Compounds, compositions and methods of use for treating parathyroid hypofunction and osteoporosis

Abstract

Disclosed are compounds that are parathyroid hormone receptor 1 agonists, and methods for the prevention or treatment of osteoporosis, bone fractures, osteomalacia, arthritis, thrombocytopenia, parathyroid hypofunction, hyperphosphatemia, or neoplastic calcaremia.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 418,754, filed on October 24, 2022, U.S. Provisional Application No. 63 / 464,457, filed on May 5, 2023, and U.S. Provisional Application No. 63 / 532,181, filed on August 11, 2023, each of which is incorporated herein by reference in its entirety. Background of the Invention

[0004] Regulation of calcium concentration is important for the normal function of the gastrointestinal tract, skeletal system, nervous system, musculo-neural system and cardiovascular system. Parathyroid hormone (PTH) synthesis and release are mainly controlled by serum calcium levels.

[0005] Osteoporosis is characterized by bone loss, causes fracture incidence to increase.This disease is most common in spine and hip, and 1 / 3 postmenopausal women are affected, though the affected number of elderly men is less, but also quite a lot, and this disease is also caused by other diseases including hypogonadism and long-term use of glucocorticoids.Current treatment of osteoporosis therapy, such as bisphosphonates, hormone replacement therapy, SERM and calcitonin, stops further bone loss by inhibiting bone resorption.Although these treatments can slow down or even prevent continuous bone loss, the new bone formation causing bone quality and strength increase will not occur.Therefore, still need a kind of therapeutic agent that can stimulate bone formation.Described therapeutic agent is all useful for the risk of suffering from osteoporosis or the patient of having diagnosed osteoporosis.

[0006] Parathyroid hormone (PTH) is an important regulator of calcium homeostasis and works in part by mobilizing calcium in the skeleton by increasing bone resorption. In addition, pulsed administration of PTH can stimulate new bone formation in laboratory animals and humans. Therefore, there is evidence that targeting PTH receptors with small molecule agonists that mimic the effects of PTH would be a suitable method for producing anabolic reactions in bone. PTH exerts its effect by binding to and activating the class B G protein-coupled receptor (called PTH1R) of the 7-transmembrane superfamily. PTH1R activates multiple signal transduction pathways, but primarily adenylate cyclase / cyclic AMP and phospholipase C / calcium mobilization pathways.

[0007] Therefore, there is a need in the art to provide small molecule therapeutics for treating or preventing hypoparathyroidism, osteoporosis, and related disorders. In particular, there is a need to provide compounds that act as PTH1R agonists. Summary of the Invention

[0008] One aspect of the invention provides compounds, compositions and methods for preventing or treating or preventing osteoporosis, bone fractures, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumor calcification.

[0009] Thus, in some embodiments, provided herein is a compound having the structure of Formula (Ia) or (Ib):

[0010]

[0011] or a pharmaceutically acceptable salt thereof;

[0012] in:

[0013] Z is O or S;

[0014] Y means:

[0015]

[0016]

[0017] X is N or CR 2 ;

[0018] L is -(C1-C6)alkylene-;

[0019] B represents (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 instances of (C1-C6)alkyl;

[0020] R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, or -O-(4- to 7-membered heterocycloalkyl); wherein (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1-C6) alkoxy, 4 to 7 membered heterocycloalkyl and -O-(4 to 7 membered heterocycloalkyl) are each optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, phenyl, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, hydroxy (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl, (C3-C8)cycloalkyl (C1-C6)alkyl and benzyl; or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is Then R 1 Not hydrogen;

[0021] R 1a 、R 1b and R 1c is independently hydrogen at each occurrence, (C 1- C6)alkyl or (C3-C8)cycloalkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group;

[0022] R 2 For hydrogen, fluorine, chlorine, cyano, hydroxyl, NH2, NHCO (C1-C6) alkyl, NHR a 、(C 1- C6) alkoxy, -CONR a R b or (C 1- C6) alkyl, wherein (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b ; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 9-membered heterocycloalkyl group optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, wherein said (C1-C6)alkyl group is further optionally substituted with: (C1-C6)alkyl; 3- C8) cycloalkyl, 4 to 7 membered heterocyclylalkyl, hydroxy, halo, (C 1- C6) alkoxy, cyano, carboxyl, -CONR a R b and-SO2R a ;

[0023] R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, aryl, carboxamide, amino, cyano, carboxyl and alkoxycarbonyl;

[0024] R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group;

[0025] R 5a 、R 5b 、R 6a and R 6b are independently hydrogen or (C 1- C6) alkyl;

[0026] R A is hydrogen or (C 1- C6) alkyl;

[0027] n, m and p are independently 0 or 1; and

[0028] q is 0, 1, or 2;

[0029] The condition is that the sum of p and q is equal to 0, 1 or 2.

[0030] In some embodiments, provided herein is a compound having the structure of Formula (Ia) or (Ib):

[0031]

[0032] or a pharmaceutically acceptable salt thereof;

[0033] in:

[0034] Y means:

[0035]

[0036] X is N or CR2 ;

[0037] L is -(C1-C6)alkylene-;

[0038] B represents (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 instances of (C1-C6)alkyl;

[0039] R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, or -O-(4- to 7-membered heterocycloalkyl); wherein (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, 4 to 7 membered heterocycloalkyl and -O-(4 to 7 membered heterocycloalkyl) are each optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, hydroxy (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl, (C3-C8)cycloalkyl (C1-C6)alkyl and benzyl; or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is Then R 1 Not hydrogen;

[0040] R 1a 、R 1b and R 1c is independently hydrogen at each occurrence, (C 1- C6)alkyl or (C3-C8)cycloalkyl; or R1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group;

[0041] R 2 For hydrogen, fluorine, chlorine, cyano, hydroxyl, NH2, NHCO (C1-C6) alkyl, NHR a 、(C 1- C6) alkoxy, -CONR a R b or (C 1- C6) alkyl, wherein (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b ; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 9-membered heterocycloalkyl group optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, wherein said (C1-C6)alkyl group is further optionally substituted with: (C1-C6)alkyl; 3- C8) cycloalkyl, 4 to 7 membered heterocyclylalkyl, hydroxy, (C 1- C6) alkoxy, cyano, carboxyl, -CONR a R b and-SO2R a ;

[0042] R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, aryl, carboxamide, amino, cyano, carboxyl and alkoxycarbonyl;

[0043] R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group;

[0044] R 5a 、R 5b 、R 6a and R 6b are independently hydrogen or (C 1- C6) alkyl;

[0045] n, m and p are independently 0 or 1; and

[0046] q is 0, 1, or 2;

[0047] The condition is that the sum of p and q is equal to 0, 1 or 2.

[0048] In other embodiments, provided herein is a compound according to Formula (Ia) and (Ib):

[0049]

[0050] or a pharmaceutically acceptable salt thereof;

[0051] in:

[0052] Y means:

[0053]

[0054]

[0055] X is N or CR 2 ;

[0056] L is -(C1-C6)alkylene-;

[0057] B represents (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 instances of (C1-C6)alkyl;

[0058] R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy or Among them (C 1-C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy and 4 to 7 membered heterocycloalkyl are each optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, and (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl and Or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is Then R 1 Not hydrogen;

[0059] R 1a 、R 1b and R 1c is independently hydrogen or (C 1- C6) alkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group;

[0060] R 2 For hydrogen, fluorine, chlorine, cyano, hydroxyl, NH2, NHCO (C1-C6) alkyl, NHR a 、(C 1- C6) alkoxy, -CONR a R b or (C 1- C6) alkyl, said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b ; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 7-membered heterocycloalkyl group;

[0061] R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, carboxamido, amino, cyano, carboxyl and alkoxycarbonyl;

[0062] R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group;

[0063] n, m and p are independently 0 or 1; and

[0064] q is 0, 1, or 2;

[0065] The condition is that the sum of p and q is equal to 0, 1 or 2.

[0066] In other embodiments, provided herein is a compound according to formula (IIa) or (IIb):

[0067]

[0068] or a pharmaceutically acceptable salt thereof;

[0069] in:

[0070] Y means:

[0071]

[0072]

[0073] X is N or CR 2 ;

[0074] L is -(C1-C6)alkylene-;

[0075] B represents (C3-C8) cycloalkyl, (C6-C 10 )aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl;

[0076] R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NRa R, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy or Among them (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy and 4 to 7 membered heterocycloalkyl are each optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, and (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl and Or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is or (C1-C6) alkylene, then R 1 Not hydrogen;

[0077] R 1a 、R 1b and R 1c is independently hydrogen or (C 1- C6) alkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group;

[0078] R 2 For hydrogen, fluorine, chlorine, -CONR a R b or (C 1- C6) alkyl, said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, and (C 1- C6) alkoxy; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 7-membered heterocycloalkyl group;

[0079] R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C3- C8) cycloalkyl, carboxamido, amino, cyano, carboxyl and alkoxycarbonyl;

[0080] R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group;

[0081] n, m and p are independently 0 or 1;

[0082] q is 0, 1, or 2;

[0083] The condition is that the sum of p and q is equal to 0, 1 or 2;

[0084] Z is S or O;

[0085] R 4 H、-C(O)NH2、(C 1- C6) alkyl or -N(R 4a )2; and

[0086] R 4a is independently hydrogen or (C 1- C6) alkyl.

[0087] In other embodiments, provided herein is a compound according to Formula (IIIa), (IIIb), (IIIc), or (IIId):

[0088]

[0089] or a pharmaceutically acceptable salt thereof; wherein:

[0090] YR 1 express:

[0091] or -(C1-C6)alkylene-R 1 ;

[0092] X is N or CR 2 ;

[0093] L is -(C1-C6)alkylene-;

[0094] B represents (C3-C8) cycloalkyl, (C6-C 10 )aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl;

[0095] R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy or Among them (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy and 4 to 7 membered heterocycloalkyl are each optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, and (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl and Or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is or (C1-C6) alkylene, then R 1 Not hydrogen;

[0096] R 1a 、R 1b and R 1c is independently hydrogen or (C 1- C6) alkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group;

[0097] R 2 For hydrogen, fluorine, chlorine, -CONR a R b or (C 1- C6) alkyl, said (C1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, and (C 1- C6) alkoxy; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 7-membered heterocycloalkyl group;

[0098] R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, carboxamido, amino, cyano, carboxyl and alkoxycarbonyl;

[0099] R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group;

[0100] n, m and p are independently 0 or 1;

[0101] q is 0, 1, or 2;

[0102] The condition is that the sum of p and q is equal to 0, 1 or 2;

[0103] R 4 H or N(R 4a )2; and

[0104] R 4a is independently hydrogen or (C 1- C6) alkyl.

[0105] Other aspects of the present disclosure provide a pharmaceutical composition comprising a compound of Formula (Ia) to (IIId) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0106] In other aspects, provided herein is a method for treating or preventing osteoporosis, bone fractures, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia, or tumor calcification, comprising administering to a subject in need thereof an effective amount of a compound of Formula (Ia) to (IIId) or a pharmaceutically acceptable salt thereof.

[0107] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present invention belongs. Although methods and materials similar or equivalent to those described herein can be used for practice or testing the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. In the event of conflict, the present invention (including definitions) will be taken as the criterion. In addition, materials, methods and embodiments are merely illustrative and are not intended to be restrictive.

[0108] Other features, objects, and advantages of the invention will be apparent from the following description and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0109] Figure 1 The table shows exemplary compounds 1 to 105 of the present invention along with their characterization data and biological activities.

[0110] Figure 2 Exemplary compounds 106 to 191 are tabulated along with their characterization data and biological activities.

[0111] Figure 3 Exemplary compounds 192 to 295 are tabulated along with their characterization data and biological activities.

[0112] Figure 4 Exemplary compounds 296 to 362 are tabulated along with their characterization data and biological activities. DETAILED DESCRIPTION

[0113] definition

[0114] For convenience, before further describing the present invention, certain terms used in this specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0115] To facilitate understanding of the present invention, certain terms and phrases are defined below and throughout the specification.

[0116] The articles "a" and "an" are used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0117] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, that is, elements that are present in combination in some cases and not in combination in other cases. Multiple elements listed using "and / or" should be interpreted in the same manner, that is, "one or more" of the elements so combined. Additional elements may optionally be present, whether related or unrelated to those specifically identified, in addition to the elements specifically identified by the "and / or" clause. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open language such as "comprising," may refer to A alone (optionally including elements other than B) in one embodiment; to B alone (optionally including elements other than A) in another embodiment; to both A and B (optionally including other elements) in another embodiment; etc.

[0118] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, that is, including at least one of a plurality or series of elements and more than one and optionally additional unlisted items. Only terms that indicate the opposite, such as "only one of..." or "exactly one of..." or "consisting of..." when used in the claims, will refer to including exactly one element of a plurality or series of elements. In general, the term "or" as used herein should be interpreted as indicating exclusive alternatives (that is, "one or the other, but not both") only when it is preceded by an exclusive term such as "either," "one of...", "only one of..." or "exactly one of...". When used in the claims, "consisting essentially of..." should have its ordinary meaning as used in the field of patent law.

[0119] As used in this specification and claims, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but does not necessarily include at least one of each and every element specifically listed in the list of elements, and does not necessarily exclude any combination of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or equivalently "at least one of A or B" or equivalently "at least one of A and / or B") may refer to at least one (optionally including more than one) A without B (and optionally including elements other than B) in one embodiment; at least one (optionally including more than one) B without A (and optionally including elements other than A) in another embodiment; at least one (optionally including more than one) A and at least one (optionally including more than one) B (and optionally including other elements) in another embodiment; etc.

[0120] It should also be understood that, unless expressly indicated to the contrary, in any method claimed herein that includes more than one step or operation, the order in which the steps or operations of the method are described is not necessarily limited to the order in which the steps or operations of the method are recited.

[0121] In the claims and throughout the foregoing description, all transitional phrases such as "comprising," "including," "with," "having," "containing," "involving," "containing," "consisting of," and the like are to be construed as open, that is, meaning including, but not limited to, including. Only the transitional phrases "consisting of" and "consisting essentially of" are to be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0122] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention encompasses all such compounds within the scope of the present invention, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric 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.

[0123] "Geometric isomers" means isomers that differ in the orientation of substituent atoms relative to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic ring system. The atoms on each side of a carbon-carbon double bond (other than H) may be in the E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans" indicate configuration relative to the core molecule. Certain of the disclosed compounds may exist in "atropisomeric" or "atrisomeric" form. Atropisomers are stereoisomers resulting from hindered rotation about a single bond, where the steric strain barrier to rotation is sufficiently high to allow separation of the configurational isomers. The compounds of the present invention can be prepared as individual isomers by isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include formation of salts of the free bases of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), formation of salts of the acid forms of each isomer of the isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), formation of esters or amides of each isomer of the isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolution of isomeric mixtures of starting materials or final products using various well-known chromatographic methods.

[0124] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by separation of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, after which the pure enantiomers are recovered.

[0125] The percent purity by mole fraction is the ratio of the moles of an enantiomer (or diastereomer) to the moles of an enantiomer (or diastereomer) plus the moles of its optical isomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction.

[0126] When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has at least one chiral center, it is understood that the name or structure encompasses the enantiomer of the compound free of the corresponding optical isomer, the racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry and has two or more chiral centers, it is understood that the name or structure encompasses the diastereomer free of the other diastereomers, multiple diastereomers free of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomers, or mixtures of diastereomers in which one or more diastereomers are enriched relative to the other diastereomers. The present invention encompasses all of these forms.

[0127] Structures depicted herein are also meant 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 13 C or 14 Compounds produced by enriching carbon in place of carbon are within the scope of the present invention.

[0128] As used herein, the term "prodrug" encompasses compounds that are converted to therapeutically active agents under physiological conditions. A common method for making prodrugs includes hydrolysis under physiological conditions to reveal selected portions of the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[0129] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which participates in carrying or transporting a target chemical from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not harmful to the patient, and substantially non-pyrogenic. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, , safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, 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) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, that is, they do not induce a significant increase in temperature when administered to a patient.

[0130] The term "pharmaceutically acceptable salt" refers to the relatively nontoxic inorganic and organic acid addition salts of the compound. These salts can be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound in the form of a free alkali with a suitable organic or inorganic acid and separating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate and laurylsulfonate, etc. (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J.Pharm.Sci.66:1-19).

[0131] In other cases, the compound that can be used in the method of the present invention may contain one or more acidic functional groups, and therefore can form a pharmaceutically acceptable salt together with a pharmaceutically acceptable base. In these cases, the term "pharmaceutically acceptable salt" refers to the relatively nontoxic inorganic and organic base addition salts of one or more compounds. These salts can also be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound in the form of a free acid with a suitable base (such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation), ammonia or a pharmaceutically acceptable organic primary amine, secondary amine or tertiary amine. Representative alkali metal salts or alkaline earth metal salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts. Representative organic amines suitable for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., supra).

[0132] The term "pharmaceutically acceptable co-crystal" refers to a solid coformer that does not form formal ionic interactions with a small molecule.

[0133] A "therapeutically effective amount" (or "effective amount") of a compound with respect to use in therapy means that amount of the compound in a preparation which, when administered (to a mammal, preferably a human) as part of a desired dosage regimen, will relieve symptoms, ameliorate symptoms, or slow the onset of a disease condition, according to clinically acceptable standards for the condition or disorder being treated, or for cosmetic purposes, for example, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0134] The terms "prophylactic or therapeutic" treatment are recognized in the art and include administering one or more of the compositions of interest to a host. If administered before clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition in the host animal), the treatment is prophylactic (i.e., it protects the host from developing the undesirable condition), while if administered after manifestation of the undesirable condition, the treatment is therapeutic (i.e., intended to alleviate, ameliorate, or stabilize an existing undesirable condition or its side effects).

[0135] The term "patient" or "subject" refers to a mammal in need of a specific treatment. In certain embodiments, the patient is a primate, a dog, a cat, or a horse. In certain embodiments, the patient is a human.

[0136] Aliphatic chains include the categories of alkyl, alkenyl and alkynyl as defined below. Aliphatic straight chains are limited to the unbranched carbon chain portion. As used herein, the term "aliphatic" refers to a straight chain, branched chain or cycloaliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl or alkynyl.

[0137] If not specified, "alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms or up to 30 carbon atoms. For example, an alkyl group having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as those that are positional isomers of these moieties. Alkyl groups having 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, a straight or branched alkyl group has 30 or fewer carbon atoms at its backbone (e.g., C1-C1 for a straight chain). 30 ; For branched chains, it is C3-C 30 ), and more preferably 20 or fewer carbon atoms. The alkyl group may be substituted or unsubstituted.

[0138] As used herein, the term "heteroalkyl" refers to an alkyl moiety as defined above containing one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in the place of a carbon atom.

[0139] As used herein, the term "haloalkyl" refers to an alkyl group as defined above that is substituted with at least one halogen.

[0140] As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined above substituted with at least one hydroxy group.

[0141] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms, for example, 2 to 12 carbon atoms, which contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene (-(CH2)-), ethylene (-(CH2CH2)-), n-propylene (-(CH2CH2CH2)-), isopropylene (-(CH2CH(CH3))-), and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moieties, and can be optionally substituted with one or more substituents.

[0142] "Cycloalkyl" means a monocyclic or bicyclic or bridged or spirocyclic or polycyclic saturated carbocyclic ring, each having 3 to 12 carbon atoms. Preferred cycloalkyl groups have 3 to 10 carbon atoms in their ring structure, and more preferably have 3 to 6 carbon atoms in the ring structure. Cycloalkyl groups can be substituted or unsubstituted.

[0143] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group as defined above that is substituted with at least one halogen.

[0144] "Cycloheteroalkyl" refers to a cycloalkyl moiety as defined above containing one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of a carbon atom. Preferred cycloheteroalkyl groups have from 4 to 8 carbon atoms and heteroatoms in their ring structure, and more preferably have from 4 to 6 carbon atoms and heteroatoms in the ring structure. Cycloheteroalkyl groups can be substituted or unsubstituted.

[0145] Unless otherwise specified, "lower alkyl" as used herein means an alkyl group as defined above but having one to ten carbon atoms, more preferably one to six carbon atoms, in its backbone 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, the substituents designated as alkyl groups herein are lower alkyl groups.

[0146] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the specified number of carbon atoms, or up to 26 carbon atoms when no limitation on the number of carbon atoms is specified, and having one or more double bonds in the moiety. Alkenyl groups of 6 to 26 carbon atoms are exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl (in their various isomeric forms), wherein the one or more unsaturated bonds may be located anywhere in the moiety and may have a (Z) or (E) configuration around the one or more double bonds.

[0147] "Alkynyl" refers to a hydrocarbon portion of the alkenyl category, but having one or more triple bonds in the portion.

[0148] As used herein, the term "aryl" includes 3 to 12 substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is carbon (i.e., carbocyclic aryl) or wherein one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl includes 5 to 12 membered rings, more preferably 6 to 10 membered rings. The term "aryl" also includes polycyclic ring systems with two or more cyclic rings, wherein two or more carbon atoms are shared by two adjacent rings, wherein at least one of the rings is aromatic, for example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic group. Carbocyclic aryl includes benzene, naphthalene, phenanthrene, phenol, aniline, etc. Heteroaryl includes substituted or unsubstituted aromatic 3 to 12 membered ring structures, more preferably 5 to 12 membered rings, more preferably 5 to 10 membered rings, and its ring structure includes one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. Aryl and heteroaryl groups may be monocyclic, bicyclic, or polycyclic.

[0149] As used herein, the term "halo", "halide" or "halogen" means a halogen and includes, for example and without limitation, fluorine, chlorine, bromine, iodine, etc. in both radioactive and non-radioactive forms. In a preferred embodiment, the halo is selected from the group consisting of fluorine, chlorine and bromine.

[0150] The term "heterocyclyl" or "heterocyclic group" or "heterocycloalkyl" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, more preferably a 5- to 10-membered ring, containing one to four heteroatoms. The heterocycle may be monocyclic, bicyclic, spirocyclic or polycyclic. Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiol, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams (such as azetidinone), and pyrrolidinones, sultams, sultones, and the like. The heterocycle may be substituted at one or more positions with substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silanyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0151] The term "substituted" refers to a portion having a substituent replacing hydrogen on one or more carbons of the main chain. It should be understood that "replacement" or "substituted" includes implicit restrictions, i.e., the substitution is consistent with the allowed valence of the substituted atom and the substituent, and the substitution produces a stable compound, for example, it will not spontaneously transform such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Permissible substituents can be one or more and can be the same or different for suitable organic compounds. For purposes of the present invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of an organic compound described herein that meet the heteroatom valence. Substituents may include any substituent described herein, for example, halogen, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidino, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl or aromatic or heteroaromatic moieties. In preferred embodiments, the substituents on the substituted alkyl group are selected from C 1-6 Alkyl, C 3-6 In some embodiments, the substituted alkyl group is selected from fluoro, fluoro, fluorocarbon ...

[0152] As used herein, when the definitions of each expression, such as alkyl, m, n, etc., occur more than one time in any structure, it is intended to be independent of its definition elsewhere in the same structure.

[0153] As used herein, "small molecule" refers to an organic or inorganic small molecule with a molecular weight lower than about 3,000 Daltons. Generally speaking, small molecules suitable for use in the present invention have a molecular weight less than 3,000 Daltons (Da). Small molecules can, for example, be at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).

[0154] In some embodiments, "small molecule" refers to an organic, inorganic, or organometallic compound that generally has a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound having a size of about 1 nm. In some embodiments, the small molecule drugs of the present invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0155] An "effective amount" is an amount sufficient to achieve a beneficial or desired result. For example, a therapeutic amount is an amount that achieves the desired therapeutic effect. This amount may be the same as or different from a prophylactic effective amount, which is the amount necessary to prevent the onset of a disease or disease symptoms. An effective amount can be administered in one or more administrations, applications, or dosage forms. The therapeutically effective amount of a composition depends on the composition selected. The composition can be administered from one or more times daily to one or more times weekly, including once every other day. The skilled artisan will appreciate that certain factors may affect the dosage and time course required to effectively treat a subject, including, but not limited to, the severity of the disease or condition, previous treatments, the general health and / or age of the subject, and the presence of other diseases. In addition, treating a subject with a therapeutically effective amount of a composition described herein may include a single treatment or a series of treatments.

[0156] The terms "reduce," "reduced," "reduction," "lower," and "inhibit" are all generally used herein to mean a decrease by a statistically significant amount relative to a reference. However, for the avoidance of doubt, "reduce," "reduction," or "lower" or "inhibit" generally means a decrease of at least 10% compared to a reference level, and can include, for example, a decrease 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%, at least about 99%, up to and including, for example, the complete absence of a given entity or parameter, or any decrease between 10-99% compared to the absence of a given treatment.

[0157] The terms "increased," "increase," "enhance," or "activate" are all generally used herein to mean an increase by a statistically significant amount; for the avoidance of any doubt, the terms "increased," "increase," "enhance," or "activate" mean an increase of at least 10% compared to a reference level, such as an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% compared to a reference level, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold, or any increase between 2-fold and 10-fold, or more compared to a reference level.

[0158] As used herein, the term "modulate" includes upregulation and downregulation, eg, enhancing or inhibiting a response.

[0159] As defined herein, "radiopharmaceutical" refers to a pharmaceutical agent containing at least one radioactive isotope that emits radiation. Radiopharmaceuticals are routinely used in nuclear medicine for diagnosis and / or treatment of various diseases. Radiolabeled pharmaceutical agents, such as radiolabeled antibodies, contain a radioisotope (RI) that acts as a radioactive source. As considered herein, the term "radioisotope" includes metal radioisotopes and non-metal radioisotopes. Radioisotopes are selected based on the medical application of radiolabeled pharmaceutical agents. When radioisotopes are metal radioisotopes, chelating agents are typically used to bind the metal radioisotopes to the remainder of the molecule. When radioisotopes are non-metal radioisotopes, the non-metal radioisotopes are typically directly or via joints connected to the remainder of the molecule.

[0160] For purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87, inside cover.

