Compounds, compositions, and methods of use for treating hypoparathyroidism and osteoporosis

Abstract

Disclosed are a compound that is a parathyroid hormone receptor 1 agonist and a method useful for preventing or treating osteoporosis, fractures, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia, or neoplastic calcification.

Description

Cross-reference of related applications

[0001] This application claims priority over U.S. Provisional Patent Application No. 63 / 418,754 filed on 24 October 2022, No. 63 / 464,457 filed on 5 May 2023, and No. 63 / 532,181 filed on 11 August 2023, each of which is incorporated herein by reference in whole. [Background technology]

[0002] The regulation of calcium levels is crucial for the normal functioning of the gastrointestinal tract, skeletal system, nervous system, muscular system, and cardiovascular system. The synthesis and release of parathyroid hormone (PTH) are primarily controlled by serum calcium levels.

[0003] Osteoporosis is characterized by bone loss that increases the incidence of fractures. While most commonly affecting the spine and hips, it impacts one in three postmenopausal women and a smaller but significant number of older men, as well as other conditions, including hypogonadism and long-term glucocorticoid use. Current therapies for treating osteoporosis, such as bisphosphonates, hormone replacement therapy, SERMs, and calcitonin, work by inhibiting bone resorption, thereby preventing further bone loss. These treatments may slow or even prevent the continuation of bone loss, but they do not promote new bone formation that improves bone mass and strength. Therefore, therapeutic agents that can stimulate bone formation remain necessary. Such agents would likely be beneficial for both patients at risk of developing osteoporosis and those with confirmed osteoporosis.

[0004] Parathyroid hormone (PTH) is a key regulator of calcium homeostasis, acting partly by mobilizing calcium from the skeleton through increased bone resorption. In addition, pulsed administration of PTH can stimulate new bone formation in both experimental animals and humans. Therefore, there is evidence suggesting that targeting PTH receptors with small molecule agonists that mimic the action of PTH may be a suitable approach to inducing an anabolic response in bone. PTH exerts its effects by binding to and activating a class B G protein-binding receptor (referred to as PTH1R) of the seven-transmembrane superfamily. PTH1R activates multiple signaling pathways, primarily the adenylyl cyclase / cyclic AMP and phospholipase C / calcium mobilization pathways.

[0005] Therefore, in this field of technology, there is a need to provide small molecule therapeutics for treating or preventing hypoparathyroidism, osteoporosis, and related conditions. In particular, there is a need to provide compounds that act as PTH1R agonists. [Overview of the project] [Means for solving the problem]

[0006] One aspect of the present invention provides compounds, compositions, and methods useful for preventing or treating osteoporosis, fractures, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia, or neoplastic calcification.

[0007] Therefore, in some embodiments, the present invention provides, Compounds having the structure of formula (Ia) or (Ib) below, [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Z is either O or S, Y is [ka] represents where X is N or CR 2 and L is -(C1-C6)alkylenyl- B is (C3-C8)cycloalkyl, (C6-C 10 )aryl, 4- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more (C1-C6)alkyl R 1 is hydrogen, -CO2R a , -CONR a R b , -SO2R a , -SONR a R b , -SO2NR a R b , -NR a R b , 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, [Chemical formula] or -O-(4- to 7-membered heterocycloalkyl), and the (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, 4- to 7-membered heterocycloalkyl and -O-(4- to 7-membered heterocycloalkyl) are each independently halo, hydroxy, oxo, cyano, amino, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, hydroxy(C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, [Chemical formula] optionally substituted with one or more substituents independently selected from (C3-C8)cycloalkyl(C1-C6)alkyl and benzyl, or when Y represents -L-B-, R1 It, together with the atom to which it is bonded, forms a 4-7 membered heterocycloalkyl ring, provided that Y is [ka] If so, R 1 Provided that it is not hydrogen, R 1a , R 1b and R 1c Each instance is independently either hydrogen, (C1-C6) alkyl, or (C3-C8) cycloalkyl, or R 1a and R 1b These, together with the atoms to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl group. R 2 These are hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6) alkyl, and NHR a (C1-C6) alkoxy, -CONR a R b Alternatively, it is a (C1-C6) alkyl group, and the (C1-C6) alkyl group may be a halo, hydroxy, cyano, (C1-C6) alkoxy, or NR group. a R b It is optionally substituted with one or more substituents independently selected from or R 1 and R 2 These, together with the atoms to which they are bonded, form 4- to 9-membered heterocycloalkyls optionally substituted with one or more substituents independently selected from (C1-C6)alkyls, and the (C1-C6)alkyl can further be (C3-C8)cycloalkyls, 4- to 7-membered heterocyclylalkyls, hydroxy, halo, (C1-C6)alkoxy, cyano, carboxy, -CONR a R b and -SO2R a It is arbitrarily replaced with, R 3is (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, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl. R a and R b Each instance is independently hydrogen, a (C1-C6) alkyl, or a 4-7 member heterocycloalkyl, and the (C1-C6) alkyl and 4-7 member heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6) alkoxy, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 4-7 member heterocycloalkyl group. R 5a , R 5b , R 6a and R 6b These are independently hydrogen or (C1-C6) alkyl, R A is hydrogen or (C1-C6) alkyl, n, m, and p are independently either 0 or 1. q is 0, 1, or 2. However, the sum of p and q must be equal to 0, 1, or 2.

[0008] In some embodiments, the present invention provides: The following formula (Ia) or (Ib) [ka] A compound having the structure, or a pharmaceutically acceptable salt thereof, During the ceremony, Y is [ka] This represents, X is N or CR 2 And, L is -(C1-C6)alkylenyl-, B is (C3-C8) cycloalkyl, (C6-C 10 ) represents an aryl, a 4- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more (C1-C6) alkyl groups. R 1 Hydrogen, -CO2R a ,-CONR a R b , -SO2R a -SONR a R b -SO2NR a R b , -NR a R b , 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy, [ka] Or -O-(4-7 member heterocycloalkyl), and the (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, 4-7 member heterocycloalkyl and -O-(4-7 member heterocycloalkyl) are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, hydroxy(C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, [ka] (C3-C8)cycloalkyl(C1-C6)alkyl and benzyl are optionally substituted with one or more substituents independently selected from these, or when Y represents -LB-, R 1It, together with the atom to which it is bonded, forms a 4-7 membered heterocycloalkyl ring, provided that Y is [ka] If so, R 1 Provided that it is not hydrogen, R 1a , R 1b and R 1c Each instance is independently either hydrogen, (C1-C6) alkyl, or (C3-C8) cycloalkyl, or R 1a and R 1b These, together with the atoms to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl group. R 2 These are hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6) alkyl, and NHR a (C1-C6) alkoxy, -CONR a R b Alternatively, it is a (C1-C6) alkyl group, and the (C1-C6) alkyl group may be a halo, hydroxy, cyano, (C1-C6) alkoxy, or NR group. a R b It is optionally substituted with one or more substituents independently selected from or R 1 and R 2 These, together with the atoms to which they are bonded, form 4- to 9-membered heterocycloalkyls optionally substituted with one or more substituents independently selected from (C1-C6)alkyls, and the (C1-C6)alkyl can further be (C3-C8)cycloalkyls, 4- to 7-membered heterocyclylalkyls, hydroxy, (C1-C6)alkoxy, cyano, carboxy, -CONR a R b and -SO2R a It is arbitrarily replaced with, R 3is (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, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl. R a and R b Each instance is independently hydrogen, a (C1-C6) alkyl, or a 4-7 member heterocycloalkyl, and the (C1-C6) alkyl and 4-7 member heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6) alkoxy, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 4-7 member heterocycloalkyl group. R 5a , R 5b , R 6a and R 6b These are independently hydrogen or (C1-C6) alkyl, n, m, and p are independently either 0 or 1. q is 0, 1, or 2. However, the sum of p and q must be equal to 0, 1, or 2.

[0009] In other embodiments, the present invention provides compounds according to the following formulas (Ia) and (Ib), [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Y is [ka] This represents, X is N or CR 2 And, L is -(C1-C6)alkylenyl-, B represents (C3-C8) cycloalkyl, (C6-C 10 ) aryl, 4- to 7-member heterocycloalkyl or 5- to 10-member heteroaryl, each of which is optionally substituted with one or more (C1-C6) alkyl, R 1 is hydrogen, -CO2R a , -CONR a R b , -SO2R a , -SONR a R b , -SO2NR a R b , -NR a R b , 4- to 7-member heterocycloalkyl, 5- to 6-member heteroaryl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy or

Chemical formula

Chemical formula

Chemical formula

[0010] In other embodiments, the present invention provides a compound according to the following formula (IIa) or (IIb), [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Y is [ka] This represents, X is N or CR 2 And, L is -(C1-C6)alkylenyl-, B is (C3-C8) cycloalkyl, (C6-C 10 ) represents an aryl or a 5-10 member heteroaryl, each of which is optionally substituted with one or more (C1-C6) alkyl groups. R 1 Hydrogen, -CO2R a ,-CONR a R b , -SO2R a -SONR a R b -SO2NR a R b , -NR a R, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy or [ka] The (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy and 4-7 member heterocycloalkyl are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl and [ka] R is optionally substituted with one or more substituents independently selected from or when Y represents -LB-. 1 It, together with the atom to which it is bonded, forms a 4-7 membered heterocycloalkyl ring, provided that Y is [ka] Or, if it is an (C1-C6) alkylene, R 1 Provided that it is not hydrogen, R 1a , R 1b and R 1c Each instance is independently either hydrogen or (C1-C6) alkyl, or R 1a and R 1b These, together with the atoms to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl group. R 2 is hydrogen, fluoro, chloro, -CONR a R b , or a (C1-C6) alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1-C6) alkoxy, or R 1 and R 2 These, together with the atoms to which they are bonded, form a 4-7 member heterocycloalkyl group. R 3is (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, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl. R a and R b Each instance is independently hydrogen, a (C1-C6) alkyl, or a 4-7 member heterocycloalkyl, and the (C1-C6) alkyl and 4-7 member heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6) alkoxy, 4-7 member heterocycloalkyl, or 5-6 member heteroaryl, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 4-7 member heterocycloalkyl group. n, m, and p are independently either 0 or 1. q is 0, 1, or 2. However, this is subject to the condition that the sum of p and q is equal to 0, 1, or 2. Z is either S or O, R 4 These are H, -C(O)NH2, (C1-C6)alkyl or -N(R 4a )2, R 4a Each instance is independently either hydrogen or a (C1-C6) alkyl group.

[0011] In yet another embodiment, the present invention provides compounds according to the following formulas (IIIa), (IIIb), (IIIc), or (IIId): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, YR 1 teeth, [ka] -(C1-C6)Alkilen-R 1 This represents, X is N or CR 2 And, L is -(C1-C6)alkylenyl-, B is (C3-C8) cycloalkyl, (C6-C 10 ) represents an aryl or a 5-10 member heteroaryl, each of which is optionally substituted with one or more (C1-C6) alkyl groups. R 1 Hydrogen, -CO2R a ,-CONR a R b , -SO2R a -SONR a R b -SO2NR a R b , -NR a R, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy or [ka] The (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy and 4-7 member heterocycloalkyl are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl and [ka] R is optionally substituted with one or more substituents independently selected from or when Y represents -LB-. 1 It, together with the atom to which it is bonded, forms a 4-7 membered heterocycloalkyl ring, provided that Y is [ka] Or, if it is an (C1-C6) alkylene, R 1 Provided that it is not hydrogen, R 1a , R 1b and R 1c Each instance is independently either hydrogen or (C1-C6) alkyl, or R 1a and R 1b These, together with the atoms to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl group. R 2 is hydrogen, fluoro, chloro, -CONR a R b , or a (C1-C6) alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1-C6) alkoxy, or R 1 and R 2 These, together with the atoms to which they are bonded, form a 4-7 member heterocycloalkyl group. R 3 is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl. R a and R b Each instance is independently hydrogen, a (C1-C6) alkyl, or a 4-7 member heterocycloalkyl, and the (C1-C6) alkyl and 4-7 member heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6) alkoxy, 4-7 member heterocycloalkyl, or 5-6 member heteroaryl, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 4-7 member heterocycloalkyl group. n, m, and p are independently either 0 or 1. q is 0, 1, or 2. However, this is subject to the condition that the sum of p and q is equal to 0, 1, or 2. R 4 is H or N(R 4a )2, R 4a Each instance is independently either hydrogen or a (C1-C6) alkyl group.

[0012] Other aspects of the present disclosure provide pharmaceutical compositions comprising compounds of formulas (Ia) to (IIId) or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

[0013] In yet another embodiment, the present invention provides a method for treating or preventing osteoporosis, fractures, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia, or neoplastic calcification, comprising administering an effective amount of a compound of formula (Ia) to (IIId) or a pharmaceutically acceptable salt thereof to a subject requiring such treatment or prevention.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which the present invention pertains. Methods and materials similar to or equivalent to those described herein may be used in the practice or testing of the present invention, but 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 any conflict, this specification shall prevail, including definitions. Furthermore, materials, methods, and examples are illustrative and not intended to limit the scope.

[0015] Other features, purposes, and advantages of the present invention will become apparent from the detailed description and claims. [Brief explanation of the drawing]

[0016] [Figure 1-1] This table shows exemplary compounds 1 to 105 of the present invention, along with their characterization data and biological activity. [Figure 1-2] This is a continuation of Figure 1-1. [Figure 1-3] This is a continuation of Figure 1-2. [Figure 1-4] This is a continuation of Figure 1-3. [Figure 1-5] This is a continuation of Figure 1-4. [Figure 1-6] This is a continuation of Figure 1-5. [Figure 1-7] This is a continuation of Figure 1-6. [Figure 1-8] This is a continuation of Figure 1-7. [Figure 1-9] This is a continuation of Figure 1-8. [Figure 1-10] This is a continuation of Figure 1-9. [Figure 1-11] This is a continuation of Figure 1-10. [Figure 1-12] This is a continuation of Figure 1-11. [Figure 1-13] This is a continuation of Figure 1-12. [Figure 1-14] This is a continuation of Figure 1-13. [Figure 1-15] This is a continuation of Figure 1-14. [Figure 1-16] This is a continuation of Figure 1-15. [Figure 1-17] This is a continuation of Figure 1-16. [Figure 1-18] This is a continuation of Figure 1-17. [Figure 1-19] This is a continuation of Figure 1-18. [Figure 1-20] This is a continuation of Figure 1-19. [Figure 1-21] This is a continuation of Figure 1-20. [Figure 1-22] This is a continuation of Figure 1-21. [Figure 1-23] This is a continuation of Figure 1-22. [Figure 1-24] This is a continuation of Figure 1-23. [Figure 2-1] This table shows exemplary compounds 106-191, along with their characterization data and biological activity. [Figure 2-2] This is a continuation of Figure 2-1. [Figure 2-3]This is a continuation of Figure 2-2. [Figure 2-4] This is a continuation of Figure 2-3. [Figure 2-5] This is a continuation of Figure 2-4. [Figure 2-6] This is a continuation of Figure 2-5. [Figure 2-7] This is a continuation of Figure 2-6. [Figure 2-8] This is a continuation of Figure 2-7. [Figure 2-9] This is a continuation of Figure 2-8. [Figure 2-10] This is a continuation of Figure 2-9. [Figure 2-11] This is a continuation of Figure 2-10. [Figure 2-12] This is a continuation of Figure 2-11. [Figure 2-13] This is a continuation of Figure 2-12. [Figure 2-14] This is a continuation of Figure 2-13. [Figure 2-15] This is a continuation of Figure 2-14. [Figure 2-16] This is a continuation of Figure 2-15. [Figure 2-17] This is a continuation of Figure 2-16. [Figure 2-18] This is a continuation of Figure 2-17. [Figure 2-19] This is a continuation of Figure 2-18. [Figure 2-20] This is a continuation of Figure 2-19. [Figure 2-21] This is a continuation of Figure 2-20. [Figure 2-22] This is a continuation of Figure 2-21. [Figure 2-23] This is a continuation of Figure 2-22. [Figure 2-24] This is a continuation of Figure 2-23. [Figure 2-25] This is a continuation of Figure 2-24. [Figure 2-26] This is a continuation of Figure 2-25. [Figure 2-27] This is a continuation of Figure 2-26. [Figure 2-28] This is a continuation of Figure 2-27. [Figure 2-29] This is a continuation of Figure 2-28. [Figure 3-1] This table shows exemplary compounds 192-295, along with their characterization data and biological activity. [Figure 3-2] This is a continuation of Figure 3-1. [Figure 3-3] This is a continuation of Figure 3-2. [Figure 3-4] This is a continuation of Figure 3-3. [Figure 3-5] This is a continuation of Figure 3-4. [Figure 3-6] This is a continuation of Figure 3-5. [Figure 3-7] This is a continuation of Figure 3-6. [Figure 3-8] This is a continuation of Figure 3-7. [Figure 3-9] This is a continuation of Figure 3-8. [Figure 3-10] This is a continuation of Figure 3-9. [Figure 3-11] This is a continuation of Figure 3-10. [Figure 3-12] This is a continuation of Figure 3-11. [Figure 3-13] This is a continuation of Figure 3-12. [Figure 3-14] This is a continuation of Figure 3-13. [Figure 3-15] This is a continuation of Figure 3-14. [Figure 3-16] This is a continuation of Figure 3-15. [Figure 3-17] This is a continuation of Figure 3-16. [Figure 3-18] This is a continuation of Figure 3-17. [Figure 3-19] This is a continuation of Figure 3-18. [Figure 3-20] This is a continuation of Figure 3-19. [Figure 3-21] This is a continuation of Figure 3-20. [Figure 3-22] This is a continuation of Figure 3-21. [Figure 3-23] This is a continuation of Figure 3-22. [Figure 3-24] This is a continuation of Figure 3-23. [Figure 3-25] This is a continuation of Figure 3-24. [Figure 3-26]This is a continuation of Figure 3-25. [Figure 3-27] This is a continuation of Figure 3-26. [Figure 4-1] This table shows exemplary compounds 296-362, along with their characterization data and biological activity. [Figure 4-2] This is a continuation of Figure 4-1. [Figure 4-3] This is a continuation of Figure 4-2. [Figure 4-4] This is a continuation of Figure 4-3. [Figure 4-5] This is a continuation of Figure 4-4. [Figure 4-6] This is a continuation of Figure 4-5. [Figure 4-7] This is a continuation of Figure 4-6. [Figure 4-8] This is a continuation of Figure 4-7. [Figure 4-9] This is a continuation of Figure 4-8. [Figure 4-10] This is a continuation of Figure 4-9. [Figure 4-11] This is a continuation of Figure 4-10. [Figure 4-12] This is a continuation of Figure 4-11. [Figure 4-13] This is a continuation of Figure 4-12. [Figure 4-14] This is a continuation of Figure 4-13. [Figure 4-15] This is a continuation of Figure 4-14. [Figure 4-16] This is a continuation of Figure 4-15. [Figure 4-17] This is a continuation of Figure 4-16. [Figure 4-18] This is a continuation of Figure 4-17. [Figure 4-19] This is a continuation of Figure 4-18. [Figure 4-20] This is a continuation of Figure 4-19. [Figure 4-21] This is a continuation of Figure 4-20. [Figure 4-22] This is a continuation of Figure 4-21. [Figure 4-23] This is a continuation of Figure 4-22. [Modes for carrying out the invention]

[0017] definition For convenience, before further description of the present invention, the specific terms used in the specification, examples, and appended claims are summarized here. These definitions should be taken in light of the remainder of this disclosure and should be understood by those skilled in the art. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art.

[0018] To facilitate a quicker understanding of the present invention, certain terms and phrases are defined below and throughout this specification.

[0019] The articles "a" and "an" are used herein to indicate that the grammatical object of the article is one or more (i.e., at least one). For example, "an element" means one or more elements.

[0020] When used herein and in the claims, the phrase "and / or" should be understood to mean "either or both" of the elements thus combined, that is, elements that may be present either conjunctively or disjunctively. Multiple elements listed using "and / or" should be interpreted in the same manner, that is, "one or more" elements are connected in this way. Other elements may optionally exist in addition to those specifically identified, whether related to or unrelated to the elements specifically identified by the "and / or" clause. Therefore, as a non-restrictive example, when referring to "A and / or B," when used in combination with an open-ended word such as "comprising," it may refer to A only in one embodiment (optionally including elements other than B), B only in another embodiment (optionally including elements other than A), and both A and B in yet another embodiment (optionally including other elements), and so on.

[0021] As used herein 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” should be interpreted as encompassing, i.e., including not only at least one of a substantial number or set of elements, but two or more, and optionally, additional items not listed. Only terms clearly indicated otherwise, such as “only one of” or “exactly one of” or, as used in the claims, “consisting of,” refer to including exactly one element of a substantial number or set of elements. In general, as used herein, the term “or” should be interpreted only as an exclusive alternative (i.e., “one or the other, but not both”) when preceded by terms indicating exclusivity, such as “either,” “one of,” “only one of” or “exactly one of.” As used in the claims, “consisting of” should have the general meaning as used in the field of patent law.

[0022] As used herein and in the claims, the phrase “at least one” should be understood to mean, with respect to a list of one or more elements, at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of all elements specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the existence of any other elements besides those specifically identified in the list of elements, which the phrase “at least one” refers to, whether related to or unrelated to the elements specifically identified in the list of elements. Therefore, as a non-limiting example, "at least one of A and B" (or similarly, "at least one of A or B" or similarly, "at least one of A and / or B") may, in one embodiment, refer to the absence of B (and optionally including elements other than B) along with at least one A (including any two or more A's); in another embodiment, refer to the absence of A (and optionally including elements other than A) along with at least one B (including any two or more B's); and in yet another embodiment, refer to at least one A (including any two or more A's) and at least one B (including any two or more B's) (and optionally including other elements), and so on.

[0023] Unless otherwise clearly indicated, in any method claimed herein that includes two or more steps or operations, it should be understood that the order of the steps or operations of the method is not necessarily limited to the order in which the steps or operations of the method are shown.

[0024] In the claims and the above specification, all transitional clauses, such as “comprising,” “including,” “carrying,” “having,” “containing,” “accompanying,” “holding,” and “composed of,” should be understood as open-ended, meaning that they include, but are not limited to, the following. As set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03, only the transitional clause “composed of” is a closed transitional clause, and only the transitional clause “essentially consisting of” is a semi-closed transitional clause.

[0025] Certain compounds included in the compositions of the present invention may exist in the form of specific geometric isomers or stereoisomers. In addition, the polymers of the present invention may also be optically active. In the present invention, all such compounds, including cis and trans isomers, R-enantiomers and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, are intended to be within the scope of the invention. Additional chiral carbon atoms may be present in substituents, such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0026] "Geometric isomers" refer to isomers in which the orientation of substituent atoms differs in relation to a carbon-carbon double bond, cycloalkyl ring, or bridging bicyclic system. The atoms (other than H) on each side of the carbon-carbon double bond may be in the configuration of the E isomer (substituents are on the opposite side of the carbon-carbon double bond) or the Z isomer (substituents are on the same side). * "R *"E", "Z", "cis", and "trans" indicate configuration relative to the core molecule. Certain of the disclosed compounds may exist in an "atropisomer" form, i.e., as "atropisomers". Atropisomers are stereoisomers resulting from rotational impairment of single bonds that is high enough to isolate their conformational isomers. The compounds of the present invention may be prepared as individual isomers by synthesis specific to each isomer, or by separation from an isomer mixture. Conventional resolution techniques include using optically active acids to form salts of the free bases of each isomer in an isomer pair (followed by fractional crystallization and regeneration of the free bases), using optically active amines to form salts of the acidic forms of each isomer in an isomer pair (followed by fractional crystallization and regeneration of the free acid), using optically pure acids, amines, or alcohols to form esters or amides of the isomers in an isomer pair (followed by chromatographic separation and removal of chiral auxiliaries), or using various well-known chromatographic methods to resolve a mixture of isomers of either the starting material or the final product.

[0027] For example, if a specific enantiomer of the compound of the present invention is desired, it may be prepared by asymmetric synthesis or by induction using a chiral auxiliary agent, in which case the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, a diastereomer salt is formed using an optically active suitable acid or base, and then the diastereomer thus formed is separated by fractional crystallization or chromatography, which is well known in the art, and then the pure enantiomer is recovered.

[0028] Purity by mole fraction (%) is the ratio of moles of an enantiomer (or diastereomer), or the ratio of moles of an enantiomer (or diastereomer) to moles of its optical isomer. When the stereochemistry of a disclosed compound is named or described by structure, the named or described stereoisomer has a purity of at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% in mole fraction relative to the other stereoisomer. When a single enantiomer is named or described by structure, the described or named enantiomer has a purity of at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% in mole fraction. When a single diastereomer is named or described by its structure, the described or named diastereomer has a purity of at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% in mole fraction.

[0029] When a disclosed compound is named or described by structure without showing its stereochemistry, and the compound has at least one chiral center, the name or structure should be understood to include any of the enantiomers of the compound that do not contain the corresponding optical isomer, a racemic mixture of the compound, or a mixture in which one enantiomer is concentrated relative to the corresponding optical isomer. When a disclosed compound is named or described by structure without showing its stereochemistry, and has two or more chiral centers, the name or structure should be understood to include a diastereomer that does not contain other diastereomers, a considerable number of diastereomers that do not contain other diastereomer pairs, a mixture of diastereomers, a mixture of diastereomer pairs, a mixture of diastereomers in which one diastereomer is concentrated relative to the other diastereomer(s), or a mixture of diastereomers in which one or more diastereomers are concentrated relative to the other diastereomer. The present invention includes all of these forms.

[0030] The structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen may be replaced with deuterium or tritium, or carbon may be replaced with 13 C concentrated carbon or 14 The compounds produced by replacing carbon-enriched carbon fall within the scope of the present invention.

[0031] The term "prodrug," as used herein, includes compounds that are converted into therapeutic agents under physiological conditions. A common method for preparing prodrugs involves including a selective moiety that is hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, prodrugs are converted by the enzymatic activity of a host animal.

[0032] The terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein mean a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which is involved in transporting or delivering the chemical substance from one organ or body part to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation, is not harmful to the patient, and is substantially nonpyrogenic. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository wax; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and sesame oil. Examples include (10) soybean oil, 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) buffers 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, and (21) other non-toxic suitable substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., they do not cause a significant rise in temperature when administered to a patient.

[0033] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of a compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by reacting the purified compound(s) in free base form separately with a suitable organic or inorganic acid and isolating the resulting salts. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitic acid, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate. (For example, see Berge et al. (1977) “Pharmaceutical Salts”, J.Pharm.Sci. 66:1-19.)

[0034] In other cases, compounds useful in the methods of the present invention may contain one or more acidic functional groups, and thus pharmaceutically acceptable salts can be formed with pharmaceutically acceptable bases. In these cases, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic base addition salts and organic base addition salts of the compound(s). These salts can similarly be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free acid form with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, with ammonia, or with a pharmaceutically acceptable organic primary, organic secondary, or organic tertiary amine. Typical alkali salts or alkaline earth salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts. Typical organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine (see, for example, Berge et al.).

[0035] The term "pharmaceutically acceptable cocrystal" refers to a solid coformer that does not form formal ionic interactions with small molecules.

[0036] The “therapeutic effective dose” (or “effective dose”) of a compound relating to its use in treatment refers to the amount of the compound in preparation form that, when administered (to a mammal, preferably a human) as part of a desired administration regimen, reduces symptoms, improves a condition, or delays the onset of a condition, according to a clinically acceptable standard or cosmetic purpose for the disorder or condition being treated, for example, in a reasonable benefit / risk ratio applicable to any medical treatment.

[0037] The terms “preventive or therapeutic” treatments are recognized in the art and include the administration of one or more of the compositions to a host. If the treatment is performed before the appearance of clinical symptoms of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), the treatment is preventive (i.e., the treatment protects the host from the appearance of the undesirable condition), and if the treatment is performed after the appearance of the undesirable condition, the treatment is therapeutic (i.e., the treatment is intended to reduce, improve or stabilize an existing undesirable condition or its side effects).

[0038] The terms “patient” or “subject” refer to a mammal requiring a specific treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is a human.

[0039] Aliphatic chains include alkyl, alkenyl, and alkynyl groups as defined below. Straight aliphatic chains are limited to unbranched carbon chain portions. As used herein, the term “aliphatic group” refers to a straight, branched, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl, or alkynyl groups.

[0040] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain portion having a specified number of carbon atoms, or, if not specified, up to 30 carbon atoms. For example, alkyls with 1 to 8 carbon atoms refer to portions such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as positional isomers of these portions. Examples of carbon atoms with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, linear or branched alkyls have 30 or fewer carbon atoms in their main chain (for example, C1-C1 in a linear chain). 30 In branched chains, C3-C 30 ), more preferably 20 or fewer alkyl groups. The alkyl groups may be substituted or unsubstituted.

[0041] As used herein, the term "heteroalkyl" refers to the alkyl portion, as defined above, that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms instead of carbon atoms.

[0042] As used herein, the term "haloalkyl" refers to the alkyl moiety as defined above, in which at least one halogen is substituted.

[0043] As used herein, the term "hydroxyalkyl" refers to the alkyl moiety as defined above, in which at least one hydroxyl group is substituted.

[0044] As used herein, the term "alkylene" refers to an alkyl group having a predetermined number of carbon atoms, for example, 2 to 12 carbon atoms, wherein the longest carbon chain contains two bonding sites to the remainder of the compound. Non-limiting examples of alkylene groups include methylene, i.e., -(CH2)-, ethylene, i.e., -(CH2CH2)-, n-propylene, i.e., -(CH2CH2CH2)-, isopropylene, i.e., -(CH2CH(CH3))-, and the like. The alkylene group can be cyclic or acyclic, branched or unbranched carbon chain portions, and may be optionally substituted with one or more substituents.

[0045] "Cycloalkyl" refers to a monocyclic, dicyclic, i.e., bridging, spirocyclic, or polycyclic saturated carbon ring, each having 3 to 12 carbon atoms. Preferred cycloalkyls have 3 to 10 carbon atoms in the ring structure, and more preferably 3 to 6 carbon atoms in the ring structure. Cycloalkyls may be substituted or unsubstituted.

[0046] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group, as defined above, that is substituted with at least one halogen.

[0047] A "cycloheteroalkyl" refers to a cycloalkyl moiety as defined above, in which one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms are present instead of carbon atoms. A preferred cycloheteroalkyl has 4 to 8 carbon atoms and heteroatoms in its ring structure, and more preferably 4 to 6 carbon atoms and heteroatoms in its ring structure. Cycloheteroalkyls may be substituted or unsubstituted.

[0048] Unless otherwise specified, “lower alkyl” as used herein means an alkyl group as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in its main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In certain embodiments, substituents defined herein as alkyl are lower alkyl groups.

[0049] An "alkenyl" refers to a carbon chain portion that is cyclic or acyclic, branched or unbranched and unsaturated, having a predetermined number of carbon atoms, or up to 26 carbon atoms if no limit on the number of carbon atoms is specified, and containing one or more double bonds. Alkenyls with 6 to 26 carbon atoms are exemplified by the various isomers of hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicocenyl, heneicocenyl, dococenyl, tricocenyl, and tetracocenyl, whose unsaturated bonds(s) can be located anywhere in the portion, and whose double bonds(s) can be in either a (Z) configuration or an (E) configuration.

