 g, 10.35 mmol) in THF (60 mL) was added cyanamide (1.31 g, 31 mmol) and bis[(Z)-1-methyl-3-oxo-but-1-enoxy]nickel (797.7 mg, 3.1 mmol). After heating at 85 °C for 12 h, the reaction was filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 10 : 1 to 0 : 1) to provide the title compound (2.2 g, 35.9%) as a yellow oil. MS (ESI): mass calcd. for C ₂₈ H ₄₈ N ₆ O ₆ Si: 592.34, found: 615.3 [M+Na] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4-dioxoim idazolidin-1-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione A solution of 1-butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4-dioxo-3 -((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (2.2 g, 3.7 mmol) in TFA (20 mL) and H2O (4 mL) was stirred at 20 °C for 2 h. The reaction was concentrated and added methanol (10 mL) and K ₂ CO ₃ (10 g). After stirring for 0.5 h, the reaction was filtered and concentrated to remove organic solvents. Citric acid monohydrate was added to adjust to pH = 5~6 and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic layer was dried, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient 27% to 57% B) to provide the title compound (1.2 g, 69.9%) as a yellow solid. MS (ESI): mass calcd. for C22H34N6O5: 462.26, found: 463.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4 -dioxoimidazolidin-1- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-tri one (138) and 1-butyl-5- (diaminomethylene)-3-((1r,4r)-4-((5,5-dimethyl-2,4-dioxoimid azolidin-1-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (139) The above step racemic material (1.2 g) was separated by chiral SFC (column: DAICEL CHIRALPAK IG (250mm*50mm, 10 um); mobile phase: [CO2-EtOH]; 40% B isocratic elution) to provide the title compound (138) (171 mg, 14.3%, early-eluting peak) as an off-white solid. MS (ESI): mass calcd. for C22H34N6O5: 462.26, found: 463.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1 H), 9.56 (s, 2H), 7.32 (s, 2H), 4.62-4.79 (m, 1H), 3.75 (t, J = 7.2 Hz, 2H), 3.26 (s, 2 H), 2.56-2.66 (m, 2H), 1.71 (d, J = 12.8 Hz, 2H), 1.41-1.51 (m, 2H), 1.15-1.35 (m, 12H), 0.84-0.92 (m, 6H). And to provide the title compound (139) (188 mg, 15.7%, later-eluting peak) as an off-white solid. MS (ESI): mass calcd. for C22H34N6O5: 462.26, found: 463.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 9.55 (s, 2H), 7.30 (s, 2H), 4.61 (t, J = 10.8 Hz, 1H), 3.74 (t, J = 7.2 Hz, 2H), 2.96 (s, 2H), 1.42-1.60 (m, 6H), 1.25-1.41 (m, 12H), 1.00 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned. Examples 155, 160, and 161 were synthesized in similar procedures as described in Example 138 and 139. Stereochemistry of 160 and 161 is arbitrarily assigned. Examples 176, 180, 181 and 185 were synthesized in similar procedures as described in Example 138 and 139. Stereochemistry is arbitrarily assigned. Examples 179, 184 and 186 was synthesized in similar procedures as described in Example 138. The ketal deprotection was incomplete on step 3, and an extra step of TsOH deprotection was added before following the route for 138. Stereochemistry of 184 and 186 is arbitrarily assigned. Example 158 and 159.1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((6,8-dioxo-2- oxa-5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl)pyrimid ine-2,4,6(1H,3H,5H)- trione (158) and 1-butyl-5-(diaminomethylene)-3-((1r,4r)-4-((6,8-dioxo-2-oxa- 5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl)pyrimid ine-2,4,6(1H,3H,5H)- trione (159) Synthetic scheme:

3-[(8-Methyl-1,4-dioxaspiro[4.5]decan-8-yl)methylamino]ox etane-3-carboxamide A mixture of methyl 3-[(8-methyl-1,4-dioxaspiro[4.5]decan-8- yl)methylamino]oxetane-3-carboxylate (synthesized in similar procedures as described in Example 138, 2.3 g, 7.7 mmol) in NH3/MeOH (7M, 2 mL) was heated at 70 °C for 12 h under N2 in a sealed tube. The reaction was filtered and concentrated under reduced pressure to provide the title compound (2.2 g, crude) as a white solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C ₁₄ H ₂₄ N ₂ O ₄ : 284.17, found: 285.2 [M+H] ⁺ . 5-[(8-Methyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl]-2-oxa-5,7 -diazaspiro[3.4]octane-6,8- dione A mixture of 3-[(8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methylamino]oxeta ne-3- carboxamide (2.2 g, 7.7 mmol), CDI (2.51 g, 15.5 mmol), and DIPEA (3 g, 23.2 mmol) in ACN (20 mL) was degassed and purged with N ₂ for 3 times. After heating at 90 °C for 12 h under N ₂ , the reaction was concentrated under reduced pressure, diluted with H ₂ O (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with H2O at 25 °C for 1 h. The precipitates were collected by filtration and dried under vacuum to provide the title compound (2 g, 83.3%) as a white solid. MS (ESI): mass calcd. for C15H22N2O5: 310.15, found: 311.2 [M+H] ⁺ . 5-[(8-Methyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl]-7-(2-trim ethylsilylethoxymethyl)-2- oxa-5,7-diazaspiro[3.4]octane-6,8-dione To a mixture of 5-[(8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl]-2-oxa-5,7 - diazaspiro[3.4]octane-6,8-dione (2 g, 6.44 mmol) and DIPEA (3.33 g, 25.8 mmol) in DCM (20 mL) was added SEM-Cl (2.15 g, 12.9 mmol) at 0 °C. After stirring at 20 °C for 12 h under N2, the reaction was quenched with H2O (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 1:0 to 0:1) to provide the title compound (2.1 g, 74%) as a colorless oil. MS (ESI): mass calcd. for C21H36N2O6Si: 440.23, found: 463.3 [M+Na] ⁺ . 5-[(1-Methyl-4-oxo-cyclohexyl)methyl]-7-(2-trimethylsilyleth oxymethyl)-2-oxa-5,7- diazaspiro[3.4]octane-6,8-dione A mixture of 5-[(8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl]-7-(2- trimethylsilylethoxymethyl)-2-oxa-5,7-diazaspiro[3.4]octane- 6,8-dione (2 g, 4.54 mmol), TsOH.H ₂ O (1.73 g, 9.1 mmol) in acetone (30 mL) H ₂ O (15 mL) was degassed and purged with N ₂ for 3 times. After heating at 50 °C for 4 h under N ₂ , the reaction was quenched with H2O (50 mL) and extracted with DCM (2 x 150 mL). The combined organic layer was washed with saturated NaHCO ₃ (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to provide the title compound (1.6 g, 88.9%) as a colorless oil, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C19H32N2O5Si: 396.21, found: 419.3 [M+Na] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((6,8-dioxo-2-oxa- 5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl)pyrimid ine-2,4,6(1H,3H,5H)- trione (158) and 1-butyl-5-(diaminomethylene)-3-((1r,4r)-4-((6,8-dioxo-2-oxa- 5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl)pyrimid ine-2,4,6(1H,3H,5H)- trione (159) H ₂ N NH ₂ H ₂ N NH ₂ O O O O O O O O N N N N O _N ^NH O _N ^{NH 158} O ¹⁵⁹ O The title compounds were synthesized from 5-[(1-methyl-4-oxo-cyclohexyl)methyl]- 7-(2-trimethylsilylethoxymethyl)-2-oxa-5,7-diazaspiro[3.4]oc tane-6,8-dione as described in Example 138 and 139. Example 158: MS (ESI): mass calcd. for C ₂ H ₃₂ N ₆ O ₆ : 476.24, found: 477.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 9.56 (s, 2H), 7.31 (s, 2H), 4.81-4.82 (d, J = 7.2 Hz, 2H), 4.65-4.74 (m, 3H), 3.73-3.77 (t, J = 6.8 Hz, 2H), 3.56 (s, 2H), 2.68-2.74 (m, 2 H), 1.76-1.79 (d, J = 12.8 Hz, 2H), 1.35-1.46 (m, 2H), 1.23-1.28 (m, 6H), 0.86 - 0.90 (m, 6H). Example 159: MS (ESI): mass calcd. for C2H32N6O6: 476.24, found: 477.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.94 (s, 1H), 9.55 (s, 2H), 7.30 (s, 2H), 4.80-4.82 (d, J = 7.2 Hz, 2H), 4.60-4.67 (m, 3H), 3.72-3.76 (t, J = 6.8 Hz, 2H), 3.27 (s, 2H), 2.51-2.65 (m, 2H), 1.05-1.51 (m, 10H), 1.05 (s, 3H), 0.86-0.90 (m, 3H). Stereochemistry is arbitrarily assigned. Example 156 is the precursor (cis/trans mixture of 158 and 159) before chiral SFC that led to Example 158 and 159. Examples 163, 168 and 173 were synthesized in similar procedures as described in Example 158 and 159. Stereochemistry of 168 and 173 is arbitrarily assigned. Example 140 and 141.1-Butyl-5-(diaminomethylene)-3-((2S,4s,7S)-2-(2,4-dioxo- 1,3- diazaspiro[4.5]decan-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2, 4,6(1H,3H,5H)-trione (140) and 1-Butyl-5-(diaminomethylene)-3-((2R,4r,7R)-2-(2,4-dioxo-1,3- diazaspiro[4.5]decan- 1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (141) Synthetic scheme: Methyl 1-(8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-ylamino)cyclohexanecarboxylate To a solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one (3.84 g, 19.6 mmol) in DCM (50 mL) was added HOAc (1.18 g, 19.6 mmol) and methyl 1- aminocyclohexanecarboxylate (4 g, 25.4 mmol) at 25 °C for 1 h. Sodium triacetoxyborohydride (8.3 g, 39.1 mmol) was added at 0 °C. After stirring at 25 °C for 11 h, the reaction was quenched with saturated NaHCO3 (20 mL) and extracted with DCM (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 1 to 10 : 1) to provide the title compound (5.5 g, 83.3%) as a colorless oil. MS (ESI): mass calcd. for C19H31NO4: 337.23, found: 338.2 [M+H] ⁺ . 1-(7-Oxospiro[3.5]nonan-2-yl)-1,3-diazaspiro[4.5]decane-2,4- dione To a solution of methyl 1-(8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2- ylamino)cyclohexanecarboxylate (5 g, 14.8 mmol) in HOAc (15 mL) was added potassium cyanate (6.01 g, 74.1 mmol). After heating at 100 °C for 12 h, the reaction was quenched with saturated NaHCO3 (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100:1 to 10:1) to provide the title compound (3 g, 66.5%) as a white solid. MS (ESI): mass calcd. for C17H24N2O3: 304.18, found: 303.2 [M-H]-. 1-(7-Oxospiro[3.5]nonan-2-yl)-3-(2-trimethylsilylethoxymethy l)-1,3- diazaspiro[4.5]decane-2,4-dione O SEM N O N O To a mixture of 1-(7-oxospiro[3.5]nonan-2-yl)-1,3-diazaspiro[4.5] decane-2,4-dione (3 g, 9.86 mmol) and DIPEA (5.1 g, 39.4 mmol) in DCM (30 mL) was added SEM-Cl (3.29 g, 19.7 mmol) in one portion at 25 °C under N2. After stirring at 25 °C for 12 h, the reaction was poured into H2O (50 mL) and extracted with DCM (3 x 20 mL). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 1 : 0 to 0 : 1) to provide the title compound (4 g, 93.4%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.90 (s, 2H), 3.59-3.77 (m, 3H), 2.88-2.96 (m, 2H), 2.31 (td, J = 6.8, 16.8 Hz, 4H), 2.12-2.19 (m, 2 H), 2.05-2.10 (m, 2 H), 1.94 (t, J = 6.8 Hz, 2 H), 1.53-1.83 (m, 8 H), 0.91-0.99 (m, 2 H), 0.00 (s, 9H). 1-(7-Aminospiro[3.5]nonan-2-yl)-3-(2-trimethylsilylethoxymet hyl)-1,3- diazaspiro[4.5]decane-2,4-dione To a mixture of 1-(7-oxospiro[3.5]nonan-2-yl)-3-(2-trimethylsilylethoxymethy l)-1,3- diazaspiro[4.5]decane-2,4-dione (1.7 g, 3.9 mmol) in MeOH (17 mL) was added NH ₃ /MeOH (7 M, 5.59 mL) in one portion at 25 °C under N2. After stirring for 1 h, 10% Pd/C (1 g) was added, and the reaction was stirred under H2 (15 Psi) for 2 h. After completion, the reaction was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to provide the title compound (1.5 g, 88%) as a yellow oil, which was used in the next step directly without further purification. 1-tert-Butyl-3-[2-[2,4-dioxo-3-(2-trimethylsilylethoxymethyl )-1,3-diazaspiro[4.5]decan-1- yl]spiro[3.5]nonan-7-yl]urea To a mixture of 1-(7-aminospiro[3.5]nonan-2-yl)-3-(2-trimethylsilylethoxymet hyl)- 1,3-diazaspiro[4.5]decane-2,4-dione (1.5 g, 3.44 mmol) in DCM (15 mL) was added 1- isocyanatobutane (341.3 mg, 3.44 mmol) in one portion at 25 °C under N ₂ . After stirring for 3 h, the reaction was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether : EtOAc = 1 : 0 to 0 : 1) to provide the title compound (1.4 g, 76%) as a yellow oil. MS (ESI): mass calcd. for C ₂₈ H ₅₀ N ₄ O ₄ Si: 534.36, found: 557.3 [M+Na] ⁺ . 1-Butyl-3-(2-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl) -1,3-diazaspiro[4.5]decan-1- yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a mixture of 1-butyl-3-[2-[2,4-dioxo-3-(2-trimethylsilylethoxymethyl)-1,3 - diazaspiro[4.5]decan-1-yl]spiro[3.5]nonan-7-yl]urea (0.7 g, 1.3 mmol) and malonic acid (204.3 mg, 1.96 mmol) in AcOH (7 mL) was added Ac2O (1.34 g, 13.1 mmol). After heating at 80 °C for 3 h, the reaction was poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 1 : 0 to 0 : 1) to provide the title compound (0.49 g, 62.1%) as a white solid. 1-Butyl-5-(diaminomethylene)-3-(2-(2,4-dioxo-3-((2-(trimethy lsilyl)ethoxy)methyl)-1,3- diazaspiro[4.5]decan-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2, 4,6(1H,3H,5H)-trione To a mixture of 1-butyl-3-(2-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl) -1,3- diazaspiro[4.5]decan-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2, 4,6(1H,3H,5H)-trione (0.49 g, 0.76 mmol) and cyanamide (191.7 mg, 4.6 mmol) in THF (5 mL) was added bis[(Z)-1- methyl-3-oxo-but-1-enoxy]nickel (58.6 mg, 0.23 mmol) in one portion at 25 °C under Ar. After heating at 80 °C for 18 h, the reaction was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to provide the title compound (0.38 g) as a yellow solid, which was used in the next step directly without further purification. MS (ESI): mass calcd. for C32H52N6O6Si: 644.37, found: 667.3 [M+Na] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-(2,4-dioxo-1,3-diazaspiro[ 4.5]decan-1- yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (Example 136) To a mixture of 1-butyl-5-(diaminomethylene)-3-(2-(2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazaspiro[4.5]decan-1-yl )spiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (0.38 g, 0.59 mmol) was added TFA (5 mL) and H ₂ O (1 mL). After stirring at 25 °C for 2 h, the reaction was filtered and concentrated under reduced pressure. The residue was diluted with MeOH (5 mL) and then adjusted to pH = 8 with saturated K ₂ CO ₃ and stirred for 16 h. Then the mixture was adjusted to pH = 5 with saturated citric acid and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (mobile phase: [H2O (10 mM NH4HCO3)- ACN]; gradient 40% to 75% B) to provide the title compound (0.069 g, 22.8%) as a white solid. MS (ESI): mass calcd. for C26H38N6O5: 514.29, found: 515.2 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((2S,4s,7S)-2-(2,4-dioxo-1,3- diazaspiro[4.5]decan-1- yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (140) and 1-Butyl-5- (diaminomethylene)-3-((2R,4r,7R)-2-(2,4-dioxo-1,3-diazaspiro [4.5]decan-1- yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (141) 1-Butyl-5-(diaminomethylene)-3-(2-(2,4-dioxo-1,3-diazaspiro[ 4.5]decan-1- yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (69 mg) was separated by chiral SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm,10 um); mobile phase: [CO ₂ - MeOH (0.1% NH3H2O)]; 20% B, isocratic elution) to provide the title compound (140) (5 mg) as a white solid. MS (ESI): mass calcd. for C26H38N6O5: 514.29, found: 515.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.56 (s, 1H), 9.54 (s, 2H), 7.33 (s, 2H), 4.49-4.74 (m, 1H), 3.62-3.87 (m, 2H), 2.63 (t, J = 9.2 Hz, 1H), 2.25-2.47 (m, 3H), 2.01-2.10 (m, 1H), 1.75-1.97 (m, 5H), 1.50-1.71 (m, 7H), 1.11-1.49 (m, 10H), 0.87 (t, J = 7.2 Hz, 3H). And to provide the title compound (141) (7 mg) as a white solid. MS (ESI): mass calcd. for C ₂₆ H ₃₈ N ₆ O ₅ : 514.29, found: 515.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.56 (s, 1H), 9.54 (s, 2H), 7.32 (s, 2H), 4.53-4.68 (m, 1H), 3.70-3.76 (m, 2H), 2.63 (t, J = 10.0 Hz, 1H), 2.25-2.47 (m, 3H), 2.01-2.09 (m, 1H), 1.76-1.96 (m, 5H), 1.51-1.71 (m, 7H), 1.13-1.50 (m, 10H), 0.87 (t, J = 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 137, Examples 142-143 were synthesized in similar procedures as described in Example 140 and 141. Examples 157, 167, 170 were synthesized in similar procedures as described in Example 140 and 141, starting from ethyl 3-amino-2,2-dimethylpropanoate. Stereochemistry of 167 and 170 is arbitrarily assigned. Example 153.1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((4-methyl-2,5 - dioxoimidazolidin-4-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H ,3H,5H)-trione (153) Synthetic scheme: tert-Butyl ((1s,4s)-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)c arbamate To a solution of 2-[4-(tert-butoxycarbonylamino)cyclohexyl]acetic acid (4.8 g, 18.7 mmol) in DCM (50 mL) was added N-methoxymethanamine hydrochloride (2 g, 20.5 mmol) and DIPEA (7.23 g, 56 mmol) followed by the addition of HATU (8.51 g, 22.4 mmol) at 0 °C under N2. After stirring at 25 °C for 12 h under N2, the reaction mixture was quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 1 to 5 : 1). Then the resulting residue was triturated with MTBE (20 mL) for 30 min. The precipitate was collected by filtration and dried to provide the title compound (4.5 g, 78.7%) as a white solid. MS (ESI): mass calcd. for C ₁₅ H ₂₈ N ₂ O ₄ : 300.20, found: 323.2 [M+Na] ⁺ . tert-Butyl ((1s,4s)-4-(2-oxopropyl)cyclohexyl)carbamate To a solution of tert-Butyl ((1s,4s)-4-(2-(methoxy(methyl)amino)-2- oxoethyl)cyclohexyl)carbamate (4.5 g, 15 mmol) in THF (45 mL) was added MeMgBr (3 M, 9.99 mL) at –20 °C under N2. After stirring at 25 °C for 12 h under N2, the reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 1 to 3 : 1) to provide the title compound (3 g, 78.4%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.60 (s, 1H), 3.70 (s, 1H), 2.36 (d, J = 6.8 Hz, 2H), 2.12 (s, 3H), 1.94-1.97 (m, 1H), 1.54-1.63 (m, 6H), 1.44 (s, 9H), 1.17-1.21 (m, 2H). tert-Butyl ((1s,4s)-4-((4-methyl-2,5-dioxoimidazolidin-4-yl)methyl)cycl ohexyl)carbamate To a solution of tert-Butyl ((1s,4s)-4-(2-oxopropyl)cyclohexyl)carbamate (3 g, 11.75 mmol) in MeOH (2 mL) and H2O (2 mL) was added TMSCN (2.33 g, 23.5 mmol) and (NH ₄ ) ₂ CO ₃ (4.52 g, 47 mmol). After heating at 90 °C for 12 h, the reaction mixture was concentrated under reduced pressure triturated with H ₂ O at 25 ^o C for 30 min. The precipitate was collected by filtration and dried under vacuum to provide the title compound (3.8 g, 95.1%) as a white solid. MS (ESI): mass calcd. for C ₁₆ H ₂₇ N ₃ O ₄ : 325.20, found: 348.1 [M+Na] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((4-methyl-2,5-dio xoimidazolidin-4- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (153) The title compound (153) was synthesized following the last six steps as described in Example 164. MS (ESI): mass calcd. for C20H30N6O5: 434.23, found: 435.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.57 (br s, 1H), 9.56 (s, 2H), 7.93 (s, 1H), 7.32 (s, 2H), 4.59- 4.66 (m, 1H), 3.75 (t, J = 7.6 Hz, 2H), 2.32-2.45 (m, 2H), 1.87 (dd, J = 4.0, 12.0 Hz, 1H), 1.53- 1.70 (m, 3H), 1.38-1.52 (m, 5H), 1.24-1.30 (m, 7H), 0.89 (t, J = 7.2 Hz, 3H). Example 164.1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((6,8-dioxo-5, 7- diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)pyrimidine-2,4,6 (1H,3H,5H)-trione (164) Synthetic scheme: 5-(((1s,4s)-4-Aminocyclohexyl)methyl)-7-((2-(trimethylsilyl) ethoxy)methyl)-5,7- diazaspiro[3.4]octane-6,8-dione A solution of tert-butyl ((1s,4s)-4-((6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)- 5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)carbamate (synthesized following the first 4 steps of Example 138 from tert-butyl ((1s,4s)-4-(hydroxymethyl)cyclohexyl)carbamate, 2.7 g) in HCOOH (20 mL) was stirred at 20 °C for 3 h. After completion, the reaction was poured into saturated NaHCO ₃ (50 mL) and extracted with DCM (2 x 25 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concetrated under reduced pressure to provide the title compound (2 g, 93.5%) as a brown oil, which was used in the next step without purification. The intermediate contained about 25% of trans isomer. MS (ESI): mass calcd. for C ₁₉ H ₃₅ N ₃ O ₃ Si: 381.24, found: 382.2 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((6,8-dioxo-5,7-di azaspiro[3.4]octan-5- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (164) The title compound (164) was synthesized following the last few steps of Example 138 (without SFC step) and was purified by reverse phase HPLC (mobile phase: [H ₂ O (10 mM NH4HCO3)-ACN]; gradient 35% to 58% B). MS (ESI): mass calcd. for C22H32N6O5: 460.24, found: 461.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.12-10.31 (br s, 1H), 9.53 (s, 2H), 7.32 (s, 2H), 4.66-4.72 (m, 1H), 3.75 (t, J = 7.2 Hz, 2H), 3.44 (d, J = 7.6 Hz, 2H), 2.47- 2.63 (m, 4H), 2.26 (t, J = 4.0 Hz, 2H), 2.14 (br s, 1H), 1.89-1.96 (m, 1H), 1.63-1.86 (m, 3H), 1.44-1.49 (m, H), 1.25-1.31 (m, 4H), 0.88 (t, J = 7.2 Hz, 3 H). Example 147 was synthesized in similar procedures as described in Example 164. Example 166 and 171.1-Butyl-5-(diaminomethylene)-3-((1s,3'S,4S)-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 (166) and 1-Butyl-5-(diaminomethylene)-3- ((1r,3'R,4R)-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)-trion e (171) Synthetic scheme: 2-(3-Bromo-2-pyridyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile O O N NC Br To a mixture of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (literature known, 5.37 g, 25.9 mmol) and 3-bromo-2-fluoro-pyridine (4.56 g, 25.9 mmol) in toluene (60 mL) was added [bis(trimethylsilyl)amino]sodium (1 M, 28.5 mL) at 0 °C under N2. The reaction was stirred at 0 °C for 1 h and 25 °C for 12 h. After completion, the reaction was poured into NH ₄ Cl (50 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 20 : 1 to 2 : 1) to afford the title compound (7.79 g, 82.8%) as a white solid. MS (ESI): mass calcd. for C ₁₇ H ₁₉ BrN ₂ O ₂ : 362.06, found: 363.2 [M+H] ⁺ . 2-(3-Bromo-2-pyridyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxamide To a solution of 2-(3-bromo-2-pyridyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2- carbonitrile (7.79 g, 21.5 mmol) in DMSO (75 mL) was added K2CO3 (5.93 g, 42.9 mmol) and 30% H2O2 (7.29 g, 64.3 mmol) at 0 °C under N2. After stirring at 25 °C for 12 h, the reaction was poured into Na ₂ S ₂ O ₃ (50 mL) and extracted with DCM (3 x 30 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 = 10 : 1 to 0 : 1) to afford the title compound (7.65 g, 93.6%) as a white solid. MS (ESI): mass calcd. for C ₁₇ H ₂₁ BrN ₂ O ₃ : 380.07, found: 381.1 [M+H] ⁺ . Trispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''-cycl ohexane-4'',2'''- [1,3]dioxolan]-2(1H)-one To a mixture of 2-(3-bromo-2-pyridyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2- carboxamide (3 g, 2.62 mmol) in 2-methylbutan-2-ol (30 mL) was added K ₃ PO ₄ (3.33 g, 5.25 mmol) and Ruphos Pd G4 (669.2 mg, 0.26 mmol) at 25 °C in glovebox. After stirring at 90 °C for 12 h, the reaction was quenched with saturated NH4Cl (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 50 : 1 to 0 : 1) to afford the title compound (1.6 g, 88.9% yield) as a white solid. MS (ESI): mass calcd. for C ₁₇ H ₂₀ N ₂ O ₃ : 300.15, found: 301.3 [M+H] ⁺ . 1-((2-(Trimethylsilyl)ethoxy)methyl)trispiro[pyrrolo[3,2-b]p yridine-3,1'-cyclobutane- 3',1''-cyclohexane-4'',2'''-[1,3]dioxolan]-2(1H)-one To a mixture of trispiro[pyrrolo[3,2-b]pyridine-3,1'-cyclobutane-3',1''-cycl ohexane- 4'',2'''-[1,3]dioxolan]-2(1H)-one (1.56 g, 5.2 mmol) in DCM (20 mL) was added DIPEA (2.69 g, 20.8 mmol) at 25 °C under N2. Then SEM-Cl (1.73 g, 10.4 mmol) was added at 0 °C under N ₂ . After heating at 40 °C for 12 h, the reaction was quenched with saturated NH ₄ Cl (20 mL), and extracted with DCM (3 x 20 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 = 50 : 1 to 1 : 1) to afford the title compound (2 g, 89.4%) as a white solid. MS (ESI): mass calcd. for C23H34N2O4Si: 430.23, found: 431.3 [M+H] ⁺ . 1''-((2-(Trimethylsilyl)ethoxy)methyl)dispiro[cyclohexane-1, 1'-cyclobutane-3',3''- pyrrolo[3,2-b]pyridine]-2'',4(1''H)-dione O N O N S ^EM To a mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)trispiro[pyrrolo[3,2-b]p yridine- 3,1'-cyclobutane-3',1''-cyclohexane-4'',2'''-[1,3]dioxolan]- 2(1H)-one (2 g, 4.6 mmol) in acetone (14 mL) and H2O (7 mL) was added TsOH.H2O (1.77 g, 9.3 mmol) at 25 °C under N ₂ . After stirring at 25 °C for 12 h, the reaction was quenched with saturated NH ₄ Cl (20 mL) and 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 = 50 : 1 to 1 : 1) to afford the title compound (1.75 g, 97.5%) as a white solid. MS (ESI): mass calcd. for C21H30N2O3Si: 386.20, found: 387.3 [M+H] ⁺ . 4-Amino-1''-((2-(trimethylsilyl)ethoxy)methyl)dispiro[cycloh exane-1,1'-cyclobutane- 3',3''-pyrrolo[3,2-b]pyridin]-2''(1''H)-one To a mixture of 1''-((2-(trimethylsilyl)ethoxy)methyl)dispiro[cyclohexane-1, 1'- cyclobutane-3',3''-pyrrolo[3,2-b]pyridine]-2'',4(1''H)-dione (1.5 g, 3.88 mmol) and ammonium acetate (5.98 g, 77.6 mmol) in MeOH (15 mL) was added NaBH(OAc) ₃ (2.06 g, 9.7 mmol) in one portion at 25 °C under N ₂ . After stirring for 12 h, the reaction was poured into saturated NaHCO3 (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to provide the title compound (1.48 g, 98.4%) as a colorless oil, which was used in the next step directly without further purification. MS (ESI): mass calcd. for C21H33N3O2Si: 387.23, found: 388.2 [M+H] ⁺ . 1-Butyl-3-(2''-oxo-1''-((2-(trimethylsilyl)ethoxy)methyl)-1' ',2''-dihydrodispiro [cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]- 4-yl)urea H O N n-Bu NH N O N SEM To a mixture of 4-amino-1''-((2-(trimethylsilyl)ethoxy)methyl) dispiro[cyclohexane- 1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-2''(1''H)-one (1.48 g, 3.8 mmol) and 1- isocyanatobutane (378.5 mg, 3.8 mmol) in DCM (15 mL) was added TEA (386.4 mg, 3.8 mmol) at 25 °C under N2. After stirring for 30 min, the reaction was added H2O (20 mL) and extracted with DCM (3 x 15 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 50 : 1 to 0 : 1) to afford the title compound (1.55 g, 83.4%) as a white solid. MS (ESI): mass calcd. for C26H42N4O3Si: 486.30, found: 487.3 [M+H] ⁺ . 1-Butyl-3-(2''-oxo-1''-((2-(trimethylsilyl)ethoxy)methyl)-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 mixture of 1-butyl-3-(2''-oxo-1''-((2-(trimethylsilyl)ethoxy) methyl)-1'',2''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3 ,2-b]pyridin]-4-yl)urea (1.45 g, 2.98 mmol) and malonic acid (310 mg, 2.98 mmol) in AcOH (15 mL) was added Ac ₂ O (2.13 g, 20.9 mmol) at 25 °C under N2. After heating at 80 °C for 4 h, the reaction was poured into water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 50 : 1 to 1 : 1) to afford the title compound (1 g, 60.5%) as a white solid. MS (ESI): mass calcd. for C ₂₉ H ₄₂ N ₄ O ₅ Si: 554.29, found: 555.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2''-oxo-1''-((2-(trimethylsi lyl)ethoxy)methyl)-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 mixture of 1-butyl-3-(2''-oxo-1''-((2-(trimethylsilyl)ethoxy) methyl)-1'',2''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',3''-pyrrolo[3 ,2-b]pyridin]-4-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (950 mg, 1.7 mmol) and cyanamide (719.9 mg, 17.1 mmol) in THF (10 mL) was added bis[(Z)-1-methyl-3-oxo-but-1-enoxy]nickel (132 mg, 0.51 mmol) at 25 °C under N ₂ . After heating at 80 °C for 12 h, the reaction was filtered through a Celite pad and washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 50 : 1 to 0 : 1) to afford the title compound (0.65 g, 63.6%) as a white solid. MS (ESI): mass calcd. for C30H44N6O5Si: 596.31, found: 597.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2''-oxo-1'',2''-dihydrodispi ro[cyclohexane-1,1'- cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4-yl)pyrimidine-2, 4,6(1H,3H,5H)-trione (Example 162) A solution of 1-butyl-5-(diaminomethylene)-3-(2''-oxo-1''-((2- (trimethylsilyl)ethoxy)methyl)-1'',2''-dihydrodispiro[cycloh exane-1,1'-cyclobutane-3',3''- pyrrolo[3,2-b]pyridin]-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trion e (0.6 g, 1.01 mmol) in TFA (1 mL) and H ₂ O (0.2 mL) was stirred for 3 h at 25 °C under N ₂ . The reaction was filtered and concentrated under reduced pressure. The crude residue was diluted with MeOH (6 mL) and then adjust to pH = 8 with saturated K ₂ CO ₃ and stirred for 0.5 hr. Then the reaction was adjusted to pH = 5 with saturated citric acid and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient 20% to 50% B) to provide the title compound (0.15 g, 32%) as a white solid. MS (ESI): mass calcd. for C24H30N6O4: 466.23, found: 467.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.43 (s, 1H), 9.54 (s, 2H), 8.15 (dd, J = 1.6, 4.8 Hz, 1H), 7.29 (s, 2H), 7.10-7.17 (m, 2H), 4.67 (t, J = 10.8 Hz, 1H), 3.73 (t, J = 7.2 Hz, 2H), 2.35-2.40 (m, 3H), 2.09-2.20 (m, 5H), 1.33-1.50 (m, 6H), 1.22-1.26 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). 1-Butyl-5-(diaminomethylene)-3-((1s,3'S,4S)-2''-oxo-1'',2''- dihydrodispiro[cyclohexane- 1,1'-cyclobutane-3',3''-pyrrolo[3,2-b]pyridin]-4-yl)pyrimidi ne-2,4,6(1H,3H,5H)-trione (166) and 1-Butyl-5-(diaminomethylene)-3-((1r,3'R,4R)-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 (171) Example 162 (150 mg) was separated by prep-SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10 um); mobile phase: [CO ₂ -IPA(0.1% NH ₃ H ₂ O)]; 30% B, isocratic elution) to provide the title compound (166) (44 mg). MS (ESI): mass calcd. for C ₂₄ H ₃₀ N ₆ O ₄ : 466.23, found: 467.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.43 (s, 1H), 9.54 (s, 2H), 8.15 (dd, J = 1.6, 4.8 Hz, 1H), 7.29 (s, 2H), 7.07-7.17 (m, 2H), 4.56-4.75 (m, 1H), 3.73 (t, J = 7.2 Hz, 2H), 2.30-2.47 (m, 3H), 2.05-2.27 (m, 5H), 1.32-1.49 (m, 6H), 1.19-1.30 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). And to provide the title compound (171) (35 mg). MS (ESI): mass calcd. for C24H30N6O4: 466.23, found: 467.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.43 (s, 1H), 9.54 (s, 2H), 8.15 (dd, J = 1.6, 4.8 Hz, 1H), 7.30 (s, 2H), 7.08-7.19 (m, 2H), 4.67 (s, 1H), 3.73 (t, J = 7.6 Hz, 2H), 2.31-2.47 (m, 3H), 2.08-2.22 (m, 5H), 1.32-1.50 (m, 6H), 1.19-1.28 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 177.1-Butyl-5-(diaminomethylene)-3-(2-(3-methyl-5-oxo-1,5-di hydro-4H-1,2,4- triazol-4-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H) -trione (177) Synthetic scheme: N-Benzyl-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-amine To a solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one (10 g, 51 mmol) in DCE (80 mL) was added phenylmethanamine (5.46 g, 51 mmol) and sodium triacetoxyborohydride (21.6 g, 101.9 mmol) under N2. After stirring at 30 °C for 16 h under N2, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with DCM (3 x 200 mL). The combined organic layer was washed with water (2 x 200 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM : MeOH = 95:5 ) to provide the title compound (11.1 g, 76%) as a white solid. MS (ESI): mass calcd. for C18H25NO2: 287.19, found: 288.2 [M+H] ⁺ . 8,11-Dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-amine To a solution of N-benzyl-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-amine (10 g, 34.8 mmol) in MeOH (200 mL) was added 20% dihydroxypalladium (6.11 g, 8.7 mmol) under N2. The suspension was degassed and purged with H2 for 3 times and the reaction was stirred under H ₂ (15 Psi.) at 25 °C for 16 h. The reaction was filtered through a Celite pad and rinsed with methanol (3 x 100 mL). The combined filtrate was concentrated under reduced pressure, diluted with water (25 mL) and acidified with a solution of citric acid (20%, pH = 5). The acidified aqueous solution was extracted with chloroform (3 x 100 mL) to remove impurities. The aqueous fraction was then basified with a solution of sodium hydroxide (2 M, pH = 8-9) and extracted with chloroform (3 x 100 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to provide the title compound (5 g, 72.8%) as a white solid, which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.82 (s, 4H), 3.16-3.27 (m, 1H), 2.00-2.07 (m, 2H), 1.44- 1.53 (m, 6H), 1.39-1.44 (m, 2H), 1.29-1.37 (m, 2H). 4-(8,11-Dioxadispiro[3.2.47.24]tridecan-2-yl)-5-methyl-2,4-d ihydro-3H-1,2,4-triazol-3- one A solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-amine (3.5 g, 17.7 mmol) and 5- methyl-3H-1,3,4-oxadiazol-2-one (1.78 g, 17.7 mmol) in MeOH (15 mL) was heated at 70 °C for 16 h under N ₂ . After concentrating under reduced pressure, an aqueous solution of sodium hydroxide (18 mL, 1M) was added, and the mixture was heated at 100 ° C for 2 h. Then 5 N hydrochloric acid (3 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 3 h and extracted with EtOAc (3 x 25 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (3 g, with impurity) as a white solid, which was used in the next step directly without further purification. MS (ESI): mass calcd. for C14H21N3O3: 279.16, found: 280.2 [M+H] ⁺ . 