[0161] Compounds of the present invention

[0162] In some embodiments, a compound of Formula (Ia) or (Ib) is provided:

[0163]

[0164] or a pharmaceutically acceptable salt thereof;

[0165] in:

[0166] Z is O or S;

[0167] Y means:

[0168]

[0169]

[0170] X is N or CR 2 ;

[0171] L is -(C1-C6)alkylene-;

[0172] B represents (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 instances of (C1-C6)alkyl;

[0173] R 1 For hydrogen, -CO2R a、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, or -O-(4- to 7-membered heterocycloalkyl); wherein (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, 4 to 7 membered heterocycloalkyl and -O-(4 to 7 membered heterocycloalkyl) are each optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, phenyl, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, hydroxy (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl, (C3-C8)cycloalkyl (C1-C6)alkyl and benzyl; or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is Then R 1 Not hydrogen;

[0174] R 1a 、R 1b and R 1c is independently hydrogen at each occurrence, (C 1- C6)alkyl or (C3-C8)cycloalkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group;

[0175] R 2 For hydrogen, fluorine, chlorine, cyano, hydroxyl, NH2, NHCO (C1-C6) alkyl, NHR a 、(C 1- C6) alkoxy, -CONR a R b or (C 1- C6) alkyl, wherein (C1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b ; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 9-membered heterocycloalkyl group optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, wherein said (C1-C6)alkyl group is further optionally substituted with: (C1-C6)alkyl; 3- C8) cycloalkyl, 4 to 7 membered heterocyclylalkyl, hydroxy, halo, (C 1- C6) alkoxy, cyano, carboxyl, -CONR a R b and-SO2R a ;

[0176] R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, aryl, carboxamide, amino, cyano, carboxyl and alkoxycarbonyl;

[0177] R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group;

[0178] R 5a 、R 5b 、R 6a and R 6b are independently hydrogen or (C 1- C6) alkyl;

[0179] R A is hydrogen or (C 1- C6) alkyl;

[0180] n, m and p are independently 0 or 1; and

[0181] q is 0, 1, or 2;

[0182] The condition is that the sum of p and q is equal to 0, 1 or 2.

[0183] In some embodiments, a compound of Formula (Ia) or (Ib) is provided:

[0184]

[0185] or a pharmaceutically acceptable salt thereof;

[0186] in:

[0187] Y means:

[0188]

[0189] X is N or CR 2 ;

[0190] L is -(C1-C6)alkylene-;

[0191] B represents (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 instances of (C1-C6)alkyl;

[0192] R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, or -O-(4- to 7-membered heterocycloalkyl); wherein (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, 4 to 7 membered heterocycloalkyl and -O-(4 to 7 membered heterocycloalkyl) are each optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1-C6) alkyl, (C3-C8) cycloalkyl, hydroxy (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl, (C3-C8)cycloalkyl (C1-C6)alkyl and benzyl; or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is Then R 1 Not hydrogen;

[0193] R 1a 、R 1b and R 1c is independently hydrogen at each occurrence, (C 1- C6)alkyl or (C3-C8)cycloalkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group;

[0194] R 2 For hydrogen, fluorine, chlorine, cyano, hydroxyl, NH2, NHCO (C1-C6) alkyl, NHR a 、(C 1- C6) alkoxy, -CONR a R b or (C 1- C6) alkyl, wherein (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b ; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 9-membered heterocycloalkyl group optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, wherein said (C1-C6)alkyl group is further optionally substituted with: (C1-C6)alkyl; 3- C8) cycloalkyl, 4 to 7 membered heterocyclylalkyl, hydroxy, (C 1- C6) alkoxy, cyano, carboxyl, -CONR a R b and-SO2R a ;

[0195] R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C1- C6) alkoxy, (C 3- C8) cycloalkyl, aryl, carboxamide, amino, cyano, carboxyl and alkoxycarbonyl;

[0196] R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group;

[0197] R 5a 、R 5b 、R 6a and R 6b are independently hydrogen or (C 1- C6) alkyl;

[0198] n, m and p are independently 0 or 1; and

[0199] q is 0, 1, or 2;

[0200] The condition is that the sum of p and q is equal to 0, 1 or 2.

[0201] In other embodiments, a compound of formula (Ia) or (Ib) is provided:

[0202]

[0203] or a pharmaceutically acceptable salt thereof;

[0204] in:

[0205] Y means:

[0206]

[0207]

[0208] X is N or CR 2 ;

[0209] L is -(C1-C6)alkylene-;

[0210] B represents (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 instances of (C1-C6)alkyl;

[0211] R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy or Among them (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy and 4 to 7 membered heterocycloalkyl are each optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, and (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl and Or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is Then R 1 Not hydrogen;

[0212] R 1a 、R 1b and R 1c is independently hydrogen or (C 1- C6) alkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group;

[0213] R 2 For hydrogen, fluorine, chlorine, cyano, hydroxyl, NH2, NHCO (C1-C6) alkyl, NHR a 、(C 1- C6) alkoxy, -CONR a R bor (C 1- C6) alkyl, said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b ; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 7-membered heterocycloalkyl group;

[0214] R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, carboxamido, amino, cyano, carboxyl and alkoxycarbonyl;

[0215] R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group;

[0216] n, m and p are independently 0 or 1; and

[0217] q is 0, 1, or 2;

[0218] The condition is that the sum of p and q is equal to 0, 1 or 2.

[0219] In a particular embodiment, Y represents:

[0220]

[0221] In other embodiments, Y represents:

[0222]

[0223] In other embodiments, Y represents:

[0224]

[0225] In some embodiments, R1 For: hydrogen,

[0226] in:

[0227] R 1d 、R 1e and R 1f is independently selected at each occurrence from hydrogen, (C 1- C6) alkyl, (C 1- C6) haloalkyl, (C 1- C6) hydroxyalkyl and (C 1- C6) alkoxy, wherein (C 1- C6)alkyl is further optionally substituted with (C3-C8)cycloalkyl or phenyl; or R 1d and R 1e Together with the carbon to which it is attached, it forms a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl, each of which is optionally substituted with hydroxy.

[0228] In some embodiments, R 1 For: hydrogen,

[0229] in:

[0230] R 1d 、R 1e and R 1f is independently selected at each occurrence from hydrogen, (C 1- C6) alkyl, (C 1- C6) haloalkyl and (C 1- C6) alkoxy; or R 1d and R 1e Together with the carbon to which it is attached, it forms a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl.

[0231] In some embodiments, R 1 for And: R a and R b Each is hydrogen, or R a is hydrogen; and R b It is a methyl group.

[0232] In some embodiments, R 1 For: hydrogen,

[0233] in:

[0234] R 1d 、R 1e and R 1fis independently selected at each occurrence from hydrogen, (C 1- C6) alkyl, (C 1- C6) haloalkyl, (C 1- C6) hydroxyalkyl and (C 1- C6) alkoxy, wherein (C 1- C6)alkyl is further optionally substituted with (C3-C8)cycloalkyl or phenyl; or R 1d and R 1e Together with the carbon to which it is attached, it forms a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl, each of which is optionally substituted with hydroxy.

[0235] In some embodiments, R 1 For: hydrogen,

[0236] in:

[0237] R 1d 、R 1e and R 1f is independently selected at each occurrence from hydrogen, (C 1- C6) alkyl, (C 1- C6) haloalkyl and (C 1- C6) alkoxy; or R 1d and R 1e Together with the carbon to which it is attached, it forms a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl.

[0238] In some embodiments, R 1 for and

[0239] R 1d and R 1e Together with the carbon to which it is attached, it forms a morpholine, cyclobutane, oxetane, azetidine, or cyclohexane.

[0240] In certain preferred embodiments, R 1d and R 1e Each is a methyl group.

[0241] In some preferred embodiments, R 1f In other preferred embodiments, R 1f For (C 1- C6) alkyl, preferably methyl or ethyl. In other embodiments, R 1f For (C 1- C6) fluoroalkyl, preferably 2,2,2-trifluoroethyl.

[0242] In some embodiments, R 1 for And R1a is cyclopropyl, 2-propyl, ethyl or methyl.

[0243] In some embodiments, R 1 For: hydrogen,

[0244] In some embodiments, R 1 for:

[0245]

[0246]

[0247] In certain embodiments, Y is

[0248]

[0249] In some embodiments, X is N, while in other embodiments, X is CR 2 .

[0250] In X is CR 2 In certain embodiments, R 2 is hydrogen, while in other embodiments, R 2 In a particularly preferred embodiment, R 2 For hydrogen.

[0251] In some embodiments, R 2 is optionally (C 1- C6) alkoxy substituted (C 1- C6) alkyl, preferably methyl or methoxymethyl.

[0252] In certain embodiments, R 1 for And R 2 It is -CH3 or -CH2-OCH3.

[0253] In some embodiments, R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 9-membered heterocycloalkyl, wherein the 4- to 9-membered heterocycloalkyl is optionally replaced by (C 1- C6) alkyl, wherein said (C 1- C6) alkyl is further optionally substituted with one or more substituents independently selected from the group consisting of: (C 3- C8) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, hydroxy, halo, (C 1- C6) alkoxy, cyano, carboxyl, -CONR a R b and-SO2Ra .

[0254] In some embodiments, wherein R 1 and R 2 Together with the atoms to which they are attached, they form:

[0255]

[0256] where R 1g and R 1h are each independently hydrogen or (C 1- C6) alkyl, wherein said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: (C 3- C8) cycloalkyl, 4 to 7 membered heterocyclylalkyl, hydroxy, halo, (C 1- C6) alkoxy, cyano, carboxyl, -CONR a R b and-SO2R a .

[0257] In some embodiments, R 1h is ethyl, methyl, propyl, isopropyl or tert-butyl, each of which is optionally substituted by hydroxy, methoxy, cyclopropyl, oxetanyl, tetrahydrofuranyl, phenyl, cyano, carboxyl, hydroxy, -CONR a R b 、-SO2R a or one to three fluorine atoms.

[0258] In some embodiments, R 1h It is trifluoromethyl.

[0259] In some embodiments, R 1g is hydrogen, methyl or ethyl, wherein the methyl or ethyl group is optionally substituted by a cyano group.

[0260] In some embodiments, R a In some embodiments, R b In other embodiments, R a and R b In certain preferred embodiments, R 1g is methyl or hydrogen.

[0261] In more specific embodiments, R 1 and R 2 Together with the atoms to which they are attached, they form:

[0262]

[0263] In some embodiments, R1 and R 2 Together with the atoms to which they are attached, they form:

[0264]

[0265] In other embodiments, R 1 and R 2 Together with the atoms to which they are attached, they form:

[0266]

[0267] In some embodiments, n is 1, while in other embodiments, n is 0.

[0268] In some embodiments, m is 1, while in other embodiments, m is 0.

[0269] In some embodiments, p is 1, while in other embodiments, p is 0.

[0270] In certain preferred embodiments, p is 0; and q is 2. In other preferred embodiments, n, m, p, and q are each 1. In other preferred embodiments, n, m, p, and q are each 0.

[0271] In some embodiments, B represents a 4- to 7-membered heterocycloalkyl group. In other specific embodiments, B represents a cyclohexyl group or a cyclopentyl group, while in other embodiments, B represents a phenyl group, a tolyl group, or a pyridyl group.

[0272] More specifically, in certain preferred embodiments, B represents:

[0273]

[0274] In some embodiments, L represents methylene, ethylene, or n-butylene.

[0275] In some preferred embodiments, R 5a 、R 5b 、R 6a and R 6b In other embodiments, R 5a 、R 5b 、R 6a and R 6b is each methyl, and in other embodiments, R 5a is methyl and R 5b 、R 6a and R 6b Each is hydrogen.

[0276] In some embodiments, Z is O.

[0277] In some embodiments, R A is hydrogen, while in other embodiments, R A It is a methyl group.

[0278] In some preferred embodiments, the compound has the structure of Formula (Ic):

[0279]

[0280] or a pharmaceutically acceptable salt thereof, wherein:

[0281] R 1 Selected from (C 1- C6) alkyl, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, NR a R b and

[0282] Among them (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl and (C 1- C6) alkoxy; and

[0283] R 1a is hydrogen or (C 1- C6) alkyl.

[0284] In other preferred embodiments, the compound has the structure of Formula (Id):

[0285]

[0286] or a pharmaceutically acceptable salt thereof, wherein

[0287] R 1 Selected from -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and

[0288]

[0289] wherein each of the 4 to 7 membered heterocycloalkyl groups is optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, (C 1- C6) alkoxy and (C 1- C6) hydroxyalkyl,

[0290] R 1a is hydrogen or (C 1- C6) alkyl, and

[0291] R 2 Selected from hydrogen, cyano, hydroxy, NH2, NHCOCH3, NHR a 、(C 1- C6) alkoxy, -CONR a R b or (C 1- C6) alkyl, said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b .

[0292] In other preferred embodiments, the compound has the structure of Formula (Ie):

[0293]

[0294] or a pharmaceutically acceptable salt thereof, wherein A represents a 4- to 7-membered heterocycloalkyl group.

[0295] In certain preferred embodiments, R 3 Methyl, n-propyl, n-butyl, And more preferably it is n-butyl.

[0296] In certain embodiments, the compound is represented by Formula Ia.

[0297] In other embodiments, the compound is represented by Formula Ib.

[0298] In some embodiments, the compound has the structure:

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313] or a pharmaceutically acceptable salt thereof.

[0314] In other embodiments, the compound has the structure:

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324] or a pharmaceutically acceptable salt thereof.

[0325] In other embodiments, the compound has the structure:

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336] or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, the compound has the structure:

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346] or a pharmaceutically acceptable salt thereof.

[0347] In some embodiments, a compound of formula (IIa) or (IIb) is provided:

[0348]

[0349] or a pharmaceutically acceptable salt thereof;

[0350] in:

[0351] Y means:

[0352]

[0353] X is N or CR 2 ;

[0354] L is -(C1-C6)alkylene-;

[0355] B represents (C3-C8) cycloalkyl, (C6-C 10 )aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl;

[0356] R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy or Among them (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy and 4 to 7 membered heterocycloalkyl are each optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, and (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl and Or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is or (C1-C6) alkylene, then R 1 Not hydrogen;

[0357] R 1a 、R 1b and R 1c is independently hydrogen or (C 1- C6) alkyl; or R 1a and R 1bTogether with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group;

[0358] R 2 For hydrogen, fluorine, chlorine, -CONR a R b or (C 1- C6) alkyl, said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, and (C 1- C6) alkoxy; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 7-membered heterocycloalkyl group;

[0359] R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, carboxamido, amino, cyano, carboxyl and alkoxycarbonyl;

[0360] R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group;

[0361] n, m and p are independently 0 or 1;

[0362] q is 0, 1, or 2;

[0363] The condition is that the sum of p and q is equal to 0, 1 or 2;

[0364] Z is S or O;

[0365] R 4 H、-C(O)NH2、(C 1- C6) alkyl, -NHSO2Me or -N(R 4a )2; and

[0366] R 4a is independently hydrogen or (C 1-C6) alkyl.

[0367] In certain embodiments, Y represents:

[0368]

[0369] In some embodiments, R 1 for:

[0370] In other embodiments, R 1 for

[0371] In some embodiments, R 1 For: hydrogen, and

[0372] R 1d 、R 1e and R 1f is independently selected at each occurrence from hydrogen, (C 1- C6) alkyl, (C 1- C6) haloalkyl and (C 1- C6) alkoxy; or R 1d and R 1e Together with the carbon to which it is attached, it forms a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl.

[0373] In certain embodiments, R 1 for And R 1d and R 1e Together with the carbon to which it is attached, it forms a morpholine, cyclobutane, oxetane, or cyclohexane.

[0374] In certain specific embodiments, R 1d and R 1e Each is a methyl group.

[0375] In certain specific embodiments, R 1f is hydrogen, while in other embodiments, R 1f For (C 1- C6) alkyl, more specifically, R 1f In other embodiments, R 1f For (C 1- C6) fluoroalkyl, such as R 1f It is 2,2,2-trifluoroethyl.

[0376] In certain specific embodiments, Y is

[0377]

[0378]

[0379] In some embodiments, X is N.

[0380] In other embodiments, X is CR 2 .

[0381] In certain preferred embodiments, R 2 In other embodiments, R 2 For fluorine.

[0382] In other embodiments, R 2 is optionally (C 1- C6) alkoxy substituted (C 1- C6) alkyl, preferably methyl or methoxymethyl.

[0383] In certain embodiments, R 1 for And R 2 is methyl or methoxymethyl.

[0384] In certain embodiments, R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 7-membered heterocycloalkyl. More specifically, in some embodiments, R 1 and R 2 Together with the atoms to which they are attached, they form:

[0385]

[0386] In certain embodiments, R 3 For: methyl, In certain preferred embodiments, R 3 for

[0387] In certain embodiments, Z is O. In other certain embodiments, Z is S.

[0388] In certain embodiments, R 4 is H, -C(O)NH2 or NH2. In certain preferred embodiments, R 4 is H or NH2.

[0389] In certain embodiments, the compound of Formula (IIa) or (IIb) has the following structure:

[0390]

[0391]

[0392]

[0393]

[0394] or a pharmaceutically acceptable salt thereof.

[0395] In other embodiments, the compound has the structure:

[0396]

[0397]

[0398] or a pharmaceutically acceptable salt thereof.

[0399] In other embodiments, the compound has the structure:

[0400]

[0401] Other aspects of the present invention provide compounds according to formula (IIIa), (IIIb), (IIIc) or (IIId):

[0402]

[0403] or a pharmaceutically acceptable salt thereof; wherein:

[0404] YR 1 express:

[0405] or -(C1-C6)alkylene-R 1 ;

[0406] X is N or CR 2 ;

[0407] L is -(C1-C6)alkylene-;

[0408] B represents (C3-C8) cycloalkyl, (C6-C 10 )aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl;

[0409] R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NRa R, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy or Among them (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy and 4 to 7 membered heterocycloalkyl are each optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, and (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl and Or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is or (C1-C6) alkylene, then R 1 Not hydrogen;

[0410] R 1a 、R 1b and R 1c is independently hydrogen or (C 1- C6) alkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group;

[0411] R 2 For hydrogen, fluorine, chlorine, -CONR a R b or (C 1- C6) alkyl, said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, and (C 1- C6) alkoxy; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 7-membered heterocycloalkyl group;

[0412] R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C3- C8) cycloalkyl, carboxamido, amino, cyano, carboxyl and alkoxycarbonyl;

[0413] R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group;

[0414] n, m and p are independently 0 or 1;

[0415] q is 0, 1, or 2;

[0416] The condition is that the sum of p and q is equal to 0, 1 or 2;

[0417] R 4 H or N(R 4a )2; and

[0418] R 4a is independently hydrogen or (C 1- C6) alkyl.

[0419] In certain embodiments, R 1 For: hydrogen,

[0420] In other embodiments,

[0421] R 1 for And R 2 It is -CH3 or -CH2-OCH3.

[0422] In other embodiments, R 1 for:

[0423] In a more specific embodiment, R 1 for:

[0424]

[0425] In some embodiments, Y is

[0426]

[0427] In certain embodiments, R 3 For: methyl, Preferred In certain preferred embodiments, R 4 is H or NH2.

[0428] In certain embodiments, the compound of Formula (IIIa), (IIIb), (IIIc), or (IIId) has the following structure:

[0429]

[0430] or a pharmaceutically acceptable salt thereof.

[0431] In certain embodiments, the compounds are atropisomers. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium or by 13 C or 14 Compounds produced by replacing carbon with carbon enriched with C are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention. For example, in the case of the variable R 1 In the case of -(C1-C4)alkyl or -O-(C1-C4)alkyl, the (C1-C4)alkyl group may be suitably deuterated (e.g., -CD3 or -OCD3, respectively).

[0432] Any of the compounds of the present invention may also be radiolabeled for the preparation of radiopharmaceuticals.

[0433] Treatment

[0434] One aspect of the present invention provides a method for treating or preventing osteoporosis, bone fractures, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumor calcification, comprising administering to a subject in need thereof an effective amount of a compound of Formula (Ia) to (IIId) or a pharmaceutically acceptable salt thereof.

[0435] Another aspect of the invention is a method for preventing or treating a condition mediated by PTH, comprising administering to a mammal in need thereof an effective amount of a compound of Formula (Ia) to (IIId), alone or in admixture with a pharmaceutical excipient, or a pharmaceutically acceptable salt thereof. Another aspect of the invention includes compounds of Formula (Ia) to (IIId), or pharmaceutically acceptable salts thereof, for use in treating and preventing diseases and conditions characterized by loss of bone mineral density, mass, or strength, and conditions in which PTH would have a beneficial pharmacological effect. The invention includes administering a compound of Formula (I) or (II) as a PTH mimetic. Another aspect of the invention includes the use of compounds of Formula (Ia) to (IIId) for the manufacture of a medicament for treating osteopenia and osteoporosis in men and women to reduce the risk of vertebral and non-vertebral fractures.

[0436] In certain embodiments, the compound is administered orally to the subject.

[0437] In certain embodiments, the compound is administered to the subject parenterally.

[0438] In certain embodiments, the disease is prevented. In other embodiments, the disease is treated.

[0439] Pharmaceutical compositions, routes of administration and dosing

[0440] In certain embodiments, the present invention is directed to a pharmaceutical composition comprising a compound of the present invention (eg, a compound of Formula (Ia) to (IIId)) and a pharmaceutically acceptable carrier.

[0441] In certain embodiments, the present invention is directed to a pharmaceutical composition comprising a compound of any of the disclosed embodiments and a pharmaceutically acceptable carrier.

[0442] In certain embodiments, pharmaceutical compositions comprise a plurality of compounds of the present invention and a pharmaceutically acceptable carrier.

[0443] Pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0444] As mentioned above, an "effective amount" refers to any amount sufficient to achieve the desired biological effect. In combination with the teachings provided herein, by selecting among various active compounds and weighing factors such as efficacy, relative bioavailability, patient weight, severity of adverse side effects, and mode of administration, an effective preventive or therapeutic treatment regimen that does not cause substantial undesirable toxicity and effectively treats a particular subject can be planned. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the specific compound of the invention being administered, the subject's body size, or the severity of the disease or condition. A person of ordinary skill in the art can empirically determine the effective amount of a specific compound of the invention and / or other therapeutic agent without excessive experimentation. A maximum dose, that is, the highest safe dose based on certain medical judgment, may be used. Multiple doses may be taken daily to achieve appropriate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring the patient's peak or sustained plasma levels of the drug. The terms "dose" and "dosage" are used interchangeably herein.

[0445] In certain embodiments, the intravenous administration of the compound may typically be 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, the intravenous administration of the compound may typically be 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, the intravenous administration of the compound may typically be 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, the intravenous administration of the compound may typically be 1 mg / kg / day to 20 mg / kg / day. In one embodiment, the intravenous administration of the compound may typically be 1 mg / kg / day to 10 mg / kg / day.

[0446] In general, for human subjects, the daily oral dose of the compound will be about 0.01 mg / kg to 1000 mg / kg per day. It is expected that the oral dose within the range of 0.5 to 50 mg / kg administered once or multiple times per day will produce therapeutic results. The dosage can be appropriately adjusted to obtain the desired drug level (local or systemic), depending on the mode of administration. For example, it is expected that the dose administered intravenously daily will be one order of magnitude lower to several orders of magnitude. In the case where the reaction in the subject is insufficient at the dose, an even higher dose (or an effective higher dose can be achieved by different, more localized delivery routes) can be used within the scope permitted by patient tolerance. It is contemplated that multiple doses are used daily to achieve the appropriate systemic level of the compound.

[0447] For any compound described herein, a therapeutically effective amount can be initially determined by an animal model. A therapeutically effective dose can also be determined by human data of compounds tested in humans and compounds known to exhibit similar pharmacological activity (such as other related active agents). Parenteral administration may require higher doses. The applied dose can be adjusted based on the relative bioavailability and efficacy of the administered compound. It is entirely within the ability of a person of ordinary skill in the art to adjust the dose to achieve maximum efficacy based on the methods described above and other methods well known in the art.

[0448] The formulations of the present invention may be administered in the form of pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0449] For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administration of the pharmaceutical composition can be achieved by any means known to those skilled in the art. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., into a tumor or abscess), mucosal (e.g., topical administration to the eye), inhalation, and topical.

[0450] For intravenous and other parenteral administration routes, the compounds of the invention can be formulated as lyophilized preparations; lyophilized preparations of active compounds inserted or encapsulated in lipid particles; lipid complexes in aqueous suspension; or salt complexes. Lyophilized preparations are generally reconstituted in a suitable aqueous solution, such as sterile water or saline, shortly before administration.

[0451] For oral administration, the compound can be easily formulated by combining one or more active compounds with pharmaceutically acceptable carriers well known in the art. The carrier can enable the compounds of the present invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use can be obtained in the form of solid excipients, the resulting mixture is optionally ground and, if necessary, the mixture of particles is processed after adding suitable adjuvants to obtain tablets or dragee cores. Suitable excipients are especially fillers such as sugars, including 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 necessary, a disintegrant such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, can be added. Optionally, oral formulations may also be formulated in saline or a buffer (such as EDTA for neutralization of internal acid conditions) or may be administered without any carriers.

[0452] Oral dosage forms of one or more of the above components are also specifically contemplated. The one or more components may be chemically modified to allow for effective oral delivery of the derivative. Generally, the chemical modifications contemplated are to attach at least one moiety to the component molecule itself, wherein the moiety permits (a) inhibition of acid hydrolysis; and (b) absorption from the stomach or intestine into the bloodstream. It is also desirable to increase the overall stability of one or more components and to increase in vivo circulation time. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts," in: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J Appl Biochem 4: 185-9 (1982). Other polymers that may be used are poly-1,3-dioxolane and poly-1,3,6-trioxocane.For pharmaceutical uses, as indicated above, polyethylene glycol moieties are suitable.

[0453] For a component (or derivative), the site of release can be the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. One skilled in the art has available formulations that will not dissolve in the stomach but will release the substance elsewhere in the duodenum or intestinal tract. Preferably, the release will avoid the deleterious effects of the gastric environment by protecting the compound (or derivative) of the invention or by releasing the biologically active substance outside the gastric environment (such as in the intestinal tract).

[0454] To ensure complete gastro-resistance, a coating that is impermeable to at least pH 5.0 is essential. Examples of more common inert ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings can be used in mixed film form.

[0455] Coatings or mixtures of coatings can also be applied to tablets that are not intended for gastric protection. This can include sugar coatings or coatings that make the tablet easier to swallow. Capsules can consist of a hard shell (such as gelatin) for delivery of dry therapeutic agents (e.g., powders); for liquid forms, a soft gelatin shell can be used. The shell material for cachets can be thick starch or other edible paper. For pills, lozenges, molded tablets, or tablet triturates, moist massing techniques can be used.

[0456] The therapeutic agent can be included in the formulation as fine multiparticulates in the form of granules or pellets having a particle size of about 1 mm. The formulation of the material for capsule administration can also be in the form of a powder, a lightly compressed plug, or even a tablet. The therapeutic agent can be prepared by compression.