[0050] "Alkinyl" refers to the hydrocarbyl portion of the alkenyl group, but specifically to those containing one or more triple bonds.

[0051] As used herein, the term "aryl" includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryls) or groups in which one or more atoms are heteroatoms (i.e., heteroaryls). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term "aryl" also includes polycyclic systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and in which at least one of the rings is aromatic, for example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Examples of carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol and aniline. Heteroaryl groups include substituted or unsubstituted 3- to 12-membered aromatic ring structures, more preferably 5- to 12-membered rings, and more preferably 5- to 10-membered rings, the ring structure containing 1 to 4 heteroatoms. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. The aryl and heteroaryl groups can be monocyclic, dicyclic, or polycyclic.

[0052] The terms “halo,” “halide,” or “halogen” as used herein mean halogens, including, but not limited to, fluoro, chloro, bromo, and iodine in both radioactive and non-radioactive forms. In preferred embodiments, the halo is selected from the group consisting of fluoro, chloro, and bromo.

[0053] The terms "heterocyclyl," "heterocyclic group," or "heterocycloalkyl" refer to a ring structure with 3 to 12 members, more preferably 5 to 12 members, and more preferably 5 to 10 members, in which the ring structure contains 1 to 4 heteroatoms. The heterocycle can be monocyclic, dicyclic, spirocyclic, or polycyclic. Examples of heterocyclyl groups include thiophene, thiantrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxatine, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, sinnoline, pteridine, carbazole, carborin, phenanthidine, acridine, pyrimidine, phenanthroline, phenazine, phenalsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolan, oxazole, piperidine, piperazine, morpholine, lactone, lactam, such as azetidinone and pyrrolidinone, sultam, and sultone. The heterocyclic ring can be substituted at one or more positions with substituents such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphine, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde ester, heterocyclyl moiety, aromatic moiety or heteroaromatic moiety, -CF3 and -CN, etc.

[0054] The term “substituted” refers to a portion having substituents that replace one or more hydrogens on the carbons of its main chain. It should be understood that “substituted” or “substituted with ~” implies an implicit condition that such substitution is subject to the possible valencies of the substituted atom and substituent, and that the substitution results in a stable compound (e.g., one that does not undergo transformation by rearrangement, cyclization, elimination, etc., spontaneously). As used herein, the term “substituted” is intended to encompass all permissible substituents of an organic compound. In a broader sense, these permissible substituents include acyclic and cyclic substituents, branched and unbranched substituents, carbocyclic and heterocyclic substituents, and aromatic and non-aromatic substituents of an organic compound. For a given organic compound, there may be one or more permissible substituents, and they may be the same or different. For the purposes of this invention, the heteroatom, for example, nitrogen, may have a hydrogen substituent and / or any of the permissible substituents of the organic compound described herein that satisfies the valency of the heteroatom. Examples of substituents include any substituents described herein, such as halogen moieties, hydroxyl moieties, carbonyl moieties (carboxyl moieties, alkoxycarbonyl moieties, formyl moieties, or acyl moieties, etc.), thiocarbonyl moieties (thioester moieties, thioacetate moieties, or thioformate moieties, etc.), alkoxy moieties, phosphoryl moieties, phosphate moieties, phosphonate moieties, phosphine moieties, amino moieties, amide moieties, amidine moieties, imine moieties, cyano moieties, nitro moieties, azide moieties, sulfhydryl moieties, alkylthio moieties, sulfate moieties, sulfonate moieties, sulfamoyl moieties, sulfonamide moieties, sulfonyl moieties, heterocyclyl moieties, aralkyl moieties, aromatic moieties, or heteroaromatic moieties. In preferred embodiments, substituents on the substituted alkyl are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In even more preferred embodiments, substituents on the substituted alkyl are selected from fluoro, carbonyl, cyano, or hydroxyl. Those skilled in the art will understand that, in appropriate cases, the substituent itself can be substituted.Unless otherwise specified, the term "chemical moiety" in this specification shall be understood to include substituted variants. For example, the term "aryl group" or "aryl moiety" implicitly includes both substituted and unsubstituted variants.

[0055] As used herein, the definitions of each expression, such as alkyl, m, and n, are intended to be independent of their definitions elsewhere in any structure when they appear more than once in the same structure.

[0056] As used herein, "small molecule" refers to an organic or inorganic small molecule with a molecular weight of less than approximately 3,000 daltons. Generally, small molecules useful in this invention have a molecular weight of less than 3,000 daltons (Da). Small molecules can be, for example, at least about 100 Da to about 3,000 Da (e.g., about 100 to about 3,000 Da, about 100 to about 2,500 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 1,500, about 500 to about 1,000, about 300 to about 1,000 Da, or about 100 to about 250 Da).

[0057] In some embodiments, “small molecule” typically refers to an organic, inorganic, or organometallic compound with a molecular weight of less than approximately 1000. In some embodiments, the small molecule is an organic compound with a size of approximately 1 nm. In some embodiments, the small molecule drug of the present invention includes oligopeptides and other biomolecules with a molecular weight of less than approximately 1000.

[0058] An "effective dose" is an amount sufficient to achieve a beneficial or desired outcome. For example, a therapeutic dose is an amount that achieves a desired therapeutic effect. This amount may be the same as or different from a prophylactic effective dose, which is the amount required to prevent the onset of a disease or symptoms of a disease. An effective dose can be administered in one or more doses, applications, or medications. The therapeutic effective dose of a composition varies depending on the composition selected. The compositions of the present invention can be administered at least once a day to at least once a week (including once every other day). It will be apparent to those skilled in the art that certain factors (including, but not limited to, the severity of the disease or disorder, history of past treatments, the subject's overall health and / or age, and other pre-existing diseases) may influence the dose and timing required to effectively treat the subject. Furthermore, treating a subject with a therapeutic effective dose of a composition described herein may include a single treatment or a series of treatments.

[0059] The terms “decrease,” “reduce,” “reduced,” “reduce,” “decrease,” and “inhibit” are all used herein to generally mean a statistically significant reduction compared to a reference. However, to avoid any ambiguity, “decrease,” “reduce,” or “decrease” or “inhibit” typically mean a reduction of at least 10% compared to a reference level, and may include reductions of 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%, and at least about 99% (including these values) compared to a reference level, for example, a reduction of 10 to 99% compared to the complete absence of a given element or parameter, or the absence of a given action.

[0060] The terms “increased,” “increased,” “improved,” or “activated” are all used herein to generally mean an increase of a statistically significant amount, and to avoid any ambiguity, the terms “increased,” “increased,” “improved,” or “activated” mean an increase of at least 10% compared to a reference level, for example, an increase of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or 100% (including this value), or any increase of 10 to 100% compared to a reference level, or an increase of at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times or at least about 10 times compared to a reference level, or any increase of 2 to 10 times or more.

[0061] As used herein, the term “regulate” includes upregulation and downregulation, for example, improving or inhibiting a response.

[0062] As defined herein, “radioactive pharmaceutical agent” means a pharmaceutical agent containing at least one radioactive isotope that emits radiation. Radioactive pharmaceutical agents are conventionally used in nuclear medicine for the diagnosis and / or treatment of various diseases. Radiolabeled pharmaceutical agents, such as radiolabeled antibodies, contain radioisotopes (RI) that function as radiation sources. As intended herein, the term “radioisotope” includes metallic and nonmetallic radioisotopes. Radioisotopes are selected based on the medical use of the radiolabeled pharmaceutical agent. When the radioisotope is a metallic radioisotope, chelating agents are typically used to bind the metallic radioisotope to the remainder of the molecule. When the radioisotope is a nonmetallic radioisotope, the nonmetallic radioisotope is typically bound to the remainder of the molecule directly or via a linker.

[0063] For the purposes of this invention, chemical elements are identified according to the inside cover of the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0064] Compound of the present invention In some embodiments, the provided compound is of the following formula (Ia) or (Ib), [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Z is either O or S, Y is [ka] This represents, X is N or CR 2 And, L is -(C1-C6)alkylenyl-, B is (C3-C8) cycloalkyl, (C6-C 10 ) represents an aryl, a 4- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more (C1-C6) alkyl groups. R 1 Hydrogen, -CO2R a ,-CONR a R b , -SO2R a -SONR a R b -SO2NR a R b , -NR a R b , 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy, [ka] Or -O-(4-7 member heterocycloalkyl), and the (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, 4-7 member heterocycloalkyl and -O-(4-7 member heterocycloalkyl) are respectively halo, hydroxy, oxo, cyano, amino, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, hydroxy(C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, [ka] (C3-C8)cycloalkyl(C1-C6)alkyl and benzyl are optionally substituted with one or more substituents independently selected from these, or when Y represents -LB-, R 1 It, together with the atom to which it is bonded, forms a 4-7 membered heterocycloalkyl ring, provided that Y is [ka] If so, R 1 Provided that it is not hydrogen, R 1a , R 1b and R 1c Each instance is independently either hydrogen, (C1-C6) alkyl, or (C3-C8) cycloalkyl, or R 1a and R 1b These, together with the atoms to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl group. R 2 These are hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6) alkyl, and NHR a (C1-C6) alkoxy, -CONR a R b Alternatively, it is a (C1-C6) alkyl group, and the (C1-C6) alkyl group may be a halo, hydroxy, cyano, (C1-C6) alkoxy, or NR group. a Rb It is optionally substituted with one or more substituents independently selected from or R 1 and R 2 These, together with the atoms to which they are bonded, form 4- to 9-membered heterocycloalkyls optionally substituted with one or more substituents independently selected from (C1-C6)alkyls, and the (C1-C6)alkyl can further be (C3-C8)cycloalkyls, 4- to 7-membered heterocyclylalkyls, hydroxy, halo, (C1-C6)alkoxy, cyano, carboxy, -CONR a R b and -SO2R a It is arbitrarily replaced with, R 3 is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl, aryl, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl. R a and R b Each instance is independently hydrogen, a (C1-C6) alkyl, or a 4-7 member heterocycloalkyl, and the (C1-C6) alkyl and 4-7 member heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6) alkoxy, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 4-7 member heterocycloalkyl group. R 5a , R 5b , R 6a and R 6b These are independently hydrogen or (C1-C6) alkyl, R A is hydrogen or (C1-C6) alkyl, n, m, and p are independently either 0 or 1. q is 0, 1, or 2. However, the sum of p and q must be equal to 0, 1, or 2.

[0065] In some embodiments, the provided compound is of the following formula (Ia) or (Ib), [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Y is [ka] This represents, X is N or CR 2 And, L is -(C1-C6)alkylenyl-, B is (C3-C8) cycloalkyl, (C6-C 10 ) represents an aryl, a 4- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more (C1-C6) alkyl groups. R 1 Hydrogen, -CO2R a ,-CONR a R b , -SO2R a -SONR a R b -SO2NR a R b , -NR a R b , 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy, [ka] Or -O-(4-7 member heterocycloalkyl), and the (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, 4-7 member heterocycloalkyl and -O-(4-7 member heterocycloalkyl) are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, hydroxy(C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, [ka] (C3-C8)cycloalkyl(C1-C6)alkyl and benzyl are optionally substituted with one or more substituents independently selected from these, or when Y represents -LB-, R 1 It, together with the atom to which it is bonded, forms a 4-7 membered heterocycloalkyl ring, provided that Y is [ka] If so, R 1 Provided that it is not hydrogen, R 1a , R 1b and R 1c Each instance is independently either hydrogen, (C1-C6) alkyl, or (C3-C8) cycloalkyl, or R 1a and R 1b These, together with the atoms to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl group. R 2 These are hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6) alkyl, and NHR a (C1-C6) alkoxy, -CONR a R b Alternatively, it is a (C1-C6) alkyl group, and the (C1-C6) alkyl group may be a halo, hydroxy, cyano, (C1-C6) alkoxy, or NR group. a Rb It is optionally substituted with one or more substituents independently selected from or R 1 and R 2 These, together with the atoms to which they are bonded, form 4- to 9-membered heterocycloalkyls optionally substituted with one or more substituents independently selected from (C1-C6)alkyls, and the (C1-C6)alkyl is further a (C3-C8)cycloalkyl, a 4- to 7-membered heterocyclylalkyl, a hydroxy, a (C1-C6)alkoxy, a cyano, a carboxy, or a -CONR a R b and -SO2R a It is arbitrarily replaced with, R 3 is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl, aryl, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl. R a and R b Each instance is independently hydrogen, a (C1-C6) alkyl, or a 4-7 member heterocycloalkyl, and the (C1-C6) alkyl and 4-7 member heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6) alkoxy, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 4-7 member heterocycloalkyl group. R 5a , R 5b , R 6a and R 6b These are independently hydrogen or (C1-C6) alkyl, n, m, and p are independently either 0 or 1. q is 0, 1, or 2. However, the sum of p and q must be equal to 0, 1, or 2.

[0066] In further embodiments, the provided compound is of the following formula (Ia) or (Ib), [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Y is [ka] This represents, X is N or CR 2 And, L is -(C1-C6)alkylenyl-, B is (C3-C8) cycloalkyl, (C6-C 10 ) represents an aryl, a 4- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more (C1-C6) alkyl groups. R 1 Hydrogen, -CO2R a ,-CONR a R b , -SO2R a -SONR a R b -SO2NR a R b , -NR a R b , 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy or [ka] The (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy and 4-7 member heterocycloalkyl are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl and [ka] R is optionally substituted with one or more substituents independently selected from or when Y represents -LB-. 1 It, together with the atom to which it is bonded, forms a 4-7 membered heterocycloalkyl ring, provided that Y is [ka] If so, R 1 Provided that it is not hydrogen, R 1a , R 1b and R 1c Each instance is independently either hydrogen or (C1-C6) alkyl, or R 1a and R 1b These, together with the atoms to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl group. R 2 These are hydrogen, fluoro, chloro, cyano, hydroxyl, NH2, NHCO(C1-C6) alkyl, and NHR a (C1-C6) alkoxy, -CONR a R b , or halo, hydroxy, cyano, (C1-C6) alkoxy and NR a R b A (C1-C6) alkyl group optionally substituted with one or more substituents independently selected from or R 1 and R 2 These, together with the atoms to which they are bonded, form a 4-7 member heterocycloalkyl group. R 3 is (C1-C6)alkyl or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl. R a and R b Each instance is independently hydrogen, a (C1-C6) alkyl, or a 4-7 member heterocycloalkyl, and the (C1-C6) alkyl and 4-7 member heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6) alkoxy, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 4-7 member heterocycloalkyl group. n, m, and p are independently either 0 or 1. q is 0, 1, or 2. However, the sum of p and q must be equal to 0, 1, or 2.

[0067] In a detailed embodiment, Y is [ka] It represents.

[0068] In other embodiments, Y is [ka] It represents.

[0069] In other embodiments, Y is [ka] It represents.

[0070] In some embodiments, R 1 teeth, hydrogen, [ka] And, During the ceremony, R 1d , R 1e and R 1f Each instance is independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxy, and the (C1-C6)alkyl is further optionally substituted with (C3-C8)cycloalkyl or phenyl, or R 1d and R 1e These, together with the carbon atoms to which they are bonded, form (C3-C8) cycloalkyl or 3- to 7-membered heterocycloalkyl groups, each of which is optionally substituted with a hydroxyl group.

[0071] In some embodiments, R 1 teeth, hydrogen, [ka] And, During the ceremony, R 1d , R 1e and R 1f Each instance is independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl and (C1-C6)alkoxy, or R 1d and R 1e These, together with the carbon atoms to which they are bonded, form (C3-C8) cycloalkyl or 3- to 7-membered heterocycloalkyl groups.

[0072] In some embodiments, R 1 teeth [ka] And R a and R b Each of them is either hydrogen or R ais hydrogen, R b It is methyl.

[0073] In some embodiments, R 1 teeth, hydrogen, [ka] And, During the ceremony, R 1d , R 1e and R 1f Each instance is independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxy, and the (C1-C6)alkyl is further optionally substituted with (C3-C8)cycloalkyl or phenyl, or R 1d and R 1e These, together with the carbon atoms to which they are bonded, form (C3-C8) cycloalkyl or 3- to 7-membered heterocycloalkyl groups, each of which is optionally substituted with a hydroxyl group.

[0074] In some embodiments, R 1 teeth, hydrogen, [ka] And, During the ceremony, R 1d , R 1e and R 1f Each instance is independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl and (C1-C6)alkoxy, or R 1d and R 1e These, together with the carbon atoms to which they are bonded, form (C3-C8) cycloalkyl or 3- to 7-membered heterocycloalkyl groups.

[0075] In some embodiments, R 1 teeth [ka] And, R 1d and R 1e These, together with the carbon atoms to which they are bonded, form morpholine, cyclobutane, oxetane, azetidine, or cyclohexane.

[0076] In certain preferred embodiments, R 1d and R 1e These are methyl compounds.

[0077] In some preferred embodiments, R 1f is hydrogen. In another preferred embodiment, R 1f is a (C1-C6) alkyl group, preferably methyl or ethyl. In other embodiments, R 1f The compound is a (C1-C6) fluoroalkyl group, preferably 2,2,2-trifluoroethyl.

[0078] In some embodiments, R 1 teeth [ka] And R 1a These are cyclopropyl, 2-propyl, ethyl, or methyl.

[0079] In some embodiments, R 1 teeth, hydrogen, [ka]

[0080] In some embodiments, R 1 teeth, [ka] That is the case.

[0081] In a particular embodiment, Y is [ka] That is the case.

[0082] In some embodiments, X is N, and in other embodiments, X is CR 2 That is the case.

[0083] X is CR 2 In a particular embodiment, R 2 is hydrogen, and in other embodiments, R 2 is fluoro. In a particularly preferred embodiment, R 2 It is hydrogen.

[0084] In some embodiments, R 2 This is a (C1-C6) alkyl group optionally substituted with a (C1-C6) alkoxy, preferably methyl or methoxymethyl.

[0085] In a particular embodiment, R 1 teeth, [ka] And R 2 It is either -CH3 or -CH2-OCH3.

[0086] In some embodiments, R 1 and R 2 These, together with the atoms to which they are bonded, form a 4- to 9-membered heterocycloalkyl, and the 4- to 9-membered heterocycloalkyl is optionally substituted with one or more (C1-C6)alkyls independently selected from (C1-C6)alkyls, and the (C1-C6)alkyl can further be (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, hydroxy, halo, (C1-C6)alkoxy, cyano, carboxy, -CONR a R b and -SO2R a It is optionally substituted with one or more substituents independently selected from the original molecule.

[0087] In some embodiments, R 1 and R 2They, together with the atoms to which they are bonded, [ka] Forming, R 1g and R 1h Each is independently hydrogen or (C1-C6)alkyl, and the (C1-C6)alkyl is a (C3-C8)cycloalkyl, a 4-7 member heterocyclylalkyl, hydroxy, halo, (C1-C6)alkoxy, cyano, carboxy, -CONR a R b and -SO2R a It is optionally substituted with one or more substituents independently selected from the original molecule.

[0088] In some embodiments, R 1h These are ethyl, methyl, ethyl, isopropyl, or t-butyl, each of which is hydroxy, methoxy, cyclopropyl, oxetanyl, tetrahydrofuranyl, phenyl, cyano, carboxy, hydroxy, -CONR a R b , -SO2R a Alternatively, it may be arbitrarily substituted with 1 to 3 fluorine atoms.

[0089] In some embodiments, R 1h It is trifluoromethyl.

[0090] In some embodiments, R 1g This is hydrogen, methyl, or ethyl, and the methyl or ethyl is optionally substituted with cyano.

[0091] In some embodiments, R a is methyl. In some embodiments, R b is methyl. In further embodiments, R a and R b Each of these is methyl. In a particular preferred embodiment, R 1g It is either methyl or hydrogen.

[0092] In a more detailed embodiment, R 1 and R 2 They, together with the atoms to which they are bonded, [ka] It forms.

[0093] In some embodiments, R 1 and R 2 They, together with the atoms to which they are bonded, [ka] It forms.

[0094] In other embodiments, R 1 and R 2 They, together with the atoms to which they are bonded, [ka] It forms.

[0095] In some embodiments, n is 1, and in other embodiments, n is 0.

[0096] In some embodiments, m is 1, and in other embodiments, m is 0.

[0097] In some embodiments, p is 1, and in other embodiments, p is 0.

[0098] In a particular preferred embodiment, p is 0 and q is 2. In another preferred embodiment, n, m, p, and q are each 1. In yet another preferred embodiment, n, m, p, and q are each 0.

[0099] In some embodiments, B represents a 4- to 7-membered heterocycloalkyl group. In other detailed embodiments, B represents cyclohexyl or cyclopentyl, and in other embodiments, B represents phenyl, tolyl, or pyridyl.

[0100] More specifically, in certain preferred embodiments, B is [ka] It represents.

[0101] In some embodiments, L represents methylene, ethylene, or n-butylene.

[0102] In some preferred embodiments, R 5a , R 5b , R 6a and R 6b Each of these is hydrogen. In other embodiments, R 5a , R 5b , R 6a and R 6b Each of these is methyl, and in other embodiments, R 5a is methyl, and R 5b , R 6a and R 6b Each of these is hydrogen.

[0103] In some embodiments, Z is O.

[0104] In some embodiments, R A is hydrogen, and in other embodiments, R A It is methyl.

[0105] In some preferred embodiments, the compound of the present invention is of the following formula (Ic) [ka] or having a pharmaceutically acceptable salt structure thereof, in the formula, R 1 (C1-C6) alkyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, NR a R b and [ka] Selected from, The (C1-C6) alkyl and 4-7 member heterocycloalkyl groups are each optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, and (C1-C6) alkoxy groups. R 1a is either hydrogen or (C1-C6) alkyl.

[0106] In another preferred embodiment, the compound is of the following formula (Id) [ka] or having a pharmaceutically acceptable salt structure thereof, in the formula, R 1 -CO2R a ,-CONR a R b , -SO2R a -SONR a R b -SO2NR a R b , -NR a R b , (C3-C8) cycloalkyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl and [ka] Selected from, Each of the 4- to 7-membered heterocycloalkyl groups is optionally substituted with one or more substituents independently selected from halo, hydroxy, oxo, cyano, amino, 4- to 7-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, carboxamides, sulfonamides, aminoalkyl groups, (C1-C6)alkyl groups, (C3-C8)cycloalkyl groups, (C1-C6)haloalkyl groups, (C1-C6)alkoxy groups, and (C1-C6)hydroxyalkyl groups. R 1ais hydrogen or (C1-C6) alkyl, R 2 is hydrogen, cyano, hydroxyl, NH2, NHCOCH3, NHR a (C1-C6) alkoxy, -CONR a R b , or halo, hydroxy, cyano, (C1-C6) alkoxy and NR a R b Selected from (C1-C6) alkyl groups optionally substituted with one or more substituents independently selected from the given group.

[0107] In another preferred embodiment, the compound is of the following formula (Ie) [ka] The formula has a structure of either or a pharmaceutically acceptable salt thereof, where A represents a 4- to 7-membered heterocycloalkyl group.

[0108] In certain preferred embodiments, R 3 These are methyl, n-propyl, n-butyl, [ka] It is n-butyl, and more preferably n-butyl.

[0109] In certain embodiments, the compound is represented by formula Ia.

[0110] In other embodiments, the compound is represented by formula Ib.

[0111] In some embodiments, the compound is [ka] JPEG2026512708000067.jpg197165 JPEG2026512708000068.jpg176165 JPEG2026512708000069.jpg208165 JPEG2026512708000070.jpg212165 JPEG2026512708000071.jpg187165 JPEG2026512708000072.jpg207165 JPEG2026512708000073.jpg181165 JPEG2026512708000074.jpg197165 JPEG2026512708000075.jpg176165 JPEG2026512708000076.jpg212165 JPEG2026512708000077.jpg207165 JPEG2026512708000078.jpg192165 JPEG2026512708000079.jpg207165 JPEG2026512708000080.jpg197165 It has the structure of JPEG2026512708000081.jpg166165 or a pharmaceutically acceptable salt thereof.

[0112] In yet another embodiment, the compound is [ka] JPEG2026512708000083.jpg197165 JPEG2026512708000084.jpg223165 JPEG2026512708000085.jpg202165 JPEG2026512708000086.jpg212165 JPEG2026512708000087.jpg187165 JPEG2026512708000088.jpg207165 JPEG2026512708000089.jpg181165 JPEG2026512708000090.jpg197165JPEG2026512708000091.jpg58165 has the structure of a pharmaceutically acceptable salt thereof.

[0113] In yet another embodiment, the compound is [ka] JPEG2026512708000093.jpg218165 JPEG2026512708000094.jpg218165 JPEG2026512708000095.jpg238165 JPEG2026512708000096.jpg233165 JPEG2026512708000097.jpg197165 JPEG2026512708000098.jpg156165 JPEG2026512708000099.jpg202165 JPEG2026512708000100.jpg233165 JPEG2026512708000101.jpg228165 JPEG2026512708000102.jpg207165 It has the structure of JPEG2026512708000103.jpg84165 or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the compound is [ka] JPEG2026512708000105.jpg207165 JPEG2026512708000106.jpg207165 JPEG2026512708000107.jpg202165 JPEG2026512708000108.jpg207165 JPEG2026512708000109.jpg202165 JPEG2026512708000110.jpg207165 JPEG2026512708000111.jpg202165 It has the structure of JPEG2026512708000112.jpg94165 or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the provided compound is of formula (IIa) or (IIb) below, [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Y is [ka] This represents, X is N or CR 2 And, L is -(C1-C6)alkylenyl-, B is (C3-C8) cycloalkyl, (C6-C 10 ) represents an aryl or a 5-10 member heteroaryl, each of which is optionally substituted with one or more (C1-C6) alkyl groups. R 1 Hydrogen, -CO2R a ,-CONR a R b , -SO2R a -SONR a R b -SO2NR a R b , -NR a R, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy or [ka] The (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy and 4-7 member heterocycloalkyl are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl and [ka] R is optionally substituted with one or more substituents independently selected from or when Y represents -LB-. 1 It, together with the atom to which it is bonded, forms a 4-7 membered heterocycloalkyl ring, provided that Y is [ka] Or, if it is an (C1-C6) alkylene, R 1 Provided that it is not hydrogen, R 1a , R 1b and R 1c Each instance is independently either hydrogen or (C1-C6) alkyl, or R 1a and R 1b These, together with the atoms to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl group. R 2 is hydrogen, fluoro, chloro, -CONR a R b , or a (C1-C6) alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1-C6) alkoxy, or R 1 and R 2 These, together with the atoms to which they are bonded, form a 4-7 member heterocycloalkyl group. R 3is (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, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl. R a and R b Each instance is independently hydrogen, a (C1-C6) alkyl, or a 4-7 member heterocycloalkyl, and the (C1-C6) alkyl and 4-7 member heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6) alkoxy, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 4-7 member heterocycloalkyl group. n, m, and p are independently either 0 or 1. q is 0, 1, or 2. However, this is subject to the condition that the sum of p and q is equal to 0, 1, or 2. Z is either S or O, R 4 These are H, -C(O)NH2, (C1-C6)alkyl, -NHSO2Me, or -N(R 4a )2, R 4a Each instance is independently either hydrogen or a (C1-C6) alkyl group.

[0116] In a particular embodiment, Y is [ka] It represents.

[0117] In some embodiments, R 1 teeth [ka] In other embodiments, R 1 teeth [ka] That is the case.

[0118] In some embodiments, R 1 teeth, hydrogen, [ka] And, During the ceremony, R 1d , R 1e and R 1f Each instance is independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl and (C1-C6)alkoxy, or R 1d and R 1e These, together with the carbon atoms to which they are bonded, form (C3-C8) cycloalkyl or 3- to 7-membered heterocycloalkyl groups.

[0119] In a particular embodiment, R 1 teeth [ka] And R 1d and R 1e These, together with the carbon atoms to which they are bonded, form morpholine, cyclobutane, oxetane, or cyclohexane.

[0120] In certain detailed embodiments, R 1d and R 1e Each of these is methyl.

[0121] In certain detailed embodiments, R 1f is hydrogen, and in other cases, R 1f is (C1-C6) alkyl, and more specifically, R 1f is methyl or ethyl. In other embodiments, R 1f is a (C1-C6) fluoroalkyl, for example, R 1f It is 2,2,2-trifluoroethyl.

[0122] In certain detailed embodiments, Y is [ka] That is the case.

[0123] In some embodiments, X is N.

[0124] In other embodiments, X is CR 2 That is the case.

[0125] In certain preferred embodiments, R 2 is hydrogen. In other embodiments, R 2 It is fluoro.

[0126] In yet another embodiment, R 2 This is a (C1-C6) alkyl group optionally substituted with a (C1-C6) alkoxy, preferably methyl or methoxymethyl.

[0127] In a particular embodiment, R 1 teeth, [ka] And R 2 It is methyl or methoxymethyl.

[0128] In a particular embodiment, R 1 and R 2 These, together with the atoms to which they are bonded, form a 4- to 7-membered heterocycloalkyl group. More specifically, in some embodiments, R 1 and R 2 They, together with the atoms to which they are bonded, [ka] It forms.

[0129] In a particular embodiment, R 3 is methyl, [ka] In a particular preferred embodiment, R 3 teeth [ka] That is the case.

[0130] In a detailed embodiment, Z is O. In another detailed embodiment, Z is S.

[0131] In a detailed embodiment, R 4 is H, -C(O)NH2, or NH2. In certain preferred embodiments, R 4 It is either H or NH2.

[0132] In certain embodiments, the compound of formula (IIa) or (IIb) is [ka] JPEG2026512708000129.jpg202165 JPEG2026512708000130.jpg218165 It has the structure of JPEG2026512708000131.jpg156165 or a pharmaceutically acceptable salt thereof.

[0133] In other embodiments, the compound is [ka] It has the structure of JPEG2026512708000133.jpg130165 or a pharmaceutically acceptable salt thereof.

[0134] In further embodiments, the compound is [ka] It has the structure of [the object].