4-(8,11-Dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)-5-methyl-2-((2- (trimethylsilyl)ethoxy)methyl)-2,4-dihydro-3H-1,2,4-triazol- 3-one To a solution of 4-(8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)-5-methyl-2,4-d ihydro- 3H-1,2,4-triazol-3-one (4 g, 14.3 mmol) in DCM (30 mL) was added DIPEA (5.55 g, 43 mmol) and 2-(chloromethoxy)ethyl-trimethyl-silane (4.77 g, 5.1 mL) at 0 °C under N ₂ . After stirring at 25 °C for 16 h under N2, the reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM : MeOH = 94 : 6) to provide the title compound (4.8 g, 81.8%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 4.92 (s, 2H), 4.35-4.45 (m, 1H), 3.84 (s, 4H), 3.54 (t, J = 8.0 Hz, 2H), 2.51-2.58 (m, 2H), 2.17 (s, 3H), 2.07-2.13 (m, 2H), 1.61-1.68 (m, 4H), 1.50-1.55 (m, 2H), 1.43-1.48 (m, 2H), 0.83 (t, J = 8.0 Hz, 2H), -0.04 (s, 9H). 5-Methyl-4-(7-oxospiro[3.5]nonan-2-yl)-2-((2-(trimethylsilyl )ethoxy)methyl)-2,4- dihydro-3H-1,2,4-triazol-3-one A solution of 4-(8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)-5-methyl-2-((2- (trimethylsilyl)ethoxy)methyl)-2,4-dihydro-3H-1,2,4-triazol- 3-one (4 g, 9.77 mmol) and TsOH.H ₂ O (3.72 g, 19.5 mmol) in H ₂ O (10 mL) and acetone (20 mL) was heated at 50 °C for 4 h under N2. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 54 : 46) to provide the title compound (1.5 g, 42%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 4.94 (s, 2H), 4.51 (t, J = 8.8 Hz, 1H), 3.52-3.59 (m, 2H), 2.63-2.74 (m, 2H), 2.20-2.31 (m, 6H), 2.20 (s, 3H), 1.86-1.94 (m, 4H), 0.79-0.88 (m, 2H), - 0.03 (s, 9H). 4-(7-Aminospiro[3.5]nonan-2-yl)-5-methyl-2-((2-(trimethylsil yl)ethoxy)methyl)-2,4- dihydro-3H-1,2,4-triazol-3-one A solution of 5-methyl-4-(7-oxospiro[3.5]nonan-2-yl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2,4-dihydro-3H-1,2,4-triazol- 3-one (1.5 g, 4.1 mmol) and NH3/MeOH (7 M, 5.86 mL) in MeOH (20 mL) was stirred at 25 °C for 1 h under N2. Raney Ni (351.6 mg, 4.1 mmol) was added and the suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H ₂ (15 Psi) for 20 h and quenched with water (15 mL). The reaction was filtered through a Celite pad and washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure to provide the title compound (1.9 g, crude) as a white solid, which was used in the next step directly without further purification. 1-Butyl-3-(2-(3-methyl-5-oxo-1-((2-(trimethylsilyl)ethoxy)me thyl)-1,5-dihydro-4H-1,2,4- triazol-4-yl)spiro[3.5]nonan-7-yl)urea A solution of 4-(7-aminospiro[3.5]nonan-2-yl)-5-methyl-2-((2- (trimethylsilyl)ethoxy)methyl)-2,4-dihydro-3H-1,2,4-triazol- 3-one (1.9 g, 5.2 mmol) and 1- isocyanatobutane (513.8 mg, 5.2 mmol) in DCM (20 mL) was stirred for 24 h at 25 °C under N2. The reaction was quenched with MeOH (6 mL), H2O (40 mL) and extracted with DCM (3 x 40 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 42 : 58) to provide the title compound (1.4 g, 58%) as a yellow oil. MS (ESI): mass calcd. for C ₂₃ H ₄₃ N ₅ O ₃ Si: 465.31, found: 488.3 [M+Na] ⁺ . 1-Butyl-3-(2-(3-methyl-5-oxo-1-((2-(trimethylsilyl)ethoxy)me thyl)-1,5-dihydro-4H-1,2,4- triazol-4-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H) -trione To a solution of 1-butyl-3-(2-(3-methyl-5-oxo-1-((2-(trimethylsilyl)ethoxy)me thyl)- 1,5-dihydro-4H-1,2,4-triazol-4-yl)spiro[3.5]nonan-7-yl)urea (0.7 g, 1.5 mmol) and malonic acid (156.4 mg, 1.5 mmol) in acetic acid (8 mL) was added acetyl acetate (1.07 g, 10.5 mmol). After heating at 80 °C for 1 h under N ₂ , the reaction was quenched with water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 69 : 31) to provide the title compound (0.6 g, 74.8%) as a yellow oil. MS (ESI): mass calcd. for C26H43N5O5Si: 533.30, found: 534.4 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-(3-methyl-5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-1,2,4-triazol- 4-yl)spiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione A solution of 1-butyl-3-(2-(3-methyl-5-oxo-1-((2-(trimethylsilyl)ethoxy)me thyl)-1,5- dihydro-4H-1,2,4-triazol-4-yl)spiro[3.5]nonan-7-yl)pyrimidin e-2,4,6(1H,3H,5H)-trione (0.6 g, 1.12 mmol) in THF (7 mL) was added cyanamide (472.6 mg, 11.2 mmol) and bis[(Z)-1- methyl-3-oxo-but-1-enoxy]nickel (43.3 mg, 0.17 mmol) at 15 °C under N2. After heating at 80 °C for 16 h under N ₂ , the reaction was filtered through a Celite pad and washed with THF (30 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 64 : 36) to provide the title compound (0.5 g, crude) as a yellow oil. MS (ESI): mass calcd. for C27H45N7O5Si: 575.33, found: 576.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-(3-methyl-5-oxo-1,5-dihydr o-4H-1,2,4-triazol-4- yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (177) A solution of 1-butyl-5-(diaminomethylene)-3-(2-(3-methyl-5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-1,2,4-triazol- 4-yl)spiro[3.5]nonan-7- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (0.16 g, 0.28 mmol) in 2,2,2-trifluoroacetic acid (2.5 mL) and H ₂ O (0.5 mL) was stirred for 5 h at 25 °C under N ₂ . The reaction was filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient 20% to 40% B) to provide the title compound (177) (0.028 g, 21.8%) as a white solid. MS (ESI): mass calcd. for C ₂₁ H ₃₁ N ₇ O ₄ : 445.24, found: 446.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.27 (s, 1 H), 9.54 (s, 2 H), 7.29 (s, 2 H), 4.57-4.71 (m, 1 H), 4.36 (q, J = 8.8 Hz, 1 H), 3.73 (t, J = 7.2 Hz, 2 H), 2.55-2.61 (m, 1 H), 2.48-2.35 (m, 2 H), 2.31 (d, J = 11.2 Hz, 1 H), 2.18-2.24 (m, 1 H), 2.15 (s, 3 H), 1.89-2.00 (m, 2 H), 1.81 (d, J = 12.4 Hz, 1 H), 1.32-1.47 (m, 6 H), 1.22-1.28 (m, 2 H), 0.88 (t, J = 7.2 Hz, 3 H). Example 187 and 188.1-Butyl-5-(diaminomethylene)-3-[4-[(5,5-dimethyl-2,4-dio xo- imidazolidin-1-yl)methyl]-4-(hydroxymethyl)cyclohexyl]hexahy dropyrimidine-2,4,6- trione (187) and 1-butyl-5-(diaminomethylene)-3-[4-[(5,5-dimethyl-2,4-dioxo- imidazolidin-1-yl)methyl]-4-(hydroxymethyl)cyclohexyl]hexahy dropyrimidine-2,4,6- trione (188) Synthetic scheme:

8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitr ile To a solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (10 g, 59.8 mmol) in THF (100 mL) was added LDA (2 M, 44.86 mL) dropwise at 0 °C. After stirring at 0 °C for 30 min, chloromethoxymethylbenzene (28.1 g, 179.4 mmol) was added dropwise at 0 °C. The reaction was warmed to 20 °C and stirred for 16 h. After completion, the reaction was diluted with H2O (150 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 80 : 1 to 1 : 1) to provide the title compound (10.8 g, 62.8%) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ ppm 7.30-7.37 (m, 5H), 4.62 (s, 2H), 3.90-4.00 (m, 4H), 3.46 (s, 2H), 2.07 (d, J = 13.6 Hz, 2H), 1.88-1.93 (m, 2H), 1.76 (d, J = 13.2 Hz, 2H), 1.18-1.44 (m, 2H). [8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl]methanami ne A solution of LiAlH4 (2.5 M, 48.72 mL) in THF (35 mL) was added dropwise to a solution of 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (7 g, 24.4 mmol) in THF (35 mL) at 0 °C. The reaction was stirred at 0-20 °C for 16 h, cooled down to 0 °C and quenched with H2O (5 mL) and 15% NaOH (5 mL). The reaction was diluted with H2O (15 mL), filtered through a Celite pad and washed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure to provide the title compound (7 g, 98.6%) as a white solid, which was used directly in the next step without further purification. ¹ H NMR (400 MHz, CDCl3) δ ppm 7.28-7.37 (m, 5H), 4.50 (s, 2H), 3.93 (s, 4H), 3.33 (s, 2H), 2.69 (s, 2H), 1.58-1.62 (m, 4H), 1.50-1.54 (m, 4H). Methyl 2-[[8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl]methyl amino]-2-methyl- propanoate To a solution of [8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl]methanami ne (7 g, 24 mmol) in DMA (70 mL) was added cesium carbonate (23.48 g, 72.1 mmol), NaI (360.1 mg, 2.4 mmol) and methyl 2-bromo-2-methyl-propanoate (21.74 g, 120.1 mmol). After heating at 60 °C for 16 h, the reaction was diluted with H ₂ O (70 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 80 : 1 to 0 : 1) to provide the title compound (7.1 g, 75.5%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.28-7.36 (m, 5H), 4.50 (s, 2H), 3.93 (s, 4H), 3.67 (s, 3H), 3.33 (s, 2H), 2.45 (s, 2H), 1.53-1.60 (m, 8H), 1.25 (s, 6H). 1-[[1-(Benzyloxymethyl)-4-oxo-cyclohexyl]methyl]-5,5-dimethy l-imidazolidine-2,4-dione To a solution of methyl 2-[[8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8- yl]methylamino]-2-methyl-propanoate (7 g, 17.9 mmol) in AcOH (50 mL) was added potassium isocyanate (7.25 g, 89.4 mmol). After heating at 100 °C for 16 h, the reaction was adjusted to pH ~6 with saturated NaHCO ₃ (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 80 : 1 to 0 : 1) to provide the title compound (2.5 g, 39%) as a yellow solid. MS (ESI): mass calcd. for C ₂₀ H ₂₆ N ₂ O ₄ : 358.19, found: 359.2 [M+H] ⁺ . 1-[4-(Benzyloxymethyl)-4-[[5,5-dimethyl-2,4-dioxo-3-(2-trime thylsilylethoxymethyl) imidazolidin-1-yl]methyl]cyclohexyl]-3-butyl-urea The title compound was synthesized in similar procedures as described in Example 138. MS (ESI): mass calcd. for C31H52N4O5Si: 588.37, found: 611.4 [M+Na] ⁺ . 1-Butyl-3-[4-[[5,5-dimethyl-2,4-dioxo-3-(2-trimethylsilyleth oxymethyl)imidazolidin-1- yl]methyl]-4-(hydroxymethyl)cyclohexyl]urea To a solution of 1-[4-(benzyloxymethyl)-4-[[5,5-dimethyl-2,4-dioxo-3-(2- trimethylsilylethoxymethyl)imidazolidin-1-yl]methyl]cyclohex yl]-3-butyl-urea (2.6 g, 4.42 mmol) in EtOH (26 mL) was added 10% Pd/C (2.6 g, 2.44 mmol) under N2. The reaction was degassed and purged with H23 times. After stirring at 25°C for 16 h under H2 (45 psi), the suspension was filtered through a Celite pad and washed with EtOH (3 x 30 mL). The filtrate was concentrated under reduced pressure to provide the title compound (2.1 g, 95.4%) as a colorless oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C ₂₆ H ₄₆ N ₄ O ₅ Si: 498.32, found: 521.3 [M+Na] ⁺ . (4-(3-Butylureido)-1-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexyl)methyl acetate To a solution of 1-butyl-3-[4-[[5,5-dimethyl-2,4-dioxo-3-(2- trimethylsilylethoxymethyl)imidazolidin-1-yl]methyl]-4-(hydr oxymethyl)cyclohexyl]urea (2.1 g, 4.2 mmol) in dioxane (21 mL) was added Ac2O (1.29 g, 12.63 mmol) and DMAP (51.4 mg, 0.42 mmol). After stirring at 25 °C for 16 h, the reaction was poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to provide the title compound (2 g, 87.8%) as a colorless oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C ₂₆ H ₄₈ N ₄ O ₆ Si: 540.33, found: 563.3 [M+Na] ⁺ . (4-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrim idin-1(2H)-yl)-1-((3- (hydroxymethyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)meth yl)cyclohexyl)methyl acetate The title compound was prepared in similar procedures as described in Example 138. SEM group was not deprotected completely with TFA/H ₂ O. MS (ESI): mass calcd. for C25H38N6O8: 550.68, found: 551.4 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4-dioxoim idazolidin-1-yl)methyl)-4- (hydroxymethyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (Example 146) To a solution of (4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrim idin- 1(2H)-yl)-1-((3-(hydroxymethyl)-5,5-dimethyl-2,4-dioxoimidaz olidin-1- yl)methyl)cyclohexyl)methyl acetate (300 mg, 0.58 mmol) in MeOH (3 mL) was added K2CO3 (238.9 mg, 1.73 mmol). After heating at 40 °C for 16 h, the reaction was added citric acid to adjust to pH = 6. The mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (mobile phase: [H2O (0.2% FA)-ACN]; gradient 35% to 65% B) to provide the title compound (146, cis/trans mixture) (70 mg, 25.4%) as a white solid. MS (ESI): mass calcd. for C22H34N6O6: 478.25, found: 479.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 10.30-10.40 (br s, 2H), 7.48 (s, 1H), 5.24-5.63 (m, 2H), 4.72-4.79 (m, 1H), 3.86-3.93 (m, 2H), 3.71 (s, 2H), 3.04 (s, 2H), 2.59-2.65 (m, 2H), 1.84 (d, J = 14.0 Hz, 2H), 1.56-1.64 (m, 2H), 1.50-1.53 (m, 2H), 1.45 (s, 6H), 1.35-1.38 (m, 2H), 1.16-1.19 (m, 26H), 0.95 (t, J = 7.2 Hz, 3 H). 1-Butyl-5-(diaminomethylene)-3-[4-[(5,5-dimethyl-2,4-dioxo-i midazolidin-1-yl)methyl]- 4-(hydroxymethyl)cyclohexyl]hexahydropyrimidine-2,4,6-trione (187) and 1-butyl-5- (diaminomethylene)-3-[4-[(5,5-dimethyl-2,4-dioxo-imidazolidi n-1-yl)methyl]-4- (hydroxymethyl)cyclohexyl]hexahydropyrimidine-2,4,6-trione (188) 1-Butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4-dioxoim idazolidin-1- yl)methyl)-4-(hydroxymethyl)cyclohexyl)pyrimidine-2,4,6(1H,3 H,5H)-trione (146) was separated by reverse phase HPLC (mobile phase: [H ₂ O (0.2% FA)-ACN]; gradient:35-65% B) to provide the title compound (187) (39.3 mg) as a white solid and the title compound (188) (30.7 mg) as a white solid. Stereochemistry is arbitrarily assigned. 187: MS (ESI): mass calcd. for C22H34N6O6: 478.25, found: 479.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 10.13-10.35 (m, 2H), 7.44-7.53 (m, 1H), 5.35-5.57 (m, 2H), 4.71-4.78 (m, 1H), 3.86-3.90 (m, 2H), 3.69 (s, 2H), 3.03 (s, 2H), 2.62-2.69 (m, 2H), 1.84 (d, J = 12.8 Hz, 2H), 1.49 - 1.59 (m, 2H), 1.45 (s, 6H), 1.36-1.40 (m, 4H), 1.17-1.19 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). 188: MS (ESI): mass calcd. for C22H34N6O6: 478.25, found: 479.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 10.14-10.44 (m, 2H), 7.42 (s, 1H), 5.17-5.38 (m, 2H), 4.84-4.88 (m, 1H), 3.90 (t, J = 7.6 Hz, 2H), 3.54 (s, 2H), 3.25 (s, 2H), 2.58-2.66 (m, 2H), 1.80 (d, J = 14.0 Hz, 2H), 1.58-1.64 (m, 2H), 1.55 (s, 6H), 1.29-1.40 (m, 4H), 1.19-1.26 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H). Examples 178, 182, 183 were synthesized in similar procedures as described in Examples 187 and 188. Stereochemistry of 182 and 183 is arbitrarily assigned. Example 190 and 191. (1r,4r)-4-(3-Butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-1-((5,5-dimethyl-2,4-dio xoimidazolidin-1- yl)methyl)cyclohexane-1-carbonitrile (190) and (1s,4s)-4-(3-Butyl-5- (diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl) -1-((5,5-dimethyl-2,4- dioxoimidazolidin-1-yl)methyl)cyclohexane-1-carbonitrile (191) Synthetic scheme: 1-((5,5-Dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)meth yl)imidazolidin-1- yl)methyl)-4-oxocyclohexane-1-carbonitrile The title compound was synthesized following Example 119, steps 4 to 7. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.04 (s, 1H), 3.54 (s, 2H), 2.44-2.48 (m, 2H), 2.22-2.37 (m, 4H), 1.92-2.02 (m, 2H), 1.39 (s, 6H). 4-Amino-1-[[5,5-dimethyl-2,4-dioxo-3-(2-trimethylsilylethoxy methyl)imidazolidin-1- yl]methyl]cyclohexanecarbonitrile To a mixture of 1-((5,5-Dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-ox ocyclohexane-1-carbonitrile (1 g, 2.54 mmol) and ammonium acetate (3.92 g, 50.8 mmol) in MeOH (10 mL) was added NaBH(OAc) ₃ (1.35 g, 6.4 mmol) in one portion at 25 °C under N ₂ . After stirring for 1 h, the reaction was poured into NaHCO3 (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to provide the title compound (0.95 g, 94.8%) as a white solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C19H34N4O3Si: 394.24, found: 395.2 [M+H] ⁺ . (1r,4r)-4-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahyd ropyrimidin-1(2H)-yl)-1- ((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexane -1-carbonitrile (190) and (1s,4s)-4-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahyd ropyrimidin-1(2H)-yl)-1- ((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexane -1-carbonitrile (191) The title compounds were synthesized in similar procedures as described in Example 138 and 139. Stereochemistry is arbitrarily assigned. Example 189 is the cis and trans mixture of 190 and 191 before chiral separation. Example 190: MS (ESI): mass calcd. for C ₂₂ H ₃₁ N ₇ O ₅ : 473.24, found: 474.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.03 (s, 1H), 9.54 (s, 2H), 7.35 (s, 2H), 4.78 (t, J = 12.4 Hz, 1H), 3.75 (t, J = 7.2 Hz, 2H), 3.59 (s, 2H), 2.71-2.73 (m, 1H), 2.59-2.67 (m, 1H), 2.28-2.31 (m, 2H), 1.78- 1.86 (m, 2H), 1.41-1.52 (m, 4H), 1.40 (s, 6H), 1.23-1.28 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). Example 191: MS (ESI): mass calcd. for C ₂₂ H ₃₁ N ₇ O ₅ : 473.24, found: 474.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (s, 1H), 9.53 (s, 2H), 7.32 (s, 2H), 4.64-4.70 (m, 1H), 3.75 (t, J = 7.2 Hz, 2H), 3.44 (s, 2H), 2.55-2.67 (m, 2H), 2.04 (d, J = 12.4 Hz, 2H), 1.52-1.61 (m, 4H), 1.42-1.49 (m, 2H), 1.37 (s, 6H), 1.23-1.31 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). Examples 192 and 195 were synthesized from Example 177 by chiral SFC separation. Example 193 was synthesized in similar procedures as described in Examples 138 and 139. Examples 194, 196 and 198 were synthesized in similar procedures as described in Examples 140 and 141. Example 197 was synthesized in similar procedures as described in Examples 138 and 139, except the cyclohexyl ketone conversion to cyclohexyl amine was performed with sodium triacetoxyborohydride, ammonium acetate in methanol as in Example 166 and 171. Example 199.1-Benzyl-5-(diaminomethylene)-3-((1r,4r)-4-((6,8-dioxo-2 -oxa-5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl)pyrimid ine-2,4,6(1H,3H,5H)- trione (199) Synthetic scheme:

1-Benzyl-3-(4-((6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)me thyl)-2-oxa-5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl)urea To 5-((4-amino-1-methylcyclohexyl)methyl)-7-((2-(trimethylsilyl )ethoxy)methyl)-2- oxa-5,7-diazaspiro[3.4]octane-6,8-dione (30.0 mg, 75.5 µmol, intermediate in the synthesis of Example 159) in DCM (0.76 mL) was added benzyl isocyanate (9.3 µL, 75.5 µmol). The reaction was stirred for 15 min then water was added, and the solution was extracted twice with DCM, dried over Na2SO4, filtered, and concentrated in vacuo to provide the crude title compound (20 mg). The crude was used directly in the next step without further purification. MS (ESI): mass calcd. for C27H42N4O5Si: 530.73, found: 531.8 [M+H] ⁺ . 1-Benzyl-3-(4-((6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methy l)-2-oxa-5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl)pyrimid ine-2,4,6(1H,3H,5H)- trione 1-Benzyl-3-(4-((6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methy l)-2-oxa-5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl)urea (20.0 mg, 37.7 µmol), malonic acid (3.96 mg, 37.7 µmol), and acetic anhydride (24.9 µL, 264 µmol) were dissolved in AcOH (377 µL) and the solution was heated to 80 °C for 18 h. The mixture was neutralized with saturated NaHCO3 and extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to provide the crude title compound (50 mg). The crude was used directly in the next step without further purification. MS (ESI): mass calcd. for C30H42N4O7Si: 598.76, found: 597.8 [M-H]-. 1-Benzyl-5-(diaminomethylene)-3-(4-((6,8-dioxo-7-((2-(trimet hylsilyl)ethoxy)methyl)-2- oxa-5,7-diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl )pyrimidine- 2,4,6(1H,3H,5H)-trione 1-Benzyl-3-(4-((6,8-dioxo-7-((2-(trimethylsilyl)ethoxy)methy l)-2-oxa-5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl)pyrimid ine-2,4,6(1H,3H,5H)-trione (50.0 mg, 83.5 µmol), cyanamide (35.5 mg, 835 µmol), and nickel(II) acetylacetonate (4.3 mg, 16.7 µmol) were dissolved in THF (1.7 mL) and heated to 80 °C for 18 h. The solution was cooled down to rt, filtered, and the solvent removed to yield the crude title compound. The crude was purified by silica gel column chromatography (C18, 0-100% MeCN/10 mM HCOONH4 water) to provide the titled compound (21 mg). MS (ESI): mass calcd. for C31H44N6O7Si: 640.80, found: 639.6 [M-H]-. 1-Benzyl-5-(diaminomethylene)-3-((1r,4r)-4-((6,8-dioxo-2-oxa -5,7-diazaspiro[3.4]octan- 5-yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-t rione (199) 1-Benzyl-5-(diaminomethylene)-3-(4-((6,8-dioxo-7-((2- (trimethylsilyl)ethoxy)methyl)-2-oxa-5,7-diazaspiro[3.4]octa n-5-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (21.0 mg, 32.0 µmol) was dissolved in TFA (585 µL) and water (195 µL) and stirred for 2 h. The reaction was diluted with MeOH and pH was adjusted to 8 with saturated Na ₂ CO ₃ and the resulting mixture was stirred for 72 h. The solution was extracted with DCM (3 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (C18, 5-80% MeCN/10 mM HCOONH4 water) to provide the title compound (3.0 mg, 7.5%). The stereochemistry was arbitrarily assigned. MS (ESI): mass calcd. for C25H30N6O6: 510.54, found: 509.6 [M-H]-. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 7.11 – 7.40 (m, 5H), 4.94 (s, 2H), 4.80 (d, J = 7.4 Hz, 2H), 4.64 (d, J = 7.4 Hz, 2H), 3.25 (s, 2H), 2.52 (s, 2H), 1.20 – 1.54 (m, 8H), 1.03 (s, 3H). Example 200.1-((1s,4s)-4-((1-Benzyl-4,4-dimethyl-2,5-dioxopyrrolidin -3- yl)oxy)cyclohexyl)-3-butyl-5-(diaminomethylene)pyrimidine-2, 4,6(1H,3H,5H)-trione (200) Synthetic scheme: 1-Benzyl-3,3-dimethylpyrrolidine-2,5-dione In a pressure tube, 2,2-dimethylsuccinic anhydride (1.02 g, 7.8 mmol) was suspended in toluene (1.0 mL). Benzylamine (1.3 mL, 11.7 mmol) was added along with 4A molecular sieves. The tube was sealed and heated at 140 °C for 4 h. The reaction was cooled down to rt and diluted with EtOAc, washed with 1 N NaOH (2 × 20 mL), 1 M HCl (2 × 20 mL) and water (20 mL). The organic layer was dried over MgSO ₄ , filtered, and concentrated in vacuo to give the title compound (1.42 g, 84%) as a yellow oil. MS (ESI): mass calcd. for C ₁₃ H ₁₅ NO ₂ : 217.26, found: 218.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.26 – 7.36 (m, 5H), 4.64 (s, 2H), 2.55 (s, 2H), 1.30 (s, 6H). 1-Benzyl-4-bromo-3,3-dimethylpyrrolidine-2,5-dione To a solution of 1-benzyl-3,3-dimethylpyrrolidine-2,5-dione (500 mg, 2.3 mmol) in THF (11.5 mL) at –78 °C was added lithium bis(trimethylsilyl)amide solution (4.6 mL, 4.6 mmol) slowly. The solution was stirred for 1 h and then N-bromosuccinimide (455 mg, 2.53 mmol) was added under nitrogen. The cooling bath was removed, and the solution was stirred at rt for 2 h. The reaction was quenched with water (1 mL) and washed with sat. Na ₂ S ₂ O ₄ (1 mL). The organic phase was then dried over MgSO ₄ , filtered, and concentrated to give the crude title compound (610 mg, 89%) as a red-orange oil. ¹ H NMR (400 MHz, CDCl3) δ ppm 7.27 – 7.36 (m, 5H), 4.68 (d, J = 2.1 Hz, 2H), 4.49 (s, 1H), 1.36 (s, 3H), 1.36 (s, 3H). tert-Butyl ((1s,4s)-4-((1-benzyl-4,4-dimethyl-2,5-dioxopyrrolidin-3- yl)oxy)cyclohexyl)carbamate Tert-butyl (cis-4-hydroxycyclohexyl)carbamate (336 mg, 1.51 mmol) was dissolved in anhydrous DMF (8.1 mL) and sodium hydride 60% dispersion in mineral oil (60.5 mg, 1.51 mmol) was added. The solution was stirred at rt for 5 min and a solution of 1-benzyl-4- bromo-3,3-dimethylpyrrolidine-2,5-dione (407 mg, 1.37 mmol) in DMF (8.1 mL) was added. The solution was stirred at rt for 1 h then was diluted with EtOAc, washed with water (2 × 10 mL) and brine (10 mL). The organic phase was dried over MgSO ₄ , filtered, and concentrated onto silica gel and purified by silica gel column chromatography (0-100% EtOAc/Heptanes) to give the title compound (146 mg, 25 %). MS (ESI): mass calcd. for C24H34N2O5: 430.54, found: 331.7 [M+H-Boc] ⁺ . 4-(((1s,4s)-4-Aminocyclohexyl)oxy)-1-benzyl-3,3-dimethylpyrr olidine-2,5-dione Tert-butyl ((1s,4s)-4-((1-benzyl-4,4-dimethyl-2,5-dioxopyrrolidin-3- yl)oxy)cyclohexyl)carbamate (120 mg, 279 µmol) was dissolved in DCM (0.47 mL) and TFA (185 µL) was added. The reaction was stirred for 2 h and then evaporated to dryness to give the title compound (92.0 mg, 100 %) as a yellow oil. MS (ESI): mass calcd. for C19H26N2O3: 330.42, found: 331.3 [M+H] ⁺ . 1-((1s,4s)-4-((1-Benzyl-4,4-dimethyl-2,5-dioxopyrrolidin-3-y l)oxy)cyclohexyl)-3- butylurea To 4-(((1s,4s)-4-aminocyclohexyl)oxy)-1-benzyl-3,3-dimethylpyrr olidine-2,5-dione (92.1 mg, 279 µmol) in anhydrous DMF (1.2 mL) were added triethylamine (117 µL, 836 µmol) and butyl isocyanate (36.2 µL, 315 µmol). The solution was stirred at rt for 2.5 h. The reaction was then diluted with EtOAc (1 mL), washed with water (2 × 1 mL) and brine (1 mL). The organic phase was dried over MgSO ₄ , filtered, and concentrated to give the title compound (120 mg, 100%) as a green oil. MS (ESI): mass calcd. for C24H35N3O4: 429.55, found: 430.8 [M+H] ⁺ . 1-((1s,4s)-4-((1-Benzyl-4,4-dimethyl-2,5-dioxopyrrolidin-3-y l)oxy)cyclohexyl)-3- butylpyrimidine-2,4,6(1H,3H,5H)-trione 1-((1s,4s)-4-((1-Benzyl-4,4-dimethyl-2,5-dioxopyrrolidin-3-y l)oxy)cyclohexyl)-3- butylurea (66.0 mg, 154 µmol) was dissolved in AcOH (0.2 mL) and malonic acid (18.6 mg, 177 µmol) was added. The solution was heated to 65 °C, acetic anhydride (58.1 µL, 615 µmol) was added. The reaction was sealed and heated at 90 °C for 1 h. The reaction was diluted with EtOAc (20 mL), concentrated and purified by silica gel column chromatography (0-100% EtOAc/Heptanes) to give the title compound (67.0 mg, 88 %) as a yellow-orange solid. MS (ESI): mass calcd. for C ₂₇ H ₃₅ N ₃ O ₆ : 497.58, found: 498.7 [M+H] ⁺ . 1-((1s,4s)-4-((1-Benzyl-4,4-dimethyl-2,5-dioxopyrrolidin-3-y l)oxy)cyclohexyl)-3-butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (200) 1-((1s,4s)-4-((1-Benzyl-4,4-dimethyl-2,5-dioxopyrrolidin-3-y l)oxy)cyclohexyl)-3- butylpyrimidine-2,4,6(1H,3H,5H)-trione (20.0 mg, 40.2 µmol), cyanamide (5.1 mg, 121 µmol) and nickel(II) acetylacetonate (3.1 mg, 12.1 µmol) were put in a vial and anhydrous THF (0.22 mL) was added. The reaction was heated at 85 °C for 18 h. The reaction was cooled down and filtered with a syringe filter, concentrated, and redissolved in DCM. The organic phase was washed with water, dried over MgSO ₄ , filtered, and concentrated to give a crude orange oil which was purified by reverse phase HPLC (C18, 45-65% MeCN/HCOONH ₄ 10 mM buffer) to give the title compound (200) (5.0 mg, 23%) as a colorless solid. MS (ESI): mass calcd. for C28H37N5O6: 539.62, found: 540.8 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl3) δ ppm 7.33 – 7.39 (m, 2H), 7.25 – 7.33 (m, 3H), 5.11 (s, 1H), 4.36 (d, J = 15.1 Hz, 1H), 3.81 – 3.88 (m, 3H), 2.69 – 2.87 (m, 2H), 2.02 (dd, J = 28.6, 15.4 Hz, 2H), 1.65 – 1.80 (m, 2H), 1.56 (dd, J = 15.1, 7.3 Hz, 2H), 1.47 (d, J = 12.1 Hz, 2H), 1.39 (s, 3H), 1.28 – 1.36 (m, 4H), 1.23 (s, 3H), 0.92 (t, J = 7.3 Hz, 3H). Example 201.1-Butyl-5-(diaminomethylene)-3-(4-((4,4-dimethyl-1,1-dio xido-1,2,5- thiadiazolidin-2-yl)methyl)-4-methylcyclohexyl)pyrimidine-2, 4,6(1H,3H,5H)-trione (201) Synthetic scheme: NH ₂ O ^O NH O ₂ S _O O O H ₂ N MgSO NaBH ^{O H} H ₂ N NH ₂ TsO 1) NH MeOH O O _{4, 4 N} O H _3, MeOH _{, 115 °C} ^N NH S ^N NH ^N NH p _yridine Acetone/H ₂ O, 50 °C ^S 2) H Pd/C _S O _2, O NH ₂ O O _{O O} H ₂ N NH ₂ ^{H H H} O O O O 2 ^N NCO _{N Ni(acac)2} O O n-Bu _N HO OH N N cyanamide N NH N S _DCM ^{O N} H S ₂ 90 °C O _N N N N Ac O, AcOH, H O ^{THF, 85 ° O O O} _S ^C O _N NH O _{O S O} ^O 2-Methyl-N1-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl) propane-1,2-diamine A mixture of 1,2-diamini-2-methylpropane (488 mg, 5.43 mmol), magnesium sulfate (1.13 g, 9.39 mmol), and 8-methyl-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (1 g, 5.43 mmol) in MeOH (10.9 mL) was stirred under N ₂ for 60 min. The mixture was then cooled to 0 °C and sodium borohydride (428 mg, 10.9 mmol) was added portion-wise. After complete addition, the mixture was stirred at rt for 18 h. The solid was filtered and rinsed with DCM (30 mL). The filtrate was washed with saturated aqueous NaHCO ₃ (20 mL) and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organics layers were dried over Na2SO4, filtered, and concentrated to give the title compound (1.17 g, 84 %) as a clear oil. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.91 (s, 4H), 2.46 (s, J = 7.0 Hz, 4H), 1.50 – 1.69 (m, 6H), 1.31 – 1.46 (m, 2H), 1.08 (s, 6H), 0.97 (s, 3H) 4,4-Dimethyl-2-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)meth yl)-1,2,5-thiadiazolidine 1,1-dioxide A mixture of 2-methyl-N1-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl) propane- 1,2-diamine (580 mg, 2.26 mmol) and sulfamide (413 µL, 6.79 mmol) in pyridine (5 mL) was stirred at 115 °C for 6 h. The reaction mixture was concentrated under reduced pressure, diluted with KHSO4 (10%, 10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to give the title compound (625 mg, 87%) as a beige solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.91 (s, 4H), 3.31 (s, 2H), 2.93 (s, 2H), 1.53 – 1.67 (m, 6H), 1.37 – 1.46 (m, 2H), 1.35 (s, 6H), 1.00 (s, 3H). 4-((4,4-Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methy l)-4-methylcyclohexanone To 4,4-dimethyl-2-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)meth yl)-1,2,5- thiadiazolidine 1,1-dioxide (625 mg, 1.96 mmol) in acetone (6 mL) and water (3 mL) was added p-toluenesulfonic acid monohydrate (758 mg, 3.93 mmol). The mixture was heated at 50 °C for 8 h and then at rt for 17 h. After completion, water (10 mL) and saturated aqueous NaHCO3 solution (10 mL) were added and extracted with DCM (3 × 20 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to give the title compound (527 mg, 98 %) as a clear oil that solidified upon standing. ¹ H NMR (400 MHz, CDCl3) δ ppm 4.03 (s, 1H), 3.34 (s, 2H), 3.09 (s, 2H), 2.32 – 2.50 (m, 4H), 1.76 – 1.86 (m, 2H), 1.65 – 1.76 (m, 2H), 1.43 (s, 6H), 1.17 (s, 3H). 2-((4-Amino-1-methylcyclohexyl)methyl)-4,4-dimethyl-1,2,5-th iadiazolidine 1,1-dioxide To 4-((4,4-dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methy l)-4- methylcyclohexanone (527 mg, 1.92 mmol) was added ammonia 7 M in MeOH (5.6 mL, 39.2 mmol) and the mixture was stirred for 3 h at rt. Under nitrogen, 10% palladium on carbon (40.9 mg) was added. The reaction was submitted to 5 cycles of vacuum/ hydrogen purges and stirred under hydrogen for 18 h. Hydrogen was replaced by nitrogen via 5 cycles of vacuum/nitrogen. The reaction was filtered with Celite, rinsed with MeOH (50 mL) and DCM (50 mL), and concentrated. The crude was dissolved in DCM (20 mL) and washed with HCl (1 M, 10 mL). The aqueous phase was basified to pH = 10 with K ₂ CO ₃ by slow addition. The basic aqueous phase was extracted with 20% IPA/CHCl3 (3 × 15 mL), and the combined organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to give the title compound (275 mg, 52%) as a white foam (cis/trans ratio =1/1). MS (ESI): mass calcd. for C12H25N3O2S: 275.41, found: 276.7 [M+H] ⁺ . 1-Butyl-3-(4-((4,4-dimethyl-1,1-dioxido-1,2,5-thiadiazolidin -2-yl)methyl)-4- methylcyclohexyl)urea To 2-((4-amino-1-methylcyclohexyl)methyl)-4,4-dimethyl-1,2,5-th iadiazolidine 1,1- dioxide (275 mg, 999 µmol) in DCM (10 mL) under nitrogen was added butyl isocyanate (121 µL, 1.05 mmol). The mixture was stirred at rt for 18 h and then concentrated. The crude was purified by reverse phase HPLC (C18, 20-100% MeCN/10 mM HCOONH4 buffer) to provide the title compound (159 mg, 43 %) as a mixture of 1:1 trans/cis isomers. MS (ESI): mass calcd. for C ₁₇ H ₃₄ N ₄ O ₃ S: 374.54, found: 375.7 [M+H] ⁺ . 1-Butyl-3-(4-((4,4-dimethyl-1,1-dioxido-1,2,5-thiadiazolidin -2-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione In a 20 mL vial containing 1-butyl-3-(4-((4,4-dimethyl-1,1-dioxido-1,2,5- thiadiazolidin-2-yl)methyl)-4-methylcyclohexyl)urea (159 mg, 425 µmol) in AcOH (2.1 mL) was added malonic acid (44.6 mg, 425 µmol) and acetic anhydride (281 µL, 2.97 mmol). The mixture was stirred at 80 °C for 18 h. The vial was cooled down to rt, water (10 mL) was added to quench the reaction. The reaction mixture was extracted with EtOAc (20 mL), and the organic phase was washed with saturated aqueous NaHCO ₃ (10 mL) followed by water (20 mL), dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase chromatography (C18, 30-100% MeCN/10 mM HCOONH ₄ buffer) to provide the title compound (63 mg, 33%) as a mixture of 1:1 trans/cis isomers. MS (ESI): mass calcd. for C20H34N4O5S: 442.57, found: 443.6 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(4-((4,4-dimethyl-1,1-dioxido -1,2,5-thiadiazolidin-2- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-tri one (201) 1-Butyl-3-(4-((4,4-dimethyl-1,1-dioxido-1,2,5-thiadiazolidin -2-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (15.0 mg, 33.9 µmol), cyanamide (4.3 mg, 102 µmol) and nickel(II) acetylacetonate (2.6 mg, 10.2 µmol) were put in a vial and anhydrous THF (0.2 mL) was added. The reaction was heated at 85 °C for 18 h, cooled down to rt, filtered with a syringe filter, concentrated, and redissolved in DCM. The organic phase was washed with water, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude was purified by reverse phase HPLC (C18, 30-50% MeCN/NH4HCO310 mM buffer). Appropriate fractions were concentrated and lyophilized to provide the title compound (201) (5.0 mg, 30 %) as a mixture of 1:1 trans/cis isomers. MS (ESI): mass calcd. for C21H36N6O5S: 484.61, found: 485.