[0457] Coloring and flavoring agents may be included.For example, a compound (or derivative) of the invention may be formulated (such as by liposome or microsphere encapsulation) and then further included in an edible product (such as a refrigerated beverage containing coloring and flavoring agents).

[0458] Inert substances can be used to dilute or increase the volume of the therapeutic agent. These diluents can include carbohydrates, particularly mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextran, and starch. Certain inorganic salts can also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents include Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicell.

[0459] Disintegrants can be included in solid dosage formulations of therapeutic agents. Materials used as disintegrants include, but are not limited to, starch, including the commercial starch-based disintegrant Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acidic carboxymethylcellulose, natural sponge, and bentonite can all be used. Another form of disintegrant is an insoluble cation exchange resin. Powdered jelly can be used as a disintegrant and binder, and these jellys can include powdered jelly such as agar, carrageenan, or tragacanth. Alginic acid and its sodium salt are also suitable for use as disintegrants.

[0460] Binders can be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as gum arabic, tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) can both be used in alcoholic solutions to granulate the therapeutic agent.

[0461] Anti-friction agents can be included in the formulation of the therapeutic agent to prevent sticking during the formulation process. Lubricants can be used as a layer between the therapeutic agent and the mold wall and can include, but are not limited to, stearic acid (including its magnesium and calcium salts), polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, and Carbowax 4000 and 6000 can also be used.

[0462] Glidants may be added which may improve the flow characteristics of the drug during formulation and aid in rearrangement during compression. Glidants may include starch, talc, fumed silica, and hydrated aluminosilicates.

[0463] In order to help the therapeutic agent dissolve in an aqueous environment, a surfactant can be added as a wetting agent. The surfactant can include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents can be used and can include benzalkonium chloride and benzethonium chloride. Potential nonionic detergents that can be included in the preparation as surfactants include lauromacrogol 400, polyoxyl stearate 40 esters, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glyceryl monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid esters, methylcellulose and carboxymethylcellulose. These surfactants can be present in the preparation of the compounds of the present invention or derivatives alone or in a mixture of different ratios.

[0464] Orally usable pharmaceutical preparations include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Insertable capsules can contain a mixture of active ingredients and fillers such as lactose, adhesives such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. Microspheres formulated for oral administration can also be used. The microspheres have been clearly defined in the art. All preparations for oral administration should be in a dosage suitable for the administration.

[0465] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0466] For topical administration, the compounds can be formulated into solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Systemic formulations include those designed for administration by injection, for example, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0467] For administration by inhalation, the compounds for use according to the present invention may conveniently be presented in the form of an aerosol spray from a pressurized pack or nebulizer, delivered with a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin, for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base (such as lactose or starch).

[0468] Pulmonary delivery of the compounds disclosed herein (or salts thereof) is also contemplated herein. The compounds are delivered to the lungs of a mammal upon inhalation and cross the epithelial lining of the lungs to the bloodstream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprol ide 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); Oswein et al., 1990, “Aerosolization of Proteins”, Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-γ and tumor necrosis factor α) and Platz et al., U.S. Pat. No. 5,284,656 (granulocyte colony-stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in Wong et al., U.S. Pat. No. 5,451,569, issued September 19, 1995 (incorporated by reference).

[0469] Contemplated for use in the practice of the present invention are mechanical devices designed for pulmonary delivery of therapeutic products, including, but not limited to, nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0470] Some specific examples of commercially available devices suitable for use in the practice of the present invention are the Ultravent nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer manufactured by Marquest Medical Products (Englewood, Colo.); the Ventolin metered-dose inhaler manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler manufactured by Fisons Corp., Bedford, Mass.

[0471] All of the devices described need to use a formulation suitable for dispensing the compounds of the present invention. Typically, each formulation is specific to the type of device used and may involve the use of an appropriate propellant substance in addition to the common diluents, adjuvants, and / or carriers suitable for therapy. In addition, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Depending on the type of chemical modification or the type of device used, the chemically modified compounds of the present invention may also be prepared in different formulations.

[0472] Formulations suitable for use with nebulizers (jet or ultrasonic) will typically contain a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of the biologically active compound of the invention per milliliter of solution. The formulation may also include a buffer and a monosaccharide (e.g., for inhibitor stabilization and to adjust osmotic pressure). The nebulizer formulation may also contain a surfactant to reduce or prevent surface-induced aggregation of the compound of the invention caused by atomization of the solution when forming an aerosol.

[0473] The formulation for use with a metered dose inhaler will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material used for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or a combination thereof. Suitable surfactants include sorbitan trioleate and soy lecithin. Oleic acid may also be suitable as a surfactant.

[0474] The formulation for dispensing from a powder inhaler device will comprise a finely divided dry powder containing the compound of the present invention (or derivative), and may also include a bulking agent, such as lactose, sorbitol, sucrose or mannitol, in an amount that promotes dispersion of the powder from the device, for example, 50% to 90% by weight of the formulation. The compound of the present invention (or derivative) should advantageously be prepared in the form of microparticles having an average particle size of less than 10 microns (μm), optimally 0.5 to 5 μm, for most effective delivery to the deep lung.

[0475] Also contemplated is nasal delivery of the pharmaceutical compositions of the present invention. Nasal delivery allows the pharmaceutical compositions of the present invention to enter the bloodstream directly after administration of the therapeutic product to the nose, without requiring the product to be deposited in the lungs. Formulations for nasal delivery include formulations with dextran or cyclodextran.

[0476] For nasal administration, a suitable device is a small rigid bottle to which a metered-dose sprayer is attached. In one embodiment, a metered dose is delivered by drawing a solution of the pharmaceutical composition of the present invention into a chamber of defined volume, the orifice of which is sized so that when the liquid in the chamber is compressed, the aerosol formulation is aerosolized by forming a spray. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston configuration. Such devices are commercially available.

[0477] Alternatively, a plastic squeeze bottle is used, the orifice or opening of which is sized to aerosolize the aerosol formulation by forming a spray when squeezed. The opening is typically found at the top of the bottle, and the top is typically tapered, partially fitting into the nasal cavity for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered aerosol formulation for administering a measured dose of the drug.

[0478] When systemic delivery of the compounds is desired, the compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations can be presented in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulators such as suspending agents, stabilizers, and / or dispersants.

[0479] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In addition, suspensions of the active compound can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil; or synthetic fatty acid esters, such as ethyl oleate or triglycerides; or lipid particles. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

[0480] Alternatively, the active compound may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0481] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0482] In addition to the formulations described above, the compound can also be formulated as a depot preparation. The long-acting preparation can be formulated with a suitable polymeric or hydrophobic substance (e.g., as an emulsion in an acceptable oil) or with an ion exchange resin, or as a sparingly soluble derivative (e.g., a sparingly soluble salt).

[0483] The pharmaceutical composition may also contain 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 glycols.

[0484] Suitable liquid or solid pharmaceutical preparation forms are aqueous solutions or saline solutions for example for suction; microencapsulation; encapsulation (encochleate); coated on microscopic gold particles; contained in lipid particles; atomization; aerosol; pellets implanted in the skin; or dried on a sharp object to scrape into the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with extended release of active compounds, and excipients and additives and / or adjuvants (such as disintegrants, adhesives, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers) are generally used as described above in the preparation of such preparations. Such pharmaceutical compositions are applicable to multiple drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249: 1527-33 (1990).

[0485] The compounds of the present invention and optionally other therapeutic agents can be administered per se (pure) or in the form of a pharmaceutically acceptable salt or co-crystal. When used in medicine, the salt or co-crystal should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts or co-crystals can be suitably used to prepare pharmaceutically acceptable salts or co-crystals thereof. Such salts include, but are not limited to, those prepared from the following acids: 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. In addition, the salts can be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0486] Suitable buffers 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).

[0487] The pharmaceutical compositions of the present invention contain an effective amount of a compound as described herein and optionally a therapeutic agent in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic organic or inorganic ingredient with which the active ingredient is combined to facilitate application. The components of the pharmaceutical composition can also be blended with the compounds of the present invention and with each other in a manner that does not interact in a manner that substantially impairs the desired pharmaceutical efficacy.

[0488] Therapeutic agents, including (specifically, but not limited to) compounds of the present invention, can be provided in the form of particles. As used herein, particles refer to nanoparticles or microparticles (or in some cases, larger particles) that may be composed entirely or in part of a compound of the present invention or other therapeutic agents as described herein. The particles may contain the therapeutic agent in a core surrounded by a coating (including, but not limited to, an enteric coating). The therapeutic agent may also be dispersed throughout the particle. The therapeutic agent may also be adsorbed into the particle. The particles may have release kinetics of any order, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the therapeutic agent, the particles may include any of those materials conventionally used in the fields of pharmaceutics and medicine, including, but not limited to, erodible, non-erodible, biodegradable, or non-biodegradable materials, or combinations thereof. The particles may be microcapsules containing the compounds of the present invention in solution or in a semi-solid state. Such particles may be in almost any shape.

[0489] Non-biodegradable and biodegradable polymeric materials can be used to manufacture the particle for delivering therapeutic agent.Described polymer can be natural or synthetic polymer.Select polymer based on the time period that needs to release.The bioadhesive polymer that receives much attention includes the biological erodible hydrogel described in people such as Sawhney HS (1993) Macromolecules 26:581-7, and its teaching content is incorporated herein.These include polyhyaluronic acid, casein, gelatin, gelatin protein, polyanhydride, polyacrylic acid, alginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (dodecyl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate) and poly (octadecyl acrylate).

[0490] The therapeutic agent 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 by the formulation. This refers to immediate and non-immediate release formulations, wherein non-immediate release formulations include, but are not limited to, sustained release and delayed release formulations. The term "sustained release" (also referred to as "extended release") is used in its conventional sense to refer to a pharmaceutical formulation that provides a gradual release of the drug over an extended period of time, and preferably, although not necessarily, produces a substantially constant blood level of the drug over an extended period of time. The term "delayed release" is used in its conventional sense to refer to a pharmaceutical formulation in which there is a time delay between the administration of the formulation and the release of the drug therefrom. "Delayed release" may or may not involve the gradual release of the drug over an extended period of time, and therefore may or may not be "sustained release."

[0491] The use of long-term sustained release implants can be particularly useful in treating chronic conditions. As used herein, "long-term" release means that the implant is constructed and configured to deliver therapeutic levels of active ingredients for at least 7 days, and preferably 30 to 60 days. Long-term sustained release implants are well known to those of ordinary skill in the art and include some of the release systems described above.

[0492] It will be understood by those skilled in the art that other suitable changes and modifications to the compositions and methods described herein will be apparent from the description of the invention contained herein and may be made without departing from the scope of the invention or any embodiment thereof, given the information known to those skilled in the art. Having now described the invention in detail, the invention will be more clearly understood with reference to the following examples, which are included for illustrative purposes only and are not intended to limit the invention.

[0493] Example

[0494] The present invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0495] The following general reaction scheme was used to prepare the pyrimidinedione core and is described in further detail in the experiments:

[0496] General process 1:

[0497]

[0498] General process 2:

[0499]

[0500] General process 3:

[0501]

[0502] abbreviation:

[0503]

[0504]

[0505]

[0506] Examples 1, 15, 19, 22, 27, 28, and 34 were synthesized by a procedure similar to that described in Example 4 below.

[0507] Example 2 is an intermediate in the synthesis of Example 3.

[0508] Example 3 was synthesized by a similar procedure as described in Example 4 using Boc as a protecting group.

[0509] Example 4: 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxamide (4)

[0510]

[0511] Synthesis process:

[0512]

[0513] 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxamide

[0514] To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (Example 17, 330 mg, 0.94 mmol) in water (4 mL) and MeOH (4 mL) was added potassium cyanate (383.02 mg, 4.72 mmol). After heating at 70 ° C for 5 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 resulting residue was purified by reverse phase HPLC (XBridge PrepOBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; gradient: 17% B to 42% B) to give the title compound 4 (143.3 mg, 38.38%) as a white solid. MS(ESI):C 18 H 28 Calculated mass of N6O4: 392.22, found: 393.25 [M+H] + .1 H 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).

[0515] Example 6 was synthesized by a procedure similar to that described below for Example 104 without chiral separation.

[0516] Example 14 was synthesized from Example 18 using a procedure similar to that described in Example 4.

[0517] Examples 11 and 16 were synthesized by similar procedures as described in Example 14.

[0518] Example 36 was synthesized from Example 37 using a procedure similar to that described in Example 4.

[0519] Example 7: 5-(2-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)ethyl)picolinamide

[0520]

[0521] Synthesis process:

[0522]

[0523] Methyl 5-(cyanomethyl)picolinate

[0524]

[0525] To a stirred mixture of methyl 5-bromopyridine-2-carboxylate (2 g, 9.26 mmol) and 2-(trimethylsilyl)acetonitrile (3.14 g, 27.77 mmol) in DMF (5 mL, 64.608 mmol) was added Pd2(dba)3 (1.70 g, 1.85 mmol), XantPhos (2.14 g, 3.70 mmol) and zinc fluoride (574.24 mg, 5.56 mmol) in portions. After heating at 90 ° C under N2 for 2 hours, the reactant was diluted with water (30 mL) and extracted with EA (3×30 mL). The combined organic layers were 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 give the title compound (863 mg, 52.91%) as a white solid. MS (ESI): Mass calculated for C9H8N2O2: 176.06, found: 177.10 [M+H] + .

[0526] 5-(2-aminoethyl)picolinic acid methyl ester

[0527]

[0528] To a stirred mixture of methyl 5-(cyanomethyl)picolinate (683 mg, 3.88 mmol) in MeOH (8 mL, 197.59 mmol) was added concentrated HCl (0.2 mL) and Pd(OH)2 (0.2 g). After stirring at room temperature under H2 for 2 hours, the reaction was basified with NaHCO3 (aq.) to pH = 8, diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 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 of N2O2: 180.09, found: 181.15 [M+H] + .

[0529] 5-(2-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)ethyl)picolinamide

[0530]

[0531] The title compound 7 was synthesized by a procedure similar to that described in steps 2, 5 to 7 of Example 17. MS (ESI): C 17 H 22 Calculated mass of N6O4: 374.17, found: 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).

[0532] Example 10 was synthesized by a procedure similar to that described in Example 7 from methyl 3-(cyanomethyl)bicyclo[1.1.1]pentane-1-carboxylate (prepared from methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate).

[0533] Example 9 was synthesized from 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine by a similar procedure to that described in Example 7.

[0534] Example 8: 1-butyl-5-(diaminomethylene)-3-(4-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)butyl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0535]

[0536] Synthesis process:

[0537]

[0538] 5,5-Dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione

[0539]

[0540] To a stirred solution of 5,5-dimethylimidazolidine-2,4-dione (5 g, 39.023 mmol) in anhydrous DCM (20 mL) was added DIPEA (15.13 g, 117.07 mmol) and SEMCl (7.81 g, 46.83 mmol) at 0 ° C. After stirring at the same temperature for 1 hour, the reactant was stirred at room temperature for 24 hours. After completion, the reactant 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 give a crude product, which was purified by silica gel column chromatography (DCM: MeOH = 10: 1) to give the title compound (5.4 g, 45.39%). MS (negative ion mode): C 11 H 22 Calculated mass of N2O3Si: 258.14, experimental value: 257.05 [MH] - .

[0541] 2-(4-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)butyl)isoindoline-1,3-dione

[0542]

[0543] To a solution of 5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (1.5 g, 5.81 mmol) and cesium carbonate (3.79 g, 11.61 mmol) in dimethylformamide (40 mL) was added N-(4-bromobutyl)phthalimide (1.97 g, 6.97 mmol). After heating at 60 ° C. under N2 overnight, the reactant 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 obtained residue was purified by silica gel column chromatography (0-50% PE / EA) to give the title compound (2.5 g, 93.7%) as a colorless oil. MS (ESI): C 23 H 33 Calculated mass of N3O5Si: 459.22, experimental value: 482.15 [M+Na] + .

[0544] 1-(4-Aminobutyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione

[0545]

[0546] To a solution of 2-(4-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)butyl)isoindoline-1,3-dione (2.4 g, 5.22 mmol) in EtOH (50 mL) was added hydrazine hydrate (1.31 g, 26.11 mmol). The reaction was heated at 50 ° C. under N2 for 3 hours, quenched with water (50 mL) and extracted with DCM / MeOH (6 / 1). 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 (0-10% DCM / MeOH) to give the title compound (1.6 g, 92.99%) as a white solid. MS (ESI): C 15 H 31 Calculated mass of N3O3Si: 329.21, found: 330.15 [M+H] + .

[0547] 1-Butyl-5-(diaminomethylene)-3-(4-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)butyl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0548]

[0549] 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 following the procedure of Example 17, 80 mg, 0.15 mmol) in TFA (1.5 mL) and DCM (4.5 mL) was stirred at room temperature for 1 hour. After concentration, 2N NH in MeOH (5 mL) was added to the crude residue and stirred for 1 hour. The reaction was concentrated and purified by silica gel column chromatography (0-10% DCM / MeOH) followed by reverse phase HPLC purification (26% to 45% (v / v) ACN and 0.05% NH4HCO3 in H2O) to afford the title compound 8 (15 mg, 24.71%) as a white solid. MS (ESI): C 18 H 28 Calculated mass of N6O5: 408.21, found: 409.20 [M+H] + . 1H 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).

[0550] 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)

[0551]

[0552] Synthesis process:

[0553]

[0554] 1-(2-Acetyl-2-azaspiro[3.5]nonan-7-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione

[0555] To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (80 mg, 0.229 mmol) in DCM (4 mL) was added TEA (69 mg, 0.69 mmol) and Ac2O (47 mg, 0.46 mmol) under N2 at 0 ° C. After stirring at room temperature for 2 hours, the reactant 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 obtained residue was purified by reverse phase HPLC (25% to 45% (v / v) ACN and H2O containing 0.05% NH4HCO3) to give the title compound 12 (19.4 mg, 21.61%) as a white solid. MS (ESI): C 19 H 29 Calculated mass of N5O4: 391.22, found: 392.25 [M+H] + . 1H 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).

[0556] Examples 5 and 20 were synthesized by a similar procedure to that described in Example 12.

[0557] Example 13: 1-Butyl-5-(diaminomethylene)-3-(2-(methylsulfonyl)-2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (13)

[0558]

[0559] Synthesis process:

[0560]

[0561] 1-Butyl-5-(diaminomethylene)-3-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0562] To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (80 mg, 0.23 mmol) in DCM (4 mL) was added DCM (0.1 mL) containing TEA (69 mg, 0.69 mmol) and MsCl (39 mg, 0.34 mmol) under N at 0 ° C. After stirring at room temperature for 3 hours, the reactant 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 obtained residue was purified by reverse phase HPLC (25% to 45% (v / v) ACN and 0.05% NH4HCO3 in H2O) to give the title compound 13 (20.5 mg, 20.89%) as a white solid. MS(ESI):C 18 H 29 Calculated mass of N5O5S: 427.19, found: 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).

[0563] Example 26 was synthesized by a similar procedure to that described in Example 13 using dimethylcarbamoyl chloride.

[0564] Example 30 was synthesized by a similar procedure to that described in Example 13.

[0565] Example 24 was synthesized from Example 18 using a procedure similar to that described in Example 13.

[0566] Example 17: 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (17)

[0567]

[0568] Synthesis process:

[0569]

[0570] tert-Butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate

[0571]

[0572] To a solution of tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (1.0 g, 4.18 mmol) in MeOH (40 mL) containing 7N NH3 was added Pd / C (10%, 0.2 g). The reaction mixture was stirred under a hydrogen atmosphere (balloon) for 16 hours. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to give 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 of N2O2: 240.18, found: 241.15 [M+H] + .

[0573] tert-Butyl 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate

[0574]

[0575] To a solution of tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (1 g, 4.16 mmol) in ClCH2CH2Cl (20 mL) was added butyl isocyanate (0.45 g, 4.58 mmol). After stirring overnight at room temperature, the reaction was concentrated and purified by silica gel column chromatography (DCM:MeOH=10:1) to give the title compound (1.2 g, 84.96%). MS (ESI): C 18 H 33 Calculated mass of N3O3: 339.25, found: 340.20 [M+H] + .

[0576] 1-Butyl-3-(2-azaspiro[3.5]non-7-yl)urea

[0577]

[0578] To a solution of tert-butyl 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate (1.2 g, 3.54 mmol) in ethyl acetate (8 mL) was added 2N HCl (in EA, 8 mL). After stirring at room temperature for 3 hours, the resulting mixture was concentrated to give the crude title compound (900 mg, 106%) as a yellow solid. MS (ESI): C 13 H 25 Calculated mass of N3O: 239.20, found: 240.20 [M+H] + The crude product was used directly in the next step without further purification.

[0579] Benzyl 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate

[0580]

[0581] To a solution of 1-butyl-3-(2-azaspiro[3.5]non-7-yl)urea (0.9 g, 3.76 mmol) in DCM (15 mL) was added CbzCl (0.77 g, 4.51 mmol) and TEA (1.14 g, 11.28 mmol). After stirring at room temperature for 16 hours, the reactant 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 give a crude residue, which was purified by silica gel column chromatography (DCM: MeOH = 10 / 1) to give the title compound (1 g, 71.21%) as a yellow solid. MS (ESI): C 21 H 31 Calculated mass of N3O3: 373.24, found: 374.25 [M+H] + .

[0582] Benzyl 7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate

[0583]

[0584] To a solution of 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylic acid benzyl ester (1 g, 2.68 mmol) in acetic acid (15 mL) was added acetic anhydride (0.96 g, 9.37 mmol) and malonic acid (0.36 g, 3.48 mmol). After heating at 80 ° C. for 4 hours, the reaction was concentrated and purified by silica gel column chromatography (DCM: MeOH = 10: 1) to give the title compound (0.7 g, 59.21%). MS (ESI): C 24 H 31 Calculated mass of N3O5: 441.23, found: 442.20 [M+H] + .

[0585] Benzyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate

[0586]

[0587] To a solution of 7-(3-butyl-2,4,6-trioxo-1,3-diazacyclohexane-1-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid benzyl ester (0.7 g, 1.585 mmol) in DMSO (10 mL) was added carbon disulfide (1.21 g, 15.85 mmol) and TEA (2.41 g, 23.78 mmol). After stirring at room temperature for 1 hour, 1,3-dibromopropane (3.20 g, 15.85 mmol) was added. Upon completion, the reactant was quenched with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the title compound (600 mg, 67.86%). MS (ESI): C 28 H 35 Calculated mass of N3O5S2: 558.20, found: 559.20 [M+H] + .

[0588] Benzyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate

[0589]

[0590] To a solution of 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid benzyl ester (600 mg, 1.08 mmol) in methanol (15 mL) was added 7N NH3 (in methanol, 2.5 mL). The reactants were heated at 100 ° C for 1 hour, cooled and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / MeOH=10:1) to give the title compound (280 mg, 53.82%). MS (ESI): C 25 H 33 Calculated mass of N5O5: 483.25, found: 484.20 [M+H] + .

[0591] 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0592]

[0593] To a solution of benzyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate (280 mg, 0.58 mmol) in methanol (20 mL) was added Pd / C (10%, 50 mg). The reaction was stirred under a hydrogen atmosphere (balloon) for 16 hours. It was then filtered through a pad of celite and concentrated under reduced pressure to give the title compound 17 (90 mg, 44.48%). MS (ESI): C 17 H 27 Calculated mass of N5O3: 349.21, found: 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).

[0594] Examples 23 and 33 were synthesized by a similar procedure to that described in Example 17.

[0595] Example 18: 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((methylamino)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (18)

[0596]

[0597] Synthesis process:

[0598]

[0599] tert-Butyl ((1s,4s)-4-((methylamino)methyl)cyclohexyl)carbamate

[0600]

[0601] To a solution of tert-butyl N-[(1s, 4s)-4-formylcyclohexyl]carbamate (950 mg, 4.18 mmol) in THF (25 mL) was added titanium (IV) isopropoxide (2850 mg, 10.03 mmol). After stirring at room temperature overnight, MeOH (25 mL) was added, and the mixture was cooled to 0 ° C. NaBH4 (790 mg, 20.90 mmol) was added, and the reactants were stirred at room temperature for 3 hours. The reactants were quenched with NH4Cl (aqueous solution) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (650 mg, 64.17%) as a light yellow solid.

[0602] Benzyl (((1s,4s)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)methyl)(methyl)carbamate

[0603]

[0604] To a solution of tert-butyl ((1s, 4s)-4-((methylamino)methyl)cyclohexyl)carbamate (630 mg, 2.599 mmol) in toluene (15 mL) was added K2CO3 (718.50 mg, 5.2 mmol) and benzyl chloroformate (886 mg, 5.2 mmol). The reactants were heated at 80 ° C under N2 for 3 hours. After cooling to room temperature, the reactants were quenched with water and extracted with ethyl acetate. 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 (0-50% ethyl acetate / petroleum ether) to give the title compound (560 mg, 57.22%) as a light yellow oil. MS (ESI): C 21 H 32 Calculated mass of N2O4: 376.24, found: 377.15 [M+H] + .

[0605] Benzyl (((1s,4s)-4-aminocyclohexyl)methyl)(methyl)carbamate

[0606]

[0607] A solution of benzyl (((1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl)(methyl)carbamate (550 mg, 1.46 mmol) in EA (4 mL) containing 2N HCl and EA (4 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated to give the crude title compound (400 mg, 99.07%) as a yellow semisolid. MS (ESI): C 16H 24 Calculated mass of N2O2: 276.18, found: 277.05 [M+H] + The crude product was used in the next step without further purification.

[0608] Benzyl (((1s,4s)-4-(3-butylureido)cyclohexyl)methyl)(methyl)carbamate

[0609]

[0610] To a solution of benzyl (((1s,4s)-4-aminocyclohexyl)methyl)(methyl)carbamate (560 mg, 2.03 mmol) in ClCH2CHCl (15 mL) was added TEA (410 mg, 4.05 mmol) and butyl isocyanate (220 mg, 2.23 mmol). After stirring at room temperature for 3 hours, the resulting mixture was concentrated and purified by silica gel column chromatography (0-10% MeOH / DCM) to give the title compound as a light yellow oil. MS (ESI): C 21 H 33 Calculated mass of N3O3: 375.25, found: 376.25 [M+H] + .

