Compounds, compositions and methods of use to treat hypoparathyroidism and osteoporosis

Abstract

Disclosed are compounds that are parathyroid hormone receptor 1 agonists, and methods useful for preventing or treating osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis.

Description

[0001] 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 CR2; 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 (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, 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- 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-, R1taken together with the atom to which it is attached forms a 4- to 7- membered heterocycloalkyl ring, provided that if Y is or , then R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen, (C1-C6)alkyl, or (C3-C8)cycloalkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHRa, (C1-C6)alkoxy, -CONRaRbor (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb; or R1and R2taken 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, halo, (C1-C6)alkoxy, cyano, carboxy, -CONRaRb, and -SO2Ra; R3is (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-C8)cycloalkyl, aryl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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 Raand Rbtaken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R5a, R5b, R6a, and R6bare independently hydrogen or (C1-C6)alkyl; RAis 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 CR2; 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 (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, 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- 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, 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-, R1taken together with the atom to which it is attached forms a 4- to 7- membered heterocycloalkyl ring, provided that if Y is or , then R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen, (C1-C6)alkyl, or (C3-C8)cycloalkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHRa, (C1- C6)alkoxy, -CONRaRbor (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb; or R1and R2taken 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- C6)alkoxy, cyano, carboxy, -CONRaRb, and -SO2Ra; R3is (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- C8)cycloalkyl, aryl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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 Raand Rbtaken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R5a, R5b, R6a, and R6bare 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 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 CR2; 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 (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, 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-, R1taken together with the atom to which it is attached forms a 4- to 7-membered heterocycloalkyl ring, provided that if Y is or , then R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen or (C1-C6)alkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHRa, (C1-C6)alkoxy, -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb; or R1and R2taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R3is (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- C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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 Raand Rbtaken 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 CR2; L is -(C1-C6)alkylenyl-; B represents (C3-C8)cycloalkyl, (C6-C10)aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaR, 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-, R1taken 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 R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen or (C1-C6)alkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, , -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1- C6)alkoxy, or R1and R2taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl ; R3is (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-C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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, 5- to 6-membered heteroaryl, or Raand Rbtaken 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; R4is H, -C(O)NH2, (C1-C6)alkyl, or -N(R4a)2; and R4ais independently for each occurrence hydrogen or (C1-C6)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-R1represents: , , , , , or -(C1-C6)alkylene-R1; X is N or CR2; L is -(C1-C6)alkylenyl-; B represents (C3-C8)cycloalkyl, (C6-C10)aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaR, 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-, R1taken 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 R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen or (C1-C6)alkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1- C6)alkoxy, or R1and R2taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R3is (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- C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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, 5- to 6-membered heteroaryl, or Raand Rbtaken 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; R4is H or N(R4a)2; and R4ais 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 a13C- or14C- enriched carbon are within the scope of this invention. The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.) In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra). The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule. A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human. An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chains, C3-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 -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents. "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. 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, -CF3, -CN, and the like. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-6 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 CR2; 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 (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, 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-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-, R1taken together with the atom to which it is attached forms a 4- to 7- membered heterocycloalkyl ring, provided that if Y is or , then R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen, (C1-C6)alkyl, or (C3-C8)cycloalkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHRa, (C1- C6)alkoxy, -CONRaRbor (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb; or R1and R2taken 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, halo, (C1-C6)alkoxy, cyano, carboxy, -CONRaRb, and -SO2Ra; R3is (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-C8)cycloalkyl, aryl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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 Raand Rbtaken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R5a, R5b, R6a, and R6bare independently hydrogen or (C1-C6)alkyl; RAis 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 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 CR2; 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 (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, 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- 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, 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-, R1taken together with the atom to which it is attached forms a 4- to 7- membered heterocycloalkyl ring, provided that if Y is or , then R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen, (C1-C6)alkyl, or (C3-C8)cycloalkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHRa, (C1-C6)alkoxy, -CONRaRbor (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb; or R1and R2taken 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- C6)alkoxy, cyano, carboxy, -CONRaRb, and -SO2Ra; R3is (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-C8)cycloalkyl, aryl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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 Raand Rbtaken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R5a, R5b, R6a, and R6bare 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 CR2; 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 (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, 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-, R1taken together with the atom to which it is attached forms a 4- to 7-membered heterocycloalkyl ring, provided that if Y is or , then R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen or (C1-C6)alkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHRa, (C1-C6)alkoxy, -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb; or R1and R2 taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R3is (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- C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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 Raand Rbtaken 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, R1is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R1d, R1e, and R1fare 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 (C3-C8)cycloalkyl or phenyl; or R1dand R1etaken together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl each of which is optionally substituted with hydroxy. In some embodiments, R1is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R1d, R1e, and R1fare independently for each occurrence selected from hydrogen, (C1- C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; or R1dand R1etaken together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl. In some embodimeents, R1is , and: Raand Rbare each hydrogen, or Rais hydrogen; and Rbis methyl. In some embodiments, R1is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R1d, R1e, and R1fare 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 (C3-C8)cycloalkyl or phenyl; or R1dand R1etaken together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl each of which is optionally substituted with hydroxy. In some embodiments, R1is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R1d, R1e, and R1fare independently for each occurrence selected from hydrogen, (C1- C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; or R1dand R1etaken together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl. In some embodiments, R1is, , and R1dand R1etaken together with the carbon to which they are attached R1dand R1etaken together with the carbon to which they are attached form morpholine, cyclobutane, oxetane, azetidine, or cyclohexane. In certain preferred embodiments, R1dand R1eare each methyl. In some preferred embodiments, R1fis hydrogen. In other preferred embodiments, R1fis (C1-C6)alkyl, preferably methyl or ethyl. In other embodiments, R1fis (C1-C6)fluoroalkyl, preferably 2,2,2-trifluorethyl. In some embodiments, R1is ; and R1ais cyclopropyl, 2-propyl, ethyl, or methyl. In some embodiments, R1is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . In some embodiments, R1is: , , , , , , , , , or . In certain embodiments, Y is , , , , , , , , , , , , , , , , , , , or . In some embodiments, X is N, while in other embodiments X is CR2. In certain embodiments where X is CR2, R2is hydrogen, while in other embodiments R2is fluoro. In particularly preferred embodiments, R2is hydrogen. In some embodiments, R2is (C1-C6)alkyl optionally substituted with (C1-C6)alkoxy, preferably methyl or methoxymethyl. In certain embodiments, R1is or , and R2is –CH3or -CH2-OCH3. In some embodiments, R1and R2taken together with the atom to which they are attached form R1and R2taken 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 (C1-C6)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, (C1-C6)alkoxy, cyano, carboxy, -CONRaRb, and -SO2Ra. In some embodiments, wherein R1and R2taken together with the atom to which they are attached form: , , , or ; wherein R1gand R1hare each independently hydrogen or (C1-C6)alkyl, wherein the (C1- C6)alkyl is optionally substituted with one or more substitutents independently selected from (C3-C8)cycloalkyl, 4- to 7-membered heterocylcylalkyl, hydroxy, halo, (C1-C6)alkoxy, cyano, carboxy, -CONRaRb, and -SO2Ra. In some embodiments, R1his ethyl, methyl, ethyl, isopropyl, or t-butyl, each of which is optionally substituted with hydroxy, methoxy, cyclopropyl, oxetanyl, tetrahydrofuranyl, phenyl, cyano, carboxy, hydroxy, -CONRaRb, -SO2Ra, or one to three fluorine atoms. In some embodiments, R1his trifluoromethyl. In some embodiments, R1ghydrogen, methyl, or ethyl, wherein methyl or ethyl is optionally substituted with cyano. In some embodiments, Rais methyl. In some embodiments, Rbis methyl. In further embodiments, Raand Rbare each methyl. In certain preferred embodiments, R1gis methyl or hydrogen. In more particular embodiments, R1and R2taken together with the atom to which they are attached form: , , , , , , , , , , or . In some embodiments, R1and R2taken together with the atom to which they are attached form: . In other embodiments, R1and R2taken 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, R5a, R5b, R6a, and R6bare each hydrogen. In other embodiments, R5a, R5b, R6a, and R6bare each methyl, and in still other embodiments, R5ais methyl and R5b, R6a, and R6bare each hydrogen. In some embodiments, Z is O. In some embodiments, RAis hydrogen, while in other embodiments, RAis methyl. In some preferred embodiments, the compound has the structure of Formula (Ic): (Ic), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from (C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, 5- to 6- membered heteroaryl, NRaRb, 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, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; and R1ais hydrogen or (C1-C6)alkyl; In other preferred embodiments, the compound has the structure of Formula (Id): (Id), or a pharmaceutically acceptable salt thereof, wherein R1is selected from -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, (C3- C8)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- C6)hydroxyalkyl, R1ais hydrogen or (C1-C6)alkyl, and R2is selected from hydrogen, cyano, hydroxyl, NH2, NHCOCH3, NHRa, (C1-C6)alkoxy, -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb. In other preferred embodiments, the compound has the structure of Formula (Ie): NH2H2N O O N A N R3O (Ie), or a pharmaceutically acceptable salt thereof, wherein A represents a 4- to 7- membered heterocycloalkyl. In certain preferred embodiments, R3is 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: , , , , , , , H2N NH2O O N N O N ONH2, ,H2N NH2O O N N O N H2N O , ,