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) δ ppm 3.80 – 3.89 (m, 2H), 3.34 (d, J = 7.6 Hz, 2H), 3.21 (s, 1H), 2.86 (s, 1H), 2.55 – 2.73 (m, 2H), 1.74 (d, J = 13.4 Hz, 1H), 1.38 – 1.61 (m, 7H), 1.37 (d, J = 4.5 Hz, 6H), 1.26 – 1.34 (m, 3H), 0.92 – 1.12 (m, 6H). Example 202.1-Butyl-5-(diaminomethylene)-3-(4-((4,4-dimethyl-2-oxoim idazolidin-1- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-tri one (202) Synthetic scheme: 4,4-Dimethyl-1-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)meth yl)imidazolidin-2-one To a solution of 2-methyl-N1-((8-methyl-1,4-dioxaspiro[4.5]decan-8- yl)methyl)propane-1,2-diamine (720 mg, 2.81 mmol) (described in Example 201) in ACN (9.4 mL) were added N,N-diisopropylethylamine (1.5 mL, 8.42 mmol) and 1,1`- carbonylimidazole (1.01 g, 5.62 mmol). The resulting solution was heated at 65 °C for 1 h. The reaction mixture was concentrated, diluted with water, and extracted with DCM (3 × 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to give the crude title compound (793 mg, 100%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.91 (s, 4H), 3.30 (s, 2H), 2.97 (s, 2H), 1.51 – 1.72 (m, 6H), 1.35 – 1.46 (m, 2H), 1.28 (s, 6H), 0.97 (s, 3H). 4,4-Dimethyl-1-((1-methyl-4-oxocyclohexyl)methyl)imidazolidi n-2-one To 4,4-dimethyl-1-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)meth yl)imidazolidin-2- one (740 mg, 2.62 mmol) in acetone (8.8 mL) and water (4.4 mL) was added p- toluenesulfonic acid monohydrate (1.01 g, 5.24 mmol). The mixture was heated at 50 °C for 18 h and cooled down to rt. The reaction mixture was added water (10 mL), saturated aqueous NaHCO ₃ (10 mL), and then extracted with DCM (3 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (530 mg, 85 %) as a white solid. ¹ H NMR (400 MHz, CD3OD) δ ppm 3.33 (s, 2H), 3.13 (s, 2H), 2.37 – 2.48 (m, 4H), 1.74 – 1.84 (m, 2H), 1.62 – 1.74 (m, 2H), 1.29 (s, 6H), 1.14 (s, 3H). 1-((4-Amino-1-methylcyclohexyl)methyl)-4,4-dimethylimidazoli din-2-one To 4,4-dimethyl-1-((1-methyl-4-oxocyclohexyl)methyl)imidazolidi n-2-one (530 mg, 2.22 mmol) was added ammonia 7 M in MeOH (6.4 mL, 44.5 mmol), and the mixture was stirred at rt for 5 h. Under nitrogen, 10% palladium on carbon (47.3 mg) was added. The reaction was submitted to 5 cycles of vacuum/ hydrogen purges and stirred under hydrogen for 18 h. Hydrogen was replaced by nitrogen via 5 cycles of vacuum/ nitrogen. The reaction was filtered over Celite, rinsed with MeOH (50 mL), DCM (50 mL), and concentrated in vacuo to give the title compound (530 mg, 100 %) as a foam, with cis/trans ratio =1/1. MS (ESI): mass calcd. for C ₁₃ H ₂₅ N ₃ O: 239.36, found: 240.7 [M+H] ⁺ . 1-Butyl-3-(4-((4,4-dimethyl-2-oxoimidazolidin-1-yl)methyl)-4 -methylcyclohexyl)urea To 1-((4-amino-1-methylcyclohexyl)methyl)-4,4-dimethylimidazoli din-2-one (530 mg, 2.21 mmol) in DCM (11 mL) under nitrogen was added butyl isocyanate (255 µL, 2.21 mmol). The mixture was stirred at rt for 1.5 h. The reaction mixture was concentrated to give a white foam. The crude was purified by reverse phase HPLC (C18, 20-100% MeCN/10 mM HCOONH4 buffer). Appropriate fractions were concentrated and lyophilized to give the title compound (289 mg, 39%) as a mixture of 1:1 trans/cis isomers. MS (ESI): mass calcd. for C18H34N4O2: 338.49, found: 339.7 [M+H] ⁺ . 1-Butyl-3-(4-((4,4-dimethyl-2-oxoimidazolidin-1-yl)methyl)-4 - methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-(4-((4,4-dimethyl-2-oxoimidazolidin-1-yl)methyl)-4 - methylcyclohexyl)urea (274 mg, 809 µmol) in AcOH (4.1 mL) were added malonic acid (85.1 mg, 809 µmol) and acetic anhydride (536 µL, 5.67 mmol). The mixture was heated at 80 °C for 18 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaHCO3 (10 mL) followed by water (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The crude was purified by reverse phase HPLC (C18, 30-100% MeCN/10 mM HCOONH ₄ buffer) to give the title compound (103 mg, 31%) as a mixture of 1:1 trans/cis isomers. MS (ESI): mass calcd. for C21H34N4O4: 406.52, found: 407.6 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(4-((4,4-dimethyl-2-oxoimidaz olidin-1-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (202) 1-Butyl-3-(4-((4,4-dimethyl-2-oxoimidazolidin-1-yl)methyl)-4 - methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (15.0 mg, 36.9 µmol), cyanamide (4.7 mg, 111 µmol) and nickel(II) acetylacetonate (2.84 mg, 11.1 µmol) were put in a vial and anhydrous THF (200 µL) was added. The reaction was stirred at 85 °C for 18 h then cooled down to rt, filtered with a syringe filter, concentrated, and redissolved in DCM. The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase HPLC (C18, 35-55% MeCN/NH4HCO310 mM buffer). Appropriate fractions were concentrated and lyophilized to provide the title compound (202) (5.8 mg, 35%) as a mixture of 1:1 trans/cis isomers. MS (ESI): mass calcd. for C ₂₁ H ₃₆ N ₆ O ₅ : 448.56, found: 449.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) δ ppm 3.79 – 3.90 (m, 2H), 3.33 (d, J = 1.3 Hz, 2H), 3.26 (s, 1H), 2.91 (s, 1H), 2.56 – 2.78 (m, 2H), 1.31 – 1.73 (m, 11H), 1.29 (d, J = 1.2 Hz, 6H), 0.90 – 1.10 (m, 6H). Example 203 was synthesized in similar procedures as described in Examples 138 and 139. Example 204 and 209.5-(Diaminomethylene)-1-((1s,4s)-4-((5,5-dimethyl-2,4- dioxoimidazolidin-1-yl)methyl)-4-methylcyclohexyl)-3-isobuty lpyrimidine- 2,4,6(1H,3H,5H)-trione (204) and 5-(Diaminomethylene)-1-((1r,4r)-4-((5,5-dimethyl-2,4- dioxoimidazolidin-1-yl)methyl)-4-methylcyclohexyl)-3-isobuty lpyrimidine- 2,4,6(1H,3H,5H)-trione (209) Synthetic scheme: O O ^{NO2 H} O ^{H H} O H N O O O 2 _N Cl O NH _{2 N N} HO OH N ^N SEM O O _N ^N SEM O _N ^N SEM 2N Ac ₂ O, AcOH, 80 ^o C O O O H ₂ N NH ₂ O O H ₂ N NH ₂ H ₂ N NH ₂ O O O N N cyanamide TFA/H O O O O O O ₂ O _N ^N N N O O SEM bis[(Z)-1-methyl-3-oxo-but- separation N N N N o O _N ^N SEM O 1-enoxy]nickel, THF, 70 C, 10 h O _N ^NH O _N ^NH O 2 ⁰⁴ O ²⁰⁹ O 4-Nitrophenyl (4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)carbamate To a solution of 1-((4-amino-1-methylcyclohexyl)methyl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (200 mg, 0.52 mmol, see Example 138 for synthesis) in DCM (3 mL) was added DIPEA (67.38 mg, 0.52 mmol) and (4- nitrophenyl) carbonochloridate (126.1 mg, 0.63 mmol). The mixture was stirred at 20 °C for 16 h under N2. After completion, the reaction mixture was diluted with H2O (10 mL), extracted with DCM (3 x 10 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 3 : 1) to give the title compound (90 mg, 31.4%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.24-8.27 (m, 2H), 7.96-8.05 (m, 1H), 7.35-7.45 (m, 2H), 6.73 (d, J = 9.2 Hz, 1H), 4.77 (t, J = 3.6 Hz, 2H), 3.50-3.55 (m, 2H), 3.02-3.19 (m, 3H), 1.60-1.76 (m, 4H), 1.41 (s, 3H), 1.32-1.36 (m, 6H), 1.18-1.24 (m, 1H), 0.89-0.95 (m, 3H), 0.81-0.86 (m, 2H), -0.04 (s, 9H). 1-(4-((5,5-Dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)m ethyl)imidazolidin-1- yl)methyl)-4-methylcyclohexyl)-3-isobutylurea To a solution of 4-nitrophenyl (4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)carbamate (0.2 g, 0.36 mmol) in DCM (2 mL) was added DIPEA (56.53 mg, 0.44 mmol) and 2- methylpropan-1-amine (26.66 mg, 0.36 mmol). After stirring at 20 °C for 2 h under N2, the reaction was poured into water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 2 : 1) to provide the title compound (35 mg, crude) as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C ₂₄ H ₄₆ N ₄ O ₄ Si: 482.33, found: 483.4 [M+H] ⁺ . 1-(4-((5,5-Dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)m ethyl)imidazolidin-1- yl)methyl)-4-methylcyclohexyl)-3-isobutylpyrimidine-2,4,6(1H ,3H,5H)-trione To a solution of 1-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)-3-isobutylurea (35 mg, 72.5 μmol) and malonic acid (7.54 mg, 72.5μmo l) in acetic acid (1 mL) was added acetyl acetate (51.81 mg, 0.51 mmol). The mixture was heated at 80 °C for 3 h under N2, poured into water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 5 : 1) to provide the title compound (30 mg, crude) as a yellow oil. MS (ESI): mass calcd. for C27H46N4O6Si: 550.32, found: 573.4 [M+Na] ⁺ . 5-(Diaminomethylene)-1-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidin-1-yl)methyl)-4-methylcyclohexyl)-3- isobutylpyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)-3- isobutylpyrimidine-2,4,6(1H,3H,5H)-trione (30 mg, 54 μmol) and cyanamide (22.9 mg, 0.54 mmol) in THF (1 mL) was added bis[(Z)-1-methyl-3-oxo-but-1-enoxy]nickel (2.1 mg, 8 μmol). The reaction was heated at 80 °C for 16 h under N ₂ . The mixture was filtered and washed with 20 mL of THF and concentrated. The crude residue was purified by prep-TLC (SiO ₂ , Petroleum ether : Ethyl acetate = 1 : 1) to give the title compound (25 mg, 77.4%) as a yellow oil. MS (ESI): mass calcd. for C ₂₈ H ₄₈ N ₆ O ₆ Si: 592.34, found: 615.4 [M+Na] ⁺ . 5-(Diaminomethylene)-1-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoim idazolidin-1-yl)methyl)-4- methylcyclohexyl)-3-isobutylpyrimidine-2,4,6(1H,3H,5H)-trion e (204) and 5- (diaminomethylene)-1-((1r,4r)-4-((5,5-dimethyl-2,4-dioxoimid azolidin-1-yl)methyl)-4- methylcyclohexyl)-3-isobutylpyrimidine-2,4,6(1H,3H,5H)-trion e (209) 5-(Diaminomethylene)-1-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)-3- isobutylpyrimidine-2,4,6(1H,3H,5H)-trione (12.5 mg, 21 μmol) was dissolved in TFA (5 mL) and H ₂ O (1 mL) at 20 °C. After stirring for 5 h under N ₂ , the reaction was filtered and concentrated under reduced pressure. The residue was diluted with MeOH (1 mL) and then adjusted to pH = 8 with saturated K ₂ CO ₃ and stirred at rt for 3 h. The combined organic layer was adjusted to pH = 5 with saturated citric acid, extracted with EtOAc (3 x 10 mL), washed with NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (30-60% H ₂ O (0.2% FA)-ACN; gradient elution) and then separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10 um; mobile phase: CO2-EtOH (0.1% NH3H2O); 40% isocratic) to give the title compound (204) (1 mg, 5%) as a white solid and the title compound (209) (1 mg, 5%) as a white solid. Stereochemistry was arbitrarily assigned. 204: MS (ESI): mass calcd. for C22H34N6O5: 462.26, found: 463.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.81 (s, 1H), 9.56 (s, 2H), 7.32 (s, 2H), 4.58-4.65 (m, 1H), 3.61 (d, J = 7.2 Hz, 2H), 2.96 (s, 2H), 1.94-2.00 (m, 1H), 1.39-1.47 (m, 2H), 1.30-1.40 (m, 6H), 1.29 (s, 6H), 0.99 (s, 3H), 0.81 (d, J = 6.8 Hz, 6H).209: MS (ESI): mass calcd. for C22H34N6O5: 462.26, found: 463.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.78-10.81 (m, 1H), 9.56 (s, 2H), 7.40 (s, 2H), 4.70-4.75 (m, 1H), 3.63 (d, J = 7.2 Hz, 2H), 3.26 (s, 2H), 2.57-2.65 (m, 2H), 1.95-2.01 (m, 1H), 1.72 (d, J = 12.8 Hz, 2H), 1.32 (s, 6H), 1.15-1.30 (m, 4H), 0.88 (s, 3H), 0.82 (d, J = 6.8 Hz, 6H). Examples 220, 226, 265, and 281 were synthesized as described in Example 204 and 209. Examples 205 and 206. 5-(Diaminomethylene)-1-((1r,4r)-4-((5,5-dimethyl-2,4- dioxoimidazolidin-1-yl)methyl)-4-methylcyclohexyl)-3-isoprop ylpyrimidine- 2,4,6(1H,3H,5H)-trione (205) and 5-(Diaminomethylene)-1-((1r,4r)-4-((5,5-dimethyl-2,4- dioxoimidazolidin-1-yl)methyl)-4-methylcyclohexyl)-3-isoprop ylpyrimidine- 2,4,6(1H,3H,5H)-trione (Error! Reference source not found.) Synthetic scheme:

1-(4-((5,5-Dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethox y)methyl)imidazolidin-1- yl)methyl)-4-methylcyclohexyl)-3-isopropylurea To 1-((4-amino-1-methylcyclohexyl)methyl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (100 mg, 261 µmol) in DCM (2.6 mL) was added isopropyl isocyanate (26.1 µL, 261 µmol). The reaction was stirred for 15 min then water (10 mL) was added, and the solution was extracted twice with DCM (3 × 10 mL), dried over Na ₂ SO ₄ , fileted, and concentrated to provide the crude title compound, which was used in the next step without further purification. MS (ESI): mass calcd. for C23H44N4O4Si: 468.71, found: 491.8 [M+Na] ⁺ 1-(4-((5,5-Dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)m ethyl)imidazolidin-1- yl)methyl)-4-methylcyclohexyl)-3-isopropylpyrimidine-2,4,6(1 H,3H,5H)-trione To 1-(4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)m ethyl)imidazolidin-1- yl)methyl)-4-methylcyclohexyl)-3-isopropylurea (122 mg, 260 µmol) in AcOH (2.6 mL) was added malonic acid (27.4 mg, 260 µmol) and acetic anhydride (123 µL, 1.30 mmol). The reaction was heated to 80 °C for 17 h, cooled down to rt, neutralized with saturated NaHCO3 (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to provide the crude title compound (140 mg, 100%). MS (ESI): mass calcd. for C26H44N4O6Si: 536.74, found: 535.7 [M-H]-. 5-(Diaminomethylene)-1-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidin-1-yl)methyl)-4-methylcyclohexyl)-3- isopropylpyrimidine-2,4,6(1H,3H,5H)-trione To 1-(4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)m ethyl)imidazolidin-1- yl)methyl)-4-methylcyclohexyl)-3-isopropylpyrimidine-2,4,6(1 H,3H,5H)-trione (140 mg, 261 µmol) in THF (2.6 mL) was added cyanamide (111 mg, 2.61 mmol), and nickel(II) acetylacetonate (13.4 mg, 52.2 µmol). The mixture was heated to 80 °C for 18 h then cooled down to rt, filtered and concentrated to yield the crude title compound (151 mg, 100%). MS (ESI): mass calcd. for C27H46N6O6Si: 578.78, found: 577.7 [M-H]-. 5-(Diaminomethylene)-1-((1r,4r)-4-((5,5-dimethyl-2,4-dioxoim idazolidin-1-yl)methyl)-4- methylcyclohexyl)-3-isopropylpyrimidine-2,4,6(1H,3H,5H)-trio ne (205) 5-(Diaminomethylene)-1-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl) imidazolidin-1-yl)methyl)-4-methylcyclohexyl)-3- isopropylpyrimidine-2,4,6(1H,3H,5H)-trione (151 mg, 261 µmol) was dissolved in TFA (0.5 mL) and water (652 µL) and stirred for 5 min. The reaction was diluted with MeOH (5 mL) and pH was adjusted to 8 with saturated aqueous Na2CO3 solution. The resulting mixture was stirred for 5 min, extracted with DCM (3 × 10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The crude was purified by Prep LCMS (C18, 25-45% MeCN/NH4HCO310 mM buffer) to provide the title compound (205) (4.5 mg, 3.8%). MS (ESI): mass calcd. for C ₂₁ H ₃₂ N ₆ O ₅ : 448.42, found: 447.7 [M-H]-. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 5.09 – 5.22 (m, 1H), 4.69 (s, 1H), 3.06 (s, 2H), 2.64 (q, J = 12.3 Hz, 2H), 1.36 – 1.59 (m, 18H), 1.11 (s, 3H). The title compound (Error! Reference source not found.) was the second peak to come out in the final separation from the Example 205 (2.0 mg, 1.7 %). MS (ESI): mass calcd. for C ₂₁ H ₃₂ N ₆ O ₅ : 448.42, found: 447.7 [M-H]-. ¹ H NMR (400 MHz, DMSO) δ ppm 9.55 (s, 2H), 8.38 (s, 1H), 7.39 (s, 2H), 4.99 – 5.11 (m, 1H), 4.67 (s, 1H), 3.24 (s, 2H), 2.60 (d, J = 13.3 Hz, 2H), 1.68 (d, J = 13.5 Hz, 2H), 1.29 – 1.34 (m, 12H), 1.11 – 1.29 (m, 4H), 0.85 (s, 3H). Stereochemistry was arbitrarily assigned. Examples Error! Reference source not found. and 264 was synthesized in similar procedures as described in Example 205 and 206. Example 207.1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,7-dioxo-4, 6- diazaspiro[2.4]heptan-4-yl)methyl)cyclohexyl)pyrimidine-2,4, 6(1H,3H,5H)-trione (207) Synthetic scheme: Methyl 1-((1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexane-1- carboxamido)cyclopropane-1-carboxylate To a solution of (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxyl ic acid (5 g, 20.6 mmol) in DMF (30 mL) was added dropwise HATU (7.97 g, 21 mmol) and DIPEA (7.97 g, 61.7 mmol) at 25 °C over 0.5 h, followed by dropwise addition of methyl 1- aminocyclopropanecarboxylate (3.55 g, 30.8 mmol) at 25 °C. The resulting mixture was stirred for 16 h under N2. After completion, the mixture was cooled to 0 °C, poured into ice- water (300 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ , 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 provide the title compound (7.9 g, crude) as a white solid. Methyl 1-((((1s,4s)-4-((tert- butoxycarbonyl)amino)cyclohexyl)methyl)amino)cyclopropane-1- carboxylate To a solution of methyl 1-((1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexane-1- carboxamido)cyclopropane-1-carboxylate (6.25 g, 18.4 mmol) in THF (100 mL) was added dropwise BH3.THF (1 M, 58.8 mL) at –20 °C over 1 h. The resulting mixture was stirred at 20 °C for 15 h under N2. After completion, methanol (20 mL) was added to the mixture at – 20 °C and stirred for 30 min. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate = 1 : 0 to 1 : 1) to provide the title compound (1.66 g, 27.7%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.56-4.71 (m, 1H), 3.70-3.78 (m, 1H), 3.68 (s, 3H), 2.55-2.63 (m, 2H), 1.52-1.69 (m, 7H), 1.44-1.46 (m, 9H), 1.17-1.28 (m, 4H), 0.93-1.00 (m, 2H). tert-Butyl ((1s,4s)-4-((5,7-dioxo-4,6-diazaspiro[2.4]heptan-4- yl)methyl)cyclohexyl)carbamate To a solution of methyl 1-((((1s,4s)-4-((tert- butoxycarbonyl)amino)cyclohexyl)methyl)amino)cyclopropane-1- carboxylate (1.6 g, 4.9 mmol) in AcOH (20 mL) was added potassium cyanate (1.99 g, 24.5 mmol). The mixture was stirred at 80 °C for 2 h under N2. After completion, the mixture was cooled to 0 °C, poured into saturated NaHCO ₃ solution (500 mL), and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate = 1 : 0 to 0 : 1) to provide the title compound (720 mg, 43.5%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.58-6.79 (m, 1H), 3.49 (s, 1H), 3.28-3.32 (m, 1H), 2.88 (d, J = 7.6 Hz, 2H), 1.50-1.63 (m, 3H), 1.39-1.42 (m, 3H), 1.38 (s, 9H), 1.25-1.34 (m, 5H), 1.07-1.19 (m, 2H). tert-Butyl ((1s,4s)-4-((5,7-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)- 4,6- diazaspiro[2.4]heptan-4-yl)methyl)cyclohexyl)carbamate To a solution of tert-butyl ((1s,4s)-4-((5,7-dioxo-4,6-diazaspiro[2.4]heptan-4- yl)methyl)cyclohexyl)carbamate (520 mg, 1.54 mmol) in DCM (5 mL) was added DIPEA (995.9 mg, 7.71 mmol) and SEM-Cl (513.9 mg, 3.08 mmol). The mixture was stirred at 25 °C for 16 h under N2. After completion, the reaction was quenched by saturated NH4Cl solution (5 mL), and extracted with DCM (3 x 10 mL). The combined organic phase was washed with 2 N HCl (5 mL) and brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate = 1:0 to 5:1) to provide the title compound (530 mg, 73.5%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.71 (d, J = 6.4 Hz, 1H), 4.81 (s, 2H), 3.45-3.59 (m, 3H), 2.95 (d, J = 7.6 Hz, 2H), 1.60-1.68 (m, 1H), 1.48-1.59 (m, 4H), 1.38 (s, 10H), 1.31-1.34 (m, 5H), 1.20-1.25 (m, 2H), 0.79-0.88 (m, 2H), -0.04 (s, 9H). 4-(((1s,4s)-4-Aminocyclohexyl)methyl)-6-((2-(trimethylsilyl) ethoxy)methyl)-4,6- diazaspiro[2.4]heptane-5,7-dione A solution of tert-butyl ((1s,4s)-4-((5,7-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)- 4,6-diazaspiro[2.4]heptan-4-yl)methyl)cyclohexyl)carbamate (730 mg, 1.56 mmol) in HCOOH (7.3 mL) and DCM (7.3 mL) was stirred at 25 °C for 24 h under N2. After completion, the reaction mixture was quenched with H2O (10 mL). The aqueous layer was extracted with DCM: isopropanol = 3 : 1 (3 x 10 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (H2O (0.1% TFA)-ACN; gradient 5-40%) to provide the title compound (440 mg, 85.4%) as a yellow oil. MS (ESI): mass calcd. for C ₁₈ H ₃₃ N ₃ O ₃ Si: 367.23, found: 368.2 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,7-dioxo-4,6-di azaspiro[2.4]heptan-4- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (207) The title compound (207) was prepared in similar procedures as described in Example 138 and 139. MS (ESI): mass calcd. for C ₂₁ H ₃₀ N ₆ O ₅ : 446.23, found: 447.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl3) δ ppm 4.75-4.83 (m, 1H), 3.86-3.92 (m, 2H), 3.20 (d, J = 7.6 Hz, 2H), 2.51-2.63 (m, 2H), 2.12-2.18 (m, 1H), 1.74 (d, J = 14.0 Hz, 2H), 1.27-1.66 (m, 12H), 0.96 (t, J = 7.2 Hz, 3H). Example 212 and 213.5-(Diaminomethylene)-1-((1r,4r)-4-((5,5-dimethyl-2,4- dioxoimidazolidin-1-yl)methyl)-4-methylcyclohexyl)-3-(4,4,4- trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (Error! Reference source not found.) and 5-(Diaminomethylene)-1- ((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl) -4-methylcyclohexyl)-3- (4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (Error! Reference source not found.) Synthetic scheme: 1-((4-Isocyanato-1-methylcyclohexyl)methyl)-5,5-dimethyl-3-( (2-(trimethylsilyl)ethoxy) methyl)imidazolidine-2,4-dione To 1-((4-amino-1-methylcyclohexyl)methyl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (800 mg, 2.09 mmol) in a mixture of DCM (20.9 mL) and saturated aqueous NaHCO3 (20.9 mL) at 0 °C was added triphosgene (221 mg, 730 µmol) slowly. The solution was warmed to rt and stirred for 3 h. Water (10 mL) was added, and the organic layer was isolated, dried over Na ₂ SO ₄ , filtered, and concentrated to give the crude title compound (850 mg, 100%). 1-(4-((5,5-Dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)m ethyl)imidazolidin-1- yl)methyl)-4-methylcyclohexyl)-3-(4,4,4-trifluorobutyl)urea To 1-((4-isocyanato-1-methylcyclohexyl)methyl)-5,5-dimethyl-3-( (2- (trimethylsilyl)ethoxy) methyl)imidazolidine-2,4-dione (285 mg, 696 µmol) in DCM (7 mL) was added 4,4,4-trifluorobutan-1-amine (97.3 mg, 765 µmol) and the reaction was stirred for 15 min. Water (10 mL) was added and the product was extracted with DCM (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude was purified by silica gel column chromatography (0-25% MeOH/DCM) to yield the title compound (370 mg, 99%). MS (ESI): mass calcd. for C24H43F3N4O4Si: 536.70, found: 581.3 [M+CHO2]-. 1-(4-((5,5-Dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)m ethyl)imidazolidin-1- yl)methyl)-4-methylcyclohexyl)-3-(4,4,4-trifluorobutyl)pyrim idine-2,4,6(1H,3H,5H)- trione To 1-(4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)m ethyl)imidazolidin-1- yl)methyl)-4-methylcyclohexyl)-3-(4,4,4-trifluorobutyl)urea (100 mg, 186 µmol) in DCM (1.9 mL) was added malonyl chloride (37.4 µL, 373 µmol) and the reaction was stirred for 15 min. The reaction was neutralized with saturated aqueous NaHCO ₃ solution, extracted with DCM (3 × 10 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude was purified by silica gel column chromatography (0-10% MeOH/DCM) to yield the title compound (112 mg, 99%). MS (ESI): mass calcd. for C27H43F3N4O6Si: 604.73, found: 603.3 [M-H]-. 5-(Diaminomethylene)-1-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (Trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)-3-(4,4,4- trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione To 1-(4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)m ethyl)imidazolidin-1- yl)methyl)-4-methylcyclohexyl)-3-(4,4,4-trifluorobutyl)pyrim idine-2,4,6(1H,3H,5H)-trione (112 mg, 185 µmol) in THF (1.9 mL) were added cyanamide (78.6 mg, 1.85 mmol), and nickel(II) acetylacetonate (9.5 mg, 37.0 µmol). The reaction was heated to 80 °C for 18 h. The reaction was cooled down to rt, filtered through Celite and concentrated. The crude was purified by silica gel column chromatography (0-10% MeOH/DCM) to yield the title compound (85.0 mg, 71%). MS (ESI): mass calcd. for C ₂₈ H ₄₅ F ₃ N ₆ O ₆ Si: 646.77, found: 645.3 [M-H]-. 5-(Diaminomethylene)-1-((1r,4r)-4-((5,5-dimethyl-2,4-dioxoim idazolidin-1-yl)methyl)-4- methylcyclohexyl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1 H,3H,5H)-trione (Error! Reference source not found.) and 5-(Diaminomethylene)-1-((1s,4s)-4-((5,5-dimethyl-2,4- dioxoimidazolidin-1-yl)methyl)-4-methylcyclohexyl)-3-(4,4,4- trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (Error! Reference source not found.) 5-(Diaminomethylene)-1-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)-3-(4,4,4- trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (85.0 mg, 131 µmol) was dissolved in TFA (1 mL) and water (329 µL). After 5 min, the reaction was diluted with MeOH (5 mL), and pH was adjusted to 8 with saturated aqueous Na ₂ CO ₃ solution and the resulting mixture was stirred for 5 min. The solution was extracted with DCM (3 × 10 mL), dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase HPLC (35-55% MeCN/NH4HCO3 10 mM buffer) to provide the title compound (212) (5.2 mg, 7.7%). MS (ESI): mass calcd. for C ₂₂ H ₃₁ F ₃ N ₆ O ₅ : 516.51, found: 517.3 [M+H] ⁺ ; 515.3 [M-H]-. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.50 (s, 2H), 7.39 (s, 2H), 4.59 (s, 1H), 3.81 (t, J = 7.2 Hz, 2H), 2.94 (s, 2H), 2.18 – 2.31 (m, 2H), 1.58 – 1.80 (m, 2H), 1.20 – 1.50 (m, 14H), 0.98 (s, 3H). And to provide the title compound (Error! Reference source not found.) (the second peak, 2.0 mg, 1.7%). MS (ESI): mass calcd. for C ₂₂ H ₃₁ F ₃ N ₆ O ₅ : 516.51, found: 517.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.50 (s, 2H), 7.53 (s, 2H), 4.68 (s, 1H), 3.82 (t, J = 7.3 Hz, 2H), 3.24 (s, 2H), 2.54 – 2.69 (m, 2H), 2.16 – 2.36 (m, 2H), 1.62 – 1.79 (m, 4H), 1.08 – 1.42 (m, 10H), 0.85 (s, 3H). Stereochemistry was arbitrarily assigned. Example Error! Reference source not found. and Error! Reference source not found. were synthesized following Example Error! Reference source not found. by using 3,3,3- trifluoropropan-1-amine hydrochloride as amine instead of 4,4,4-trifluorobutan-1-amine. Example Error! Reference source not found. and 239 were synthesized in similar procedures as described in Example 212. Examples Error! Reference source not found. and Error! Reference source not found. were synthesized following the last few steps of Example Error! Reference source not found. and by using 2-fluorobutan-1-amine hydrochloride as amine instead of 4,4,4-trifluorobutan-1- amine. Examples Error! Reference source not found. and 290 were synthesized following the last few steps of Example Error! Reference source not found. and by using 3-fluoro-3- methylbutan-1-amine hydrochloride as amine instead of 4,4,4-trifluorobutan-1-amine. Example 214.1-((1s,4s)-4-((5,5-Bis(hydroxymethyl)-2,4-dioxoimidazoli din-1-yl)methyl)- 4-methylcyclohexyl)-3-butyl-5-(diaminomethylene)pyrimidine-2 ,4,6(1H,3H,5H)-trione (214) Synthetic scheme: 1-((1s,4s)-4-((5,5-Bis(hydroxymethyl)-2,4-dioxoimidazolidin- 1-yl)methyl)-4- methylcyclohexyl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4 ,6(1H,3H,5H)-trione (214) To a solution of 1-butyl-5-(diaminomethylene)-3-((1s,4s)-4-((6,8-dioxo-2-oxa- 5,7- diazaspiro[3.4]octan-5-yl)methyl)-4-methylcyclohexyl)pyrimid ine-2,4,6(1H,3H,5H)-trione (Example 158, 30 mg, 63 μmol) in CH3CN (0.2 mL) was added TFA (0.2 mL) and H2O (0.2 mL). The mixture was stirred at 100 °C for 12 h and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (H ₂ O (10 mM NH ₄ HCO ₃ )-CAN; gradient 15-45%) to provide the title compound (214) (0.01 g, 31.2%) as a white solid. MS (ESI): mass calcd. for C ₂₂ H ₃₄ N ₆ O ₇ : 494.25, found: 495.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.55-10.64 (m, 1H), 9.57 (s, 2H), 7.31 (s, 2H), 5.08 (t, J = 4.4 Hz, 2H), 4.69 (d, J = 9.2 Hz, 1H), 3.76 (t, J = 7.2 Hz, 2H), 3.51-3.55 (m, 2H), 3.41-3.44 (m, 2H), 3.25-3.30 (m, 2H), 2.55-2.66 (m, 2H), 1.76 (d, J = 13.6 Hz, 2H), 1.42-1.52 (m, 2H), 1.24-1.31 (m, 4H), 1.16-1.24 (m, 2H), 0.96 (s, 3H), 0.89 (t, J = 7.2 Hz, 3H). Example 215 was synthesized in similar procedures as descried in Example 214. Example 216 and 217 were synthesized in similar procedures as described in Examples 138 and 139. Examples 218 and 219 were synthesized in similar procedures as described in Example 197. The deprotection of the ketal was performed with an extra step of TsOH in acetone at 50 °C, then to SEM group protection. Example 225.1-Butyl-5-(diaminomethylene)-3-(3,3-dimethyl-1-oxo-2- oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (225) Synthetic scheme: 2-(2-Methylallyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile To a solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (500 mg, 2.41 mmol) in THF (12.1 mL) at –78 °C was added lithium diisopropylamide solution (1.8 mL, 3.62 mmol) and the mixture was stirred at –78 °C for 60 min. 3-Iodo-2-methylpropene (348 µL, 3.14 mmol) was added dropwise. The mixture was slowly warmed up to rt and stirred for 18 h. The reaction was quenched by adding saturated aqueous NH ₄ Cl solution (10 mL) and water (10 mL). The reaction was diluted with EtOAc (30 mL) and the aqueous phase was extracted EtOAc (2 × 15 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel column chromatography (10- 100% EtOAc/heptane) to give the title compound (430 mg, 68%) as a clear oil that solidified upon standing. MS (ESI): mass calcd. for C16H23NO2: 261.36, found: 262.7 [M+H] ⁺ . 1-Imino-3,3-dimethyl-2-oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-one To 2-(2-methylallyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (385 mg, 1.47 mmol) in water (3 mL) was added sulfuric acid (3 mL, 53.5 mmol). The solution was stirred at 65 °C for 15 min. The reaction was cooled down and poured on ice. Solid Na ₂ CO ₃ was added to the crude mixture till basic. The aqueous phase was extracted with DCM (3 × 30 mL). The combined DCM layer was dried over Na2SO4, filtered, and concentrated to give the title compound (319 mg, 92%) as a light-yellow solid. MS (ESI): mass calcd. for C ₁₄ H ₂₁ NO ₂ : 235.32, found: 236.7 [M+H] ⁺ . 3,3-Dimethyl-1-(((2-(trimethylsilyl)ethoxy)methyl)imino)-2- oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-one To 1-imino-3,3-dimethyl-2-oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-one (305 mg, 1.3 mmol) in DMF (6.5 mL) was added sodium hydride 60% dispersion in mineral oil (62.2 mg, 1.56 mmol). The mixture was stirred at rt for 30 min and (2-chloromethoxyethyl)trimethylsilane (351 µL, 1.94 mmol) was added dropwise. The solution was stirred at rt for 18 h and diluted with EtOAc (15 mL), washed with water (10 mL), brine (2 x 5 mL), dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (10- 100% EtOAc/heptane) to give the title compound (93 mg, 20%) a clear oil. MS (ESI): mass calcd. for C ₂₀ H ₃₅ NO ₃ Si: 365.58, found: 366.3 [M+H] ⁺ . 3,3-Dimethyl-1-(((2-(trimethylsilyl)ethoxy)methyl)imino)-2- oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-amine To a solution of 3,3-dimethyl-1-(((2-(trimethylsilyl)ethoxy)methyl)imino)-2- oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-one (78.0 mg, 213 µmol) in MeOH (711 µL) was added ammonia (0.1 mL, 4.57 mmol). The mixture was stirred at rt for 2 h. Under nitrogen, 10% palladium on carbon (8 mg) was added and the flask was submitted to 5 vacuums/hydrogen cycles and stirred under hydrogen at rt for 18 h. The reaction mixture was filtered and concentrated to give the crude title compound (71.0 mg, 91%) as a colorless oil. MS (ESI): mass calcd. for C20H38N2O2Si: 366.61, found: 367.4 [M+H] ⁺ . 1-Butyl-3-(3,3-dimethyl-1-oxo-2-oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)urea Under nitrogen and to a mixture of 3,3-dimethyl-1-(((2- (trimethylsilyl)ethoxy)methyl)imino)-2-oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-amine (72.0 mg, 196 µmol) in DCM (982 µL) was added butyl isocyanate (23.7 µL, 206 µmol). The mixture was stirred at rt for 1.5 h and then concentrated under reduced pressure to give a white foam. The crude was purified by reverse phase HPLC (C18, 25-100% MeCN/10 mM HCOONH4 buffer) to give the title compound (9 mg, 14%). MS (ESI): mass calcd. for C ₁₉ H ₃₂ N ₂ O ₃ : 336.47, found: 337.4 [M+H] ⁺ . 