[0611] Benzyl (((1s,4s)-4-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate

[0612]

[0613] To a solution of benzyl (((1s,4s)-4-(3-butylureido)cyclohexyl)methyl)(methyl)carbamate (470 mg, 1.25 mmol) in AcO (3 mL) and AcOH (4.5 mL) was added malonic acid (143 mg, 1.38 mmol). The resulting mixture was stirred at 80 ° C for 4 hours and concentrated. The crude residue was purified by silica gel column chromatography to give the title compound (330 mg, 59.44%) as a yellow solid. MS (ESI): C 24 H 33 Calculated mass of N3O5: 443.24, found: 444.25 [M+H] + .

[0614] Benzyl (((1s,4s)-4-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate

[0615]

[0616] To a solution of benzyl (((1s,4s)-4-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate (300 mg, 0.68 mmol) in DMSO (8 mL) was added TEA (273, 2.70 mmol) followed by carbon disulfide (154 mg, 2.03 mmol). After stirring at room temperature for 3 hours, 1,3-dibromopropane (163 mg, 0.81 mmol) was added. The reactants were 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 give the title compound (250 mg, 66.03%) as a yellow viscous oil. MS (ESI): C 28 H 37 Calculated mass of N3O5S2: 559.22, found: 560.20 [M+H] + .

[0617] Benzyl (((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate

[0618]

[0619] A solution of benzyl (((1s,4s)-4-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate (270 mg, 0.48 mmol) in MeOH (5 mL) containing 2N NH3 was stirred at 100 ° C for 2 hours. After cooling to room temperature, the reaction was quenched with water (10 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. The crude residue was purified by silica gel column chromatography to give the title compound (200 mg, 85.39%) as a light yellow solid. MS (ESI): C 25 H 35 Calculated mass of N5O5: 485.26, found: 486.25 [M+H] + .

[0620] 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((methylamino)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0621]

[0622] To a solution of benzyl (((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)methyl)(methyl)carbamate (200 mg, 0.41 mmol) in DCM (3 mL) was added 40% HBr in AcOH (1 mL) at 0°C. After stirring at room temperature for 2 hours, the reaction was neutralized with NaHCO3 (aq.) to pH = 7 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 give the title compound 18 (100 mg, 69%). MS (ESI): C 17 H 29 Calculated mass of N5O3: 351.23, found: 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).

[0623] Example 44 was synthesized from Example 18 using a procedure similar to that described in Example 39.

[0624] Example 25: 1-Butyl-5-(diaminomethylene)-3-(2-(oxetane-3-yl)-2-azaspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (25)

[0625]

[0626] Synthesis process:

[0627]

[0628] 1-Butyl-5-(diaminomethylene)-3-(2-(oxetan-3-yl)-2-azaspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0629] To a stirred solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (45 mg, 0.13 mmol) in MeOH (2 mL) was added 3-oxetanes (19 mg, 0.26 mmol) and AcOH (15 mg, 0.26 mmol). After stirring at room temperature for 0.5 hours, sodium cyanoborohydride (16 mg, 0.26 mmol) was added to the reactant. The resulting mixture was stirred at room temperature for 5 hours. The reactant 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 to 42% B) to give the title compound 25 (12.1 mg, 20.58%) as a white solid. MS (ESI): C 20 H 31 Calculated mass of N5O4: 405.24, found: 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).

[0630] Examples 46 and 53 were synthesized by a similar procedure to that described in Example 25.

[0631] Examples 56 and 57 were synthesized from butyl-5-(diaminomethylene)-3-(2-(methylamino)spiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione by a procedure similar to that described in Example 25 (see Example 51 for procedures).

[0632] Examples 60 and 61 were synthesized by a procedure similar to that described in Example 25 from 1-butyl-5-(diaminomethylene)-3-(piperidin-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared by a procedure similar to that in Example 18).

[0633] 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 by a procedure similar to that of Example 25 (see Example 66 for the procedure).

[0634] Example 71 was synthesized from the same starting materials as Example 60 and tert-butyl 3-oxopyrrolidine-1-carboxylate in a similar procedure to that described in Example 25, followed by TFA deprotection of the Boc group, and then the same procedure as described in Example 4.

[0635] Example 72 was synthesized by a similar procedure as in Example 71, except that the last step followed the same procedure as in Example 12.

[0636] Example 37: 1-(1-(azetidin-3-yl)piperidin-4-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (37)

[0637]

[0638] Synthesis process:

[0639]

[0640] tert-Butyl 3-(4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)azetidine-1-carboxylate

[0641]

[0642] To a solution of 1-butyl-5-(diaminomethylene)-3-(piperidin-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared from 4-aminopiperidine-1-carboxylic acid benzyl ester, 200 mg, 0.65 mmol) in MeOH (5 mL) was added tert-butyl 3-oxoazetidine-1-carboxylate (553 mg, 3.23 mmol) and AcOH (116 mg, 1.94 mmol) at room temperature. After stirring for 1 hour, NaBHCN (121 mg, 1.938 mmol) was added at 0 ° C. The resulting mixture was stirred at room temperature for another 1 hour. The reactant was quenched with water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-20% MeOH / DCM) to give the title compound (200 mg, 66.47%) as a white solid. MS (ESI): C22 H 36 Calculated mass of N6O5: 464.27, found: 465.30 [M+H] + .

[0643] 1-(1-(azetidin-3-yl)piperidin-4-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione

[0644]

[0645] A solution of tert-butyl 3-(4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)azetidine-1-carboxylate (196 mg, 0.42 mmol) in TFA (2 mL) and DCM (6 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give the title compound 37 (160 mg, 73.01%) as a white solid. MS (ESI): C 17 H 28 Calculated mass of N6O3: 364.22, found: 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).

[0646] Example 39: 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-sulfonamide (39)

[0647]

[0648] Synthesis process:

[0649]

[0650] Benzyl ((7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonan-2-yl)sulfonyl)carbamate

[0651]

[0652] To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (80 mg, 0.23 mmol) in THF (3 mL) was added Et3N (46 mg, 0.46 mmol) and N-(chlorosulfonyl)benzylcarbamate (57 mg, 0.23 mmol). After stirring at room temperature for 3 hours, the reactant 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 obtained residue was purified by silica gel column chromatography (0-20% DCM / MeOH) to give the title compound (90 mg, 69.87%) as a light yellow solid. MS (ESI): C 25 H 34 Calculated mass of N6O7S: 562.22, found: 563.25 [M+H] + .

[0653] 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-sulfonamide

[0654]

[0655] To a solution of benzyl ((7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonan-2-yl)sulfonyl)carbamate (90 mg, 0.16 mmol) in MeOH (1 mL) and DCM (4 mL) was added Pd / C (30 mL) under N2. The reactants were 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 to 57% B) to give 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, found: 429.20 [M+H] + . 1HNMR(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).

[0656] Example 40: 1-Butyl-5-(diaminomethylene)-3-(2-(S-methylsulfonylimino)-2-azaspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (40)

[0657]

[0658] Synthesis process:

[0659]

[0660] 1-Butyl-3-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-2-azaspiro[3.5]nonan-7-yl)-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione

[0661]

[0662] To a solution of 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (78 mg, 0.29 mmol, trifluoromethanesulfonate) in CHCN (3 mL) was added triethylamine (29 mg, 0.29 mmol) and 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (50 mg, 0.14 mmol) under N atmosphere at 0 ° C. After stirring at room temperature for 3 hours, the reaction 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 give 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, found: 541.20 [M+H] + .

[0663] 1-Butyl-5-(diaminomethylene)-3-(2-(S-methylsulfonylimino)-2-azaspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0664]

[0665] To a solution of 1-butyl-3-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-2-azaspiro[3.5]nonan-7-yl)-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (60 mg, 0.11 mmol) in THF (2 mL) was added Et3N at 0°C. . 3HF (0.5 mL). After stirring at room temperature for 2 hours, the reaction was quenched with water (10 mL) and extracted with EA (3×30 mL). 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 (mobile phase A: water (0.1% FA), mobile phase B: ACN; 16% B to 40% B) to give the title compound 40 (22.5 mg, 46.57%) as a white solid. MS (ESI): C 18 H 30 Calculated mass of N6O4S: 426.20, found: 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).

[0666] Examples 41 and 42: 1-Butyl-5-(diaminomethylene)-3-(((1s,4s)-4-(5-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (41) and 1-Butyl-5-(diaminomethylene)-3-(((1r,4r)-4-(5-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (42)

[0667]

[0668] Synthesis process:

[0669]

[0670] Methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate

[0671]

[0672] A solution of 4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (3.0 g, 16.11 mmol) in tetrahydrofuran (50 mL) was cooled to -78 ° C. Borane-methyl sulfide complex (2.09 mL, 20.94 mmol) was added and the reaction was allowed to warm to room temperature. After stirring at room temperature for 1 hour, the reaction 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 to give the title compound (2.4 g, 86.5%) as a yellow oil. MS (ESI): C9H 16 Calculated mass of O3: 172.11, found: 173.20 [M+H] + .

[0673] Methyl 4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylate

[0674]

[0675] To a solution of methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate (2.4 g, 13.94 mmol) in DCM (50 mL) was added TBSCl (2.52 g, 16.72 mmol) and imidazole (1.90 g, 27.87 mmol). After stirring at room temperature for 2 hours, the reactant 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 obtained residue was purified by silica gel column chromatography (0-20% EA / PE) to give the title compound (3.0 g, 75.14%) as a yellow oil. MS (ESI): C 15 H 30 Calculated mass of O3Si: 286.20, Found: 287.20 [M+H] + .

[0676] 4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbohydrazide

[0677]

[0678] To a solution of methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylate (2.0 g, 6.98 mmol) in ethanol (20 mL) was added hydrazine (1.12 g, 34.91 mmol). The mixture was heated at 100 ° C for 4 hours. After cooling to room temperature, the reaction 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 obtained residue was purified by silica gel column chromatography (0-50% EA / PE) to give the title compound (1.6 g, 80.0%) as a yellow oil. MS (ESI): C 14 H 30 Calculated mass of N2O2Si: 286.21, found: 287.20 [M+H] + .

[0679] 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-methyl-4H-1,2,4-triazole

[0680]

[0681] To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carbohydrazide (1.8 g, 6.28 mmol) in n-butanol (20 mL) was added acetamidine hydrochloride (0.59 g, 6.28 mmol) and K2CO3 (0.52 g, 3.77 mmol). The mixture was heated at 120 ° C for 16 hours. After cooling to room temperature, the reactant 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 obtained residue was purified by silica gel column chromatography (0-50% EA / PE) to give the title compound (1.5 g, 77.13%) as a yellow solid. MS (ESI): C 16 H 31 Calculated mass of N3OSi: 309.22, found: 310.20 [M+H] + .

[0682] 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole

[0683]

[0684] 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 another 2 hours, the reactant was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (0-50% EA / PE) to give the title compound (1.3 g, 61.0%) as a yellow solid. MS (ESI): C 22 H 45 Calculated mass of N3O2Si2: 439.31, found: 440.30 [M+H] + .

[0685] (4-(5-Methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohexyl)methanol

[0686]

[0687] To a solution of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole (1.1 g, 2.50 mmol) in THF (20 mL) was added TBAF (0.72 g, 2.75 mmol). After heating at 50 ° C for 2 hours, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (0-50% EA / PE) to give the title compound (615 mg, 75.53%) as a yellow solid. MS (ESI): C 16 H 31 Calculated mass of N3O2Si: 325.22, found: 326.20 [M+H] + .

[0688] 1-Butyl-5-(1,3-dithian-2-ylidene)-3-((4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0689]

[0690] To a solution of (4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohexyl)methanol (400 mg, 1.23 mmol) in DCM (10 mL) was added 1-butyl-5-(1,3-dithian-2-ylidene)-1,3-diazacyclohexane-2,4,6-trione (369 mg, 1.23 mmol) and PPh (322 mg, 1.23 mmol). The reactants were cooled to 0 ° C. and diethyl azodicarboxylate (214 mg, 1.23 mmol) was added under N2. After warming to room temperature and stirring for 3 hours, the reactants were 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 obtained residue was purified by silica gel chromatography (0-50% EA / PE) to give the title compound (486 mg, 65.06%) as a yellow solid. MS (ESI): C 28 H 45 Calculated mass of N5O4S2Si: 607.27, found: 608.25 [M+H] + .

[0691] 1-Butyl-5-(diaminomethylene)-3-((4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0692]

[0693] To a solution of 1-butyl-5-(1,3-dithian-2-ylidene)-3-((4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (486 mg, 0.82 mmol) in methanol (10 mL) was added 7N NH3 in MeOH (2 mL). The reaction was heated at 100 ° C for 1 hour. After cooling to room temperature, the reaction 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 obtained residue was purified by silica gel column chromatography (0-10% MeOH / DCM) to give the title compound (203 mg, 46.48%) as a yellow solid. MS (ESI): C 25 H 43 Calculated mass of N7O4Si: 533.31, found: 534.40 [M+H]+ .

[0694] 1-Butyl-5-(diaminomethylene)-3-(((1s,4s)-4-(5-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (41) and 1-Butyl-5-(diaminomethylene)-3-(((1r,4r)-4-(5-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (42)

[0695]

[0696] To a solution of 1-butyl-5-(diaminomethylene)-3-((4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)cyclohexyl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione (30 mg, 0.056 mmol) in DCM (3 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for 4 hours, the reaction was concentrated to dryness under reduced pressure to give the crude product, which was purified by reverse phase HPLC (26-45% (v / v) ACN and 0.05% NH4HCO3 in HO) to give the title compound 41 (3.8 mg, 16.73%) as a white solid. MS (ESI): C 19 H 29 Calculated mass of N7O3: 403.23, found: 404.20 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.53 (s, 2H), 7.33 (s, 2H), 3.65-3.81 (m, 4H), 2.71-2.88 (m, 1H), 2.18-2.34 (m, 3H), 1.91-2.07 (m, 3H), 1.81-1.90 (m, 1H), 1.54-1.68 (m, 2H), 1.21-1.54 (m, 7H), 0.88 (t, J = 7.2 Hz, 3H); and the title compound 42 (2.0 mg, 8.80%) was obtained as a white solid. MS (ESI): C 19 H 29 Calculated mass of N7O3: 403.23, found: 404.20 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 13.13 (s, 1H), 9.54 (s, 2H), 7.35 (s, 2H), 3.77 (t, J = 7.3 Hz, 2H), 3.68 (d, J = 6.7 Hz, 2H), 2.51-2.63 (m, 1H), 2.15-2.30 (m, 3H), 1.93 (d, J = 13.0 Hz, 2H), 1.65 (d, J = 12.9 Hz, 3H), 1.38-1.56 (m, 2H), 1.17-1.38 (m, 4H), 0.99-1.17 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). Stereochemistry is arbitrarily assigned.

[0697] Example 38 was synthesized from (3-methyl-4-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)phenyl)methanol following a similar procedure to that described in Example 41.

[0698] Example 43 was synthesized from (2-oxaspiro[3.5]nonan-7-yl)methanol using a procedure similar to that described in Steps 7 and 8 of Example 41.

[0699] Examples 51 and 52: 1-((2S,4s,7S)-7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (51) and 1-((2R,4r,7R)-7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (52)

[0700]

[0701] Synthesis process:

[0702]

[0703] N-Benzyl-N-methyl-8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecane-2-amine

[0704]

[0705] At room temperature, 8,11-dioxadispiro[3.2.4 7 .2 4] To a stirred solution of tridecane-2-one (1.4 g, 7.13 mmol) in methanol (15 mL) was added N-methylbenzylamine (1.73 g, 14.27 mmol). After stirring for 2 hours, NaBH3CN (0.9 g, 14.27 mmol) was added. After stirring for another 16 hours at room temperature, the reactant 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 give a crude product, which was further purified by silica gel column chromatography (PE / EA=3:1) to give the title compound (1.4 g, 65.11%) as a colorless oil. MS (ESI): C 19 H 27 Calculated mass of NO2: 301.20, Found: 302.20 [M+H] + .

[0706] 2-(Benzyl(methyl)amino)spiro[3.5]nonan-7-one

[0707]

[0708] To N-benzyl-N-methyl-8,11-dioxadispiro[3.2.4 7 .2 4 ] To a solution of tridecane-2-amine (1.68 g, 5.57 mmol) in tetrahydrofuran (10 mL) was added 4N HCl (5 mL). After heating at 60 ° C for 5 hours, the reactant was neutralized to pH = 7 with saturated NaHCO 3 solution. 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 give the title compound (1.0 g, 69.71%) as a white solid. MS (ESI): C 17 H 23 Calculated mass of NO: 257.18, found: 258.20 [M+H] + .

[0709] 2-(Benzyl(methyl)amino)spiro[3.5]nonan-7-ol

[0710]

[0711] To a solution of 2-(benzyl(methyl)amino)spiro[3.5]nonan-7-one (800 mg, 3.11 mmol) in methanol (10 mL) was added NaBH4 (176 mg, 4.66 mmol) in portions at 0 ° C. After stirring at room temperature for 2 hours, the reaction was quenched with water (10 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=15:1) to give the title compound (600 mg, 74.42%) as a colorless oil. MS (ESI): C 17 H 25 Calculated mass of NO: 259.19, found: 260.30 [M+H] + .

[0712] 2-(Methylamino)spiro[3.5]nonan-7-ol

[0713]

[0714] To a solution of 2-(benzyl(methyl)amino)spiro[3.5]nonan-7-ol (300 mg, 1.16 mmol) in methanol (10 mL) was added Pd / C (50 mg). The reaction was stirred under a hydrogen atmosphere (balloon) for 2 hours. The reaction mixture was then filtered through a pad of celite and concentrated under reduced pressure to give the title compound (0.2 g, 99%) as a white solid. MS (ESI): C 10 H 19 Calculated mass of NO: 169.15 m / z, observed mass: 170.20 [M+H] + .

[0715] Benzyl (7-hydroxyspiro[3.5]nonan-2-yl)(methyl)carbamate

[0716]

[0717] 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) at room temperature for 10 minutes, followed by the dropwise addition of CbzCl (221 mg, 1.30 mmol) 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 phases were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was further purified by silica gel column chromatography (PE / EA=2: 1) to give the title compound (0.3 g, 83.8%) as a white solid. MS (ESI): C18 H 25 The calculated mass value of NO3 is 303.18 m / z, and the experimental value is 304.20 [M+H]+.

[0718] Benzyl (7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-1(2I)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate

[0719]

[0720] To a solution of benzyl (7-hydroxyspiro [3.5] nonan-2-yl) (methyl) carbamate (0.29 g, 0.96 mmol) in toluene (6 mL) was added 1-butyl-5-(1,3-dithiane-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). Tributylphosphine (388 mg, 1.92 mmol) was then added to the mixture at 0 ° C under a nitrogen atmosphere. The resulting mixture was heated at 100 ° C for 16 hours 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 give a crude product, which was purified by silica gel column chromatography (PE / EA=2:1) to give the title compound (120 mg, 21.35%) as a yellow solid. MS (ESI): C 30 H 39 Calculated mass of N3O5S2: 585.23, found: 586.20 [M+H] + .

[0721] Benzyl (7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate

[0722]

[0723] To a solution of benzyl (7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (120 mg, 0.20 mmol) in methanol (5 mL) was added 7N NH 3 in methanol (0.7 mL). 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 give the title compound (90 mg, 88.23%) as a white solid. MS (ESI): C 27 H 37 Calculated mass of N5O5: 511.28, found: 512.30 [M+H] + .

[0724] Butyl-5-(diaminomethylene)-3-(2-(methylamino)spiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0725]

[0726] To a solution of benzyl (7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (90 mg, 0.17 mmol) in methanol was added Pd / C (30 mg). The reaction mixture was stirred under a hydrogen atmosphere (balloon) for 0.5 h. The reaction mixture was then filtered through a pad of celite and concentrated under reduced pressure to give the title compound (60 mg, 90.9%) as a white solid. MS (ESI): C 19 H 31 Calculated mass of N5O3: 377.24, found: 378.05 [M+H] + .

[0727] 1-((2S,4s,7S)-7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (51) and 1-((2R,4r,7R)-7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (52)

[0728]

[0729] To a solution of butyl-5-(diaminomethylene)-3-(2-(methylamino)spiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (135 mg, 0.36 mmol) in DCM (5 mL) was added TEA (182 mg, 1.80 mmol) followed by isocyanatotrimethylsilane (124 mg, 1.08 mmol) at room temperature. After stirring at room temperature for 2 hours, the reaction was quenched with water (10 mL) and extracted with DCM (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was directly purified by silica gel column chromatography (DCM / MeOH=8:1). The resulting purified product was purified by chiral HPLC to give the title compound 51 (25 mg) as a white solid (MS (ESI): C 20 H 32 Calculated mass of N6O4: 420.25, found: 421.20 [M+H] + ); 1 H NMR (300 MHz; CD3OD) δ 4.73 (tt, J = 12.2, 3.5 Hz, 1H), 4.55 (quintet, J = 8.7 Hz, 1H), 3.84 (t, J = 7.5 Hz, 2H), 2.86 (s, 3H), 2.50 (dqd, J = 24.4, 12.3, 3.4 Hz, 2H), 2.30 (ddd, J = 11.3, 8.3, 2.9 Hz, 1H), 1.83-1.97 (m, 4H), 1.69 (dq, J = 13.0, 2.7 Hz, 1H), 1.28-1.59 (m, 8H), 0.95 (t, J = 7.3 Hz, 3H); and the title compound 52 (25 mg) as a white solid (MS (ESI): C 20 H 32 Calculated mass of N6O4: 420.25, found: 421.20 [M+H] + ); 1 H NMR (300 MHz; CD3OD) δ 4.73 (tt, J = 12.2, 3.5 Hz, 1H), 4.55 (quintet, J = 8.7 Hz, 1H), 3.84 (t, J = 7.5 Hz, 2H), 2.86 (s, 3H), 2.50 (dqd, J = 24.4, 12.3, 3.4 Hz, 2H), 2.30 (ddd, J = 11.3, 8.3, 2.9 Hz, 1H), 1.83-1.97 (m, 4H), 1.69 (dq, J = 13.0, 2.7 Hz, 1H), 1.28-1.59 (m, 8H), 0.95 (t, J = 7.3 Hz, 3H). Stereochemistry was arbitrarily assigned.

[0730] Example 21 is the product before chiral separation in the above synthesis.

[0731] Example 29 was synthesized from tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate using a procedure similar to that described in Steps 6 to 9 of Example 51. TFA was used in place of Pd to deprotect the Boc group in Step 8.

[0732] Examples 45 and 54 were synthesized by procedures similar to those described in Example 29 from respective isomers of tert-butyl 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.

[0733] Example 97 was synthesized by a procedure similar to 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.

[0734] Examples 65, 68 and 73 were synthesized by a similar procedure to Example 21.

[0735] Examples 92 and 93 were synthesized by similar procedures to those described in Examples 51 and 52.

[0736] Example 55: 7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-methylspiro[3.5]nonane-2-carboxamide (55)

[0737]

[0738] Synthesis process:

[0739]

[0740] 7-Oxospiro[3.5]nonane-2-carboxylic acid methyl ester

[0741]

[0742] To a solution of 7-oxospiro[3.5]nonane-2-carboxylic acid (3 g, 16.46 mmol) in acetone (30 mL) was added potassium carbonate (6.88 g, 49.39 mmol) and MeI (11.68 g, 82.32 mmol) at room temperature. After stirring overnight, the reactant 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 give a crude product, which was purified by silica gel column chromatography (0-100% EA / PE) to give the title compound (2.2 g, 68.09%) as a yellow solid. MS (ESI): C 11 H 16 Calculated mass of O3: 196.14, found: 197.15 [M+H] + .

[0743] 7-Hydroxyspiro[3.5]nonane-2-carboxylic acid methyl ester

[0744]

[0745] To a solution of methyl 7-oxospiro[3.5]nonane-2-carboxylate (2.1 g, 10.70 mmol) in MeOH (20 mL) was added NaBH4 (2.02 g, 53.51 mmol) at 0 ° C. After stirring for 2 hours at the same temperature, the reactant 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 give the crude product, which was purified by silica gel column chromatography (0-100% EA / PE) to give the title compound (1.5 g, 70.7%) as a yellow solid. MS (ESI): C 11 H 18 Calculated mass of O3: 198.13, Found: 181.10 [M-OH] + .

[0746] Methyl 7-[(tert-Butyldiphenylsilyl)oxy]spiro[3.5]nonane-2-carboxylate

[0747]

[0748] To a solution of methyl 7-hydroxyspiro[3.5]nonane-2-carboxylate (500 mg, 2.52 mmol) in dimethylformamide (10 mL) was added imidazole (515.07 mg, 7.57 mmol) and TBDPSCl (1.04 g, 3.78 mmol) at 0 ° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reactants were 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 give a crude product, which was purified by silica gel column chromatography (0-100% EA / PE) to give the title compound (1 g, 90.81%) as a yellow solid. MS (ESI): C 27 H 36 Calculated mass of O3Si: 436.24, Found: 437.30 [M+H] + .

[0749] Methyl 7-[(tert-Butyldiphenylsilyl)oxy]-2-methylspiro[3.5]nonane-2-carboxylate

[0750]

[0751] To a solution of methyl 7-[(tert-butyldiphenylsilyl)oxy]spiro[3.5]nonane-2-carboxylate (50 mg, 0.12 mmol) in THF (2 mL) was added LDA (0.07 mL, 0.14 mmol) dropwise under N2 atmosphere at -78 ° C. The reaction mixture was stirred at the same temperature for 30 minutes. A solution of MeI (48.76 mg, 0.35 mmol) in 1 mL of THF was subsequently added dropwise, and the reactants were stirred for another 60 minutes. The reactants were quenched with water / saturated NH4Cl (5 mL) and extracted with ether / EtOAc (2 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by silica gel chromatography (PE: EA = 10: 1) to give the title compound (400 mg, 77.51%) as a yellow solid. MS (ESI): C 28 H 38 Calculated mass of O3Si: 450.26, Found: 451.30 [M+H] + .

[0752] 7-Hydroxy-2-methylspiro[3.5]nonane-2-carboxylic acid methyl ester

[0753]

[0754] To a solution of methyl 7-[(tert-butyldiphenylsilyl)oxy]-2-methylspiro[3.5]nonane-2-carboxylate (380 mg, 0.84 mmol) in tetrahydrofuran (3 mL) was added triethylamine trihydrofluoride (3 mL) at 0 ° C. The reaction was allowed to warm to room temperature and heated at 70 ° C for 2 hours. The reactant 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 give the crude product, which was purified by silica gel column chromatography (0-100% EA / PE) to give the title compound (100 mg, 55.87%) as a yellow solid.