[0135] Other aspects of this disclosure relate to compounds of the following formulas (IIIa), (IIIb), (IIIc), or (IIId): [ka] or provide a pharmaceutically acceptable salt thereof, During the ceremony, YR 1 teeth, [ka] -(C1-C6)Alkilen-R 1 This represents, X is N or CR 2 And, L is -(C1-C6)alkylenyl-, B is (C3-C8) cycloalkyl, (C6-C 10 ) represents an aryl or a 5-10 member heteroaryl, each of which is optionally substituted with one or more (C1-C6) alkyl groups. R 1 Hydrogen, -CO2R a ,-CONR a R b , -SO2R a -SONR a R b -SO2NR a R b , -NR a R, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy or [ka] The (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) alkoxy and 4-7 member heterocycloalkyl are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl and [ka] R is optionally substituted with one or more substituents independently selected from or when Y represents -LB-. 1 It, together with the atom to which it is bonded, forms a 4-7 membered heterocycloalkyl ring, provided that Y is [ka] Or, if it is an (C1-C6) alkylene, R 1 Provided that it is not hydrogen, R 1a , R 1b and R 1c Each instance is independently either hydrogen or (C1-C6) alkyl, or R 1a and R 1b These, together with the atoms to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl group. R 2 is hydrogen, fluoro, chloro, -CONR a R b , or a (C1-C6) alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, and (C1-C6) alkoxy, or R 1 and R 2 These, together with the atoms to which they are bonded, form a 4-7 member heterocycloalkyl group. R 3is (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, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl. R a and R b Each instance is independently hydrogen, a (C1-C6) alkyl, or a 4-7 member heterocycloalkyl, and the (C1-C6) alkyl and 4-7 member heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C1-C6) alkoxy, 4-7 member heterocycloalkyl, or 5-6 member heteroaryl, or R a and R b These, together with the nitrogen atom to which they are bonded, form a 4-7 member heterocycloalkyl group. n, m, and p are independently either 0 or 1. q is 0, 1, or 2. However, this is subject to the condition that the sum of p and q is equal to 0, 1, or 2. R 4 is H or N(R 4a )2, R 4a Each instance is independently either hydrogen or a (C1-C6) alkyl group.

[0136] In a particular embodiment, R 1 teeth, hydrogen, [ka] That is the case.

[0137] In other embodiments, R 1 teeth, [ka] And R 2 It is either -CH3 or -CH2-OCH3.

[0138] In yet another embodiment, R 1 teeth, [ka] In a more detailed embodiment, R 1 teeth, [ka] That is the case.

[0139] In some embodiments, Y is [ka] That is the case.

[0140] In a particular embodiment, R 3 is methyl, [ka] Preferably [ka] That is the case.

[0141] In certain preferred embodiments, R 4 It is either H or NH2.

[0142] In certain embodiments, the compounds of formula (IIIa), (IIb), (IIIc), or (IIId) are: [ka] or having the structure of a pharmaceutically acceptable salt thereof.

[0143] In certain embodiments, the compound is an atropisomer. In addition, unless otherwise specified, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or by replacing carbon with 13 C concentrated carbon or 14 Compounds produced by replacing 13C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes for biological assays, or therapeutic agents according to the present invention. For example, variable group R 1 In this case, the (C1-C4)alkyl or -O-(C1-C4)alkyl can be properly deuterated (e.g., -CD3 or -OCD3, respectively).

[0144] Any of the compounds of the present invention can also be radiolabeled for the preparation of radiopharmaceutical agents.

[0145] Treatment method One aspect of the present invention provides a method for treating or preventing osteoporosis, fractures, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia, or tumor-like calcification, comprising administering an effective amount of a compound of formula (Ia) to (IIId) or a pharmaceutically acceptable salt thereof to a subject requiring such treatment or prevention.

[0146] Another aspect of the present invention is a method for preventing or treating a PTH-mediated condition, comprising administering a compound of formula (Ia) to (IIId) or a pharmaceutically acceptable salt thereof in an effective amount to a mammal in need of such prevention or treatment, either alone or in a mixture with a pharmaceutical excipient. Another aspect of the present invention comprises a compound of formula (Ia) to (IIId) or a pharmaceutically acceptable salt thereof for use in the treatment and prevention of diseases and conditions characterized by decreased bone mineral density, bone mass or bone strength, and conditions in which PTH has a beneficial pharmacological effect. The present invention comprises administering a compound of formula (I) or (II) for use as a PTH mimetic. Another aspect of the present invention comprises using a compound of formula (Ia) to (IIId) in the manufacture of a pharmaceutical for use in the treatment of osteopenia and osteoporosis in men and women to reduce the risk of fractures of both vertebral and non-vertebral bones.

[0147] In certain embodiments, the compound is administered orally to the subject.

[0148] In certain embodiments, the compound is administered to the subject parenterally.

[0149] In certain embodiments, the disease is prevented. In other embodiments, the disease is treated.

[0150] Pharmaceutical composition, route of administration, and dosage In certain embodiments, the present invention relates to pharmaceutical compositions comprising the compounds of the present invention, for example, compounds of formulas (Ia) to (IIId), and a pharmaceutically acceptable carrier.

[0151] In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound of any disclosed embodiment and a pharmaceutically acceptable carrier.

[0152] In certain embodiments, the pharmaceutical composition comprises a plurality of the compounds of the present invention and a pharmaceutically acceptable carrier.

[0153] The pharmaceutical compositions of the present invention can be prepared by combining one or more of the compounds of the present invention with a pharmaceutically acceptable carrier and optionally one or more additional pharmaceutically active agents.

[0154] As stated above, “effective dose” refers to any amount sufficient to achieve the desired biological effect. By combining the teachings provided in this invention, selecting from a variety of active compounds, and carefully considering factors such as efficacy, relative bioavailability, patient weight, severity of adverse side effects, and method of administration, an effective prophylactic or therapeutic regimen can be planned that does not cause substantially undesirable toxicity and is effective in treating a particular target. The effective dose for any particular use may vary depending on factors such as the disease or condition being treated, the specific compound of this invention being administered, the size of the target, or the severity of the disease or condition. Those skilled in the art can empirically determine the effective dose of the specific compound and / or other therapeutic agents of this invention without requiring excessive experimentation. The maximum dose, i.e., the safest dose based on several medical judgments, may be used. Multiple daily administrations may be planned to achieve adequate systemic levels of the compound. Adequate systemic levels can be determined, for example, by measuring the patient's peak or sustained plasma levels of the drug. “Dose” and “administered dose” are used synonymously herein.

[0155] In certain embodiments, intravenous administration of the compound may typically be 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be 1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be 1 mg / kg / day to 10 mg / kg / day.

[0156] Generally, the daily oral dose of the compound in human subjects ranges from approximately 0.01 mg / kg to 1000 mg / kg per day. Therapeutic effects are expected with oral doses ranging from 0.5 to 50 mg / kg, administered once or more times daily. Depending on the method of administration, the dose may be adjusted as appropriate to achieve the desired drug level locally or systemically. For example, intravenous administration is expected to result in daily doses that are one to several orders of magnitude smaller. If the response in the subject is insufficient at such doses, higher doses (effectively higher doses via a different, more localized delivery route) may be used, to the extent that patient tolerance allows. Multiple daily administrations are intended to achieve appropriate systemic levels of the compound of the present invention.

[0157] For any of the compounds described herein, the therapeutic dose can initially be determined from animal models. The therapeutic dose can also be determined from human data of compounds tested in humans and compounds known to exhibit similar pharmacological activity, such as other relevant activators. Higher doses may be required for parenteral administration. The dose applied can be adjusted based on the relative bioavailability and efficacy of the compound being administered. Adjusting the dose to achieve maximum efficacy based on the above methods and other methods well known in the art is well within the capabilities of those skilled in the art.

[0158] The formulations of the present invention can be administered in a pharmaceutically acceptable solution, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, suitable carriers, adjuvants, and optionally other therapeutic components.

[0159] When used in therapeutic applications, the compound can be administered to a target in an effective amount by any means of delivering the compound to the desired surface. Administration of the pharmaceutical composition may be carried out by any means known to those skilled in the art. Methods of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., injection into a tumor or abscess), mucosal administration (e.g., local administration into the eye), inhalation, and topical administration.

[0160] For intravenous and other parenteral administration methods, the compounds of the present invention can be formulated as lyophilized preparations, as lyophilized preparations of active compounds intercalated or encapsulated in liposomes, as lipid complexes in aqueous suspensions, or as salt complexes. The lyophilized preparations are generally reconstituted immediately before administration with a suitable aqueous solution, such as sterile water or physiological saline.

[0161] For oral administration, the compound can be readily formulated by combining the active compound(s) with a pharmaceutically acceptable carrier known in the art. Such carriers allow the compound of the present invention to be formulated as tablets, pills, sugar-coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral intake by the target of treatment. Pharmaceutical preparations for oral use can be obtained as solid excipients, and optionally, if desired, appropriate adjuvants may be added, after which the resulting mixture may be pulverized and the granular mixture processed to obtain a tablet or sugar-coated tablet core. Suitable excipients include fillers, such as sugars containing lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, a disintegrant, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof, such as sodium alginate, may be added. Optionally, the oral formulation may be formulated in saline or a buffer, such as EDTA, to neutralize the acidic state in the body, or it may be administered without any carrier.

[0162] Furthermore, the specific target is an oral dosage form of the above-mentioned component(s). The component(s) may be chemically modified to facilitate oral delivery of its derivatives. Generally, the intended chemical modification involves attaching at least one moiety to the component molecule itself, which enables (a) inhibition of acid hydrolysis and (b) uptake into the bloodstream from the stomach or intestines. Also desired is improved overall stability of the component(s) and extended circulation time in the body. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp.367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-trioxocan. For pharmaceutical applications, the polyethylene glycol portion is suitable, as shown above.

[0163] The release site for the component (or derivative) may be the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. Those skilled in the art will know that formulations are available that do not dissolve in the stomach but release the substance in the duodenum or other part of the intestine. Preferably, the release avoids adverse effects in the gastric environment by either protecting the compound (or derivative) of the present invention or by passing through the gastric environment and releasing the bioactive substance, for example, in the intestines.

[0164] To ensure complete gastric tolerance, a coating that is impermeable to at least pH 5.0 is essential. Examples of more common inert components used as enteric coatings include cellulose acetate trimellilate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP50, HPMCP55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed coatings.

[0165] Coatings or coating mixtures can also be used for tablets that are not intended to protect from the stomach. Examples of such coatings include sugar coatings or coatings that facilitate swallowing tablets. Capsules may consist of a hard shell (such as gelatin) for the delivery of dry therapeutic agents (e.g., powders), while liquid forms may use a soft gelatin shell. The shell material for cachets may be thick starch or other food paper. Wet mashing techniques can be used for pills, lozenges, molded tablets, or powder tablets.

[0166] The therapeutic agent can be incorporated into the formulation as fine multiparticles in the form of granules or pellets with a particle size of approximately 1 mm. Formulations for capsule administration can also be in the form of powders, lightly compressed plugs, or tablets. The therapeutic agent can be prepared by compression.

[0167] The compound may include both a coloring agent and a flavoring agent. For example, the compound (or derivative) of the present invention may be formulated (such as by encapsulation in liposomes or microspheres) and then further included in an edible product, such as a chilled beverage containing a coloring agent and a flavoring agent.

[0168] The therapeutic agent may be diluted or its volume increased using an inert material. Examples of such diluents include carbohydrates, particularly mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextran, and starch. Certain inorganic salts, including calcium triphosphate, magnesium carbonate, and sodium chloride, may also be used as fillers. Some commercially available diluents include Fast-Flo, Emdex, STA-Rx1500, Emcompress, and Avicell.

[0169] The disintegrant may be included in the formulation of the therapeutic agent of the present invention to form a solid dosage form. Materials used as disintegrants include, but are not limited to, starch, including commercially available starch-based disintegrants such as Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, carboxymethylcellulose acid, natural sponges, and bentonite may all be used. Another form of disintegrant is an insoluble cation exchange resin. Powdered gum may be used as both a disintegrant and binder; examples of such gums include powdered gums such as agar, karaya, or tragacanth. Alginic acid and its sodium salts are also useful as disintegrants.

[0170] The therapeutic agents may be bound together with a binder to form a hard tablet, and examples of such binders include natural products such as acacia, tragacanth, starch, and gelatin. Other examples include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Both polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) can be used in an alcoholic solution to granulate the therapeutic agents of the present invention.

[0171] To prevent sticking during the formulation process, antifriction agents may be included in the formulation of the therapeutic agent. Lubricants may be used as a layer between the therapeutic agent and the acetabular wall, and these lubricants include, but are not limited to, stearic acid (including its magnesium and calcium salts), polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Soluble lubricants, such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000, and Carbowax 6000, may also be used.

[0172] A flow enhancer may be added to improve the fluidity of the drug during formulation and to assist in rearrangement during compression. Examples of such flow enhancers include starch, talc, calcined silica, and hydrated aluminosilicate.

[0173] To aid in the dissolution of the therapeutic agent in an aqueous environment, surfactants may be added as wetting agents. Examples of surfactants include anionic detergents, such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate. Cationic detergents may be used, such as benzalkonium chloride and benzethonium chloride. Potential nonionic detergents that can be included in the formulations of the present invention as surfactants include lauromacrogol 400, polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants can be present in the formulations of the compounds or derivatives of the present invention either alone or in mixtures of various proportions.

[0174] Pharmaceutical preparations for oral administration include push-fit capsules made of gelatin, and soft, sealable capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient in an additive mixture with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Stabilizers may also be added. Microspheres formulated for oral administration may also be used. Such microspheres are well defined in the art. All oral formulations must be in a dose suitable for oral administration.

[0175] For oral administration, the composition may take the form of tablets or lozenges formulated using conventional methods.

[0176] For topical administration, the compound may be formulated as a solution, gel, ointment, cream, suspension, etc., as is well known in the art. Systemic formulations include formulations designed for administration by injection, such as subcutaneous injection, intravenous injection, intramuscular injection, intrathecal injection, or intraperitoneal injection, and formulations designed for transdermal administration, transmucosal administration, oral administration, or pulmonary administration.

[0177] The compounds for use according to the present invention may also be conveniently delivered for inhalation administration in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the unit of the dose may be determined by incorporating a valve that delivers a quantified amount. For use in an inhaler or injector, for example, gelatin capsules and gelatin cartridges may be formulated to contain a powder mix of the compounds of the present invention and a suitable powder base, such as lactose or starch.

[0178] Furthermore, the present invention aims at the pulmonary delivery of the compounds (or salts thereof) disclosed herein. The compounds are delivered to the lungs of mammals during inhalation, pass through the lining of the pulmonary epithelium, and reach the bloodstream. Other reports on inhalation 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 (α-1-proteinase), and Oswein et al., 1990, “Aerosolization of Proteins”, Proceedings of Symposium on Respiratory Drug Delivery. Examples include 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. Patent No. 5,284,656 (granulocyte colony-stimulating factor, as incorporated by reference). Methods and compositions for delivering systemic drugs to the lungs are described in U.S. Patent No. 5,451,569, issued to Wong et al. on September 19, 1995 (as incorporated by reference).

[0179] The devices intended for use in carrying out the present invention are those designed for the lung delivery of therapeutic products, including, but not limited to, nebulizers, metered-dose inhalers, and powder inhalers, all of which are well known to those skilled in the art.

[0180] Some specific examples of commercially available devices suitable for carrying out the present invention include the Ultravent nebulizer from Mallinckrodt, Inc. (St. Louis, Mo.), the Acorn II nebulizer from Marquest Medical Products (Englewood, Col.), the Ventolin metered-dose inhaler from Glaxo Inc. (Research Triangle Park, North Carolina), and the Spinhaler powder inhaler from Fisons Corp. (Bedford, Mass.).

[0181] Any such apparatus requires the use of a formulation suitable for dispensing the compounds of the present invention. Typically, each formulation is specific to the type of apparatus used and may involve the use of an appropriate propellant in addition to conventional diluents, adjuvants, and / or carriers useful for the treatment. The use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is also intended. The chemically modified compounds of the present invention may be prepared in different formulations depending on the type of chemical modification or the type of apparatus used.

[0182] Formulations suitable for use in either jet or ultrasonic nebulizers typically contain the compound (or derivative) of the present invention dissolved in water at a concentration of about 0.1 to 25 mg per 1 mL of solution. The formulation may also contain buffers and monosaccharides (for example, for stabilizing the inhibitor and regulating osmotic pressure). The nebulizer formulation may also contain surfactants to reduce or prevent surface-induced aggregation of the compound of the present invention as the solution is atomized when forming an aerosol.

[0183] Formulations used in metered-dose inhalers generally consist of a finely powdered substance containing the compound (or derivative) of the present invention suspended in a propellant with the help of a surfactant. The propellant may be any of the conventional materials used for this purpose, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, or hydrocarbons (including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof). Suitable surfactants include sorbitan trioleate and soy lecithin. Oleic acid may also be useful as a surfactant.

[0184] The formulation for dispensing from a powder inhaler will contain a finely powdered, dried powder comprising the compound (or derivative) of the present invention, and may also contain an extender, such as lactose, sorbitol, sucrose, or mannitol, in an amount that allows the powder to disperse easily from the device, for example, at 50-90% by weight of the formulation. The compound (or derivative) of the present invention must be prepared in the form of fine particles with an average particle size of less than 10 micrometers (μm), most preferably 0.5-5 μm, so that it is most effectively delivered to the deep parts of the lungs.

[0185] Nasal delivery of the pharmaceutical composition of the present invention is also intended. Nasal delivery allows the pharmaceutical composition of the present invention to enter the bloodstream directly after the therapeutic product has been administered through the nose, without the need for the product to be deposited in the lungs. Nasal delivery formulations include formulations containing dextran or cyclodextran.

[0186] For nasal administration, a useful device is a small, rigid bottle fitted with a metered-dose sprayer. In one embodiment, the metered dose is delivered by drawing a solution of the pharmaceutical composition of the present invention into a chamber of a predetermined volume, which has holes sized to aerosolize the aerosol formulation by forming a spray when the liquid inside the chamber is compressed. The pharmaceutical composition of the present invention is administered by compressing the chamber. In one specific embodiment, the chamber is an array of pistons. Such devices are commercially available.

[0187] Alternatively, it is a plastic squeeze bottle with a hole or opening sized to aerosolize an aerosol formulation by forming a spray when squeezed. The opening is usually located at the top of the bottle, which is generally tapered to partially fit through the nose for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will dispense a quantified amount of the aerosol formulation to administer a measured dose of the drug.

[0188] The compound may be formulated for parenteral administration by injection, such as bolus injection or continuous infusion, when systemic delivery is desired. The injectable formulation may be provided in unit dosage forms, for example in ampoules or multi-dose containers, with preservatives added. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulation agents, such as suspending agents, stabilizers and / or dispersants.

[0189] The parenteral pharmaceutical formulation comprises an aqueous solution of the active compound in a water-soluble form. In addition, the suspension of the active compound may be prepared as a suitable oily injectable suspension. Suitable oily solvents or vehicles include fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. The aqueous injectable suspension may contain a substance that improves the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain a suitable stabilizer or an agent that increases the solubility of the compound of the present invention to enable the preparation of a highly concentrated solution.

[0190] Alternatively, the active compound may be in powder form for preparation with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0191] The compound may be formulated into a composition for rectal or vaginal use, such as a conventional suppository base, such as a suppository or retaining enema containing cocoa butter or other glycerides.

[0192] In addition to the above formulations, the compound may also be formulated as a depot preparation. Such long-acting formulations may be formulated using a suitable polymer or hydrophobic material or ion exchange resin (for example, as an emulsion in an acceptable oil), or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0193] The pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient. 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 glycol.

[0194] Suitable liquid or solid pharmaceutical preparations include, for example, aqueous or saline solutions for inhalation, microencapsulated, spiral-shaped, coated on microscopic gold particles, contained in liposomes, atomized, aerosol, pellets for skin implantation, or dried on a sharp object for rubbing onto the skin. Examples of pharmaceutical compositions include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations for sustained release of active compounds, in which excipients, additives and / or auxiliaries, such as disintegrants, binders, coatings, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers, are conventionally used as described above. These pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief discussion of drug delivery methods, see Langer R, Science 249:1527-33 (1990).

[0195] The compounds of the present invention and optionally other therapeutic agents may be administered neat or in the form of pharmaceutically acceptable salts or cocrystals. When used in medicine, the salts or cocrystals must be pharmaceutically acceptable, but conventionally, pharmaceutically acceptable salts or cocrystals can be prepared using salts or cocrystals that are not pharmaceutically acceptable. Examples of such salts include, but are not limited to, those prepared from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Furthermore, such salts can be prepared as alkali metal salts or alkaline earth metal salts, for example, sodium, potassium, or calcium salts of the carboxylic acid group.

[0196] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (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).

[0197] The pharmaceutical compositions of the present invention include compounds as described herein and optionally a therapeutic agent contained in an effective amount in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents, or encapsulating materials suitable for administration to humans or other vertebrates. The term "carrier" means a natural or synthetic organic or inorganic component that, in combination with its active ingredient, facilitates application. The components of the pharmaceutical composition may also be mixed with and with the compounds of the present invention in such a way that there are no interactions that substantially impair the desired pharmaceutical effect.

[0198] Therapeutic agents (multiple) (specifically, the compounds of the present invention, but not limited to them) may be provided as particles. As used herein, particles mean nanoparticles or microparticles (or, in some cases, larger particles) that may consist, in whole or in part, of the compounds of the present invention or other therapeutic agents (multiple) as described herein. The particles may contain the therapeutic agent (multiple) in a core surrounded by a coating (including, but not limited to, enteric coatings). The therapeutic agent (multiple) may be dispersed throughout the particles. The therapeutic agent (multiple) may be adsorbed onto the particles. The particles may have a release kinetic sequence in any order, including zero-order release, primary release, secondary release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the therapeutic agent (multiple), the particles may contain any substance commonly used in the fields of pharmacy and medicine, such as disintegrating, non-disintegrating, biodegradable, or non-biodegradable substances, or combinations thereof. The particles may be microcapsules containing the compounds of the present invention in solution or semi-solid state. The particles can take virtually any form.

[0199] Both non-biodegradable and biodegradable polymer materials can be used to manufacture particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic. The polymer is selected based on the desired release period. Of particular interest are the biodegradable hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein by reference. Examples of these polymers include polyhyaluronic acid, casein, gelatin, glutin, polyanhydride, polyacrylic acid, alginate, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0200] The therapeutic agent(s) may be included in a controlled-release system. The term “controlled-release” is intended to refer to any drug-containing formulation that controls the mode and profile of drug release from the formulation. This formulation includes, but is not limited to, immediate-release and non-immediate-release formulations, including sustained-release and delayed-release formulations. The term “sustained-release” (also called “sustained-release”) is used in its conventional sense to refer to a drug formulation that releases the drug gradually over a long period of time, preferably, but not necessarily, delivers the drug at substantially constant blood levels over a long period of time. The term “delayed-release” is used in its conventional sense to refer to a drug formulation in which there is a time lag between the administration of the formulation and the release of the drug from that formulation. “Delayed-release” may or may not involve sustained-release of the drug over a long period of time, and therefore may not be “sustained-release”.

[0201] For the treatment of chronic conditions, the use of long-term sustained-release implants may be particularly appropriate. “Long-term” release, as used herein, means that the implant is configured and positioned to deliver therapeutic levels of the active ingredient for at least 7 days, preferably 30 to 60 days. Long-term sustained-release implants are well known to those skilled in the art, and examples of such implants include some of the release systems described above.

[0202] Other suitable modifications and alterations to the compositions and methods described herein are readily apparent from the description of the invention contained herein, in light of information known to those skilled in the art, and may be made without departing from the scope of the invention or any of its embodiments, as will be understood by those skilled in the art in the relevant field. While the invention has been described in detail above, the invention will be more clearly understood by referring to the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention. [Examples]

[0203] The present invention will be further illustrated by the following examples, but these examples are not intended to limit the scope of the present invention as described in the claims.

[0204] Pyrimidinedione-centered tablets were prepared using the following general reaction scheme, which is described in more detail in the Examples.

[0205] [ka] [Table 1-1] [Table 1-2]

[0206] Examples 1, 15, 19, 22, 27, 28, and 34 were synthesized using the same procedure as described in Example 4 below.

[0207] Example 2 was an intermediate in the synthesis of Example 3.

[0208] Example 3 was synthesized using the same procedure as described in Example 4, but with Boc as the protecting group.

[0209] Example 4: 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxamide(4) [ka]

[0210] 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-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), potassium cyanate (383.02 mg, 4.72 mmol) was added. After heating at 70°C for 5 hours, the resulting mixture was extracted with DCM / MeOH. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by reverse-phase HPLC (column: XBridge Prep OBD C18, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: ACN; gradient: 17% B → 42% B) to obtain title compound 4 (143.3 mg, 38.38%) as a white solid. MS(ESI):C 18 H 28 Calculated mass for N6O4: 392.22, Measured mass: 393.25 [M+H] + . 1H NMR(400MHz;DMSO-d6)δ9.54(s,2H),7.31(s,2H),5.78(s,2H),4.61-4.67(m,1H),3.73(t,J=7.4Hz,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=14.8,7.4Hz,2H),0.88(t,J=7.3Hz,3H).

[0211] Example 6 was synthesized without chiral separation, using the same procedure as described for Example 104 below.

[0212] Example 14 was synthesized using the same procedure as described in Example 4, following the steps from Example 18.

[0213] Examples 11 and 16 were synthesized using the same procedure as described in Example 14.

[0214] Example 36 was synthesized using the same procedure as described in Example 4, following Example 37.

[0215] Example 7: 5-(2-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)ethyl)picolinamide [ka]

[0216] Methyl 5-(cyanomethyl)picolinate [ka] 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), Pd2(dba)3 (1.70 g, 1.85 mmol), xanthophos (2.14 g, 3.70 mmol), and zinc fluoride (574.24 mg, 5.56 mmol) were added in fractions. After heating at 90°C under N2 for 2 hours, the reaction product was diluted with water (30 mL) and extracted with EA (3 × 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 obtain the title compound (863 mg, 52.91%) as a white solid. MS(ESI): Calculated mass for C9H8N2O2: 176.06, Measured mass: 177.10 [M+H] + .

[0217] Methyl 5-(2-aminoethyl) picolinate [ka] To a stirred mixture of methyl 5-(cyanomethyl) picolinate (683 mg, 3.88 mmol) in MeOH (8 mL, 197.59 mmol), concentrated HCl (0.2 mL) and Pd(OH)2 (0.2 g) were added. After stirring at room temperature under H2 for 2 hours, the reaction product was made basic with NaHCO3 (aqueous solution) to pH=8, diluted with water (50 mL), and extracted with EA (3 × 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (680 mg, 97.98%) as a white solid, which was used in the next step without further purification. MS(ESI):C9H 12 Calculated mass value for N2O2: 180.09, measured value: 181.15 [M+H] + .

[0218] 5-(2-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)ethyl)picolinamide [ka] Title compound 7 was synthesized using the same procedure as described in Example 17, Steps 2, 5-7. MS(ESI):C 17 H 22 Calculated mass for N6O4: 374.17, Measured mass: 375.15 [M+H] + . 1 H NMR(300MHz;DMSO-d6)δ9.48(s,2H),8.39(d,J=1.3Hz,1H),8.05(s,1H),7.93(d,J=8.0Hz,1H),7.76(dd,J=8.0,2.0Hz,1H),7.55(s,1H),7.34(d ,J=0.6Hz,2H),4.05(t,J=7.1Hz,2H),3.70(t,J=7.2Hz,2H),2.93(t,J= 7.1Hz,2H),1.31-1.41(m,2H),1.11-1.23(m,2H),0.85(t,J=7.2Hz,3H).

[0219] 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) using the same procedure as described in Example 7.

[0220] Example 9 was synthesized from 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine using the same procedure as described in Example 7.

[0221] Example 8: 1-Butyl-5-(diaminomethylene)-3-(4-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)butyl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka]

[0222] 5,5-Dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-2,4-dione [ka] To a stirred solution of 5,5-dimethylimidazolidine-2,4-dione (5 g, 39.023 mmol) in anhydrous DCM (20 mL), DIPEA (15.13 g, 117.07 mmol) and SEMCl (7.81 g, 46.83 mmol) were added at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was stirred at room temperature for 24 hours. After completion, the reaction mixture was quenched with water (60 mL) and extracted with DCM (3 × 60 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound (5.4 g, 45.39%). MS (negative mode): C 11 H 22 Calculated mass of N2O3Si: 258.14 MHz, measured mass: 257.05 MHz.

[0223] 2-(4-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)butyl)isoindoline-1,3-dione [ka] 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), N-(4-bromobutyl)phthalimide (1.97 g, 6.97 mmol) was added. After heating overnight at 60 °C under N2, the reaction product was quenched with water (50 mL) and extracted with EA (3 × 50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0-50% PE in EA) to obtain the title compound (2.5 g, 93.7%) as a colorless oil. MS(ESI):C 23 H 33 Calculated mass for N3O5Si: 459.22, measured mass: 482.15 [M+Na] + .

[0224] 1-(4-aminobutyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-2,4-dione [ka] 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), hydrazine hydrate (1.31 g, 26.11 mmol) was added. The reaction mixture was heated at 50 °C for 3 hours 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 resulting residue was purified by silica gel column chromatography (0 → 10% DCM / MeOH) to obtain the title compound (1.6 g, 92.99%) as a white solid. MS(ESI):C 15 H 31 Calculated mass for N3O3Si: 329.21, Measured mass: 330.15 [M+H] + .

[0225] 1-Butyl-5-(diaminomethylene)-3-(4-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)butyl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] 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 from the product of the previous step according to the procedure of Example 17, 80 mg, 0.15 mmol) in TFA (1.5 mL) and DCM (4.5 mL) was stirred at rt for 1 hour. After concentration, 2N NH3 was added to the crude residue in MeOH (5 mL) and stirred for 1 hour. The reaction product was concentrated and purified by silica gel column chromatography (0-10% DCM in MeOH), followed by reverse-phase HPLC (26-45% (v / v) ACN and H2O, and 0.05% NH4HCO3) to obtain title compound 8 (15 mg, 24.71%) as a white solid. MS(ESI):C 18 H 28 Calculated mass for N6O5: 408.21, Measured mass: 409.20 [M+H] + . 1 H NMR(400MHz;DMSO-d6)δ10.74(s,1H),9.53(s,2H),7.34(s,2H),3.76(t,J=7.8Hz,4H),3.1 7(t,J=6.4Hz,2H),1.47(dt,J=15.5,7.3Hz,6H),1.20-1.29(m,8H),0.87(t,J=7.3Hz,3H).

[0226] 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) [ka]

[0227] 1-(2-acetyl-2-azaspiro[3,5]nonane-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), TEA (69 mg, 0.69 mmol) and Ac2O (47 mg, 0.46 mmol) were added at 0°C under N2. After stirring at room temperature for 2 hours, the reaction product 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 resulting residue was purified by reverse-phase HPLC (25% → 45% (v / v) ACN and H2O, and 0.05% NH4HCO3) to obtain the title compound 12 (19.4 mg, 21.61%) as a white solid. MS(ESI):C 19 H 29 Calculated mass for N5O4: 391.22, Measured mass: 392.25 [M+H] + . 1 H NMR(400MHz;DMSO-d6)δ9.53(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=13.0Hz,2H),1.74(d,J=6.8Hz,3H),1.46(ddd,J=20.3,12.8,6.8Hz,6H),1.25(dq,J=14.9,7.4Hz,2H),0.88(d,J=14.6Hz,3H).

[0228] Examples 5 and 20 were synthesized using the same procedure as described in Example 12.