1-Butyl-3-(3,3-dimethyl-1-oxo-2-oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione To 1-butyl-3-(3,3-dimethyl-1-oxo-2-oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)urea (9.0 mg, 26.7 µmol) in DCM (267 µL) at 0 °C was added malonyl chloride (3.4 µL, 34.7 µmol). The mixture was stirred at rt for 18 h. DCM and saturated aqueous NaHCO3 solution were added to the reaction and phases were separated. The aqueous phase was extracted with DCM (3 × 10 mL) and the combined organic layer was dried over Na2SO4, filtered, and concentrated to give the crude title compound (10.8 mg.100%). MS (ESI): mass calcd. for C ₂₂ H ₃₂ N ₂ O ₅ : 404.50, found: 403.4 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-(3,3-dimethyl-1-oxo-2-oxadisp iro[4.1.57.15]tridecan- 10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (225) 1-Butyl-3-(3,3-dimethyl-1-oxo-2-oxadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (10.0 mg, 24.7 µmol), cyanamide (3.15 mg, 74.2 µmol) and nickel(II) acetylacetonate (1.91 mg, 7.42 µmol) were added to a vial containing anhydrous THF (300 µL). The reaction was stirred at 85 °C for 18 h then was cooled down to rt, filtered with a syringe filter, concentrated, and redissolved in DCM (10 mL). The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel column chromatography (C18, 25-100% MeCN/10 mM NH4HCO3 buffer) to give the title compound (225) (3 mg, 27%). MS (ESI): mass calcd. for C ₂₃ H ₃₄ N ₄ O ₅ : 446.54, found: 447.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) δ ppm 3.79 – 3.89 (m, 2H), 2.26 – 2.58 (m, 7H), 2.01 – 2.14 (m, 2H), 1.83 – 1.99 (m, 2H), 1.40 – 1.62 (m, 6H), 1.39 (s, 3H), 1.37 (s, 3H), 1.25 – 1.36 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). Example 227 and 228.1-Butyl-5-(diaminomethylene)-3-((5R,7r,10R)-3-methyl-1- (oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tri decan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (227) and 1-butyl-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 (228) Synthetic scheme: 2-Methyl-4-(oxetan-3-ylmethyl)-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-1,3,10-trione To a solution of 2-methyl-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-1,3,10-trione (5 g, 21.2 mmol, see Example 130 for synthesis) and 3-(bromomethyl)oxetane (3.83 g, 25.40 mmol) in DMF (50 mL) was added K ₂ CO ₃ (5.85 g, 42.33 mmol). The mixture was stirred at 50 °C for 12 h under N2. After completion, the reaction was poured into H2O (50 mL) and extracted was EtOAc (3 x 50 mL). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate = 100 : 1 to 3 : 2) to provide the title compound (4.5 g, 61%) as a white solid. MS (ESI): mass calcd. for C16H22N2O4: 306.16, found: 307.1 [M+1] ⁺ . 10-Amino-2-methyl-4-(oxetan-3-ylmethyl)-2,4-diazadispiro[4.1 .5 ⁷ .1 ⁵ ]tridecane-1,3-dione To a solution of 2-methyl-4-(oxetan-3-ylmethyl)-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane- 1,3,10-trione (4.5 g, 14.7 mmol) and NH ₃ in MeOH (7 M, 21 mL) in MeOH (45 mL) was added Raney-Ni (4.5 g, 52.53 mmol) under N2. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 psi) at 25 °C for 2 h. After completion, the mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to provide the title compound (4.5 g, impure) as a colorless oil. MS (ESI): mass calcd. for C16H25N3O3: 307.19, found: 308.2 [M+1] ⁺ . Example 208.1-Butyl-5-(diaminomethylene)-3-(3-methyl-1-(oxetan-3-ylm ethyl)-2,4- dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2 ,4,6 (1H,3H,5H)-trione The title compound (208) was synthesized in similar procedures as described in Example 138. MS (ESI): mass calcd. for C ₂₅ H ₃₆ N ₆ O ₆ : 516.27, found: 517.1 [M+1] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((5R,7r,10R)-3-methyl-1-(oxet an-3-ylmethyl)-2,4-dioxo- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1 H,3H,5H)-trione (227) and 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-1-(oxet an-3-ylmethyl)-2,4-dioxo- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1 H,3H,5H)-trione (228) The title compounds 227 and 228 were obtained through chiral SFC separation of Example 208. Stereochemistry was arbitrarily assigned. Column: DAICEL CHIRALPAK IC (250mm*30mm,10 um); mobile phase: CO2-IPA (0.1% NH3H2O); 70% isocratic elution. 227: MS (ESI): mass calcd. for C ₂₅ H ₃₆ N ₆ O ₆ : 516.27, found: 517.3 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.53 (s, 2H), 7.34 (s, 2H), 4.61-4.65 (m, 3H), 4.40-4.44 (m, 2H), 3.71-3.75 (m, 2H), 3.65-3.68 (m, 2H), 2.82 (s, 3H), 2.35-2.46 (m, 2H), 2.22-2.29 (m, 2H), 2.12-2.16 (m, 3H), 1.84 (d, J = 11.6 Hz, 1H), 1.38-1.47 (m, 5H), 1.21-1.26 (m, 4H), 0.86- 0.89 (t, J = 7.2 Hz, 3H).228: MS (ESI): mass calcd. for C ₂₅ H ₃₆ N ₆ O ₆ : 516.27, found: 517.1 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.30 (s, 2H), 4.61-4.65 (m, 3H), 4.40-4.44 (m, 2H), 3.71-3.75 (m, 2H), 3.66 (d, J = 6.8 Hz, 2H), 2.82 (s, 3H), 2.35-2.47 (m, 2H), 2.22-2.30 (m, 2H), 2.12-2.17 (m, 3H), 1.85 (d, J = 16.0 Hz, 1H), 1.38-1.49 (m, 5H), 1.15-1.31 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H). Examples 210, 211, 221, 222, 230, and 231 were synthesized in similar procedures as described in Examples 227 and 228. Example 229.1-Butyl-5-(diaminomethylene)-3-(2-(5-methyl-2,4-dioxo-3, 4- dihydropyrimidin-1(2H)-yl)spiro[3.5]nonan-7-yl)pyrimidine-2, 4,6(1H,3H,5H)-trione (229) 3-Benzoyl-5-methylpyrimidine-2,4(1H,3H)-dione To a solution of 5-methyl-1H-pyrimidine-2,4-dione (5 g, 39.7 mmol) in ACN (40 mL) and pyridine (20 mL) was added benzoyl chloride (12.26 g, 87.2 mmol). The mixture was stirred at 20 °C for 16 h. After completion, the reaction was filtered and concentrated under reduced pressure. The mixture was poured into water (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate = 89 : 11) to provide the title compound (6.3 g, 69%) as a white solid. MS (ESI): mass calcd. for C12H10N2O3: 230.07, found: 253.1 [M+Na] ⁺ . 3-Benzoyl-1-(8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)-5-methylpyrimidine-2,4(1H,3H)- dione To a solution of 3-benzoyl-5-methyl-1H-pyrimidine-2,4-dione (0.59 g, 2.58 mmol), 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-ol (767.30 mg, 3.87 mmol) and PPh ₃ (1.35 g, 5.16 mmol) in THF (8 mL) was added DIAD (1.04 g, 5.16 mmol) under N2 and the mixture was stirred at 50 °C for 2 h. After completion, the reaction was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether: Ethyl acetate = 100: 1 to 8: 1) to provide the title compound (0.8 g, impure) as a yellow oil. 3-Benzoyl-5-methyl-1-(7-oxospiro[3.5]nonan-2-yl)pyrimidine-2 ,4(1H,3H)-dione To a solution of 3-benzoyl-1-(8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)-5-methyl- pyrimidine-2,4-dione (0.7 g, 1.71 mmol) in acetone (7 mL) and H ₂ O (3.5 mL) was added TsOH.H2O (486.59 mg, 2.56 mmol). The mixture was stirred at 25 °C for 12 h, poured into water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to provide the title compound (0.5 g, impure) as a white solid, which was used directly in the next step without further purification. 1-(7-Aminospiro[3.5]nonan-2-yl)-3-benzoyl-5-methylpyrimidine -2,4(1H,3H)-dione To a solution of 3-benzoyl-5-methyl-1-(7-oxospiro[3.5]nonan-2-yl)pyrimidine-2 ,4- dione (0.4 g, 1.09 mmol) and NH4OAc (1.68 g, 21.83 mmol) in MeOH (5 mL) was added NaBH(OAc) ₃ (578.43 mg, 2.73 mmol), the mixture was stirred at 25 °C for 1 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The aqueous phase was extracted with DCM : i-PrOH = 3 : 1 (2 x 20 mL). The combined organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to provide the title compound (0.25 g) as a white solid, which was used directly in the next step without further purification. 1-(2-(3-Benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H )-yl)spiro[3.5]nonan-7- yl)-3-butylurea To a solution of 1-(7-aminospiro[3.5]nonan-2-yl)-3-benzoyl-5-methyl-pyrimidin e-2,4- dione (0.2 g, 544 μmol) and TEA (66.09 mg, 653 μmol) in DCM (3 mL) was added 1- isocyanatobutane (59.35 mg, 599 μmol). The mixture was stirred at 25 °C for 1 h. The mixture was poured into water and extracted with DCM (2 x 20 mL). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 0:1) to provide the title compound (0.14 g) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ ppm 7.93 (d, J = 7.2 Hz, 2H), 7.61-7.66 (m, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.19-7.23 (m, 1H), 4.83 (t, J = 8.6 Hz, 1H), 3.50-3.63 (m, 1H), 3.14 (t, J = 7.2 Hz, 2H), 2.37-2.49 (m, 1H), 2.21- 2.33 (m, 1H), 1.95-2.09 (m, 5H), 1.78-1.93 (m, 4H), 1.61-1.67 (m, 2H), 1.45-1.50 (m, 2H), 1.32-1.39 (m, 2H), 1.08-1.32 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). 1-(2-(3-Benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H )-yl)spiro[3.5]nonan-7- yl)-3-butylpyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-[2-(3-benzoyl-5-methyl-2,4-dioxo-pyrimidin-1-yl)spiro[3.5] nonan- 7-yl]-3-butyl-urea (0.12 g, 257 μmol) and malonic acid (29.44 mg, 282.9 μmol) in AcOH (2 mL) was added Ac ₂ O (183.8 mg, 1.8 mmol) under N ₂ . The reaction was stirred at 80 °C for 4 h. The mixture was poured into saturated NaHCO ₃ (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 1) to provide the title compound (40 mg, 29%) as a white solid. MS (ESI): mass calcd. for C29H34N4O6: 534.25, found: 535.4 [M+H] ⁺ . 1-(2-(3-Benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H )-yl)spiro[3.5]nonan-7- yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-t rione To a solution of 1-[2-(3-benzoyl-5-methyl-2,4-dioxo-pyrimidin-1-yl)spiro[3.5] nonan- 7-yl]-3-butyl-hexahydropyrimidine-2,4,6-trione (40 mg, 74.8 μmol) and cyanamide (31.5 mg, 748 μmol) in THF (2 mL) was added bis[(Z)-1-methyl-3-oxo-but-1-enoxy]nickel (5.77 mg, 22 μmol) under N ₂ . The mixture was stirred at 80 °C for 12 h, poured into water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated to provide the title compound (20 mg, 46%) as a yellow oil. MS (ESI): mass calcd. for C30H36N6O6: 576.27, found: 599.3 [M+Na] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-(5-methyl-2,4-dioxo-3,4-di hydropyrimidin-1(2H)- yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (229) NH ₂ H ₂ N O O NH O N N O N O To a solution of 1-[2-(3-benzoyl-5-methyl-2,4-dioxo-pyrimidin-1-yl)spiro[3.5] nonan- 7-yl]-3-butyl-5-(diaminomethylene)hexahydropyrimidine-2,4,6- trione (20 mg, 35 μmol) in THF (2 mL) was added NH ₃ /MeOH (7 M, 99 μL) under N ₂ . The mixture was stirred at 25 °C for 12 h, poured into water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase HPLC (H ₂ O (0.2% FA)-ACN; gradient 30-60%) to provide the title compound (229) (5 mg, 26%) as a white solid. MS (ESI): mass calcd. for C23H32N6O5: 472.24, found: 473.2 [M+Na] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.17 (s, 1H), 9.54 (s, 2H), 7.64 (s, 1H), 7.29 (s, 2H), 4.56-4.84 (m, 2H), 3.74 (t, J = 7.2 Hz, 2H), 2.24-2.45 (m, 3H), 1.93-2.10 (m, 3H), 1.75-1.92 (m, 5H), 1.19-1.50 (m, 8H), 0.88 (t, J = 7.2 Hz, 3H). Example 232 and 233.1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl -2,4- dioxoimidazolidin-1-yl)methyl)-4-methoxycyclohexyl)pyrimidin e-2,4,6(1H,3H,5H)- trione (232) & 1-Butyl-5-(diaminomethylene)-3-((1r,4r)-4-((5,5-dimethyl-2,4 - dioxoimidazolidin-1-yl)methyl)-4-methoxycyclohexyl)pyrimidin e-2,4,6(1H,3H,5H)- trione (233) Synthetic scheme: 8-Hydroxy-1,4-dioxaspiro[4.5]decane-8-carbonitrile To a solution of 1,4-dioxaspiro[4.5]decan-8-one (100 g, 640 mmol) in DMSO (1000 mL) and H2O (200 mL) was added TMSCN (88.93 g, 896 mmol) at 15 °C and the reaction was stirred at 15 °C for 0.5 h. After completion, the reaction was diluted with H ₂ O (500 mL) and extracted with EtOAc (3 x 500 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 : Ethyl acetate = 1 : 0 to 1 : 1) to provide the title compound (108 g, 92%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.97 (s, 4H), 2.12-2.22 (m, 2H), 1.99-2.10 (m, 2H), 1.83-1.92 (m, 2H), 1.74-1.82 (m, 2H). 8-Methoxy-1,4-dioxaspiro[4.5]decane-8-carbonitrile To a solution of 8-hydroxy-1,4-dioxaspiro[4.5]decane-8-carbonitrile (20 g, 109 mmol) in DCM (200 mL) was added N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (28.07 g, 131 mmol) and trimethyloxonium tetrafluoroborate (19.38 g, 131 mmol) at 25 °C. After stirring for 2 h, the reaction was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layer was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate=10 : 1 to 1 : 1) to provide the title compound (10 g, 46.4%) as a yellow oil. ¹ H NMR (400 MHz, CD3OD) δ ppm 3.96 (s, 4H), 3.45 (s, 3H), 2.01-2.16 (m, 4H), 1.77-1.85 (m, 2H), 1.65-1.74 (m, 2H). 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4 -dioxoimidazolidin-1- yl)methyl)-4-methoxycyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-tr ione (232) & 1-Butyl-5- (diaminomethylene)-3-((1r,4r)-4-((5,5-dimethyl-2,4-dioxoimid azolidin-1-yl)methyl)-4- methoxycyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (233) The title compounds were synthesized from 8-methoxy-1,4-dioxaspiro[4.5]decane-8- carbonitrile following similar synthetic route for steps 2-5 as shown in Examples 187 and 188, then steps 5-9 in Examples 190 and 191, except malonyl dichloride was used instead of malonic acid. Separation of the diastereomers happens at the 1-butyl-3-(4-((5,5-dimethyl-2,4- dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl) methyl)-4- methoxycyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione step by reverse phase HPLC, before the introduction of the diaminomethylene group. Example 232: MS (ESI): mass calcd. for C22H34N6O6: 478.25, found: 479.49 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.90 (s, 2H), 6.05 (s, 2H), 4.71-4.77 (m, 1H), 3.80 (t, J = 13.6 Hz, 2H), 3.21-3.29 (m, 5H), 2.49-2.61 (m, 2H), 1.27-1.55 (m, 16H), 0.92 (t, J = 7.2 Hz, 3H). Example 233: MS (ESI): mass calcd. for C22H34N6O6: 478.25, found: 479.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 9.56 (s, 2H), 7.32 (s, 2H), 4.68 (t, J = 11.6 Hz, 1H), 4.64-3.71 (m, 2H), 3.48 (s, 2H), 3.13 (s, 3H), 2.68-2.82 (m, 2H), 1.57-1.69 (m, 4H), 1.36-1.51 (m, 4H), 1.20-1.34 (m, 8H), 0.88 (t, J = 7.2 Hz, 3H). Stereochemistry was arbitrarily assigned. Examples 234 and 235 were synthesized in similar procedures as Examples 232 and 233 with malonic acid used. Instead of methoxy group formation at step 2, the hydroxy group was protected as a benzyl group using TMSOTf and benzyl 2,2,2-trichloroethanimidate. The benzyl group and TMS group were deprotected at last using TFA, followed by NH ₄ OH in ACN (1:1) for 1 h. Stereochemistry was arbitrarily assigned. Examples 236 and 237. (E)-5-(Amino(methylamino)methylene)-1-butyl-3-((5S,7s,10S)- 1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (236) and 5-(Bis(dimethylamino) methylene)-1-butyl-3- ((5S,7s,10S)-1,3-dimethyl-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ] tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (237) Synthetic scheme: To a solution of 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-methyl-2,4-dio xo- 1,3-diazadispiro[4. ¹ .5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (Example 172, 0.45 g, 1 mmol) in DMF (5 mL) was added MeI (157.5 mg, 1.1 mmol) and Cs2CO3 (0.49 g, 1.52 mmol). The mixture was stirred at 50 °C for 12 h, diluted with H2O (20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (H2O (10 mM NH4HCO3)-ACN; gradient 25-55%) and a second purification (H2O (10 mM NH ₄ HCO ₃ )-ACN; gradient 30-60%) to provide the title compound (236) (103 mg, 21%) as a white solid and the title compound (237) (89 mg, 17.5%) as a white solid. 236: MS (ESI): mass calcd. for C23H34N6O5: 474.26, found: 475.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.38 (d, J = 4.4 Hz, 1H), 10.05 (s, 1H), 7.65 (s, 1H), 4.64 (s, 1H), 3.73 (t, J = 6.8 Hz, 2H), 2.95 (s, 3H), 2.77-2.90 (m, 6H), 2.15-2.44 (m, 6H), 2.09 (d, J = 12.8 Hz, 1H), 1.82 (d, J = 12.0 Hz, 1H), 1.33-1.50 (m, 5H), 1.16-1.32 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H). The methyl group on the diaminomethylene group in 236 was arbitrarily assigned. 237: MS (ESI): mass calcd. for C ₂₆ H ₄₀ N ₆ O ₅ : 516.31, found: 517.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 4.62 (s, 1H), 3.70 (t, J = 7.2 Hz, 2H), 2.97 (d, J = 15.6 Hz, 9H), 2.84 (d, J = 10.0 Hz, 9H), 2.15-2.46 (m, 6H), 2.09 (d, J = 12.8 Hz, 1H), 1.81 (d, J = 12.0 Hz, 1H), 1.30- 1.30 (m, 5H), 1.17-1.29 (m, 3H), 0.86 (t, J = 7.2 Hz, 3H). Example 240.1-Butyl-5-(diaminomethylene)-3-((1S,4s)-4-(((2S,4s)-2-hy droxy-6,8-dioxo- 5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)pyrimidine-2 ,4,6(1H,3H,5H)-trione (240) Synthetic scheme: Cis-N-boc-4-(hydroxymethyl)cyclohexanamine Cis-4-(Boc-amino)cyclohexanecarboxylic acid (5.0 g, 20.1 mmol) was dissolved in anhydrous THF (50.3 mL) and cooled to –15 °C under N ₂ . Borane dimethylsulfide complex (3.1 mL, 32.6 mmol) was slowly added and the solution was warmed up to rt for 3 h. The reaction was then quenched with MeOH (15 mL) and concentrated. The crude was dissolved in MeCN (20 mL), reconcentrated, dissolved in DCM (50 mL) and washed with saturated aqueous Na2CO3 solution. The organic phase was dried over MgSO4, filtered and concentrated to give the crude title compound (4.62 g, 100%). ¹ H NMR (400 MHz, CDCl3) δ ppm 4.30-4.82 (m, 1 H), 3.75 (brs, 1 H), 3.51 (d, J = 6.2 Hz, 2 H), 1.52-1.77 (m, 7 H), 1.45 (s, 9 H), 1.16-1.36 (m, 2 H). Cis-N-boc-4-(bromomethyl)cyclohexanamine To a crude solution of cis-N-Boc-4-(hydroxymethyl)cyclohexanamine (4.62 g, 20.1 mmol) in DCM (101 mL) was added carbon tetrabromide (8.28 g, 25.0 mmol). The solution was cooled to 0 °C and triphenylphosphine (6.30 g, 23.8 mmol) was slowly added. The reaction was then stirred at rt for 16 h, concentrated onto silica gel and purified by silica gel column chromatography (0-100% EtOAc/Heptanes) to provide the title compound (2.23 g, 38%) as a yellow oil. ¹ H NMR (400 MHz, CD3OD) δ ppm 3.31 (d, J = 6.4 Hz, 2H), 3.25 (dd, J = 15.0, 6.9 Hz, 1H), 1.91 (d, J= 9.6 Hz, 4H), 1.50 - 1.64 (m, 1H), 1.42 (s, 9H), 1.05 - 1.28 (m, 4H). 2-(Benzyloxy)-5,7-diazaspiro[3.4]octane-6,8-dione To ammonium carbonate (1.75 g, 18.2 mmol) in MeOH (20.6 mL) was added potassium cyanide (610 mg, 9.08 mmol). The mixture was heated to 40 °C for 30 min until a solution was obtained. 3-(Benzyloxy)cyclobutanone (1.50 g, 8.26 mmol) was added and the reaction was stirred for 3 d at rt. Solvent was removed in vacuo and the resulting residue was treated with 6 M HCl until pH 1 was reached. The solid formed was filtered and washed with water to yield the title compoud (1.5 g, 74%) as a white solid. MS (ESI): mass calcd. for C ₁₃ H ₁₄ N ₂ O ₃ : 246.26, found: 245.6 [M-H]-. (2s,4s)-2-(Benzyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-5 ,7-diazaspiro[3.4]octane-6,8- dione and (2r,4r)-2-(benzyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-5 ,7- diazaspiro[3.4]octane-6,8-dione To 2-(benzyloxy)-5,7-diazaspiro[3.4]octane-6,8-dione (1.00 g, 4.06 mmol) in DMF (8.1 mL) at 0 °C was added triethylamine (1.7 mL, 12.2 mmol) and (2- chloromethoxyethyl)trimethylsilane (1.76 mL, 9.75 mmol). The reaction was stirred for 1 h, added water and extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (0-100% EtOAc/heptanes) to provide the two title compounds (stereochemistry was arbitrarily assigned) (100 mg, 6.5%) and (130 mg, 8.5%). MS (ESI): mass calcd. for C19H28N2O4Si: 376.52, found: 375.6 [M-H]-. tert-Butyl ((1S,4s)-4-(((2S,4s)-2-(benzyloxy)-6,8-dioxo-7-((2- (trimethylsilyl)ethoxy)methyl)-5,7-diazaspiro[3.4]octan-5- yl)methyl)cyclohexyl)carbamate To (2s,4s)-2-(benzyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-5 ,7- diazaspiro[3.4]octane-6,8-dione (one of the diastereomer from the above step, 80.0 mg, 212 µmol) in DMF (1.2 mL) was added cis-N-boc-4-(bromomethyl)cyclohexanamine (93.1 mg, 319 µmol), and Cs ₂ CO ₃ (125 mg, 382 µmol). The reaction was heated at 60 °C for 2 h. The reaction was diluted with EtOAc/water (20 mL/20 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel column chromatography (0-70% EtOAc/Heptanes) to provide the title compound (69.0 mg, 55%). MS (ESI): mass calcd. for C ₃₁ H ₄₉ N ₃ O ₆ Si: 587.82, found: 488.7 [M+H-Boc] ⁺ . (2S,4s)-5-(((1s,4S)-4-Aminocyclohexyl)methyl)-2-(benzyloxy)- 7-((2- (trimethylsilyl)ethoxy)methyl)-5,7-diazaspiro[3.4]octane-6,8 -dione Tert-butyl ((1S,4s)-4-(((2S,4s)-2-(benzyloxy)-6,8-dioxo-7-((2- (trimethylsilyl)ethoxy)methyl)-5,7-diazaspiro[3.4]octan-5-yl )methyl)cyclohexyl)carbamate (69.0 mg, 117 µmol) was dissolved in formic acid (1.0 mL, 117 µmol) and the solution was stirred at rt for 30 min. The reaction was concentrated in vacuo at rt in a water bath. The crude was diluted with EtOAc (30 mL) and saturated aqueous Na2CO3 (20 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give the title compound (56.0 mg, 98 %). MS (ESI): mass calcd. for C ₂₆ H ₄₁ N ₃ O ₄ Si: 487.71, found: 488.3 [M+H] ⁺ . 1-((1S,4s)-4-(((2S,4s)-2-(Benzyloxy)-6,8-dioxo-7-((2-(trimet hylsilyl)ethoxy)methyl)-5,7- diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)-3-butylurea (2S,4s)-5-(((1s,4S)-4-Aminocyclohexyl)methyl)-2-(benzyloxy)- 7-((2- (trimethylsilyl)ethoxy)methyl)-5,7-diazaspiro[3.4]octane-6,8 -dione (56.0 mg, 115 µmol) was dissolved in DMF (2 mL) and to the solution was added butyl isocyanate (12.9 µL, 115 µmol). The reaction was stirred at rt for 1 h and the crude was directly purified by reverse phase HPLC (C18, 0-70% MeCN/10 mM HCOONH ₄ buffer) to provide the title compound (31.0 mg, 46%). MS (ESI): mass calcd. for C31H50N4O5Si: 586.84, found: 587.8 [M+H] ⁺ . 1-((1S,4s)-4-(((2S,4s)-2-(Benzyloxy)-6,8-dioxo-7-((2-(trimet hylsilyl)ethoxy)methyl)-5,7- diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)-3-butylpyrimidi ne-2,4,6(1H,3H,5H)-trione To 1-((1S,4s)-4-(((2S,4s)-2-(benzyloxy)-6,8-dioxo-7-((2- (trimethylsilyl)ethoxy)methyl)-5,7-diazaspiro[3.4]octan-5-yl )methyl)cyclohexyl)-3-butylurea (31.0 mg, 52.8 µmol) in AcOH (1.9 mL) were added malonic acid (5.5 mg, 52.8 µmol) and acetic anhydride (30 µL, 317 µmol). The reaction was stirred at 80 °C for 21 h. The reaction was cooled down to rt, MeOH was added, and the mixture was concentrated. The crude was purified by reverse phase HPLC (C18, 0-100% MeCN/10 mM HCOONH4 buffer) to provide the title compound (30.0 mg, 87%). MS (ESI): mass calcd. for C ₃₄ H ₅₀ N ₄ O ₇ Si: 654.87, found: 653.4 [M-H]-. 1-((1S,4s)-4-(((2S,4s)-2-(Benzyloxy)-6,8-dioxo-7-((2-(trimet hylsilyl)ethoxy)methyl)-5,7- diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)-3-butyl-5-(diam inomethylene)pyrimidine- 2,4,6(1H,3H,5H)-trione 1-((1S,4s)-4-(((2S,4s)-2-(Benzyloxy)-6,8-dioxo-7-((2-(trimet hylsilyl)ethoxy)methyl)- 5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)-3-butylpyri midine-2,4,6(1H,3H,5H)-trione (30.0 mg, 45.8 µmol) , cyanamide (9.7 mg, 229 µmol) and nickel(II) acetylacetonate (3.5 mg, 13.7 µmol) were added in a vial followed by anhydrous THF (248 µL). After heating at 85 °C for 22 h, the reaction was filtered with a syringe filter, concentrated, and redissolved in DCM (10 mL). The organic phase was washed with water (5 mL), dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase HPLC (C18, 0-100% MeCN in 10 mM NH ₄ HCO ₃ buffer) to provide the title compound (16.0 mg, 50%). MS (ESI): mass calcd. for C35H52N6O7Si: 696.91, found: 695.4 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-((1S,4s)-4-(((2S,4s)-2-hydrox y-6,8-dioxo-7-((2- (trimethylsilyl)ethoxy)methyl)-5,7-diazaspiro[3.4]octan-5- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione 1-((1S,4s)-4-(((2S,4s)-2-(Benzyloxy)-6,8-dioxo-7-((2-(trimet hylsilyl)ethoxy)methyl)- 5,7-diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)-3-butyl-5-( diaminomethylene)pyrimidine- 2,4,6(1H,3H,5H)-trione (16.0 mg, 23.0 µmol) was dissolved in MeOH (5 mL) and to the solution was added 10% Pd/C (10.0 mg). The reaction was stirred under hydrogen (1 atm) for 6 h. Then the reaction was filtered through Celite and concentrated in vacuo to give the crude title compound (13.9 mg, 100%). MS (ESI): mass calcd. for C28H46N6O7Si: 606.79, found: 605.3 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-((1S,4s)-4-(((2S,4s)-2-hydrox y-6,8-dioxo-5,7- diazaspiro[3.4]octan-5-yl)methyl)cyclohexyl)pyrimidine-2,4,6 (1H,3H,5H)-trione (240) 1-Butyl-5-(diaminomethylene)-3-((1S,4s)-4-(((2S,4s)-2-hydrox y-6,8-dioxo-7-((2- (trimethylsilyl)ethoxy)methyl)-5,7-diazaspiro[3.4]octan-5-yl )methyl)cyclohexyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (14.0 mg, 23.1 µmol) was dissolved in TFA (500 µL) and stirred for 30 min. The reaction was concentrated to remove TFA. MeOH (0.3 mL) was added followed by (NH4)2CO3 (200 mg). The reaction was stirred at rt for 30 min. To the reaction was added 0.5 mL of DMF and the mixture was concentrated. The crude was purified by reverse phase HPLC (C18, 0-60% MeCN in 10 mM NH ₄ HCO ₃ buffer) to give the title compound (240) (3.6 mg, 33 %) as a white solid. MS (ESI): mass calcd. for C22H32N6O6: 476.53, found: 477.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (s, 2H), 7.37 (s, 2H), 5.28 (s, 1H), 4.66 (s, 1H), 4.17 (s, 1H), 3.71 – 3.77 (m, 2H), 3.39 (d, J = 4.8 Hz, 2H), 2.62 (d, J = 22.4 Hz, 1H), 2.24 (s, 3H), 1.99 (s, 1H), 1.71 (d, J = 13.9 Hz, 2H), 1.46 (t, J = 10.7 Hz, 5H), 1.21 – 1.31 (m, 5H), 0.86 (d, J = 7.4 Hz, 3H). Stereochemistry was arbitrarily assigned. Example 241 was synthesized in similar procedures as described in Example 240 from the other diastereomer (2r,4r)-2-(benzyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-5 ,7- diazaspiro[3.4]octane-6,8-dione. Example 242.1-Butyl-5-(diaminomethylene)-3-(6''-oxo-5'',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (242) Synthetic scheme 2-(3-Chloropyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile 8,11-Dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (300 mg, 1.45 mmol) was dissolved in THF (6.2 mL) and cooled to 0 °C. Lithium bis(trimethylsilyl)amide solution (1.5 mL, 1.52 mmol) was slowly added, and the mixture was stirred at 0 °C for 15 min. 2,3- Dichloropyrazine (330 mg, 2.21 mmol) was dissolved in THF (750 µL) and slowly added at 0 °C. The resulting solution was stirred at rt for 1.5 h then concentrated with silica gel and purified by silica gel column chromatography (0-50% EtOAc/Heptanes) to provide the title compound (259 mg, 56%) as an orange solid. MS (ESI): mass calcd. for C16H18ClN3O2: 319.79, found: 320.3 [M+H] ⁺ . 2-(3-Chloropyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxamide To 2-(3-Chloropyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (259 mg, 810 µmol) in DMSO (2.0 mL) was added potassium carbonate (224 mg, 1.62 mmol). The reaction was cooled to 0 °C and hydrogen peroxide (827 µL, 8.1 mmol) was added. The cooling bath was removed, and the reaction was stirred at rt for 1 h, diluted with EtOAc (50 mL), and washed with water (2 × 50 mL) and brine (25 mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the title compound (260 mg, 95%) as a colorless solid. MS (ESI): mass calcd. for C ₁₆ H ₂₀ ClN ₃ O ₃ : 337.80, found: 338.2 [M+H] ⁺ . Trispiro[pyrrolo[2,3-b]pyrazine-7,1'-cyclobutane-3',1''-cycl ohexane-4'',2'''- [1,3]dioxolan]-6(5H)-one 2-(3-Chloropyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxamide (260 mg, 770 µmol) was dissolved in DMSO (7.7 mL) and cesium carbonate (512 mg, 1.54 mmol) was added. The reaction was heated at 100 °C for 1 h then was diluted with EtOAc (50 mL), washed with water (2 × 50 mL) and brine (25 mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the title compound (166 mg, 72%) as a colorless solid. MS (ESI): mass calcd. for C ₁₆ H ₁₉ N ₃ O ₃ : 301.34, found: 302.3 [M+H] ⁺ . Dispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2,3-b]py razine]-4,6''(5''H)-dione To a solution of trispiro[pyrrolo[2,3-b]pyrazine-7,1'-cyclobutane-3',1''-cycl ohexane- 4'',2'''-[1,3]dioxolan]-6(5H)-one (166 mg, 551 µmol) in acetone (1.6 mL) and water (809 µL) was added p-toluenesulfonic acid monohydrate (53.2 mg, 275 µmol) and the reaction was heated at 50 °C for 1 h. The reaction was diluted with EtOAc (50 mL), washed with 50% K2CO3 (2 x 50 mL) and brine (50mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the title compound (104 mg, 73%) as a colorless solid. MS (ESI): mass calcd. for C ₁₄ H ₁₅ N ₃ O ₂ : 257.29, found: 258.3 [M+H] ⁺ . 5''-((2-(Trimethylsilyl)ethoxy)methyl)dispiro[cyclohexane-1, 1'-cyclobutane-3',7''- pyrrolo[2,3-b]pyrazine]-4,6''(5''H)-dione To a solution of dispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2,3-b]py razine]- 4,6''(5''H)-dione (104 mg, 404 µmol) in DMF (1 mL) and DCM (1 mL) at 0 °C was added N,N-diisopropylethylamine (213 µL, 1.21 mmol) and (2-chloromethoxyethyl)trimethylsilane (146 µL, 808 µmol). The mixture was stirred for 1 h at 0 °C and was diluted with EtOAc (50 mL), washed with 50% Na ₂ CO ₃ (2 × 50 mL) and brine (1 × 25 mL). The organic phase was dried over MgSO4, concentrated with silica gel, and purified by silica gel column chromatography (0-100% EtOAc/Heptanes) to give (71 mg, 45%) as a colorless solid. MS (ESI): mass calcd. for C ₂₀ H ₂₉ N ₃ O ₃ Si: 387.55, found: 388.3[M+H] ⁺ . 4-Amino-5''-((2-(trimethylsilyl)ethoxy)methyl)dispiro[cycloh exane-1,1'-cyclobutane- 3',7''-pyrrolo[2,3-b]pyrazin]-6''(5''H)-one 5''-((2-(Trimethylsilyl)ethoxy)methyl)dispiro[cyclohexane-1, 1'-cyclobutane-3',7''- pyrrolo[2,3-b]pyrazine]-4,6''(5''H)-dione (150 mg, 387 µmol) was dissolved in 7 M ammonia in MeOH (553 µL, 3.87 mmol) and stirred for 4 h. MeOH (1.3 mL) was added, the mixture was purged with nitrogen.10% Palladium on carbon (41.2 mg) was added. The reaction was purged with hydrogen and stirred for 18 h, filtered with a syringe filter, and concentrated to give the title compound (36.0 mg, 24%) as a colorless oil. MS (ESI): mass calcd. for C20H32N4O2Si: 388.58, found: 389.2[M+H] ⁺ . 1-Butyl-3-(6''-oxo-5''-((2-(trimethylsilyl)ethoxy)methyl)-5' ',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4-yl)urea 4-Amino-5''-((2-(trimethylsilyl)ethoxy)methyl)dispiro[cycloh exane-1,1'-cyclobutane- 3',7''-pyrrolo[2,3-b]pyrazin]-6''(5''H)-one (36.0 mg, 92.6 µmol) was dissolved in DMF (371 µL). Triethylamine (12.9 µL, 92.6 µmol) was added followed by butyl isocyanate (11.7 µL, 102 µmol). The reaction was stirred at rt for 1 h, diluted with EtOAc (2 mL), and washed with 1 M HCl (2 mL), 50% Na ₂ CO ₃ (2 mL) and brine (1 mL). The organic phase was dried over MgSO ₄ , filtered, and concentrated to give the title compound (29.0 mg, 64%) as a colorless solid. MS (ESI): mass calcd. for C25H41N5O3Si: 487.71, found: 488.3 [M+H] ⁺ . 1-Butyl-3-(6''-oxo-5''-((2-(trimethylsilyl)ethoxy)methyl)-5' ',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione 1-Butyl-3-(6''-oxo-5''-((2-(trimethylsilyl)ethoxy)methyl)-5' ',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4-yl)urea (29.0 mg, 59.5 µmol) and malonic acid (7.2 mg, 68.4 µmol) were dissolved in AcOH (119 µL). Upon heating to 60 °C, acetic anhydride (22.5 µL, 238 µmol) was added. The reaction was sealed and stirred at 90 °C for 1 h, cooled down to rt, concentrated onto silica gel and purified by silica gel column chromatography (0-100% EtOAc/Heptanes) to provide the title compound (19.0 mg, 57%) as a colorless solid. MS (ESI): mass calcd. for C ₂₈ H ₄₁ N ₅ O ₅ Si: 555.74, found: 554.4 [M-H]- 1-Butyl-5-(diaminomethylene)-3-(6''-oxo-5''-((2-(trimethylsi lyl)ethoxy)methyl)-5'',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione 1-Butyl-3-(6''-oxo-5''-((2-(trimethylsilyl)ethoxy)methyl)-5' ',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (19.0 mg, 34.2 µmol), cyanamide (4.4 mg, 103 µmol) and nickel(II) acetylacetonate (2.6 mg, 10.3 µmol) were put in a vial. THF (185 µL) was added and the reaction was stirred at 85 °C for 7 h. The reaction was concentrated, redissolved in DCM, filtered with a syringe filter, and was concentrated to give the crude title compound (20 mg) as an orange oil, which was used directly in the next step. MS (ESI): mass calcd. for C ₂₉ H ₄₃ N ₇ O ₅ Si: 597.31, found: 596.5 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-(6''-oxo-5'',6''-dihydrodispi ro[cyclohexane-1,1'- cyclobutane-3',7''-pyrrolo[2,3-b]pyrazin]-4-yl)pyrimidine-2, 4,6(1H,3H,5H)-trione (242) 1-Butyl-5-(diaminomethylene)-3-(6''-oxo-5''-((2-(trimethylsi lyl)ethoxy)methyl)-5'',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (20.0 mg, 33.5 µmol) was dissolved in DCM (181 µL) and trifluoroacetic acid (59.2 µL, 773 µmol) was added. The reaction was stirred at rt for 5 h and concentrated. MeOH (169 µL) and saturated aqueous (NH ₄ ) ₂ CO ₃ solution (100 µL) were added and the solution was stirred for 2 h. The reaction was filtered, concentrated, and purified by reverse phase HPLC (C18, 30-50% MeCN/NH4HCO310 mM buffer) to give the title compound (242) (5.1 mg, 33%) as a colorless solid. MS (ESI): mass calcd. for C23H29N7O4: 467.52, found: 468.