[0755] 7-[3-Butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxo-1,3-diazacyclohexan-1-yl]-2-methylspiro[3.5]nonane-2-carboxylic acid methyl ester

[0756]

[0757] To a solution of 7-hydroxy-2-methylspiro[3.5]nonane-2-carboxylic acid methyl ester (80 mg, 0.38 mmol) in toluene (3 mL) was added 1-butyl-5-(1,3-dithiane-2-ylidene)-1,3-diazacyclohexane-2,4,6-trione (113.20 mg, 0.38 mmol), TMAD (194.66 mg, 1.131 mmol), n-Bu3P (228.73 mg, 1.13 mmol) at room temperature. The resulting mixture was heated at 100 ° C for 2.5 hours. The reactant 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 give a crude product, which was purified by silica gel column chromatography (0-100% EA / PE) to give the title compound (30 mg, 16.09%) as a yellow solid. MS(ESI):C 24 H 34 Calculated mass of N2O5S2: 494.19, found: 495.15 [M+H] + .

[0758] 7-[3-Butyl-5-(diaminomethylene)-2,4,6-trioxo-1,3-diazacyclohexan-1-yl]-2-methylspiro[3.5]nonane-2-carboxylic acid methyl ester

[0759]

[0760] To a solution of methyl 7-[3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxo-1,3-diazacyclohexane-1-yl]-2-methylspiro[3.5]nonane-2-carboxylate (50 mg, 0.10 mmol) was added 7N ammonia in methanol (6 mL) at room temperature. After heating at 100 ° C for 1 hour, the reactant 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 give the crude product, which was purified by silica gel column chromatography (0-100% EA / PE) to give the title compound (30 mg, 70.58%) as a yellow solid. MS (ESI): C 21 H 32 Calculated mass of N4O5: 420.14, found: 421.30 [M+H] + .

[0761] 7-[3-Butyl-5-(diaminomethylene)-2,4,6-trioxo-1,3-diazacyclohexan-1-yl]-2-methylspiro[3.5]nonane-2-carboxylic acid

[0762]

[0763] To a solution of methyl 7-[3-butyl-5-(diaminomethylene)-2,4,6-trioxo-1,3-diazacyclohexane-1-yl]-2-methylspiro[3.5]nonane-2-carboxylate (30 mg, 0.071 mmol) in water (1 mL), THF (3 mL) and MeOH (1 mL) was added LiOH (17.09 mg, 0.71 mmol) at room temperature. After heating at 65 ° C for 3 hours, the reaction was quenched with water and extracted with EA (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (0-100% EA / PE) to give the title compound (20 mg, 68.97%) as a white solid. MS (ESI): C 20 H 30 Calculated mass of N4O5: 406.22, found: 407.10 [M+H] + .

[0764] 7-[3-Butyl-5-(diaminomethylene)-2,4,6-trioxo-1,3-diazacyclohexan-1-yl]-2-methylspiro[3.5]nonane-2-carboxamide

[0765]

[0766] To a solution of 7-[3-butyl-5-(diaminomethylene)-2,4,6-trioxo-1,3-diazacyclohexane-1-yl]-2-methylspiro[3.5]nonane-2-carboxylic acid (15 mg, 0.037 mmol) in DMF (2 mL) was added NH4Cl (5.92 mg, 0.11 mmol), HATU (21.05 mg, 0.055 mmol), DIPEA (9.54 mg, 0.074 mmol) at room temperature. After stirring at room temperature for 3 hours, the reactant was quenched with water and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (0-100% EA / PE) to give an impure product. The impure product was further purified by reverse phase HPLC (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; 17% B to 42% B) to give the title compound 55 (3.1 mg, 20.69%) as a white solid. MS (ESI): C 20 H 31 Calculated mass of N5O4: 405.24, found: 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).

[0767] Example 64 was synthesized by a procedure similar to that described in Example 55.

[0768] Example 58: 1-(1-(1H-pyrazole-4-carbonyl)piperidin-4-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (58)

[0769]

[0770] Synthesis process:

[0771]

[0772] 1-Butyl-5-(diaminomethylene)-3-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonyl)piperidin-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0773]

[0774] To a solution of 1-butyl-5-(diaminomethylene)-3-(piperidin-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared from 4-aminopiperidine-1-carboxylic acid benzyl ester, 58 mg, 0.19 mmol) in DMF (2 mL) was added DIPEA (49 mg, 0.38 mmol) and HATU (107 mg, 0.28 mmol). After stirring overnight at room temperature, the reaction was quenched with water (10 mL) and extracted with EA (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography to give the title compound (70 mg, 69.93%) as a yellow oil. MS (ESI): C 24 H 39 Calculated mass of N7O5Si: 533.28, found: 534.25 [M+H] + .

[0775] 1-(1-(1H-pyrazole-4-carbonyl)piperidin-4-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione

[0776]

[0777] A solution of 1-butyl-5-(diaminomethylene)-3-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonyl)piperidin-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (60 mg, 0.11 mmol) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at room temperature for 2 hours. The mixture was neutralized to pH = 7 with NaHCO 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. To this crude residue was added NH3.H2O (3 mL). After stirring at room temperature 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 obtained residue was purified by reverse phase HPLC (17% to 42% (v / v) ACN and water containing 0.05% NH4HCO3) to give the title compound 58 (5.1 mg, 11.24%) as a white solid. MS (ESI): C 18 H 25 Calculated mass of N7O4: 403.20, found: 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).

[0778] Example 62: 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (62)

[0779]

[0780] Synthesis process:

[0781]

[0782] tert-Butyl ((1s,4s)-4-(bromomethyl)cyclohexyl)carbamate

[0783]

[0784] To a solution of tert-butyl ((1s, 4s)-4-(hydroxymethyl)cyclohexyl)carbamate (1.5 g, 6.54 mmol) in DCM (50 mL) was added carbon tetrabromide (2.39 g, 7.20 mmol) at 0 ° C., followed by the slow addition of triphenylphosphine (2.06 g, 7.85 mmol). The mixture was allowed to warm to room temperature and stirred for 4 hours. The reactants were quenched with water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-20% PE / EA) to give the title compound (1.2 g, 62.78%) as a white solid. MS (ESI): C 12 H 22 Calculated mass of BrNO2: 291.08, experimental value: 236.15 [M- t Bu+H] + .

[0785] tert-Butyl ((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)carbamate

[0786]

[0787] To a solution of tert-butyl ((1s, 4s)-4-(bromomethyl)cyclohexyl)carbamate (1.2 g, 4.11 mmol) in N,N-dimethylformamide (20 mL) was added CsCO (2.01 g, 6.16 mmol) and 5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (1.06 g, 4.11 mmol). The reactants were heated at 50 ° C for 4 hours. After cooling to room temperature, the reactants were quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-50% EA / PE) to give the title compound (812 mg, 42.10%) as a yellow oil. MS (ESI): C 23 H 43 Calculated mass of N3O5Si: 469.30, experimental value: 492.30 [M+Na] + .

[0788] 1-(((1s,4s)-4-aminocyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione

[0789]

[0790] A solution of tert-butyl ((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)carbamate (812 mg, 1.73 mmol) in formic acid (10 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated and then basified 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 give the title compound (501 mg, 78.41%) as a yellow oil. MS (ESI): C 18 H 35 Calculated mass of N3O3Si: 369.24, found: 370.20 [M+H] + .

[0791] 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)urea

[0792]

[0793] To a solution of 1-(((1s,4s)-4-aminocyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (501 mg, 1.36 mmol) in 1,2-dichloroethane (10 mL) was added TEA (411.53 mg, 4.07 mmol) and 1-isocyanatobutane (268 mg, 2.71 mmol). After stirring at room temperature for 2 hours, the reactant was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-100% EA / PE) to give the title compound (482 mg, 75.86%) as a yellow solid. MS (ESI): C 23 H 44 Calculated mass of N4O4Si: 468.31, found: 469.35 [M+H] + .

[0794] 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

[0795]

[0796] To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)urea (486 mg, 1.04 mmol) in DCM (10 mL) was added malonyl dichloride (438 mg, 3.11 mmol). After stirring at room temperature for 5 hours, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-100% EA / PE) to give the title compound (381 mg, 68.46%) as a yellow solid.

[0797] 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

[0798]

[0799] To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (380 mg, 0.71 mmol) in DMSO (10 mL) was added carbon disulfide (538 mg, 7.08 mmol) and TEA (1074 mg, 10.62 mmol). After stirring at room temperature for 3 hours, the reaction was cooled to 0 ° C., followed by the addition of 1,3-dibromopropane (1429 mg, 7.08 mmol). After stirring for an additional 2 hours, the reaction 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 crude residue was purified by silica gel column chromatography (0-70% EA / PE) to give the title compound (201 mg, 43.48%) as a yellow solid. MS (ESI): C 30 H 48 Calculated mass of N₄O₆S₂Si: 652.28, found: 653.30 [M+H] + .

[0800] 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

[0801]

[0802] To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)-5-(1,3-dithian-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (201 mg, 0.31 mmol) in methanol (5 mL) was added ammonia (7N solution in methanol, 2 mL). After stirring at 100 ° C. for 1 hour, the reaction was cooled to room temperature and concentrated. The obtained residue was purified by silica gel column chromatography (0-100% EA / PE) to give the title compound (115 mg, 64.54%) as a yellow solid. MS (ESI): C 27 H 46 Calculated mass of N6O6Si: 578.32, found: 579.35 [M+H] + .

[0803] 1-Butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0804]

[0805] To a solution of 1-butyl-5-(diaminomethylene)-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (120 mg, 0.21 mmol) in DCM (4 mL) was added TFA (1 mL). After stirring at room temperature for 4 hours, the reaction was concentrated to dryness under reduced pressure and then dissolved in ammonia (2N solution in methanol, 2 mL). After stirring at room temperature for 2 hours, the reaction was concentrated to dryness to give the crude product, which was purified by reverse phase HPLC (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; 26% B to 45% B) to give the title compound 62 (17.4 mg, 18.68%) as a white solid. MS(ESI):C21 H 32 Calculated mass of N6O5: 448.24, found: 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).

[0806] Examples 31, 32 and 67 were synthesized by similar procedures to those described in Example 62.

[0807] Example 35 was synthesized from tert-butyl (4-(3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)phenethyl)carbamate (prepared by CuI-mediated coupling of 3,5,5-trimethylimidazolidine-2,4-dione and tert-butyl (4-bromophenethyl)carbamate) by a procedure similar to that described in Example 62.

[0808] Example 66: 7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)-2-azaspiro[3.5]nonane-2-carboxamide (66)

[0809]

[0810] Synthesis process:

[0811]

[0812] tert-Butyl 7-(N-(butylcarbamoyl)-2-cyanoacetamido)-2-azaspiro[3.5]nonane-2-carboxylate (minor) and tert-Butyl 7-(3-butyl-3-(2-cyanoacetyl)ureido)-2-azaspiro[3.5]nonane-2-carboxylate (major)

[0813]

[0814] To a stirred solution of tert-butyl 7-(3-butylureido)-2-azaspiro[3.5]nonane-2-carboxylate (see Example 17 for the procedure, 790 mg, 2.78 mmol) in acetic anhydride (10 mL) was added cyanoacetic acid (284 mg, 3.34 mmol). After heating at 60° C. for 3 hours, the reaction was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (40% to 50% EA / PE) to give the title compound, tert-butyl 7-(N-(butylcarbamoyl)-2-cyanoacetamido)-2-azaspiro[3.5]nonane-2-carboxylate (200 mg, 17.69%, minor isomer). MS (ESI): C 21 H 34 Calculated mass of N4O4: 406.26 m / z, found: 407.30 [M+H] + and the title compound tert-butyl 7-(3-butyl-3-(2-cyanoacetyl)ureido)-2-azaspiro[3.5]nonane-2-carboxylate (700 mg, 61.92%, major isomer). MS (ESI): C 21 H 34 Calculated mass of N4O4: 406.26, found: 407.30 [M+H] + .

[0815] tert-Butyl 7-(4-amino-3-butyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate

[0816]

[0817] To a stirred solution of tert-butyl 7-(N-(butylcarbamoyl)-2-cyanoacetamido)-2-azaspiro[3.5]nonane-2-carboxylate (minor isomer from above, 180 mg, 0.44 mmol) in ethanol (5 mL) was added dropwise EtOH containing sodium ethoxide (9 mg, 0.13 mmol). After heating at 70 ° C for 1 hour, the reaction was quenched with water (5 mL) and extracted with DCM (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (0-10% MeOH / DCM) to give the title compound (0.1 g, 55.86%). MS (ESI): C 21 H 34 Calculated mass of N4O4: 406.26, found: 407.20 [M+H] + .

[0818] tert-Butyl 7-{7-butyl-3-cyano-4,6-dioxo-[1,2]thiazolo[3,4-d]pyrimidin-5-yl}-2-azaspiro[3.5]nonane-2-carboxylate

[0819]

[0820] To a stirred solution of 4,5-dichloro-5H-1,2,3-dithiazol-3-ium chloride (85 mg, 0.49 mmol) in DCM (5 mL) was added tert-butyl 7-(4-amino-3-butyl-2,6-dioxopyrimidin-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate (100 mg, 0.24 mmol) at room temperature, followed by pyridine (89 mg, 1.13 mmol). After stirring overnight, the reactant was quenched with water (5 mL) and extracted with DCM (15 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was further purified by column chromatography (30-35% EA / PE) to give the title compound (55 mg, 47.21%) as a yellow oil. MS (ESI): C 23 H 31 Calculated mass of N5O4S: 473.21, Found: 496.25 [M+Na] + .

[0821] tert-Butyl 7-(7-butyl-3-{[(4-methoxyphenyl)methyl]amino}-4,6-dioxo-[1,2]thiazolo[3,4-d]pyrimidin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate

[0822]

[0823] A solution of tert-butyl 7-{7-butyl-3-cyano-4,6-dioxo-[1,2]thiazolo[3,4-d]pyrimidin-5-yl}-2-azaspiro[3.5]nonane-2-carboxylate (55 mg, 0.12 mmol) and (4-methoxyphenyl)methanamine (159 mg, 1.16 mmol) in dimethylformamide (3 mL) was heated at 90° C. for 1 hour. The crude residue was purified by silica gel column chromatography eluting with PE / EA (30%) to give 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, found: 584.35 [M+H] + .

[0824] 3-Amino-5-{2-azaspiro[3.5]nonan-7-yl}-7-butyl-[1,2]thiazolo[3,4-d]pyrimidine-4,6-dione

[0825]

[0826] A solution of tert-butyl 7-(7-butyl-3-{[(4-methoxyphenyl)methyl]amino}-4,6-dioxo-[1,2]thiazolo[3,4-d]pyrimidin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate (40 mg, 0.069 mmol) in trifluoroacetic acid (2.7 mL) and water (0.3 mL) was stirred at room temperature overnight. The reaction was concentrated, and the crude residue was purified by reverse phase HPLC to give the title compound (25 mg, 99%) as a colorless oil. MS (ESI): C 17 H 25 Calculated mass of N5O2S: 363.17 m / z, found: 364.20 [M+H] + .

[0827] 7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)-2-azaspiro[3.5]nonane-2-carboxamide

[0828]

[0829] To a solution of 3-amino-5-{2-azaspiro[3.5]non-7-yl}-7-butyl-[1,2]thiazolo[3,4-d]pyrimidine-4,6-dione (15 mg, 0.041 mmol) in DCM (2 mL) and triethylamine (13.78 mg, 0.13 mmol) was added isocyanatotrimethylsilane (10.46 mg, 0.090 mmol). After stirring at room temperature for 1 hour, the reactant was quenched with water (3 mL) and extracted with DCM (5 mL). The combined organic layers were purified by reverse phase HPLC (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; 17% B to 42% B, 42% B in 9 min) to give the title compound 66 (3 mg, 17.76%) as a white solid. MS (ESI): C 18 H 26 Calculated mass of N6O3S: 406.18, found: 407.15 [M+H] + . 1H 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).

[0830] Example 59 was synthesized by a similar procedure to that described in Example 66 from the major isomer in the first step.

[0831] Examples 69, 70 and 76 (mixed with 30% of 70) were synthesized by a procedure similar to that described in Example 66 starting with a cis- and trans-mixture of 1-((4-aminocyclohexyl)methyl)-3,5,5-trimethylimidazolidine-2,4-dione and obtained by chiral separation.

[0832] Example 74: 1-(2-(3-(aminomethyl)oxetan-3-yl)-2-azaspiro[3.5]nonan-7-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (74)

[0833]

[0834] Synthesis process:

[0835]

[0836] 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonan-2-yl)oxetane-3-carbonitrile

[0837]

[0838] To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (70 mg, 0.2 mmol) in acetic acid (3 mL) was added 3-oxetanedone (144 mg, 2.0 mmol) and trimethylsilyl cyanide (298 mg, 3.0 mmol). After heating at 80 ° C for 6 hours, the reaction 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 give the crude product, which was purified by silica gel column chromatography (DCM / MeOH=10:1) to give the title compound (40 mg, 46.38%). MS (ESI): C 21 H 30 Calculated mass of N6O4: 430.23, found: 431.20 [M+H] + .

[0839] 1-(2-(3-(aminomethyl)oxetan-3-yl)-2-azaspiro[3.5]nonan-7-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione

[0840]

[0841] To a solution of 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]non-2-yl)oxetane-3-carbonitrile (20 mg, 0.046 mmol) in tetrahydrofuran (3 mL) was added LiAlH4 (9 mg, 0.23 mmol). After stirring at 0°C for 0.5 h, the reaction was quenched with saturated Na2SO4 (aqueous solution, 0.1 mL). MeOH (5 mL) was added, and the mixture was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by reverse phase HPLC (mobile phase A: water (0.1% FA), mobile phase B: ACN; 10% B to 19% B) to give the title compound 74 (0.8 mg, 3.78%) as a light yellow solid. MS (ESI): C 21 H 34 Calculated mass of N6O4: 434.26, found: 435.20 [M+H] + . 1H 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).

[0842] 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)

[0843]

[0844] Synthesis process:

[0845]

[0846] 8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecane-2-carbonitrile

[0847]

[0848] To 8,11-dioxadispiro[3.2.4 7 .2 4 ] To a solution of tridecane-2-one (1.0 g, 5.1 mmol) in DME (10 mL) and t-BuOH (10 mL) was added TosMIC (2.09 g, 10.7 mmol). The resulting mixture was stirred at room temperature for 10 minutes, and t-BuOK (2.52 g, 22.42 mmol) was added in batches at 0 ° C. After stirring at room temperature overnight, the reactant 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 give the title compound (400 mg, 37.87%) as a yellow solid.

[0849] 2-(Methoxymethyl)-8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecane-2-carbonitrile

[0850]

[0851] Under N2 atmosphere at -78 °C, 8,11-dioxadispiro[3.2.4 7 .2 4 ] To a solution of tridecane-2-carbonitrile (400 mg, 1.93 mmol) in THF (10 mL) was added 2M LDA (in THF, 1.9 mL, 3.86 mmol). 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 reactant was quenched with NH4Cl (aqueous solution, 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 = 10: 1) to give the title compound (330 mg, 68.04%) as a yellow oil.

[0852] (2-(Methoxymethyl)-8,11-dioxadispiro[3.2.4 7 .2 4 ]tridec-2-yl)methylamine

[0853]

[0854] To a solution of 2-(methoxymethyl)-8,11-dioxadispiro[3.2.47.24]tridecane-2-carbonitrile (390 mg, 1.55 mmol) in THF (8 mL) was added LiAlH4 (117 mg, 3.10 mmol) under N2 atmosphere at 0 ° C. After stirring at room temperature for 4 hours, the reactant 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 give the crude material (2-(methoxymethyl)-8,11-dioxadispiro[3.2.47.24]tridecane-2-carbonitrile) as a yellow oil. 7 .2 4 ]tridec-2-yl)methanamine (380 mg, 95.9%), which was used in the next step without further purification.

[0855] ((2-(Methoxymethyl)-8,11-dioxadispiro[3.2.4 7 .2 4 ]tridec-2-yl)methyl)carbamic acid benzyl ester

[0856]

[0857] 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) was added TEA (475 mg, 4.7 mmol) and CbzCl (320 mg, 1.88 mmol) under N2 atmosphere at 0 ° C. After stirring at room temperature for 3 hours, the reactant was quenched with water (30 mL) and extracted with DCM (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 to give the title compound (430 mg, 70.48%) as a light yellow oil. MS (ESI): C 22 H 31 Calculated mass of NO5: 389.22, experimental value: 412.30 [M+Na] + .

[0858] Benzyl ((2-(methoxymethyl)-7-oxospiro[3.5]nonan-2-yl)methyl)carbamate

[0859]

[0860] ((2-(methoxymethyl)-8,11-dioxadispiro[3.2.4 7 .2 4 ] A solution of benzyl tridecane-2-yl)methyl)carbamate (440 mg, 1.13 mmol) in 2N HCl (3 mL) and THF (3 mL) was heated at 60 ° C for 2 hours. The reactant was neutralized with NaHCO3 solution to pH = 7 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 obtained residue was purified by silica gel column chromatography to give the title compound (350 mg, 89.69%) as a light yellow oil. MS (ESI): C 20 H 27 Calculated mass of NO4: 345.19, experimental value: 368.20 [M+Na] + .

[0861] Benzyl ((7-hydroxy-2-(methoxymethyl)spiro[3.5]nonan-2-yl)methyl)carbamate

[0862]

[0863] To a solution of benzyl ((2-(methoxymethyl)-7-oxospiro[3.5]nonan-2-yl)methyl)carbamate (340 mg, 0.98 mmol) in MeOH (5 mL) was added NaBH4 (56 mg, 1.48 mmol) at 0 ° C. After stirring at room temperature for 2 hours, the reaction was quenched with ice water (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=5:1) to give the title compound (300 mg, 87.72%) as a light yellow oil. MS (ESI): C 20 H 29 Calculated mass of NO4: 347.21, experimental value: 370.15 [M+Na] + .

[0864] Benzyl ((7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-(methoxymethyl)spiro[3.5]nonan-2-yl)methyl)carbamate

[0865]

[0866] To a solution of benzyl ((7-hydroxy-2-(methoxymethyl)spiro[3.5]nonan-2-yl)methyl)carbamate (130 mg, 0.37 mmol) in toluene (3 mL) was added 1-butyl-5-(1,3-dithian-2-ylidene)-1,3-diazacyclohexane-2,4,6-trione (112.39 mg, 0.37 mmol), TMAD (193.27 mg, 1.12 mmol) and n-Bu3P (227.10 mg, 1.12 mmol) at room temperature. After heating at 100 ° C overnight, the reaction was quenched with water and 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 give the title compound (50 mg, 19.62%) as a light yellow solid. MS (ESI): C 32 H 43 Calculated mass of N3O6S2: 629.26, Found: 652.10 [M+Na] + .

[0867] Benzyl ((7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-(methoxymethyl)spiro[3.5]nonan-2-yl)methyl)carbamate

[0868]

[0869] To a solution of benzyl ((7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-(methoxymethyl)spiro[3.5]nonan-2-yl)methyl)carbamate (50 mg, 0.079 mmol) in MeOH (2 mL) was added 7N NH in MeOH (2 mL). After heating at 110 ° C for 2 hours, the reaction 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 obtained residue was purified by silica gel chromatography to give the title compound (40 mg, 86.86%) as a light yellow solid. MS (ESI): C 29 H 41 Calculated mass of N5O6: 555.31, found: 556.30 [M+H] + .

[0870] 1-(2-(Aminomethyl)-2-(methoxymethyl)spiro[3.5]nonan-7-yl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione

[0871]

[0872] To a solution of benzyl ((7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-(methoxymethyl)spiro[3.5]nonan-2-yl)methyl)carbamate (40 mg, 0.072 mmol) in DCM (1.5 mL) at 0°C was added 40% HBr (in AcOH, 0.5 mL). After stirring at room temperature for 2 hours, the reaction was purified by reverse phase HPLC to give the title compound 75 (TFA salt, 7.5 mg, 17.79%) as a light grey solid. MS (ESI): C 21 H 35 Calculated mass of N5O4: 421.27, found: 422.25 [M+H] + . 1H 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).

[0873] Example 78: 1-Butyl-5-(diaminomethylene)-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (78)

[0874]

[0875] Synthesis process:

[0876]

[0877] Ethyl 2-((8,11-dioxadispiro[3.2.47.24]tridec-2-yl)amino)-2-methylpropanoate

[0878]

[0879] At room temperature, 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) was added ethyl 2-amino-2-methylpropanoate (0.43 g, 3.32 mmol) and AcOH (0.1 mL). After stirring for 1 hour, NaBH(OAc)3 (1.08 g, 5.10 mmol) was added to the reactant, and the reactant was stirred for 16 hours. The reactant 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 give a crude product, which was purified by silica gel column chromatography (PE / EA=2:1) to give the title compound (0.2 g, 37.0%) as a colorless oil. MS (ESI): C 17 H 29 Calculated mass of NO4: 311.20, Found: 312.30 [M+H] + .

[0880] 5,5-Dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)imidazolidine-2,4-dione

[0881]

[0882] To a stirred solution of ethyl 2-((8,11-dioxadispiro[3.2.47.24]tridec-2-yl)amino)-2-methylpropanoate (0.2 g, 0.64 mmol) in AcOH (3 mL) was added KOCN (0.26 g, 3.21 mmol) at room temperature. The reaction mixture was heated at 100 ° C for 16 hours. After completion, the reaction was cooled and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (DCM / MeOH = 10: 1) to give the title compound (150 mg, 88.2%) as a yellow solid. MS (ESI): C 14 H 20 Calculated mass of N2O3: 264.15, found: 265.15 [M+H] + .

[0883] 1-(7-aminospiro[3.5]nonan-2-yl)-5,5-dimethylimidazolidine-2,4-dione

[0884]

[0885] To a solution of 5,5-dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)imidazolidine-2,4-dione (180 mg, 0.68 mmol) in 7N NH3 in methanol (5 mL) was added Pd / C (50 mg). The reaction was stirred under a hydrogen atmosphere (balloon) for 0.5 h. The reaction was filtered through a pad of celite and concentrated under reduced pressure to give the title compound (0.15 g, 83.3%) as a yellow oil. MS (ESI): C 14 H 23 Calculated mass of N3O2: 265.18, found: 266.30 [M+H] + .

[0886] 1-Butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)urea

[0887]

[0888] To a solution of 1-(7-aminospiro[3.5]nonan-2-yl)-5,5-dimethylimidazolidine-2,4-dione (0.15 g, 0.56 mmol) in ClCH2CH2Cl (3 mL) was added butyl isocyanate (83 mg, 0.84 mmol). After stirring overnight at room temperature, the resulting mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH=10:1) to give the title compound (0.12 g, 59.1%) as a yellow solid. MS (ESI): C 19 H 32 Calculated mass of N4O3: 364.25, found: 365.20 [M+H] + .