[0002] , , , , , , , ,

[0003] , , , , , , , , , , , , , , , , , NH2H2N O O N N O N ONH2, H2N NH2O O N N O O N NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , H2N NH2H2N NH2O O O O O O N N N N ONNHONNHO , O , H2N NH2H2N NH2O O O O O O N N N N ONNHONNHO , O , H H2N NH2 2N NH2O O O O OOON N N N ONNHONNHO , O , H2N NH2H2N NH2O O O O OOOON N N N ONNHONNHO , O , H2N NH2O O O N N ONNHO , , ; , , , NH2H2N O H O O N NNNHO O , O , O NH2NH2O H2N O H2N O H O NNHO N NNNHO N N H O O O O , , NH2NH O2H2N O H2N O O NNHO NO NNHN N H N O O O O , O , NH2NH2OH2N O O H2N O N ONHNNONN N NHO O O O , , NH2NH2OH2N O H2N O O HNHONNON NNN NHO O O O , , , , NH NH2 2H H 2N O O2N O O O NNNH2ONHNN2N N O O , , NH2NH2H2N O O H2N O O N NH OHNNONNO N O N O O O , , NH2H2N O H O O N NNHN O O ,O, NH2O H2N O N NH O N N H O O , , NH2O O H2N O NNHO N N H O O , , NH2H2N O H O O N N N NH O O , , NH2NH2H2N O O H2N O O NH N O N O N NNO N HNH O O O , , NH2NH2H O HN O O 2NHO2NN O N O N N N N N O OOO H , , NH2NH2H N O HN O O 2HO2NN O N O N N N NNO OOOH, , NH2H O 2NHN O O N N N CF3O O , NH2NH2H2N O O H2N OHN O N CF3O N O N NNNH O N OHOO, , NH2NH2O H2N O O H2N N O N O N O N N N N O N O H O O , , NH2NH2H N O O O O 2 H2N NH N O N O N N N N O O N O , , NH2NH2N H2N O H O O 2N N O N O N N NH N N O O O O , , NH2H2N O O NH O N N O N . , or ; or a pharmaceutically acceptable salt thereof. In yet other embodiments, the compound has the structure: , , , , , , ,

[0004] H2N NH2O O N N O N ONH2, ,H2N NH2O O N N O N H2N O , , , , , ,

[0005] , , , , , , , , , , , , , , , , , , , , , NH2H2N O O N N O N ONH2, H2N NH2O O N N O O N NH2, , , , ,

[0006] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , H2N NH2H2N NH2O O O O N N N N O O H2N NH2O O O N NH2N N N NH N NH N N O , , , H2N NH2H2N NH2O O O O N N N N O O H2N N O OHH N H2N NNO O N ONNO,NH2, orH, or a pharmcaeutically acceptable salt thereof. In still other embodiments, the compound has the structure: , , , NH2N H2N O NH N O N O N H O , , NH2O H2N O NH N O N H N O O , , , , , , , , , , , , , , , , , , , , , , , , NH2O H2N O N O N N N O O , , , , , , , , , , NH2O H2N O N O N N N O O , , , , , , , , , , , , , , , , , , , , HO NH2O H2N O N O N N N O O , , O NH2O H2N O N O N NH N O O , , , , , , MeO NH2O H2N O N O N N N O O , , , , , , , , , , , , , , , , , , , , NH2NH2O O H2N O H2N NH H N O O N O N N N O N NCNO O O , , , , , , , , , , , , NH2NH2COOH H2NON O H2N O NH N N O N O N H NH N O N O O O , , HO NH2O H2N O N O N NH N O O , or a pharmaceutically acceptable salt thereof. In some embodiments, a compound has the structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

[0007] , , or a pharmaceutically acceptable salt thereof. In some embodiments, provided is a compound of Formula (IIa) or (IIb): R4 R4 ZZN OON3NNNNRYR3YO (IIa); or O (IIb); or a pharmaceutically acceptable salt thereof; wherein: Y represents: n p mX 1qR, n XR1, n XR1, R1, or ; X is N or CR2; L is -(C1-C6)alkylenyl-; B represents (C3-C8)cycloalkyl, (C6-C10)aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaR, 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-, R1taken 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 R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen or (C1-C6)alkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1- C6)alkoxy; or R1and R2taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R3is (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- C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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 Raand Rbtaken 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; R4is H, -C(O)NH2, (C1-C6)alkyl, -NHSO2Me, or -N(R4a)2; and R4ais independently for each occurrence hydrogen or (C1-C6)alkyl. In certain embodiments, Y represents: or . In some embodiments, R1is: , while in other embodiments R1is . In some embodiments, R1is: hydrogen, , , , , , , , , , , , , or , , , , , , , , , , , , , , or ; and R1d, R1e, and R1fare independently for each occurrence selected from hydrogen, (C1- C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; or R1dand R1etaken together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl. In certain embodiments, R1is, ; and R1dand R1etaken together with the carbon to which they are attached form morpholine, cyclobutane, oxetane, or cyclohexane. In certain particular embodiments, R1dand R1eare each methyl. In certain particular embodiments, R1fis hydrogen, while in others, R1fis (C1-C6)alkyl, more particularly, R1fis methyl or ethyl. In other embodiments, R1fis (C1-C6)fluoroalkyl, such as R1fis 2,2,2-trifluorethyl. In certain particular embodiments, Y is , , , , , , , , , , , , , , , , , , , or . In some embodiments, X is N. In other embodiments, X is CR2. In certain preferred embodiments, R2is hydrogen. In other embodiments, R2is fluoro. In still other embodiments, R2is (C1-C6)alkyl optionally substituted with (C1- C6)alkoxy, preferably methyl or methoxymethyl. In certain embodiments,R1is or , and R2is methyl or methoxymethyl. In certain embodiments, R1and R2taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl. More particularly, in some embodiments, R1and R2taken together with the atom to which they are attached form: , , , or . In certain embodiments R3is: methyl, , , , , , , or . In certain preferred embodiments, R3is . In particular embodiments, Z is O. In other particular embodiments, Z is S. In particular embodiments, R4is H, -C(O)NH2, or NH2. In certain preferred embodiments, R4is H or NH2.In certain embodiments, a compound of formula (IIa) or (IIb) has the structure: , , , , , , NH2O O S NH2N N N N O ,,, , , ; , , , , , , , , , , , , , , , , , , , H2NOOO S NH N N N O N O , , , or ; or a pharmaceutically acceptable salt thereof. In other embodiments, the compound has the structure: , , , , , , NH2O O S NH2N 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-R1represents: , , , , , or -(C1-C6)alkylene-R1; X is N or CR2; L is -(C1-C6)alkylenyl-; B represents (C3-C8)cycloalkyl, (C6-C10)aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaR, 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-, R1taken 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 R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen or (C1-C6)alkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1-C6)alkoxy, or R1and R2taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R3is (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-C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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, 5- to 6-membered heteroaryl, or Raand Rbtaken 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; R4is H or N(R4a)2; and R4ais independently for each occurrence hydrogen or (C1-C6)alkyl. In certain embodiments, R1is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , or . In other embodiments, R1is or , and R2is –CH3or -CH2-OCH3. In still other embodiments, R1is: , while in more particular embodiments R1is: or . In some embodiments, Y is , , , , , , , , , , , , , , , , , , , or . In certain embodiments, R3is: methyl, , , , , , or , preferably . In certain preferred embodiments, R4is 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 a13C- or14C-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 R1, 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:

[0008] Abbreviations: ACN Acetonitrile Ac2O Acetic anhydride AcOH Acetic acid CBr4Carbon 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 H2HydrogenHATUHexafluorophosphate azabenzotriazole tetramethyl uroniumHF Hydrogen fluoride K2CO3 Potassium carbonate KCN Potassium cyanide KOCN Potassium cyanate LDA Lithium diisopropylamide LiAlH4Lithium aluminum hydride LiOH Lithium hydroxide MeI Methyl iodide MeOH Methanol MsCl Mesyl chloride N2 nitrogen NaBH4Sodium borohydride NaBH3CN Sodium cyanoborohydride NaBH(OAc)3 Sodium triacetoxyborohydride NaHCO3 Sodium bicarbonate NaHSO3Sodium bisulfite Na2SO4Sodium sulfate n-Bu3P Tri-n-butylphosphine NaH Sodium hydride NH4Cl Ammonium chloride NH4HCO3 Ammonium bicarbonate NH2OH.HCl Hydroxylamine hydrochloride Pd / C Palladium on carbon PE Petroleum ether PMBNH2 4-Methoxybenzylamine POCl3Phosphorus oxychloride PPh3Triphenylphosphine 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-trioxotetrahydropyrimidin-1(2H)- yl)-2-azaspiro[3.5]nonane-2-carboxamide (4) Synthetic scheme: 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-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)pyrimidine- 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]+.1H 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-trioxotetrahydropyrimidin-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 N2, 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 C9H8N2O2: 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 H2, 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-trioxotetrahydropyrimidin-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]+.1H 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-dioxoimidazolidin-1- yl)butyl)pyrimidine-2,4,6(1H,3H,5H)-trione Synthetic scheme: 5,5-Dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-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 C11H22N2O3Si: 258.14, found: 257.05 [M-H]-. 2-(4-(5,5-Dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1- yl)butyl)isoindoline-1,3-dione To a solution of 5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-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 C23H33N3O5Si: 459.22, found: 482.15 [M+Na]+. 1-(4-Aminobutyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)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)isoindoline-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 N2, 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-dioxoimidazolidin-1- yl)butyl)pyrimidine-2,4,6(1H,3H,5H)-trione O NH2O NH2H2N ONH2N ONN ONHO 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)pyrimidine-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 C18H28N6O5: 408.21, found: 409.20 [M+H]+.1H 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-(diaminomethylene)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 Ac2O (47 mg, 0.46 mmol) at 0 °C under N2. 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]+.1H 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-azaspiro[3.5]nonan- 7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (13) Synthetic scheme: 1-Butyl-5-(diaminomethylene)-3-(2-(methylsulfonyl)-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 (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 N2. 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 H2O 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]+.1H 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)pyrimidine- 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 NH3in 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 ClCH2CH2Cl (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 C13H25N3O: 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-azaspiro[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 C24H31N3O5: 441.23 found: 442.20 [M+H]+. Benzyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-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-trioxotetrahydropyrimidin-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 C25H33N5O5: 483.25 found: 484.20 [M+H]+. 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[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)-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 C17H27N5O3: 349.21 found: 350.2 [M+H]+.1H NMR (400 MHz; CD3OD) 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)-trione (18) Synthetic scheme:

[0009] 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. NaBH4(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)(methyl)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 K2CO3(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 C21H32N2O4: 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 C16H24N2O2: 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)carbamate To a solution of benzyl (((1s,4s)-4-aminocyclohexyl)methyl)(methyl)carbamate (560 mg, 2.03 mmol) in ClCH2CH2Cl (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)carbamate (470 mg, 1.25 mmol) in Ac2O (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 C24H33N3O5: 443.24, found: 444.25 [M+H]+. Benzyl (((1s,4s)-4-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin- 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 C28H37N3O5S2: 559.22, found: 560.20 [M+H]+. Benzyl (((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin- 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 NH3in 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)-trione 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]+.1H 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 C20H31N5O4: 405.24, found: 406.15 [M+H]+.1H 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)pyrimidine-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-trioxotetrahydropyrimidin-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 Na2SO4, 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 C22H36N6O5: 464.27, found: 465.30 [M+H]+. 1-(1-(Azetidin-3-yl)piperidin-4-yl)-3-butyl-5-(diaminomethylene)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]+.1H 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-trioxotetrahydropyrimidin-1(2H)- yl)-2-azaspiro[3.5]nonane-2-sulfonamide (39) Synthetic scheme: H2N NH2H2N NH2H2N NH2O O O O Cl O O O S N NCbzHNON N Pd / C,H2N N O Et N, THF O NH3, rt N O MeOH\DCM, rt O SNNH2ple 17ONH SExamO Cbz O Benzyl ((7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-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)pyrimidine- 2,4,6(1H,3H,5H)-trione (80 mg, 0.23 mmol) in THF (3 mL) was added Et3N (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 C25H34N6O7S: 562.22, found: 563.25 [M+H]+. 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-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-yl)sulfonyl)carbamate (90 mg, 0.16 mmol) in MeOH (1 mL) and DCM (4 mL) was added Pd / C (30 mL) under N2. 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]+.1H 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-methylsulfonimidoyl)-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-methyl-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 N2atmosphere 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-methylsulfonimidoyl)-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 Et3N.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]+.1H 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)-trione (41) & 1-Butyl-5-(diami nomethylene)-3-(((1r,4r)-4-(5-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidin e-2,4,6(1H,3H,5H)-trione (42) Synthetic scheme:

[0010] 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 C9H16O3: 172.11, found: 173.20 [M+H]+. Methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylate 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 C15H30O3Si: 286.20, found: 287.20 [M+H]+. 4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbohydrazide 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 C14H30N2O2Si: 286.21, found: 287.20 [M+H]+. 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-methyl-4H-1,2,4-triazole To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbohydrazide (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 C16H31N3Osi: 309.22, found: 310.20 [M+H]+. 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-methyl-4-((2- (trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole A solution of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-methyl-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 C22H45N3O2Si2: 439.31, found: 440.30 [M+H]+. (4-(5-Methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3- yl)cyclohexyl)methanol To a solution of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-methyl-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-(trimethylsilyl)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-triazol-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 C28H45N5O4S2Si: 607.27, found: 608.25 [M+H]+. 1-Butyl-5-(diaminomethylene)-3-((4-(5-methyl-4-((2-(trimethylsilyl)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)cyclohexyl)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)cyclohexyl)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 H2O with 0.05% NH4HCO3) 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]+.1H 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]+.1H 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-trioxotetrahyd 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:

[0011] N-benzyl-N-methyl-8,11-dioxadispiro[3.2.47.24]tridecan-2-amine To a stirred solution of 8,11-dioxadispiro[3.2.47.24]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, NaBH3CN (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[3.2.47.24]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 NaBH4(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 C18H25NO3: 303.18 m / z, found: 304.20 [M+H]+. Benzyl (7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-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-trioxotetrahydropyrimidin-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)(methyl)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 C27H37N5O5: 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)(methyl)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 C19H31N5O3: 377.24, found: 378.05 [M+H]+. 1-((2S,4s,7S)-7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-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]+);1H 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]+;1H 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). 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-trioxotetrahydropyrimidin-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 C11H16O3: 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 NaBH4(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-carboxylate 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 N2atmosphere. 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 Na2SO4, 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 C28H38O3Si: 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-diazinan-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 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, 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 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 (20 mg, 68.97%) as a white solid. MS (ESI): mass calcd. for C20H30N4O5: 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 NH4HCO3), 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 C20H31N5O4: 405.24, found: 406.05 [M+H]+.1H 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)ethoxy)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-(diaminomethylene)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)piperidin-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]+.1H 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)-trione (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 C12H22BrNO2: 291.08, found: 236.15 [M-tBu+H]+. tert-Butyl ((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)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 Cs2CO3(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)cyclohexyl)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)cyclohexyl)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)cyclohexyl)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)cyclohexyl)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)cyclohexyl)-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)cyclohexyl)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 C30H48N4O6S2Si: 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)cyclohexyl)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)cyclohexyl)-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 NH4HCO3), 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]+.1H 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]pyrimidin-5(4H )-yl)-2-azaspiro[3.5]nonane-2-carboxamide (66) Synthetic scheme: tert-Butyl 7-(N-(butylcarbamoyl)-2-cyanoacetamido)-2-azaspiro[3.5]nonane-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-carboxylate (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 C21H34N4O4: 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 C21H34N4O4: 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 C30H41N5O5S: 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 C17H25N5O2S: 363.17 m / z, found: 364.20 [M+H]+. 7-(3-Amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-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 NH4HCO3), 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]+.1H 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-dione 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-trioxotetrahydropyrimidin-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 C21H30N6O4: 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-trioxotetrahydropyrimidin- 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 C21H34N6O4: 434.26 found: 435.20[M+H]+.1H 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: OtBuOK, TosMIC OLDA,O BrOLiAlH O O CN O4O O EtOH, DME, rt O THF, -78 - -40 °COCNTHF, rt O NH2O CbzCl, TEA O2N HCl, THFOOHO O NaBH4, MeOH DCM, rt OHNHNCbzHNCbz CbzS S O O NH S NH N2SO HCbzH NO HNCbzO N2O N O N TMAD, n-Bu3PNNH3(in MeOH)N toluene, 110 °C O O O O NH2H2N O NH240% HBr (in AcOH) O N DCM, 0°C-rt N O O 8,11-Dioxadispiro[3.2.47.24]tridecane-2-carbonitrile To a solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (1.0 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[3.2.47.24]tridecane-2-carbonitrile To a solution of 8,11-dioxadispiro[3.2.47.24]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 N2atmosphere. 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 NH4Cl (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[3.2.47.24]tridecan-2-yl)methanamine To a solution of 2-(methoxymethyl)-8,11-dioxadispiro[3.2.47.24]tridecane-2-carbonitrile (390 mg, 1.55 mmol) in THF (8 mL) was added LiAlH4 (117 mg, 3.10 mmol) at 0 °C under a N2atmosphere. After stirring at room temperature for 4 h, the reaction was quenched with saturated Na2SO4(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[3.2.47.24]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[3.2.47.24]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 N2atmosphere. 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)carbamate A solution of benzyl ((2-(methoxymethyl)-8,11-dioxadispiro[3.2.47.24]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 NaHCO3solution 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 C20H27NO4: 345.19, found: 368.20 [M+Na]+. Benzyl ((7-hydroxy-2-(methoxymethyl)spiro[3.5]nonan-2-yl)methyl)carbamate To a solution of benzyl ((2-(methoxymethyl)-7-oxospiro[3.5]nonan-2-yl)methyl)carbamate (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 C20H29NO4: 347.21, found: 370.15 [M+Na]+. 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 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 C32H43N3O6S2: 629.26, found: 652.10 [M+Na]+. Benzyl ((7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-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 NH3in 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 C21H35N5O4: 421.27, found: 422.25 [M+H]+.1H 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-dioxoimidazolidin-1- yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (78) Synthetic scheme: O O OHO O OH2NNOHOAc, 100 °C NH NH , Pd / O N3C, H2O O MeOH, rt O O O O ONO O O O NH NH C HN C N Cl Cl O N N H2N NOH HN N N O O ClCH2CH2Cl, rt O DCM, rt O NH S2H2N O O 1) S C S S O O NH TEA, DMSO NHNH3(in MeOH)O N N ONN N O Br B N O 2) r O O Ethyl 2-((8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)amino)-2-methylpropanoate 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 C14H20N2O3: 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 ClCH2CH2Cl (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 C19H32N4O3: 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-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)-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]+.1H 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[3.2.47.24]tridecan-2-ol To a solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (1.0 g, 5.1 mmol) in methanol (20 mL) was added NaBH4(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[3.2.47.24]tridecane A solution of 8,11-dioxadispiro[3.2.47.24]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[3.2.47.24]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 NaBH4(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)pyrimidine- 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 C18H26N4O4: 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 C22H35N5O4: 433.27 found: 434.25 [M+H]+.1H 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-butyl-5- (diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione Synthetic scheme: O O O 1) S C SHN NHIHNNHN NH TEA, DMSO O O K2CO3, O O O O 2) Br Br S S DMF, rt S S S O S N S NH NOS2O O H2N O H NaBH4DEAD, PPh3ONN BocNH3(in MeOH)O N BocHO N BocO N N Boc MeOH, rt DCM, rt N 100 °C N O O H N NH2NH NH22H2N O H2N O H2N O TFA / DCMCuI, KN 2CO3NH O N NN1, TFA, DCM, rtNO N NNO N NH tolueN N 2, NH3in MeOH, rt N N Nne 100 °COSEMO 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 C8H8N2O3S2: 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 C12H16N2O3S2: 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 C13H23NO3: 241.17, found: 242.25 [M+H]+. 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 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 C25H37N3O5S2: 523.22, found: 524.20 [M+H]+. tert-Butyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-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 NH3(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 C22H35N5O5: 449.26, found: 450.20 [M+H]+. 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7-yl)pyrimidine- 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 NaHCO3(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)ethoxy)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)-N1,N2- dimethylcyclohexane-1,2-diamine (16 mg, 0.11 mmol). The reaction was heated at 100 °C for 3 h under N2. 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-butyl-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-azaspiro[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]+.1H 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-dihydroisothiazolo[ 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)spiro[3.5]non an-2-yl)-1-methylurea (82) Synthetic scheme:

[0012] tert-Butyl (8,11-dioxadispiro[3.2.47.24]tridecan-2-yl)(methyl)carbamate To a solution of N-benzyl-N-methyl-8,11-dioxadispiro[3.2.47.24]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[3.2.47.24]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 C15H25NO3: 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 C15H27NO3: 267.20 m / z, found: 214.25 [M-tBu+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 N2. 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 C23H38N4O4: 434.29, found: 435.35 [M+H]+. 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 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 C25H35N5O4S: 501.24, found: 524.30 [M+Na]+. 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 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)isothiazolo[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 H2O (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 C19H29N5O2S: 391.20, found: 392.30[M+H]+. 1-((2R,4r,7R)-7-(3-Amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[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)spiro[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 NH3-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 C20H30N6O3S: 434.21, found: 435.15 [M+H]+.1H 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 C20H30N6O3S: 434.21, found: 435.15 [M+H]+.1H 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-trioxotetrahydropyrimidin- 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-trioxotetrahydropyrimidin-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-trioxotetrahydropyrimidin- 1(2H)-yl)-2-azaspiro[3.5]nonan-2-yl)oxetane-3-carbonitrile (30 mg, 0.070 mmol) in DMSO (3 mL) was added K2CO3(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 H2O with 0.05% NH4HCO3) 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]+.1H 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-dioxoimidazolidin-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 C16H22O3: 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 LiAlH4(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 Na2SO4, 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 CBr4(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 H2O (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)imidazolidine-2,4-dione (0.71 g, 2.75 mmol) and Cs2CO3(1.35 g, 4.13 mmol) in DMF (15 mL) was heated at 50 °C for 12 h. The reaction was quenched with H2O (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 C25H40N2O4Si: 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 N2atmosphere. 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 C18H34N2O4Si: 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)cyclohexyl)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 N2. 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-dioxoimidazolidin-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)imidazolidin-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]+.1H 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 MeNH2replacing PMBNH2. 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:

[0013] tert-Butyl (2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin- 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 C22H38N6O5: 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)amino)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)carbamate (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 C25H42N6O6: 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)amino)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 H2O with 0.05% NH4HCO3) 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]+.1H NMR (400 MHz; DMSO-d6) 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]pyrimidine-4,6(5H)-dione (87) Synthetic scheme: O O O SEMCl,K2CO3LiOH, Me HN OSEMNOOH SEM N OH N DMF NHNH 2NH2 2O, THFNNH2SEMONHONH2O O NNNSEM HATU, DIEASEMCDINNN NH O NHDMFNH2DMF O DEAD, PPh3SEM N NH O N O N O O N N N N TFA / DCM ONNSEM ONNHNH3O O Ethyl 3-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (3 g, 19.34 mmol) in DMF (80 mL) was added K2CO3(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-carboxylic 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-pyrazole-4-carboxamide To a solution of 3-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylic 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 C14H28N4O2Si: 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-pyrazole-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 C15H26N4O3Si: 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)cyclohexyl)-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 ONNSEM 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)imidazolidine-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 N2atmosphere. 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)cyclohexyl)-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 NH3in 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 C21H30N6O4: 430.23, found: 431.15 [M+H]+.1H 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]pyrimidine-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-carbaldehyde 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 POCl3(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 Na2SO4, 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-tetrahydropyrimidine-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) CH3CN and H2O with 10 mmol / L NH4HCO3) 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]+.1H 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-dioxoimidazolidin-1- yl)methyl)cyclohexyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (98) Synthetic scheme:

[0014] 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)cyclohexyl)-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 N2. 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)cyclohexyl)-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)cyclohexyl)-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)cyclohexyl)-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)cyclohexyl)-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)cyclohexyl)-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)cyclohexyl)-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 NH2OH.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)cyclohexyl)-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)cyclohexyl)-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 CH2Cl2(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 C28H45N5O5Si: 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)cyclohexyl)-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)cyclohexyl)-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)cyclohexyl)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)cyclohexyl)-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 C29H46N6O5Si: 586.33, found: 587.35 [M+H]+. 5-Amino-1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1- yl)methyl)cyclohexyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione 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)cyclohexyl)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 NH3in 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]+.1H 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[4.1.57.15]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[4.1.57.15]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 (NH4)2CO3(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 H2O with 0.05% NH4HCO3) 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]+.1H 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 NH4Cl (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 C9H12N4O2: 208.10, found: 209.2 [M+H]+. 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl) imidazolidin-1-yl)methyl)cyclohexyl)imidazo[1,2-a][1,3,5]triazine-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)cyclohexyl)imidazo[1,2- a][1,3,5]triazine-2,4(1H,3H)-dione (0.17 g, 0.30 mmol) in DCM (2 mL) and H2O (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 Na2SO4and 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 C21H30N6O4: 430.23, found: 431.2 [M+H]+.1H 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-trioxotetrahydropyrimidin- 1(2H)-yl)spiro[3.5]nonan-2-yl)-1-cyclopropylurea (110) Synthetic scheme: N-Cyclopropyl-8,11-dioxadispiro[3.2.47.24]tridecan-2-amine To a solution of 8,11-dioxadispiro[3.2.47.24]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 H2O (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.1H 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[3.2.47.24]tridecan-2-yl)carbamate To a solution of N-cyclopropyl-8,11-dioxadispiro[3.2.47.24]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 H2O (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.1H NMR (400 MHz, CDCl3) 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[3.2.47.24]tridecan-2- yl)carbamate (3.1 g, 8.35 mmol) in acetone (30 mL) and H2O (15 mL) was added TsOH.H2O (3.17 g, 16.69 mmol) at 25 °C. After stirring for 2 h, the reaction was diluted with H2O (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 NH4OAc (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 N2. After heating at 50 °C for 12 h, the reaction was concentrated under reduced pressure. The residue was adjusted to pH = 8 by saturated NaHCO3. The mixture was diluted with H2O (40 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 g, crude) as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C2H28N2O2: 328.22, found: 329.3 [M+H]+. Benzyl (7-(3-butylureido)spiro[3.5]nonan-2-yl)(cyclopropyl)carbamate 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 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 (4.1 g, 52.5%) as a white solid. MS (ESI): mass calcd. for C25H37N3O3: 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 Ac2O (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)pyrimidine-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 C24H31N3O3: 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)pyrimidine- 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 C21H32N4O4: 404.24, found: 405.3 [M+H]+. 1-(7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-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 Na2SO4, 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 C22H34N6O4: 446.26, found: 447.3 [M+H]+.1H 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-dioxoimidazolidin-1- yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[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)cyclohexyl)-4,6-dioxo-4,5,6,7- tetrahydroisothiazolo[3,4-d]pyrimidine-3-carboxamide O NH S2N O O N N ONNSEM 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)cyclohexyl)-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 N2. 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 (SiO2, 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-carboxamide 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)cyclohexyl)-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 (NH4HCO3)-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]+.1H NMR (400 MHz, CDCl3) 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-tetrahydroisothiazolo[3,4-d]pyrimidin-3- yl)methanesulfonamide Synthetic scheme: 7-Butyl-3-((2,4-dimethoxybenzyl)amino)-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)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)cyclohexyl)-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 H2O (60 mL) and extracted with EtOAc (3 x 50 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 : 1 to 2 : 1) to provide the title compound (1.2 g, 72%) as a yellow solid.1H 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-dioxoimidazolidin-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-dimethyl- 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 Na2SO4, 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-dioxoimidazolidin- 1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-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 NH4Cl (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 (NH4HCO3)-ACN) to provide the title compound (9.8 mg, 7%) as a white solid. MS (ESI): mass calcd. for C22H32N6O6S2: 540.18, found: 540.2 [M+H]+.1H 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-dioxoimidazolidin-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 NH4Cl (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-(trimethylsilyl)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 NaBH4(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 K2CO3(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 C8H11ClN2O2: 202.05, found: 203.2 [M+H]+. 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 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-λ5-phosphanylidene)acetonitrile (3.62 g, 15.00 mmol) was added dropwise. After stirring at 120 °C for 12 h under N2, 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-(trimethylsilyl)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 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 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)ethoxy)methyl)imidazolidin-1- yl)spiro[3.5]nonan-7-yl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[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 Na2SO4, 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 C30H44N6O5SSi: 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]nonan-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 C38H56N6O7SSi: 768.37, found: 769.3 [M+H]+. 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 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). K2CO3(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 (NH4HCO3)-ACN]; 40% to 70% B) to provide the title compound (15 mg, 11.5%) as a white solid. MS (ESI): mass calcd. for C23H32N6O4S: 488.22, found: 489.3 [M+H]+. 3-Amino-7-butyl-5-(2-(3-ethyl-5,5-dimethyl-2,4-dioxoimidazolidin-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 K2CO3(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 ( NH4HCO3)-ACN]; 40% to 70%B) to provide the title compound (113) as a white solid. MS (ESI): mass calcd. for C25H36N6O4S: 516.25, found: 517.2 [M+H]+.1H 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 Na2SO4, 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 C6H10N2O2: 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 Na2SO4, 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 C13H15BrN2O2: 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 H2O (2 mL) was added NaN3(313.4 mg, 4.8 mmol), CuSO4(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 Na2CO3(5 mL), diluted with H2O (10 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 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 C13H15N5O2: 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 H2O (2 mL) was added PPh3(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 C13H17N3O2: 247.13, found: 248.3 [M+H]+. 1-Butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)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 C18H26N4O3: 346.20, found: 347.3 [M+H]+. 1-Butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1yl)methyl)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 (SiO2, petroleum ether : EtOAc = 0 : 1) to provide the title compound (0.4 g) as a white solid. MS (ESI): mass calcd. for C21H26N4O5: 414.19, found: 415.2 [M+H]+. 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) H2N NH2O O O N N ONNO 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 (NH4HCO3)-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]+.1H 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]pyrimidine-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]pyrimidine-4,6(5H,7H)-dione (120) Synthetic scheme:

[0015] HOO CN N SEM CN SOHN O O O S SEM DMBNH N2N NH N N DMoCMBP, tolue A, 90 C, 4h N ne, o N N Bu O 1 O n- 00 C, 12 h n-Bu O H NH NHDMB2O O O O S S SEM TFA / H2O N NH N N N N N N N N O O n-Bu O H n-Bu O H NH2NH2O O O O S S SFC separation N NH N NH N N N NONN O O H O H 1-Butyl-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-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 N2. After stirring at 25 °C for 12 h, the reaction was quenched with saturated NH4Cl (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.1H 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)pyrimidine-2,4(1H,3H)-dione To a solution of 1-butyl-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine- 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 NH4Cl (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)pyrimidine- 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.1H 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]pyrimidine-3-carbonitrile (INT A) A mixture of 7-butyl-4,6-dioxo-5-(2-trimethylsilylethoxymethyl)isothiazolo[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 Na2SO4and 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.1H NMR (400 MHz, CDCl3) 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[4.1.57.15]tridecane-2,4,10-trione To a solution of 11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]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 C11H14N2O3: 222.10, found: 223.2 [M+H]+. 3-((2-(Trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.57.15]tridecane-2,4,10-trione To a solution of 1,3-diazadispiro[4.1.57.15]tridecane-2,4,10-trione (5 g, 22.5 mmol) in DMA (50 mL) was added K2CO3(6.22 g, 45 mmol) and SEM-Cl (5.63 g, 33.8 mmol). After stirring at 25 °C for 3 h, the reaction was diluted with H2O (150 mL) and extracted with EtOAc (3 x 70 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 100 : 0 to 1 : 2) to provide the title compound (1.33 g, 16.8%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 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-diazadispiro[4.1.57.15]tridecane- 2,4-dione (INT B) To a solution of 2-(2-trimethylsilylethoxymethyl)-2,4- diazadispiro[4.1.57.15]tridecane-1,3,10-trione (1.7 g, 4.82 mmol) in MeOH (15 mL) was added NaBH4(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 Na2SO4,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[4.1.57.15] 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-carbonitrile (INTA, 430 mg, 1.72 mmol) and 10-hydroxy-2-(2-trimethylsilylethoxymethyl)-2,4- diazadispiro[4.1.57.15]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 H2O (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 C27H38N6O5SSi 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[4.1.57.15]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[4.1.57.15]tridecan-10-yl]-4,6-dioxo-isothiazolo[3,4-d]pyrimidine-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 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 (240 mg, 84.2%) as a white solid. MS (ESI): mass calcd. for C35H50N6O7SSi: 726.32, found: 727.3 [M+H]+. 3-Amino-7-butyl-5-(2,4-dioxo-1,3-diazadispiro[4.1.57.15]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[4.1.57.15]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 H2O (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 Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase HPLC (mobile phase: [water (NH4HCO3)-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[4.1.57.15]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[4.1.57.15]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[4.1.57.15]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]+.1H NMR (400 MHz, DMSO-d6) 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]+.1H 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-dioxoimidazolidin-1- yl)methyl)-4-fluorocyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (119) Synthetic scheme: 2,7,10-Trioxadispiro[2.2.46.23]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 N2. 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 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 (12.19 g, 56.5%) as a yellow oil.1H NMR (400 MHz, CDCl3) 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[2.2.46.23]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 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 (3.56 g, 26.1%) as a yellow oil.1H NMR (400 MHz, CDCl3) 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.1H 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-methyl-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.1H NMR (400 MHz, CDCl3) 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-dimethyl-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 N2. After heating at 100 °C for 12 h, the reaction was quenched with addition of NaHCO3and 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-imidazolidine-2,4-dione To a mixture of 1-[(8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methyl]-5,5-dimethyl- imidazolidine-2,4-dione (0.62 g, 2.06 mmol) in acetone (4 mL) and H2O (2 mL) was added TsOH.H2O (785.4 mg, 4.1 mmol) in one portion at 25 °C under N2. 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 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 afford the title compound (0.27 g, 51%) as a white solid.1H NMR (400 MHz, CDCl3) 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-imidazolidine- 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 N2. SEM-Cl (663.6 mg, 3.98 mmol) was added at 0 °C under N2. 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 Na2SO4, 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 NaBH4(44 mg, 1.16 mmol) in one portion at 0 °C under N2. 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 Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether : EtOAc = 20 : 1 to 1 : 1) to afford the title compound (0.3 g, 60%) as a colorless oil.1H NMR (400 MHz, CDCl3) 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-dimethyl-2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)-4- fluorocyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione 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 N2. The reaction was cooled down to 0 °C and DEAD (250.1 mg, 1.44 mmol) was added under N2. After heating at 40 °C for 12 h, the reaction was poured into H2O (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-dioxoimidazolidin-1-yl)methyl)-4- fluorocyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (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)imidazolidin-1-yl)methyl)-4- fluorocyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (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 Na2SO4, 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]+.1H 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: [CO2-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[4.1.57.15]tridecan-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione Synthetic scheme: 11,14-Dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione To a mixture of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (15 g, 76.4 mmol) in MeOH (150 mL) and H2O (150 mL) was added TMSCN (15.17 g, 152.9 mmol) and (NH4)2CO3 (29.38 g, 305.7 mmol) in one portion at 25 °C under N2. After heating at 90 °C for 12 h, the reaction was concentrated under reduced pressure to remove MeOH. The precipitate was collected by filtration, washed with H2O (3 x 100 mL) and dried under vacuum to provide the title compound (13.65 g, 67.1%) as a white solid, which was used directly in the next step without further purification.1H NMR (400 MHz, DMSO-d6) 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[4.1.2.410.27.15]heptadecane-1,3-dione To a mixture of 11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione (6 g, 22.5 mmol) in DMF (50 mL) was added MeI (3.52 g, 24.8 mmol) and K2CO3(3.43 g, 24.8 mmol) in one portion at 0 °C under N2. The reaction was stirred at 25 °C for 1...

Claims

We claim:

1. 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 CR2; 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 (C1-C6)alkyl;R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, 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-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-, R1taken together with the atom to which it is attached forms a 4- to 7- membered heterocycloalkyl ring, provided that if Y is or , then R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen, (C1-C6)alkyl, or (C3-C8)cycloalkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHRa, (C1- C6)alkoxy, -CONRaRbor (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb; or R1and R2taken 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, halo, (C1-C6)alkoxy, cyano, carboxy, -CONRaRb, and -SO2Ra; R3is (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-C8)cycloalkyl, aryl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare independently for each occurrence hydrogen, (C1-C6)alkyl, or 4- to 7- membered heterocycloalkyl, wherein (C1-C6)alkyl and 4- to 7-membered heterocycloalkyl areoptionally 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 Raand Rbtaken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R5a, R5b, R6a, and R6bare independently hydrogen or (C1-C6)alkyl; RAis 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.

2. A compound of Formula (Ia) or (Ib): (Ia); or (Ib); or a pharmaceutically acceptable salt thereof; wherein: Y represents: , , , , or ;X is N or CR2; 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 (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, 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- 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, 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-, R1taken together with the atom to which it is attached forms a 4- to 7- membered heterocycloalkyl ring, provided that if Y is or , then R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen, (C1-C6)alkyl, or (C3-C8)cycloalkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHRa, (C1-C6)alkoxy, -CONRaRbor (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb; or R1and R2taken 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- C6)alkoxy, cyano, carboxy, -CONRaRb, and -SO2Ra;R3is (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-C8)cycloalkyl, aryl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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 Raand Rbtaken together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R5a, R5b, R6a, and R6bare 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.

3. A compound of Formula (Ia) or (Ib): (Ia); or (Ib); or a pharmaceutically acceptable salt thereof; wherein: Y represents: , , ,, or ; X is N or CR2; 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 (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, 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-, R1taken together with the atom to which it is attached forms a 4- to 7-membered heterocycloalkyl ring, provided that if Y is or , then R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen or (C1-C6)alkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6)alkyl, NHRa, (C1-C6)alkoxy, -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb; or R1and R2taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R3is (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- C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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 Raand Rbtaken 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.

4. The compound of any one of claims 1 to 3, wherein Y represents: .

5. The compound of any one of claims 1 to 3, wherein Y represents: .

6. The compound of any one of claims 1 to 3, wherein Y represents: .

7. The compound of any one of claims 1 to 6, wherein R1is:hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R1d, R1e, and R1fare 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 (C3-C8)cycloalkyl or phenyl; or R1dand R1etaken together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl each of which is optionally substituted with hydroxy.

8. The compound of claim 7, wherein R1is , and: Raand Rbare each hydrogen, or Rais hydrogen; and Rbis methyl.

9. The compound of any one of claims 1 to 6, wherein R1is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R1d, R1e, and R1fare 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 (C3-C8)cycloalkyl or phenyl; or R1dand R1etaken together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl each of which is optionally substituted with hydroxy.

10. The compound of any one of claims 1 to 6, wherein R1is:hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein: R1d, R1e, and R1fare independently for each occurrence selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; or R1dand R1etaken together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl.

11. The compound of any one of claims 7, 9, and 10, wherein R1is, , and R1dand R1etaken together with the carbon to which they are attached form morpholine, cyclobutane, oxetane, azetidine, or cyclohexane.