[0229] 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) [ka]

[0230] 1-Butyl-5-(diaminomethylene)-3-(2-(methylsulfonyl)-2-azaspiro[3,5]nonane-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), TEA (69 mg, 0.69 mmol) and MsCl (39 mg, 0.34 mmol) in DCM (0.1 mL) were added under N2 conditions at 0°C. After stirring at room temperature for 3 hours, the reaction product was quenched with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reverse-phase HPLC (25% → 45% (v / v) ACN and H2O, and 0.05% NH4HCO3) to obtain title compound 13 (20.5 mg, 20.89%) as a white solid. MS(ESI):C 18 H 29 Calculated mass of N5O5S: 427.19, Measured mass: 428.25 [M+H] + . 1 H NMR(400MHz;DMSO-d6)δ9.54(s,2H),7.33(s,2H),4.65(t,J=11.7Hz,1H),3.74(t,J=7.3Hz,2H),3.65(s,2H),3.53(s,2H),3.01 (s,3H),2.32(q,J=12.0Hz,2H),1.95(d,J=13.0Hz,2H),1.42-1.51(m,6H),1.26(dq,J=14.8,7.4Hz,2H),0.88(t,J=7.3Hz,3H).

[0231] Example 26 was synthesized using dimethylcarbamate chloride in the same manner as described in Example 13.

[0232] Example 30 was synthesized using the same procedure as described in Example 13.

[0233] Example 24 was synthesized from Example 18 using the same procedure as described in Example 13.

[0234] Example 17: 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione(17) [ka]

[0235] tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate [ka] A solution of tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (1.0 g, 4.18 mmol) in 7N NH3 was added to MeOH (40 mL), to which Pd / C (10%, 0.2 g) was added. The reaction mixture was stirred under a hydrogen atmosphere (balloon) for 16 hours. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the title compound (1.0 g, 99.57%), which was used in the next step without further purification. MS(ESI):C 13 H 24 Calculated mass for N2O2: 240.18 Measured mass: 241.15 [M+H] + .

[0236] tert-butyl7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate [ka] To a solution of tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (1 g, 4.16 mmol) in ClCH2CH2Cl (20 mL), butyl isocyanate (0.45 g, 4.58 mmol) was added. After stirring overnight at room temperature, the reaction product was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound (1.2 g, 84.96%). MS(ESI):C 18 H 33 Calculated mass for N3O3: 339.25 Measured mass: 340.20 [M+H] + .

[0237] 1-Butyl-3-(2-Azaspiro[3.5]nonan-7-yl)urea [ka] 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), 2N HCl (in EA, 8 mL) was added. After stirring at room temperature for 3 hours, the resulting mixture was concentrated to obtain the crude title compound (900 mg, 106%) as a yellow solid. MS(ESI):C 13 H 25 Calculated mass for N3O: 239.20 Measured mass: 240.20 [M+H] + The crude product was used directly in the next step without further purification.

[0238] Benzyl 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate [ka] 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), CbzCl (0.77 g, 4.51 mmol) and TEA (1.14 g, 11.28 mmol) were added. After stirring at rt for 16 hours, the reaction product was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by silica gel column chromatography (DCM: MeOH = 10 / 1) to obtain the title compound (1 g, 71.21%) as a yellow solid. MS(ESI):C 21 H 31 Calculated mass for N3O3: 373.24 Measured mass: 374.25 [M+H] + .

[0239] Benzyl 7-(3-butyl-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate [ka] 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), acetic anhydride (0.96 g, 9.37 mmol) and malonic acid (0.36 g, 3.48 mmol) were added. After heating at 80°C for 4 hours, the reaction product was concentrated and purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain the title compound (0.7 g, 59.21%). MS(ESI):C 24 H 31 Calculated mass for N3O5: 441.23 Measured mass: 442.20 [M+H] + .

[0240] Benzyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate [ka] To a solution of benzyl 7-(3-butyl-2,4,6-trioxo-1,3-diadinan-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate (0.7 g, 1.585 mmol) in DMSO (10 mL), carbon disulfide (1.21 g, 15.85 mmol) and TEA (2.41 g, 23.78 mmol) were added. After stirring at room temperature for 1 hour, 1,3-dibromopropane (3.20 g, 15.85 mmol) was added. After completion, the reaction product was quenched with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound (600 mg, 67.86%). MS(ESI):C 28 H 35 Calculated mass of N3O5S2: 558.20 Measured mass: 559.20 [M+H] + .

[0241] Benzyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate [ka] To a solution of benzyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate (600 mg, 1.08 mmol) in methanol (15 mL), 7N NH3 (2.5 mL in methanol) was added. The reaction mixture was heated at 100 °C for 1 h, cooled, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to obtain the title compound (280 mg, 53.82%). MS(ESI):C 25 H 33Calculated mass for N5O5: 483.25 Measured mass: 484.20 [M+H] + .

[0242] 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[3,5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka]

[0243] To a solution of benzyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate (280 mg, 0.58 mmol) in methanol (20 mL), Pd / C (10%, 50 mg) was added. The reaction mixture was stirred for 16 hours under a hydrogen atmosphere (balloon). Subsequently, it was filtered through a Celite pad and concentrated under reduced pressure to obtain the title compound 17 (90 mg, 44.48%). MS(ESI):C 17 H 27 Calculated mass for N5O3: 349.21 Measured mass: 350.2 [M+H] + . 1 H NMR(400MHz;CD3OD)δ4.74-4.83(m,1H),3.90(s,2H),3.82(dd,J=8.5,6.6Hz,2H),3.75(s,2H),2.37-2 .49(m,2H),2.11-2.15(m,2H),1.49-1.67(m,6H),1.33(tt,J=13.2,6.6Hz,2H),0.94(t,J=7.3Hz,3H).

[0244] Examples 23 and 33 were synthesized using the same procedure as described in Example 17.

[0245] Example 18: 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((methylamino)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione(18) [ka]

[0246] tert-butyl((1s,4s)-4-((methylamino)methyl)cyclohexyl)carbamate [ka] To a solution of tert-butyl N-[(1s,4s)-4-formylcyclohexyl]carbamate (950 mg, 4.18 mmol) in THF (25 mL), titanium(IV) isopropoxide (2850 mg, 10.03 mmol) was added. After stirring overnight at rt, MeOH (25 mL) was added, and the mixture was cooled to 0°C. NaBH4 (790 mg, 20.90 mmol) was added, and the reaction product was stirred at rt for 3 hours. The reaction product was quenched with NH4Cl (aqueous solution) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (650 mg, 64.17%) as a pale yellow solid.

[0247] Benzyl(((1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl)(methyl)carbamate [ka] To a solution of tert-butyl((1s,4s)-4-((methylamino)methyl)cyclohexyl)carbamate (630 mg, 2.599 mmol) in toluene (15 mL), K2CO3 (718.50 mg, 5.2 mmol) and benzyl chloroformate (886 mg, 5.2 mmol) were added. The reaction mixture was heated at 80°C under N2 for 3 hours. After cooling to room temperature, the reaction mixture 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 obtain the title compound (560 mg, 57.22%) as a pale yellow oil. MS(ESI):C 21 H32 Calculated mass for N2O4: 376.24, Measured mass: 377.15 [M+H] + .

[0248] Benzyl(((1s,4s)-4-aminocyclohexyl)methyl)(methyl)carbamate [ka] A solution of 2N HCl (4 mL) and benzyl (((1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl (methyl)carbamate (550 mg, 1.46 mmol) in EA (4 mL) was stirred at rt for 2 hours. The resulting mixture was concentrated to obtain the crude title compound (400 mg, 99.07%) as a yellow semi-solid. MS(ESI):C 16 H 24 Calculated mass for N2O2: 276.18, measured mass: 277.05 [M+H] + The crude product was used in the next step without further purification.

[0249] Benzyl(((1s,4s)-4-(3-butylureido)cyclohexyl)methyl)(methyl)carbamate [ka] To a solution of benzyl (((1s,4s)-4-aminocyclohexyl)methyl)(methyl)carbamate (560 mg, 2.03 mmol) in ClCH2CH2Cl (15 mL), TEA (410 mg, 4.05 mmol) and butyl isocyanate (220 mg, 2.23 mmol) were added. After stirring at room temperature for 3 hours, the resulting mixture was concentrated and purified by silica gel column chromatography (0 → 10% MeOH / DCM) to obtain the title compound as a pale yellow oil. MS(ESI):C 21 H 33 Calculated mass for N3O3: 375.25, measured mass: 376.25 [M+H] + .

[0250] Benzyl(((1s,4s)-4-(3-butyl-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate [ka] Malonic acid (143 mg, 1.38 mmol) was added 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). The resulting mixture was stirred at 80°C for 4 hours and concentrated. The crude residue was purified by silica gel column chromatography to obtain the title compound (330 mg, 59.44%) as a yellow solid. MS(ESI):C 24 H 33 Calculated mass for N3O5: 443.24, Measured mass: 444.25 [M+H] + .

[0251] Benzyl(((1s,4s)-4-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate [ka] To a solution of benzyl(((1s,4s)-4-(3-butyl-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate (300 mg, 0.68 mmol) in DMSO (8 mL), TEA (273 mg, 2.70 mmol) was added, followed by carbon disulfide (154 mg, 2.03 mmol). After stirring at room temperature for 3 hours, 1,3-dibromopropane (163 mg, 0.81 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and quenched with water. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to obtain the title compound (250 mg, 66.03%) as a yellow viscous oil. MS(ESI):C 28 H 37 Calculated mass of N3O5S2: 559.22, Measured mass: 560.20 [M+H] + .

[0252] Benzyl(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate [ka] A solution of benzyl(((1s,4s)-4-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate (270 mg, 0.48 mmol) in 2N NH3 (5 mL) in MeOH was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction product 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 obtain the title compound (200 mg, 85.39%) as a pale yellow solid. MS(ESI):C 25 H 35Calculated mass for N5O5: 485.26, Measured mass: 486.25 [M+H] + .

[0253] 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((methylamino)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] A solution of benzyl(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate (200 mg, 0.41 mmol) in DCM (3 mL) was mixed with 40% HBr (1 mL) in AcOH at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was neutralized with NaHCO3 (aqueous solution) to pH=7 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 yield the title compound 18 (100 mg, 69%). MS(ESI):C 17 H 29 Calculated mass for N5O3: 351.23, Measured mass: 352.25 [M+H] + . 1 H NMR(400MHz;DMSO-d6)δ9.55(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).

[0254] Example 44 was synthesized using the same procedure as described in Example 18 and Example 39.

[0255] Example 25: 1-Butyl-5-(diaminomethylene)-3-(2-(oxetan-3-yl)-2-azaspiro[3.5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione(25) [ka]

[0256] 1-Butyl-5-(diaminomethylene)-3-(2-(oxetan-3-yl)-2-azaspiro[3,5]nonane-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), 3-oxetanone (19 mg, 0.26 mmol) and AcOH (15 mg, 0.26 mmol) were added. After stirring at rt for 0.5 h, sodium borohydride (16 mg, 0.26 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were 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 → 42% B) to obtain the title compound 25 (12.1 mg, 20.58%) as a white solid. MS(ESI):C 20 H 31 Calculated mass for N5O4: 405.24, Measured mass: 406.15 [M+H] + . 1 H NMR(400MHz;DMSO-d6)δ9.54(s,2H),7.31(s,2H),4.64(t,J=12.0Hz,1H),4.56(t,J=6.5Hz,2H),4.33-4.40(m,2H),3.69-3.78(m,3H) ,2.89-3.12(m,4H),2.33(q,J=12.5Hz,2H),1.93-1.96(m,2H),1.39-1.49(m,6H),1.26(dq,J=14.9,7.4Hz,2H),0.88(t,J=7.3Hz,3H).

[0257] Examples 46 and 53 were synthesized using the same procedure as described in Example 25.

[0258] Examples 56 and 57 were synthesized 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 the procedure) using the same procedure as described in Example 25.

[0259] Examples 60 and 61 were synthesized from 1-butyl-5-(diaminomethylene)-3-(piperidine-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared in the same manner as in Example 18) using the same procedure as described in Example 25.

[0260] Example 63 was synthesized 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) using the same procedure as in Example 25.

[0261] Example 71 was synthesized using the same starting materials and tert-butyl 3-oxopyrrolidine-1-carboxylate as in Example 60, following the same procedure as described in Example 25. Subsequently, its Boc group was deprotected with TFA, and then it was synthesized again following the same procedure as described in Example 4.

[0262] Example 72 was synthesized using the same procedure as Example 71, except that the final step followed the same procedure as in Example 12.

[0263] Example 37: 1-(1-(azetidine-3-yl)piperidine-4-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione(37) [ka]

[0264] tert-butyl3-(4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)piperidine-1-yl)azetidine-1-carboxylate [ka] To a solution of 1-butyl-5-(diaminomethylene)-3-(piperidine-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared from benzyl 4-aminopiperidine-1-carboxylate, 200 mg, 0.65 mmol) in MeOH (5 mL), tert-butyl 3-oxoazetidine-1-carboxylate (553 mg, 3.23 mmol) and AcOH (116 mg, 1.94 mmol) were added at room temperature. After stirring for 1 hour, NaBH3CN (121 mg, 1.938 mmol) was added at 0°C. The resulting mixture was stirred for a further 1 hour at room temperature. The reaction product was quenched with water (10 mL) and extracted with DCM (3 × 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 obtain the title compound (200 mg, 66.47%) as a white solid. MS(ESI):C 22 H 36 Calculated mass for N6O5: 464.27, Measured mass: 465.30 [M+H] + .

[0265] 1-(1-(azetidine-3-yl)piperidine-4-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] A solution of tert-butyl 3-(4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)piperidine-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 hours. The mixture was concentrated under reduced pressure and purified by reverse-phase HPLC to obtain the title compound 37 (160 mg, 73.01%) as a white solid. MS(ESI):C 17 H 28 Calculated mass for N6O3: 364.22, Measured mass: 365.25 [M+H] + . 1 H NMR(400MHz;DMSO-d6)δ9.54(s,2H),7.34(s,2H),4.67(t,J=11.9Hz,1H),3.70-3.80(m,2H),3.34-3.62(m,4H),2.98(dt,J=12.1,6.1Hz,1H ),2.78(d,J=10.9Hz,2H),2.59-2.50(m,2H),1.78(t,J=11.0Hz,2H),1.37-1.55(m,4H),1.25(dq,J=14.8,7.4Hz,2H),0.88(t,J=7.3Hz,3H).

[0266] Example 39: 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-sulfonamide (39) [ka] Benzyl((7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-yl)sulfonyl)carbamate [ka] 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), Et3N (46 mg, 0.46 mmol) and benzyl N-(chlorosulfonyl)carbamate (57 mg, 0.23 mmol) were added. After stirring at room temperature for 3 hours, the reaction product 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 resulting residue was purified by silica gel column chromatography (0 → 20% DCM / MeOH) to obtain the title compound (90 mg, 69.87%) as a pale yellow solid. MS(ESI):C 25 H 34 Calculated mass of N6O7S: 562.22, Measured mass: 563.25 [M+H] + .

[0267] 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-sulfonamide [ka] To a solution of benzyl ((7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-yl)sulfonyl) carbamate (90 mg, 0.16 mmol) in MeOH (1 mL) and DCM (4 mL), Pd / C (30 mL) was added under N2. The reaction mixture was then stirred at room temperature for 1 hour under an 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 → 57% B) to obtain the title compound 39 (22.3 mg, 32.50%) as a white solid. MS(ESI):C 17 H 28 Calculated mass of N6O5S: 428.18, Measured mass: 429.20 [M+H]+ . 1 H NMR(400MHz;DMSO-d6)δ9.53(s,2H),7.31(s,2H),6.88(s,2H),4.63(t,J=11.2Hz,1 H),3.73(t,J=7.4Hz,2H),3.49(s,2H),3.39(s,2H),2.30(q,J=12.8Hz,2H),1.91(br d,J=12.9Hz,2H),1.38-1.51(m,6H),1.25(dq,J=14.9,7.4Hz,2H),0.87(t,J=7.3Hz,3H).

[0268] 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) [ka]

[0269] 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 [ka] To a solution of 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)-3-methyl-1H-imidazole-3-iumtrifluoromethanesulfonate (78 mg, 0.29 mmol) triflate) in CH3CN (3 mL), 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) were added under an N2 atmosphere at 0°C. After stirring at rt for 3 hours, the reaction product was quenched with water (10 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (60 mg, 77.54%). The crude product was used directly in the next step without further purification. MS(ESI):C 24 H 44 Calculated mass of N6O4SSi: 540.29, measured mass: 541.20 [M+H] + .

[0270] 1-Butyl-5-(diaminomethylene)-3-(2-(S-methylsulfonimidoyl)-2-azaspiro[3,5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] In 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), Et3N .3HF (0.5 mL) was added at 0°C. After stirring at rt for 2 hours, the reaction product was quenched with water (10 mL) and extracted with EA (3 × 30 mL). 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 (mobile phase A: water (0.1% FA), mobile phase B: ACN, 16% B → 40% B) to obtain the title compound 40 (22.5 mg, 46.57%) as a white solid. MS(ESI):C 18 H 30 Calculated mass for N6O4S: 426.20, Measured mass: 427.20 [M+H] + . 1 H NMR(400MHz;DMSO-d6)δ9.53(s,2H),7.32(s,2H),4.65(t,J=11.8Hz,1H),3.73(t,J=7.4Hz, 2H),3.58-3.62(m,2H),3.49(q,J=7.0Hz,2H),3.00(s,3H),2.32(q,J=12.0Hz,2H),1.92(br d,J=13.0Hz,2H),1.35-1.54(m,6H),1.25(dq,J=14.9,7.4Hz,2H),0.88(t,J=7.3Hz,3H).

[0271] Examples 41 and 42: 1-Butyl-5-(diaminomethylene)-3-(((1s,4s)-4-(5-methyl-4H-1,2,4-triazole-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (41) and 1-Butyl-5-(diaminomethylene)-3-(((1r,4r)-4-(5-methyl-4H-1,2,4-triazole-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (42) [ka]

[0272] Methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate [ka] A solution of 4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (3.0 g, 16.11 mmol) in tetrahydrofuran (50 mL) was cooled to -78°C. A borane-methyl sulfide complex (2.09 mL, 20.94 mmol) was added, and the reaction mixture was raised to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (2.4 g, 86.5%) as a yellow oil. MS(ESI):C9H 16 Calculated mass for O3: 172.11, Measured mass: 173.20 [M+H] + .

[0273] Methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylate [ka] To a solution of methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate (2.4 g, 13.94 mmol) in DCM (50 mL), TBSCl (2.52 g, 16.72 mmol) and imidazole (1.90 g, 27.87 mmol) were added. After stirring at room temperature for 2 hours, the reaction product was quenched with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 20% EA / PE) to obtain the title compound (3.0 g, 75.14%) as a yellow oil. MS(ESI):C 15 H 30 Calculated mass for O3Si: 286.20, Measured mass: 287.20 [M+H] + .

[0274] 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbozide [ka] To a solution of methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylate (2.0 g, 6.98 mmol) in ethyl alcohol (20 mL), hydrazine (1.12 g, 34.91 mmol) was added. The mixture was heated at 100 °C for 4 hours. After cooling to room temperature, the reaction product was quenched with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 50% EA in PE) to obtain the title compound (1.6 g, 80.0%) as a yellow oil. MS(ESI):C 14 H 30 Calculated mass for N2O2Si: 286.21, Measured mass: 287.20 [M+H] + .

[0275] 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-methyl-4H-1,2,4-triazole [ka] To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbohydrazide (1.8 g, 6.28 mmol) in n-butanol (20 mL), acetimidomidamide hydrochloride (0.59 g, 6.28 mmol) and K2CO3 (0.52 g, 3.77 mmol) were added. The mixture was heated at 120 °C for 16 h. After cooling to room temperature, the reaction product was quenched with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 50% EA in PE) to obtain the title compound (1.5 g, 77.13%) as a yellow solid. MS(ESI): C 16 H 31 Calculated mass for N3Osi: 309.22, measured mass: 310.20 [M+H] + .

[0276] 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole [ka] 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 hours, [2-(chloromethoxy)ethyl]trimethylsilane (1.21 g, 7.27 mmol) was added. After stirring at room temperature for a further 2 hours, the reaction product was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 50% EA in PE) to obtain the title compound (1.3 g, 61.0%) as a yellow solid. MS(ESI):C 22 H 45 Calculated mass for N3O2Si2: 439.31, Measured mass: 440.30 [M+H] + .

[0277] (4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)methanol [ka] 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), TBAF (0.72 g, 2.75 mmol) was added. After heating at 50 °C for 2 hours, the reaction product was quenched with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 50% EA in PE) to obtain the title compound (615 mg, 75.53%) as a yellow solid. MS(ESI): C 16 H 31 Calculated mass for N3O2Si: 325.22, Measured mass: 326.20 [M+H] + .

[0278] 1-Butyl-5-(1,3-Dithian-2-ylidene)-3-((4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of (4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)methanol (400 mg, 1.23 mmol) in DCM (10 mL), 1-butyl-5-(1,3-dithian-2-ylidene)-1,3-diadinane-2,4,6-trione (369 mg, 1.23 mmol) and PPh3 (322 mg, 1.23 mmol) were added. The reaction mixture was cooled to 0°C, and diethyl azodicarboxylate (214 mg, 1.23 mmol) was added under N2. The temperature was raised to rt, and after stirring for 3 hours, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-50% EA / PE) to obtain the title compound (486 mg, 65.06%) as a yellow solid. MS(ESI):C 28 H 45 Calculated mass of N5O4S2Si: 607.27, measured mass: 608.25 [M+H] + .

[0279] 1-Butyl-5-(diaminomethylene)-3-((4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] 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-triazole-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (486 mg, 0.82 mmol) in methanol (10 mL), 7N NH3 was added to MeOH (2 mL). The reaction mixture was heated at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 10% MeOH in DCM) to obtain the title compound (203 mg, 46.48%) as a yellow solid. MS(ESI):C 25 H 43 Calculated mass for N7O4Si: 533.31, Measured mass: 534.40 [M+H] + .

[0280] 1-Butyl-5-(diaminomethylene)-3-(((1s,4s)-4-(5-methyl-4H-1,2,4-triazole-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (41) and 1-Butyl-5-(diaminomethylene)-3-(((1r,4r)-4-(5-methyl-4H-1,2,4-triazole-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (42) [ka] To a solution of 1-butyl-5-(diaminomethylene)-3-((4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (30 mg, 0.056 mmol) in DCM (3 mL), trifluoroacetic acid (1 mL) was added. After stirring at room temperature for 4 hours, the reaction product was concentrated to dryness under reduced pressure to obtain the crude product, which was purified by reverse-phase HPLC (26 → 45% (v / v) ACN and H2O, and 0.05% NH4HCO3) to obtain the title compound 41 (3.8 mg, 16.73%) as a white solid. MS(ESI):C 19 H 29 Calculated mass for N7O3: 403.23 Measured mass: 404.20 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ13.16(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,3H),1.81-1.90(m,1H),1.54-1.68(m,2H),1.21-1.54(m,7H),0.88(t,J=7.2Hz,3H) Title compound 42 (2.0 mg, 8.80%) was obtained as a white solid. MS(ESI):C 19 H 29 Calculated mass for N7O3: 403.23 Measured mass: 404.20 [M+H] + . 1 ¹H NMR (300MHz, DMSO-d6) δ 13.13 (s,1H), 9.54 (s,2H), 7.35 (s,2H), 3.77 (t,J=7.3Hz,2H), 3.68 (d,J=6.7Hz,2H), 2.51-2.63 (m,1H), 2.15-2.30 (m,3H), 1.93 (d,J=13.0Hz,2H), 1.65 (d,J=12.9Hz,3H), 1.38-1.56 (m,2H), 1.17-1.38 (m,4H), 0.99-1.17 (m,2H), 0.89 (t,J=7.3Hz,3H). Stereochemistry is arbitrarily assigned.

[0281] Example 38 was synthesized from (3-methyl-4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-yl)phenyl)methanol using the same procedure as described in Example 41.

[0282] Example 43 was synthesized from (2-oxaspiro[3.5]nonane-7-yl)methanol using the same procedure as described in Example 41, steps 7 and 8.

[0283] Examples 51 and 52: 1-((2S,4s,7S)-7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonane-2-yl)-1-methylurea (51) and 1-((2R,4r,7R)-7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonane-2-yl)-1-methylurea (52) [ka]

[0284] N-benzyl-N-methyl-8,11-dioxadispiro[3.2.4 7 .2 4 Tridecane-2-amine [ka] 8,11-dioxadispiro in methanol (15 mL) [3.2.4 7 .2 4To a stirred solution of tridecane-2-one (1.4 g, 7.13 mmol), N-methylbenzylamine (1.73 g, 14.27 mmol) was added at rt. After stirring for 2 hours, NaBH3CN (0.9 g, 14.27 mmol) was added. After stirring at rt for a further 16 hours, the reaction product was quenched with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was further purified by silica gel column chromatography (PE / EA = 3:1) to obtain the title compound (1.4 g, 65.11%) as a colorless oil. MS(ESI):C 19 H 27 Calculated mass value for NO2: 301.20, Measured value: 302.20 [M+H] + .

[0285] 2-(benzyl(methyl)amino)spiro[3.5]nonane-7-one [ka] N-benzyl-N-methyl-8,11-dioxadispiro [3.2.4] in tetrahydrofuran (10 mL) 7 .2 4 To a solution of tridecane-2-amine (1.68 g, 5.57 mmol), 4N HCl (5 mL) was added. After heating at 60°C for 5 hours, the reaction product was neutralized with saturated NaHCO3 solution to pH=7. The aqueous layer was extracted with EA (3 × 50 mL). The combined organic layers were concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3:1) to obtain the title compound (1.0 g, 69.71%) as a white solid. MS(ESI):C 17 H 23 Calculated mass value for NO: 257.18, Measured value: 258.20 [M+H] + .

[0286] 2-(benzyl(methyl)amino)spiro[3.5]nonan-7-ol [ka] To a solution of 2-(benzyl(methyl)amino)spiro[3.5]nonane-7-one (800 mg, 3.11 mmol) in methanol (10 mL), NaBH4 (176 mg, 4.66 mmol) was added in fractions at 0°C. After stirring at rt for 2 hours, the reaction product was quenched with water (10 mL) and extracted with DCM (3 × 30 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain the title compound (600 mg, 74.42%) as a colorless oil. MS(ESI):C 17 H 25 Calculated mass value for NO: 259.19, Measured value: 260.30 [M+H] + .

[0287] 2-(methylamino)spiro[3.5]nonan-7-ol [ka] To a solution of 2-(benzyl(methyl)amino)spiro[3.5]nonan-7-ol (300 mg, 1.16 mmol) in methanol (10 mL), Pd / C (50 mg) was added. The reaction mixture was stirred for 2 hours under a hydrogen atmosphere (balloon). Subsequently, the reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the title compound (0.2 g, 99%) as a white solid. MS(ESI):C 10 H 19 Calculated mass value for NO: 169.15 m / z, measured value: 170.20 [M+H] + .

[0288] Benzyl(7-hydroxyspiro[3.5]nonan-2-yl)(methyl)carbamate [ka] 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 minutes at rt, and then CbzCl (221 mg, 1.30 mmol) was added dropwise at 0°C. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was further purified by silica gel column chromatography (PE / EA = 2:1) to obtain the title compound (0.3 g, 83.8%) as a white solid. MS(ESI): C 18 H 25 Calculated mass value for NO3: 303.18 m / z, measured value: 304.20 [M+H]+.

[0289] Benzyl(7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidine-1(2I)-yl)spiro[3.5]nonane-2-yl)(methyl)carbamate [ka] To a solution of benzyl(7-hydroxyspiro[3,5]nonan-2-yl)(methyl)carbamate (0.29 g, 0.96 mmol) in toluene (6 mL), 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) were added. Subsequently, tributylphosphine (388 mg, 1.92 mmol) was added to the mixture at 0°C under a nitrogen atmosphere. The resulting mixture was heated for 16 hours at 100°C under nitrogen. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (PE / EA = 2:1) to obtain the title compound (120 mg, 21.35%) as a yellow solid. MS(ESI):C 30 H 39 Calculated mass of N3O5S2: 585.23, Measured mass: 586.20 [M+H] + .

[0290] Benzyl(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonane-2-yl)(methyl)carbamate [ka] To a solution of benzyl(7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonane-2-yl)(methyl)carbamate (120 mg, 0.20 mmol) in methanol (5 mL), 0.7 mL of 7N NH3 was added to methanol. The resulting mixture was heated at 100 °C for 1 hour and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE / EA = 1:1) to obtain the title compound (90 mg, 88.23%) as a white solid. MS(ESI):C 27 H 37Calculated mass for N5O5: 511.28, Measured mass: 512.30 [M+H] +: .

[0291] Butyl-5-(diaminomethylene)-3-(2-(methylamino)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of benzyl(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (90 mg, 0.17 mmol) in methanol, Pd / C (30 mg) was added. The reaction mixture was stirred for 0.5 hours under a hydrogen atmosphere (balloon). Subsequently, the reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the title compound (60 mg, 90.9%) as a white solid. MS(ESI):C 19 H 31 Calculated mass for N5O3: 377.24, Measured mass: 378.05 [M+H] + .

[0292] 1-((2S,4s,7S)-7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonane-2-yl)-1-methylurea (51) and 1-((2R,4r,7R)-7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonane-2-yl)-1-methylurea (52) [ka] 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, TEA (182 mg, 1.80 mmol) was added, followed by isocyanatotrimethylsilane (124 mg, 1.08 mmol). After stirring at room temperature for 2 hours, the reaction product was quenched with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic extract was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was directly purified by silica gel column chromatography (DCM / MeOH = 8:1). The purified product was further purified by chiral HPLC to obtain the title compound 51 (25 mg) as a white solid (MS(ESI):C). 20 H 32 Calculated mass for N6O4: 420.25, Measured mass: 421.20 [M+H] + ); 1 H NMR(300MHz;CD3OD)δ4.73(tt,J=12.2,3.5Hz,1H),4.55(quintet,J=8.7Hz,1H), 3.84(t,J=7.5Hz,2H),2.86(s,3H),2.50(dqd,J=24.4,12.3,3.4Hz,2H),2.30(d dd,J=11.3,8.3,2.9Hz,1H),1.83-1.97(m,4H),1.69(dq,J=13.0,2.7Hz,1H),1. 28-1.59(m,8H),0.95(t,J=7.3Hz,3H)), title compound 52 (25mg) was obtained as a white solid (MS(ESI):C 20 H 32 Calculated mass for N6O4: 420.25, Measured mass: 421.20 [M+H] + ; 1¹H NMR (300MHz; CD3OD) δ 4.73 (tt, J=12.2, 3.5Hz, 1H), 4.55 (quintet, J=8.7Hz, 1H), 3.84 (t, J=7.5Hz, 2H), 2.86 (s, 3H), 2.50 (dqd, J=24.4, 12.3, 3.4Hz, 2H), 2.30 (ddd, J=11.3, 8.3, 2.9Hz, 1H), 1.83-1.97 (m, 4H), 1.69 (dq, J=13.0, 2.7Hz, 1H), 1.28-1.59 (m, 8H), 0.95 (t, J=7.3Hz, 3H)). Its stereochemistry is arbitrarily assigned.

[0293] Example 21 was the product before chiral separation in the above synthesis.