[0889] 1-Butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0890]

[0891] To a solution of 1-butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)urea (120 mg, 0.33 mmol) in DCM (3 mL) was added malonyl dichloride (93 mg, 0.66 mmol) at 0 ° C. After stirring at room temperature for 4 hours, the reaction mixture 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 give the crude product, which was purified by silica gel column chromatography (DCM / MeOH=10:1) to give the title compound (55 mg, 38.7%) as a yellow oil. MS (ESI): C 22 H 32 Calculated mass of N4O5: 432.24, found: 433.35 [M+H] + .

[0892] 1-Butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)-5-(1,3-dithian-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione

[0893]

[0894] To a solution of 1-butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (50 mg, 0.12 mmol) in DMSO (2 mL) was added carbon disulfide (26 mg, 0.35 mmol) and TEA (46 mg, 0.460 mmol) at room temperature. After stirring at room temperature for 1 hour, 1,3-dibromopropane (46 mg, 0.23 mmol) was added. The resulting mixture was stirred for 2.5 hours. Upon completion, the reactant 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 give a crude product, which was purified by silica gel column chromatography (DCM / MeOH=10:1) to give the title compound (45 mg, 71.4%) as a yellow solid. MS (ESI): C 26 H 36 Calculated mass of N4O5S2: 548.21, found: 549.15 [M+H] + .

[0895] 1-Butyl-5-(diaminomethylene)-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0896]

[0897] To a solution of 1-butyl-3-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)-5-(1,3-dithian-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (40 mg, 0.07 mmol) in methanol (3 mL) was added 7N NH3 in methanol (0.4 mL). After heating at 100°C for 1 hour, the reaction was concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC to give the title compound 78 (2.4 mg, 6.8%) as a white solid. MS (ESI): C 23 H 34 Calculated mass of N6O5: 474.26, found: 475.20 [M+H] + . 1H 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).

[0898] Example 79: (R)-1-Butyl-5-(diaminomethylene)-3-(2-(3-hydroxypyrrolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (79)

[0899]

[0900] Synthesis process:

[0901]

[0902] 8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecane-2-ol

[0903]

[0904] At 0 ° C to 8,11-dioxadispiro [3.2.4 7 .2 4 ] To a solution of tridecane-2-one (1.0 g, 5.1 mmol) in methanol (20 mL) was added NaBH4 (289 mg, 7.64 mmol). The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (0-50% EA / PE) to give the title compound (812 mg, 80.37%) as a yellow oil. MS (ESI): C 11 H 18 Calculated mass of O3: 198.13, found: 199.20 [M+H] + .

[0905] 2-(Benzyloxy)-8,11-dioxadispiro[3.2.4 7 .2 4 Tridecane

[0906]

[0907] 8,11-dioxadispiro[3.2.4 7 .2 4 ] A solution of tridecan-2-ol (780 mg, 3.93 mmol) in tetrahydrofuran (20 mL) was cooled to 0 ° C. NaH (60% in mineral oil, 236.03 mg, 5.90 mmol) was added. After stirring 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 reactant 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 obtained residue was purified by silica gel column chromatography (0-50% EA / PE) to give the title compound (821 mg, 72.36%) as a yellow solid. MS (ESI): C 18 H 24 Calculated mass of O3: 288.17, found: 289.25 [M+H] + .

[0908] 2-(Benzyloxy)spiro[3.5]nonan-7-one

[0909]

[0910] To 2-(benzyloxy)-8,11-dioxadispiro[3.2.4 7 .2 4 ] To a solution of tridecane (821 mg, 2.85 mmol) in tetrahydrofuran (5 mL) was added 4N HCl (10 mL). The reactants were heated at 70 ° C for 3 hours. After cooling to room temperature, the reactants were concentrated, alkalized 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 obtained residue was purified by silica gel column chromatography (0-50% EA / PE) to give the title compound (527 mg, 75.76%) as a yellow solid. MS (ESI): C 16 H 20 Calculated mass of O2: 244.15, found: 245.10 [M+H] + .

[0911] 2-(Benzyloxy)spiro[3.5]nonan-7-ol

[0912]

[0913] A solution of 2-(benzyloxy)spiro[3.5]nonan-7-one (500 mg, 2.05 mmol) in methanol (10 mL) was cooled to 0 ° C and NaBH4 (116 mg, 3.07 mmol) was added. After stirring at room temperature for 1 hour, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (0-50% EA / PE) to give the title compound (345 mg, 68.44%) as a yellow solid. MS (ESI): C 16 H 22 Calculated mass of O2: 246.16, found: 247.10 [M+H] + .

[0914] 1-Butyl-5-(diaminomethylene)-3-(2-oxospiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0915]

[0916] To a solution of 1-butyl-5-(diaminomethylene)-3-(2-hydroxyspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (synthesized from 2-(benzyloxy)spiro[3.5]nonan-7-ol following Example 51, 10 mg, 0.027 mmol) in DCM (1 mL) was added Dess-Martin (23 mg, 0.054 mmol). After stirring at room temperature for 2 hours, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (0-50% EA / PE) to give the title compound Int B (72 mg, 80.44%) as a yellow solid. MS (ESI): C 18 H 26 Calculated mass of N4O4: 362.20, found: 363.10 [M+H] + .

[0917] (R)-1-Butyl-5-(diaminomethylene)-3-(2-(3-hydroxypyrrolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0918]

[0919] To a solution of 1-butyl-5-(diaminomethylene)-3-(2-oxospiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (50 mg, 0.14 mmol) in MeOH (2 mL) was added (3R)-pyrrolidin-3-ol (18 mg, 0.21 mmol) and AcOH (8.28 mg, 0.138 mmol). The reaction was stirred for 0.5 h and NaBHCN (17.34 mg, 0.28 mmol) was added. After stirring at room temperature for 2 h, the reaction was concentrated to dryness under reduced pressure to give the crude product, which was purified by reverse phase HPLC (26% to 45% (v / v) ACN and 0.05% NHHCO in H0) to give the title compound 79 (15.3 mg, 24.32%) as a white solid. MS (ESI): C 22 H 35 Calculated mass of N5O4: 433.27, found: 434.25 [M+H] + .

[0920] 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).

[0921] Examples 94, 95, and 96 were synthesized from Int B using a procedure similar to that described in Example 79.

[0922] 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

[0923]

[0924] Synthesis process:

[0925]

[0926] 5-(1,3-Dithian-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione

[0927]

[0928] To a solution of pyrimidine-2,4,6(1H,3H,5H)-trione (4 g, 31.22 mmol) in DMSO (60 mL) was added carbon disulfide (7.13 g, 93.66 mmol) and TEA (15.76 g, 156.10 mmol). After stirring at room temperature for 1 hour, the reactants were cooled to 0 ° C and 1,3-dibromopropane (18.90 g, 93.66 mmol) was added. After stirring at room temperature for another 3 hours, ice water (500 mL) was added and the precipitate was collected to give the title compound (5.33 g, 70.0%) as a white solid. MS (ESI): mass calculated for C8H8N2O3S2: 244.00, found: 245.15 [M+H] + .

[0929] 1-Butyl-5-(1,3-dithian-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione

[0930]

[0931] To a solution of 5-(1,3-dithiane-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (2.0 g, 8.18 mmol) in DMF (30 mL) was added iodobutane (1.51 g, 8.18 mmol) and K2CO3 (2.26 g, 16.37 mmol) at room temperature. After heating at 50 ° C for 3 hours, the reaction 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 give the crude product, which was purified by silica gel column chromatography (0-100% PE / EA) to give the title compound (1.4 g, 56.92%) as a yellow solid. MS (ESI): C 12 H 16 Calculated mass of N2O3S2: 300.06, found: 301.20 [M+H] + .

[0932] tert-Butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate

[0933]

[0934] To a solution of tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (1.0 g, 4.18 mmol) in methanol (15 mL) was added NaBH4 (317 mg, 8.36 mmol) at 0°C. After stirring at 0°C for 3 hours, the reactant 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 give a crude product, which was purified by silica gel column chromatography (PE / EA=2:1) to give the title compound (0.8 g, 79.33%). MS (ESI): C 13 H 23 Calculated mass of NO3: 241.17, Found: 242.25 [M+H] + .

[0935] tert-Butyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate

[0936]

[0937] Under N2 atmosphere, 1-butyl-5-(1,3-dithiane-2-ylidene)-1,3-diazacyclohexane-2,4,6-trione (597 mg, 1.99 mmol) and triphenylphosphine (978 mg, 3.73 mmol) were added to a solution of tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (600 mg, 2.49 mmol) in DCM (10 mL), followed by DEAD (649 mg, 3.73 mmol). 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 layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE / EA=2:1) to give the title compound (800 mg, 61.44%). MS (ESI): C 25 H 37 Calculated mass of N3O5S2: 523.22, found: 524.20 [M+H] + .

[0938] tert-Butyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate

[0939]

[0940] To a solution of tert-butyl 7-(3-butyl-5-(1,3-dithian-2-ylidene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate (200 mg, 0.38 mmol) in methanol (8 mL) was added 7N NH 3 (in methanol, 1.2 mL). The resulting mixture was heated at 100 ° C for 1 hour. After cooling, the reaction was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 10: 1) to give the title compound (600 mg, 87.37%). MS (ESI): C 22 H 35 Calculated mass of N5O5: 449.26, found: 450.20 [M+H] + .

[0941] 1-Butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0942]

[0943] To a solution of tert-butyl 7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylate (600 mg, 1.34 mmol) in DCM (20 mL) was added trifluoroacetic acid (5 mL). After stirring at room temperature for 1 hour, the reaction was concentrated under reduced pressure and then quenched by NaHCO (aqueous solution). The resulting crude material was further purified by reverse phase HPLC to give the title compound (Example 17, 420 mg, 90.35%). MS (ESI): C 17 H 27 Calculated mass of N5O3: 349.21, found: 350.30 [M+H] + This is a different synthetic route for preparing Example 17.

[0944] 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

[0945]

[0946] To a solution of 1-butyl-5-(diaminomethylene)-3-(2-azaspiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (100 mg, 0.286 mmol) in toluene (3 mL) was added 3-bromo-4-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4-triazole (87 mg, 0.32 mmol), CuI (11 mg, 0.057 mmol), potassium carbonate (119.52 mg, 0.86 mmol) and (1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (16 mg, 0.11 mmol). The reactants were heated at 100 ° C for 3 hours under N2. After completion, the reactants were 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 give a crude product, which was further purified by silica gel column chromatography (DCM: MeOH = 10: 1) to give the title compound (30 mg, 19.17%). MS (ESI): C 25 H 42 Calculated mass of N8O4Si: 546.31, found: 547.30 [M+H] + .

[0947] 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

[0948]

[0949] To a solution of 1-butyl-5-(diaminomethylene)-3-(2-(4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-2-azaspiro[3.5]nonan-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (30 mg, 0.055 mmol) in DCM (2 mL) was added TFA (0.5 mL). After stirring at room temperature for 1 hour, the reaction was concentrated under reduced pressure and ammonia (2 mL) was added. After stirring at room temperature for another hour, the mixture was concentrated to dryness to give the crude product, which was purified by reverse phase HPLC (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; 25% B to 45% B) to give the title compound 80 (3.2 mg, 14.00%) as a white solid. MS (ESI): C 19 H 28Calculated mass of N8O3: 416.23, found: 417.20 [M+H] + . 1 H 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).

[0950] Examples 47, 48, 49, and 50 were synthesized by a procedure analogous to that described for the synthesis of Example 17 in Example 80, followed by a procedure analogous to that described for the synthesis of Example 4, and subsequently subjected to chiral separation to afford four stereoisomers. The stereochemistry of each isomer was arbitrarily assigned.

[0951] Examples 81 and 82: 1-((2R,4r,7R)-7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (81) and 1-((2S,4s,7S)-7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (82)

[0952]

[0953] Synthesis process:

[0954]

[0955] (8,11-dioxadispiro[3.2.4 7 .2 4 tert-Butyl ]Tridec-2-yl)(methyl)carbamate

[0956]

[0957] Under nitrogen atmosphere, N-benzyl-N-methyl-8,11-dioxadispiro[3.2.4 7 .2 4] To a solution of tridecane-2-amine (synthesis see Example 51, 300 mg, 0.995 mmol) and di-tert-butyl dicarbonate (434.43 mg, 1.99 mmol) in methanol (5 mL) was added Pd / C (10%, 55 mg). The reactants were then stirred at room temperature for 3 hours under a hydrogen atmosphere (balloon). The reactants were filtered through a celite pad and concentrated under reduced pressure to give 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 of NO4: 311.21, Found: 312.25 [M+H] + .

[0958] tert-Butyl methyl(7-oxospiro[3.5]nonan-2-yl)carbamate

[0959]

[0960] (8,11-dioxadispiro[3.2.4 7 .2 4 A solution of tert-butyl ] tridecane-2-yl)(methyl)carbamate (420 mg, 1.35 mmol) and TsOH (464.48 mg, 2.7 mmol) in acetone (3 mL) and water (1.5 mL) was stirred at room temperature for 2 hours. After completion, the reactant was quenched with water (3 mL) and extracted with EA (10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE: EA = 2: 1) to give the title compound. MS (ESI): C 15 H 25 Calculated mass of NO3: 267.18, Found: 212.25 [M-tBu+H] + .

[0961] tert-Butyl (7-hydroxyspiro[3.5]nonan-2-yl)(methyl)carbamate

[0962]

[0963] To a stirred solution of tert-butyl methyl (7-oxospiro [3.5] nonan-2-yl) carbamate (150 mg, 0.56 mmol) in methanol (3 mL) was added NaBH4 (42.45 mg, 1.12 mmol) in portions at 0 ° C. After stirring at room temperature for 2 hours, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (30-35% EA / PE) to give the title compound (125 mg, 82.71%). MS (ESI): C 15 H 27 The calculated mass value of NO3 is 267.20 m / z, and the experimental value is 214.25 [M- t Bu+H] + .

[0964] tert-Butyl (7-(3-butyl-4-chloro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate

[0965]

[0966] Under N2 at 0 ° C, a solution of tert-butyl (7-hydroxyspiro [3.5] nonan-2-yl) (methyl) carbamate (270 mg, 1.0 mmol) in DCM (5 mL) was treated with 1-butyl-6-chloro-3H-pyrimidine-2,4-dione (203 mg, 1.0 mmol) and triphenylphosphine (394.34 mg, 1.5 mmol), followed by dropwise addition of DEAD (261.83 mg, 1.5 mmol). After stirring at room temperature for 16 hours, the reactant was quenched with water (5 mL) and extracted with DCM (15 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (15-25% EA / PE) to give the title compound (130 mg, 28.57%). MS (ESI): C 23 H 36 Calculated mass of ClN3O4: 453.24, Found: 476.30 [M+Na] + .

[0967] tert-Butyl (7-(4-amino-3-butyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate

[0968]

[0969] A solution of tert-butyl (7-(3-butyl-4-chloro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (150 mg, 0.33 mmol) and ammonium hydroxide (578 mg, 16.5 mmol) in CH3CN (3 mL) was heated at 80 ° C overnight. After completion, the reaction was quenched with water (2 mL) and extracted with ethyl acetate (15 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was further purified by silica gel column chromatography (DCM:MeOH=10:1) to give the title compound (80 mg, 55.72%). MS (ESI): C 23 H 38 Calculated mass of N4O4: 434.29, found: 435.35 [M+H] + .

[0970] tert-Butyl (7-(7-butyl-3-cyano-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate

[0971]

[0972] A solution of 4-chloro-5H-1,2,3-dithiazolium chloride (76 mg, 0.37 mmol) in DCM (3 mL) was treated with tert-butyl (7-(4-amino-3-butyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (80 mg, 0.18 mmol) and pyridine (66 mg, 0.85 mmol) at room temperature for 5 minutes. After stirring for 16 hours, the reaction was quenched with water (5 mL) and extracted with DCM (10 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the title compound (50 mg, 54.14%) as a yellow oil. MS (ESI): C 25 H 35 Calculated mass of N5O4S: 501.24, found: 524.30 [M+Na] + .

[0973] tert-Butyl (7-(7-butyl-3-((4-methoxybenzyl)amino)-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate

[0974]

[0975] A solution of tert-butyl (7-(7-butyl-3-cyano-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (50 mg, 0.100 mmol) and (4-methoxyphenyl)methanamine (136 mg, 1.000 mmol) in DMF (3 mL) was heated at 90 ° C for 1 hour. After completion, the reactant was quenched with water (2 mL) and extracted with DCM (5 mL×3). The combined organic layer was washed with brine (2 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (30-35% EA / PE) to give the title compound (50 mg, 82.0%). MS (ESI): C 32 H 45 Calculated mass of N5O5S: 611.31, found: 612.40 [M+H] + .

[0976] 3-Amino-7-butyl-5-(2-(methylamino)spiro[3.5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

[0977]

[0978] A solution of tert-butyl (7-(7-butyl-3-((4-methoxybenzyl)amino)-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)(methyl)carbamate (50 mg, 0.082 mmol) and TFA (2.7 mL, 36.35 mmol) in H2O (0.3 mL, 16.65 mmol) was heated at 50°C overnight. The residue was purified by reverse phase HPLC (10-50% ACN / water + TFA as a modifier) to give the title compound (30 mg, 93.76%) as an oil. MS (ESI): C 19 H 29 Calculated mass of N5O2S: 391.20, found: 392.30 [M+H] + .

[0979] 1-((2R,4r,7R)-7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (81) and 1-((2S,4s,7S)-7-(3-amino-7-butyl-4,6-dioxo-6,7-dihydroisothiazolo[3,4-d]pyrimidin-5(4H)-yl)spiro[3.5]nonan-2-yl)-1-methylurea (82)

[0980]

[0981] At room temperature, a solution of 3-amino-7-butyl-5-[2-(methylamino)spiro[3.5]nonan-7-yl]-[1,2]thiazolo[3,4-d]pyrimidine-4,6-dione (30 mg, 0.077 mmol) in DCM (3 mL) was treated with TEA (26 mg, 0.25 mmol) followed by the dropwise addition of isocyanatotrimethylsilane (19.42 mg, 0.17 mmol). After stirring for 1 hour, the reaction 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 give the crude product, which was 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 to 15% B in 16 min) to give the title compound 81 (2.3 mg, 6.89%, RT1: 11.03 min) as a white solid. MS (ESI): C 20 H 30 Calculated mass of N6O3S: 434.21, found: 435.15 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 2H), 5.79 (s, 2H), 4.36-4.69 (m, 2H), 3.89 (t, J = 7.5 Hz, 2H), 2.73 (s, 3H), 2.23-2.48 (m, 2H), 2.08 (t, J = 9.7 Hz, 1H), 1.50-1.93 (m, 6H), 1.17-1.48 (m, 7H), 0.90 (t, J = 7.3 Hz, 3H); and the title compound 82 (2.7 mg, 8.10%, RT2: 15.096 min) as a white solid. MS (ESI): C 20 H 30Calculated mass of N6O3S: 434.21, found: 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).

[0982] Examples 104 and 105 were prepared starting from 1-(7-hydroxyspiro[3.5]nonan-2-yl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (prepared from 5,5-dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)imidazolidine-2,4-dione in Example 78) using procedures similar to those described in Examples 81 and 82. Tributylphosphoranylidene)acetonitrile was used as the reagent for the Mistunobu coupling.

[0983] Example 83: 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonan-2-yl)oxetane-3-carboxamide (83)

[0984]

[0985] Synthesis process:

[0986]

[0987] 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonan-2-yl)oxetane-3-carboxamide

[0988] To a solution of 3-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-2-azaspiro[3.5]nonan-2-yl)oxetane-3-carbonitrile (30 mg, 0.070 mmol) in DMSO (3 mL) was added KCO (29 mg, 0.210 mmol). The mixture was stirred until homogeneous 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 give the crude product, which was purified by reverse phase HPLC (25% to 45% (v / v) ACN and 0.05% NH4HCO3 in H2O) to give the title compound 83 (9.4 mg, 30.07%) as a white solid. MS (ESI): C 21 H 32 Calculated mass of N6O5: 448.24, found: 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).

[0989] Example 84 was prepared by a procedure similar to that described in Example 83 from 1-butyl-5-(diaminomethylene)-3-(piperidin-4-ylmethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (prepared according to Example 51).

[0990] Example 85: 3-amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

[0991]

[0992] Synthesis process:

[0993]

[0994] Ethyl (1r,4r)-4-(Benzyloxy)cyclohexane-1-carboxylate

[0995]

[0996] A solution of (1r, 4r)-4-hydroxycyclohexane-1-carboxylic acid ethyl ester (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 reactant 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 obtained residue was purified by silica gel column chromatography (0-20% PE / EA) to give the title compound (4 g, 52.06%) as a colorless oil. MS (ESI): C 16 H 22 Calculated mass of O3: 262.16, found: 263.15 [M+H] + .

[0997] ((1r,4r)-4-(Benzyloxy)cyclohexyl)methanol

[0998]

[0999] To a solution of ethyl (1r,4r)-4-(benzyloxy)cyclohexane-1-carboxylate (4.7 g, 17.92 mmol) in THF (40 mL) was added LiAlH (1.70 g, 44.79 mmol) 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 was quenched with saturated aqueous NaSO at 0°C, dried over NaSO, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (0-30% PE / EA) to give the title compound (2.9 g, 73.48%) as a colorless oil.

[1000] ((((1r,4r)-4-(Bromomethyl)cyclohexyl)oxy)methyl)benzene

[1001]

[1002] To a solution of ((1r,4r)-4-(benzyloxy)cyclohexyl)methanol (950 mg, 4.31 mmol) in DCM (10 mL) was added CBr (1573 mg, 4.74 mmol) in DCM (2 mL) under a nitrogen atmosphere at 0°C, followed by the dropwise addition of PPh (1131.02 mg, 4.31 mmol) in DCM (2 mL) at 0°C. After stirring at room temperature for 3 hours, the reaction was quenched with H2O (50 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (0-10% PE / EA) to give the title compound (800 mg, 65.51%) as a colorless oil.

[1003] 1-(((1r,4r)-4-(benzyloxy)cyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione

[1004]

[1005] A solution of ((((1r,4r)-4-(bromomethyl)cyclohexyl)oxy)methyl)benzene (0.78 g, 2.75 mmol), 5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (0.71 g, 2.75 mmol) and CsCO (1.35 g, 4.13 mmol) in DMF (15 mL) was heated at 50 ° C for 12 hours. The reaction was quenched with H O (50 mL) and extracted with ethyl acetate. The organic layer was concentrated to give the title compound (0.8 g, 63.05%) as a light yellow oil. MS (ESI): C 25 H 40 Calculated mass of N2O4Si: 460.28, experimental value: 483.30 [M+Na] + .

[1006] 1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione

[1007]

[1008] To a solution of 1-(((1r,4r)-4-(benzyloxy)cyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (0.8 g, 1.74 mmol) in MeOH (10 mL) was added Pd / C (10%, 0.1 g) under N2 atmosphere. The reaction was then stirred under a hydrogen atmosphere (balloon) for 1 hour. The reaction was filtered through a pad of celite and concentrated under reduced pressure to give the title compound Int A (0.5 g, 77.70%) as a colorless oil. MS (ESI): C 18 H 34 Calculated mass of N2O4Si: 370.23, experimental value: 393.3 [M+Na] + .

[1009] 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

[1010]

[1011] To a solution of 1-butyl-6-chloropyrimidine-2,4(1H,3H)-dione (300 mg, 1.48 mmol) in DCM (5 mL) was added 1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione IntA (548 mg, 1.48 mmol) and triphenylphosphine (581 mg, 2.22 mmol) at 0° C. under N2, followed by the dropwise addition of DEAD (261.83 mg, 1.50 mmol). After stirring overnight at room temperature, the reaction 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 give a crude product, which was purified by silica gel column chromatography (PE:EA=3:1) to give the title compound (107 mg, 13.0%). MS (ESI): C 26 H 43 Calculated mass of ClN4O5Si: 554.27, found: 555.35 [M+H] + .

[1012] 3-Amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

[1013]

[1014] 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 by a procedure similar to that described in Example 81. MS (ESI): C 21 H 30 Calculated mass of N6O4S: 462.20, found: 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),1.20-1.32m,8H),0.90(t,J=7.3Hz,3H).

[1015] Example 90 was synthesized by a procedure similar to that described in Example 85.

[1016] Example 99 was synthesized by a similar procedure as described in Example 85, using DMBNH2 instead of PMBNH2.

[1017] Example 101 was synthesized by a similar procedure as described in Example 85, substituting MeNH 2 for PMBNH 2 .

[1018] Example 102 was synthesized by a similar procedure to that described in Example 85, using isopropylamine instead of PMBNH2.

[1019] 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

[1020]

[1021] Synthesis process:

[1022]

[1023] tert-Butyl (2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)amino)ethyl)carbamate

[1024]

[1025] To a solution of 1-((1s, 4s)-4-aminocyclohexyl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H, 3H, 5H)-trione (prepared with a procedure similar to that described in Example 18, 140 mg, 0.43 mmol) in MeOH (3 mL) was added tert-butyl N-(2-oxoethyl)carbamate (83 mg, 0.52 mmol) and AcOH (78 mg, 1.299 mmol). After stirring for 30 minutes, 1-boranyl-2-methyl-1λ4-pyridine (138 mg, 1.3 mmol) was added in portions at 0 ° C. The resulting mixture was stirred at room temperature overnight. The reactant 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 give the title compound (90 mg, 44.56%). MS(ESI):C 22 H 38 Calculated mass of N6O5: 466.29, found: 467.25 [M+H] + .

[1026] tert-Butyl (2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)(oxetan-3-yl)amino)ethyl)carbamate

[1027]

[1028] To a solution of tert-butyl (2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)amino)ethyl)carbamate (70 mg, 0.15 mmol) in DMF (3 mL) was added CsCO (98 mg, 0.30 mmol) and 3-bromooxetane (103 mg, 0.75 mmol). After heating at 50 ° C overnight, the reaction was quenched with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography to give the title compound (30 mg, 38.26%) as a yellow solid. MS (ESI): C 25 H 42Calculated mass of N6O6: 522.32, found: 523.25 [M+H] + .