12. The compound of any one of claims 7 and 9-11, wherein R1dand R1eare each methyl.

13. The compound of any one of claims 7 and 9-12, wherein R1fis hydrogen.

14. The compound of any one of claims 7 and 9-12, wherein R1fis (C1-C6)alkyl.

15. The compound of claim 14, wherein R1fis methyl or ethyl.

16. The compound of any one of claims 7 and 9-12, wherein R1fis (C1-C6)fluoroalkyl.

17. The compound of claim 16, wherein R1fis 2,2,2-trifluorethyl.

18. The compound of any one of claims 7, 9, and 10, wherein R1is ; and R1ais cyclopropyl, 2-propyl, ethyl, or methyl.

19. The compound of any one of claims 1 to 6, wherein R1is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

20. The compound of any one of claims 1 to 6, wherein R1is: , , , , , , , , , or .

21. The compound of any one of claims 1 to 17, wherein Y is, , , , , , , , , , , , , , , , , , , or .

22. The compound of any one of claims 1 to 5 and 7 to 20, wherein X is N.

23. The compound of any one of claims 1 to 5 and 6 to 20, wherein X is CR2.

24. The compound of claim 23, wherein R2is hydrogen.

25. The compound of claim 23, wherein R2is fluoro.

26. The compound of claim 23, wherein R2is (C1-C6)alkyl optionally substituted with (C1-C6)alkoxy.

27. The compound of claim 26 wherein R2is methyl.

28. The compound of claim 26, wherein R2is methoxymethyl.

29. The compound of claim 23, wherein R1is or ; and R2is –CH3 or -CH2-OCH3.

30. The compound of claim 23, wherein R1and R2taken 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 (C1-C6)alkyl, wherein the (C1-C6)alkyl is further optionally substituted with one or moresubstitutents independently selected from (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocyloalkyl, hydroxy, halo, (C1-C6)alkoxy, cyano, carboxy, -CONRaRb, and -SO2Ra.

31. The compound of claim 30, wherein R1and R2taken together with the atom to which they are attached form: , , , or ; wherein R1gand R1hare each independently hydrogen or (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted with one or more substitutents independently selected from (C3-C8)cycloalkyl, 4- to 7-membered heterocylcylalkyl, hydroxy, halo, (C1-C6)alkoxy, cyano, carboxy, -CONRaRb, and -SO2Ra.

32. The compound of claim 31, wherein R1his ethyl, methyl, ethyl, isopropyl, or t-butyl, each of which is optionally substituted with hydroxy, methoxy, cyclopropyl, oxetanyl, tetrahydrofuranyl, phenyl, cyano, carboxy, hydroxy, -CONRaRb, -SO2Ra, or one to three fluorine atoms.

33. The compound of claim 32, wherein R1his trifluoromethyl.

34. The compound of any one of claims 31 to 33, wherein R1ghydrogen, methyl, or ethyl, wherein methyl or ethyl is optionally substituted with cyano.

35. The compound of any one of claims 1 to 34, wherein Rais methyl.

36. The compound of any one of claims 1 to 35, wherein Rbis methyl.

37. The compound of claim 30, wherein R1and R2taken together with the atom to which they are attached form:, , , , , , , , , , or .

38. The compound of claim 30, wherein R1and R2taken together with the atom to which they are attached form: .

39. The compound of claim 30, wherein R1and R2taken together with the atom to which they are attached form: .

40. The compound of any one of claims 1 to 5 and 7 to 39, wherein n is 1.

41. The compound of any one of claims 1 to 5 and 7 to 39, wherein n is 0.

42. The compound of any one of claims 1 to 5 and 7 to 41, wherein m is 1.

43. The compound of any one of claims 1 to 5 and 7 to 41, wherein m is 0.

44. The compound of any one of claims 1 to 5 and 7 to 43, wherein p is 1.

45. The compound of any one of claims 1 to 5 and 7 to 43, wherein p is 0.

46. The compound of any one of claims 1 to 5 and 7 to 45, wherein, q is 1.

47. The compound of any one of claims 1 to 5 and 7 to 45, wherein, q is 0.

48. The compound of any one of claims 1 to 5 and 7 to 43, wherein p is 0; and q is 2.

49. The compound of any one of claims 1 to 5 and 7 to 39, wherein n, m, p, and q are each 1.

50. The compound of any one of claims 1 to 5 and 7 to 39, wherein n, m, p, and q are each 0.

51. The compound of any one of claims 1-3 and 6 to 20, wherein B represents cyclohexyl or cyclopentyl.

52. The compound of any one of claims 1-3 and 6 to 20, wherein B represents phenyl, tolyl, or pyridyl.

53. The compound of any one of claims 1-3 and 6 to 20, wherein B represents 4- to 7- membered hetercycloalkyl.

54. The compound of any one of claims 1, 2, and 5 to 17, wherein B represents: , , , , , , , , , , , or .

55. The compound of any one of claims 11-3 and 6 to 20, and 51-54, wherein L represents methylene, ethylene, or n-butylene.

56. The compound of any one of claims 1 to 55, wherein R5a, R5b, R6a, and R6bare each hydrogen.

57. The compound of any one of claims 1 to 55, wherein R5a, R5b, R6a, and R6bare each methyl.

58. The compound of any one of claims 1 to 55, wherein R5ais methyl and R5b, R6a, and R6bare each hydrogen.

59. The compound of any one of claims 1 and 4 to 58, wherein Z is O.

60. The compound of any one of claims 1 and 4 to 20, wherein RAis hydrogen.

61. The compound of claim 60, wherein RAis methyl.

62. The compound of claim 1, wherein the compound has the structure of Formula (Ic): (Ic), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from (C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, 5- to 6- membered heteroaryl, NRaRb, or ;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, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy.

63. The compound of claim 1, wherein the compound has the structure of Formula (Id): (Id), or a pharmaceutically acceptable salt thereof, wherein R1is selected from -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaRb, C3- C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or ; 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-C6)hydroxyalkyl, R1ais hydrogen or (C1-C6)alkyl; R2is selected from hydrogen, cyano, hydroxyl, NH2, NHCOCH3, NHRa, (C1- C6)alkoxy. -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6)alkoxy, and NRaRb.

64. The compound of claim 1, wherein the compound has the structure of Formula (Ie): (Ie),or a pharmaceutically acceptable salt thereof, wherein A represents a 4- to 7- membered heterocycloalkyl.

65. The compound of any one of claims 1 to 64, wherein R3is methyl, n-propyl, n-butyl, , , , , or .

66. The compound of any one of claims 1 to 64, wherein R3is methyl, n-butyl, , , , , or .

67. The compound of any one of claims 1 to 66, wherein the compound is represented by Formula Ia.

68. The compound of any one of claims 1 to 66, wherein the compound is represented by Formula Ib.

69. A compound having the structure: , , , , ,, , H2N NH2O O N N O N ONH2, ,H2N NH2O O N N O N H2N O , , , , , ,, , , , , , , , , , , ,, , , , , , , , ,, , , , , ,, , , , , , , , , , , , , ,, , , , , , , , ,, , , , , , , , , , ,, , , , , , , , , , , , ,H2N NH2H2N NH2O O O O O O N N N N ONNHONNHO , O , H2N NH2H2N NH2O O O O O O N N N N ONNHONNHO , O , H H2N NH2 2N NH2O O O O OOON N N N ONNHONNHO , O , H2N NH2H2N NH2O O O O OOOON N N N ONNHONNHO , O , H2N NH2O O O N N ONNHO , , ; ,, , NH2H2N O H O O N NNNHO O , O , O NH2NH2O H2N O H2N O H O NNHO N NNNHO N N H O O O O , , NH NH 2 O2H H 2N O2N O O NNHO NO NNHN N H N O O O O , O , NH2NH2OH2N O O H2N O N ONHNNONN N NHO O O O , , NH2NH2OH2N O H2N O O HNHONNON NNN NHO O O O , ,, , NH NH22H H 2N O O2N O O NH2ONHNN2O NNN N O O , , NH2NH2H2N O OH2NOO N NH OHNNONNO N O N O O O , , NH2H2N O H O O N NNHN O O ,O, NH2O H2N O N NH O N N H O O , ,NH2O O H2N O NNHO N N H O O , , NH2H2N O H O O N N N NH O O , , NH2NH2H2N O O H2N O O NH N O N O N NNO N HNH O O O , , NH2NH2H O H N O O 2NHO2NN O N O N N N N N O OOO H , , NH2NH2O O H2N OHO H2N N N O N O N N N NNO OOOH, , NH2H2N OHN O O N N N CF3O O ,NH2NH2H2N O O H2N OHO N CF3 NO N O N NNNH H O N O OO, , NH2NH2O O HN O H2N2N O N O N O N N N N N O O H O O , , NH2NH2HN O O HN O O 22NH N O N O N N N N O O N O , , NH2NH2N H2N O H O O 2N N O N O N N NH N N O O O O , , NH2H2N O O NH O N N O N , , , or ; or a pharmaceutically acceptable salt thereof.