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) δ ppm 8.11 (d, J = 3.2 Hz, 1H), 7.98 (d, J = 3.2 Hz, 1H), 4.75 - 4.79 (m, 1H), 3.80 – 3.85 (m, 2H), 2.52 (d, J = 10.9 Hz, 3H), 2.37 (dt, J = 24.0, 11.8 Hz, 4H), 2.21 (d, J = 12.3 Hz, 1H), 1.42 – 1.61 (m, 6H), 1.28 – 1.36 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). Examples 243, 282, and 293 were synthesized in similar procedures as described in Example 177. Example 246.1-Butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4-dio xoimidazolidin- 1-yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione (246) Synthetic scheme 5,5-Dimethyl-1-(4-nitrobenzyl)-3-((2-(trimethylsilyl)ethoxy) methyl)imidazolidine-2,4- dione A solution of 1-(bromomethyl)-4-nitrobenzene (1.0 g, 4.63 mmol), 5,5-dimethyl-3- ((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (1.2 g, 4.63 mmol), and potassium carbonate (1.96 g, 13.9 mmol) in DMF (15.4 mL) was stirred for 2 h at rt. The reaction was diluted with water (100 mL) and EtOAc (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with saturated aqueous LiCl (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (10-40% EtOAc/heptanes) to provide the title compound (1.55 g, 85 %). MS (ESI): mass calcd. for C ₁₈ H ₂₇ N ₃ O ₅ Si: 393.51, found: 392.3 [M-H]-. 1-(4-Aminobenzyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy) methyl)imidazolidine-2,4- dione 5,5-Dimethyl-1-(4-nitrobenzyl)-3-((2-(trimethylsilyl)ethoxy) methyl)imidazolidine- 2,4-dione (850 mg, 2.16 mmol) in EtOH (21.6 mL) was placed under nitrogen and 10% palladium on carbon (115 mg, 1.08 mmol) was added. The reaction was purged with hydrogen and stirred under hydrogen for 2 h. The reaction was filtered through Celite and concentrated to provide the crude title compound (785 mg, 100%), which was used in the next step without further purification. MS (ESI): mass calcd. for C ₁₈ H ₂₉ N ₃ O ₃ Si: 363.53, found: 386.3 [M+Na] ⁺ . 1-Butyl-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl) ethoxy)methyl)imidazolidin- 1-yl)methyl)phenyl)urea To a solution of 1-(4-aminobenzyl)-5,5-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (693 mg, 1.91 mmol) in THF (9.5 mL) was added butyl isocyanate (329 µL, 2.86 mmol). The reaction was heated to 60 °C for 3 h and diluted with water. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude was purified by silica gel column chromatography (10-60% EtOAc/heptanes) to yield the title compound (750 mg, 85%). MS (ESI): mass calcd. for C23H38N4O4Si: 462.66, found: 507.3 [M+CHO ₂ ]-. 1-Butyl-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl) ethoxy)methyl)imidazolidin- 1-yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione To 1-butyl-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)pheny l)urea (700 mg, 1.51 mmol) in DCM (15.1 mL) was added malonyl chloride (167 µL, 1.66 mmol). The reaction was stirred for 1 h, diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layer was washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by silica gel column chromatography (20-80% EtOAc/heptanes) to provide the title compound (640 mg, 80%). MS (ESI): mass calcd. for C ₂₆ H ₃₈ N ₄ O ₆ Si: 530.69, found: 529.3 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4-dioxo-3 -((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)pheny l)pyrimidine- 2,4,6(1H,3H,5H)-trione 1-Butyl-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)pheny l)pyrimidine-2,4,6(1H,3H,5H)- trione (500 mg, 942 µmol), cyanamide (400 mg, 9.42 mmol), and nickel(II) acetylacetonate (48.4 mg, 188 µmol) were placed in a vial and THF (4.8 mL) was added. The reaction was heated to 80 °C for 18 h, filtered with a syringe filter and concentrated. The crude was purified by silica gel column chromatography (20-80% EtOAc/heptanes) to yield the title compound (270 mg, 50%). MS (ESI): mass calcd. for C ₂₇ H ₄₀ N ₆ O ₆ Si: 572.73, found: 571.3 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4-dioxoim idazolidin-1- yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione (246) To 1-butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4-dioxo-3 -((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)pheny l)pyrimidine-2,4,6(1H,3H,5H)- trione (500 mg, 873 µmol) in DCM (4.4 mL) was added trifluoroacetic acid (669 µL, 8.73 mmol) and the reaction was stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO ₃ (20 mL) and extracted with DCM (30 mL). The crude was purified by reverse phase HPLC (15-35% MeCN/NH4HCO310 mM buffer) to provide the title compound (246) (120 mg, 31%). MS (ESI): mass calcd. for C21H26N6O5: 442.47, found: 443.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.42 (s, 2H), 8.29 (s, 1H), 7.35 (d, J = 8.3 Hz, 4H), 7.13 (d, J = 8.4 Hz, 2H), 4.46 (s, 2H), 3.68 – 3.82 (m, 2H), 1.48 (dt, J = 14.9, 7.5 Hz, 2H), 1.20 – 1.31 (m, 8H), 0.86 (t, J = 7.3 Hz, 3H). Example 253 was synthesized in similar procedures as described in Example 246, with 1- (bromomethyl)-3-nitrobenzene as starting materiel instead of 1-(bromomethyl)-4- nitrobenzene. Example 247. 1-Butyl-5-(diaminomethylene)-3-(2,4-dioxo-1-oxa-3- azadispiro[5.1.5 ⁸ .1 ⁶ ]tetradecan-11-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (247) Synthetic scheme: O O O O L ^DA O O O _LiOH.H2O O OEt O _{NH4Cl, HTAU} ^O O O OH OH OH OH NH ₂ H ₂ N NH ₂ O O O CDI O O N N O NH O O O 247 O NH O Ethyl 2-(2-hydroxy-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)acetate To a solution of ethyl acetate (6.73 g, 76.44 mmol) in THF (80 mL) was added LDA (2 M, 38.22 mL) at –70 °C. The reaction was stirred at –70 °C for 0.5 hr. A solution of 8,11- dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one (10 g, 51 mmol) in THF (20 mL) was added dropwise. After stirring at –70 °C for 2 h, the reaction was quenched with saturated NH4Cl (50 mL), and extracted with EtOAc (2 x 100 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate = 20 : 1 to 0 : 1) to provide the title compound (10.6 g, 73%) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ ppm 4.17 (q, J = 7.2 Hz, 2H), 3.92 (s, 4H), 3.59 (s, 1H), 2.62 (s, 2H), 1.94-2.01 (m, 2H), 1.86-1.92 (m, 2H), 1.74-1.82 (m, 2H), 1.51- 1.63 (m, 6H), 1.27 (t, J = 7.2 Hz, 3H). 2-(2-Hydroxy-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)acetic acid To a solution of ethyl 2-(2-hydroxy-8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)aceta te (5 g, 17.6 mmol) in THF (25 mL) was added LiOH.H ₂ O (1.48 g, 35.2 mmol) and H ₂ O (25 mL). After stirring at 20 °C for 2 h, the reaction was adjusted pH = 6 with HCl (40 mL, 1 M) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to provide the title compound (4.3 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ ppm 3.94 (s, 4H), 2.71 (s, 2H), 1.99 (q, J = 9.2 Hz, 4H), 1.76-1.82 (m, 2H), 1.53-1.64 (m, 6H). 2-(2-Hydroxy-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)acetamide To a solution of 2-(2-hydroxy-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)acetic acid (3 g, 11.7 mmol) in DMF (30 mL) was added DIPEA (3.03 g, 23.4 mmol), NH4Cl (1.25 g, 23.4 mmol) and HATU (4.90 g, 12.9 mmol). After stirring at 20 °C for 2 h, the reaction was quenched with H ₂ O (80 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate = 10 : 1 to 0 : 1) to provide the title compound (2.9 g, 97%) as a white solid. 1,4,11-Trioxa-13-azatrispiro[4.2.1.5 ¹⁰ .1 ⁸ .2 ⁵ ]octadecane-12,14-dione To a solution of 2-(2-hydroxy-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)acetamide (2.9 g, 11.4 mmol) in CH3CN (30 mL) was added CDI (2.76 g, 17 mmol). After stirring at 20 °C for 12 h, the reaction was quenched with H ₂ O (30 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by silica gel column chromatography (Ethyl acetate : Methanol = 100 : 1 to 10 : 1) to provide the title compound (2.6 g, 81%) as a white solid. MS (ESI): mass calcd. for C ₁₄ H ₁₉ NO ₅ : 281.13, found: 280.2 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-(2,4-dioxo-1-oxa-3-azadispiro [5.1.5 ⁸ .1 ⁶ ]tetradecan-11- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (247)

The title compound (247) was synthesized in similar procedures as described in Example 177 starting from the SEM protection step. Reductive amination was carried out with NH4OAc and NaBH(OAc)3 conditon.247: MS (ESI): mass calcd. for C21H29N5O6: 447.21, found: 448.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (s, 1H), 9.54 (s, 2H), 7.30 (s, 2H), 4.58-4.65 (m, 1H), 3.70-3.75 (m, 2H), 2.84-2.86 (m, 2H), 2.31-2.37 (m, 2H), 2.02-2.10 (m, 4H), 1.71-1.88 (m, 2H), 1.34-1.47 (m, 6H), 1.24-1.26 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). Examples 249, 256 and 257 were synthesized in similar procedures as described in Example 188. Example 250 and 260.1-Butyl-5-(diaminomethylene)-3-((5S,7s,10S)-1-(2-methoxy ethyl)- 3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (250) and 1-Butyl-5-(diaminomethylene)-3-((5R,rs,10R)-1-(2- methoxyethyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (260) Synthetic scheme: 1-Butyl-5-(diaminomethylene)-3-(1-(2-methoxyethyl)-3-methyl- 2,4-dioxo-1,3- diazadispiro[4. ¹ .5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (Example 244) To a solution of 1-butyl-5-(diaminomethylene)-3-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (Example 107, 0.25 g, 560 μmol) and 1-iodo-2-methoxy-ethane (520.7 mg, 2.8 mmol) in DMF (3 mL) was added Cs2CO3 (364.86 mg, 1.12 mmol). The reaction was stirred at 25 °C for 12 h under N2. After completion, the reaction was quenched by H ₂ O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (H ₂ O (10 mM NH ₄ HCO ₃ )-ACN; gradient 25-55%) to provide the title compound (244) (80 mg, 27.6%) as a white solid. MS (ESI): mass calcd. for C ₂₄ H ₃₆ N ₆ O ₆ : 504.37, found: 505.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((5S,7s,10S)-1-(2-methoxyethy l)-3-methyl-2,4-dioxo- 1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (250) and 1- Butyl-5-(diaminomethylene)-3-((5R,rs,10R)-1-(2-methoxyethyl) -3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (260) The title compounds were obtained through chiral SFC separation of Example 244 (DAICEL CHIRALCEL OJ (250mm*30mm,10 μm); mobile phase: CO2-MeOH (0.1% NH ₃ H ₂ O); 35% B, isocratic elution). Stereochemistry was arbitrarily assigned. Example 250: MS (ESI): mass calcd. for C24H36N6O6: 504.37, found: 505.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.63 (t, J = 10.4 Hz, 1H), 3.73 (t, J = 7.2 Hz, 2H), 3.50-3.54 (m, 4H), 3.27 (s, 3H), 2.84 (s, 3H), 2.42-2.46 (m, 1H), 2.20-2.33 (m, 5H), 2.13 (d, J = 12.8 Hz, 1H), 1.83 (d, J = 14.0 Hz, 1H), 1.37-1.45 (m, 5H), 1.22-1.28 (m, 3H), 0.88 (t, J =7.2 Hz, 3H). Example 260: MS (ESI): mass calcd. for C24H36N6O6: 504.37, found: 505.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.54 (s, 2H), 7.29 (s, 2H), 4.63 (t, J = 9.6 Hz, 1H), 3.73 (t, J = 7.2 Hz, 2H), 3.50-3.54 (m, 4H), 3.27 (s, 3H), 2.84 (s, 3H), 2.43-2.46 (m, 1H), 2.19-2.35 (m, 5H), 2.13 (d, J = 12.8 Hz, 1H), 1.83 (d, J = 12.0 Hz, 1H), 1.35-1.49 (m, 5H), 1.20-1.28 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H). Example 285 was synthesized in similar procedures as in the first step of Examples 250 and 260, using potassium carbonate instead of cesium carbonate and starting from the chiral starting material. Example 286 was synthesized in similar procedures as described in Example 285, using 2- bromoacetamide. The alkylation was performed at 50 °C. Examples 251 and 252.1-Butyl-5-(diaminomethylene)-3-((5S,7s,10S)-1-(2- hydroxyethyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (251) and 1-butyl-5-(diaminomethylene)-3-((5R,7r,10R)-1-(2- hydroxyethyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (252) Synthetic scheme: Ethyl 2-(10-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropy rimidin-1(2H)-yl)- 3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-1-yl)acetate To a solution of 1-butyl-5-(diaminomethylene)-3-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (Example 107, 500 mg, 1.1 mmol) in DMF (5 mL) was added Cs2CO3 (1.09 g, 3.4 mmol) and ethyl 2-iodoacetate (1.2 g, 5.6 mmol). The reaction was stirred at 25 °C for 12 h under N2. After completion, the reaction was quenched with H ₂ O (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate = 100 : 1 to 0 : 1) to provide the title compound (150 mg, 23%) as a yellow solid. MS (ESI): mass calcd. for C25H36N6O7: 532.26, found: 533.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(1-(2-hydroxyethyl)-3-methyl- 2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (Example 245) To a solution of ethyl 2-(10-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-3-methyl-2,4-dioxo-1,3-d iazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan- 1-yl)acetate (0.15 g, 282 μmol) in THF (1.5 mL) was added NaBH ₄ (21.3 mg) at 0 °C. The reaction was stirred at 50 °C for 3 h under N ₂ . After completion, the mixture was poured into saturated NH4Cl (5 mL), extracted with ethyl acetate (3 x 3 mL). The combined organic layer was washed with brine (3 x 3 mL), dried with anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (H ₂ O (10 mM NH4HCO3)-ACN; gradient 30-60% B) to provide the title compound (245) (40 mg, 29%) as a white solid. MS (ESI): mass calcd. for C23H34N6O6: 490.25, found: 491.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((5S,7s,10S)-1-(2-hydroxyethy l)-3-methyl-2,4-dioxo- 1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione and 1- butyl-5-(diaminomethylene)-3-((5R,7r,10R)-1-(2-hydroxyethyl) -3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (252) The title compounds were obtained through chiral SFC separation of Example 245 (DAICEL CHIRALPAK IC (250mm*30mm, 10 μm); mobile phase: CO ₂ -IPA (0.1% NH ₃ H ₂ O); 45% B, isocratic elution). Example 251: MS (ESI): mass calcd. for C ₂₃ H ₃₄ N ₆ O ₆ : 490.25, found: 491.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.90 (t, J = 5.6 Hz, 1H), 4.58-4.73 (m, 1H), 3.73 (t, J = 6.8 Hz, 2H), 3.57-3.64 (m, 2H), 3.34-3.44 (m, 2H), 2.84 (s, 3H), 2.43-2.46 (m, 1H), 2.20-2.36 (m, 5H), 2.10-2.15 (m, 1H), 1.84 (d, J = 12.0 Hz, 1H), 1.36-1.49 (m, 5H), 1.21-1.28 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H). Example 252: MS (ESI): mass calcd. for C23H34N6O6: 490.25, found: 491.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.90 (t, J = 5.6 Hz, 1H), 4.58- 4.73 (m, 1H), 3.73 (t, J = 6.8 Hz, 2H), 3.57-3.64 (m, 2H), 3.34-3.44 (m, 2H), 2.84 (s, 3H), 2.43-2.46 (m, 1H), 2.20-2.36 (m, 5H), 2.10-2.15 (m, 1H), 1.84 (d, J = 12.0 Hz, 1H), 1.36- 1.49 (m, 5H), 1.21-1.28 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H). Stereochemistry was arbitrarily assigned. Example 272 was synthesized in similar procedures as described in Example 251, starting from 1-butyl-5-(diaminomethylene)-3-(2,4-dioxo-3-((2-(trimethylsi lyl)ethoxy)methyl)-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (see Example 254), followed by SEM group deprotection with TFA. Examples 254 and 259.1-Butyl-5-(diaminomethylene)-3-((5R,7r,10R)-1-(oxetan-3- ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (254) and 1-butyl-5-(diaminomethylene)-3-((5S,7s,10S)-1- (oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (259) Synthetic scheme: 1-Butyl-5-(diaminomethylene)-3-(2,4-dioxo-3-((2-(trimethylsi lyl)ethoxy)methyl)-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione The title compound was synthesized starting from 3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4,10-trione (in Example 117), following Example 177 synthesis before the SEM deprotection step. 1-Butyl-5-(diaminomethylene)-3-[4-(oxetan-3-ylmethyl)-1,3-di oxo-2-(2- trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10- yl]hexahydropyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (0.3 g, 533 μmol) in DMF (3 mL) was added K ₂ CO ₃ (294.7 mg, 2.13 mmol) and 3-(bromomethyl)oxetane (322 mg, 2.13 mmol). After heating at 50 °C for 12 h under N2, the reaction was quenched by H2O (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether : Ethyl acetate = 100 : 1 to 2 : 3) to provide the title compound (170 mg, 47.4%) as a colorless solid. MS (ESI): mass calcd. for C ₃₀ H ₄₈ N ₆ O ₇ Si: 632.34, found: 633.4 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(1-(oxetan-3-ylmethyl)-2,4-di oxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (Example 248) The title compound (Example 248) was obtained by deprotection of the SEM group from 1-butyl-5-(diaminomethylene)-3-[4-(oxetan-3-ylmethyl)-1,3-di oxo-2-(2- trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl]hexahydropyrimidine- 2,4,6(1H,3H,5H)-trione using TBAF in THF, heating at 75 °C for 16 hr and through reverse phase HPLC purification. MS (ESI): mass calcd. for C ₂₄ H ₃₄ N ₆ O ₆ : 502.25, found: 503.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((5R,7r,10R)-1-(oxetan-3-ylme thyl)-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (254) and 1- butyl-5-(diaminomethylene)-3-((5S,7s,10S)-1-(oxetan-3-ylmeth yl)-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (259) The title compounds were separated by chiral SFC (column: ChiralPak IH, 250*30mm, 10 μm; mobile phase: (CO ₂ -IPA (0.1% NH ₃ H ₂ O); 40% B, isocratic elution). Example 254: MS (ESI): mass calcd. for C ₂₄ H ₃₄ N ₆ O ₆ : 502.25, found: 503.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.54 (s, 2H), 7.34 (s, 2H), 4.99 (d, J = 2.0 Hz, 1H), 4.60- 4.69 (m, 2H), 4.51-4.55 (m, 1H), 4.27- 4.35 (m, 2H), 3.71-3.75 (m, 3H), 1.98-2.38 (m, 8H), 1.78 (d, J = 12.0 Hz, 1H), 1.36-1.51 (m, 5H), 1.23-1.28 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H). Example 259: MS (ESI): mass calcd. for C ₂₄ H ₃₄ N ₆ O ₆ : 502.25, found: 503.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.33 (s, 2H), 4.97-4.99 (m, 1H), 4.57-4.74 (m, 1H), 4.51-4.55 (m, 1H), 4.20-4.40 (m, 1H), 3.67-3.82 (m, 2H), 3.42-3.65 (m, 3H), 1.98- 2.38 (m, 8H), 1.75-1.81 (m, 1H), 1.36- 1.49 (m, 5H), 1.23-1.28 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H). Stereochemistry was arbitrarily assigned. Examples 258, 273, and 280 were synthesized in similar procedures as described in Examples 254 and 259. Examples 277, 283, and 294 were synthesized in similar procedures as described in Examples 254 and 259 starting from alkylation of Example 100 with tert-butyl 2- bromoacetate, followed by TFA deprotection of the tert-butyl ester and chiral separation. Example 255 was synthesized in similar procedures as described in Example 177. The SEMCl protection step was replaced with methylation using NaH and MeI. Malonyl chloride was used instead of malonic acid. Example 261.1-Butyl-5-(diaminomethylene)-3-((trans)-4-(2-hydroxyprop an-2- yl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (261) Synthetic scheme: Trans-methyl 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate To a solution of trans-4-(Boc-amino)cyclohexanecarboxylic acid (1.0 g, 4.11 mmol) in DMF (20 mL) were added potassium carbonate (852 mg, 6.17 mmol) and iodomethane (388 µL, 6.17 mmol). The reaction was stirred at rt for 18 h. Water (50 mL) was added to the reaction, and the mixture was extracted twice with EtOAc. The combined organic layer was washed with saturated brine, dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (10-100% EtOAc/hexanes) to give the title compound (0.75 g, 71%) as a white solid. ¹ H NMR (400 MHz, DSMO-d ₆ ) δ ppm 6.73 (d, J = 7.7 Hz, 1H), 3.58 (s, 3H), 3.15 (dd, J = 7.5, 3.6 Hz, 1H), 2.19 (tt, J = 12.0, 3.6 Hz, 1H), 1.92 – 1.75 (m, 4H), 1.37 (s, 9H), 1.36 – 1.27 (m, 2H), 1.22 – 1.08 (m, 2H). Trans-methyl 4-aminocyclohexanecarboxylate To a solution of trans-methyl 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (650 mg, 2.53 mmol) in DCM (2.4 mL) was added trifluoroacetic acid (1.6 mL, 20.2 mmol) and the solution was stirred at rt for 45 min. The reaction was concentrated to dryness to give the crude title compound which was used directly in the next step. Trans-Methyl 4-(3-butylureido)cyclohexanecarboxylate To trans-methyl 4-aminocyclohexanecarboxylate (380 mg, 2.42 mmol) in DMF (2.9 mL) was added triethylamine (1.4 mL, 9.67 mmol) and stirred for 5 min. Butyl isocyanate (1.39 mL, 12.1 mmol) was added. After stirring at rt for 18 h, the reaction was directly purified by reverse phase HPLC (C18, 0-70% MeCN/HCOONH410 mM buffer) to give the title compound (426 mg, 69%). MS (ESI): mass calcd. for C13H24N2O3: 256.34, found: 257.2 [M+H] ⁺ . Trans-Methyl 4-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)- yl)cyclohexanecarboxylate To trans-methyl 4-(3-butylureido)cyclohexanecarboxylate (340 mg, 1.33 mmol) in AcOH (12 mL) was added malonic acid (223 mg, 2.12 mmol). The reaction was heated to 60 °C, acetic anhydride (502 µL, 5.31 mmol) was added. The reaction was then sealed and heated at 90 °C for 3.5 h. The mixture was neutralized with saturated aqueous NaHCO3, extracted with DCM (3x), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude title compound (165 mg, 38%). MS (ESI): mass calcd. for C16H24N2O5: 324.37 found: 323.3 [M- H]-. Trans-Methyl 4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)- yl)cyclohexanecarboxylate Trans-Methyl 4-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)- yl)cyclohexanecarboxylate (162 mg, 499 µmol), cyanamide (212 mg, 4.99 mmol) and nickel(II) acetylacetonate (38.5 mg, 150 µmol) were put in a vial and added THF (3 mL). The reaction was stirred at 85 °C for 10 h, concentrated, re-dissolved in DCM and filtered with a syringe filter. The filtrate was concentrated to give the crude title compound as an orange oil which was used directly in the next step. MS (ESI): mass calcd. for C ₁₇ H ₂₆ N ₄ O ₅ : 366.41 found: 365.3 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-((trans)-4-(2-hydroxypropan-2 - yl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (261) To a solution of trans-methyl 4-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)cyclohexanecarboxylate (29.0 mg, 79.1 µmol) in THF (500 µL) at 0 °C was added methylmagnesium chloride, 3.0 M in THF (158 µL, 475 µmol). The solution was stirred for 30 min, quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (x3). The combined organic layer was further washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase chromatography (C18, 5-100% MeCN/10 mM HCOONH4 buffer) to provide the title compound (261). MS (ESI): mass calcd. for C ₁₈ H ₃₀ N ₄ O ₄ : 366.46, found: 365.3 [M-H]-. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (s, 2H), 7.31 (s, 2H), 4.56 – 4.67 (m, 1H), 4.03 (s, 1H), 3.71 – 3.78 (m, 2H), 2.23 – 2.37 (m, 2H), 1.85 (d, J = 11.1 Hz, 2H), 1.40 – 1.57 (m, 4H), 1.21 – 1.32 (m, 3H), 1.05 – 1.19 (m, 2H), 1.03 (s, 6H), 0.88 (t, J = 7.3 Hz, 3H). Example 262 was synthesized following the last few steps of Example 261 and by using sodium borohydride instead of methyl magnesium chloride. Example 266 was synthesized in similar procedures as described in Example 177. Examples 267 and 268.1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-(hydroxymethyl )-4- ((3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)cy clohexyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (267) and 1-Butyl-5-(diaminomethylene)-3-((1r,4r)-4- (hydroxymethyl)-4-((3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-tria zol-4- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (268) Synthetic scheme: 4-((8-((Benzyloxy)methyl)-1,4-dioxaspiro[4.5]decan-8-yl)meth yl)-5-methyl-2,4-dihydro- 3H-1,2,4-triazol-3-one To a mixture of [8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl]methanami ne (from Example 187, 2.2 g, 7.55 mmol) in MeOH (20 mL) was added 5-methyl-3H-1,3,4- oxadiazol-2-one (1.28 g, 12.84 mmol). The mixture was stirred at 70 °C for 16 h and concentrated under reduced pressure. The residue was added NaOH (1 N, 20 mL) and heated at 100 °C for 16 h. The reaction was diluted with H2O (100 mL) and extracted with EtOAc (200 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 : Ethyl acetate = 1 : 0 to 0 : 1) to provide the title compound (1.9 g, 67.4%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (s, 1H), 7.35-7.44 (m, 5H), 4.51-4.59 (m, 2H), 3.88 (d, J = 1.6 Hz, 4H), 3.56 (s, 2H), 3.33 (s, 2H), 1.92 – 2.19 (m, 3H), 1.49-1.70 (m, 8H). 1-(4-((Benzyloxy)methyl)-4-((3-methyl-5-oxo-1-((2-(trimethyl silyl)ethoxy)methyl)-1,5- dihydro-4H-1,2,4-triazol-4-yl)methyl)cyclohexyl)-3-butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione The title compound was synthesized in similar procedures as described in Example 166, starting from SEMCl protection step. Malonyl chloride was used instead of malonic acid. 1-Butyl-5-(diaminomethylene)-3-(4-(hydroxymethyl)-4-((3-meth yl-5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-1,2,4-triazol- 4- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione A mixture of 1-(4-((benzyloxy)methyl)-4-((3-methyl-5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-1,2,4-triazol- 4-yl)methyl)cyclohexyl)-3- butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (75 mg, 112 μmol), 10% Pd/C (119 mg) in EtOH (2 mL) was degassed and purged with H ₂ for 3 times. The mixture was stirred at 25 °C for 16 h under H2 atmosphere. After completion, the mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to provide the title compound (46 mg, 71%) as a white solid. MS (ESI): mass calcd. for C26H45N7O6Si: 579.32, found: 580.4 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-(hydroxymethyl)-4- ((3-methyl-5-oxo-1,5- dihydro-4H-1,2,4-triazol-4-yl)methyl)cyclohexyl)pyrimidine-2 ,4,6(1H,3H,5H)-trione (267) and 1-Butyl-5-(diaminomethylene)-3-((1r,4r)-4-(hydroxymethyl)-4- ((3-methyl-5- oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)cyclohexyl)pyri midine-2,4,6(1H,3H,5H)- trione (268) A mixture of 1-butyl-5-(diaminomethylene)-3-(4-(hydroxymethyl)-4-((3-meth yl-5- oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-1,2, 4-triazol-4- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (51 mg, 88 μmol) in TFA (0.5 mL) and H2O (0.1 mL) was stirred at 25 °C for 30 min and concentrated under reduced pressure. MeOH (0.5 mL) and K ₂ CO ₃ was added to adjust to pH = 9. After stirring at 25 °C for 16 h, the mixture was acidified to pH = 5 with citric acid (0.4 mL), diluted with H ₂ O (30 mL), and extracted with EtOAc (2 x 60 mL). 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 (H ₂ O (0.2% FA)-ACN; gradient 20-45%) to provide the title compound (267) (2 mg) as a white solid and the title compound (268) (2 mg) as a white solid. Stereochemistry was arbitrarily assigned.267: MS (ESI): mass calcd. for C20H31N7O5: 449.24, found: 450.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.54 (s, 1H), 9.53 (s, 2H), 7.34 (s, 2H), 4.90-4.92 (m, 1H), 4.60-4.69 (m, 1H), 3.72-3.74 (m, 2H), 3.36-3.41 (m, 3H), 2.42-2.46 (m, 2H), 2.17 (s, 3H), 1.57 (d, J = 9.6 Hz, 2H), 1.45 (d, J = 7.2 Hz, 2H), 1.1-1.35 (m, 6H), 0.87 (t, J = 7.2 Hz, 3H). 268: MS (ESI): mass calcd. for C ₂₀ H ₃₁ N ₇ O ₅ : 449.24, found: 450.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.54 (s, 1H), 9.56 (s, 2H), 7.37 (s, 2H), 4.96-5.00 (m, 1H), 4.63-4.71 (m, 1H), 3.75 (t, J = 7.2 Hz, 2H), 3.63 (s, 2H), 3.27-3.29 (m, 1H), 3.00 (d, J = 6.0 Hz, 2H), 2.19 (s, 3H), 1.14-1.63 (m, 10H), 0.88 (t, J = 7.2 Hz, 3H). Example 269 was synthesized from 4-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)-1-((5,5-dimethyl-2,4-dio xo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclo hexane-1-carbonitrile (second to last step intermediate from Example 190) by hydrogenation with Raney-Ni in MeOH followed by TFA deprotection of the SEM group. Examples 270 and 275 were synthesized in similar procedures as described in Examples 187 and 188. Example 271 was synthesized from Example 100 using cyanomethyl 4- methylbenzenesulfonate, K2CO3 in DMSO. Examples 276 and 279 were obtained through chiral SFC separation of Example 271. Example 274.1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((4,4-dimethyl -2,5- dioxopyrrolidin-3-yl)oxy)cyclohexyl)pyrimidine-2,4,6(1H,3H,5 H)-trione (274) Synthetic scheme:

1-(Benzyloxy)-3,3-dimethylpyrrolidine-2,5-dione Triethylamine (1.12 mL, 8.03 mmol) was added to a solution of 2,2-dimethylsuccinic anhydride (1.00 g, 7.65 mmol) in DCM (5.1 mL) at 0 °C followed by addition of O- benzylhydroxylamine hydrochloride (1.31 g, 8.03 mmol). The mixture was warmed to rt overnight, and then 1,1`-carbonylimidazole (1.39 g, 8.41 mmol) was added in portions. The mixture was stirred at rt for 1.5 h and then heated at 35 °C for 30 min. The mixture was cooled to rt, and the organic layer was washed with 10% hydrochloric acid (2 × 10 mL), 50% sat. Na2CO3 (10 mL), dried over MgSO4, filtered, and concentrated to give the title compound (1.3 g, 73%) as a colorless solid. ¹ H NMR (400 MHz, CDCl3) δ ppm 7.47 (dd, J = 6.6, 3.0 Hz, 2H), 7.37 (q, J = 3.7 Hz, 3H), 5.15 (s, 2H), 2.42 (s, 2H), 1.20 (s, 6H). 3,3-Dimethylpyrrolidine-2,5-dione 1-(Benzyloxy)-3,3-dimethylpyrrolidine-,5-dione (1.0 g, 4.29 mmol) was dissolved in MeOH (21.4 mL) and the reaction was purged with nitrogen. 10% Palladium on carbon (456 mg) was added and the reaction was purged with hydrogen and stirred under hydrogen for 1 h. The reaction was filtered over Celite and concentrated in vacuo. The residue was dissolved in acetonitrile (18.6 mL) and was added to a solution of 2-bromoacetophenone (871 mg, 4.29 mmol) in acetonitrile (3.1 mL). Then a solution of triethylamine (896 µL, 6.43 mmol) in acetonitrile (3.1 mL) was very slowly added and the reaction was stirred at rt for 1.5 h. The reaction was concentrated and redissolved in DCM (15 mL). The solution was washed with 1 M HCl (10 mL), dried over MgSO4, filtered and concentrated onto silica gel. The crude was purified by silica gel column chromatography (30% EtOAc/Heptanes) to give the title compound (520 mg, 95%) a colorless solid which was used directly in the next step. 3,3-Dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolidine -2,5-dione To 3,3-dimethylpyrrolidine-2,5-dione (520 mg, 4.09 mmol) in DCM (10.2 mL) and DMF (10.2 mL) at 0 °C was added N,N-diisopropylethylamine (2.2 mL, 12.3 mmol) and (2- chloromethoxyethyl)trimethylsilane (2.2 mL, 12.3 mmol). The reaction was stirred at rt for 3 h and then was diluted with EtOAc (10 mL), washed with 1 M HCl (2 × 10 mL) and 50% saturated aqueous NaHCO3 solution. The organic phase was dried over MgSO4 filtered and concentrated to give the crude title compound (1.00 g) as a yellow oil, which was used directly in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.90 (s, 2H), 3.59 (dd, J = 8.7, 7.7 Hz, 2H), 2.58 (s, 2H), 1.34 (s, 6H), 0.91-0.95 (m, 2H), 0.01-0.02 (m, 9H). 4-Bromo-3,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyr rolidine-2,5-dione To a solution of 3,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolidine -2,5- dione (200 mg, 777 µmol) in THF (4.90 mL) at –78 °C was slowly added lithium bis(trimethylsilyl)amide solution (1.6 mL, 1.55 mmol) and the mixture was stirred for 1 h and then N-bromosuccinimide (154 mg, 855 µmol) was added under nitrogen. The cooling bath was removed, and the solution was stirred at rt for 2 h. The reaction was quenched with water (1 mL) and washed with saturated aqueous Na2S2O4 (1 mL). The organic layer was then dried over MgSO4, filtered, and concentrated to give the title compound (231 mg, 88%) as an orange oil which was directly used in the next step. MS (ESI): mass calcd. for C ₁₂ H ₂₂ BrNO ₃ Si: 335.06, found: 206.2 [M+H-SEM] ⁺ . tert-Butyl ((1s,4s)-4-((4,4-dimethyl-2,5-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)pyrrolidin-3-yl)oxy)cyclohexyl )carbamate tert-Butyl (cis-4-hydroxycyclohexyl)carbamate (168 mg, 756 µmol) was dissolved in anhydrous DMF (4.1 mL) and sodium hydride 60% dispersion in mineral oil (30.2 mg, 756 µmol) was added. The mixture was stirred at rt for 5 min and 4-bromo-3,3-dimethyl-1-((2- (trimethylsilyl)ethoxy)methyl)pyrrolidine-2,5-dione (231 mg, 687 µmol) in DMF (4.1 mL) was added. The reaction was stirred at rt for 1 h and quenched with water (10 mL), diluted with EtOAc (10 mL) and washed with water (2 × 10 mL). The combined aqueous phase was extracted with EtOAc (10 mL). The combined organic phase was then dried over MgSO4, filtered, and concentrated onto silica gel and purified by silica gel column chromatography (0-100% EtOAc/Heptanes) to provide the title compound (116 mg, 36%). MS (ESI): mass calcd. for C23H42N2O6Si: 470.28, found: 471.2 [M+H] ⁺ . 1-Butyl-3-((1s,4s)-4-((4,4-dimethyl-2,5-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)pyrrolidin-3-yl)oxy)cyclohexyl )urea A solution of tert-butyl ((1s,4s)-4-((4,4-dimethyl-2,5-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)pyrrolidin-3-yl)oxy)cyclohexyl )carbamate (111 mg, 236 µmmol) in formic acid (1.1 mL, 28.1 mmol) was stirred at rt for 1.5 h. The reaction was diluted with toluene (200 µL) and concentrated. The residue was redissolved in DCM (1.1 mL) and DIPEA (205 µL, 1.18 mmol) was added followed by butyl isocyanate (29.8 µL, 259 µmol). The reaction was stirred at rt for 1 h, concentrated onto silica gel and purified by silica gel column chromatography (0-100% EtOAc/Heptanes) to give the title compound (76.0 mg, 69%) as a colorless oil. MS (ESI): mass calcd. for C ₂₃ H ₄₃ N3O ₅ Si: 469.69, found: 514.3 [M-H+formate]-. 1-Butyl-3-((1s,4s)-4-((4,4-dimethyl-2,5-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)pyrrolidin-3-yl)oxy)cyclohexyl )pyrimidine- 2,4,6(1H,3H,5H)-trione 1-Butyl-3-((1s,4s)-4-((4,4-dimethyl-2,5-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)pyrrolidin-3-yl)oxy)cyclohexyl )urea (66.0 mg, 141 µmol) and malonic acid (17.0 mg, 162 µmol) were dissolved in AcOH (281 µL). The reaction was heated to 60 °C, acetic anhydride (53.1 µL, 562 µmol) was added. The reaction was sealed and heated at 90 °C for 1 h then was diluted with EtOAc (2 mL), washed with water (2 × 2mL) and brine (1 mL). The organic phase was dried over MgSO ₄ , filtered, and concentrated to give the crude title compound as a yellow oil. MS (ESI): mass calcd. for C26H43N3O7Si: 537.72, found: 536.3 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((4,4-dimethyl-2,5 -dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)pyrrolidin-3-yl)oxy)cyclohexyl )pyrimidine- 2,4,6(1H,3H,5H)-trione 1-Butyl-3-((1s,4s)-4-((4,4-dimethyl-2,5-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)pyrrolidin-3-yl)oxy)cyclohexyl )pyrimidine-2,4,6(1H,3H,5H)- trione (75.6 mg, 141 µmol), cyanamide (17.9 mg, 422 µmol) and nickel(II) acetylacetonate (10.8 mg, 42.2 µmol) were put in a vial and THF (760 µL) was added. The vial was sealed and was stirred at 85 °C for 10 h. The reaction was concentrated, redissolved in DCM, filtered with a syringe filter and concentrated to give the crude title compound as an orange oil, which was used directly in the next step. MS (ESI): mass calcd. for C27H45N5O7Si: 579.76, found: 578.4 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((1-(hydroxymethyl )-4,4-dimethyl-2,5- dioxopyrrolidin-3-yl)oxy)cyclohexyl)pyrimidine-2,4,6(1H,3H,5 H)-trione To 1-butyl-5-(diaminomethylene)-3-((1s,4s)-4-((4,4-dimethyl-2,5 -dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)pyrrolidin-3-yl)oxy)cyclohexyl )pyrimidine-2,4,6(1H,3H,5H)- trione (81.5 mg, 141 µmol) in DCM (500 µL) was added TFA (500 µL) and the solution was stirred for 2 h and then concentrated. The residue was dissolved in DMSO (1 mL) and directly purified by reverse phase HPLC (25-45% MeCN/NH ₄ HCO ₃ 10 mM buffer) to give the title compound as a white solid. MS (ESI): mass calcd. for C22H33N5O7: 479.53, found: 478.2 [M-H]- 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((4,4-dimethyl-2,5 -dioxopyrrolidin-3- yl)oxy)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (274) 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((1-(hydroxymethyl )-4,4-dimethyl-2,5- dioxopyrrolidin-3-yl)oxy)cyclohexyl)pyrimidine-2,4,6(1H,3H,5 H)-trione (67.4 mg, 141 µmol) was dissolved in MeCN (5 mL), water (5.00 mL) and 28% ammonia solution (100 µL, 2.57 mmol) were added. The mixture was stirred for 18 h and diluted with water (2 mL) and lyophilized. The residue was then purified by reverse phase HPLC (25-45% MeCN/NH ₄ HCO ₃ 10 mM) to give the title compound (274) (5.0 mg, 7.9%) as a colorless powder. MS (ESI): mass calcd. for C21H31N5O6: 449.50, found: 448.4 [M-H]-. ¹ H NMR (400 MHz, CD3OD) δ ppm 5.10 (s, 1H), 4.09 (s, 1H), 3.82 – 3.89 (m, 2H), 2.70 – 2.86 (m, 2H), 2.02 (d, J = 12.3 Hz, 2H), 1.69 (t, J = 14.0 Hz, 2H), 1.56 (dt, J = 20.9, 7.5 Hz, 2H), 1.46 (d, J = 3.8 Hz, 4H), 1.41 (s, 1H), 1.34 (dd, J = 15.1, 7.4 Hz, 2H), 1.18 – 1.23 (m, 3H), 0.95 (t, J = 7.4 Hz, 3H). Example 278 was synthesized from Example 100 through alkylation with 2-bromoethanol, K ₂ CO ₃ in DMSO at 50 °C. Examples 284 and 295 were obtained through chiral separation of Example 278. Example 297.1-((5S,7s,10S)-1-Benzyl-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-butyl-5-(diaminomethylene)pyrimidin e- 2,4,6(1H,3H,5H)-trione (297) Synthetic scheme: 1-((5S,7s,10S)-1-Benzyl-3-methyl-2,4-dioxo-1,3-diazadispiro[ 4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3- butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (297) To a solution of 1-butyl-5-(diaminomethylene)-3-(2-methyl-1,3-dioxo-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (60 mg, 0.13 mmol) in DMF (1 mL) was added K ₂ CO ₃ (37.14 mg, 0.27 mmol) at 20 °C. The reaction was cooled to 0 °C and bromo methylbenzene (22.98 mg, 0.13 mmol) was added. After stirring for 24 h at 20 °C, the reaction was added EtOAc (15 mL) and H2O (5 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (H ₂ O (10 mM NH ₄ HCO ₃ )/ACN; gradient 30- 70%) and re-purified by SFC column: REGIS (s,s) WHELK-O1 (250 mm*30 mm, 5 um; CO ₂ -MeOH (0.1% NH ₃ H ₂ O); 50% isocratic elution) to provide the title compound (297) (19.6 mg, 27%) as a white solid. MS (ESI): mass calcd. for C ₂₈ H ₃₆ N ₆ O ₅ : 536.27, found: 537.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.51 (s, 2H), 7.23-7.40 (m, 7H), 4.50-4.79 (m, 3H), 3.71 (t, J = 7.2 Hz, 2H), 2.91 (s, 3H), 2.44 (d, J = 10.8 Hz, 1H), 2.1-2.25 (m, 6H), 1.70 (s, 1H), 1.13-1.48 (m, 8H), 0.86 (t, J = 7.2 Hz, 3H). Example 296 was synthesized in similar procedures as described in Example 297. Example 298 was synthesized from 8-Methyl-1,4-dioxaspiro[4.5]decane-8-methanamine in similar procedures as described in Examples 267 and 268. Examples 299 and 300 were synthesized in similar procedures as described in Example 270. Example 301 was synthesized in similar procedures as described in Examples 158 and 159 starting from 1-(tert-butyl) 3-methyl 3-aminoazetidine-1,3-dicarboxylate. Malonyl dichloride was used to form the pyrimidine-2,4,6-trione and the final deprotection of the Boc and SEM groups was completed using TFA/H2O followed by K2CO3 in MeOH. Example 302.2-(10-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahyd ropyrimidin- 1(2H)-yl)-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-1-yl)acetamide (302) Synthetic scheme: NH NH ₂ NH _{2 2} H H ^2N O O H ₂ N O O 2N O O SEM S _EM Ts SEM H O N N O CN N _{2 2} O N O N O N N N N ^N Cs ₂ CO ₃ , 50 ^o C N N O K ₂ CO ₃ O O _H O O O NH ₂ CN O NH ₂ H ₂ N O O TFA, H ₂ O NH O N N N O O NH ₂ O 2-(10-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropy rimidin-1(2H)-yl)-2,4- dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[ 4.1.5 ⁷ .1 ⁵ ]tridecan-1- yl)acetonitrile The starting material 1-butyl-5-(diaminomethylene)-3-(2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione was synthesized using a similar procedure to the scheme described in Example 344. To a solution of 1-butyl-5-(diaminomethylene)-3-(2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (200 mg, 0.36 mmol) and cyanomethyl 4-methylbenzenesulfonate (113 mg, 0.53 mmol) in DMF (2 mL) was added Cs2CO3 (232 mg, 0.71 mmol). The mixture was stirred at 50 °C for 16 h. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine, dried with Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9 : 1 to 7 : 3) to give the title compound (302) (80 mg, 37%) as a white solid. MS (ESI): mass calcd. for C ₂₈ H ₄₃ N ₇ O ₆ Si: 601.30, found: 602.3 [M+H] ⁺ . 2-[10-[3-Butyl-5-(diaminomethylene)-2,4,6-trioxo-hexahydropy rimidin-1-yl]-1,3-dioxo- 2-(2-trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-4-yl]acetamide To a solution of 2-[10-[3-butyl-5-(diaminomethylene)-2,4,6-trioxo- hexahydropyrimidin-1-yl]-1,3-dioxo-2-(2-trimethylsilylethoxy methyl)-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ] tridecan-4-yl]acetonitrile (80 mg, 0.13 mmol) and K ₂ CO ₃ (37 mg, 0.27 mmol) in DMSO (2 mL) was added H2O2 (38 μL, 30% in water, 0.40 mmol) under N2. After stirring at 25 °C for 1 h, the reaction was quenched with saturated Na2SO3 (10 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (83 mg) as a white solid. MS (ESI): mass calcd. for C28H45N7O7Si: 619.31, found: 592.3 [M-28+H] ⁺ . 2-[10-[3-Butyl-5-(diaminomethylene)-2,4,6-trioxo-hexahydropy rimidin-1-yl]-1,3-dioxo- 2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-4-yl]acetamide A solution of 2-[10-[3-butyl-5-(diaminomethylene)-2,4,6-trioxo-hexahydropy rimidin- 1-yl]-1,3-dioxo-2-(2-trimethylsilylethoxymethyl)-2,4-diazadi spiro[4.1.5 ⁷ .1 ⁵ ] tridecan-4- yl]acetamide (82 mg, 0.13 mmol) in TFA (1 mL) and H ₂ O (0.2 mL) was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and K2CO3 (110 mg, 0.80 mmol) was added. After stirring at 25 °C for 0.5 h, the reaction was filtered and purified by reverse phase HPLC (H2O (0.2% FA)-ACN; gradient 10-45%) to provide the title compound (302) (30 mg, 45.4%) as a white solid. MS (ESI): mass calcd. for C22H31N7O6: 489.23, found: 490.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.75-10.79 (m, 1H), 9.54 (s, 2H), 7.60 (s, 1H), 7.32 (s, 2H), 7.19 (s, 1H), 4.58-4.67 (m, 1H), 3.85-3.95 (m, 2H), 3.73 (t, J = 7.6 Hz, 2H), 2.20-2.36 (m, 5H), 2.12-2.15 (m, 2H), 1.75-1.79 (m, 1H), 1.38-1.45 (m, 5H), 1.22-1.29 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H). Example 303 was synthesized in similar procedures as described in Example 297, using Cs ₂ CO ₃ , isopropyl iodide and heating at 50 °C for 3 days. Examples 305 and 306.1-Butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-ethyl-1-(o xetan- 3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (305) and 1-Butyl-5-(diaminomethylene)-3-((5R,7r,10R)-3-ethyl- 1-(oxetan-3-ylmethyl)-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (306) Synthetic scheme: 1-Butyl-5-(diaminomethylene)-3-(1,3-dioxo-2,4-diazadispiro[4 .1.5 ⁷ .1 ⁵ ]tridecan-10- yl)hexahydropyrimidine-2,4,6-trione 1-butyl-5-(diaminomethylene)-3-[1,3-dioxo-2-(2-trimethylsily lethoxymethyl)-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (220 mg, 0.39 mmol) was added to a solution of TFA (2.20 mL, 29.6 mmol) and H2O (0.88 mL). After stirring at 25 °C for 2 h, the reaction was concentrated under reduced pressure. The residue was dissolved with MeOH (2.2 mL) and K ₂ CO ₃ (396 mg, 2.87 mmol) was added. After another 2 h of stirring at 25 °C, the reaction mixture was adjusted to pH = 5-6 with aqueous citric acid and extracted with EtOAc (5 mL x 2). The combined organic layer was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to provide the title compound (167 mg, 99%) as a light yellow solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C20H28N6O5: 432.21, found: 433.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(2-ethyl-1,3-dioxo-2,4-diazad ispiro[4.1.5 ⁷ .1 ⁵ ]tridecan- 10-yl)hexahydropyrimidine-2,4,6-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(1,3-dioxo-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (197 mg, 0.45 mmol) in DMF (2 mL) was added K2CO3 (126 mg, 0.91 mmol) and iodoethane (0.04 mL, 0.50 mmol). After stirring at 25 °C for 16 h under N ₂ , the reaction was quenched by H ₂ O (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO ₂ , petroleum ether : ethyl acetate =1 : 2) to give the title compound (148 mg, 71%) as a white solid. MS (ESI): mass calcd. for C ₂₂ H ₃₂ N ₆ O ₅ : 460.24, found: 461.4 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-((5S,7s,10S)-3-ethyl-1-(oxeta n-3-ylmethyl)-2,4-dioxo- 1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (305) and 1- Butyl-5-(diaminomethylene)-3-((5R,7r,10R)-3-ethyl-1-(oxetan- 3-ylmethyl)-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (306) To a solution of 1-butyl-5-(diaminomethylene)-3-(2-ethyl-1,3-dioxo-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (125 mg, 0.27 mmol) in DMF (1.5 mL) was added Cs ₂ CO ₃ (177 mg, 0.54 mmol) and 3-(iodomethyl)oxetane (59.1 mg, 0.30 mmol). The mixture was stirred at 40 °C for 16 h. After completion, the reaction was quenched by addition of H ₂ O (20 mL). The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (H2O (10 mM NH4HCO3)-ACN; gradient 30-60% to provide the racemic product, which was purified by SFC to provide Example 305: MS (ESI): mass calcd. for C26H38N6O6: 530.29, found: 531.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.59-4.65 (m, 3H), 4.40-4.44 (m, 2H), 3.61-3.78 (m, 4H), 3.33-3.41 (m, 2H), 2.22-2.52 (m, 5H), 2.10-2.20 (m, 3H), 1.84 (d, J = 11.2 Hz, 1H), 1.33-1.50 (m, 5H), 1.17-1.33 (m, 3H), 1.06 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). Example 306: MS (ESI): mass calcd. for C26H38N6O6: 530.29, found: 531.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.31 (s, 2H), 4.59-4.65 (m, 3H), 4.40-4.44 (m, 2H), 3.61-3.78 (m, 4H), 3.33-3.41 (m, 2H), 2.22-2.52 (m, 5H), 2.10-2.20 (m, 3H), 1.84 (d, J = 11.2 Hz, 1H), 1.33-1.50 (m, 5H), 1.17-1.33 (m, 3H), 1.06 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned. Examples 309, 310, 311 and 323 were synthesized in similar procedures to those described in Examples 305 and 306. Examples 307 and 308 were synthesized through chiral separation of Example 153. Example 312 was synthesized in similar procedures to those described in Example 246. Examples 313 and 314 were synthesized by chiral SFC separation of Example 275. Examples 315 and 316.1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-(hydroxymethyl )-4- ((2-oxo-1,2-dihydropyridin-3-yl)methyl)cyclohexyl)pyrimidine -2,4,6(1H,3H,5H)-trione (315) and 1-Butyl-5-(diaminomethylene)-3-((1r,4r)-4-(hydroxymethyl)-4- ((2-oxo-1,2- dihydropyridin-3-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H ,5H)-trione (316) Synthetic scheme:

3-(Bromomethyl)-2-methoxy-pyridine To a mixture of (2-methoxy-3-pyridyl) methanol (5.00 g, 35.9 mmol) and PPh ₃ (14.1 g, 53.9 mmol) in DCM (50 mL) was added CBr4 (14.3 g, 43.1 mmol) in DCM (50 mL) at 0 °C under N2. After stirring at 25 °C for 3 h, the reaction was poured into water (50 mL) and extracted with ethyl acetate (50 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 silica gel column chromatography (petroleum ether : ethyl acetate = 100 : 1 to 5 : 1) to give the title compound (4.63 g, 64% yield) as a colorless oil. MS (ESI): mass calcd. for C ₇ H ₈ BrNO: 200.98, found: 202.0 [M+H] ⁺ . Methyl 8-[(2-methoxy-3-pyridyl) methyl]-1,4-dioxaspiro[4.5]decane-8-carboxylate To a mixture of methyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (4.10 g, 20.5 mmol) in THF (80 mL) was added dropwise LDA (2 M, 15.4 mL) at –78 °C under N ₂ . After stirring for 30 min, 3-(bromomethyl)-2-methoxy-pyridine (4.55 g, 22.5 mmol) was added dropwise at –78 °C and the reaction was allowed to proceed for 4 h at –78 °C. After completion, the mixture was poured into saturated aqueous NH ₄ Cl (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 100 : 1 to 5 : 1) to afford the title compound (3.15 g, 48% yield) as a colorless oil. MS (ESI): mass calcd. for C ₁₇ H ₂₃ NO ₅ : 321.16, found: 322.1 [M+H] ⁺ . Methyl 1-[(2-methoxy-3-pyridyl) methyl]-4-oxo-cyclohexanecarboxylate To a mixture of methyl 8-[(2-methoxy-3-pyridyl)methyl]-1,4-dioxaspiro[4.5]decane- 8-carboxylate (3.15 g, 9.80 mmol) in acetone (20 mL) and H ₂ O (10 mL) was added TsOH•H2O (3.73 g, 19.6 mmol) in one portion at 25 °C under N2. After heating at 50 °C for 5 h, the reaction was quenched with saturated aqueous NaHCO3 (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 to give the title compound (2.62 g 96%) as a colorless oil, which was used directly to the next step without purification. MS (ESI): mass calcd. for C ₁₅ H ₁₉ NO ₄ : 277.13, found: 278.2 [M+H] ⁺ . Methyl 4-amino-1-[(2-methoxy-3-pyridyl)methyl]cyclohexanecarboxylat e To a mixture of methyl 1-[(2-methoxy-3-pyridyl)methyl]-4-oxo- cyclohexanecarboxylate (2.60 g, 9.38 mmol) and NH4OAc (14.5 g, 188 mmol) in MeOH (30 mL) was added NaBH(OAc) ₃ (4.97 g, 23.4 mmol) in one portion at 25 °C under N ₂ . After stirring at 25 °C for 12 h, the reaction was poured into saturated aqueous NaHCO3 (30 mL) and extracted with ethyl acetate (20 mL x 5). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (2 g, 77%) as a colorless oil, which was used directly in the next step without purification. MS (ESI): mass calcd. for C15H22N2O3: 278.16, found: 279.1 [M+H] ⁺ . Methyl 4-(butylcarbamoylamino)-1-[(2-methoxy-3- pyridyl)methyl]cyclohexanecarboxylate To a mixture of methyl 4-amino-1-[(2-methoxy-3- pyridyl)methyl]cyclohexanecarboxylate (2.00 g, 7.19 mmol) and 1-isocyanatobutane (0.71 g, 7.19 mmol) in DCM (20 mL) was added triethylamine (1.00 mL, 7.19 mmol) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C for 30 min. After completion, the reaction was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 50 : 1 to 1 : 1) to give the title compound (1.3 g, 48%) as a white solid. MS (ESI): mass calcd. for C20H31N3O4: 377.23, found: 378.2 [M+H] ⁺ . Methyl 4-(3-butyl-2,4,6-trioxo-hexahydropyrimidin-1-yl)-1-[(2-metho xy-3- pyridyl)methyl]cyclohexanecarboxylate To a mixture of methyl 4-(butylcarbamoylamino)-1-[(2-methoxy-3- pyridyl)methyl]cyclohexanecarboxylate (1.0 g, 2.65 mmol) and malonic acid (0.28 g, 2.65 mmol) in AcOH (10 mL) was added Ac ₂ O (1.74 g, 18.5 mmol) in one portion at 25 °C under N2. After heating at 80 °C for 6 h, the reaction was poured into H2O (20 mL) and was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, petroleum ether : ethyl acetate = 50 : 1 to 1 : 1) to give the title compound (1.0 g, 85%) as a white solid. MS (ESI): mass calcd. for C ₂₃ H ₃₁ N ₃ O ₆ : 445.22, found: 446.2 [M+H] ⁺ . Methyl 4-[3-butyl-5-(diaminomethylene)-2,4,6-trioxo-hexahydropyrimi din-1-yl]-1-[(2- methoxy-3-pyridyl)methyl]cyclohexanecarboxylate To a mixture of methyl 4-(3-butyl-2,4,6-trioxo-hexahydropyrimidin-1-yl)-1-[(2- methoxy-3-pyridyl)methyl]cyclohexanecarboxylate (1.0 g, 2.24 mmol) and cyanamide (0.94 g, 22.4 mmol) in THF (10 mL) was added Ni(acac)2 (0.17 g, 0.67 mmol) in one portion at 25 °C under N2. After heating at 80 °C for 12 h, the reaction was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 50 : 1 to 0 : 1) to give the title compound (0.57 g, 52%) as a white solid. MS (ESI): mass calcd. for C24H33N5O6: 487.24, found: 488.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-[4-(hydroxymethyl)-4-[(2-meth oxy-3- pyridyl)methyl]cyclohexyl]hexahydropyrimidine-2,4,6-trione To a mixture of methyl 4-[3-butyl-5-(diaminomethylene)-2,4,6-trioxo- hexahydropyrimidin-1-yl]-1-[(2-methoxy-3-pyridyl)methyl]cycl ohexanecarboxylate (0.52 g, 1.07 mmol) in THF (5 mL) was added LiBH4 (2 M in THF, 1.07 mL) at 0 °C under N2. The reaction was warmed to 25 °C and allowed to proceed for 12 h. After completion, the mixture was poured into saturated aqueous NH ₄ Cl (5 mL) and extracted with ethyl acetate (20 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 silica gel column chromatography (petroleum ether : ethyl acetate = 50 : 1 to 1 : 1) to give the title compound (0.39 g, 80%) as a white solid. MS (ESI): mass calcd. for C23H33N5O5: 459.25, found: 460.2 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(4-(hydroxymethyl)-4-((2-oxo- 1,2-dihydropyridin-3- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (Example 304) To a mixture of 1-butyl-5-(diaminomethylene)-3-[4-(hydroxymethyl)-4-[(2-meth oxy- 3-pyridyl)methyl]cyclohexyl]hexahydropyrimidine-2,4,6-trione (0.39 g, 0.84 mmol) and LiCl (0.18 g, 4.24 mmol) in DMF (5 mL) was added PTSA (0.73 g, 4.24 mmol) at 25 °C under N2. The reaction was stirred at 120 °C for 1 hr. After completion, the reaction was poured into H2O (20 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 reduced pressure. The residue was purified by reverse phase HPLC (H ₂ O (10 mM NH ₄ HCO ₃ )-ACN, gradient 10-40%) to give the title compound (0.2 g, 53%) as a white solid. MS (ESI): mass calcd. for C22H31N5O5: 445.23, found: 446.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (s, 1H), 9.57 (s, 2H), 7.30-7.38 (m, 3H), 7.26-7.28 (m, 1H), 6.23-6.30 (m, 1H), 5.21- 5.40 (m, 1H), 4.66-4.71 (m, 1H), 3.73-3.81 (m, 2H), 2.82 (d, J = 6.8 Hz, 2H), 2.64-2.75 (m, 2H), 2.59-2.64 (m, 2H), 1.44-1.57 (m, 4H), 1.36 (d, J = 10.8 Hz, 2H), 1.24-1.30 (m, 2H), 1.01-1.15 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-(hydroxymethyl)-4- ((2-oxo-1,2- dihydropyridin-3-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H ,5H)-trione (315) and 1- Butyl-5-(diaminomethylene)-3-((1r,4r)-4-(hydroxymethyl)-4-(( 2-oxo-1,2-dihydropyridin- 3-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (316) 1-Butyl-5-(diaminomethylene)-3-(4-(hydroxymethyl)-4-((2-oxo- 1,2-dihydropyridin- 3-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione was separated by chiral SFC column: DAICEL CHIRALPAK IG (250mm*30mm,10 um; CO ₂ -IPA (0.1% NH ₃ H ₂ O); 40% isocratic elution) to give the title compounds (315) (9.4 mg) and (316) (121 mg) as white solids. Example 315: MS (ESI): mass calcd. for C22H31N5O5: 445.23, found: 446.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (s, 1H), 9.54 (s, 2H), 7.39 (s, 2H), 7.31-7.36 (m, 2H), 6.24 (t, J = 6.8 Hz, 1H), 5.22 (t, J = 6.8 Hz, 1H), 4.61-4.72 (m, 1H), 3.71-3.76 (m, 2H), 3.20-3.24 (m, 2H), 2.36-2.43 (m, 2H), 2.34 (s, 2H), 1.59 (d, J = 12.8 Hz, 2H), 1.42-1.48 (m, 2H), 1.20-1.29 (m, 6H), 0.87 (t, J = 7.2 Hz, 3H). Example 316: MS (ESI): mass calcd. for C ₂₂ H ₃₁ N ₅ O ₅ : 445.23, found: 446.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 9.56 (s, 2H), 7.30-7.45 (m, 3H), 7.27 (dd, J = 6.8, 1.6 Hz, 1H), 6.29 (t, J = 6.8 Hz, 1H), 5.38 (t, J = 6.8 Hz, 1H), 4.60-4.79 (m, 1H), 3.73-3.81 (m, 2H), 2.82 (d, J = 6.4 Hz, 2H), 2.64- 2.74 (m, 2H), 2.60-2.64 (m, 2H), 1.43-1.56 (m, 4H), 1.36 (d, J = 10.8 Hz, 2H), 1.23-1.30 (m, 2H), 1.03-1.13 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned. Examples 319, 328, 329, and 330 were synthesized in similar procedures as described in Examples 315 and 316. Examples 317, 321, and 322 were synthesized in similar procedures to those described in Examples 160 and 161. Examples 318 and 324.1-Butyl-5-(diaminomethylene)-3-(3-ethyl-1-(2-hydroxyethy l)-2,4- dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (318) and 1-Butyl-5-(diaminomethylene)-3-(3-ethyl-1-(2-hydroxyethyl)-2 ,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (324) Synthetic scheme:

1-Butyl-3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-et hyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-5-(diaminomethylene)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-5-(diaminomethylene)-3-(2-ethyl-1,3-dioxo-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)hexahydropyrimidine-2,4,6-trione (120 mg, 0.26 mmol) in DMF (1 mL) was added Cs2CO3 (170 mg, 0.52 mmol) and tert-butyl-(2-iodoethoxy)- dimethyl-silane (82 mg, 0.29 mmol) at 20 °C. The reaction was heated to 40 °C for 16 h and partitioned between H ₂ O (5 mL) and EtOAc (8 mL). The organic phase was separated, 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 (30 mg, 19%) as a white solid. MS (ESI): mass calcd. for C ₃₀ H ₅₀ N ₆ O ₆ Si: 618.36, found: 619.4 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(3-ethyl-1-(2-hydroxyethyl)-2 ,4-dioxo-1,3-diazadispiro [4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-butyl-3-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-ethyl -1,3- dioxo-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl]-5-(diaminomethylene)hexahydropyrimidi ne- 2,4,6-trione (30 mg, 0.048 mmol) in THF (0.5 mL) was added TBAF (1 M, 0.048 mL) at 20 °C. The reaction was stirred at 20 °C for 0.5 h and partitioned between EtOAc (5 mL) and H ₂ O (5 mL). The organic phase was separated, washed with H ₂ O (5 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (25 mg, crude) as a colorless oil, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C ₂₄ H ₃₆ N ₆ O ₆ : 504.27, found: 505.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(3-ethyl-1-(2-hydroxyethyl)-2 ,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (318) and 1- Butyl-5-(diaminomethylene)-3-(3-ethyl-1-(2-hydroxyethyl)-2,4 -dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (324) 1-Butyl-5-(diaminomethylene)-3-[2-ethyl-4-(2-hydroxyethyl)-1 ,3-dioxo-2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (35 mg) was further separated by SFC column: DAICEL CHIRALPAK IC (250 mm*30 mm,10 um; CO2-IPA (0.1%NH ₃ H ₂ O); 40%, isocratic elution) to give the title compounds (318) (4.17 mg) and (324) (5.89 mg) as white solids. Example 318: MS (ESI): mass calcd. for C ₂₄ H ₃₆ N ₆ O ₆ : 504.27, found: 505.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.30 (s, 2H), 4.90 (t, J = 6.0 Hz, 1H), 4.59-4.68 (m, 1H), 3.71-3.76 (m, 2H), 3.58-3.64 (m, 2H), 3.35- 3.41 (m, 4H), 2.10-2.47 (m, 7H), 1.84 (d, J = 12.4 Hz, 1H), 1.33-1.49 (m, 5H), 1.19-1.29 (m, 3H), 1.07 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). Example 324: MS (ESI): mass calcd. for C24H36N6O6: 504.27, found: 505.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.30 (s, 2H), 4.90 (t, J = 5.8 Hz, 1H), 4.59-4.68 (m, 1H), 3.71-3.76 (m, 2H), 3.58- 3.64 (m, 2H), 3.36-3.40 (m, 4H), 2.10-2.47 (m, 7H), 1.84 (d, J = 12.4 Hz, 1H), 1.33-1.49 (m, 5H), 1.19-1.29 (m, 3H), 1.07 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). Examples 320 and 342 were synthesized in similar procedures as described in Example 297, using 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of benzyl bromide. Example 326 and 327.1-Butyl-5-(diaminomethylene)-3-((1r,4r)-4-(hydroxymethyl )-4- ((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)cy clohexyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (326) and 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4- (hydroxymethyl)-4-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)- yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (327) Synthetic scheme: O O N O O OEt O ^OEt O _{LiAl O} ^OH HN Ph O O BOMCl _H4 O TsOH.H O O N ₂ N O O O _O DIAD, PPh ₃ ^O N Ph N Ph LDA OBn OBn O O O O OBn OBn O O O NH ₄ OAc O O O O O NaBH(OAc) ₃ N n-BuNCO N Cl Cl O N cyanamide N Ph N Ph N Ph HN O N bis[(Z)-1-methyl-3-oxo-but-1- H ₂ N O O O HN enoxy]nickel OBn OBn N OBn n-Bu O n-Bu O O O O O NH ₂ O NH ₂ NH ₂ NH ₂ H ₂ N O N BCl ₃ H ₂ N O NH SFC separation H ₂ N O NH H ₂ N O NH N Ph N N N O N O O N O O N O O N O N OBn N OH N OH N OH n-Bu O O O O Example 325 326 327 Ethyl 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate To a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (25.0 g, 117 mmol) in THF (250 mL) was added dropwise LDA (2 M, 117 mL) at 0 °C. After stirring at 0 °C for 30 min, chloromethoxymethylbenzene (21.9 g, 140 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (25.5 g, 65%) as a yellow oil. MS (ESI): mass calcd. for C ₁₉ H ₂₆ O ₅ : 334.18, found: 335.1 [M+H] ⁺ . [8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl]methanol To a solution of ethyl 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (20.92 g, 62.6 mmol) in THF (290 mL) was added dropwise LiAlH4 (2.5 M, 30.0 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 2 h. The reaction was carefully quenched with dropwise addition of H ₂ O (2.85 mL), followed by aqueous NaOH (15%, 2.85 mL), and H2O (8.55 mL). The mixture was filtered to remove the resulting precipitate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (18 g, 90%) as a yellow oil. MS (ESI): mass calcd. for C17H24O4: 292.17, found: 293.2 [M+H] ⁺ . 3-Benzoyl-1-[[8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8 -yl]methyl]-5-methyl- pyrimidine-2,4-dione To a solution of [8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl]methanol (5.71 g, 19.6 mmol), 3-benzoyl-5-methyl-1H-pyrimidine-2,4-dione (3.00 g, 13.0 mmol) and PPh ₃ (6.84 g, 26.1 mmol) in THF (100 mL) was added DIAD (5.27 g, 26.1 mmol) dropwise at 0 °C. The resulting mixture was heated to 50 °C for 16 h. The mixture was poured into H ₂ O (100 mL) and extracted with EtOAc (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 reverse phase HPLC (mobile phase: H2O (10 mM NH4HCO3)- ACN; gradient:45-75%) to give the title compound (2.87 g, 44%) as a white solid. MS (ESI): mass calcd. for C29H32N2O6: 504.23, found: 505.3 [M+H] ⁺ . 3-Benzoyl-1-[[1-(benzyloxymethyl)-4-oxo-cyclohexyl]methyl]-5 -methyl-pyrimidine-2,4- dione To a solution of 3-benzoyl-1-[[8-(benzyloxymethyl)-1,4-dioxaspiro[4.5] decan-8- yl]methyl]-5-methyl-pyrimidine-2,4-dione (2.50 g, 4.95 mmol) in acetone (50 mL) and H ₂ O (25 mL) was added TsOH•H ₂ O (1.88 g, 9.91 mmol). The mixture was stirred at 25 °C for 12 h, poured into saturated NaHCO3 (50 mL), and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (2.2 g, 96%) as a white solid, which was used directly in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.89-7.92 (m, 2H), 7.68-7.71 (m, 1H), 7.48-7.51 (m, 2H), 7.37-7.40 (m, 5H), 7.28 (d, J =1.2 Hz, 1H), 4.58 (s, 2H), 3.96 (s, 2H), 3.41 (s, 2H), 2.48-2.54 (m, 2H), 2.21-2.32 (m, 2H), 1.84-1.89 (m, 5H), 1.71-1.82 (m, 2H). 1-[[4-Amino-1-(benzyloxymethyl)cyclohexyl]methyl]-5-methyl-p yrimidine-2,4-dione To a solution of 3-benzoyl-1-[[1-(benzyloxymethyl)-4-oxo-cyclohexyl]methyl]-5 - methyl-pyrimidine-2,4-dione (2.20 g, 4.78 mmol) and NH4OAc (7.36 g, 95.6 mmol) in MeOH (40 mL) was added NaBH(OAc)3 (2.53 g, 11.9 mmol). The reaction was stirred at 25 °C for 12 h, poured into water (50 mL), and extracted with DCM : i-PrOH (10 : 1, 100 mL x 2). The combined organic phase was washed with brine, dried with Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (1.4 g, crude) as a white solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C ₂₇ H ₃₁ N ₃ O ₄ : 461.23, found: 462.3 [M+H] ⁺ . 1-[4-[(3-Benzoyl-5-methyl-2,4-dioxo-pyrimidin-1-yl)methyl]-4 -(benzyloxymethyl) cyclohexyl]-3-butyl-urea To a solution of 1-[[4-amino-1-(benzyloxymethyl)cyclohexyl] methyl]-3-benzoyl-5- methyl-pyrimidine-2,4-dione (1.4 g, 3.03 mmol) and triethylamine (0.63 mL, 4.55 mmol) in DCM (20 mL) was added 1-isocyanatobutane (0.33 g, 3.34 mmol). The mixture was stirred at 25 °C for 1 h, poured into water (20 mL), and extracted with DCM (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 silica gel column chromatography (petroleum ether : ethyl acetate = 100 : 1 to 3 : 7) to give the title compound (1.4 g, 82%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.89-8.00 (m, 2H), 7.85- 7.88 (m, 1H), 7.65-7.71 (m, 1H), 7.45-7.49 (m, 3H), 7.33-7.39 (m, 5H), 7.09-7.18 (m, 1H), 4.56 (s, 2H), 3.71-3.87 (m, 2H), 3.42-3.61 (m, 1H), 3.21-3.39 (m, 2H), 3.04-3.14 (m, 2H), 1.72-1.96 (m, 6H), 1.12-1.45 (m, 9H), 0.86-0.93 (m, 3H). 1-[4-[(3-Benzoyl-5-methyl-2,4-dioxo-pyrimidin-1-yl)methyl]-4 - (benzyloxymethyl)cyclohexyl] -3-butyl-hexahydropyrimidine-2,4,6-trione To a solution of 1-[4-[(3-benzoyl-5-methyl-2,4-dioxo-pyrimidin-1-yl)methyl]-4 - (benzyloxymethyl)cyclohexyl]-3-butyl-urea (1.4 g, 2.50 mmol) in DCM (15 mL) was added propanedioyl dichloride (1.06 g, 7.49 mmol). The reaction was stirred at 25 °C for 4 h, poured into water (50 mL), and extracted with DCM (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 = 100 : 1 to 1 : 1) to give the title compound (0.84 g, 54%) as a white solid. MS (ESI): mass calcd. for C35H40N4O7: 628.29, found: 629.2 [M+H] ⁺ . 1-[4-(Benzyloxymethyl)-4-[(5-methyl-2,4-dioxo-pyrimidin-1-yl )methyl]cyclohexyl]-3- butyl-5-(diaminomethylene)hexahydropyrimidine-2,4,6-trione To a solution of 1-[4-[(3-benzoyl-5-methyl-2,4-dioxo-pyrimidin-1-yl)methyl]-4 - (benzyloxymethyl)cyclohexyl]-3-butyl-hexahydropyrimidine-2,4 ,6-trione (0.84 g, 1.34 mmol) and cyanamide (0.56 g, 13.4 mmol) in THF (10 mL) was added Ni(acac)2 (103 mg, 0.4 mmol). The mixture was heated to 80 °C for 12 h, 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 silica gel column chromatography (petroleum ether : ethyl acetate = 100 : 1 to 7 : 3) to give the title compound (0.4 g, 45%) as a white solid. MS (ESI): mass calcd. for C ₃₆ H ₄₂ N ₆ O ₇ : 670.31, found: 671.2 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-[4-(hydroxymethyl)-4-[(5-meth yl-2,4-dioxo-pyrimidin- 1-yl)methyl]cyclohexyl]hexahydropyrimidine-2,4,6-trione (Example 325) To a solution of 1-[4-[(3-benzoyl-5-methyl-2,4-dioxo-pyrimidin-1-yl)methyl]-4 - (benzyloxymethyl)cyclohexyl]-3-butyl-5-(diaminomethylene)hex ahydropyrimidine-2,4,6- trione (0.3 g, 0.45 mmol) in DCM (5 mL) was added BCl3 (1 M, 1.79 mL, 1.79 mmol) dropwise at 0 °C under N2. The reaction was stirred under N2 at 25 °C for 0.5 h, poured into saturated NaHCO ₃ (20 mL) and extracted with DCM (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (H2O (0.2% FA)-ACN; gradient 15-50%) to give the title compound (80 mg, 37%) as a white solid. MS (ESI): mass calcd. for C ₂₂ H ₃₂ N ₆ O ₆ : 476.24, found: 477.