[1029] 1-((1s,4s)-4-((2-aminoethyl)(oxetan-3-yl)amino)cyclohexyl)-3-butyl-5-(diaminomethylene)pyrimidine-2,4,6(1H,3H,5H)-trione

[1030]

[1031] A solution of tert-butyl (2-(((1s,4s)-4-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)cyclohexyl)(oxetan-3-yl)amino)ethyl)carbamate (30 mg, 0.057 mmol) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated and purified by reverse phase HPLC (20% to 50% (v / v) ACN and 0.05% NH4HCO3 in H2O) to give the title compound 86 (2.1 mg, 8.26%) as a yellow solid. MS (ESI): C 20 H 30 Calculated mass of N6O4: 422.26, found: 423.20 [M+H] + . 1 H 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).

[1032] Example 77 was synthesized by a procedure similar to that described in Example 86.

[1033] Example 87: 5-Butyl-7-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione (87)

[1034]

[1035] Synthesis process:

[1036]

[1037] 3-Amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[1038]

[1039] To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (3 g, 19.34 mmol) in DMF (80 mL) was added KCO (4.01 g, 29.0 mmol) and SEMCl (3.87 g, 23.20 mmol). After stirring overnight at room temperature, the reactant 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 obtained residue was purified by silica gel column chromatography (PE: EA = 3: 1) to give the title compound as a yellow oil. MS (ESI): C 12 H 23 Calculated mass of N3O3Si: 285.15, found: 286.10 [M+H] + .

[1040] 3-Amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylic acid

[1041]

[1042] 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 H O (1 mL) was added LiOH (503 mg, 21.02 mmol). The resulting mixture was stirred at room temperature overnight. The reaction 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 give the crude title compound (450 mg, 83.18%), which was used in the next step without further purification.

[1043] 3-Amino-N-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide

[1044]

[1045] To a solution of 3-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylic acid (450 mg, 1.748 mmol) and butylamine (153 mg, 2.1 mmol) in DMF (7 mL) was added DIPEA (451 mg, 3.5 mmol) and HATU (997.26 mg, 2.62 mmol). After stirring at room temperature overnight, the reaction was quenched with water (20 mL) and extracted with EA (3×30 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 (400 mg, 73.21%) as a yellow oil. MS (ESI): C 14 H 28 Calculated mass of N4O2Si: 312.20, found: 313.15 [M+H] + .

[1046] 5-Butyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione

[1047]

[1048] To a solution of 3-amino-N-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (200 mg, 0.64 mmol) in DMF (5 mL) was added DIPEA (248 mg, 1.92 mmol) and CDI (622 mg, 3.84 mmol). After heating at 70 ° C for 5 hours, the reaction was cooled, quenched with water (20 mL) and extracted with EA (3×30 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 (150 mg, 69.24%) as a white solid. MS (ESI): C 15 H 26 Calculated mass of N4O3Si: 338.18, found: 339.25 [M+H] + .

[1049] 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

[1050]

[1051] To a solution of 5-butyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrazolo[3,4-d]pyrimidine-4,6-dione (125 mg, 0.37 mmol) and 1-(((1r, 4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (IntA in Example 85, 136 mg, 0.37 mmol) in DCM (5 mL) was added PPh (193 mg, 0.74 mmol) and DEAD (128 mg, 0.74 mmol) under N2 atmosphere at 0 ° C. After stirring at room temperature for 3 hours, the reactant 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 of N6O6Si2: 690.40, found: 691.35 [M+H] + .

[1052] 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

[1053]

[1054] 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 room temperature for 1 hour. The reactant was neutralized with NaHCO solution to pH = 7 and extracted with DCM / MeOH. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. To the crude product was added NH in MeOH (3 mL) and stirred at room temperature for 1 hour. The resulting mixture was concentrated and purified by reverse phase HPLC (22-52% ACN / H2O containing 0.05% NH4HCO3) to give the title compound 87 (8.8 mg, 17.63%) as a white solid. MS (ESI): C 21 H 30 Calculated mass of N6O4: 430.23, found: 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).

[1055] Example 88 was synthesized by a procedure similar to that described in Example 87.

[1056] Example 89: 7-Butyl-5-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)-1,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione (89)

[1057]

[1058] Synthesis process:

[1059]

[1060] 1-Butyl-6-chloro-2,4-dioxo-3-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde

[1061]

[1062] To a solution of 1-butyl-3-((1s, 4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)pyrimidine-2,4,6(1H,3H,5H)-trione (see Example 62 for procedure, 600 mg, 1.43 mmol) in POCl3 (10 mL) was added DMF (2 mL) at 0 ° C. The resulting mixture was heated at 100 ° C for 3 hours. After cooling, the reactant was concentrated, quenched with ice water, and extracted with EA (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography (0-15% DCM / MeOH) to give the title compound (100 mg, 15.0%) as a yellow oil. MS (ESI): C 22 H 31 Calculated mass of ClN4O5: 466.20, found: 489.10 [M+Na] + .

[1063] 7-Butyl-5-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)-1,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione

[1064]

[1065] To a solution of 1-butyl-6-chloro-2,4-dioxo-3-((1s,4s)-4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (150 mg, 0.32 mmol) in MeOH (8 mL) was added hydrazine hydrochloride (44 mg, 0.64 mmol) at room temperature, followed by TEA (163 mg, 1.605 mmol) at 0°C. After heating at 70°C for 1.5 hours, the reaction was quenched with water (20 mL) and extracted with DCM / MeOH (5:1, 3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The obtained residue was purified by reverse phase HPLC (17% to 42% (v / v) CH 3 CN and H 2 O containing 10 mmol / L NH 4 HCO 3 ) to give the title compound 89 (8.7 mg, 6.51%) as a white solid. MS (ESI): C 22 H 32 Calculated mass of N6O4: 444.25, found: 445.20 [M+H] + . 1 HNMR(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).

[1066] Example 98. 5-Amino-1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (98)

[1067]

[1068] Synthesis process:

[1069]

[1070] 1-Butyl-6-methylpyrimidine-2,4(1H,3H)-dione

[1071]

[1072] Under nitrogen atmosphere at 0 DEG C, to a solution of butyl urea (6.91g, 59.471mmol) in pyridine (50mL) 4-methylene oxetane-2-one (5g, 59.47mmol) was added. After stirring at room temperature overnight, most of the solvent was evaporated. The obtained solid was collected by filtration, washed with ether and dried in vacuo to give N- (butylcarbamoyl) -3- oxobutanamide. AcOH (60mL) was added thereto, and the resulting mixture was heated at 115 DEG C under a nitrogen atmosphere for 2 hours. The reactant was cooled and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (0-100% PE / EA) to give the title compound (1.2g, 64.30%) as a yellow oil. MS (ESI): C9H 14 Calculated mass of N2O2: 182.11, found: 183.20 [M+H] + .

[1073] 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

[1074]

[1075] To a solution of 1-butyl-6-methylpyrimidine-2,4(1H,3H)-dione (250 mg, 1.37 mmol) in DCM (5 mL) was added 1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (IntA in Example 85, 510 mg, 1.38 mmol), PPh3 (719 mg, 2.74 mmol), followed by DEAD (477 mg, 2.74 mmol) under N2 at room temperature. After stirring for 2.5 hours at room temperature, the reaction 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 give the crude product, which was purified by silica gel column chromatography (0-100% PE / EA) to give the title compound (400 mg, 54.52%) as a yellow solid. MS (ESI): C 27 H 46 Calculated mass of N4O5Si: 534.32, found: 535.30 [M+H] + .

[1076] 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

[1077]

[1078] To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)-6-methylpyrimidine-2,4(1H,3H)-dione (360 mg, 0.67 mmol) in AcOH (10 mL) was added HCHO (80 mg, 2.692 mmol). The reaction mixture was heated at 100 ° C for 6 hours. The reaction was concentrated under reduced pressure to give the crude product, which was suspended in 1% aqueous NaOH (10 mL), DMF (10 mL) and heated at reflux for 1 hour. The reaction mixture was acidified to pH = 5 with 10% HCl and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was directly purified by silica gel column chromatography to afford the title compound (120 mg, 31.56%) as a yellow solid. MS (ESI): C 28 H 48 Calculated mass of N4O6Si: 564.33, found: 565.15 [M+H] + .

[1079] 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

[1080]

[1081] To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)-5-(hydroxymethyl)-6-methylpyrimidine-2,4(1H,3H)-dione (110 mg, 0.195 mmol) in DCM (3 mL) was added Dess-Martin reagent (165 mg, 0.390 mmol). After stirring at room temperature for 3 hours, the reaction 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 give the crude product (0.1 g, 90.9%) as a yellow oil, which was used directly in the next step.

[1082] (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

[1083]

[1084] To a solution of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (100 mg, 0.18 mmol) in MeOH (3 mL) / HO (3 mL) was added NHOH.HCl (245 mg, 3.56 mmol). After stirring at room temperature for 0.5 h, the reaction 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 give the crude title compound (0.1 g, 98.5%) as a yellow oil, which was used directly in the next step.

[1085] 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

[1086]

[1087] 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 AcO (4 mL) was heated at 90 ° C for 3 hours. After completion, the reaction was quenched with water (2 mL) and extracted with CHCl (10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (60 mg, 68.97%) as a yellow oil. MS (ESI): C 28 H 45 Calculated mass of N5O5Si: 559.32, found: 560.35 [M+H] + .

[1088] 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

[1089]

[1090] 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. After cooling to room temperature, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (50 mg, 75.76%) as a yellow oil, which was used directly in the next step.

[1091] 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

[1092]

[1093] 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 at 100 ° C overnight. 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 give the crude product, which was purified by column chromatography using (0-10% MeOH / DCM) to give the title compound (30 mg, 62.89%) as a yellow oil. MS (ESI): C 29 H 46 Calculated mass of N6O5Si: 586.33, found: 587.35 [M+H] + .

[1094] 5-Amino-1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione

[1095]

[1096] 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 at room temperature for 1 hour and concentrated under reduced pressure. To the above mixture was added MeOH (1 mL) containing 7N NH3. The resulting mixture was stirred for another 30 minutes. The residue was purified by reverse phase HPLC (ACN / TFA in water, 10-50% ACN / water + TFA as a modifier) to give the title compound 98 (8.8 mg, 45.08%) as a white solid. MS (ESI): C 23 H 32 Calculated mass of N6O4: 456.25, found: 457.10 [M+H] + . 1H 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).

[1097] Example 100: 1-butyl-5-(diaminomethylene)-3-(2,4-dioxo-1,3-diazadispiro[4.1.5 7 .1 5 ]Tridec-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (100)

[1098]

[1099] Synthesis process:

[1100]

[1101] 1-butyl-5-(diaminomethylene)-3-(2,4-dioxo-1,3-diazadispiro[4.1.5 7 .1 5 ]Tridec-10-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[1102]

[1103] To a solution of IntB (50 mg, 0.138 mmol) in EtOH (2 mL) was added NaHSO (5.74 mg, 0.055 mmol), KCN (17.97 mg, 0.28 mmol) and (NH)CO (106 mg, 1.10 mmol). The reactants were heated at 130 ° C for 24 hours. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by reverse phase HPLC (26% to 45% (v / v) ACN and 0.05% NHHCO in H O) to give the title compound 100 (10.8 mg, 18.06%) as a white solid. MS (ESI): C 20 H 28 Calculated mass of N6O5: 432.21, found: 433.10 [M+H] + . 1H 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).

[1104] Example 103: 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)imidazo[1,2-a][1,3,5]triazine-2,4(1H,3H)-dione (103)

[1105]

[1106] Synthesis process:

[1107]

[1108] 1-Butylimidazo[1,2-a][1,3,5]triazine-2,4(1H,3H)-dione

[1109]

[1110] To a solution of 1H-imidazo[1,2-a][1,3,5]triazine-2,4-dione (1 g, 6.57 mmol) in DMSO (50 mL) was added NaH (657.35 mg, 16.44 mmol, 60% in mineral oil) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes, and 1-iodobutane (1.21 g, 6.57 mmol, 746.77 μL) was added at 25 ° C. After stirring for 2 hours, the reactant was poured into saturated NH4Cl (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EA=5:1 to 3:1) to give the title compound (0.26 g, 19%) as a white solid. MS (ESI): C9H 12 Calculated mass of N4O2: 208.10, found: 209.2 [M+H] + .

[1111] 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

[1112]

[1113] Under Ar at 25 ° C, to a mixture of 1-butylimidazo[1,2-a][1,3,5]triazine-2,4(1H,3H)-dione (0.2 g, 0.960 mmol) and 1-[(4-hydroxycyclohexyl)methyl]-5,5-dimethyl-3-(2-trimethylsilylethoxymethyl)imidazolidine-2,4-dione (IntA in Example 85, 355.93 mg, 0.96 mmol) in toluene (2 mL) was added 2-(tributyl-λ5-phosphinyl)acetonitrile (811.40 mg, 3.36 mmol) in one portion. The reactants were 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 layers were 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 give the title compound (0.17 g, 19%) as a white solid. MS (ESI): C 27 H 44 Calculated mass of N6O5Si: 560.31, found: 561.3 [M+H] + .

[1114] 1-Butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)imidazo[1,2-a][1,3,5]triazine-2,4(1H,3H)-dione

[1115]

[1116] To a mixture of 1-butyl-3-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)imidazo[1,2-a][1,3,5]triazine-2,4(1H,3H)-dione (0.17 g, 0.30 mmol) in DCM (2 mL) and H2O (0.2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL) in one portion at 25°C. The mixture was stirred at 25°C for 0.5 h, poured into aqueous NaHCO3 (5 mL) and extracted with DCM (2×5 mL). The combined organic layers were 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 / water (NH4HCO3)) to give the title compound 103 (5.5 mg, 4.21%) as a white solid. MS (ESI): C 21 H 30 Calculated mass of N6O4: 430.23, found: 431.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 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=7.2Hz,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).

[1117] Example 106 was synthesized by a similar procedure to that described in Example 81 and Example 82 without chiral separation.

[1118] Example 108 and Example 109 were synthesized by similar procedures as described in Example 104 and Example 105. Stereochemistry was arbitrarily assigned.

[1119] Example 110. 1-(7-(3-Butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)-1-cyclopropylurea (110)

[1120]

[1121] Synthesis process:

[1122]

[1123] N-cyclopropyl-8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecane-2-amine

[1124]

[1125] At 25 °C, 8,11-dioxadispiro[3.2.4 7 .2 4 ] To a solution of tridecane-2-one (500 mg, 2.55 mmol) in MeOH (5 mL) was added cyclopropylamine (290.9 mg, 5.1 mmol) and AcOH (306 mg, 5.1 mmol). After 1 hour, NaBH3CN (400.3 mg, 6.4 mmol) was added to the reactant and heated at 60 ° C for 12 hours. After completion, the reactant was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6.8 g, crude material) as a yellow oil, which was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δppm 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).

[1126] Cyclopropyl(8,11-dioxadispiro[3.2.4 7 .2 4 ]tridec-2-yl)benzyl carbamate

[1127]

[1128] At 25 ° C, N-cyclopropyl-8,11-dioxadispiro[3.2.4 7 .2 4] To a solution of tridecane-2-amine (1.7 g, 7.16 mmol) in DCM (20 mL) was added CbzCl (1.23 g, 7.23 mmol) and TEA (1.45 g, 14.33 mmol). After stirring for 1 hour, the reactant 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: EtOAc = 100: 0 to 0: 100) to give the title compound (6.2 g, 58.3%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm 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).

[1129] Benzyl cyclopropyl(7-oxospiro[3.5]nonan-2-yl)carbamate

[1130]

[1131] At 25 ° C, cyclopropyl (8,11-dioxadispiro [3.2.4 7 .2 4 ] tridecane-2-yl) benzyl carbamate (3.1 g, 8.35 mmol) was added to a solution of acetone (30 mL) and H2O (15 mL) with TsOH.H2O (3.17 g, 16.69 mmol). After stirring for 2 hours, the reactant was diluted with H2O (30 mL) and extracted with EtOAc (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: EtOAc = 100:0 to 0:100) to give the title compound (5.5 g, crude material) 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, Found: 328.1 [M+H] + .

[1132] Benzyl (7-aminospiro[3.5]nonan-2-yl)(cyclopropyl)carbamate

[1133]

[1134] To a mixture of cyclopropyl (7-oxospiro [3.5] nonan-2-yl) benzyl carbamate (5.5 g, 16.8 mmol) and NH4OAc (25.9 g, 0.34 mmol) in MeOH (60 mL) was added NaBH (OAc) 3 (8.9 g, 42 mmol) at 25 ° C under N2. After heating at 50 ° C for 12 hours, the reactant was concentrated under reduced pressure. The residue was adjusted to pH = 8 by saturated NaHCO3. The mixture was diluted with H2O (40 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6 g, crude material) as a yellow oil, which was used in the next step without further purification. MS (ESI): C2H 28 Calculated mass of N2O2: 328.22, found: 329.3 [M+H] + .

[1135] Benzyl (7-(3-butylureido)spiro[3.5]nonan-2-yl)(cyclopropyl)carbamate

[1136]

[1137] To a solution of (7-aminospiro[3.5]nonan-2-yl)(cyclopropyl)benzyl carbamate (6 g, 18.3 mmol) in DCM (60 mL) was added 1-isocyanatobutane (2.72 g, 27.4 mmol) and TEA (3.7 g, 36.5 mmol) at 25 ° C. After stirring for 1 hour, the reactant was quenched with H2O and extracted with 60 mL of DCM (3 × 20 mL). The combined organic layer was washed with 30 mL of brine (2 × 15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 100: 0 to 0: 100) to give the title compound (4.1 g, 52.5%) as a white solid. MS (ESI): C 25 H 37 Calculated mass of N3O3: 427.28, found: 428.4 [M+H] + .

[1138] Benzyl (7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(cyclopropyl)carbamate

[1139]

[1140] To a solution of benzyl (7-(3-butylureido)spiro[3.5]nonan-2-yl)(cyclopropyl)carbamate (1.2 g, 2.8 mmol) in AcOH (12 mL) was added malonic acid (292.1 mg, 2.8 mmol) and Ac2O (2.01 g, 19.7 mmol) at 25 ° C. After heating at 80 ° C. under N2 for 12 hours, the reaction was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 100: 0 to 0: 100) to give the title compound (1.3 g, 93.5%) as a yellow solid. MS (ESI): C 28 H 37 Calculated mass of N3O5: 495.27, found: 496.4 [M+H] + .

[1141] 1-Butyl-3-(2-(cyclopropylamino)spiro[3.5]non-7-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

[1142]

[1143] To a solution of (7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)(cyclopropyl)carbamic acid benzyl ester (1.3 g, 2.62 mmol) in MeOH (20 mL) was added 5% Pd / C (300 mg, 0.14 mmol) under N2. The suspension was degassed and purged with H2 three times. The reactants were stirred at 20 ° C under H2 (15 Psi) for 48 hours. After completion, the reactants were filtered through a celite pad and washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to give the title compound (1.25 g, crude material) as a white solid, which was used directly in the next step without further purification. MS (ESI): C 24 H 31 Calculated mass of N3O3: 361.24, found: 362.2 [M+H] + .

[1144] 1-(7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)-1-cyclopropylurea

[1145]

[1146] At 15 ° C, 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 then isocyanato(trimethyl)silane (1.53 g, 13.3 mmol) was added dropwise. After stirring for 16 hours, the reaction was concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC [HO (10 mM NH4HCO3)-ACN]; gradient 10% to 40% B) to give the title compound (300 mg, 22.3%) as a red solid. MS (ESI): C 21 H 32 Calculated mass of N4O4: 404.24, found: 405.3 [M+H] + .

[1147] 1-(7-(3-butyl-5-(diaminomethylene)-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]nonan-2-yl)-1-cyclopropylurea (110)

[1148]

[1149] To a solution of 1-(7-(3-butyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)spiro[3.5]non-2-yl)-1-cyclopropylurea (80 mg, 0.2 mmol) in THF (0.1 mL) was added bis[(Z)-1-methyl-3-oxo-but-1-enyloxy]nickel (25.4 mg, 0.099 mmol) and cyanamide (24.9 mg, 0.59 mmol) at 15°C. After heating at 85°C for 12 hours, the reaction was diluted with H2O (5 mL) and extracted with EtOAc (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% to 55% B) to give the title compound as a white solid (racemic, 4.2 mg, 4.6%). MS (ESI): C 22 H 34 Calculated mass of N6O4: 446.26, found: 447.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 9.54(s,2H),7.29(s,2H),5.78(s,2H),4.52-4.70(m,1H),4.03-4.21(m,1H), 3.67-3.80(m,2H),2.29-2.42(m,2H),2.10-2.18(m,1H),1.92-2.05(m,2H),1 .84-1.92(m,1H),1.74-1.83(m,1H),1.55-1.66(m,1H),1.40-1.49(m,2H),1. 19-1.38(m,6H),0.88(t,J=7.2Hz,3H),0.70-0.84(m,2H),0.52-0.60(m,2H).

[1150] Example 169 was synthesized by a procedure similar to that described in Example 110.

[1151] Example 175 was synthesized by a similar procedure as described in Example 110, using Boc instead of Cbz as the protecting group.

[1152] Example 111. 7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carboxamide (111)

[1153]

[1154] Synthesis process:

[1155]

[1156] 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

[1157]

[1158] 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 from the synthesis of Example 85, 100 mg, 0.17 mmol) was added KCO (27.51 mg, 0.2 mmol) and 30% HO (94 mg, 0.83 mmol) in DMSO (1 mL). The reaction was stirred at 25 ° C. under N for 1 hour. After completion, the reaction 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 (SiO 2 , petroleum ether:EtOAc=3:1) to give the title compound (90 mg, 87.4%) as a yellow oil. MS (ESI): C 28 H 44 Calculated mass of N6O6SSi: 620.28, Found: 643.2 [M+Na] + .

[1159] 7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carboxamide

[1160]

[1161] To a solution of 7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carboxamide (90 mg, 0.14 mmol) in TFA (0.5 mL) was added HO (0.1 mL). After stirring at 25 °C for 1 hour, the reaction was concentrated under reduced pressure, and MeOH (5 mL) and KCO (100 mg) were added. After stirring for 10 minutes, the reaction was concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (mobile phase: [water(NH4HCO3)-ACN]; 30% to 60% B) to give the title compound (3.6 mg, 5.1%) as a white solid. MS(ESI):C 22 H 30 Calculated mass of N6O5S: 490.20, found: 491.2 [M+H] + . 1H NMR (400MHz, CDCl3) δppm 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).

[1162] Example 112. N-(7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidin-3-yl)methanesulfonamide

[1163]

[1164] Synthesis process:

[1165]

[1166] 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

[1167]

[1168] 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 from the synthesis of Example 85, 1.35 g, 2.2 mmol) in DMA (20 mL) was added (2,4-dimethoxyphenyl)methanamine (3.74 g, 22.4 mmol). After heating at 90 °C for 3 h, the reaction was diluted with H2O (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organic 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:EtOAc=100:1 to 2:1) to give the title compound (1.2 g, 72%) as a yellow solid. 1HNMR(400MHz,CDCl3)δppm 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).

[1169] 3-Amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

[1170]

[1171] 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 EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.66 g, 83.9%) as a white solid, which was used directly in the next step without further purification.

[1172] N-(7-Butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidin-3-yl)methanesulfonamide

[1173]

[1174] To a solution of 3-amino-7-butyl-5-((1s,4s)-4-((5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)cyclohexyl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.1 g, 0.22 mmol) in DCM (2 mL) was added TEA (218.8 mg, 2.2 mmol) and MsCl (123.8 mg, 1.1 mmol) at 0 ° C. After stirring at 25 ° C for 2 hours, the reaction was diluted with NH4Cl (5 mL) and extracted with DCM (3×3 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 (water (NH4HCO3)-ACN) to give the title compound (9.8 mg, 7%) as a white solid. MS (ESI): C 22 H 32 Calculated mass of N6O6S2: 540.18, found: 540.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δppm 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).

[1175] Example 113. 3-Amino-7-butyl-5-(2-(3-ethyl-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (113)

[1176]

[1177] Synthesis process:

[1178]

[1179] 5,5-Dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione

[1180]

[1181] To a solution of 5,5-dimethyl-1-(7-oxospiro[3.5]nonane-2-yl)imidazolidine-2,4-dione (see Example 78 for synthesis, 10 g, 37.8 mmol) in DCM (100 mL) was added DIPEA (19.6 g, 151.3 mmol) and SEM-Cl (12.6 g, 75.7 mmol) at 0 ° C. After stirring at 25 ° C for 12 hours, the reactant 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: EtOAc=10: 1 to 5: 1) to give the title compound (10 g, 667%) as a yellow oil. MS (ESI): C 20 H 34 Calculated mass of N2O4Si: 394.23, experimental value: 393.4 [MH] - .

[1182] 1-(7-Hydroxyspiro[3.5]nonan-2-yl)-5,5-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (INT 3)

[1183]

[1184] To a solution of 5,5-dimethyl-1-(7-oxospiro[3.5]nonan-2-yl)-3-(2-trimethylsilylethoxymethyl)imidazolidine-2,4-dione (10 g, 25.3 mmol) in MeOH (100 mL) was added NaBH4 (527.3 mg, 13.9 mmol) in portions at 0 ° C. After stirring at 25 ° C for 1 hour, the reactant was quenched with H2O (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 5: 1 to 1: 1) to give the title compound (5.3 g, 52.7%) as a white solid. MS (ESI): C 20 H 36 Calculated mass of N2O4Si: 396.24, experimental value: 419.2 [M+Na] + .

[1185] 1-Butyl-6-chloropyrimidine-2,4(1H,3H)-dione

[1186]

[1187] Under N2 at 25 ° C, to a mixture of 6- chloro-1H-pyrimidine-2,4-dione (5g, 34.1mmol) and 1-iodobutane (6.91g, 37.5mmol) in DMSO (25mL) was added K2CO3 (2.36g, 17.1mmol) at one time. After stirring at 25 ° C for 12 hours, the combined mixture was poured into water (30mL) and EtOAc (30mL). The aqueous phase was extracted with EtOAc (3×20mL). The combined organic layer was washed with brine (3×20mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was ground with petroleum ether (20mL) and stirred for 5 minutes. The precipitate was collected by filtration, washed with petroleum ether (3×20mL) and dried in vacuo to give the title compound (4.5g, 22.2mmol, 65.1%) as a white solid, which was used directly in the next step without further purification. MS (ESI): C8H 11 Calculated mass of ClN2O2: 202.05, found: 203.2 [M+H] + .