[0294] Example 29 was synthesized from tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate using the same procedure as described in Example 51, steps 6-9. In step 8, the Boc group was deprotected using TFA instead of Pd.

[0295] Examples 45 and 54 were synthesized from their respective isomers of tert-butyl 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate using the same procedure as described in Example 29.

[0296] Example 97 was synthesized using the same procedure as in Example 45, with the last two steps being Buchwald coupling with 3-chloro-5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole and deprotection of the SEM group.

[0297] Examples 65, 68, and 73 were synthesized using the same procedure as in Example 21.

[0298] Examples 92 and 93 were synthesized using the same procedure as described in Examples 51 and 52.

[0299] Example 55: 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-methylspiro[3.5]nonane-2-carboxamide (55) [ka]

[0300] Methyl 7-oxospiro[3.5]nonane-2-carboxylate [ka] To a solution of 7-oxospiro[3.5]nonane-2-carboxylic acid (3 g, 16.46 mmol) in acetone (30 mL), potassium carbonate (6.88 g, 49.39 mmol) and MeI (11.68 g, 82.32 mmol) were added at rt. After stirring overnight, the reaction product was quenched with water and extracted with EA (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (EA / PE from 0 to 100%) to obtain the title compound (2.2 g, 68.09%) as a yellow solid. MS(ESI):C 11 H 16 Calculated mass for O3: 196.14, Measured mass: 197.15 [M+H] + .

[0301] Methyl 7-hydroxyspiro[3.5]nonane-2-carboxylate [ka] To a solution of methyl 7-oxospiro[3.5]nonane-2-carboxylate (2.1 g, 10.70 mmol) in MeOH (20 mL), NaBH4 (2.02 g, 53.51 mmol) was added at 0°C. After stirring for 2 hours at 0°C, the reaction product was quenched with water and extracted with EA (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (EA / PE from 0 to 100%) to obtain the title compound (1.5 g, 70.7%) as a yellow solid. MS(ESI):C 11 H 18 Calculated mass relative to O3: 198.13, measured value: 181.10 [M-OH] + .

[0302] Methyl 7-[(tert-butyldiphenylsilyl)oxy]spiro[3.5]nonane-2-carboxylate [ka] To a solution of methyl 7-hydroxyspiro[3.5]nonane-2-carboxylate (500 mg, 2.52 mmol) in dimethylformamide (10 mL), imidazole (515.07 mg, 7.57 mmol) and TBDPSCl (1.04 g, 3.78 mmol) were added at 0°C. The mixture was heated to rt and stirred for 2 hours. The reaction product was quenched with water and extracted with EA (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (EA / PE from 0 to 100%) to obtain the title compound (1 g, 90.81%) as a yellow solid. MS(ESI):C 27 H 36 Calculated mass value for O3Si: 436.24, Measured value: 437.30 [M+H] + .

[0303] Methyl 7-[(tert-butyldiphenylsilyl)oxy]-2-methylspiro[3.5]nonane-2-carboxylate [ka] To a solution of methyl 7-[(tert-butyldiphenylsilyl)oxy]spiro[3.5]nonane-2-carboxylate (50 mg, 0.12 mmol) in THF (2 mL), LDA (0.07 mL, 0.14 mmol) was added dropwise at -78°C under an N2 atmosphere. The reaction mixture was stirred at -78°C for 30 minutes. Subsequently, a solution of MeI (48.76 mg, 0.35 mmol) in 1 mL of THF was added dropwise, and the reaction mixture was stirred for a further 60 minutes. The reaction mixture was quenched with water / saturated NH4Cl (5 mL) and extracted with ether / Âxal (2 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated to obtain the crude product, which was purified by silica gel chromatography (PE:EA = 10:1) to obtain the title compound (400 mg, 77.51%) as a yellow solid. MS(ESI):C 28 H 38 Calculated mass for O3Si: 450.26, Measured mass: 451.30 [M+H] + .

[0304] Methyl 7-hydroxy-2-methylspiro[3.5]nonane-2-carboxylate [ka] 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), triethylamine trihydrofluoride (3 mL) was added at 0°C. The reaction mixture was heated to rt and heated at 70°C for 2 hours. The reaction mixture was quenched with water and extracted with EA (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (EA / PE from 0 to 100%) to obtain the title compound (100 mg, 55.87%) as a yellow solid.

[0305] Methyl 7-[3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxo-1,3-diadinane-1-yl]-2-methylspiro[3.5]nonane-2-carboxylate [ka] To a solution of methyl 7-hydroxy-2-methylspiro[3.5]nonane-2-carboxylate (80 mg, 0.38 mmol) in toluene (3 mL), 1-butyl-5-(1,3-dithian-2-ylidene)-1,3-diadinane-2,4,6-trione (113.20 mg, 0.38 mmol), TMAD (194.66 mg, 1.131 mmol), and n-Bu3P (228.73 mg, 1.13 mmol) were added at rt. The resulting mixture was heated at 100 °C for 2.5 h. The reaction product was quenched with water and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (0→100% EA / PE) to obtain the title compound (30 mg, 16.09%) as a yellow solid. MS(ESI):C 24 H 34 Calculated mass of N2O5S2: 494.19, measured mass: 495.15 [M+H] + .

[0306] Methyl 7-[3-butyl-5-(diaminomethylidene)-2,4,6-trioxo-1,3-diadinane-1-yl]-2-methylspiro[3.5]nonane-2-carboxylate [ka] To a solution of methyl 7-[3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxo-1,3-diadinane-1-yl]-2-methylspiro[3.5]nonane-2-carboxylate (50 mg, 0.10 mmol), 7N ammonia was added at rt in methanol (6 mL). After heating at 100 °C for 1 hour, the reaction product was quenched with water and extracted with EA (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (EA / PE from 0 to 100%) to obtain the title compound (30 mg, 70.58%) as a yellow solid. MS(ESI):C 21 H 32 Calculated mass for N4O5: 420.14, Measured mass: 421.30 [M+H] + .

[0307] 7-[3-butyl-5-(diaminomethylidene)-2,4,6-trioxo-1,3-diadinan-1-yl]-2-methylspiro[3.5]nonane-2-carboxylic acid [ka] To a solution of methyl 7-[3-butyl-5-(diaminomethylidene)-2,4,6-trioxo-1,3-diadinan-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), LiOH (17.09 mg, 0.71 mmol) was added at rt. After heating at 65°C for 3 hours, the reaction product was quenched with water and extracted with EA (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (EA / PE from 0 to 100%) to obtain the title compound (20 mg, 68.97%) as a white solid. MS(ESI):C 20 H 30 Calculated mass for N4O5: 406.22, Measured mass: 407.10 [M+H] + .

[0308] 7-[3-butyl-5-(diaminomethylidene)-2,4,6-trioxo-1,3-diadinane-1-yl]-2-methylspiro[3.5]nonane-2-carboxamide [ka] To a solution of 7-[3-butyl-5-(diaminomethylidene)-2,4,6-trioxo-1,3-diadinan-1-yl]-2-methylspiro[3.5]nonane-2-carboxylic acid (15 mg, 0.037 mmol) in DMF (2 mL), NH4Cl (5.92 mg, 0.11 mmol), HATU (21.05 mg, 0.055 mmol), and DIPEA (9.54 mg, 0.074 mmol) were added at rt. After stirring at rt for 3 hours, the reaction product was quenched with water and extracted with EA (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (EA / PE from 0 to 100%) to obtain the impurity product. The impurity product was further purified by reverse-phase HPLC (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, 17% B → 42% B) to obtain the title compound 55 (3.1 mg, 20.69%) as a white solid. MS(ESI):C 20 H 31 Calculated mass for N5O4: 405.24, Measured mass: 406.05 [M+H] + . 1 H NMR(300MHz;DMSO-d6)δ9.54(s,2H),7.31(s,2H),7.08(s,1H),6.71(s,1H),4.57(t,J=11.5Hz,1H),3 .73(t,J=7.3Hz,2H),2.13-2.40(m,4H),1.35-1.79(m,6H),1.15-1.34(m,9H),0.87(t,J=7.2Hz,3H).

[0309] Example 64 was synthesized using the same procedure as described in Example 55.

[0310] Example 58: 1-(1-(1H-pyrazole-4-carbonyl)piperidine-4-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione(58) [ka]

[0311] 1-Butyl-5-(diaminomethylene)-3-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonyl)piperidine-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of 1-butyl-5-(diaminomethylene)-3-(piperidine-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared from benzyl 4-aminopiperidine-1-carboxylate, 58 mg, 0.19 mmol) in DMF (2 mL), DIPEA (49 mg, 0.38 mmol) and HATU (107 mg, 0.28 mmol) were added. After stirring overnight at room temperature, the reaction product was quenched with water (10 mL) and extracted with EA (3 × 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 obtain the title compound (70 mg, 69.93%) as a yellow oil. MS(ESI):C 24 H 39 Calculated mass of N7O5Si: 533.28, measured mass: 534.25 [M+H] + .

[0312] 1-(1-(1H-pyrazole-4-carbonyl)piperidine-4-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] A solution of 1-butyl-5-(diaminomethylene)-3-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonyl)piperidine-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 hours. The mixture was neutralized to pH=7 with NaHCO3 solution. The resulting mixture was extracted with DCM / MeOH. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. NH3.H2O (3 mL) was added to this crude residue. After stirring at rt for 1 hour, the resulting mixture was extracted with DCM / MeOH. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reverse-phase HPLC (17% → 42% (v / v) ACN and water, and 0.05% NH4HCO3) to obtain the title compound 58 (5.1 mg, 11.24%) as a white solid. MS(ESI):C 18 H 25 Calculated mass for N7O4: 403.20, Measured mass: 404.30 [M+H] + . 1 H NMR(400MHz;DMSO-d6)δ13.18(s,1H),9.52(s,2H),8.07(s,1H),7.70(s,1H),7.33(s,2H),4.97(t,J=11.5Hz,1H),4.04-4.59(br m,2H),3.74(t,J=7.3Hz,2H),2.37-2.47(m,2H),1.53-1.60(m,2H),1.46(dt,J=14.7,7.4Hz,2H),1.30-1.21(m,4H),0.88(t,J=7.3Hz,3H).

[0313] Example 62: 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione(62) [ka]

[0314] tert-butyl((1s,4s)-4-(bromomethyl)cyclohexyl)carbamate [ka] To a solution of tert-butyl((1s,4s)-4-(hydroxymethyl)cyclohexyl)carbamate (1.5 g, 6.54 mmol) in DCM (50 mL), carbon tetrabromide (2.39 g, 7.20 mmol) was added at 0°C, followed by the slow addition of triphenylphosphine (2.06 g, 7.85 mmol). The mixture was heated to room temperature and stirred for 4 hours. The reaction product was quenched with water (50 mL) and extracted with DCM (3 × 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 obtain the title compound (1.2 g, 62.78%) as a white solid. MS(ESI):C 12 H 22 Calculated mass for BrNO2: 291.08, measured mass: 236.15 [M- t [AD+H] + .

[0315] tert-butyl((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)carbamate [ka] To a solution of tert-butyl((1s,4s)-4-(bromomethyl)cyclohexyl)carbamate (1.2 g, 4.11 mmol) in N,N-dimethylformamide (20 mL), Cs2CO3 (2.01 g, 6.16 mmol) and 5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-2,4-dione (1.06 g, 4.11 mmol) were added. The reaction mixture was heated at 50 °C for 4 hours. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 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 obtain the title compound (812 mg, 42.10%) as a yellow oil. MS(ESI):C 23 H 43 Calculated mass for N3O5Si: 469.30, Measured mass: 492.30 [M+Na] + .

[0316] 1-(((1s,4s)-4-aminocyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidined-2,4-dione [ka] A solution of tert-butyl((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidined-1-yl)methyl)cyclohexyl)carbamate (812 mg, 1.73 mmol) in formic acid (10 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated and then made basic to pH=9. The mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (501 mg, 78.41%) as a yellow oil. MS(ESI):C 18 H 35 Calculated mass for N3O3Si: 369.24, Measured mass: 370.20 [M+H] + .

[0317] 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidined-1-yl)methyl)cyclohexyl)urea [ka] 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), TEA (411.53 mg, 4.07 mmol) and 1-isocyanatobutane (268 mg, 2.71 mmol) were added. After stirring at room temperature for 2 hours, the reaction product was quenched with water (30 mL) and extracted with ethyl acetate (3 × 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 (EA / PE from 0 to 100%) to obtain the title compound (482 mg, 75.86%) as a yellow solid. MS(ESI):C 23 H 44 Calculated mass for N4O4Si: 468.31, Measured mass: 469.35 [M+H] + .

[0318] 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 [ka] To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidined-1-yl)methyl)cyclohexyl)urea (486 mg, 1.04 mmol) in DCM (10 mL), malonyl dichloride (438 mg, 3.11 mmol) was added. After stirring at room temperature for 5 hours, the reaction product was quenched with water (30 mL) and extracted with ethyl acetate (3 × 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 obtain the title compound (381 mg, 68.46%) as a yellow solid.

[0319] 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 [ka] 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), carbon disulfide (538 mg, 7.08 mmol) and TEA (1074 mg, 10.62 mmol) were added. After stirring at room temperature for 3 hours, the reaction mixture was cooled to 0°C, and then 1,3-dibromopropane (1429 mg, 7.08 mmol) was added. After stirring for a further 2 hours, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 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 obtain the title compound (201 mg, 43.48%) as a yellow solid. MS(ESI):C 30 H48 Calculated mass of N4O6S2Si: 652.28, measured mass: 653.30 [M+H] + .

[0320] 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 [ka] 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), ammonia (7 N solution in methanol, 2 mL) was added. After stirring at 100°C for 1 hour, the reaction product was cooled to room temperature and concentrated. The resulting residue was purified by silica gel column chromatography (0→100% EA / PE) to obtain the title compound (115 mg, 64.54%) as a yellow solid. MS(ESI):C 27 H 46 Calculated mass for N6O6Si: 578.32, Measured mass: 579.35 [M+H] + .

[0321] 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] 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), TFA (1 mL) was added. After stirring at room temperature for 4 hours, the reaction product was concentrated to dryness under reduced pressure and then dissolved in ammonia (2 N solution in methanol, 2 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated to dryness to obtain the crude product, which was purified by reverse-phase HPLC (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, 26% B → 45% B) to obtain the title compound 62 (17.4 mg, 18.68%) as a white solid. MS(ESI):C 21 H 32 Calculated mass for N6O5: 448.24 Measured mass: 449.20 [M+H] + . 1 H NMR(300MHz;DMSO-d6)δ10.78(s,1H),9.56(s,2H),7.32(s,2H),4.67(t,J=11.7Hz,1H),3.75(t,J=7.2Hz,2H),3.29-3.35(m,2H), 2.50-2.63(m,2H),2.01(t,J=6.1Hz,1H),1.71(d,J=12.9Hz,2H),1.45(q,J=6.9Hz,4H),1.23-1.30(m,10H),0.88(t,J=7.3Hz,3H).

[0322] Examples 31, 32, and 67 were synthesized using the same procedure as described in Example 62.

[0323] Example 35 was synthesized from tert-butyl(4-(3,5,5-trimethyl-2,4-dioxoimidazolidine-1-yl)phenethyl)carbamate (prepared by coupling of 3,5,5-trimethylimidazolidine-2,4-dione and tert-butyl(4-bromophenethyl)carbamate with CuI) using the same procedure as described in Example 62.

[0324] Example 66: 7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidine-5(4H)-yl)-2-azaspiro[3.5]nonane-2-carboxamide (66) [ka]

[0325] tert-butyl 7-(N-(butylcarbamoyl)-2-cyanoacetamide)-2-azaspiro[3.5]nonane-2-carboxylate (secondary isomer) and tert-butyl 7-(3-butyl-3-(2-cyanoacetyl)ureido)-2-azaspiro[3.5]nonane-2-carboxylate (major isomer) [ka] 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), cyanoacetic acid (284 mg, 3.34 mmol) was added. After heating at 60°C for 3 hours, the reaction product was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (40% → 50% EA in PE) to obtain the title compound tert-butyl 7-(N-(butylcarbamoyl)-2-cyanoacetamide)-2-azaspiro[3.5]nonane-2-carboxylate (200 mg, 17.69%, subisomer) (MS(ESI):C 21 H 34 Calculated mass value for N4O4: 406.26 m / z, measured value: 407.30 [M+H] + ), and the title compound tert-butyl7-(3-butyl-3-(2-cyanoacetyl)ureido)-2-azaspiro[3.5]nonane-2-carboxylate (700 mg, 61.92%, major isomer) was obtained (MS(ESI):C 21 H 34 Calculated mass for N4O4: 406.26, Measured mass: 407.30 [M+H] + ).

[0326] tert-butyl7-(4-amino-3-butyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate [ka] To a stirred solution of tert-butyl 7-(N-(butylcarbamoyl)-2-cyanoacetamide)-2-azaspiro[3.5]nonane-2-carboxylate (the above isomer, 180 mg, 0.44 mmol) in ethyl alcohol (5 mL), sodium ethoxide (9 mg, 0.13 mmol) in EtOH was added dropwise. After heating at 70°C for 1 hour, the reaction product 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 obtain the crude product, which was purified by silica gel column chromatography (0 → 10% MeOH in DCM) to obtain the title compound (0.1 g, 55.86%). MS(ESI):C 21 H 34 Calculated mass for N4O4: 406.26, Measured mass: 407.20 [M+H] + .

[0327] tert-butyl7-{7-butyl-3-cyano-4,6-dioxo-[1,2]thiazolo[3,4-d]pyrimidine-5-yl}-2-azaspiro[3,5]nonane-2-carboxylate [ka] 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), tert-butyl 7-(4-amino-3-butyl-2,6-dioxopyrimidine-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate (100 mg, 0.24 mmol), followed by pyridine (89 mg, 1.13 mmol), was added at room temperature. After stirring overnight, the reaction product 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 obtain the crude product, which was further purified by column chromatography (30 → 35% EA in PE) to obtain the title compound (55 mg, 47.21%) as a yellow oil. MS(ESI):C 23 H 31 Calculated mass of N5O4S: 473.21, Measured mass: 496.25 [M+Na] + .

[0328] tert-butyl7-(7-butyl-3-{[(4-methoxyphenyl)methyl]amino}-4,6-dioxo-[1,2]thiazolo[3,4-d]pyrimidine-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate [ka] A solution of tert-butyl 7-{7-butyl-3-cyano-4,6-dioxo-[1,2]thiazolo[3,4-d]pyrimidine-5-yl}-2-azaspiro[3.5]nonane-2-carboxylate (55 mg, 0.12 mmol) and (4-methoxyphenyl)methaneamine (159 mg, 1.16 mmol) in dimethylformamide (3 mL) was heated at 90°C for 1 H. The crude residue was purified by silica gel column chromatography and eluted with PE / EA (30%) to obtain the title compound (40 mg, 59.70%) as a white solid. MS(ESI):C 30 H 41 Calculated mass of N5O5S: 583.28 m / z, measured mass: 584.35 [M+H] + .

[0329] 3-amino-5-{2-azaspiro[3,5]nonan-7-yl}-7-butyl-[1,2]thiazolo[3,4-d]pyrimidine-4,6-dione [ka] A solution of tert-butyl 7-(7-butyl-3-{[(4-methoxyphenyl)methyl]amino}-4,6-dioxo-[1,2]thiazolo[3,4-d]pyrimidine-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 product was concentrated, and the crude residue was purified by reverse-phase HPLC to obtain the title compound (25 mg, 99%) as a colorless oil. MS(ESI):C 17 H 25 Calculated mass of N5O2S: 363.17 m / z, measured mass: 364.20 [M+H] + .

[0330] 7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidine-5(4H)-yl)-2-azaspiro[3.5]nonane-2-carboxamide [ka] 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), isocyanatotrimethylsilane (10.46 mg, 0.090 mmol) was added. After stirring at rt for 1 hour, the reaction product 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 → 42% B, 42% B after 9 mins) to obtain the title compound 66 (3 mg, 17.76%) as a white solid. MS(ESI):C 18H 26 Calculated mass of N6O3S: 406.18, Measured mass: 407.15 [M+H] + . 1 H NMR(300MHz;DMSO-d6)δ8.11(t,J=1.0Hz,2H),5.79(s,2H),4.60(t,J=11.3Hz,1H),3.88(t,J=6.6Hz,2H),3.54(s,4H),2.3 3(dd,J=25.2,11.7Hz,2H),1.87(d,J=11.0Hz,2H),1.47-1.59(m,6H),1.28(td,J=14.1,6.9Hz,2H),0.88(t,J=7.2Hz,3H).

[0331] Example 59 was synthesized from the major isomer in the first step using the same procedure as described in Example 66.

[0332] Examples 69, 70, and 76 (mixed with 30% 70) were synthesized starting from a cis-trans mixture of 1-((4-aminocyclohexyl)methyl)-3,5,5-trimethylimidazolidin-2,4-dione, using the same procedure as described in Example 66, and obtained by chiral separation.

[0333] Example 74: 1-(2-(3-(aminomethyl)oxetan-3-yl)-2-azaspiro[3.5]nonane-7-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione(74) [ka]

[0334] 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-yl)oxetane-3-carbonitrile [ka] 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), 3-oxetanone (144 mg, 2.0 mmol) and trimethylsilyl cyanide (298 mg, 3.0 mmol) were added. After heating at 80°C for 6 hours, the reaction product was cooled, quenched with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 10:1) to obtain the title compound (40 mg, 46.38%). MS(ESI):C 21 H 30 Calculated mass for N6O4: 430.23 Measured mass: 431.20 [M+H] + .

[0335] 1-(2-(3-(aminomethyl)oxetane-3-yl)-2-azaspiro[3,5]nonane-7-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-yl)oxetane-3-carbonitrile (20 mg, 0.046 mmol) in tetrahydrofuran (3 mL), LiAlH4 (9 mg, 0.23 mmol) was added. After stirring at 0°C for 0.5 hours, the reaction product was quenched with saturated Na2SO4 (aqueous solution, 0.1 mL). MeOH (5 mL) was added, and the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by reverse-phase HPLC (mobile phase A: water (0.1% FA), mobile phase B: ACN, 10% B → 19% B) to obtain the title compound 74 (0.8 mg, 3.78%) as a pale yellow solid. MS(ESI):C 21 H 34Calculated mass for N6O4: 434.26 Measured mass: 435.20 [M+H] + . 1 H NMR(300MHz;DMSO-d6)δ9.37-9.65(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=3.9Hz,2H),1.23-1.42(m,10H),0.87(t,J=7.2Hz,3H).

[0336] 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) [ka]

[0337] 8,11-Dioxadispiro[3.2.4 7 .2 4 Tridecane-2-Carbonitrile [ka] 8,11-dioxadispiro in DME (10 mL) and t-BuOH (10 mL) [3.2.4 7 .2 4 To a solution of tridecane-2-one (1.0 g, 5.1 mmol), TosMIC (2.09 g, 10.7 mmol) was added. The resulting mixture was stirred at rt for 10 minutes, and t-BuOK (2.52 g, 22.42 mmol) was added in fractions at 0°C. After stirring overnight at rt, the reaction product was quenched with ice water and extracted with EA (3 × 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 obtain the title compound (400 mg, 37.87%) as a yellow solid.

[0338] 2-(methoxymethyl)-8,11-dioxadispiro[3.2.4 7 .2 4 Tridecane-2-Carbonitrile [ka] 8,11-dioxadispiro in THF (10 mL) [3.2.4 7 .2 4 To a solution of tridecane-2-carbonitride (400 mg, 1.93 mmol), 2 M LDA (in THF, 1.9 mL, 3.86 mmol) was added under N2 atmosphere at -78°C. After stirring at -78°C to -40°C for 0.5 hours, 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 hours. The reaction product was quenched with NH4Cl (aqueous solution, 30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were 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 obtain the title compound (330 mg, 68.04%) as a yellow oil.

[0339] (2-(methoxymethyl)-8,11-dioxadispiro[3.2.4 7 .2 4 Tridecane-2-yl)methanamine [ka] 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), LiAlH4 (117 mg, 3.10 mmol) was added at 0°C under an N2 atmosphere. After stirring at room temperature for 4 hours, the reaction product was quenched with saturated Na2SO4 (aqueous solution, 1 mL) and extracted with EA (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude (2-(methoxymethyl)-8,11-dioxadispiro[3.2.47.24]tridecane-2-carbonitrile (390 mg, 1.55 mmol) in THF (8 mL). 7 .2 4Tridecane-2-yl)methaneamine (380 mg, 95.9%) was obtained as a yellow oil and used in the next step without further purification.

[0340] Benzyl((2-(methoxymethyl)-8,11-dioxadispiro[3.2.4 7 .2 4 Tridecane-2-yl(methyl)carbamate [ka] To a solution of (2-(methoxymethyl)-8,11-dioxadispiro[3.2.47.24]tridecane-2-yl)methanamine (400 mg, 1.57 mmol) in DCM (8 mL), TEA (475 mg, 4.7 mmol) and CbzCl (320 mg, 1.88 mmol) were added at 0°C under a N2 atmosphere. After stirring at room temperature for 3 hours, the reaction product was quenched with water (30 mL) and extracted with DCM (3 × 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 obtain the title compound (430 mg, 70.48%) as a pale yellow oil. MS(ESI):C 22 H 31 Calculated mass for NO5: 389.22, Measured mass: 412.30 [M+Na] + .

[0341] Benzyl((2-(methoxymethyl)-7-oxospiro[3.5]nonan-2-yl)methyl)carbamate [ka] Benzyl((2-(methoxymethyl)-8,11-dioxadispiro[3.2.4] in 2N HCl (3 mL) and THF (3 mL) 7 .2 4A solution of tridecane-2-yl(methyl)carbamate (440 mg, 1.13 mmol) was heated at 60°C for 2 hours. The reaction product was neutralized with NaHCO3 solution to pH=7 and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain the title compound (350 mg, 89.69%) as a pale yellow oil. MS(ESI):C 20 H 27 Calculated mass for NO4: 345.19, measured mass: 368.20 [M+Na] + .

[0342] Benzyl((7-hydroxy-2-(methoxymethyl)spiro[3.5]nonan-2-yl)methyl)carbamate [ka] 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 mixed with NaBH4 (56 mg, 1.48 mmol) at 0°C. After stirring at rt for 2 hours, the reaction product was quenched with ice water (30 mL) and extracted with EA (3 × 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 obtain the title compound (300 mg, 87.72%) as a pale yellow oil. MS(ESI):C 20 H 29 Calculated mass for NO4: 347.21, Measured mass: 370.15 [M+Na] + .

[0343] Benzyl((7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-(methoxymethyl)spiro[3.5]nonane-2-yl)methyl)carbamate [ka] 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), 1-butyl-5-(1,3-dithian-2-ylidene)-1,3-diadinane-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) were added at rt. After heating overnight at 100 °C, the reaction product 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 obtain the title compound (50 mg, 19.62%) as a pale yellow solid. MS(ESI):C 32 H 43 Calculated mass for N3O6S2: 629.26, Measured mass: 652.10 [M+Na] + .

[0344] Benzyl((7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-(methoxymethyl)spiro[3.5]nonane-2-yl)methyl)carbamate [ka] To a solution of benzyl((7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-(methoxymethyl)spiro[3.5]nonane-2-yl)methyl)carbamate (50 mg, 0.079 mmol) in MeOH (2 mL), 7N NH3 (2 mL) was added to the MeOH. After heating at 110 °C for 2 hours, the reaction product was quenched with water (10 mL) and extracted with DCM / MeOH (6:1). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography to obtain the title compound (40 mg, 86.86%) as a pale yellow solid. MS(ESI):C 29H 41 Calculated mass for N5O6: 555.31, measured mass: 556.30 [M+H] + .

[0345] 1-(2-(aminomethyl)-2-(methoxymethyl)spiro[3.5]nonan-7-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] A solution of benzyl((7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-(methoxymethyl)spiro[3.5]nonane-2-yl)methyl)carbamate (40 mg, 0.072 mmol) in DCM (1.5 mL) was mixed with 40% HBr (in AcOH, 0.5 mL) at 0°C. After stirring at room temperature for 2 hours, the reaction product was purified by reverse-phase HPLC to obtain the title compound 75 (TFA salt, 7.5 mg, 17.79%) as a pale gray solid. MS(ESI):C 21 H 35 Calculated mass for N5O4: 421.27, Measured mass: 422.25 [M+H] + . 1 H NMR(400MHz;CD3OD)δ4.72(t,J=9.0Hz,1H),3.84(t,J=7.5Hz,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=15.2,7.6Hz,2H),0.95(t,J=7.3Hz,3H).

[0346] Example 78: 1-Butyl-5-(diaminomethylene)-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)spiro[3.5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione(78) [ka]

[0347] Ethyl 2-((8,11-dioxadispiro[3.2.47.24]tridecane-2-yl)amino)-2-methylpropanoate [ka] To a stirred solution of 8,11-dioxadispiro[3.2.47.24]tridecane-2-one (0.5 g, 2.55 mmol) in DCM (5 mL), ethyl 2-amino-2-methylpropanoate (0.43 g, 3.32 mmol) and AcOH (0.1 mL) were added at rt. After stirring for 1 hour, NaBH(OAc)3 (1.08 g, 5.10 mmol) was added to the reaction mixture, and the mixture was stirred for 16 hours. The reaction mixture was quenched by adding NaHCO3 / H2O (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 2:1) to obtain the title compound (0.2 g, 37.0%) as a colorless oil. MS(ESI):C 17 H 29 Calculated mass for NO4: 311.20, Measured mass: 312.30 [M+H] + .

[0348] 5,5-dimethyl-1-(7-oxospiro[3.5]nonane-2-yl)imidazolidin-2,4-dione [ka] To a stirred solution of ethyl 2-((8,11-dioxadispiro[3.2.47.24]tridecane-2-yl)amino)-2-methylpropanoate (0.2 g, 0.64 mmol) in AcOH (3 mL), KOCN (0.26 g, 3.21 mmol) was added at rt. The reaction mixture was heated at 100 °C for 16 hours. After completion, the reaction product was cooled and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to obtain the title compound (150 mg, 88.2%) as a yellow solid. MS(ESI):C 14 H 20 Calculated mass for N2O3: 264.15, Measured mass: 265.15 [M+H] + .

[0349] 1-(7-aminospiro[3,5]nonane-2-yl)-5,5-dimethylimidazolidin-2,4-dione [ka] To a solution of 5,5-dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)imidazolidin-2,4-dione (180 mg, 0.68 mmol) in 7N NH3 (5 mL) in methanol, Pd / C (50 mg) was added. The reaction mixture was stirred for 0.5 hours under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the title compound (0.15 g, 83.3%) as a yellow oil. MS(ESI):C 14 H 23 Calculated mass for N3O2: 265.18, Measured mass: 266.30 [M+H] + .

[0350] 1-Butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)spiro[3.5]nonane-7-yl)urea [ka] 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), butyl isocyanate (83 mg, 0.84 mmol) was added. After stirring overnight at room temperature, the resulting mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain the title compound (0.12 g, 59.1%) as a yellow solid. MS(ESI):C 19 H 32 Calculated mass for N4O3: 364.25, Measured mass: 365.20 [M+H] + .