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.17 (s, 1H), 9.56 (s, 1H), 7.39 (s, 1H), 7.34 (s, 2H), 4.74-4.86 (m, 1H), 4.65-4.73 (m, 1H), 3.54-3.78 (m, 4H), 3.44-3.46 (m, 1H), 3.08 (d, J = 3.6 Hz, 2H), 2.59-2.78 (m, 1H), 2.31-2.45 (m, 1H), 1.75 (s, 3H), 1.41-1.63 (m, 4H), 1.10-1.36 (m, 6H), 0.88 (t, J = 7.2 Hz, 3H). 1-Butyl-5-(diaminomethylene)-3-((1r,4r)-4-(hydroxymethyl)-4- ((5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)methyl)cyclohexyl)pyrimidine-2,4,6 (1H,3H,5H)-trione (326) and 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-(hydroxymethyl)-4- ((5-methyl-2,4-dioxo- 3,4-dihydropyrimidin-1(2H)-yl)methyl)cyclohexyl)pyrimidine-2 ,4,6(1H,3H,5H)-trione (327) 1-Butyl-5-(diaminomethylene)-3-[4-(hydroxymethyl)-4-[(5-meth yl-2,4-dioxo- pyrimidin-1-yl)methyl]cyclohexyl]hexahydropyrimidine-2,4,6-t rione was purified by SFC: DAICEL CHIRALPAK IG (25mm*30mm,10 um); mobile phase: CO2-IPA (0.1%NH3H2O); 50% isocratic elution to give the title compounds (326) (31 mg, 39%) and (327) (38 mg, 47%) as white solids. Example 326: MS (ESI): mass calcd. for C ₂₂ H ₃₂ N ₆ O ₆ : 476.24, found: 477.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.17 (s, 1H), 9.56 (s, 2H), 7.39 (s, 1H), 7.34 (s, 2H), 4.85 (s, 1H), 4.58-4.70 (m, 1H), 3.74-3.80 (m, 4H), 3.07 (d, J = 3.6 Hz, 2H), 2.64-2.71 (m, 2H), 1.75 (s, 3H), 1.41-1.60 (m, 4H), 1.24-1.35 (m, 4H), 1.16-1.20 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). Example 327: MS (ESI): mass calcd. for C22H32N6O6: 476.24, found: 477.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.23 (s, 1H), 9.54 (s, 2H), 7.40 (s, 1H), 7.34 (s, 2H), 4.74 (t, J = 4.8 Hz, 1H), 4.62-4.69 (m, 1H), 3.73 (t, J = 7.2 Hz, 2H), 3.54 (s, 2H), 3.46 (d, J = 4.8 Hz, 2H), 2.38-2.47 (m, 2H), 1.76 (s, 3H), 1.57 (d, J = 13.2 Hz, 2H), 1.15-1.47 (m, 2H), 1.15-1.28 (m, 6H), 0.88 (t, J = 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 332 was synthesized in a similar procedure to the one described in Example 153. Malonyl dichloride was used for formation of the pyrimidine-(2,4,6)-trione Example 333.1-Butyl-3-(1-(cyclopropylmethyl)-2-oxo-1-azadispiro[4.1. 5 ⁷ .1 ⁵ ]tridecan- 10-yl)-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (333) Synthetic scheme: 8,11-Dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one oxime To a solution of NH2OH•HCl (3.54 g, 51.0 mmol) and NaOAc (5.23 g, 63.7 mmol) in EtOH (50 mL) and H ₂ O (25 mL) was added 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one (5.0 g, 25.5 mmol). The reaction was heated to 85 °C for 1 h under N ₂ . After completion, the reaction was cooled to 25 °C, quenched by addition of H2O (100 mL) and extracted with EtOAc (40 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to give the title compound (5 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ ppm 3.93-3.97 (m, 4H), 2.68 (d, J = 2.4 Hz, 2H), 2.62 (d, J = 2.4 Hz, 2H), 1.71-1.78 (m, 4H), 1.59-1.66 (m, 4H). 2-Nitro-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane To a suspension of urea hydrogen peroxide (6.68 g, 71.0 mmol) in MeCN (125 mL) was added a solution of TFAA (14.9 g, 71.0 mmol) in MeCN (62.5 mL) dropwise over 0.5 h at –10 °C. The reaction mixture was warmed to 25 °C for 1 h. A solution of 8,11- dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one oxime (5.00 g, 23.7 mmol) was added followed by disodium hydrogen phosphate (37.0 g, 260 mmol) in MeCN (125 mL) dropwise. The reaction was heated to 80 °C for 2 h, cooled to 25 °C, and filtered through a pad of celite. The filter cake was washed with MeCN (20 mL). The filtrate was diluted with EtOAc (120 mL) and washed with H2O (20 mL x 3). The combined organic layer was washed with saturated Na2SO3 (30 mL x 3), brine (60 mL), dried over 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 (1.35 g, 25%) as a white solid. ¹ H NMR (400 MHz, CDCl3) δ ppm 4.87-4.95 (m, 1H), 3.94 (s, 4H), 2.41-2.45 (m, 4H), 1.66- 1.77 (m, 4H), 1.58-1.65 (m, 4H). Ethyl 3-(2-nitro-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)propanoate To a solution of 2-nitro-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane (1.35 g, 5.94 mmol) in MeCN (14 mL) was added ethyl prop-2-enoate (0.71 g, 7.13 mmol) and DBU (0.45 g, 2.97 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h under N ₂ . The reaction was quenched by saturated aqueous NH ₄ Cl (30 mL), and extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.7 g, 87%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.10-4.17 (m, 2H), 3.93 (s, 4H), 2.67 (d, J = 14.4 Hz, 2H), 2.35-2.46 (m, 2H), 2.22-2.31 (m, 2H), 2.17 (d, J = 14.8 Hz, 2H), 1.66-1.72 (m, 4H), 1.59 (s, 3H), 1.54-1.57 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H). 11,14-Dioxa-1-azatrispiro[4.1.2.4 ¹⁰ .2 ⁷ .1 ⁵ ]heptadecan-2-one To a solution of ethyl 3-(2-nitro-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl)propanoate (1.40 g, 4.28 mmol) and NH4Cl (2.20 g, 41.1 mmol) in EtOH (14 mL) and H2O (4.5 mL) was added Fe (2.29 g, 41.1 mmol) in portions. The mixture was heated to 80 °C for 16 h under N ₂ . The reaction was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was diluted with H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 99 : 1 to 10 : 1) to give the title compound (540 mg, 45%) as a white solid. MS (ESI): mass calcd. for C ₁₄ H ₂₁ NO ₃ : 251.15, found: 252.2 [M+H] ⁺ . 1-Butyl-3-(1-(cyclopropylmethyl)-2-oxo-1-azadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (333) The title compound (333) was synthesized from 11,14-dioxa-1- azatrispiro[4.1.2.4 ¹⁰ .2 ⁷ .1 ⁵ ]heptadecan-2-one following similar procedures (steps 4-8) as described in Example 236. MS (ESI): mass calcd. for C ₂₅ H ₃₇ N ₅ O ₄ : 471.28, found: 472.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.30 (s, 2H), 4.58-4.70 (m, 1H), 3.73 (t, J = 7.2 Hz, 2H), 3.08 (d, J = 6.8 Hz, 2H), 2.29-2.42 (m, 2H), 2.00-2.23 (m, 7H), 1.81-1.93 (m, 2H), 1.68 (s, 1H), 1.32-1.49 (m, 6H), 1.20-1.30 (m, 2H), 0.92-1.01 (m, 1H), 0.88 (t, J = 7.2 Hz, 3H), 0.41-0.48 (m, 2H), 0.23-0.29 (m, 2H). Example 334.1-Butyl-5-(diaminomethylene)-3-(3-oxo-2-azadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan- 10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione Synthetic scheme: Ethyl 2-(8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-ylidene)acetate A suspension of NaH (1.53 g, 38.2 mmol, 60% in mineral oil) in THF (30 mL) under N ₂ was cooled to with 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 (5.00 g, 25.5 mmol) in THF (20 mL) was added dropwise. The reaction was heated to 25 °C for 16 h under N ₂ , 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] ⁺ . Ethyl 2-[2-(nitromethyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl]acetate To a solution of ethyl 2-(8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-ylidene)acetate (5.4 g, 20.3 mmol) in THF (54 mL) was added nitromethane (6.3 g, 103 mmol, 5.60 mL) and TBAF (1 M, 31.4 mL). The mixture was heated to 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[3.2.4 ⁷ .2 ⁴ ]tridecan-2-yl]acetate To a solution of ethyl 2-[2-(nitromethyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2- yl]acetate (4.75 g, 14.5 mmol) in EtOH (35.7 mL) and H ₂ O (11.8 mL) was added Fe (3.89 g, 69.7 mmol) and NH ₄ Cl (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 H ₂ O (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, 86%) 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[4.1.2.4 ¹⁰ .2 ⁷ .1 ⁵ ]heptadecan-2-one A mixture of ethyl 2-[2-(aminomethyl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2- yl]acetate (3.69 g, 12.4 mmol) and NaOH (0.55 g, 13.7 mmol) in H ₂ O (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, 78%) as a white solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C ₁₄ H ₂₁ NO ₃ : 251.15, found: 252.3 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(3-oxo-2-azadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (334) The title compound (334) was synthesized from 11,14-dioxa-3- azatrispiro[4.1.2.4 ¹⁰ .2 ⁷ .1 ⁵ ]heptadecan-2-one following similar procedures (steps 4-8) to those described in Example 236. MS (ESI): mass calcd. for C ₂₁ H ₃₁ N ₅ O ₄ : 417.24, found: 418.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.46 (s, 1H), 7.30 (s, 2H), 4.56- 4.62 (m, 1H), 3.73 (t, J = 7.2 Hz, 2H), 3.18-3.25 (m, 2H), 2.26-2.41 (m, 2H), 2.12-2.26 (m, 2H), 1.86 (s, 2H), 1.78 (s, 2H), 1.65-1.72 (m, 2H), 1.38-1.46 (m, 2H), 1.18-1.38 (m, 6H), 0.87 (t, J = 7.2 Hz, 3H). Example 335 was synthesized in similar procedures as described in Example 246, with an additional step of methylation as the last step, using MeI, K ₂ CO ₃ in DMF in a similar procedure to the one shown in Example 297. Examples 336, 337 were synthesized in a similar procedure to the ones described in Example 297, using Cs ₂ CO ₃ and 3-(bromomethyl)tetrahydrofuran with heating at 50 °C. Example 338 was synthesized from tert-butyl ((1s,4s)-4-(2-oxoethyl)cyclohexyl)carbamate in similar procedures as described in Example 153. Examples 339 and 340 were synthesized from 10-amino-1,3-dimethyl-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4-dione (synthesized in similar procedures as described in Example 130, with excess methyl iodide to do bis-methylation at step 2) in similar procedures as those described in Examples 204 and 209. Example 341.2-(10-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahyd ropyrimidin- 1(2H)-yl)-1-(2-methoxyethyl)-2,4-dioxo-1,3-diazadispiro[4.1. 5 ⁷ .1 ⁵ ]tridecan-3- yl)acetonitrile (341) 1-Butyl-5-(diaminomethylene)-3-[4-(2-methoxyethyl)-1,3-dioxo -2-(2- trimethylsilylethoxy methyl)-2,4-diazadispiro[4.1.5 ⁷ .1 ⁵ ]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[4.1.5 ⁷ .1 ⁵ ]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 to 80 °C for 12 h under N ₂ . After completion, the reaction was quenched with H ₂ O (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 NH ₄ HCO ₃ )-ACN; gradient 40-70%) 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[4.1.5 ⁷ .1 ⁵ ] 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[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl]hexahydropyrimidine- 2,4,6-trione (80 mg, 0.129 mmol) in TFA (0.5 mL) and H2O (0.1 mL) was stirred for 2 h under N ₂ at 25 °C. K ₂ CO ₃ (17.81 mg, 0.13 mmol) and MeOH (0.5 mL) were added under N ₂ . 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 (SiO ₂ , 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-trioxotetrahydropy rimidin-1(2H)-yl)-1-(2- methoxyethyl)-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-3-yl)acetonitrile (341) To a solution of 1-butyl-5-(diaminomethylene)-3-[4-(2-methoxyethyl)-1,3-dioxo -2,4- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl]hexahydropyrimidine-2,4,6-trione (20 mg, 0.041 mmol) in DMSO (0.5 mL) was added K ₂ CO ₃ (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 N ₂ , the reaction mixture was filtered and concentrated. The residue was purified by reverse phase HPLC (H2O (10mM NH4HCO3)-ACN; gradient 30-60%) to give the title compound (341) (2.3 mg, 11%) as a white solid. MS (ESI): mass calcd. for C ₂₅ H ₃₅ N ₇ O ₆ : 529.26, found: 530.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.50-9.60 (m, 2H), 7.31 (s, 2H), 4.57-4.75 (m, 1H), 4.52 (s, 2H), 3.70-3.76 (m, 2H), 3.53-3.57 (m, 4H), 3.26-3.29 (m, 3H), 2.40 (d, J = 11.2 Hz, 1H), 2.22-2.37 (m, 5H), 2.14-2.22 (m, 1H), 1.83 (d, J = 12.0 Hz, 1H), 1.33-1.51 (m, 5H), 1.18-1.33 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H). Example 343.1-Butyl-5-(diaminomethylene)-3-((5S,7s,10S)-1-(2-hydroxy -2- methylpropyl)-3-methyl-2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (343) Synthetic scheme: 1-Butyl-5-(diaminomethylene)-3-((5S,7s,10S)-1-(2-hydroxy-2-m ethylpropyl)-3-methyl- 2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (343) To a solution of Example 130 (60 mg, 0.134 mmol) in NMP (2 mL) in a sealed tube was added 2,2-dimethyloxirane (194 mg, 2.69 mmol) and K ₂ CO ₃ (37 mg, 0.269 mmol). The sealed tube was heated at 150 °C for 2 h. After completion, the reaction was filtered over Celite and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (H ₂ O (10 mM NH ₄ HCO ₃ )-ACN; gradient 30-60%) to give the title compound (343) (0.97 mg, 1.3%) as a white solid. m/z (ESI, +ve ion) = 519.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.32 (s, 2H), 4.73 (s, 1H), 4.62-4.67 (m, 1H), 3.73 (t, J = 7.6 Hz, 2H), 3.25-3.30 (m, 2H), 2.85 (s, 3H), 2.66-2.76 (m, 2H), 2.56 (s, 1H), 2.33-2.39 (m, 1H), 2.21-2.30 (m, 1H), 2.16 (d, J = 12.4 Hz, 1H), 2.06 (d, J = 12.8 Hz, 1H), 1.97 (d, J = 11.6 Hz, 1H), 1.30-1.49 (m, 5H), 1.20-1.28 (m, 3H), 1.14 (d, J = 2.0 Hz, 6H), 0.87 (t, J = 7.2 Hz, 3H). Example 331 was synthesized in similar procedures as described in Example 343. Example 344 and 345.5-(Diaminomethylene)-1-((5S,7s,10S)-3-methyl-2,4-dioxo-1 ,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-tr ione (344) and 5-(Diaminomethylene)-1-((5R,7r,10R)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-tr ione (345) Synthetic scheme:

1,3-Diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4,10-trione Ammonium carbonate (5.12 g, 53.3 mmol) was dissolved in MeOH (40.0 mL). Potassium cyanide (1.79 g, 26.6 mmol) and then water (40.0 mL) were added, and the suspension was heated to 40 °C for 30 min until a clear solution was obtained.8,11- Dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecan-2-one (5.0 g, 24.2 mmol) was added and the solution was stirred for 2 d at rt. The solvent was removed under vacuum and the residue was treated with 6 M HCl until pH 1. The solid was filtered and washed with water to give the title compound (2.01 g, 37%). ¹ H NMR: (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 8.43 (s, 1H), 2.41 (d, J = 13.7 Hz, 2H), 2.16-2.23 (m, 4H), 2.11 (d, J = 13.7 Hz, 2H), 1.98 (t, J = 6.9 Hz, 2H), 1.88 (t, J = 6.6 Hz, 2H). 3-((2-(Trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4,10-trione To a solution of 11,14-dioxa-1,3-diazatrispiro[4.1.2.4 ¹⁰ .2 ⁷ .1 ⁵ ]heptadecane-2,4-dione (1.85 g, 8.32 mmol) in DMF (35.0 mL) was added N,N-diisopropylethylamine (4.4 mL, 25.0 mmol) at 0 °C. The reaction was allowed to stir for 10 min followed by addition of (2- chloromethoxyethyl)trimethylsilane (1.7 mL, 9.16 mmol). The solution was stirred at rt for 17 h. The reaction was cooled to 0 °C, quenched with saturated aqueous NH4Cl solution, and extracted with EtOAc (x3). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (5-100%, EtOAc/heptane) to provide the title compound (1.43 g, 49%) as a pale-yellow oil. MS (ESI): mass calcd. for C ₁₇ H ₂₈ N ₂ O ₄ Si: 352.18, found: 351.2 [M-H]-. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.86 (s, 1H), 4.72 (s, 2H), 3.53 (t, J = 7.8 Hz, 2H), 2.45 (d, J = 13.7 Hz, 2H), 2.20-2.28 (m, J = 7.2 Hz, 4H), 2.18 (d, J = 13.6 Hz, 2H), 2.02 (t, J = 6.5 Hz, 2H), 1.92 (t, J = 6.5 Hz, 2H), 0.83 (t, J = 7.8 Hz, 2H), -0.03 (s, 9H). 10-Amino-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadispi ro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4- dione H ₂ N O N SEM H _N O To a solution of ammonia (7N in MeOH) (1.7 mL, 11.6 mmol) was added 3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4,10-trione (200 mg, 567 µmol) and the mixture was stirred for 3 h. Under a nitrogen atmosphere was added Raney 2800 nickel (50.0 mg, 851 µmol). The reaction was submitted to 5 cycles of vacuum/ hydrogen purges and stirred under hydrogen for 17 h. The suspension was filtered over Celite, and concentrated to give the crude title compound which was carried to the next step without any further purification. MS (ESI): mass calcd. for C17H31N3O3Si: 353.21, found: 354.2 [M+H] ⁺ . 1-(2,4-Dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazad ispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10- yl)-3-propylurea To a solution of 10-amino-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4-dione (210 mg, 594 µmol) in DCM (2.0 mL), propyl isocyanate (100 µL, 891 µmol) was added and stirred at 20 °C for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-20% MeOH/DCM) to give the title compound (253 mg, 97%). MS (ESI): mass calcd. for C21H38N4O4Si: 438.27, found: 437.5 [M-H]-. 1-(2,4-Dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazad ispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10- yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-trione 1-(2,4-Dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazad ispiro[4.1.5 ⁷ .1 ⁵ ]tridecan- 10-yl)-3-propylurea (253 mg, 577 µmol), malonic acid (72.0 mg, 692 µmol) and acetic anhydride (491 µL, 5.19 mmol) were mixed in AcOH (5.9 mL) and heated at 80 °C for 18 h. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-10% MeOH/DCM) to give the title compound (290 mg, 84%). MS (ESI): mass calcd. for C ₂₄ H ₃₈ N ₄ O ₆ Si: 506.26, found: 505.6 [M-H]-. 5-(Diaminomethylene)-1-(2,4-dioxo-3-((2-(trimethylsilyl)etho xy)methyl)-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-tr ione 1-(2,4-Dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazad ispiro[4.1.5 ⁷ .1 ⁵ ]tridecan- 10-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-trione (290 mg, 572 µmol), cyanamide (122 mg, 2.86 mmol) and nickel (II) acetylacetonate (44.1 mg, 172 µmol) were put in a vial and anhydrous THF (3.1 mL) was added. The reaction was stirred at 85 °C for 18 h, diluted with EtOAc (20 mL), washed with brine (10 mL), dried over MgSO ₄ , filtered, and concentrated to give a crude oil which was purified by reverse phase HPLC (C18, 0-100% MeCN/NH ₄ HCO ₃ 10 mM buffer) to give the title compound (168 mg, 53%). MS (ESI): mass calcd. for C ₂₅ H ₄₀ N ₆ O ₆ Si: 548.28, found: 547.2 [M-H]-. 5-(Diaminomethylene)-1-(2,4-dioxo-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3- propylpyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 5-(diaminomethylene)-1-(2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-propylpyrimidine- 2,4,6(1H,3H,5H)-trione (168 mg, 306 µmol) in DCM (6.8 mL) at 20 °C was added trifluoracetic acid (0.3 mL, 306 µmol) and the resulting mixture was stirred for 1 h. The reaction was concentrated and redissolved in MeOH (6.8 mL). Ammonium bicarbonate (200 mg, 306 µmol) was added to the reaction mixture and stirred for 1 h. The reaction was filtered, concentrated, and purified by reverse phase HPLC (C18, 0-100% MeCN/ NH ₄ HCO ₃ 10 mM buffer) to provide the title compound (98.0 mg, 76%). MS (ESI): mass calcd. for C19H26N6O5: 418.20, found: 417.4 [M-H]-. 5-(Diaminomethylene)-1-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-tr ione (344) and 5-(Diaminomethylene)-1-((5R,7r,10R)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-tr ione (345) To a solution of 5-(diaminomethylene)-1-(2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-tr ione (50.0 mg, 119 µmol) in DMF (1.7 mL) at 20 °C was added potassium carbonate (165 mg, 1.19 mmol) and iodomethane (8.9 µL, 143 mmol) and the resulting mixture was stirred for 16 h. The reaction was filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (C18, 0-100% MeCN/NH4HCO310 mM buffer) to provide the title compound (40.0 mg, 77%) as a racemate. The racemic mixture was subjected to chiral separation (Phenomenex, i-Amylose, 80% MeCN/MeOH), to provide the title compound (344) (first peak) (15.0 mg, 29%) as a white solid. MS (ESI): mass calcd. for C20H28N6O5: 432.21, found: 431.4 [M-H]-. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (s, 2H), 8.63 (s, 1H), 7.29 (s, 2H), 4.58-4.62 (m, 1H), 3.65-3.73 (m, 2H), 2.78 (s, 3H), 2.14-2.33 (m, 6H), 1.97 (t, J = 13.0 Hz, 2H), 1.86 (d, J = 13.2 Hz, 1H), 1.44-1.51 (m, 2H), 1.30-1.39 (m, 3H), 0.80 (t, J = 7.1 Hz, 3H). The title compound (345) was the second peak from the final separation (15.0 mg, 29%). MS (ESI): mass calcd. For C20H28N6O5: 432.21, found: 431.5 [M-H]-. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (s, 2H), 8.63 (s, 1H), 7.29 (s, 2H), 4.58-4.62 (m, 1H), 3.65-3.73 (m, 2H), 2.78 (s, 3H), 2.14-2.33 (m, 6H), 1.97 (t, J = 13.0 Hz, 2H), 1.86 (d, J = 13.2 Hz, 1H), 1.44-1.51 (m, 2H), 1.30-1.39 (m, 3H), 0.80 (t, J = 7.1 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 346 and 347.5-(Diaminomethylene)-1-((5S,7s,10S)-1,3-dimethyl-2,4-dio xo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-tr ione (346) and 5-(diaminomethylene)-1-((5R,7r,10R)-1,3-dimethyl-2,4-dioxo-1 ,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-tr ione (347) Synthetic scheme: H ₂ N NH ₂ H ₂ N NH ₂ H ₂ N NH ₂ O O O O O O N N K ₂ CO , MeI N N N N O ₃ O O O DMF O N NH N O HN 346 N 347 N O O O To a solution of 5-(diaminomethylene)-1-(2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-tr ione (49.0 mg, 117 µmol) in DMF (1.7 mL) at 20 °C was added potassium carbonate (162 mg, 1.17 mmol) and iodomethane (18.2 µL, 293 mmol) and the resulting mixture was stirred for 16 h. The reaction was filtered, and then concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (C18, 0-100% MeCN/NH4HCO310 mM buffer) to provide the title compound (24.0 mg, 46%) as a racemate. The racemic mixture was subjected to chiral separation (Phenomenex, i-Amylose, 50% MeCN/EtOH), and the first peak to elute was collected to give the title compound (346) (5.0 mg, 10%) as a white solid. MS (ESI): mass calcd. for C ₂₁ H ₃₀ N ₆ O ₅ : 446.23, found: 445.5 [M-H]-. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (s, 2H), 7.32 (s, 2H), 4.60-4.65 (m, 1H), 3.63-3.73 (m, 2H), 2.93 (s, 3H), 2.82 (s, 3H), 2.07-2.40 (m, 7H), 1.78-1.83 (m, 1H), 1.33-1.51 (m, 5H), 1.24 (t, J = 11.5 Hz, 1H), 0.80 (t, J = 7.4 Hz, 3H). The title compound (347) was the second peak to elute in the final separation (5.0 mg, 10%). MS (ESI): mass calcd. for C ₂₁ H ₃₀ N ₆ O ₅ : 446.23, found: 445.5 [M- H]-. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (s, 2H), 7.32 (s, 2H), 4.60-4.65 (m, 1H), 3.63-3.73 (m, 2H), 2.93 (s, 3H), 2.82 (s, 3H), 2.07-2.40 (m, 7H), 1.78-1.83 (m, 1H), 1.33- 1.51 (m, 5H), 1.24 (t, J = 11.5 Hz, 1H), 0.80 (t, J = 7.4 Hz, 3H). Example 348.5-(Diaminomethylene)-1-(3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)-3-pentylpyrimidine-2,4,6(1H,3H,5H)-tr ione (348) The title compound (348) was synthesized following a similar procedure to the one described in Example (344) by using pentyl isocyanate instead of propyl isocyanate. The final step was purified by reverse phase HPLC (C18, 0-100% MeCN/NH4HCO310 mM buffer) to provide the title compound (348) (21.0 mg, 48%). MS (ESI): mass calcd. for C ₂₂ H ₃₂ N ₆ O ₅ : 460.24, found: 461.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (s, 2H), 8.63 (s, 1H), 7.30 (s, 2H), 4.58-4.62 (m, 1H), 3.66-3.73 (m, 2H), 2.78 (s, 3H), 2.18-2.33 (m, 5H), 1.97 (t, J = 13.2 Hz, 2H), 1.83-1.88 (m, 1H), 1.33-1.46 (m, 5H), 1.19-1.28 (m, 5H), 0.82 (t, J = 7.1 Hz, 3H). Example 349.1-Butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4- dioxotetrahydropyrimidin-1(2H)-yl)methyl)-4-methylcyclohexyl )pyrimidine- 2,4,6(1H,3H,5H)-trione (349) Synthetic scheme: Ethyl 2,2-dimethyl-3-(((8-methyl-1,4-dioxaspiro[4.5]decan-8- yl)methyl)amino)propanoate To a mixture of ethyl 3-amino-2,2-dimethylpropanoate hydrochloride (800 mg, 4.27 mmol), 8-methyl-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (866 mg, 4.70 mmol) and sodium acetate (354 mg, 4.27 mmol) in DCM (14.2 mL) was added molecular sieves and then the suspension was stirred for 2 h. To the reaction was added sodium triacetoxyborohydride (1.87 g, 8.54 mmol) and the mixture was stirred at rt for 17 h. The molecular sieves were removed by filtration over cotton and a saturated aqueous NaHCO ₃ solution was added. The mixture was extracted 3 times with DCM, and the combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.25 g, 93%) as a clear oil. 5,5-Dimethyl-1-((1-methyl-4-oxocyclohexyl)methyl)dihydropyri midine-2,4(1H,3H)- dione To a sealed tube was added ethyl 2,2-dimethyl-3-(((8-methyl-1,4- dioxaspiro[4.5]decan-8-yl)methyl)amino)propanoate (730 mg, 2.33 mmol) in AcOH (7.3 mL) and water (1.5 mL). Potassium cyanate (795 mg, 9.32 mmol) was added in a single portion and the tube was sealed quickly. The solution was heated at 100 °C for 48 h and then was cooled down to rt. The reaction was poured into a mixture of ice/water, neutralized by a slow addition of solid Na ₂ CO ₃ ,and extracted with DCM (3x). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0-20% MeOH/DCM) to yield the title compound (541 mg, 87%) as a pale orange solid. MS (ESI): mass calcd. for C ₁₄ H ₂₂ N ₂ O ₃ : 266.16, found: 267.4 [M+H] ⁺ . 1-((4-Amino-1-methylcyclohexyl)methyl)-5,5-dimethyldihydropy rimidine-2,4(1H,3H)- dione To 5,5-dimethyl-1-((1-methyl-4-oxocyclohexyl)methyl)dihydropyri midine- 2,4(1H,3H)-dione (300 mg, 1.13 mmol) was added ammonia (7 N in MeOH) (6.4 mL, 45.1 mmol) and the reaction was stirred for 2 h. Under nitrogen, palladium on carbon 10% (30.0 mg, 282 µmol) was added. The flask was purged with hydrogen and added additional ammonia (7 N in MeOH) (6.4 mL, 45.1 mmol). After stirring under a hydrogen atmosphere for 17 h, the reaction was filtered over Celite, then concentrated to give the crude title compound (302 mg, 100%). MS (ESI): mass calcd. for C14H25N3O2: 267.19, found: 268.5 [M+H] ⁺ . 1-Butyl-3-(4-((5,5-dimethyl-2,4-dioxotetrahydropyrimidin-1(2 H)-yl)methyl)-4- methylcyclohexyl)urea To a solution of 1-((4-amino-1-methylcyclohexyl)methyl)-5,5- dimethyldihydropyrimidine-2,4(1H,3H)-dione (302 mg, 1.13 mmol) in DCM (5.7 mL) was added butyl isocyanate (130 µL, 1.13 mmol). The reaction was stirred at rt for 1 h then was concentrated to dryness under reduced pressure. The crude was purified by silica gel column chromatography (0-10% MeOH/DCM) to yield the title compound (257 mg, 62%) as a white solid. MS (ESI): mass calcd. for C ₁₉ H ₃₄ N ₄ O ₃ : 366.26, found: 367.5 [M+H] ⁺ . 1-Butyl-3-(4-((5,5-dimethyl-2,4-dioxotetrahydropyrimidin-1(2 H)-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione To 1-butyl-3-(4-((5,5-dimethyl-2,4-dioxotetrahydropyrimidin-1(2 H)-yl)methyl)-4- methylcyclohexyl)urea (110 mg, 0.3 mmol) in AcOH (600 µL) was added malonic acid (36.3 mg, 345 µmol) and the flask was heated to 60 °C. Acetic anhydride (113 µL, 1.2 mmol) was then added to the reaction. The reaction was heated at 90 °C for 4 h then cooled down to rt. The reaction was diluted with EtOAc, concentrated with silica gel, and purified by silica gel column chromatography (15-100% EtOAc/heptanes) to give the title compound (62.0 mg, 48%) as a pale-yellow foam. MS (ESI): mass calcd. for C22H34N4O5: 434.25, found: 435.5 [M+H] ⁺ . 1-Butyl-5-(diaminomethylene)-3-(4-((5,5-dimethyl-2,4-dioxote trahydropyrimidin-1(2H)- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-tri one (349) To a solution of 1-butyl-3-(4-((5,5-dimethyl-2,4-dioxotetrahydropyrimidin-1(2 H)- yl)methyl)-4-methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-tri one (96.0 mg, 221 µmol) in THF (2.2 mL) was added cyanamide (93.8 mg, 2.21 mmol) and nickel (II) acetylacetonate (11.4 mg, 44.2 µmol). The reaction was heated to 80 °C for 17 h. The crude was filtered with a syringe filter and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (CSH-C18, 30-50% MeCN/NH ₄ HCO ₃ 10 mM buffer) to provide the title compound (42.0 mg, 40%) as a white solid and as a mixture of cis and trans isomers. MS (ESI): mass calcd. for C23H36N6O5: 476.27, found: 477.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) δ ppm 4.62-4.80 (m, 1H), 3.77-3.91 (m, 2H), 3.36 (s, 2H), 3.24 (s, 2H), 1.49-1.63 (m, 5H), 1.27-1.49 (m, 7H), 1.23 (s, 6H), 1.13 (s, 3H), 0.90-1.02 (m, 3H). Example 350 and 354.1-Butyl-5-(diaminomethylene)-3-(6''-oxo-5'',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (350) and 1-Butyl-5-(diaminomethylene)-3-(6''- oxo-5'',6''-dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7 ''-pyrrolo[2,3-b]pyrazin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione Synthetic scheme: 2-(3-Chloropyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile 8,11-Dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (2,0 g, 9.65 mmol) was dissolved in THF (41.3 mL) and cooled to 0 °C. Lithium bis(trimethylsilyl)amide solution (10.6 mL, 10.6 mmol) was slowly added, and the reaction was stirred at 0 °C for 1 h.2,3- Dichloropyrazine (2.20 g, 14.8 mmol) was dissolved in THF (5.0 mL) and was quickly added at 0 °C and then the reaction was stirred at rt for 2.5 h. The reaction was concentrated onto silica and purified by silica gel column chromatography (0-100% EtOAc/heptanes) to provide the title compound (1.88 g, 61%) as an orange solid. MS (ESI): mass calcd. for C ₁₆ H ₁₈ ClN ₃ O ₂ : 319.11, found: 320.3 [M+H] ⁺ . 2-(3-Chloropyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxamide 2-(3-Chloropyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (1.88 g, 5.88 mmol) was dissolved in DMSO (14.7 mL) and potassium carbonate (1.63 g, 11.8 mmol) was added. The reaction was cooled to 0 °C and hydrogen peroxide (6.0 mL, 58.8 mmol) was added. After stirring at rt for 1 h, the reaction was diluted with EtOAc (75 mL), washed with water (2 x 50 mL) and extracted with EtOAc (30 mL). The combined organic layer was dried over MgSO ₄ , filtered, and concentrated to give the crude title compound (1.99 g, 100%) as a colorless solid which was directly used in the next step. MS (ESI): mass calcd. for C16H20ClN3O3: 337.12, found: 338.4 [M+H] ⁺ . Trispiro[pyrrolo[2,3-b]pyrazine-7,1'-cyclobutane-3',1''-cycl ohexane-4'',2'''- [1,3]dioxolan]-6(5H)-one 2-(3-Chloropyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxamide (1.99 g, 5.89 mmol) was dissolved in DMSO (58.9 mL) and cesium carbonate (3.92 g, 11.8 mmol) was added. The reaction was heated at 100 °C for 1.5 h, cooled down to rt, diluted with EtOAc (50 mL), and washed with water (50 mL x 2) and brine (25 mL). The organic layer was dried over MgSO4 and concentrated to give the title compound (920 mg, 52%) as a colorless solid. MS (ESI): mass calcd. for C ₁₆ H ₁₉ N ₃ O ₃ : 301.14, found: 302.2 [M+H] ⁺ . Dispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2,3-b]py razine]-4,6''(5''H)-dione To trispiro[pyrrolo[2,3-b]pyrazine-7,1'-cyclobutane-3',1''-cycl ohexane-4'',2'''- [1,3]dioxolan]-6(5H)-one (1.93 g, 6.42 mmol) in acetone (18.9 mL) and water (9.4 mL) was added p-toluenesulfonic acid monohydrate (1.24 g, 6.42 mmol) and the reaction was stirred at 50 °C for 1 h. The reaction was diluted with EtOAc (10 mL), washed with 50% aqueous K ₂ CO ₃ (2 x 10 mL) and brine (1 x 10 mL). The organic phase was dried over MgSO ₄ , filtered, and concentrated to give the title compound (1.39 g, 84%) as a colorless solid. MS (ESI): mass calcd. for C14H15N3O2: 257.12, found: 258.4 [M+H] ⁺ . 5''-((2-(Trimethylsilyl)ethoxy)methyl)dispiro[cyclohexane-1, 1'-cyclobutane-3',7''- pyrrolo[2,3-b]pyrazine]-4,6''(5''H)-dione To dispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2,3-b]py razine]-4,6''(5''H)- dione (1.39 g, 5.40 mmol) in DMF (13.5 mL) and DCM (13.5 mL) was added N,N- diisopropylethylamine (2.9 mL, 16.2 mmol). The reaction was cooled to 0 °C and (2- chloromethoxyethyl)trimethylsilane (1.9 mL, 10.8 mmol) was added. After stirring for 1 h at 0 °C, the reaction was diluted with EtOAc (50 mL), washed with 50% aqueous Na2CO3 (2 x 50 mL), 1 N HCl (50 mL x 2) and brine (25 mL). The organic layer was dried over MgSO ₄ , filtered, and concentrated to give the crude title compound which was directly used in the next step without further purification. MS (ESI): mass calcd. for C20H29N3O3Si: 387.20, found: 388.5 [M+H] ⁺ . 4-Amino-5''-((2-(trimethylsilyl)ethoxy)methyl)dispiro[cycloh exane-1,1'-cyclobutane- 3',7''-pyrrolo[2,3-b]pyrazin]-6''(5''H)-one 5''-((2-(Trimethylsilyl)ethoxy)methyl)dispiro[cyclohexane-1, 1'-cyclobutane-3',7''- pyrrolo[2,3-b]pyrazine]-4,6''(5''H)-dione (2.09 g, 5.39 mmol) was dissolved in ammonia (7 N in MeOH) (7.7 mL, 53.9 mmol) and stirred for 3 h. MeOH (18.0 mL) was added. The reaction was purged with nitrogen and palladium on carbon (10% w/w) (574 mg, 5.39 mmol) was added. The reaction was purged with hydrogen again and the suspension was stirred for 18 h. The reaction was filtered and concentrated to give the title compound as a yellow oil which was directly used in the next step. MS (ESI): mass calcd. for C ₂₀ H ₃₂ N ₄ O ₂ Si: 388.23, found: 389.5 [M+H] ⁺ . 