70. A compound having the structure:, , , , , , , ,H2N NH2O O N N O N ONH2, ,H2N NH2O O N N O N H2N O , , , , , ,, , , , , , , , , , , ,, , , , , , , , , ,, , , , , , ,, , , , , , , , , , , , , ,, , , , , , , , ,, , , , , , , , , , ,H2N NH2H2N NH2O O O O N N N N O O H2N NH2O O O N NH2N N N NH N NH N N O , , , H2N NH2H2N NH2O O O O N N N N O O H2N N O OHH N H2N NNO O N ONNO,NH2, orH, or a pharmaceutically acceptable salt thereof.

71. A compound having the structure: , , ,NH2N H2N O NH N O N O N H O , , NH2O H2N O NH N O N H N O O , , , , , , , , , , , , ,, , , , , , , , , , , NH2O H2N O N O N N N O O , ,, , , , , , , , NH2O H2N O N O N N N O O , ,, , , , , , , , , ,, , , , , , , , HO NH2O H2N O N O N N N O O , ,O NH2O H2N O N O N NH N O O , , , , , , MeO NH2O H2N O N O N N N O O , , , ,, , , , , , , , , ,, , , , , , NH2NH2O O H2N O H2N NH H O N O N O N N N O N NCNO O O , , , ,, , , , , , , ,NH2NH2COOH H2NON O H2N O NH N N O N O N H NH N O N O O O , , HO NH2O H2N O N O N NH N O O , or a pharmaceutically acceptable salt thereof.

72. A compound having the structure: , , , , , ,, , , , , , , , , ,, , , , , , , , , ,, , , , , , , , , ,, , , , , , , , , ,, , , , , , , , , ,, , , , , , , ,, , or a pharmaceutically acceptable salt thereof.

73. A compound according to Formula (IIa) or (IIb): R4 R4 ZZN OON3NNY3NNR RYO (IIa); or O (IIb); or a pharmaceutically acceptable salt thereof; wherein: Y represents: n p mXR1q, n XR1, n XR1, R1,or; X is N or CR2; L is -(C1-C6)alkylenyl-; B represents (C3-C8)cycloalkyl, (C6-C10)aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaR, 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-, R1taken 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 R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen or (C1-C6)alkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1- C6)alkoxy; or R1and R2taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R3is (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- C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl;Raand Rbare 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 Raand Rbtaken 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; R4is H, -C(O)NH2, (C1-C6)alkyl, -NHSO2Me, or -N(R4a)2; and R4ais independently for each occurrence hydrogen or (C1-C6)alkyl.

74. The compound of claim 73, wherein Y represents: .

75. The compound of claim74, wherein Y represents: .

76. The compound of any one of claims 73 to 75, wherein R1is: .

77. The compound of any one of claims 73 to 75, wherein R1is: .

78. The compound of any one of claims 73 to 77, wherein R1is:hydrogen, , , , , , , , , , , , , or , , , , , , , , , , , , , , or ; and R1d, R1e, and R1fare independently for each occurrence selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; or R1dand R1etaken together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl.

79. The compound of claim 78, wherein R1is, ; and R1dand R1etaken together with the carbon to which they are attached form morpholine, cyclobutane, oxetane, or cyclohexane.

80. The compound of claim 79, wherein R1dand R1eare each methyl.

81. The compound of any one of claims 78 to 80, wherein R1fis hydrogen.

82. The compound of any one of claims 78 to 80, wherein R1fis (C1-C6)alkyl.

83. The compound of claim 82, wherein R1fis methyl or ethyl.

84. The compound of any one of claims 78 to 80, wherein R1fis (C1-C6)fluoroalkyl.

85. The compound of claim 84, wherein R1fis 2,2,2-trifluorethyl.

86. The compound of any one of claims 73 to 77, wherein R1is: hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , or .

87. The compound of any one of claims 73 to 86, wherein Y is , , , , , , , , , , , , , , , , , , , or .

88. The compound of any one of claims 73 and 74 to 84, wherein X is N.

89. The compound of any one of claims 73 and 74 to 84, wherein X is CR2.

90. The compound of claim 89, wherein R2is hydrogen.

91. The compound of claim 89, wherein R2is fluoro.

92. The compound of claim 89, wherein R2is (C1-C6)alkyl optionally substituted with (C1- C6)alkoxy.

93. The compound of claim 92, wherein R2is methyl.

94. The compound of claim 92, wherein R2is methoxymethyl.

95. The compound of claim 89, wherein R1is or , and R2is –CH3or -CH2-OCH3.

96. The compound of claim 89, wherein R1and R2taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl.

97. The compound of claim96, wherein R1and R2taken together with the atom to which they are attached form: , , , or .

98. The compound of any one of claims 73 to 97, wherein R3is: methyl, , , , , , , , or .

99. The compound of any one of claims 73 to 98, wherein Z is O.

100. The compound of any one of claims 73 to 98, wherein Z is S.

101. The compound of any one of claims 73 to 100, wherein R4is H.

102. The compound of any one of claims 73 to 100, wherein R4is NH2.

103. A compound having the structure: , , , , , , NH2O O S NH2N N N N O ,,, , , ; , , , , , , ,, , , , , , , , , , , ,H2NOOO S NH N N N O N O , , , or ; or a pharmaceutically acceptable salt thereof.

104. A compound having the structure: , , , , , , , ,, , , ; , or , or a pharmaceutically acceptable salt thereof.

105. A compound having the structure: ,, , , , , , , , , or ; or a pharmaceutically acceptable salt thereof.

106. A compound according to Formula (IIIa), (IIIb), (IIIc), or (IIId): R4 NONHNNR1R3Y(IIIa); O (IIIb);(IIIc); or (IIId); or a pharmaceutically acceptable salt thereof; wherein: Y-R1represents: , , , , , or -(C1-C6)alkylene-R1; X is N or CR2; L is -(C1-C6)alkylenyl-; B represents (C3-C8)cycloalkyl, (C6-C10)aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R1is hydrogen, -CO2Ra-CONRaRb, -SO2Ra, -SONRaRb, -SO2NRaRb, -NRaR, 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 moresubstituents 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-, R1taken 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 R1is not hydrogen; R1a, R1b, and R1care independently for each occurrence hydrogen or (C1-C6)alkyl; or R1aand R1btaken together with the atoms to which they are attached form a 5- or 6- membered heterocycloalkyl; R2is hydrogen, fluoro, chloro, -CONRaRbor (C1-C6)alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1- C6)alkoxy; or R1and R2taken together with the atom to which they are attached form a 4- to 7-membered heterocycloalkyl; R3is (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-C8)cycloalkyl, carboxamido, amino, cyano, carboxy, and alkoxycarbonyl; Raand Rbare 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 Raand Rbtaken 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; R4is H or N(R4a)2; and R4ais independently for each occurrence hydrogen or (C1-C6)alkyl.

107. The compound of claim 106, wherein R1is:hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , or .

108. The compound of claim 106, wherein R1is or ; and R2is –CH3or -CH2-OCH3.

109. The compound of claim 106, wherein R1is: .

110. The compound of claim 106, wherein R1is: or .

111. The compound of any one of claims 106 to 110, wherein Y is, , , , , , , , , , , , , , , , , , , or .

112. The compound of any one of claims 106 to 111, wherein R3is: methyl, , , , , , or .

113. The compound of any one of claims 106 to 110, wherein R4is H.

114. The compound of any one of claims 106 to 110, wherein R4is NH2.

115. A compound having the structure:, , , , or ; or a pharmaceutically acceptable salt thereof.

116. A pharmaceutical composition, comprising a compound of any one of claims 1 to 115, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

117. 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 any one of claims 1 to 115, or a pharmaceutically acceptable salt thereof.

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