[0351] 1-Butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)spiro[3,5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of 1-butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)spiro[3.5]nonan-7-yl)urea (120 mg, 0.33 mmol) in DCM (3 mL), propanedioyl dichloride (93 mg, 0.66 mmol) was added at 0°C. After stirring at rt for 4 hours, the reaction mixture was quenched with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 10:1) to obtain the title compound (55 mg, 38.7%) as a yellow oil. MS(ESI):C 22 H 32 Calculated mass for N4O5: 432.24, measured mass: 433.35 [M+H] + .

[0352] 1-Butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)spiro[3,5]nonane-7-yl)-5-(1,3-dithian-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of 1-butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidine-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), carbon disulfide (26 mg, 0.35 mmol) and TEA (46 mg, 0.460 mmol) were added at rt. After stirring at rt for 1 hour, 1,3-dibromopropane (46 mg, 0.23 mmol) was added. The resulting mixture was stirred for 2.5 hours. After completion, the reaction product was quenched with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (DCM / MeOH = 10:1) to obtain the title compound (45 mg, 71.4%) as a yellow solid. MS(ESI):C 26 H 36 Calculated mass of N4O5S2: 548.21, Measured mass: 549.15 [M+H] + .

[0353] 1-Butyl-5-(diaminomethylene)-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)spiro[3.5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of 1-butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)spiro[3.5]nonane-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), 7N NH3 (0.4 mL) was added to methanol. After heating at 100 °C for 1 hour, the reaction product was concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC to obtain the title compound 78 (2.4 mg, 6.8%) as a white solid. MS(ESI):C 23 H 34 Calculated mass for N6O5: 474.26, Measured mass: 475.20 [M+H] + . 1 H NMR(300MHz;DMSO-d6)δ10.67(s,1H),9.54(s,2H),7.30(d,J=0.9Hz,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=14.5Hz,3H).

[0354] Example 79: (R)-1-butyl-5-(diaminomethylene)-3-(2-(3-hydroxypyrrolidine-1-yl)spiro[3.5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione(79) [ka]

[0355] 8,11-Dioxadispiro[3.2.4 7 .2 4 Tridecane-2-ol [ka] 8,11-dioxadispiro in methanol (20 mL) [3.2.4 7 .2 4To a solution of tridecane-2-one (1.0 g, 5.1 mmol), NaBH4 (289 mg, 7.64 mmol) was added at 0°C. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 50% EA / PE) to obtain the title compound (812 mg, 80.37%) as a yellow oil. MS(ESI):C 11 H 18 Calculated mass for O3: 198.13, Measured mass: 199.20 [M+H] + .

[0356] 2-(benzyloxy)-8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecan [ka] 8,11-dioxadispiro [3.2.4] in tetrahydrofuran (20 mL) 7 .2 4 A solution of tridecane-2-ol (780 mg, 3.93 mmol) was cooled to 0°C. NaH (60% in mineral oil, 236.03 mg, 5.90 mmol) was added. After stirring at 0°C for 0.5 hours, benzyl bromide (807 mg, 4.72 mmol) was added. After stirring at room temperature for 2 hours, the reaction product was quenched with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 50% EA / PE) to obtain the title compound (821 mg, 72.36%) as a yellow solid. MS(ESI):C 18 H 24 Calculated mass value for O3: 288.17, Measured value: 289.25 [M+H] + .

[0357] Methyl 2-(benzyloxy)spiro[3.5]nonane-7-one [ka] 2-(benzyloxy)-8,11-dioxadispiro[3.2.4] in tetrahydrofuran (5 mL) 7 .2 4 To a solution of tridecane (821 mg, 2.85 mmol), 10 mL of 4N HCl was added. The reaction mixture was heated at 70°C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated, made basic to pH=10, and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 50% EA / PE) to obtain the title compound (527 mg, 75.76%) as a yellow solid. MS(ESI):C 16 H 20 Calculated mass relative to O2: 244.15, measured value: 245.10 [M+H] + .

[0358] 2-(benzyloxy)spiro[3.5]nonane-7-ol [ka] A solution of 2-(benzyloxy)spiro[3.5]nonane-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 at room temperature for 1 hour, the reaction product was quenched with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 50% EA / PE) to obtain the title compound (345 mg, 68.44%) as a yellow solid. MS(ESI):C 16 H 22 Calculated mass relative to O2: 246.16, Measured mass: 247.10 [M+H] + .

[0359] 1-Butyl-5-(diaminomethylene)-3-(2-oxospiro[3,5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] 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 according to Example 51, 10 mg, 0.027 mmol) in DCM (1 mL), Dess-Martin (23 mg, 0.054 mmol) was added. After stirring at room temperature for 2 hours, the reaction product was quenched with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 50% EA / PE) to obtain intermediate B of the title compound (72 mg, 80.44%) as a yellow solid. MS(ESI):C 18 H 26 Calculated mass for N4O4: 362.20, Measured mass: 363.10 [M+H] + .

[0360] (R)-1-butyl-5-(diaminomethylene)-3-(2-(3-hydroxypyrrolidine-1-yl)spiro[3.5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] 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), (3R)-pyrrolidine-3-ol (18 mg, 0.21 mmol) and AcOH (8.28 mg, 0.138 mmol) were added. The reaction mixture was stirred for 0.5 hours, and NaBH3CN (17.34 mg, 0.28 mmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated to dryness under reduced pressure to obtain the crude product, which was purified by reverse-phase HPLC (26% → 45% (v / v) ACN and H2O, and 0.05% NH4HCO3) to obtain the title compound 79 (15.3 mg, 24.32%) as a white solid. MS(ESI):C 22 H 35 Calculated mass for N5O4: 433.27 Measured mass: 434.25 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ9.55(s,2H),7.31(s,2H),4.80(s,1H),4.54-4.68 (m,1H),4.21(d,J=1.4Hz,1H),3.74(t,J=7.4Hz,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=7.3Hz,3H).

[0361] Examples 94, 95, and 96 were synthesized from intermediate B using the same procedure as described in Example 79.

[0362] 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 [ka]

[0363] 5-(1,3-Dithian-2-Iridene)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of pyrimidine-2,4,6(1H,3H,5H)-trione (4 g, 31.22 mmol) in DMSO (60 mL), carbon disulfide (7.13 g, 93.66 mmol) and TEA (15.76 g, 156.10 mmol) were added. After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0°C, and 1,3-dibromopropane (18.90 g, 93.66 mmol) was added. After stirring at room temperature for a further 3 hours, ice water (500 mL) was added, and the precipitate was collected to obtain the title compound (5.33 g, 70.0%) as a white solid. MS(ESI): Calculated mass relative to C8H8N2O3S2: 244.00, Measured value: 245.15 [M+H] + .

[0364] 1-Butyl-5-(1,3-Dithiane-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] 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), butyl iodide (1.51 g, 8.18 mmol) and K2CO3 (2.26 g, 16.37 mmol) were added at rt. After heating at 50°C for 3 hours, the reaction product was quenched with water and extracted with EA (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (0 → 100% PE / EA) to yield the title compound (1.4 g, 56.92%) as a yellow solid. MS(ESI):C 12 H 16 Calculated mass of N2O3S2: 300.06, Measured mass: 301.20 [M+H] + .

[0365] tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate [ka] A solution of tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (1.0 g, 4.18 mmol) in methanol (15 mL) is prepared by adding NaBH 4( 317 mg (8.36 mmol) was added at 0°C. After stirring at 0°C for 3 hours, the reaction product was quenched with water (10 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 2:1) to obtain the title compound (0.8 g, 79.33%). MS(ESI):C 13 H 23 Calculated mass for NO3: 241.17, measured mass: 242.25 [M+H] + .

[0366] tert-butyl7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate [ka] To a solution of tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (600 mg, 2.49 mmol) in DCM (10 mL), 1-butyl-5-(1,3-dithian-2-ylidene)-1,3-diadinane-2,4,6-trione (597 mg, 1.99 mmol) and triphenylphosphine (978 mg, 3.73 mmol) were added, followed by the addition of DEAD (649 mg, 3.73 mmol) under an N2 atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was quenched with water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 2:1) to obtain the title compound (800 mg, 61.44%). MS(ESI):C 25 H 37 Calculated mass of N3O5S2: 523.22, Measured mass: 524.20 [M+H] + .

[0367] tert-butyl7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate [ka] To a solution of tert-butyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate (200 mg, 0.38 mmol) in methanol (8 mL), 1.2 mL of 7N NH3 (in methanol) was added. The resulting mixture was heated at 100 °C for 1 hour. After cooling, the reaction product was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 10:1) to obtain the title compound (600 mg, 87.37%). MS(ESI):C 22 H 35 Calculated mass for N5O5: 449.26, Measured mass: 450.20 [M+H] + .

[0368] 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[3,5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of tert-butyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate (600 mg, 1.34 mmol) in DCM (20 mL), trifluoroacetic acid (5 mL) was added. After stirring at room temperature for 1 hour, the reaction product was concentrated under reduced pressure and then quenched with NaHCO3 (aqueous solution). The resulting crude product was further purified by reverse-phase HPLC to obtain the title compound (Example 17, 420 mg, 90.35%). MS(ESI):C 17 H 27 Mass calculation value for N5O3: 349.21, Measured value: 350.30 M+H] + This is a different synthetic route for preparing Example 17.

[0369] 1-Butyl-5-(diaminomethylene)-3-(2-(4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-2-azaspiro[3.5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] 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) is mixed with 3-bromo-4-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4-triazole (87 mg, 0.32 mmol), CuI (11 mg, 0.057 mmol), potassium carbonate (119.52 mg, 0.86 mmol), and (1R,2R)-N 1 ,N2 -Dimethylcyclohexane-1,2-diamine (16 mg, 0.11 mmol) was added. The reaction mixture was heated at 100°C for 3 hours under N2. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was further purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound (30 mg, 19.17%). MS(ESI):C 25 H 42 Calculated mass for N8O4Si: 546.31, Measured mass: 547.30 [M+H] + .

[0370] 1-(2-(4H-1,2,4-triazole-3-yl)-2-azaspiro[3,5]nonane-7-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] 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), TFA (0.5 mL) was added. After stirring at room temperature for 1 hour, the reaction product was concentrated under reduced pressure, and ammonia (2 mL) was added. After stirring for a further 1 hour at room temperature, the mixture was concentrated to dryness to obtain the crude product, which was purified by reverse-phase HPLC (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, 25% B → 45% B) to obtain the title compound 80 (3.2 mg, 14.00%) as a white solid. MS(ESI):C 19 H 28 Calculated mass for N8O3: 416.23, Measured mass: 417.20 [M+H] + . 1H NMR(400MHz;DMSO-d6)δ12.52(s,1H),9.54(s,2H),7.42(s,1H),7.33(s,2H),4.62-4.69(m,1H),3.74(t,J=7.2Hz,2H),3.68(s,2H),3 .58(s,2H),2.35(dd,J=24.9,12.1Hz,2H),1.99(dd,J=18.2,10.4Hz,2H),1.42-1.58(m,4H),1.23-1.34(m,4H),0.88(t,J=7.3Hz,3H).

[0371] Examples 47, 48, 49, and 50 were synthesized using the same procedure as described for the synthesis of Example 17 in Example 80, followed by the same procedure as described for the synthesis of Example 4, and then chiral separation to obtain four stereoisomers. The stereochemistry of each isomer is arbitrarily assigned.

[0372] Examples 81 and 82: 1-((2R,4r,7R)-7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidine-5(4H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (81) and 1-((2S,4s,7S)-7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidine-5(4H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (82) [ka]

[0373] tert-butyl(8,11-dioxadispiro[3.2.4 7 .2 4 Tridecane-2-yl (methyl)carbamate [ka] N-benzyl-N-methyl-8,11-dioxadispiro in methanol (5 mL) [3.2.4 7 .2 4A solution of tridecan-2-amine (see Example 51 for synthesis, 300 mg, 0.995 mmol) and di-tert-butyl dicarbonate (434.43 mg, 1.99 mmol) was added with Pd / C (10%, 55 mg) under a nitrogen atmosphere. Subsequently, the reaction mixture was stirred for 3 h at rt under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the crude title compound (280 mg, 93.33%), which was used in the next step without further purification. MS (ESI): C 17 H 29 Calculated mass for C + .

[0374] tert-Butyl methyl(7-oxospiro[3.5]nonan-2-yl)carbamate

Chemical formula

[0375] tert-Butyl(7-hydroxylspiro[3.5]nonan-2-yl)(methyl)carbamate

Chemical formula

[0376] tert-butyl(7-(3-butyl-4-chloro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate

Chem.

[0377] tert-butyl(7-(4-amino-3-butyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate [ka] A solution of tert-butyl(7-(3-butyl-4-chloro-2,6-dioxo-3,6-dihydropyrimidine-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 product 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 obtain the crude product, which was further purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain the title compound (80 mg, 55.72%). MS(ESI):C 23 H 38 Calculated mass for N4O4: 434.29, Measured mass: 435.35 [M+H] + .

[0378] tert-butyl(7-(7-butyl-3-cyano-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidine-5(4H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate [ka] 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-dihydropyrimidine-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 minutes at rt. After stirring for 16 hours, the reaction product 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 obtain the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound (50 mg, 54.14%) as a yellow oil. MS(ESI):C 25 H 35 Calculated mass for N5O4S: 501.24, Measured mass: 524.30 [M+Na] + .

[0379] tert-butyl(7-(7-butyl-3-((4-methoxybenzyl)amino)-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidine-5(4H)-yl)spiro[3.5]nonane-2-yl)(methyl)carbamate [ka] A solution of tert-butyl(7-(7-butyl-3-cyano-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidine-5(4H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (50 mg, 0.100 mmol) and (4-methoxyphenyl)methaneamine (136 mg, 1.000 mmol) in DMF (3 mL) was heated at 90°C for 1 hour. After completion, the reaction product 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 obtain the crude product, which was purified by silica gel column chromatography (30 → 35% EA in PE) to obtain the title compound (50 mg, 82.0%). MS(ESI):C 32 H 45 Calculated mass of N5O5S: 611.31, Measured mass: 612.40 [M+H] + .

[0380] 3-Amino-7-butyl-5-(2-(methylamino)spiro[3,5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione [ka] A solution of tert-butyl(7-(7-butyl-3-((4-methoxybenzyl)amino)-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidine-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 overnight at 50°C. The residue was purified by reverse-phase HPLC (with 10 → 50% ACN in water and TFA as a modifier) ​​to obtain the title compound (30 mg, 93.76%) as oil. MS(ESI):C 19 H 29 Calculated mass of N5O2S: 391.20, Measured mass: 392.30 [M+H] + .

[0381] 1-((2R,4r,7R)-7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidine-5(4H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (81) and 1-((2S,4s,7S)-7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidine-5(4H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (82) [ka] 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), and then isocyanatotrimethylsilane (19.42 mg, 0.17 mmol) was added dropwise at rt. After stirring for 1 hour, the reaction product was quenched with water (2 mL) and extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by chiral HPLC under 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 → 15% B in 16 mins) to obtain the title compound 81 (2.3 mg, 6.89%, RT1: 11.03 mins) as a white solid (MS(ESI): C 20 H 30 Calculated mass of N6O3S: 434.21, Measured mass: 435.15 [M+H] + . 1Along with the 1H NMR (300MHz, DMSO-d6) δ8.14(s,2H),5.79(s,2H),4.36-4.69(m,2H),3.89(t,J=7.5Hz,2H),2.73(s,3H),2.23-2.48(m,2H),2.08(t,J=9.7Hz,1H),1.50-1.93(m,6H),1.17-1.48(m,7H),0.90(t,J=7.3Hz,3H)), the title compound 82 (2.7mg, 8.10%, RT2:15.096 min) was obtained as a white solid (MS(ESI):C) 20 H 30 Calculated mass of N6O3S: 434.21, Measured mass: 435.15 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.14(s,2H),5.79(s,2H),4.36-4.69(m,2H),3.89(t,J=7.5Hz,2H),2.73(s,3H) ,2.23-2.48(m,2H),2.08(t,J=9.7Hz,1H),1.50-1.93(m,6H),1.17-1.48(m,7H),0.90(t,J=7.3Hz,3H)).

[0382] Examples 104 and 105 were prepared using the same procedure as described in Examples 81 and 82, starting with 1-(7-hydroxyspiro[3.5]nonan-2-yl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidined-2,4-dione (prepared from 5,5-dimethyl-1-(7-oxospiro[3.5]nonanan-2-yl)imidazolidined-2,4-dione in Example 78). (Tributylphosphoranylidene)acetonitrile was used as the reagent for the Mitsunobu coupling.

[0383] Example 83: 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-yl)oxetane-3-carboxamide (83) [ka]

[0384] 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-yl)oxetane-3-carboxamide To a solution of 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)-2-azaspiro[3.5]nonane-2-yl)oxetane-3-carbonitrile (30 mg, 0.070 mmol) in DMSO (3 mL), K2CO3 (29 mg, 0.210 mmol) was added. The mixture was stirred until homogenized and then cooled to 0°C. 30% hydrogen peroxide (0.6 mL) was added. After stirring at 0°C for 30 minutes and then at room temperature for 3 hours, the mixture was concentrated to dryness under reduced pressure to obtain the crude product, which was purified by reverse-phase HPLC (25% → 45% (v / v) ACN and H2O, and 0.05% NH4HCO3) to obtain the title compound 83 (9.4 mg, 30.07%) as a white solid. MS(ESI):C 21 H 32 Calculated mass for N6O5: 448.24, Measured mass: 449.20 [M+H] + . 1 H NMR(300MHz;DMSO-d6)δ9.54(d,J=0.8Hz,2H),7.31(s,2H),7.20(br d,J=18.3Hz,2H),4.64-4.71(m,3H),4.51(d,J=6.6Hz,2H),3.73(t,J=7.1Hz,2H),3.16(s,2H),3.06(s,2H) ),2.27-2.37(m,2H),2.04(d,J=12.2Hz,2H),1.35-1.50(m,4H),1.19-1.31(m,4H),0.87(t,J=7.2Hz,3H).

[0385] Example 84 was prepared from 1-butyl-5-(diaminomethylene)-3-(piperidine-4-ylmethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared according to Example 51) using the same procedure as described in Example 83.

[0386] Example 85: 3-Amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione [ka]

[0387] Ethyl(1r,4r)-4-(benzyloxy)cyclohexane-1-carboxylate [ka] 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 hours. After cooling to room temperature, the reaction product was quenched with 2N HCl (50 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 20% PE / EA) to obtain the title compound (4 g, 52.06%) as a colorless oil. MS(ESI):C 16 H 22 Calculated mass for O3: 262.16, Measured mass: 263.15 [M+H] + .

[0388] ((1r,4r)-4-(benzyloxy)cyclohexyl)methanol [ka] To a solution of ethyl (1r,4r)-4-(benzyloxy)cyclohexane-1-carboxylate (4.7 g, 17.92 mmol) in THF (40 mL), LiAlH4 (1.70 g, 44.79 mmol) was added at 0°C under a nitrogen atmosphere. The resulting mixture was heated at 60°C for 3 hours. After cooling to room temperature, the reaction product was quenched at 0°C with saturated Na2SO4 aqueous solution, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 30% PE / EA) to obtain the title compound (2.9 g, 73.48%) as a colorless oil.

[0389] ((((1r,4r)-4-(bromomethyl)cyclohexyl)oxy)methyl)benzene [ka] To a solution of ((1r,4r)-4-(benzyloxy)cyclohexyl)methanol (950 mg, 4.31 mmol) in DCM (10 mL), CBr4 (1573 mg, 4.74 mmol) in DCM (2 mL) was added at 0°C under a nitrogen atmosphere, followed by the dropwise addition of PPh3 (1131.02 mg, 4.31 mmol) in DCM (2 mL) at 0°C. After stirring at rt for 3 hours, the reaction product was quenched with H2O (50 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 → 10% PE / EA) to obtain the title compound (800 mg, 65.51%) as a colorless oil.

[0390] 1-(((1r,4r)-4-(benzyloxy)cyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-2,4-dione [ka] 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)imidazolidined-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 hours. The reaction product was quenched with H2O (50 mL) and extracted with ethyl acetate. The organic layer was concentrated to obtain the title compound (0.8 g, 63.05%) as a pale yellow oil. MS(ESI):C 25 H 40 Calculated mass for N2O4Si: 460.28, Measured mass: 483.30 [M+Na] + .

[0391] 1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidined-2,4-dione [ka] To a solution of 1-(((1r,4r)-4-(benzyloxy)cyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-2,4-dione (0.8 g, 1.74 mmol) in MeOH (10 mL), Pd / C (10%, 0.1 g) was added under an N2 atmosphere. The reaction mixture was then stirred for 1 hour under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain intermediate A (0.5 g, 77.70%) of the title compound as a colorless oil. MS(ESI):C 18 H 34 Calculated mass value for N2O4Si: 370.23, Measured value: 393.3 [M+Na] + .

[0392] 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 [ka] To a solution of 1-butyl-6-chloropyrimidine-2,4(1H,3H)-dione (300 mg, 1.48 mmol) in DCM (5 mL), intermediate A, 1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (548 mg, 1.48 mmol) and triphenylphosphine (581 mg, 2.22 mmol) were added, and then DEAD (261.83 mg, 1.50 mmol) was added dropwise at 0°C under N2. After stirring overnight with rt, the reaction product was quenched with water (10 mL) and extracted with DCM (15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (PE:EA=3:1) to obtain the title compound (107 mg, 13.0%). MS(ESI):C 26 H 43 Calculated mass of ClN4O5Si: 554.27, measured mass: 555.35 [M+H] + .

[0393] 3-Amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione [ka] 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 using the same procedure as described in Example 81. MS(ESI):C 21 H 30 Calculated mass of N6O4S: 462.20, Measured mass: 463.15 [M+H] +. 1 H NMR(300MHz,DMSO-d6)δ10.82(s,1H),8.13(s,2H),4.42-4.81(m,1H),3.91(t,J=7.4Hz,2H) ,2.55-2.85(m,3H),1.95-2.10(m,2H),1.75(d,J=13.5Hz,2H),1.41-1.67(m,6H),1.20-1.32 m,8H),0.90(t,J=7.3Hz,3H).

[0394] Example 90 was synthesized using the same procedure as described in Example 85.

[0395] Example 99 was synthesized using the same procedure as described in Example 85, but with DMBNH2 instead of PMBNH2.

[0396] Example 101 was synthesized using the same procedure as described in Example 85, but with MeNH2 instead of PMBNH2.

[0397] Example 102 was synthesized using the same procedure as described in Example 85, but with isopropylamine instead of PMBNH2.

[0398] 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 [ka]

[0399] tert-butyl(2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)cyclohexyl)amino)ethyl)carbamate [ka] To a solution of 1-((1s,4s)-4-aminocyclohexyl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared in the same manner as described in Example 18, 140 mg, 0.43 mmol) in MeOH (3 mL), tert-butyl N-(2-oxoethyl)carbamate (83 mg, 0.52 mmol) and AcOH (78 mg, 1.299 mmol) were added. After stirring for 30 minutes, 1-boranyl-2-methyl-1λ4-pyridine (138 mg, 1.3 mmol) was added in fractions at 0°C. The resulting mixture was stirred overnight at rt. The reaction product was quenched with ice water and extracted with DCM / MeOH (6:1). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to obtain the title compound (90 mg, 44.56%). MS(ESI):C 22 H 38 Calculated mass for N6O5: 466.29, measured mass: 467.25 [M+H] + .

[0400] Tert-butyl(2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)cyclohexyl)(oxetan-3-yl)amino)ethyl)carbamate [ka] To a solution of tert-butyl(2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)cyclohexyl)amino)ethyl)carbamate (70 mg, 0.15 mmol) in DMF (3 mL), Cs2CO3 (98 mg, 0.30 mmol) and 3-bromooxetane (103 mg, 0.75 mmol) were added. After heating overnight at 50°C, the reaction product 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 resulting residue was purified by silica gel column chromatography to obtain the title compound (30 mg, 38.26%) as a yellow solid. MS(ESI):C 25 H 42 Calculated mass for N6O6: 522.32, measured mass: 523.25 [M+H] + .

[0401] 1-((1s,4s)-4-((2-aminoethyl)(oxetan-3-yl)amino)cyclohexyl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] A solution of tert-butyl(2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)cyclohexyl)(oxetane-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 hour. The resulting mixture was concentrated and purified by reverse-phase HPLC (20% → 50% (v / v) ACN and H2O, and 0.05% NH4HCO3) to obtain the title compound 86 (2.1 mg, 8.26%) as a yellow solid. MS(ESI):C 20 H 30 Calculated mass for N6O4: 422.26, Measured mass: 423.20 [M+H] + . 1H NMR(400MHz;DMSO-d6)δ9.08(s,2H),8.95(s,2H),5.06(s,2H),4.64(t,J=11.3Hz,1H),4.01(td,J=10.5,5.0Hz,2H),3.65-3. 80(m,5H),2.50-2.71(m,7H),1.77(d,J=13.5Hz,2H),1.35-1.49(m,4H),1.24(td,J=15.5,7.5Hz,4H),0.88(t,J=7.3Hz,3H).

[0402] Example 77 was synthesized using the same procedure as described in Example 86.

[0403] Example 87: 5-Butyl-7-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione(87) [ka]

[0404] Ethyl 3-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate [ka] To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (3 g, 19.34 mmol) in DMF (80 mL), K2CO3 (4.01 g, 29.0 mmol) and SEMCl (3.87 g, 23.20 mmol) were added. After stirring overnight at rt, the reaction product was quenched with water (50 mL) and extracted with EA (3 × 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE:EA = 3:1) to obtain the title compound as a yellow oil. MS(ESI):C 12 H 23Calculated mass for N3O3Si: 285.15, Measured mass: 286.10 [M+H] + .

[0405] 3-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylic acid [ka] 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), LiOH (503 mg, 21.02 mmol) was added. The resulting mixture was stirred overnight in rt. The reaction product was acidified to pH=6 with 2N HCl, diluted with water (20 mL), and extracted with DCM / MeOH (6:1). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude title compound (450 mg, 83.18%), which was used in the next step without further purification.

[0406] 3-amino-N-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide [ka] 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), DIPEA (451 mg, 3.5 mmol) and HATU (997.26 mg, 2.62 mmol) were added. After stirring overnight at room temperature, the reaction product was quenched with water (20 mL) and extracted with EA (3 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE:EA = 2:1) to obtain the title compound (400 mg, 73.21%) as a yellow oil. MS(ESI):C 14H 28 Calculated mass for N4O2Si: 312.20, Measured mass: 313.15 [M+H] + .

[0407] 5-Butyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione [ka] 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), DIPEA (248 mg, 1.92 mmol) and CDI (622 mg, 3.84 mmol) were added. After heating at 70°C for 5 hours, the reaction product was cooled, quenched with water (20 mL), and extracted with EA (3 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE:EA = 2:1) to obtain the title compound (150 mg, 69.24%) as a white solid. MS(ESI):C 15 H 26 Calculated mass of N4O3Si: 338.18, measured mass: 339.25 [M+H] + .

[0408] 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 [ka] 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 (Intermediate A in Example 85, 136 mg, 0.37 mmol) in DCM (5 mL) was added with PPh3 (193 mg, 0.74 mmol) and DEAD (128 mg, 0.74 mmol) at 0 °C under a N2 atmosphere. After stirring at rt for 3 h, the reaction was quenched with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (PE:EA = 2:1) to give the title compound as a pale yellow oil. MS(ESI): C 33 H 58 Calculated mass for C + .

[0409] 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 [Chemical Structure] <00055,13> 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 hour. The reaction product was neutralized to pH=7 with NaHCO3 solution and extracted with DCM / MeOH. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. NH3 in MeOH (3 mL) was added to the crude product and stirred at rt for 1 hour. The resulting mixture was concentrated and purified by reverse-phase HPLC (ACN22 in H2O → 52%, and 0.05% NH4HCO3) to obtain the title compound 87 (8.8 mg, 17.63%) as a white solid. MS(ESI):C 21 H 30 Calculated mass for N6O4: 430.23, Measured mass: 431.15 [M+H] + . 1 H NMR(400MHz;DMSO-d6)δ13.54(br,1H),10.82(br,1H),8.46(s,1H),4.63(t,J=12.0H z,1H),3.84(dd,J=7.4,7.2Hz,2H),3.37(d,J=7.6Hz,2H),2.66-2.77(m,2H),2.07(br s,1H),1.77(br d,J=13.1Hz,2H),1.40-1.58(m,6H),1.23-1.36(m,8H),0.89(d,J=14.7Hz,3H).

[0410] Example 88 was synthesized using the same procedure as described in Example 87.

[0411] Example 89: 7-Butyl-5-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)-1,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione(89) [ka]

[0412] 1-Butyl-6-chloro-2,4-dioxo-3-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde [ka] To a solution of 1-butyl-3-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidine-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), DMF (2 mL) was added at 0°C. The resulting mixture was heated at 100°C for 3 hours. After cooling, the reaction product was concentrated, quenched with ice water, and extracted with EA (3 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated to obtain the crude product, which was purified by silica gel column chromatography (0 → 15% DCM / MeOH) to obtain the title compound (100 mg, 15.0%) as a yellow oil. MS(ESI):C 22 H 31 Mass calculation value for ClN4O5: 466.20, measured value: 489.10 [M+Na] + .

[0413] 7-Butyl-5-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)-1,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione [ka] To a solution of 1-butyl-6-chloro-2,4-dioxo-3-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (150 mg, 0.32 mmol) in MeOH (8 mL), hydrazine hydrochloride (44 mg, 0.64 mmol) was added at rt, followed by the addition of TEA (163 mg, 1.605 mmol) at 0°C. After heating at 70°C for 1.5 hours, the reaction product was quenched with water (20 mL) and extracted with DCM / MeOH (5:1, 3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The resulting residue was purified by reverse-phase HPLC (17% → 42% (v / v) CH3CN and H2O, and 10 mmol / L NH4HCO3) to obtain the title compound 89 (8.7 mg, 6.51%) as a white solid. MS(ESI):C 22 H 32 Calculated mass for N6O4: 444.25, Measured mass: 445.20 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ13.43(br s,1H),8.45(s,1H),4.74(s,1H),3.92(t,J=7.4Hz,2H),3.39(d,J=7.6Hz,2H),2.87(s,3H),2.57-2.75(m,2H),2.0 4-2.14(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=7.3Hz,3H).

[0414] Example 98. 5-Amino-1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione(98) [ka]

[0415] 1-Butyl-6-methylpyrimidine-2,4(1H,3H)-dione [ka] To a solution of butylurea (6.91 g, 59.471 mmol) in pyridine (50 mL), 4-methyleneoxetan-2-one (5 g, 59.47 mmol) was added at 0°C under a nitrogen atmosphere. After stirring overnight at rt, most of the solvent was evaporated. The resulting solid was collected by filtration, washed with ether, and dried under vacuum to obtain N-(butylcarbamoyl)-3-oxobutanamide. AcOH (60 mL) was added thereto, and the resulting mixture was heated at 115°C for 2 hours under a nitrogen atmosphere. The reaction product was cooled and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (0→100% PE / EA) to obtain the title compound (1.2 g, 64.30%) as a yellow oil. MS(ESI):C9H 14 Calculated mass for N2O2: 182.11, measured mass: 183.20 [M+H] + .