1-Butyl-3-(6''-oxo-5''-((2-(trimethylsilyl)ethoxy)methyl)-5' ',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4-yl)urea To 4-amino-5''-((2-(trimethylsilyl)ethoxy)methyl)dispiro[cycloh exane-1,1'- cyclobutane-3',7''-pyrrolo[2,3-b]pyrazin]-6''(5''H)-one (2.1 g, 5.4 mmol) in DMF (21.6 mL) was added triethylamine (753 µL, 5.4 mmol) followed by butyl isocyanate (683 µL, 5.94 mmol). The reaction was stirred at rt for 1 h then was diluted with EtOAc (20 mL), washed with 1 N HCl (20 mL), 50% Na2CO3 (20 mL) and brine (10 mL). The organic layer was dried over MgSO ₄ , filtered, and concentrated to give the title compound (2.05 g, 78%) as a colorless solid. MS (ESI): mass calcd. for C25H41N5O3Si: 487.30, found: 488.5 [M+H] ⁺ . 1-Butyl-3-(6''-oxo-5''-((2-(trimethylsilyl)ethoxy)methyl)-5' ',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione 1-Butyl-3-(6''-oxo-5''-((2-(trimethylsilyl)ethoxy)methyl)-5' ',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4-yl)urea (1.98 g, 4.06 mmol) and malonic acid (491 mg, 4.67 mmol) were dissolved in AcOH (8.12 mL). The reaction was heated to 60 °C and acetic anhydride (1.5 mL, 16.2 mmol) was added. The reaction was sealed and heated to 90 °C for 1 h. The reaction was concentrated onto silica and purified by silica gel column chromatography (0-100% EtOAc/heptanes) to give the title compound (1.20 g, 53%) as a colorless solid. MS (ESI): mass calcd. for C28H41N5O5Si: 555.29, found: 554.5 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-(6''-oxo-5''-((2-(trimethylsi lyl)ethoxy)methyl)-5'',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione 1-Butyl-3-(6''-oxo-5''-((2-(trimethylsilyl)ethoxy)methyl)-5' ',6''- dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-pyrrolo[2 ,3-b]pyrazin]-4-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (1.20 g, 2.16 mmol), cyanamide (275 mg, 6.48 mmol) and nickel (II) acetylacetonate (166 mg, 648 µmol) were added to a vial and diluted with THF (11.7 mL). The resulting suspension was stirred at 85 °C for 10 h. The reaction was concentrated, redissolved in DCM, filtered with a syringe filter, and was concentrated to give the title compound as a crude orange oil which was used directly in the next step. MS (ESI): mass calcd. for C ₂₉ H ₄₃ N ₇ O ₅ Si: 597.31, found: 596.5 [M-H]-. 1-Butyl-5-(diaminomethylene)-3-(6''-oxo-5'',6''-dihydrodispi ro[cyclohexane-1,1'- cyclobutane-3',7''-pyrrolo[2,3-b]pyrazin]-4-yl)pyrimidine-2, 4,6(1H,3H,5H)-trione (350) and 1-Butyl-5-(diaminomethylene)-3-(6''-oxo-5'',6''-dihydrodispi ro[cyclohexane-1,1'- cyclobutane-3',7''-pyrrolo[2,3-b]pyrazin]-4-yl)pyrimidine-2, 4,6(1H,3H,5H)-trione (354) To 1-butyl-5-(diaminomethylene)-3-(6''-oxo-5''-((2-(trimethylsi lyl)ethoxy)methyl)- 5'',6''-dihydrodispiro[cyclohexane-1,1'-cyclobutane-3',7''-p yrrolo[2,3-b]pyrazin]-4- yl)pyrimidine-2,4,6(1H,3H,5H)-trione (1.0 g, 1.67 mmol) in DCM (9.0 mL) was added trifluoroacetic acid (3.0 mL, 38.6 mmol) and stirred at rt for 3 h. The reaction was concentrated and redissolved in MeCN (8.5 mL). Saturated aqueous ammonium bicarbonate (2 mL) was added, and the mixture was stirred for 1 h. The reaction was directly purified by reverse phase HPLC (C18, 30-50% MeCN/10 mM NH4HCO3 buffer) to give 194 mg (25%) of the desired product as a mixture of enantiomers. The above racemic mixture was further separated by chiral SFC column: Lux Cellulose‐4 LC (250 mm*10 mm, 5 µm; CO ₂ -MeOH(0.1% NH ₄ OH)) to afford the first eluting peak as title compound (350) (27.5 mg, 3.5%) as a colorless solid. MS (ESI): mass calcd. for C23H29N7O4: 467.23, found: 468.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) δ ppm 8.11 (d, J = 3.2 Hz, 1H), 7.98 (d, J = 3.2 Hz, 1H), 4.71-4.78 (m, 1H), 3.79 – 3.88 (m, 2H), 2.31 - 2.60 (m, 7H), 2.21 (d, J = 12.4 Hz, 1H), 1.43-1.58 (m, 6H), 1.28 - 1.38 (m, 3H), 0.94 (t, J = 7.4 Hz, 3H). The title compound (354) was the second eluting peak from the chiral SFC separation (27.1 mg, 3.5%). MS (ESI): mass calcd. for C ₂₃ H ₂₉ N ₇ O ₄ : 467.23, found: 468.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.11 (d, J = 3.2 Hz, 1H), 7.98 (d, J = 3.2 Hz, 1H), 4.71-4.78 (m, 1H), 3.79-3.88 (m, 2H), 2.31-2.60 (m, 7H), 2.21 (d, J = 12.4 Hz, 1H), 1.43-1.58 (m, 6H), 1.28- 1.38 (m, 3H), 0.94 (t, J = 7.4 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 351 and 352.1-Butyl-5-(diaminomethylene)-3-(1-methyl-2,4-dioxo-1,3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (351) and 1- butyl-5-(diaminomethylene)-3-(1-methyl-2,4-dioxo-1,3-diazadi spiro[4.1.5 ⁷ .1 ⁵ ]tridecan- 10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (352) The title compounds (351, 352) were synthesized following a similar procedure to the last few steps of Example 344. Butyl isocyanate was used in place of propyl isocyanate. The sequence of the last 2 steps were also reversed, opting for alkylation first followed by SEM deprotection. The final step was purified by reverse phase HPLC (C18, 0-100% MeCN/NH ₄ HCO ₃ 10 mM buffer) and the racemic mixture was subjected to chiral separation (Phenomenex, i-Amylose-3, 5% MeCN/MeOH). The first product to elute from the separation was the title compound (351). MS (ESI): mass calcd. for C21H30N6O5: 446.23, found: 447.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.49 (s, 2H), 8.51 (s, 1H), 7.68 (s, 2H), 4.61-4.66 (m, 1H), 3.71 (t, J = 12.0 Hz, 2H), 2.87 (s, 3H), 2.02-2.36 (m, 6H), 1.76- 1.79 (m, 1H), 1.38-1.46 (m, 4H), 1.19-1.29 (m, 5H), 0.86 (t, J = 7.2 Hz, 3H). The title compound (352) was the second peak to come out in the final separation. MS (ESI): mass calcd. for C ₂₁ H ₃₀ N ₆ O ₅ : 446.23, found: 447.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DSMO) δ ppm 9.49 (s, 2H), 8.51 (s, 1H), 7.68 (s, 2H), 4.61-4.66 (m, 1H), 3.71 (t, J = 12.0 Hz, 2H), 2.87 (s, 3H), 2.02-2.36 (m, 6H), 1.76-1.79 (m, 1H), 1.38-1.46 (m, 4H), 1.19-1.29 (m, 5H), 0.86 (t, J = 7.2 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 353.10-(3-butyl-5-(diaminomethylene)-4,6-dioxo-2- thioxotetrahydropyrimidin-1(2H)-yl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4-dione (353) Synthetic scheme: 1-Butyl-3-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1, 3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)thiourea O SEM N _H ^N NH ^N H O S 10-Amino-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadispi ro[4.1.5 ⁷ .1 ⁵ ]tridecane- 2,4-dione (260 mg, 735 µmol) was dissolved in DCM (2.5 mL) and to the solution was added butyl isothiocyanate (133 µL, 1.10 mmol). The reaction was stirred at rt for 1 h and was purified directly by silica gel column chromatography (0-20% MeOH in DCM) to give the title compound (260 mg, 75%). MS (ESI): mass calcd. for C22H40N4O3SSi: 468.26, found: 469.6 [M+H] ⁺ . 10-(3-Butyl-4,6-dioxo-2-thioxotetrahydropyrimidin-1(2H)-yl)- 3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4-dione 1-Butyl-3-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1, 3- diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecan-10-yl)thiourea (150 mg, 320 µmol), malonic acid (40.0 mg, 384 µmol) and acetic anhydride (272 µL, 2.88 mmol) were mixed in AcOH (3.3 mL). The reaction was stirred at 80 °C for 17 h, concentrated under reduced pressure and purified by reverse phase HPLC (CSH-C18, 45-65% MeCN/NH4HCO310 mM buffer) to provide the title compound (59.0 mg, 29%). MS (ESI): mass calcd. for C ₂₅ H ₄₀ N ₄ O ₅ SSi: 536.25, found: 535.5 [M-H]-. 10-(3-Butyl-5-(diaminomethylene)-4,6-dioxo-2-thioxotetrahydr opyrimidin-1(2H)-yl)-3- ((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4-dione Cyanamide (19.4 mg, 456 µmol), nickel (II) acetylacetonate (7.04 mg, 27.4 µmol) and 10-(3-butyl-4,6-dioxo-2-thioxotetrahydropyrimidin-1(2H)-yl)- 3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4-dione (49.0 mg, 91.3 µmol) were put in a vial and anhydrous THF (495 µL) was added. The reaction was heated to 85 °C for 18 h, diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (CSH-C18, 55-75% MeCN/NH4HCO3 10 mM buffer) to provide the title compound (26.0 mg, 49%). MS (ESI): mass calcd. for C26H42N6O5SSi: 578.27, found: 577.5 [M-H]-. 10-(3-Butyl-5-(diaminomethylene)-4,6-dioxo-2-thioxotetrahydr opyrimidin-1(2H)-yl)- 1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4-dione (353) 10-(3-Butyl-5-(diaminomethylene)-4,6-dioxo-2-thioxotetrahydr opyrimidin-1(2H)-yl)- 3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 ⁷ .1 ⁵ ]tridecane-2,4-dione (26.0 mg, 44.9 µmol) was dissolved in DCM (864 µL), and to the solution was added trifluoracetic acid (0.3 mL, 44.9 µmol). The reaction was stirred at rt for 1 h and the reaction mixture was concentrated. The residue was dissolved in MeOH (5 mL) and ammonium bicarbonate (200 mg, 260 µmol) was added. After stirring for 1 h, the reaction was filtered, concentrated, and purified by reverse phase HPLC (C18, 0-100% MeCN/NH ₄ HCO ₃ 10 mM buffer) to provide the title compound (4.2 mg, 21%). MS (ESI): mass calcd. for C ₂₀ H ₂₈ N ₆ O ₄ S: 448.19, found: 449.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H), 9.42 (s, 2H), 8.35 (s, 1H), 7.48 (s, 2H), 5.71 (s, 1H), 4.26-4.41 (m, 2H), 2.13-2.33 (m, 5H), 1.94 (t, J = 12.5 Hz, 2H), 1.86 (d, J = 11.2 Hz, 1H), 1.52-1.59 (m, 2H), 1.15-1.40 (m, 5H), 0.88 (t, J = 7.3 Hz, 3H). Example 355 was synthesized following the last few steps of Example Error! Reference source not found. and by using 4,4-difluorobutan-1-amine hydrochloride. Example 356 was synthesized following the last few steps of Example (Error! Reference source not found.) and by using 4-aminobutanenitrile hydrochloride. Example 357.5-(Diaminomethylene)-1-((1s,4s)-4-((5,5-dimethyl-2,4-dio xoimidazolidin- 1-yl)methyl)-4-methylcyclohexyl)-3-(4-hydroxybutyl)pyrimidin e-2,4,6(1H,3H,5H)-trione (357) Synthetic scheme: 1-(4-(Benzyloxy)butyl)-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)urea A solution of 1-((4-isocyanato-1-methylcyclohexyl)methyl)-5,5-dimethyl-3-( (2- (trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (268 mg, 654 µmol) in DCM (6.5 mL) was added to a solution of 4-(benzyloxy)butan-1-amine (123 mg, 687 µmol) in DCM (6.5 mL) and the resulting was stirred for one minute.1 N HCl was added, and the reaction was extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (1-8% MeOH/DCM) to give the title compound (385 mg, 100%). MS (ESI): mass calcd. for C ₃₁ H ₅₂ N ₄ O ₅ Si: 588.37, found: 589.7 [M+H] ⁺ . 1-(4-(Benzyloxy)butyl)-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-(4-(benzyloxy)butyl)-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)urea (385 mg, 654 µmol) in DCM (6.5 mL) was added malonyl chloride (131 µL, 1.31 mmol). After stirring for 1 h, the reaction was quenched with water and extracted with DCM (3x). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20- 60% EtOAc/heptanes) to yield the title compound (103 mg, 24%). MS (ESI): mass calcd. for C ₃₄ H ₅₂ N ₄ O ₇ Si: 656.36, found: 655.7 [M-H]-. 1-(4-(Benzyloxy)butyl)-5-(diaminomethylene)-3-(4-((5,5-dimet hyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione 1-(4-(Benzyloxy)butyl)-3-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (104 mg, 158 µmol), cyanamide (67.2 mg, 1.58 mmol), and nickel (II) acetylacetonate (8.13 mg, 31.7 µmol) were dissolved in THF (1.6 mL) and heated to 80 °C for 17 h. The mixture was cooled down to rt, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (30-50% EtOAc/heptanes) to provide the title compound (357) (40.0 mg, 36%). MS (ESI): mass calcd. for C35H54N6O7Si: 698.38, found: 697.7 [M-H]-. 5-(Diaminomethylene)-1-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4-me thylcyclohexyl)-3-(4- hydroxybutyl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 1-(4-(benzyloxy)butyl)-5-(diaminomethylene)-3-(4-((5,5-dimet hyl- 2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1 -yl)methyl)-4- methylcyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (40.0 mg, 57.2 µmol) in EtOH (572 µL) was added palladium on carbon (10% w/w) (6.09 mg, 57.2 µmol) and purged with hydrogen. The suspension was stirred at rt under hydrogen for 2 h, filtered through Celite and concentrated under reduced pressure to provide the crude title compound which was used directly in the next step without further purification. MS (ESI): mass calcd. for C ₂₈ H ₄₈ N ₆ O ₇ Si: 608.34, found: 607.6 [M-H]-. 5-(Diaminomethylene)-1-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoim idazolidin-1-yl)methyl)-4- methylcyclohexyl)-3-(4-hydroxybutyl)pyrimidine-2,4,6(1H,3H,5 H)-trione (357) To a solution of 5-(diaminomethylene)-1-(4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy) methyl)imidazolidin-1-yl)methyl)-4-methylcyclohexyl)-3-(4- hydroxybutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (20.0 mg, 32.9 µmol) in DCM (329 µL) was added trifluoroacetic acid (75.5 µL, 986 µmol) and stirred for 30 min. A saturated aqueous NaHCO3 solution was added, and the reaction was stirred for 10 min then was extracted with DCM (3x). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (CSH-C18, 15-35% MeCN/NH4HCO310 mM buffer) to provide the title compound (357) (9.0 mg, 57%). MS (ESI): mass calcd. for C22H34N6O6: 478.25, found: 479.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 2H), 7.36 (s, 2H), 4.69 (s, 1H), 4.35 (t, J = 5.1 Hz, 1H), 3.74 (t, J = 7.1 Hz, 2H), 3.24 (s, 2H), 2.54-2.68 (m, 2H), 1.69 (d, J = 13.5 Hz, 2H), 1.44-1.54 (m, 2H), 1.33-1.41 (m, 2H), 1.29 (s, 8H), 1.11-1.24 (m, 4H), 0.85 (s, 3H). Example 359 was synthesized in similar procedures as described in Example 357. Example 358.7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropy rimidin-1(2H)- yl)-2-(pyrazin-2-yl)spiro[3.5]nonane-2-carboxamide (358) Synthetic scheme: 2-(Pyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile To a solution 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (4.14 g, 20.0 mmol) in THF (85.6 mL) at 0 °C was added lithium bis(trimethylsilyl)amide solution (41.3 mL, 41.3 mmol) slowly and stirred at 0 °C for 1 h.2-Chloropyrazine (2.73 mL, 30.6 mmol) was dissolved in THF (10.3 mL) and was quickly added at 0 °C and the reaction was stirred at rt for 1 h. The reaction was quenched with water and extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-100% EtOAc/heptanes) to yield the title compound (1.60 g, 39%) as an orange solid. MS (ESI): mass calcd. for C16H19N3O2: 285.15, found: 286.4 [M+H] ⁺ . 2-(Pyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxamide 2-(Pyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (1.10 g, 3.86 mmol) was dissolved in DMSO (9.6 mL) and potassium carbonate (1.07 g, 7.71 mmol) was added. The solution was cooled to 0 °C and hydrogen peroxide (3.9 mL, 30% in water, 38.6 mmol) was added. The reaction was allowed to warm to room temperature over 1 h, diluted with EtOAc (75 mL), and washed with water (2 x 50 mL). The combined aqueous phase was back extracted with EtOAc (30 mL). The combined organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give the title compound (1.07 g, 91%) as a colorless solid which was directly used in the next step without further purification. MS (ESI): mass calcd. for C ₁₆ H ₂₁ N ₃ O ₃ : 303.16, found: 304.4 [M+H] ⁺ . 7-Oxo-2-(pyrazin-2-yl)spiro[3.5]nonane-2-carboxamide To 2-(pyrazin-2-yl)-8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxamide (1.68 g, 5.54 mmol) in acetone (16.3 mL) and water (8.1 mL) was added p-toluenesulfonic acid monohydrate (214 mg, 1.11 mmol) and the solution was heated at 50 °C for 1.5 h. The reaction was diluted with EtOAc (10 mL), washed with 50% aqueous K2CO3 (2 x 10 mL) and brine (1 x 10mL). The organic phase was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to provide the title compound as a colorless solid which was directly used in the next step without further purification. MS (ESI): mass calcd. for C14H17N3O2: 259.13, found: 260.4 [M+H] ⁺ . 7-Amino-2-(pyrazin-2-yl)spiro[3.5]nonane-2-carboxamide 7-Oxo-2-(pyrazin-2-yl)spiro[3.5]nonane-2-carboxamide (1.44 g, 5.55 mmol) was dissolved in ammonia (7 N in MeOH) (7.9 mL, 55.5 mmol) and the solution was stirred for 3 h. MeOH (18.5 mL) was added, and the reaction was purged with nitrogen. Palladium on carbon (10% w/w) (591 mg, 5.55 mmol) was added. The reaction was purged with hydrogen again and stirred for 18 h. The reaction was purged with nitrogen, filtered, and concentrated under reduced pressure to give (743 mg, 51%) as a colorless oil which was used in the next step without further purification. MS (ESI): mass calcd. for C ₁₄ H ₂₀ N ₄ O: 260.16, found: 261.4 [M+H] ⁺ . 7-(3-Butylureido)-2-(pyrazin-2-yl)spiro[3.5]nonane-2-carboxa mide To a solution of 7-amino-2-(pyrazin-2-yl)spiro[3.5]nonane-2-carboxamide (743 mg, 2.85 mmol) in DMF (11.4 mL) was added triethylamine (398 µL, 2.85 mmol) followed by butyl isocyanate (361 µL, 3.14 mmol). The reaction was stirred at rt for 1 h then was diluted with EtOAc, washed with 1 M HCl, 50% aqueous Na ₂ CO ₃ and brine (1 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil which was used directly in the next step without further purification. MS (ESI): mass calcd. for C19H29N5O2: 359.23, found: 360.4 [M+H] ⁺ . 7-(3-Butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-(pyra zin-2-yl)spiro[3.5]nonane- 2-carboxamide 7-(3-Butylureido)-2-(pyrazin-2-yl)spiro[3.5]nonane-2-carboxa mide (1.03 g, 2.87 mmol) and malonic acid (346 mg, 3.30 mmol) were dissolved in AcOH (5.7 mL). The reaction was heated to 60 °C and acetic anhydride (1.08 mL, 11.5 mmol) was added. The reaction was then sealed and stirred at 90 °C for 1 h. The reaction was diluted with EtOAc, concentrated onto silica, and purified by silica gel column chromatography (0-100% EtOAc/heptanes, then flushed with 100% isopropanol) to yield the title compound which was used directly in the next step. MS (ESI): mass calcd. for C ₂₂ H ₂₉ N ₅ O ₄ : 427.22, found: 428.5 [M+H] ⁺ . 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)-yl)-2-(pyrazin- 2-yl)spiro[3.5]nonane-2-carboxamide (358) 7-(3-Butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-(pyra zin-2- yl)spiro[3.5]nonane-2-carboxamide (422 mg, 987 µmol), cyanamide (126 mg, 2.96 mmol) and nickel (II) acetylacetonate (76.1 mg, 296 µmol) were put in a vial and THF (5.34 mL) was added. The vial was sealed, and the solution was stirred at 85 °C for 18 h. The mixture was filtered, concentrated under reduced pressure, and purified by reverse phase HPLC (C18, 25-45% MeCN/NH4HCO310 mM buffer) to provide the title compound as a mixture of enantiomers (358) (31.0 mg, 6.7%). MS (ESI): mass calcd. for C ₂₃ H ₃₁ N ₇ O ₄ : 469.24 found: 470.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.67 (d, J = 1.4 Hz, 1H), 8.60 (dd, J = 2.5, 1.6 Hz, 1H), 8.45 (d, J = 2.6 Hz, 1H), 4.61-4.76 (m, 1H), 3.79-3.87 (m, 2H), 2.81 (d, J = 12.6 Hz, 1H), 2.66 (d, J = 12.5 Hz, 2H), 2.54 (t, J = 9.6 Hz, 2H), 1.91 (d, J = 12.2 Hz, 1H), 1.29-1.57 (m, 10H), 0.90-0.97 (m, 3H). Example 360.7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropy rimidin-1(2H)- yl)-N-methylspiro[3.5]nonane-2-carboxamide (360) Synthetic scheme: 8,11-Dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxylic acid To a solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carbonitrile (2.00 g, 9.65 mmol) in EtOH (27.8 mL) and water (4.39 mL) in a vial was added lithium hydroxide (707 mg, 28.9 mmol). The vial was sealed and stirred at 90 °C for 3 d. The reaction was cooled down to rt, diluted with water (100 mL), and washed with DCM (75ml x 2). The aqueous phase was cooled to 0 °C and slowly acidified with 3 N HCl. The resulting solution was extracted with DCM (75 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (2.02 g) as an off-white solid which was used in the next step without further purification. MS (ESI): mass calcd. for C12H18O4: 226.12, found: 225.3 [M-H]-. Ethyl 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxylate To a solution of 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxylic acid (400 mg, 1.77 mmol) in DMF (5.9 mL) was added cesium carbonate (882 mg, 2.65 mmol) and iodoethane (172 µL, 2.12 mmol) and the suspension was stirred at rt for 16 h. The reaction was quenched by the addition of water (20 mL) and diluted with EtOAc (75 mL). The organic phase was washed twice with aqueous LiCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-70% EtOAc/heptanes) to give the title compound (375 mg, 83%). ¹ H NMR (400 MHz, CDCl3) δ ppm 4.12 (q, J = 7.1 Hz, 2H), 3.92 (s, 4H), 3.03 (p, J = 8.8 Hz, 1H), 2.04 (s, 2H), 2.02 (s, 2H), 1.65-1.73 (m, 2H), 1.57-1.65 (m, 4H), 1.50-1.57 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). Ethyl 7-oxospiro[3.5]nonane-2-carboxylate To ethyl 8,11-dioxadispiro[3.2.4 ⁷ .2 ⁴ ]tridecane-2-carboxylate (0.26 g, 1.02 mmol) in acetone (3.0 mL) and water (1.5 mL) was added p-toluenesulfonic acid monohydrate (39.5 mg, 204 µmol) and the mixture was heated at 50 °C for 1.5 h. The reaction was diluted with EtOAc (50 mL), washed with saturated aqueous KHCO3 solution (20 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the title compound (190 mg, 88%) as a white solid, which was directly used in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.16 (q, J = 6.0 Hz, 2H), 3.13 (p, J = 8.7 Hz, 1H), 2.25-2.37 (m, 2H), 2.19 (s, 2H), 2.17 (s, 2H), 1.90 (dt, J = 14.2, 6.7 Hz, 4H), 1.27 (t, J = 7.1 Hz, 3H). Ethyl 7-aminospiro[3.5]nonane-2-carboxylate O H ₂ N O To a solution of ammonia (7 N in MeOH) (2.6 mL, 18.08 mmol) was added ethyl 7- oxospiro[3.5]nonane-2-carboxylate (190 mg, 904 µmol) and the reaction was stirred for 3 h. Raney 2800 nickel (79.6 mg, 1.36 mmol) was added to the solution under an atmosphere of nitrogen. The reaction was submitted to 5 cycles of vacuum/ hydrogen purges and then stirred under hydrogen for 17 h. The suspension was filtered over Celite and concentrated to give the crude title compound which was carried to the next step without any further purification. Ethyl 7-(3-butylureido)spiro[3.5]nonane-2-carboxylate To ethyl 7-aminospiro[3.5]nonane-2-carboxylate (126 mg, 594 µmol) in DCM (2.0 mL) was added butyl isocyanate (115 µL, 891 µmol). The reaction was stirred at rt for 5 h. The reaction was purified directly by silica gel column chromatography (0-20% MeOH/DCM) to give the title compound (140 mg, 76%). Ethyl 7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3. 5]nonane-2- carboxylate Ethyl 7-(3-butylureido)spiro[3.5]nonane-2-carboxylate (140 mg, 451 µmol) and malonic acid (56.3 mg, 541 µmol) were dissolved in AcOH (4.6 mL). The reaction was heated to 60 °C and acetic anhydride (384 µL, 4.06 mmol) was added. After heating at 80 °C for 17 h, the reaction was cooled down to rt, EtOAc was added and then concentrated onto silica and purified by silica gel column chromatography (0 to 10%, MeOH/DCM) to provide the title compound (150 mg, 88%). MS (ESI): mass calcd. for C20H30N2O5: 378.22, found: 377.3 [M-H]-. Ethyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)- yl)spiro[3.5]nonane-2-carboxylate Cyanamide (61.7 mg, 1.45 mmol), nickel (II) acetylacetonate (22.4 mg, 87.2 µmol) and ethyl 7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3. 5]nonane-2- carboxylate (110 mg, 291 µmol) were added to a vial with THF (1.6 mL). The vial was sealed, and the reaction was stirred at 85 °C for 18 h. The reaction was concentrated onto silica gel and purified by silica gel column chromatography (0-10% MeOH/ DCM) to give the title compound (106 mg, 87%). MS (ESI): mass calcd. for C ₂₁ H ₃₂ N ₄ O ₅ : 420.24, found: 421.5 [M+H] ⁺ . 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)-yl)-N- methylspiro[3.5]nonane-2-carboxamide (360) To ethyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)- yl)spiro[3.5]nonane-2-carboxylate (35.0 mg, 83.2 µmol) in EtOH (3.0 mL) was added methylamine solution (218 µL, 2.08 mmol). The reaction was stirred at 80 °C for 17 h. Another volume of methylamine solution (33% in ethanol, 218 µL, 2.08 mmol) was added and the reaction was stirred for 72 h at 80 °C. The reaction was directly purified by reverse phase HPLC (C18, 0-100% MeCN/NH4HCO310 mM buffer) to provide the title compound (360) (14.1 mg, 42%) as a white solid. MS (ESI): mass calcd. for C ₂₀ H ₃₁ N ₅ O ₄ : 405.24, found: 406.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.53 (s, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.28 (s, 2H), 4.59 (t, J = 12.1 Hz, 1H), 3.68-3.77 (m, 2H), 2.87 (p, J = 8.6 Hz, 1H), 2.55 (d, J = 4.6 Hz, 3H), 2.21-2.42 (m, 2H), 1.89-1.98 (m, 1H), 1.78-1.88 (m, J = 10.2 Hz, 3H), 1.71-1.78 (m, 1H), 1.63-1.70 (m, 1H), 1.39-1.49 (m, 2H), 1.19-1.35 (m, 6H), 0.87 (t, J = 7.3 Hz, 3H). Example 361.7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropy rimidin-1(2H)- yl)spiro[3.5]nonane-2-carboxamide (361) Synthetic scheme: 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)- yl)spiro[3.5]nonane-2-carboxylic acid To a solution of ethyl 7-(3-butyl-5-(diaminomethylene)-2,4,6- trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonane-2-carbox ylate (50.0 mg, 119 µmol in THF (2.0 mL) and EtOH (3.0 mL) in a vial was added 1 N aqueous LiOH solution (501 µL, 501 µmol). The reaction was stirred at rt for 18 h and extracted with DCM. The organic layer was washed with saturated aqueous NH4Cl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound which was used in the next step without further purification. MS (ESI): mass calcd. for C ₁₉ H ₂₈ N ₄ O ₅ : 392.21, found: 393.5 [M+H] ⁺ . 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din-1(2H)- yl)spiro[3.5]nonane-2-carboxamide (361) To a solution of 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimi din- 1(2H)-yl)spiro[3.5]nonane-2-carboxylic acid (46.7 mg, 119.0 µmol) in DMF (1.0 mL) in a vial was added ammonium chloride (6.4 mg, 0.12 mmol), HATU (49.8 mg, 131 µmol) and N,N-diisopropylethylamine (20.9 µL, 0.12 mmol). After stirring at rt for 1 h, the reaction was concentrated and directly purified by reverse phase HPLC (C18, 15-60% MeCN/NH4HCO3 10 mM buffer) to provide the title compound (361) (11.3 mg, 24%). MS (ESI): mass calcd. for C19H29N5O4: 391.22, found: 392.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, J = 8.2 Hz, 2H), 7.33 (s, 2H), 7.12 (s, 1H), 6.66 (s, 1H), 4.59 (t, J = 11.9 Hz, 1H), 3.69- 3.76 (m, 2H), 2.81-2.93 (m, 1H), 2.32 (dt, J = 24.4, 12.7 Hz, 2H), 1.91-1.99 (m, 1H), 1.70- 1.89 (m, 4H), 1.62-1.69 (m, J = 13.2 Hz, 1H), 1.39-1.49 (m, 2H), 1.19-1.38 (m, 6H), 0.87 (t, J = 7.3 Hz, 3H). Example 362.1-Butyl-5-(diaminomethylene)-3-(9-methyl-8,10-dioxo-7,9- diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecan-2-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (362) Synthetic scheme: Tert-Butyl (8,10-dioxo-7,9-diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecan-2-yl)carbamate Ammonium carbonate (938 mg, 9.77 mmol) was dissolved in MeOH (11.1 mL) and potassium cyanide (328 mg, 4.88 mmol) was added. The suspension was heated to 40 °C for 30 min until a clear solution was obtained. Tert-butyl (6-oxospiro[3.3]heptan-2-yl)carbamate (1.00 g, 4.44 mmol) was added and the mixture was stirred at rt for 72 h. The solvent was partially concentrated and was treated with 6 N HCl until pH = 1. The precipitate was filtered and washed with water to give the title compound (500 mg, 38%) as a white solid. MS (ESI): mass calcd. for C14H21N3O4: 295.15, found: 294.3 [M-H]-. Tert-Butyl (9-methyl-8,10-dioxo-7,9-diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecan-2-yl)carbamate To a solution of tert-butyl (8,10-dioxo-7,9-diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecan-2- yl)carbamate (500 mg, 1.69 mmol) in MeCN (7.1 mL) and DMF (1.4 mL) was added K ₂ CO ₃ (1.17 g, 8.46 mmol) followed by iodomethane (426 µL, 6.77 mmol). After stirring for 17 h, water was added and the reaction was extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20-100% EtOAc/heptanes) to give the title compound (230 mg, 44%). MS (ESI): mass calcd. for C ₁₅ H ₂₃ N ₃ O ₄ : 309.27, found: 308.4 [M-H]-. 2-Amino-9-methyl-7,9-diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecane-8,10-dione To tert-butyl (9-methyl-8,10-dioxo-7,9-diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecan-2-yl)carbamate (230 mg, 743 µmol) in DCM (1.9 mL) was added trifluoroacetic acid (1.9 mL). After stirring for 15 min, toluene was added, and solvent was removed under reduced pressure to give the title compound (150 mg, 96%), which was used in the next step without further purification. 1-Butyl-3-(9-methyl-8,10-dioxo-7,9-diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecan-2-yl)urea To a solution of 2-amino-9-methyl-7,9-diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecane-8,10-dione (156 mg, 746 µmol) in THF (3.7 mL) was added triethylamine (313 µL, 2.24 mmol) and butyl isocyanate (129 µL, 1.12 mmol). After stirring for 30 min, water was added, and the reaction was extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound (165 mg, 72%) which was used in the next step without further purification. MS (ESI): mass calcd. for C15H24N4O3: 308.18, found: 309.4 [M+H] ⁺ . 1-Butyl-3-(9-methyl-8,10-dioxo-7,9-diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecan-2-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione 1-Butyl-3-(9-methyl-8,10-dioxo-7,9-diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecan-2-yl)urea (165 mg, 535 µmol) and malonic acid (64.7 mg, 615 µmol) were dissolved in AcOH (1.8 mL). The reaction was heated to 60 °C, and acetic anhydride (202 µL, 2.14 mmol) was added. The reaction was sealed and stirred at 90 °C for 1 h. Then the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20-80% EtOAc/heptanes) to provide the title compound (180 mg, 89%). MS (ESI): mass calcd. for C ₁₈ H ₂₄ N ₄ O ₅ : 376.17, found: 375.4 [M- H]-. 1-Butyl-5-(diaminomethylene)-3-(9-methyl-8,10-dioxo-7,9- diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecan-2-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (362) 1-Butyl-3-(9-methyl-8,10-dioxo-7,9-diazadispiro[3.1.4 ⁶ .1 ⁴ ]undecan-2-yl)pyrimidine- 2,4,6(1H,3H,5H)-trione (180 mg, 478 µmol), cyanamide (203 mg, 4.78 mmol), and nickel (II) acetylacetonate (24.6 mg, 95.6 µmol) were dissolved in THF (4.8 mL) and the reaction was heated to 80 °C for 17 h. The reaction was cooled to rt, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (CSH-C18, 20- 40% MeCN/NH4HCO310 mM buffer) to give the title compound (362) (9.0 mg, 4.5%). MS (ESI): mass calcd. for C19H26N6O5: 418.20, found: 419.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 5.15 (p, J = 9.0 Hz, 1H), 3.79-3.89 (m, 2H), 2.93-3.05 (m, 2H), 2.91 (s, 3H), 2.67 (ddd, J = 16.1, 12.1, 2.9 Hz, 2H), 2.53-2.61 (m, 1H), 2.43 (dd, J = 12.1, 8.5 Hz, 2H), 2.28-2.37 (m, 1H), 1.48-1.64 (m, 2H), 1.34 (dq, J = 14.6, 7.3 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). Biology assay procedure A: 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% CO ₂ , 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% CO ₂ , 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 Echo 650 liquid handler (Beckman Coulter) 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 10 ⁶ 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 Clariostar plate reader optimized for HTRF assays. The HTRF ratio was determined by dividing the signal output at 655 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 assay data for compounds 1 to 105 according to procedure A are set forth in the Table in Figure 1. The pEC ₅₀ activity bins are: pEC ₅₀ >7: +++; pEC ₅₀ between 6 and 7: ++; and pEC ₅₀ <6: +. Biological Assay procedure B 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 10 ⁶ 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 assay data for compounds 106 to 191 according to procedure B are set forth in the Table in Figure 2. The pEC50 activity bins are: pEC50 >7: +++; pEC50 between 6 and 7: ++; and pEC50 <6: +. A complete listing of the compounds, characterization data, and assay data for compounds 192 to 295 according to procedure B are set forth in the Table in Figure 3. The pEC50 activity bins are: pEC50 >7: +++; pEC50 between 6 and 7: ++; and pEC50 <6: +. A complete listing of the compounds, characterization data, and assay data for compounds 296 to 362 according to procedure B are set forth in the Table in Figure 4. The pEC50 activity bins are: pEC50 >7: +++; pEC50 between 6 and 7: ++; and pEC50 <6: +. 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.