[0416] 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 [ka] To a solution of 1-butyl-6-methylpyrimidine-2,4(1H,3H)-dione (250 mg, 1.37 mmol) in DCM (5 mL), 1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidinedione-2,4-dione (intermediate A from Example 85, 510 mg, 1.38 mmol) and PPh3 (719 mg, 2.74 mmol) were added at rt, and then DEAD (477 mg, 2.74 mmol) was added under N2. After stirring at rt for 2.5 hours, the reaction product was quenched with water (50 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (0→100% PE / EA) to obtain the title compound (400 mg, 54.52%) as a yellow solid. MS(ESI):C 27 H 46 Calculated mass for N4O5Si: 534.32, Measured mass: 535.30 [M+H] + .

[0417] 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 [ka] 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), HCHO (80 mg, 2.692 mmol) was added. The reaction mixture was heated at 100 °C for 6 hours. The reaction product was concentrated under reduced pressure to obtain the crude product, which was suspended in a 1% aqueous solution of NaOH (10 mL) and DMF (10 mL) and heated under reflux for 1 hour. The reaction mixture was acidified to pH=5 with 10% HCl and extracted with ELISA (3 × 100 mL). The combined organic layers were dried over Na2SO4 and concentrated to obtain the crude product, which was then directly purified by silica gel column chromatography to obtain the title compound (120 mg, 31.56%) as a yellow solid. MS(ESI):C 28 H 48 Calculated mass of N4O6Si: 564.33, measured mass: 565.15 [M+H] + .

[0418] 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 [ka] 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), Dess-Martin reagent (165 mg, 0.390 mmol) was added. After stirring at rt for 3 hours, the reaction product was quenched with water (5 mL) and extracted with DCM (2 × 10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (0.1 g, 90.9%) as a yellow oil, which was used directly in the next step.

[0419] (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-carbaldehydeoxime [ka] 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) is prepared by adding NH2OH . HCl (245 mg, 3.56 mmol) was added. After stirring at rt for 0.5 h, the reaction product was quenched with water (5 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound (0.1 g, 98.5%) as a yellow oil, which was used directly in the next step.

[0420] 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 [ka] A stirred solution 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 hours. After completion, the reaction product 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 obtain the title compound (60 mg, 68.97%) as a yellow oil. MS(ESI):C 28 H 45 Calculated mass for N5O5Si: 559.32, Measured mass: 560.35 [M+H] + .

[0421] 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 [ka] 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 at 80°C for 2 hours.

[0422] After cooling 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 obtain the title compound (50 mg, 75.76%) as a yellow oil, which was used directly in the next step.

[0423] 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 [ka] 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 layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0 → 10% MeOH in DCM) to obtain the title compound (30 mg, 62.89%) as a yellow oil. MS(ESI):C 29 H 46 Calculated mass of N6O5Si: 586.33, measured mass: 587.35 [M+H] + .

[0424] 5-amino-1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione [ka] 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, 7N NH3 (1 mL) in MeOH was added. The resulting mixture was stirred for a further 30 minutes. The residue was purified by reverse-phase HPLC (ACN in TFA aqueous solution, 10 → 50% ACN in water, and TFA as a modifier) ​​to obtain the title compound 98 (8.8 mg, 45.08%) as a white solid. MS(ESI):C23 H 32 Calculated mass for N6O4: 456.25, measured mass: 457.10 [M+H] + . 1 H NMR (300MHz, acetonitrile-d3) δ8.13(d,J=7.5Hz,1H),7.03(d,J=7.5Hz,1H),4.91-5.10( m,1H),4.29(t,J=7.4Hz,2H),3.63(d,J=8.0Hz,2H),2.80(q,J=12.1Hz,2H),2.33(br s,1H),1.99(br d,J=13.5Hz,2H),1.73-1.89(m,4H),1.52-1.70(m,10H),1.13(t,J=7.3Hz,3H).

[0425] Example 100: 1-Butyl-5-(diaminomethylene)-3-(2,4-dioxo-1,3-diazadispiro[4.1.5 7 .1 5 Tridecane-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione(100) [ka]

[0426] 1-Butyl-5-(diaminomethylene)-3-(2,4-dioxo-1,3-diazadispiro[4.1.5 7 .1 5 Tridecane-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of intermediate B (50 mg, 0.138 mmol) in EtOH (2 mL), NaHSO3 (5.74 mg, 0.055 mmol), KCN (17.97 mg, 0.28 mmol), and (NH4)2CO3 (106 mg, 1.10 mmol) were added. The reaction mixture was heated at 130 °C for 24 hours. The mixture was concentrated to dryness under reduced pressure to obtain the crude product, which was purified by reverse-phase HPLC (26% → 45% (v / v) ACN and H2O, and 0.05% NH4HCO3) to obtain the title compound 100 (10.8 mg, 18.06%) as a white solid. MS(ESI):C 20 H 28 Calculated mass for N6O5: 432.21, measured mass: 433.10 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.42-10.58(m,1H),9.55(s,2H),8.40(s,1H),7.31(s,2H),4.55-4.70(m,1H),3.73(t,J=7.4Hz,2H), 2.13-2.37(m,5H),1.97(t,J=12.9Hz,2H),1.87(d,J=12.5Hz,1H),1.32-1.51(m,5H),1.17-1.31(m,3H),0.88(t,J=7.3Hz,3H).

[0427] Example 103: 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)imidazo[1,2-a][1,3,5]triazine-2,4(1H,3H)-dione(103) [ka]

[0428] 1-Butylimidazo[1,2-a][1,3,5]triazine-2,4(1H,3H)-zion [ka] 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), NaH (657.35 mg, 16.44 mmol, 60% in mineral oil) was added at 0°C. The mixture was stirred at 0°C for 30 minutes, and 1-iodobutane (1.21 g, 6.57 mmol, 746.77 μL) was added at 25°C. After stirring for 2 hours, the reaction product was poured into saturated NH4Cl (20 mL) and extracted with ethyl acetate (2 × 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 → 3:1) to yield the title compound (0.26 g, 19%) as a white solid. MS(ESI):C9H 12 Calculated mass for N4O2: 208.10, Measured mass: 209.2 [M+H] + .

[0429] 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 [ka] 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)imidazolidin-2,4-dione (intermediate A in Example 85, 355.93 mg, 0.96 mmol) in toluene (2 mL), 2-(tributyl-λ5-phosphanylidene)acetonitrile (811.40 mg, 3.36 mmol) was added all at once at 25 °C under Ar. The reaction mixture was heated at 100 °C for 12 hours. After completion, the mixture was poured into H₂O (10 mL) and extracted with ethyl acetate (2 × 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 preparative TLC (PE:EA=1:1) to yield the title compound (0.17g, 19%) as a white solid. MS(ESI):C 27 H 44 Calculated mass for N6O5Si: 560.31, Measured mass: 561.3 [M+H] + .

[0430] 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)imidazo[1,2-a][1,3,5]triazine-2,4(1H,3H)-dione [ka] 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), TFA (1.54 g, 13.51 mmol, 1 mL) was added all at once at 25°C. The mixture was stirred at 25°C for 0.5 hours, poured into an aqueous solution of NaHCO3 (5 mL), and extracted with DCM (2 × 5 mL). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC (25-55% ACN(NH4HCO3) in water) to yield the title compound 103 (5.5 mg, 4.21%) as a white solid. MS(ESI):C 21 H 30 Calculated mass for N6O4: 430.23, Measured mass: 431.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.78(s,1H),7.46(d,J=1.6Hz,1H),7.01(d,J=1.6Hz,1H),4.51-4.64(m,1H),3.95(t,J=7.2 Hz,2H),2.53-2.61(m,2H),1.99-2.09(m,1H),1.62-1.78(m,5H),1.46-1.53(m,4H),1.28-1.39(m,9H),0.87-0.94(m,3H).

[0431] Example 106 was synthesized without chiral separation using the same procedure as described in Examples 81 and 82.

[0432] Examples 108 and 109 were synthesized using the same procedure as described in Examples 104 and 105. The stereochemistry was assigned arbitrarily.

[0433] Example 110. 1-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonane-2-yl)-1-cyclopropylurea(110) [ka]

[0434] N-Cyclopropyl-8,11-Dioxadispiro[3.2.4 7 .2 4 Tridecane-2-amine [ka] 8,11-dioxadispiro in MeOH (5 mL) [3.2.4 7 .2 4 To a solution of tridecane-2-one (500 mg, 2.55 mmol), cyclopropanamine (290.9 mg, 5.1 mmol) and AcOH (306 mg, 5.1 mmol) were added at 25°C. After 1 hour, NaBH3CN (400.3 mg, 6.4 mmol) was added to the reaction mixture, and the mixture was heated at 60°C for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and extracted with siRNA (3 × 40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound (6.8 g, crude) as a yellow oil, which was used directly in the next step without further purification. 1 H NMR(400MHz,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).

[0435] Benzylcyclopropyl(8,11-dioxadispiro[3.2.4 7 .2 4 Tridecane-2-yl carbamate [ka] N-cyclopropyl-8,11-dioxadispiro [3.2.4] in DCM (20 mL) 7 .2 4 To a solution of tridecane-2-amine (1.7 g, 7.16 mmol), CbzCl (1.23 g, 7.23 mmol) and TEA (1.45 g, 14.33 mmol) were added at 25°C. After stirring for 1 hour, the reaction product was diluted with H2O (60 mL) and extracted with DCM (3 × 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: siRNA = 100:0 → 0:100) to yield the title compound (6.2 g, 58.3%) as a yellow oil. 1 H NMR(400MHz,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).

[0436] Benzylcyclopropyl(7-oxospiro[3.5]nonan-2-yl)carbamate [ka] Benzylcyclopropyl (8,11-dioxadispiro [3.2.4] in acetone (30 mL) and H2O (15 mL) 7 .2 4To a solution of tridecane-2-yl carbamate (3.1 g, 8.35 mmol), TsOH.H2O (3.17 g, 16.69 mmol) was added at 25°C. After stirring for 2 hours, the reaction product was diluted with H2O (30 mL) and extracted with HCl (3 × 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: HCl = 100:0 → 0:100) to yield the title compound (5.5 g, crude) as a yellow oil, which was used in the next step without further purification. MS(ESI):C 20 H 25 Calculated mass of NO3: 327.18, Measured mass: 328.1 [M+H] + .

[0437] Benzyl(7-aminospiro[3.5]nonan-2-yl)(cyclopropyl)carbamate [ka] A mixture of benzylcyclopropyl (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 to be combined with NaBH(OAc)3 (8.9 g, 42 mmol) in a single addition at 25°C under N2. After heating at 50°C for 12 hours, the reaction product was concentrated under reduced pressure. The residue was adjusted to pH=8 with saturated NaHCO3. The mixture was diluted with H2O (40 mL) and extracted with ELISA (3 × 40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound (6 g, crude) as a yellow oil, which was used in the next step without further purification. MS(ESI):C2H 28 Calculated mass value for N2O2: 328.22, measured value: 329.3 [M+H] + .

[0438] Benzyl(7-(3-butylureido)spiro[3.5]nonan-2-yl)(cyclopropyl)carbamate [ka] To a solution of benzyl(7-aminospiro[3,5]nonan-2-yl)(cyclopropyl)carbamate (6 g, 18.3 mmol) in DCM (60 mL), 1-isocyanatobutane (2.72 g, 27.4 mmol) and TEA (3.7 g, 36.5 mmol) were added at 25°C. After stirring for 1 hour, the reaction product was quenched with H2O and extracted with 60 mL (3 × 20 mL) of DCM. The combined organic layer was washed with 30 mL (2 × 15 mL) of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: siRNA = 100:0 → 0:100) to yield the title compound (4.1 g, 52.5%) as a white solid. MS(ESI):C 25 H 37 Calculated mass for N3O3: 427.28, Measured mass: 428.4 [M+H] + .

[0439] Benzyl(7-(3-butyl-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonane-2-yl)(cyclopropyl)carbamate [ka] 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), malonic acid (292.1 mg, 2.8 mmol) and Ac2O (2.01 g, 19.7 mmol) were added at 25 °C. After heating at 80 °C under N2 for 12 hours, the reaction product was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: ELISA = 100:0 → 0:100) to yield the title compound (1.3 g, 93.5%) as a yellow solid. MS(ESI):C 28 H 37 Calculated mass for N3O5: 495.27, measured mass: 496.4 [M+H] + .

[0440] 1-Butyl-3-(2-(cyclopropylamino)spiro[3.5]nonane-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of benzyl(7-(3-butyl-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonan-2-yl)(cyclopropyl)carbamate (1.3 g, 2.62 mmol) in MeOH (20 mL), 5% Pd / C (300 mg, 0.14 mmol) was added under N2. The suspension was degassed and purged three times with H2. The reaction mixture was stirred under H2 (15 Psi) at 20°C for 48 hours. After completion, the reaction mixture was filtered through a Celite pad and washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to yield the title compound (1.25 g, crude) as a white solid, which was used directly in the next step without further purification. MS(ESI):C 24 H 31 Calculated mass for N3O3: 361.24, Measured mass: 362.2 [M+H] + .

[0441] 1-(7-(3-butyl-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonane-2-yl)-1-cyclopropylurea [ka] 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), and isocyanato(trimethyl)silane (1.53 g, 13.3 mmol) was added dropwise at 15°C. After stirring for 16 hours, the reaction product was concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC ([H2O(10 mM NH4HCO3)-ACN], gradient: 10% → 40% B) to yield the title compound (300 mg, 22.3%) as a red solid. MS(ESI):C 21 H 32 Calculated mass for N4O4: 404.24, Measured mass: 405.3 [M+H] + .

[0442] 1-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonane-2-yl)-1-cyclopropylurea(110) [ka] To a solution of 1-(7-(3-butyl-2,4,6-trioxotetrahydropyrimidine-1(2H)-yl)spiro[3.5]nonan-2-yl)-1-cyclopropylurea (80 mg, 0.2 mmol) in THF (0.1 mL), bis[(Z)-1-methyl-3-oxobuta-1-enoxy]nickel (25.4 mg, 0.099 mmol) and cyanamide (24.9 mg, 0.59 mmol) were added at 15°C. After heating at 85°C for 12 hours, the reaction product was diluted with H2O (5 mL) and extracted with ELISA (3 × 5 mL). The combined organic layers were 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% → 55% B) to yield the title compound (racemate, 4.2 mg, 4.6%) as a white solid. MS(ESI):C 22 H 34Calculated mass for N6O4: 446.26, Measured mass: 447.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.54(s,2H),7.29(s,2H),5.78(s,2H),4.52-4.70(m,1 H),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=7.2Hz,3H),0.70-0.84(m,2H),0.52-0.60(m,2H).

[0443] Example 169 was synthesized using the same procedure as described in Example 110.

[0444] Example 175 was synthesized using the same procedure as described in Example 110, with Boc used as the protecting group instead of Cbz.

[0445] Example 111. 7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carboxamide (111) [ka]

[0446] 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 [ka] 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 (intermediate derived from the synthesis of Example 85, 100 mg, 0.17 mmol), K2CO3 (27.51 mg, 0.2 mmol) and 30% H2O2 (94 mg, 0.83 mmol) in DMSO (1 mL) were added. The reaction mixture was stirred at 25°C for 1 hour under N2. After completion, the reaction mixture was quenched with water (1 mL). The aqueous layer was extracted with DCM (3 × 2 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO2, petroleum ether: Â=3:1) to yield the title compound (90 mg, 87.4%) as a yellow oil. MS(ESI):C 28 H 44 Calculated mass of N6O6SSi: 620.28, measured mass: 643.2 [M+Na] + .

[0447] 7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carboxamide [ka] 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), H2O (0.1 mL) was added. After stirring at 25°C for 1 hour, the reaction product was concentrated under reduced pressure, and MeOH (5 mL) and K2CO3 (100 mg) were added. After stirring for 10 minutes, the reaction product was concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC (mobile phase: [water (NH4HCO3)-ACN], 30% → 60% B) to yield the title compound (3.6 mg, 5.1%) as a white solid. MS(ESI):C 22 H 30 Calculated mass of N6O5S: 490.20, Measured mass: 491.2 [M+H] + . 1 H NMR(400MHz,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=7.6Hz,2H),3.47(d,J=8.0Hz,2H),2.72-2.76(m,2H),2.20(br s,1H),1.84(br d,J=12.8Hz,2H),1.63-1.79(m,5H),1.38-1.49(m,9H),0.99(t,J=7.2Hz,3H).

[0448] Example 112. N-(7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-yl)methanesulfonamide [ka]

[0449] 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 [ka] 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 (intermediate derived from the synthesis of Example 85, 1.35 g, 2.2 mmol), (2,4-dimethoxyphenyl)methaneamine (3.74 g, 22.4 mmol) was added. After heating at 90°C for 3 hours, the reaction product was diluted with H2O (60 mL) and extracted with ELISA (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: SiO₂ = 100:1 → 2:1) to yield the title compound (1.2 g, 72%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ(ppm)7.90(t,J=6.0Hz,1H),7.19(d,J=8.0Hz,1H),6.43-6.49(m,2H),4.94(s,2H),4.71-4.83(m,1H),4.32(d,J=6 .0Hz,2H),3.98-4.05(m,2H),3.86(s,3H),3.81(s,3H),3.59-3.65(m,2H),3.46(d,J=7.6Hz,2H),2.70(dq,J=12.8,3.2Hz,2H),2.23(br s,1H),1.79(br d,J=13.6Hz,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).

[0450] 3-Amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione [ka] 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 hour. The crude residue was diluted with H2O (15 mL) and extracted with ELISA (3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound (0.66 g, 83.9%) as a white solid, which was used directly in the next step without further purification.

[0451] N-(7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-yl)methanesulfonamide [ka] To a solution of 3-amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.1 g, 0.22 mmol) in DCM (2 mL), TEA (218.8 mg, 2.2 mmol) and MsCl (123.8 mg, 1.1 mmol) were added at 0°C. After stirring at 25°C for 2 hours, the reaction product was diluted with NH4Cl (5 mL) and extracted with DCM (3 × 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 yield the title compound (9.8 mg, 7%) as a white solid. MS(ESI):C 22 H 32 Calculated mass of N6O6S2: 540.18, Measured mass: 540.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.11(s,1H),4.57-4.71(m,1H),3.88-3.92(d,J=7.2Hz,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,6H),1.24-1.37(m,5H),0.89(t,J=7.2Hz,3H).

[0452] Example 113. 3-amino-7-butyl-5-(2-(3-ethyl-5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)spiro[3.5]nonane-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(113) [ka]

[0453] 5,5-Dimethyl-1-(7-oxospiro[3.5]nonanane-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidined-2,4-dione [ka] To a solution of 5,5-dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)imidazolidin-2,4-dione (see Example 78 for synthesis, 10 g, 37.8 mmol) in DCM (100 mL), DIPEA (19.6 g, 151.3 mmol) and SEM-Cl (12.6 g, 75.7 mmol) were added at 0°C. After stirring at 25°C for 12 hours, the reaction product was quenched with saturated NH4Cl (55 mL) and extracted with DCM (2 × 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: siRNA = 10:1 → 5:1) to yield the title compound (10 g, 667%) as a yellow oil. MS(ESI):C 20 H 34 Calculated mass of N2O4Si: 394.23 MHz, measured mass: 393.4 MHz.

[0454] 1-(7-hydroxyspiro[3.5]nonan-2-yl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-2,4-dione (intermediate 3) [ka] To a solution of 5,5-dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-(2-trimethylsilylethoxymethyl)imidazolidined-2,4-dione (10 g, 25.3 mmol) in MeOH (100 mL), NaBH4 (527.3 mg, 13.9 mmol) was added in several portions at 0°C. After stirring at 25°C for 1 hour, the reaction product was quenched with H2O (50 mL) and extracted with HCl (2 × 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: HCl = 5:1 → 1:1) to yield the title compound (5.3 g, 52.7%) as a white solid. MS(ESI):C 20 H 36Calculated mass for N2O4Si: 396.24, Measured mass: 419.2 [M+Na] + .

[0455] 1-Butyl-6-chloropyrimidine-2,4(1H,3H)-dione [ka] 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 to be mixed with K2CO3 (2.36 g, 17.1 mmol) in one step at 25°C under N2. After stirring at 25°C for 12 hours, the combined mixture was poured into water (30 mL) and siRNA (30 mL). The aqueous phase was extracted with siRNA (3 × 20 mL). The combined organic layer was washed with brine (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was triturated with petroleum ether (20 mL) and stirred for 5 minutes. The precipitate was recovered by filtration, washed with petroleum ether (3 × 20 mL), and dried under vacuum to yield 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):C8H 11 Calculated mass for ClN2O2: 202.05, measured mass: 203.2 [M+H] + .

[0456] 1-Butyl-6-chloro-3-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[3.5]nonane-7-yl)pyrimidine-2,4(1H,3H)-dione [ka] To a solution of 1-butyl-6-chloropyrimidine-2,4(1H,3H)-dione (1.04 g, 5.14 mmol) in toluene (10 mL), 1-(7-hydroxyspiro[3.5]nonan-2-yl)-5,5-dimethyl-3-(2-trimethylsilylethoxymethyl)imidazolidin-2,4-dione (intermediate 3, 1.7 g, 4.3 mmol) was added. The reaction mixture was heated to 120 °C, and 2-(tributyl-λ) was added. 5 Phosphanylidene acetonitrile (3.62 g, 15.00 mmol) was added dropwise. After stirring at 120°C for 12 hours under N2, the reaction product was quenched with H2O (20 mL) and extracted with HCl (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: HCl = 5:1 → 1:1) to yield the title compound (1.4 g, 24%) as a colorless oil. MS(ESI):C 28 H 45 Calculated mass of ClN4O5Si: 580.28, measured mass: 581.3 [M+H] + .

[0457] 6-Amino-1-butyl-3-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[3.5]nonane-7-yl)pyrimidine-2,4(1H,3H)-dione [ka] 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), NH3.H2O (6 mL) was added. The reaction mixture was heated in a sealed tube at 90°C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound (0.5 g, 92.4%) as a white solid, which was used directly in the next step without further purification. MS(ESI):C 28 H 47 Calculated mass of N5O5Si: 561.33, measured mass: 562.3 [M+H] + .

[0458] 7-Butyl-5-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[3.5]nonane-7-yl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbonitrile [ka] 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), 4,5-dichlorodithiazole-2-ium chloride (1.01 g, 4.8 mmol) was added. After cooling to 0°C, pyridine (0.88 g, 11.14 mmol) was added, and the reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: Â=10:1 → 1:1) to yield the title compound (756.9 mg, 42.3%) as a colorless oil. MS(ESI):C 30 H 44 Calculated mass of N6O5SSi: 628.29, measured mass: 651.3 [M+Na] + .

[0459] 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]nonane-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione [ka] To a solution of (2,4-dimethoxyphenyl)methaneamine (971.8 mg, 5.8 mmol) in DMA (10 mL), 7-butyl-5-[2-[5,5-dimethyl-2,4-dioxo-3-(2-trimethylsilylethoxymethyl)imidazolidin-1-yl]spiro[3.5]nonane-7-yl]-4,6-dioxo-isothiazolo[3,4-d]pyrimidine-3-carbonitrile (731 mg, 1.2 mmol) was added. The reaction mixture was stirred at 50°C for 2 hours and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: Â=3:1 → 1:1) to yield the title compound (303 mg, 33.9%) as a colorless oil. MS(ESI):C 38 H 56 Calculated mass of N6O7SSi: 768.37, measured mass: 769.3 [M+H] + .

[0460] 3-amino-7-butyl-5-(2-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)spiro[3,5]nonane-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione [ka] 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]nonane-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 hours. The reaction product was concentrated under reduced pressure, and the crude residue was dissolved in MeOH (5 mL). K2CO3 (20 mg) was added. The mixture was stirred at 25°C for 1 hour, 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×10um, mobile phase: [water (NH4HCO3)-ACN], 40%→70% B) to yield the title compound (15 mg, 11.5%) as a white solid. MS(ESI):C 23 H 32 Calculated mass of N6O4S: 488.22, Measured mass: 489.3 [M+H] + .

[0461] 3-amino-7-butyl-5-(2-(3-ethyl-5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)spiro[3,5]nonane-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(113) [ka] To a solution of 3-amino-7-butyl-5-(2-(5,5-dimethyl-2,4-dioxoimidazolidine-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), EtI (6.38 mg, 0.04 mmol) and K2CO3 (4.53 mg, 0.03 mmol) were added. After stirring at 20°C for 2 hours, the reaction product was filtered to remove the insoluble solid. The filtrate was purified by reverse-phase HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], 40% → 70% B) to yield the title compound (113) as a white solid. MS(ESI):C 25 H 36 Calculated mass of N6O4S: 516.25, Measured mass: 517.2 [M+H] + . 1 H NMR(400MHz,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,2 H),1.26(d,J=6.0Hz,6H),1.08(t,J=7.2Hz,3H),0.89(t,J=7.2Hz,3H).

[0462] Example 144 was synthesized from Example 62 according to the final step of Example 113 (along with heating at 90°C for 12 hours).

[0463] Examples 114 and 115 were synthesized using chiral separation via the same route as Example 6. The stereochemistry was assigned arbitrarily.

[0464] Example 116. 1-Butyl-5-(diaminomethylene)-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidine-1-yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione(116) [ka]

[0465] 3,5,5-Trimethylimidazolidined-2,4-dione [ka] To a solution of 5,5-dimethylimidazolidine-2,4-dione (5 g, 39 mmol) in EtOH (50 mL), MeI (11.08 g, 78.1 mmol) and NaOH (1.56 g, 39 mmol) were added. After heating at 60 °C for 12 hours, the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography ( Depositphotos:MeOH = 100:0 → 10:1) to yield the title compound (1.6 g, 28.8%) as a yellow solid. MS(ESI):C6H 10 Calculated mass value for N2O2: 142.07, measured value: 143.3 [M+H] + .

[0466] 1-(4-bromobenzyl)-3,5,5-trimethylimidazolidined-2,4-dione [ka] To a solution of 1-bromo-4-(bromomethyl)benzene (1.58 g, 6.33 mmol) and 3,5,5-trimethylimidazolidined-2,4-dione (900 mg, 6.33 mmol) in THF (20 mL), NaH (253.2 mg, 6.33 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours, quenched with saturated NH4Cl (20 mL), and extracted with HCl (3 × 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: HCl = 100:0 → 10:1) to yield the title compound (1.4 g, 71%) as a colorless oil. MS(ESI):C 13 H 15 Calculated mass for BrN2O2: 310.03, Measured mass: 311.1 [M+H] + .

[0467] Ethyl 2-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate [ka] To a solution of 1-[(4-bromophenyl)methyl]-3,5,5-trimethyl-imidazolidined-2,4-dione (0.5 g, 1.61 mmol) in EtOH (10 mL) and H2O (2 mL), 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) were added. The reaction mixture was stirred at 80°C for 3 hours, quenched with saturated Na2CO3 (5 mL), diluted with H2O (10 mL), and extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound (0.35 g, 88.1%) as a colorless oil, which was used in the next step without further purification. MS(ESI):C 13 H 15Calculated mass for N5O2: 273.12, Measured mass: 274.2 [M+H] + .

[0468] 1-(4-aminobenzyl)-3,5,5-trimethylimidazolidined-2,4-dione [ka] To a solution of 1-[(4-azidophenyl)methyl]-3,5,5-trimethyl-imidazolidined-2,4-dione (0.8 g, 2.93 mmol) in THF (10 mL) and H2O (2 mL), PPh3 (767.8 mg, 2.93 mmol) was added. After stirring at 25°C for 2 hours, the reaction product was concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO2, petroleum ether: SiO=2:1) ​​to yield the title compound (0.3 g, 41.4%) as a white solid. MS(ESI):C 13 H 17 Calculated mass for N3O2: 247.13, Measured mass: 248.3 [M+H] + .

[0469] 1-Butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidine-1-yl)methyl)phenyl)urea [ka] To a solution of 1-[(4-aminophenyl)methyl]-3,5,5-trimethyl-imidazolidined-2,4-dione (0.3 g, 1.2 mmol) in DCM (3 mL), n-BuNCO (120.1 mg, 1.2 mmol) and TEA (368.3 mg, 3.64 mmol) were added. The reaction mixture was stirred at 25°C for 1 hour, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO2, petroleum ether: siRNA = 2:1) to yield the title compound (0.2 g, 47.6%) as a white solid. MS(ESI):C 18 H 26 Calculated mass for N4O3: 346.20, Measured mass: 347.3 [M+H] + .

[0470] 1-Butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidine-1yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione [ka] To a solution of 1-butyl-3-[4-[(3,5,5-trimethyl-2,4-dioxoimidazolidined-1-yl)methyl]phenyl]urea (0.3 g, 0.87 mmol) in DCM (5 mL), malonyl dichloride (3.66 g, 26 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO2, petroleum ether: Â=0:1) to yield the title compound (0.4 g) as a white solid. MS(ESI):C 21 H 26 Calculated mass for N4O5: 414.19, measured mass: 415.2 [M+H] + .

[0471] 1-Butyl-5-(diaminomethylene)-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidine-1-yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione(116) [ka] To a solution of 1-butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidine-1yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione (0.2 g, 0.48 mmol) in THF (1 mL), cyanamide (608.6 mg, 14.5 mmol) and bis[(Z)-1-methyl-3-oxobuta-1-enoxy]nickel (124 mg, 0.48 mmol) were added. After heating at 85°C for 16 hours, the residue was diluted with H2O (20 mL) and extracted with ELISA (3 × 20 mL). The combined organic layers were 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% → 45% B) to yield the title compound (0.04 g, 18.2%) as a white solid. MS(ESI):C 22 H 28 Calculated mass for N6O5: 456.21, measured mass: 457.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.44(s,2H),7.34-7.40(m,4H),7.14(d,J=8.0Hz,2H),4.54(s,2H) ,3.77(t,J=7.2Hz,2H),2.92(s,3H),1.46-1.52(m,2H),1.26-1.30(m,8H),0.88(t,J=7.2Hz,3H).

[0472] Examples 117 and 120. 3-amino-7-butyl-5-((5S,7s,10S)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecane-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]tridecane-10-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (120) [ka]

[0473] 1-Butyl-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione [ka] 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), DIPEA (3.83 g, 29.6 mmol) and SEM-Cl (3.95 g, 23.7 mmol) were added at 0°C under N2. After stirring at 25°C for 12 hours, the reaction product was quenched with saturated NH4Cl (20 mL) and extracted with DCM (3 × 50 mL). The combined organic layer was washed with HCl (1 N, 2 × 10 mL) and brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: HCl = 100:0 → 20:1) to yield the title compound (2.99 g, 85.98%) as a yellow oil. 1 H NMR(400MHz,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).

[0474] 6-Amino-1-butyl-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione [ka] 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), NH3.H2O (25 mL) was added. After heating at 80°C for 12 hours, the reaction product was quenched with saturated NH4Cl (50 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with HCl (1 N, 2 × 30 mL) and brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether: HCl = 100:1 → 1:100) to yield the title compound (4.5 g, 93.5%) as a colorless oil. MS(ESI):C 14 H 27 Calculated mass of N3O3Si: 313.38, measured mass: 314.3 [M+H] + .

[0475] 7-Butyl-4,6-Dioxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-Tetrahydroisothiazolo[3,4-d]pyrimidine-3-Carbonitrile [ka] To a solution of 4,5-dichlorodithiazole-2-ium chloride (2.99 g, 14.4 mmol) in DCM (50 mL), 6-amino-1-butyl-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione (4.5 g, 14.4 mmol) was added, followed by the addition of pyridine (5.22 g, 66 mmol) at 25°C. The reaction mixture was stirred at 25°C for 3 hours. After completion, the reaction mixture was quenched with water (50 mL) and extracted with DCM (3 × 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: siRNA = 100:1 → 20:1) to yield the title compound (1.5 g, 27.5%) as a brown oil. 1H NMR(400MHz,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...

Claims

1. Compounds of the following formulas (Ia) or (Ib), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, Z is either O or S, Y is, 【Chemistry 2】 This represents, X is N or CR ２ And, L is -(C １ -C ６ ) is alkylenyl, B is (C ３ -C ８ ) cycloalkyl, (C ６ -C １０ ) aryl, 4- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more (C １ -C ６ ) alkyl, R １ is hydrogen, -CO ２ R ａ , -CONR ａ R ｂ , -SO ２ R ａ ,-SONR ａ R ｂ , -SO ２ NR ａ R ｂ , -NR ａ R ｂ , 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Alkyl, 【Transformation 3】 Alternatively, it is -O- (a 4- to 7-membered heterocycloalkyl group), and the above (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ )alkoxy, 4-7 member heterocycloalkyl and -O-(4-7 member heterocycloalkyl) are respectively halo, hydroxy, oxo, cyano, amino, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, hydroxy(C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Hydroxyalkyl, 【Chemistry 4】 (C ３ -C ８ ) Cycloalkyl (C １ -C ６ ) optionally substituted with one or more substituents independently selected from alkyl and benzyl; or, when Y represents -L-B-, R １ It, together with the atom bonded to it, forms a 4-7 membered heterocycloalkyl ring, where Y is 【Transformation 5】 If so, R １ The condition is that it is not hydrogen, R １ａ , R １ｂ and R １ｃ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl or (C ３ -C ８ ) Cycloalkyl or R １ａ and R １ｂ These, together with the atoms bonded to them, form a 5-membered or 6-membered heterocycloalkyl group. R ２ is hydrogen, fluoro, chloro, cyano, hydroxyl, NH ２ , NHCO(C １ -C ６ ), alkyl, NHR ａ , (C １ -C ６ ), alkoxy, -CONR ａ R ｂ or (C １ -C ６ ), alkyl, and the (C １ -C ６ ) alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, (C １ -C ６ ) alkoxy, and NR ａ R ｂ ; or R １ and R<9000081>together with the atoms to which they are attached form a 4- to 9-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from (C １ -C ６ ), alkyl, and the (C １ -C ６ ) alkyl is further optionally substituted with (C ３ -C ８ ) cycloalkyl, 4- to 7-membered heterocyclylalkyl, hydroxy, halo, (C １ -C ６ ) alkoxy, cyano, carboxy, -CONR ａ R ｂ and -SO ２ R ａ ; R ３ is (C １ -C ６ ) alkyl or (C ３ -C ８ ) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, (C １ -C ６ ) alkoxy, (C ３ -C ８ ) cycloalkyl, aryl, carboxamide, amino, cyano, carboxy and alkoxycarbonyl, R ａ and R ｂ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl or 4-7 member heterocycloalkyl, and the (C １ -C ６ ) Alkyl and 4-7 member heterocycloalkyl groups are halo, hydroxy, cyano, (C １ -C ６ ) optionally substituted with one or more substituents independently selected from alkoxy, 4- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl; or R ａ and R ｂ These, together with the nitrogen atoms bonded to them, form a 4-7 member heterocycloalkyl group. R ５ａ , R ５ｂ , R ６ａ and R ６ｂ These are independently hydrogen or (C １ -C ６ ) is alkyl, R Ａ is hydrogen or (C １ -C ６ ) is alkyl, n, m, and p are independently 0 or 1. q is 0, 1, or 2. However, this is subject to the condition that the sum of p and q is equal to 0, 1, or 2. The aforementioned compound or a pharmaceutically acceptable salt thereof.

2. Compounds of the following formulas (Ia) or (Ib), 【Transformation 6】 or a pharmaceutically acceptable salt thereof During the ceremony, Y is, 【Transformation 7】 This represents, X is N or CR ２ And, L is -(C １ -C ６ ) is alkylenyl, B is (C ３ -C ８ ) Cycloalkyl, (C ６ -C １０ ) represents an aryl, a 4- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, each of which contains one or more (C １ -C ６ ) optionally substituted with alkyl, R １ is hydrogen, -CO ２ R ａ , -CONR ａ R ｂ , -SO ２ R ａ ,-SONR ａ R ｂ , -SO ２ NR ａ R ｂ , -NR ａ R ｂ , 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Alkyl, 【Transformation 8】 Alternatively, it is -O- (a 4- to 7-membered heterocycloalkyl group), and the above (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ )alkoxy, 4-7 member heterocycloalkyl and -O-(4-7 member heterocycloalkyl) are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, hydroxy(C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Hydroxyalkyl, 【Chemistry 9】 (C ３ -C ８ ) Cycloalkyl (C １ -C ６ ) optionally substituted with one or more substituents independently selected from alkyl and benzyl; or, when Y represents -L-B-, R １ It, together with the atom bonded to it, forms a 4-7 membered heterocycloalkyl ring, where Y is 【Chemistry 10】 If so, R １ The condition is that it is not hydrogen, R １ａ , R １ｂ and R １ｃ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl or (C ３ -C ８ ) Cycloalkyl, or R １ａ and R １ｂ These, together with the atoms bonded to them, form a 5-membered or 6-membered heterocycloalkyl group. R ２ is hydrogen, fluoro, chloro, cyano, hydroxyl, NH ２ , NHCO (C １ -C ６ ) alkyl, NHR ａ , (C １ -C ６ ) Alkyl, -CONR ａ R ｂ Or (C １ -C ６ ) is alkyl, and the above (C １ -C ６ Alkyl is a compound of halo, hydroxy, cyano, (C １ -C ６ ) Alkoxy and NR ａ R ｂ It is optionally substituted with one or more substituents independently selected from R; or R １ and R ２ However, together with the atoms bonded to them, (C １ -C ６ ) Form a 4- to 9-membered heterocycloalkyl group which is optionally substituted with one or more substituents independently selected from the alkyl group, and the (C １ -C ６ ) Alkyl is further (C ３ -C ８ ) Cycloalkyl, 4-7 member heterocyclylalkyl, hydroxy, (C １ -C ６ ) Alkyl, cyano, carboxy, -CONR ａ R ｂ and -SO ２ R ａ It is arbitrarily replaced with, R ３ is, (C １ -C ６ ) alkyl or (C ３ -C ８ ) are cycloalkyl, and each of them is a halo, hydroxy, (C １ -C ６ ) Alkoxy, (C ３ -C ８ ) optionally substituted with one or more substituents independently selected from cycloalkyl, aryl, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl, R ａ and R ｂ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl or 4-7 member heterocycloalkyl, and the (C １ -C ６ ) Alkyl and 4-7 member heterocycloalkyl groups are halo, hydroxy, cyano, (C １ -C ６ ) optionally substituted with one or more substituents independently selected from alkoxy, 4- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl; or R ａ and R ｂ These, together with the nitrogen atoms bonded to them, form a 4-7 member heterocycloalkyl group. R ５ａ , R ５ｂ , R ６ａ and R ６ｂ These are independently hydrogen or (C １ -C ６ ) is alkyl, n, m, and p are independently 0 or 1. q is 0, 1, or 2. However, this is subject to the condition that the sum of p and q is equal to 0, 1, or 2. The aforementioned compound or a pharmaceutically acceptable salt thereof.

3. Compounds of the following formulas (Ia) or (Ib), 【Chemistry 11】 or a pharmaceutically acceptable salt thereof During the ceremony, Y is, 【Chemistry 12】 This represents, X is N or CR ２ And, L is -(C １ -C ６ ) is alkylenyl, B is (C ３ -C ８ ) Cycloalkyl, (C ６ -C １０ ) represents an aryl, a 4- to 7-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, each of which contains one or more (C １ -C ６ ) optionally substituted with alkyl, R １ is hydrogen, -CO ２ R ａ , -CONR ａ R ｂ , -SO ２ R ａ ,-SONR ａ R ｂ , -SO ２ NR ａ R ｂ , -NR ａ R ｂ , 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Alkyl or 【Chemistry 13】 And the above (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Alkoxy and 4-7 member heterocycloalkyls are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Hydroxyalkyl and 【Chemistry 14】 It is optionally substituted with one or more substituents independently selected from; or, when Y represents -L-B, R １ It, together with the atom bonded to it, forms a 4-7 membered heterocycloalkyl ring, where Y is 【Chemistry 15】 If so, R １ The condition is that it is not hydrogen, R １ａ , R １ｂ and R １ｃ Each instance is independently of hydrogen or (C １ -C ６ ) Alkyl or R １ａ and R １ｂ These, together with the atoms bonded to them, form a 5-membered or 6-membered heterocycloalkyl group. R ２ is hydrogen, fluoro, chloro, cyano, hydroxyl, NH ２ , NHCO (C １ -C ６ ) alkyl, NHR ａ , (C １ -C ６ ) Alkyl, -CONR ａ R ｂ , or halo, hydroxy, cyano, (C １ -C ６ ) Alkoxy and NR ａ R ｂ (C) optionally substituted with one or more substituents independently selected from １ -C ６ ) is alkyl; or R １ and R ２ However, together with the atoms bonded to them, they form a 4-7 member heterocycloalkyl group. R ３ is, (C １ -C ６ ) alkyl or (C ３ -C ８ ) are cycloalkyl, and each of them is a halo, hydroxy, (C １ -C ６ ) Alkoxy, (C ３ -C ８ ) optionally substituted with one or more substituents independently selected from cycloalkyl, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl groups, R ａ and R ｂ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl or 4-7 member heterocycloalkyl, and the (C １ -C ６ ) Alkyl and 4-7 member heterocycloalkyl groups are halo, hydroxy, cyano, (C １ -C ６ ) optionally substituted with one or more substituents independently selected from alkoxy, 4- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl; or R ａ and R ｂ These, together with the nitrogen atoms bonded to them, form a 4-7 member heterocycloalkyl group. n, m, and p are independently 0 or 1. q is 0, 1, or 2. However, this is subject to the condition that the sum of p and q is equal to 0, 1, or 2. The aforementioned compound or a pharmaceutically acceptable salt thereof.

4. Y, 【Chemistry 16】 A compound according to any one of claims 1 to 3, which represents the compound.

5. Y, 【Chemistry 17】 A compound according to any one of claims 1 to 3, which represents the compound.

6. Y, [Chemistry 18] A compound according to any one of claims 1 to 3, which represents the compound.

7. R １ but, hydrogen, 【Chemistry 19】 And, During the ceremony, R １ｄ , R １ｅ and R １ｆ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Hydroxyalkyl and (C １ -C ６ ) Selected from alkoxy, and the (C １ -C ６ ) Alkyl is further (C ３ -C ８ ) optionally substituted with cycloalkyl or phenyl; or R １ｄ and R １ｅ However, together with the carbon atoms bonded to them, (C ３ -C ８ The compound according to any one of claims 1 to 6, wherein it forms a cycloalkyl or a 3- to 7-membered heterocycloalkyl, each of which is optionally substituted with a hydroxyl group.

8. R １ but 【Chemistry 20】 And, R ａ and R ｂ Each of them is either hydrogen, or R ａ is hydrogen, R ｂ The compound according to claim 7, wherein is methyl.

9. R １ but, hydrogen, 【Chemistry 21】 And, During the ceremony, R １ｄ , R １ｅ and R １ｆ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Hydroxyalkyl and (C １ -C ６ ) Selected from alkoxy, and the (C １ -C ６ ) Alkyl is further (C ３ -C ８ ) optionally substituted with cycloalkyl or phenyl; or R １ｄ and R １ｅ However, together with the carbon atoms bonded to them, (C ３ -C ８ The compound according to any one of claims 1 to 6, wherein it forms a cycloalkyl or a 3- to 7-membered heterocycloalkyl, each of which is optionally substituted with a hydroxyl group.

10. R １ but, hydrogen, 【Chemistry 22】 And, During the ceremony, R １ｄ , R １ｅ and R １ｆ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl and (C １ -C ６ ) Selected from alkoxy; or R １ｄ and R １ｅ However, together with the carbon atoms bonded to them, (C ３ -C ８ The compound according to any one of claims 1 to 6, which forms a cycloalkyl or a 3- to 7-membered heterocycloalkyl.

11. R １ but 【Chemistry 23】 And, R １ｄ and R １ｅ The compound according to any one of claims 7, 9, and 10, wherein the carbon atoms bonded to them together form morpholine, cyclobutane, oxetane, azetidine, or cyclohexane.

12. R １ｄ and R １ｅ The compound according to any one of claims 7 and 9 to 11, wherein each of them is methyl.

13. R １ｆ The compound according to any one of claims 7 and 9 to 12, wherein is hydrogen.

14. R １ｆ But (C １ -C ６ The compound according to any one of claims 7 and 9 to 12, wherein it is alkyl.

15. R １ｆ The compound according to claim 14, wherein the compound is methyl or ethyl.

16. R １ｆ But (C １ -C ６ The compound according to any one of claims 7 and 9 to 12, wherein it is a fluoroalkyl compound.

17. R １ｆ The compound according to claim 16, wherein is 2,2,2-trifluoroethyl.

18. R １ but 【Chemistry 24】 And R １ａ The compound according to any one of claims 7, 9, and 10, wherein the compound is cyclopropyl, 2-propyl, ethyl, or methyl.

19. R １ but, hydrogen, 【Chemistry 25】 The compound according to any one of claims 1 to 6.

20. R １ but, 【Chemistry 26】 The compound according to any one of claims 1 to 6.

21. Y, 【Chemistry 27】 The compound according to any one of claims 1 to 17.

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

23. X is CR ２ The compound according to any one of claims 1 to 5 and 6 to 20.

24. R ２ The compound according to claim 23, wherein is hydrogen.

25. R ２ The compound according to claim 23, wherein is fluoro.

26. R ２ However, (C １ -C ６ (C) optionally substituted with alkoxy １ -C ６ The compound according to claim 23, wherein it is alkyl.

27. R ２ The compound according to claim 26, wherein is methyl.

28. R ２ The compound according to claim 26, wherein is methoxymethyl.

29. R １ but, 【Chemistry 28】 And, R ２ However, -CH ３ or -CH ２ - OCH ３ The compound according to claim 23.

30. R １ and R ２ However, together with the atoms bonded to them, they form a 4- to 9-membered heterocycloalkyl group, and the 4- to 9-membered heterocycloalkyl group is (C １ -C ６ ) optionally substituted with one or more elements independently selected from alkyl, and the (C １ -C ６ ) Alkyl is further (C ３ -C ８ ) Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, hydroxy, halo, (C １ -C ６ ) Alkyl, cyano, carboxy, -CONR ａ R ｂ and -SO ２ R ａ The compound according to claim 23, which is optionally substituted with one or more substituents independently selected from the compound.

31. R １ and R ２ However, together with the atoms bonded to them, 【Chemistry 29】 Forming, R １ｇ and R １ｈ Each is independently of hydrogen or (C １ -C ６ ) is alkyl, and the above (C １ -C ６ ) Alkyl is (C ３ -C ８ ) Cycloalkyl, 4-7 member heterocyclylalkyl, hydroxy, halo, (C １ -C ６ ) Alkyl, cyano, carboxy, -CONR ａ R ｂ and -SO ２ R ａ The compound according to claim 30, which is optionally substituted with one or more substituents independently selected from the compound.

32. R １ｈ The compounds are ethyl, methyl, ethyl, isopropyl, or t-butyl, each of which is hydroxy, methoxy, cyclopropyl, oxetanyl, tetrahydrofuranyl, phenyl, cyano, carboxy, hydroxy, -CONR ａ R ｂ , -SO ２ R ａ The compound according to claim 31, or optionally substituted with 1 to 3 fluorine atoms.

33. R １ｈ The compound according to claim 32, wherein is trifluoromethyl.

34. R １ｇ The compound according to any one of claims 31 to 33, wherein the compound is hydrogen, methyl, or ethyl, and the methyl or ethyl is optionally substituted with cyano.

35. R ａ The compound according to any one of claims 1 to 34, wherein is methyl.

36. R ｂ The compound according to any one of claims 1 to 35, wherein is methyl.

37. R １ and R ２ However, together with the atoms bonded to them, 【Transformation 30】 The compound according to claim 30, which forms a compound.

38. R １ and R ２ However, together with the atoms bonded to them, 【Chemistry 31】 The compound according to claim 30, which forms a compound.

39. R １ and R ２ However, together with the atoms bonded to them, 【Chemistry 32】 The compound according to claim 30, which forms a compound.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

54. B, 【Transformation 33】 A compound according to any one of claims 1, 2, and 5 to 17, representing the compound.

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

56. R ５ａ , R ５ｂ , R ６ａ and R ６ｂ The compound according to any one of claims 1 to 55, wherein each of them is hydrogen.

57. R ５ａ , R ５ｂ , R ６ａ and R ６ｂ The compound according to any one of claims 1 to 55, wherein each of them is methyl.

58. R ５ａ is methyl, R ５ｂ , R ６ａ and R ６ｂ The compound according to any one of claims 1 to 55, wherein each of them is hydrogen.

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

60. R Ａ The compound according to any one of claims 1 and 4 to 20, wherein is hydrogen.

61. R Ａ The compound according to claim 60, wherein is methyl.

62. The aforementioned compound is given by the following formula (Ic): 【Transformation 34】 or having a pharmaceutically acceptable salt structure thereof, in the formula, R １ is, (C １ -C ６ ) alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, NR ａ R ｂ or 【Chemistry 35】 Selected from, Said (C １ -C ６ ) Alkyl and 4-7 member heterocycloalkyls are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Haloalkyl and (C １ -C ６ The compound according to claim 1, wherein it is optionally substituted with one or more substituents independently selected from the alkoxy.

63. The aforementioned compound is given by the following formula (Id) 【Transformation 36】 or having a pharmaceutically acceptable salt structure thereof, in the formula, R １ is, -CO ２ R ａ , -CONR ａ R ｂ , -SO ２ R ａ ,-SONR ａ R ｂ , -SO ２ NR ａ R ｂ , -NR ａ R ｂ , C ３ -C ８ ) Cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl or 【Chemistry 37】 Selected from, The aforementioned 4- to 7-membered heterocycloalkyls are, respectively, halo, hydroxy, oxo, cyano, amino, 4- to 7-membered heterocycloalkyls, 5- to 6-membered heteroaryls, carboxamides, sulfonamides, aminoalkyls, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Alkoxy and (C １ -C ６ ) optionally substituted with one or more substituents independently selected from hydroxyalkyl, R １ａ is hydrogen or (C １ -C ６ ) is alkyl, R ２ is hydrogen, cyano, hydroxyl, NH ２ , NHCOCH ３ NHR ａ , (C １ -C ６ ) Alkyl, -CONR ａ R ｂ , or halo, hydroxy, cyano, (C １ -C ６ ) Alkoxy and NR ａ R ｂ (C) optionally substituted with one or more substituents independently selected from １ -C ６ The compound according to claim 1, selected from alkyl groups.

64. The aforementioned compound is given by the following formula (Ie) 【Transformation 38】 The compound according to claim 1, or having the structure of a pharmaceutically acceptable salt thereof, wherein A represents a 4- to 7-membered heterocycloalkyl group.

65. R ３ However, methyl, n-propyl, n-butyl, 【Chemistry 39】 The compound according to any one of claims 1 to 64.

66. R ３ However, methyl, n-butyl, 【Chemistry 40】 The compound according to any one of claims 1 to 64.

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

68. The compound according to any one of claims 1 to 66, wherein the compound is represented by formula Ib. 【Request Item 69】 【Chemistry 41】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a compound having the structure of a pharmaceutically acceptable salt thereof. 【Request Item 70】 【Chemistry 42】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a compound having the structure of a pharmaceutically acceptable salt thereof. 【Request Item 71】 【Chemistry 43】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a compound having the structure of a pharmaceutically acceptable salt thereof. 【Request Item 72】 【Chemistry 44】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a compound having the structure of a pharmaceutically acceptable salt thereof.

73. Compounds according to the following formula (IIa) or (IIb) 【Chemistry 45】 or a pharmaceutically acceptable salt thereof During the ceremony, Y is, 【Chemistry 46】 This represents, X is N or CR ２ And, L is -(C １ -C ６ ) is alkylenyl, B is (C ３ -C ８ ) Cycloalkyl, (C ６ -C １０ ) represents an aryl or a 5- to 10-membered heteroaryl, each of which contains one or more (C １ -C ６ ) optionally substituted with alkyl, R １ is hydrogen, -CO ２ R ａ , -CONR ａ R ｂ , -SO ２ R ａ ,-SONR ａ R ｂ , -SO ２ NR ａ R ｂ , -NR ａ R, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Alkyl or 【Chemistry 47】 And the above (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Alkoxy and 4-7 member heterocycloalkyls are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Hydroxyalkyl and 【Chemistry 48】 It is optionally substituted with one or more substituents independently selected from; or, when Y represents -L-B-, R １ It, together with the atom bonded to it, forms a 4-7 membered heterocycloalkyl ring, where Y is 【Chemistry 49】 or (C １ -C ６ ) If it is alkylene, R １ The condition is that it is not hydrogen, R １ａ , R １ｂ and R １ｃ Each instance is independently of hydrogen or (C １ -C ６ ) Alkyl or R １ａ and R １ｂ However, together with the atoms bonded to them, they form a 5-membered or 6-membered heterocycloalkyl group. R ２ is hydrogen, fluoro, chloro, -CONR ａ R ｂ , or halo, hydroxy, cyano and (C １ -C ６ (C) optionally substituted with one or more substituents independently selected from the alkoxy １ -C ６ ) Alkyl or R １ and R ２ However, together with the atoms bonded to them, they form a 4-7 member heterocycloalkyl group. R ３ is, (C １ -C ６ ) alkyl or (C ３ -C ８ ) are cycloalkyl, and each of them is a halo, hydroxy, (C １ -C ６ ) Alkoxy, (C ３ -C ８ ) optionally substituted with one or more substituents independently selected from cycloalkyl, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl groups, R ａ and R ｂ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl or 4-7 member heterocycloalkyl, and the (C １ -C ６ ) Alkyl and 4-7 member heterocycloalkyl groups are halo, hydroxy, cyano, (C １ -C ６ ) optionally substituted with one or more substituents independently selected from alkoxy, 4- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl; or R ａ and R ｂ These, together with the nitrogen atoms bonded to them, form a 4-7 member heterocycloalkyl group. n, m, and p are independently 0 or 1. q is 0, 1, or 2. However, provided that the sum of p and q is equal to 0, 1, or 2, Z is either S or O, R ４ is H, -C(O)NH ２ , (C １ -C ６ ) alkyl, -NHSO ２ Me or -N(R) ４ａ ) ２ And, R ４ａ Each instance is independently of hydrogen or (C １ -C ６ ) is alkyl, The aforementioned compound or a pharmaceutically acceptable salt thereof.

74. Y, [Transformation 50] The compound according to claim 73, which represents the compound described in claim 73.

75. Y, 【Chemistry 51】 The compound according to claim 74, which represents the compound described in claim 74.

76. R １ but, 【Chemistry 52】 The compound according to any one of claims 73 to 75.

77. R １ but, 【Chemistry 53】 The compound according to any one of claims 73 to 75.

78. R １ but, hydrogen, 【Chemistry 54】 And, During the ceremony, R １ｄ , R １ｅ and R １ｆ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl and (C １ -C ６ ) Selected from alkoxy; or R １ｄ and R １ｅ However, together with the carbon atoms bonded to them, (C ３ -C ８ The compound according to any one of claims 73 to 77, which forms a cycloalkyl or a 3- to 7-membered heterocycloalkyl.

79. R １ but 【Transformation 55】 And, R １ｄ and R １ｅ The compound according to claim 78, wherein, together with the carbons bonded to them, it forms morpholine, cyclobutane, oxetane, or cyclohexane.

80. R １ｄ and R １ｅ The compound according to claim 79, wherein each of them is methyl.

81. R １ｆ The compound according to any one of claims 78 to 80, wherein is hydrogen.

82. R １ｆ But (C １ -C ６ The compound according to any one of claims 78 to 80, wherein it is alkyl.

83. R １ｆ The compound according to claim 82, wherein the compound is methyl or ethyl.

84. R １ｆ But (C １ -C ６ The compound according to any one of claims 78 to 80, wherein it is a fluoroalkyl compound.

85. R １ｆ The compound according to claim 84, wherein is 2,2,2-trifluoroethyl.

86. R １ but, hydrogen, 【Transformation 56】 The compound according to any one of claims 73 to 77.

87. Y, 【Chemistry 57】 The compound according to any one of claims 73 to 86.

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

89. X is CR ２ The compound according to any one of claims 73 and 74 to 84.

90. R ２ The compound according to claim 89, wherein is hydrogen.

91. R ２ The compound according to claim 89, wherein is fluoro.

92. R ２ However, (C １ -C ６ (C) optionally substituted with alkoxy １ -C ６ The compound according to claim 89, wherein it is alkyl.

93. R ２ The compound according to claim 92, wherein is methyl.

94. R ２ The compound according to claim 92, wherein is methoxymethyl.

95. R １ but, 【Transformation 58】 And, R ２ However, -CH ３ or -CH ２ - OCH ３ The compound according to claim 89.

96. R １ and R ２ The compound according to claim 89, wherein the atoms bonded to them combine to form a 4- to 7-membered heterocycloalkyl group.

97. R １ and R ２ However, together with the atoms bonded to them, 【Chemistry 59】 The compound according to claim 96, which forms a compound.

98. R ３ However, methyl, 【Transformation 60】 The compound according to any one of claims 73 to 97.

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

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

101. R ４ A compound according to any one of claims 73 to 100, wherein is H.

102. R ４ NH ２ The compound according to any one of claims 73 to 100. 【Request Item 103】 【Chemistry 61】 【change】 【change】 【change】 or a compound having the structure of a pharmaceutically acceptable salt thereof. 【Request Item 104】 【Chemistry 62】 【change】 or a compound having the structure of a pharmaceutically acceptable salt thereof. 【Request Item 105】 【Chemistry 63】 【change】 or a compound having the structure of a pharmaceutically acceptable salt thereof.

106. Compounds according to the following formulas (IIIa), (IIIb), (IIIc), or (IIId), 【Chemistry 64】 or a pharmaceutically acceptable salt thereof During the ceremony, Y-R １ teeth, 【Transformation 65】 or -(C １ -C ６ ) Alkilen-R １ This represents, X is N or CR ２ And, L is -(C １ -C ６ ) is alkylenyl, B is (C ３ -C ８ ) Cycloalkyl, (C ６ -C １０ ) represents an aryl or a 5- to 10-membered heteroaryl, each of which contains one or more (C １ -C ６ ) optionally substituted with alkyl, R １ is hydrogen, -CO ２ R ａ , -CONR ａ R ｂ , -SO ２ R ａ ,-SONR ａ R ｂ , -SO ２ NR ａ R ｂ , -NR ａ R, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Alkyl or 【Chemical Formula 66】 And the above (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Alkoxy and 4-7 member heterocycloalkyls are respectively halo, hydroxy, oxo, cyano, amino, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Cycloalkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Hydroxyalkyl and 【Transformation 67】 It is optionally substituted with one or more substituents independently selected from; or, when Y represents -L-B-, R １ It, together with the atom bonded to it, forms a 4-7 membered heterocycloalkyl ring, where Y is 【Transformation 68】 or (C １ -C ６ ) If it is alkylene, R １ The condition is that it is not hydrogen, R １ａ , R １ｂ and R １ｃ Each instance is independently of hydrogen or (C １ -C ６ ) Alkyl or R １ａ and R １ｂ However, together with the atoms bonded to them, they form a 5-membered or 6-membered heterocycloalkyl group. R ２ is hydrogen, fluoro, chloro, -CONR ａ R ｂ , or halo, hydroxy, cyano and (C １ -C ６ (C) optionally substituted with one or more substituents independently selected from the alkoxy １ -C ６ ) Alkyl or R １ and R ２ However, together with the atoms bonded to them, they form a 4-7 member heterocycloalkyl group. R ３ is, (C １ -C ６ ) alkyl or (C ３ -C ８ ) are cycloalkyl, and each of them is a halo, hydroxy, (C １ -C ６ ) Alkoxy, (C ３ -C ８ ) optionally substituted with one or more substituents independently selected from cycloalkyl, carboxamide, amino, cyano, carboxy, and alkoxycarbonyl groups, R ａ and R ｂ Each instance is independently of hydrogen, (C １ -C ６ ) alkyl or 4-7 member heterocycloalkyl, and the (C １ -C ６ ) Alkyl and 4-7 member heterocycloalkyl groups are halo, hydroxy, cyano, (C １ -C ６ ) optionally substituted with one or more substituents independently selected from alkoxy, 4- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl; or R ａ and R ｂ These, together with the nitrogen atoms bonded to them, form a 4-7 member heterocycloalkyl group. n, m, and p are independently 0 or 1. q is 0, 1, or 2. However, provided that the sum of p and q is equal to 0, 1, or 2, R ４ is H or N (R ４ａ ) ２ And, R ４ａ However, each instance is independent of hydrogen or (C １ -C ６ ) is alkyl, The aforementioned compound or a pharmaceutically acceptable salt thereof.

107. R １ but, hydrogen, 【Transformation 69】 The compound according to claim 106.

108. R １ but, 【Transformation 70】 And, R ２ However, -CH ３ or -CH ２ - OCH ３ The compound according to claim 106.

109. R １ but, 【Chemistry 71】 The compound according to claim 106.

110. R １ but, 【Chemistry 72】 The compound according to claim 106.

111. Y, 【Transformation 73】 The compound according to any one of claims 106 to 110.

112. R ３ However, methyl, 【Chemistry 74】 The compound according to any one of claims 106 to 111.

113. R ４ The compound according to any one of claims 106 to 110, wherein is H.

114. R ４ NH ２ The compound according to any one of claims 106 to 110. 【Request Item 115】 【Chemistry 75】 or a compound having the structure of a pharmaceutically acceptable salt thereof.

116. A pharmaceutical composition comprising a compound according to 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, fractures, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia, or neoplastic calcification, comprising administering an effective amount of a compound according to any one of claims 1 to 115, or a pharmaceutically acceptable salt thereof, to a subject requiring such treatment or prevention.

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