[1188] 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

[1189]

[1190] To a solution of 1-butyl-6-chloropyrimidine-2,4(1H,3H)-dione (1.04 g, 5.14 mmol) in toluene (10 mL) was added 1-(7-hydroxyspiro[3.5]nonan-2-yl)-5,5-dimethyl-3-(2-trimethylsilylethoxymethyl)imidazolidine-2,4-dione (INT 3, 1.7 g, 4.3 mmol). The reaction was heated to 120° C., and 2-(tributyl-λ 5 -phosphinyl)acetonitrile (3.62 g, 15.00 mmol). After stirring at 120 ° C under N2 for 12 hours, the reactant was quenched with H2O (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 5: 1 to 1: 1) to give the title compound (1.4 g, 24%) as a colorless oil. MS (ESI): C 28 H 45 Calculated mass of ClN4O5Si: 580.28, found: 581.3 [M+H] + .

[1191] 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

[1192]

[1193] To a solution of 1-butyl-6-chloro-3-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4(1H,3H)-dione (0.56 g, 0.96 mmol) in CH3CN (6 mL) was added NH3.H2O (6 mL). The reaction was heated to 90°C in a sealed tube for 12 hours. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 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, found: 562.3 [M+H] + .

[1194] 7-Butyl-5-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[3.5]nonan-7-yl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbonitrile

[1195]

[1196] To a solution of 6-amino-1-butyl-3-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[3.5]nonan-7-yl)pyrimidine-2,4(1H,3H)-dione (1.36 g, 2.4 mmol) in DCM (15 mL) was added 4,5-dichlorodithiazol-2-ium chloride (1.01 g, 4.8 mmol). After cooling to 0 °C, pyridine (0.88 g, 11.14 mmol) was added and the reaction was stirred at 20 °C for 2 hours. The reaction 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:EtOAc=10:1 to 1:1) to give the title compound (756.9 mg, 42.3%) as a colorless oil. MS (ESI): C 30 H 44 Calculated mass of N6O5SSi: 628.29, Found: 651.3 [M+Na] + .

[1197] 7-Butyl-3-((2,4-dimethoxybenzyl)amino)-5-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[3.5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

[1198]

[1199] To a solution of (2,4-dimethoxyphenyl)methanamine (971.8 mg, 5.8 mmol) in DMA (10 mL) was added 7-butyl-5-[2-[5,5-dimethyl-2,4-dioxo-3-(2-trimethylsilylethoxymethyl)imidazolidin-1-yl]spiro[3.5]non-7-yl]-4,6-dioxo-isothiazolo[3,4-d]pyrimidine-3-carbonitrile (731 mg, 1.2 mmol). The reaction was stirred at 50 ° C for 2 hours and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 3: 1 to 1: 1) to give the title compound (303 mg, 33.9%) as a colorless oil. MS (ESI): C 38 H 56 Calculated mass of N6O7SSi: 768.37, found: 769.3 [M+H] + .

[1200] 3-Amino-7-butyl-5-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

[1201]

[1202] A solution of 7-butyl-3-((2,4-dimethoxybenzyl)amino)-5-(2-(5,5-dimethyl-2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidin-1-yl)spiro[3.5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (205 mg, 0.27 mmol) in TFA (2.5 mL) and H O (0.5 mL) was stirred at 20 ° C for 2 hours. The reaction was concentrated under reduced pressure, and the crude residue was dissolved in MeOH (5 mL). K CO (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*10μm; mobile phase: [water(NH4HCO3)-ACN]; 40% to 70% B) to give the title compound (15 mg, 11.5%) as a white solid. MS (ESI): C 23 H 32 Calculated mass of N6O4S: 488.22, found: 489.3 [M+H] + .

[1203] 3-Amino-7-butyl-5-(2-(3-ethyl-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (113)

[1204]

[1205] To a solution of 3-amino-7-butyl-5-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)spiro[3.5]nonan-7-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (20 mg, 0.04 mmol) in DMF (2 mL) was added EtI (6.38 mg, 0.04 mmol) and K2CO3 (4.53 mg, 0.03 mmol). After stirring at 20°C for 2 hours, the reaction was filtered to remove insoluble solids. The filtrate was purified by reverse phase HPLC (Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water(NH4HCO3)-ACN]; 40% to 70% B) to give the title compound (113) as a white solid. MS (ESI): C 25 H 36 Calculated mass of N6O4S: 516.25, found: 517.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm8.09-8.14(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).

[1206] Example 144 was synthesized from Example 62 following the last step of Example 113 with heating at 90°C for 12 hours.

[1207] Examples 114 and 115 were synthesized by the same route and with chiral separation as Example 6. Stereochemistry was arbitrarily assigned.

[1208] Example 116. 1-Butyl-5-(diaminomethylene)-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione (116)

[1209]

[1210] Synthesis process:

[1211]

[1212] 3,5,5-Trimethylimidazolidine-2,4-dione

[1213]

[1214] To a solution of 5,5-dimethylimidazolidine-2,4-dione (5 g, 39 mmol) in EtOH (50 mL) was added MeI (11.08 g, 78.1 mmol) and NaOH (1.56 g, 39 mmol). After heating at 60 ° C for 12 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 and concentrated under reduced pressure, which was purified by silica gel column chromatography (EtOAc: MeOH = 100: 0 to 10: 1) to give the title compound (1.6 g, 28.8%) as a yellow solid. MS (ESI): CH 10 Calculated mass of N2O2: 142.07, found: 143.3 [M+H] + .

[1215] 1-(4-Bromobenzyl)-3,5,5-trimethylimidazolidine-2,4-dione

[1216]

[1217] To a solution of 1-bromo-4-(bromomethyl)benzene (1.58 g, 6.33 mmol) and 3,5,5-trimethylimidazolidine-2,4-dione (900 mg, 6.33 mmol) in THF (20 mL) was added NaH (253.2 mg, 6.33 mmol) at 0 ° C. The reactant was stirred at 25 ° C for 2 hours, quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (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: EtOAc = 100: 0 to 10: 1) to give the title compound (1.4 g, 71%) as a colorless oil. MS (ESI): C 13 H 15 Calculated mass of BrN2O2: 310.03, found: 311.1 [M+H] + .

[1218] Ethyl 2-(2-((tert-Butoxycarbonyl)amino)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate

[1219]

[1220] To a solution of 1-[(4-bromophenyl)methyl]-3,5,5-trimethyl-imidazolidine-2,4-dione (0.5 g, 1.61 mmol) in EtOH (10 mL) and H2O (2 mL) was added NaN3 (313.4 mg, 4.8 mmol), CuSO4 (256.5 mg, 1.6 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (137.1 mg, 0.96 mmol). The reaction was stirred at 80 ° C for 3 hours, quenched with saturated Na2CO3 (5 mL), diluted with H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 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 15 Calculated mass of N5O2: 273.12, found: 274.2 [M+H] + .

[1221] 1-(4-Aminobenzyl)-3,5,5-trimethylimidazolidine-2,4-dione

[1222]

[1223] To a solution of 1-[(4-azidophenyl)methyl]-3,5,5-trimethyl-imidazolidine-2,4-dione (0.8 g, 2.93 mmol) in THF (10 mL) and H 2 O (2 mL) was added PPh 3 (767.8 mg, 2.93 mmol). After stirring at 25 ° C. for 2 hours, the reaction was concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO 2, petroleum ether: EtOAc = 2: 1) to give the title compound (0.3 g, 41.4%) as a white solid. MS (ESI): C 13 H 17 Calculated mass of N3O2: 247.13, found: 248.3 [M+H] + .

[1224] 1-Butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)phenyl)urea

[1225]

[1226] To a solution of 1-[(4-aminophenyl)methyl]-3,5,5-trimethyl-imidazolidine-2,4-dione (0.3 g, 1.2 mmol) in DCM (3 mL) was added n-BuNCO (120.1 mg, 1.2 mmol) and TEA (368.3 mg, 3.64 mmol). The reactants were stirred at 25 ° C for 1 hour, filtered and concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO 2, petroleum ether: EtOAc = 2: 1) to give the title compound (0.2 g, 47.6%) as a white solid. MS (ESI): C 18 H 26 Calculated mass of N4O3: 346.20, found: 347.3 [M+H] + .

[1227] 1-Butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione

[1228]

[1229] To a solution of 1-butyl-3-[4-[(3,5,5-trimethyl-2,4-dioxo-imidazolidin-1-yl)methyl]phenyl]urea (0.3 g, 0.87 mmol) in DCM (5 mL) was added malonyl dichloride (3.66 g, 26 mmol). The reaction was stirred at 25 ° C. for 1 hour, filtered and concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO 2, petroleum ether: EtOAc = 0: 1) to give the title compound (0.4 g) as a white solid. MS (ESI): C 21 H 26 Calculated mass of N4O5: 414.19, found: 415.2 [M+H] + .

[1230] 1-Butyl-5-(diaminomethylene)-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione (116)

[1231]

[1232] To a solution of 1-butyl-3-(4-((3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)methyl)phenyl)pyrimidine-2,4,6(1H,3H,5H)-trione (0.2 g, 0.48 mmol) in THF (1 mL) was added cyanamide (608.6 mg, 14.5 mmol) and bis[(Z)-1-methyl-3-oxo-but-1-enyloxy]nickel (124 mg, 0.48 mmol). After heating at 85 ° C. for 16 hours, the residue was diluted with H2O (20 mL) and extracted with EtOAc (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% to 45% B) to give the title compound (0.04 g, 18.2%) as a white solid. MS (ESI): C 22 H 28 Calculated mass of N6O5: 456.21, found: 457.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 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=7.2 Hz, 2H), 2.92 (s, 3H), 1.46-1.52 (m, 2H), 1.26-1.30 (m, 8H), 0.88 (t, J = 7.2Hz, 3H).

[1233] Examples 117 and 120. 3-Amino-7-butyl-5-((5S,7s,10S)-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridec-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]tridec-10-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (120)

[1234]

[1235] Synthesis process:

[1236]

[1237] 1-Butyl-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione

[1238]

[1239] Under N2 at 0 ° C, to a solution of 1-butyl-6-chloropyrimidine-2,4 (1H, 3H)-dione (synthesis see Example 113, 2g, 2.87mmol) in DCM (20mL) was added DIPEA (3.83g, 29.6mmol) and SEM-Cl (3.95g, 23.7mmol). After stirring at 25 ° C for 12 hours, the reactant was quenched with saturated NH4Cl (20mL) and extracted with DCM (3 × 50mL). The combined organic layer was washed with HCl (1N, 2 × 10mL) and brine (15mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 100: 0 to 20: 1) to give the title compound (2.99g, 85.98%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm 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).

[1240] 6-Amino-1-butyl-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione

[1241]

[1242] To a solution of 1-butyl-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione (5 g, 15 mmol) in CH3CN (25 mL) was added NH3.H2O (25 mL). After heating at 80 ° C. for 12 hours, the reaction was quenched with saturated NH4Cl (50 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with HCl (1N, 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: EtOAc = 100: 1 to 1: 100) to give the title compound (4.5 g, 93.5%) as a colorless oil. MS (ESI): C 14 H 27 Calculated mass of N3O3Si: 313.38, Found: 314.3 [M+H] + .

[1243] 7-Butyl-4,6-dioxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbonitrile

[1244]

[1245] To a solution of 4,5-dichlorodithiazol-2-ium chloride (2.99 g, 14.4 mmol) in DCM (50 mL) was added 6-amino-1-butyl-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione (4.5 g, 14.4 mmol) at 25 ° C., followed by pyridine (5.22 g, 66 mmol). The reactants were stirred at 25 ° C. for 3 hours. After completion, the reactants were quenched with water (50 mL) and extracted with DCM (3×50 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 100: 1 to 20: 1) to give the title compound (1.5 g, 27.5%) as a brown oil. 1 H NMR (400MHz, CDCl3) δppm 5.47-5.49(m,2H),4.18-4.24(m,2H),3.69-3.75(m,2H),1.71-1.81(m,2H),1.36-1.48(m,2H),0.96-1.02(m,5H),0.015(s,9H).

[1246] 7-Butyl-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbonitrile (INT A)

[1247]

[1248] A mixture of 7-butyl-4,6-dioxo-5-(2-trimethylsilylethoxymethyl)isothiazolo[3,4-d]pyrimidine-3-carbonitrile (1.5 g, 3.94 mmol), TFA (5 mL) and H2O (1 mL) was stirred at 25 ° C under N2 for 12 hours. After completion, the reaction was quenched with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (INTA, 600 mg, 55.7%) as a brown oil, which was used in the next step without further purification. 1H NMR (400MHz, CDCl3) δppm 4.15-4.20(m,2H), 1.71-1.79(m,2H), 1.37-1.46(m,2H), 0.96-1.01(m,3H).

[1249] 1,3-diazadispiro[4.1.5 7 .1 5 ]Tridecane-2,4,10-trione

[1250]

[1251] To 11,14-dioxa-2,4-diazatrispiro[4.1.2.4 10 .2 7 .1 5 ] To a solution of heptadecane-1,3-dione (synthesis see Example 130, 20 g, 75.1 mmol) in acetone (400 mL) was added HCl (1 M, 225.3 mL). After heating at 70 ° C for 2 hours, the reactants were filtered. The solid was washed with H2O (3×50 mL) and dried under vacuum to give the title compound (13.9 g, 83.3%) as a white solid, which was used in the next step without further purification. MS (ESI): C 11 H 14 Calculated mass of N2O3: 222.10, found: 223.2 [M+H] + .

[1252] 3-((2-(Trimethylsilyl)ethoxy)methyl)-1,3-diazabispiro[4.1.5 7 .1 5 ]Tridecane-2,4,10-trione

[1253]

[1254] To 1,3-diazabispiro[4.1.5 7 .1 5 To a solution of tridecane-2,4,10-trione (5 g, 22.5 mmol) in DMA (50 mL) was added K2CO3 (6.22 g, 45 mmol) and SEM-Cl (5.63 g, 33.8 mmol). After stirring at 25 ° C for 3 hours, the reactant was diluted with H2O (150 mL) and extracted with EtOAc (3×70 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 100: 0 to 1: 2) to give the title compound (1.33 g, 16.8%) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δppm 5.12-5.99(m,1H),4.91-4.95(m,2H),3.60-3.67(m,2H),2.72(d,J=14.4Hz,1H),2.57( q,J=13.6Hz,1H),2.15-2.41(m,8H),1.96-2.05(m,2H),0.88-1.02(m,2H),0.01(s,9H).

[1255] 10-hydroxy-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazabispiro[4.1.5 7 .1 5 ]Tridecane-2,4-dione (INT B)

[1256]

[1257] At 0 ° C, 2-(2-trimethylsilylethoxymethyl)-2,4-diazabisspiro[4.1.5 7 .1 5 ] To a solution of tridecane-1,3,10-trione (1.7 g, 4.82 mmol) in MeOH (15 mL) was added NaBH4 (91.23 mg, 2.41 mmol). After stirring at 25 ° C for 2 hours, the reaction was quenched with H2O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (INTB, 900 mg, 52.6%) as a white solid, which was used in the next step without further purification. MS (ESI): C 17 H 30 Calculated mass of N2O4Si: 354.20, experimental value: 377.2 [M+Na] + .

[1258] 7-butyl-5-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 7 .1 5 ]tridec-10-yl)-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbonitrile

[1259]

[1260] At 20 ° C, 7-butyl-4,6-dioxo-isothiazolo[3,4-d]pyrimidine-3-carbonitrile (INTA, 430 mg, 1.72 mmol) and 10-hydroxy-2-(2-trimethylsilylethoxymethyl)-2,4-diazabisspiro[4.1.5 7 .1 5 ] To a mixture of tridecane-1,3-dione (INTB, 609.1 mg, 1.72 mmol) in toluene (2 mL) was added 2-(tributyl-λ5-phosphino)acetonitrile (1.45 g, 6.0 mmol). The reactants were heated at 120 ° C under Ar for 12 hours. After cooling, the reactants were poured into H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (280 mg, 27.8%) as a yellow oil, which was used in the next step without further purification. MS (ESI): C 27 H 38 Calculated mass of N6O5SSi: 586.24, Found: 609.2 [M+Na] + .

[1261] 7-butyl-3-((2,4-dimethoxybenzyl)amino)-5-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 7 .1 5 ]tridec-10-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

[1262]

[1263] To 7-butyl-5-[1,3-dioxo-2-(2-trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.5 7 .1 5 To a mixture of ] tridecane-10-yl] -4,6-dioxo-isothiazolo[3,4-d] pyrimidine-3-carbonitrile (230 mg, 0.39 mmol) in DMA (1 mL) was added (2,4-dimethoxyphenyl)methylamine (655.4 mg, 3.9 mmol) in one portion. After heating at 90 ° C for 3 hours, the reactants were cooled and extracted with EtOAc (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 silica gel column chromatography (petroleum ether: EtOAc = 1: 0 to 0: 1) to give the title compound (240 mg, 84.2%) as a white solid. MS (ESI): C 35H 50 Calculated mass of N6O7SSi: 726.32, found: 727.3 [M+H] + .

[1264] 3-amino-7-butyl-5-(2,4-dioxo-1,3-diazadispiro[4.1.5 7 .1 5 ]tridec-10-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

[1265]

[1266] To 7-butyl-3-((2,4-dimethoxybenzyl)amino)-5-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.5 7 .1 5 ] tridecane-10-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (274.2 mg, 0.39 mmol) in TFA (0.5 mL) was added H2O (0.1 mL). The reactant was stirred at 25 ° C for 1 hour and concentrated under reduced pressure. The crude residue was diluted with MeOH (2 mL) and K2CO3 was added until pH = 8 to 9. After stirring for 1 hour, the mixture was acidified to pH = 5 to 6 by monohydrated citric acid and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase HPLC (mobile phase: [water (NH4HCO3)-ACN]; gradient 25% to 55% B) to give the title compound (110 mg, 64%) as a white solid. MS (ESI): C 20 H 26 Calculated mass of N6O4S: 446.17, found: 447.2 [M+H] + .

[1267] 3-amino-7-butyl-5-((5S,7s,10S)-2,4-dioxo-1,3-diazadispiro[4.1.5 7 .1 5 ]tridec-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-diazabisspiro[4.1.5 7 .1 5 ]tridec-10-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (120)

[1268]

[1269] 3-amino-7-butyl-5-(2,4-dioxo-1,3-diazadispiro[4.1.5 7 .1 5 ]tridec-10-yl)isothiazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (110 mg, 0.25 mmol) was separated by chiral SFC (column: DAICELCHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO2-IPA (0.1% NH3H2O)]; 47% isocratic) to give the title compound (117) as a white solid (25.5 mg, 14.8%, later eluting peak). MS (ESI): C 20 H 26 Calculated mass of N6O4S: 446.17, found: 447.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (s, 1H), 8.39 (s, 1H), 8.13 (br s, 2H), 4.47-4.64 (m, 1H), 3.88 (t, J = 8.0 Hz, 2H), 2.16-2.39 (m, 5H), 1.85-2.01 (m, 3H), 1.52-1.61 (m, 2H), 1.39-1.48 (m, 3H), 1.22-1.30 (m, 3H), 0.89 (t, J = 7.2 Hz, 3H); and the title compound (120) (29.3 mg, 17%, earlier eluting peak) as a white solid. MS (ESI): C 20 H 26 Calculated mass of N6O4S: 446.17, found: 447.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 8.40 (s, 1H), 8.15 (br s, 2H), 4....

Claims

1. A compound of formula (Ia) or (Ib): or a pharmaceutically acceptable salt thereof; in: Z is O or S; Y means: X is N or CR 2 ; L is -(C1-C6)alkylene-; B represents (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 instances of (C1-C6)alkyl; R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, or -O-(4- to 7-membered heterocycloalkyl); wherein (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, 4 to 7 membered heterocycloalkyl and -O-(4 to 7 membered heterocycloalkyl) are each optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, phenyl, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, hydroxy (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl, (C3-C8)cycloalkyl (C1-C6)alkyl and benzyl; or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is Then R 1 Not hydrogen; R 1a 、R 1b and R 1c is independently hydrogen at each occurrence, (C 1- C6)alkyl or (C3-C8)cycloalkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group; R 2 For hydrogen, fluorine, chlorine, cyano, hydroxyl, NH2, NHCO (C1-C6) alkyl, NHR a 、(C 1- C6) alkoxy, -CONR a R b or (C 1- C6) alkyl, wherein (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b ; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 9-membered heterocycloalkyl group optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, wherein said (C1-C6)alkyl group is further optionally substituted with: (C1-C6)alkyl; 3- C8) cycloalkyl, 4 to 7 membered heterocyclylalkyl, hydroxy, halo, (C 1- C6) alkoxy, cyano, carboxyl, -CONR a R b and-SO2R a ; R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, aryl, carboxamide, amino, cyano, carboxyl and alkoxycarbonyl; R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group; R 5a 、R 5b 、R 6a and R 6b are independently hydrogen or (C 1- C6) alkyl; R A is hydrogen or (C 1- C6) alkyl; n, m and p are independently 0 or 1; and q is 0, 1, or 2; The condition is that the sum of p and q is equal to 0, 1 or 2.

2. A compound of formula (Ia) or (Ib): or a pharmaceutically acceptable salt thereof; in: Y means: X is N or CR 2 ; L is -(C1-C6)alkylene-; B represents (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 instances of (C1-C6)alkyl; R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, or -O-(4- to 7-membered heterocycloalkyl); wherein (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy, 4 to 7 membered heterocycloalkyl and -O-(4 to 7 membered heterocycloalkyl) are each optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, hydroxy (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl, (C3-C8)cycloalkyl (C1-C6)alkyl and benzyl; or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is Then R 1 Not hydrogen; R 1a 、R 1b and R 1c is independently hydrogen at each occurrence, (C 1- C6)alkyl or (C3-C8)cycloalkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group; R 2 For hydrogen, fluorine, chlorine, cyano, hydroxyl, NH2, NHCO (C1-C6) alkyl, NHR a 、(C 1- C6) alkoxy, -CONR a R b or (C 1- C6) alkyl, wherein (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b ; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 9-membered heterocycloalkyl group optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, wherein said (C1-C6)alkyl group is further optionally substituted with: (C1-C6)alkyl; 3- C8) cycloalkyl, 4 to 7 membered heterocyclylalkyl, hydroxy, (C 1- C6) alkoxy, cyano, carboxyl, -CONR a R b and-SO2R a ; R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, aryl, carboxamide, amino, cyano, carboxyl and alkoxycarbonyl; R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group; R 5a 、R 5b 、R 6a and R 6b are independently hydrogen or (C 1- C6) alkyl; n, m and p are independently 0 or 1; and q is 0, 1, or 2; The condition is that the sum of p and q is equal to 0, 1 or 2.

3. A compound of formula (Ia) or (Ib): or a pharmaceutically acceptable salt thereof; in: Y means: X is N or CR 2 ; L is -(C1-C6)alkylene-; B represents (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 instances of (C1-C6)alkyl; R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy or Among them (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy and 4 to 7 membered heterocycloalkyl are each optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, and (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl and Or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is Then R 1 Not hydrogen; R 1a 、R 1b and R 1c is independently hydrogen or (C 1- C6) alkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group; R 2 For hydrogen, fluorine, chlorine, cyano, hydroxyl, NH2, NHCO (C1-C6) alkyl, NHR a 、(C 1- C6) alkoxy, -CONR a R b or (C 1- C6) alkyl, said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b ; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 7-membered heterocycloalkyl group; R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, carboxamido, amino, cyano, carboxyl and alkoxycarbonyl; R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group; n, m and p are independently 0 or 1; and q is 0, 1, or 2; The condition is that the sum of p and q is equal to 0, 1 or 2.

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

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

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

7. The compound of any one of claims 1 to 6, wherein R 1 for: hydrogen, in: R 1d 、R 1e and R 1f is independently selected at each occurrence from hydrogen, (C 1- C6) alkyl, (C 1- C6) haloalkyl, (C 1- C6) hydroxyalkyl and (C 1- C6) alkoxy, wherein (C 1- C6)alkyl is further optionally substituted with (C3-C8)cycloalkyl or phenyl; or R 1d and R 1e Together with the carbon to which it is attached, it forms a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl, each of which is optionally substituted with hydroxy.

8. The compound of claim 7, wherein R 1 for and: R a and R b each is hydrogen, or R a is hydrogen; and R b It is a methyl group.

9. The compound of any one of claims 1 to 6, wherein R 1 for: hydrogen, in: R 1d 、R 1e and R 1f is independently selected at each occurrence from hydrogen, (C 1- C6) alkyl, (C 1- C6) haloalkyl, (C 1- C6) hydroxyalkyl and (C 1- C6) alkoxy, wherein (C 1- C6)alkyl is further optionally substituted with (C3-C8)cycloalkyl or phenyl; or R 1d and R 1e Together with the carbon to which it is attached, it forms a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl, each of which is optionally substituted with hydroxy.

10. The compound of any one of claims 1 to 6, wherein R 1 for: hydrogen, in: R 1d 、R 1e and R 1f is independently selected at each occurrence from hydrogen, (C 1- C6) alkyl, (C 1- C6) haloalkyl and (C 1- C6) alkoxy; or R 1d and R 1e Together with the carbon to which it is attached, it forms a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl.

11. The compound of any one of claims 7, 9 and 10, wherein R 1 for and R 1d and R 1e Together with the carbon to which it is attached, it forms a morpholine, cyclobutane, oxetane, azetidine, or cyclohexane.

12. A compound as claimed in any one of claims 7 and 9 to 11, wherein R 1d and R 1e Each is a methyl group.

13. A compound as described in any one of claims 7 and 9 to 12, wherein R 1f For hydrogen.

14. A compound as described in any one of claims 7 and 9 to 12, wherein R 1f For (C 1- C6) alkyl.

15. The compound of claim 14, wherein R 1f It is methyl or ethyl.

16. A compound as described in any one of claims 7 and 9 to 12, wherein R 1f For (C 1- C6) fluoroalkyl.

17. The compound of claim 16, wherein R 1f It is 2,2,2-trifluoroethyl.

18. The compound of any one of claims 7, 9 and 10, wherein R 1 for And R 1a is cyclopropyl, 2-propyl, ethyl or methyl.

19. The compound of any one of claims 1 to 6, wherein R 1 for: hydrogen, 20. The compound of any one of claims 1 to 6, wherein R 1 for:

21. A compound as described in any one of claims 1 to 17, wherein Y is 22. The compound of any one of claims 1 to 5 and 7 to 20, wherein X is N.

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

24. The compound of claim 23, wherein R 2 For hydrogen.

25. The compound of claim 23, wherein R 2 For fluorine.

26. The compound of claim 23, wherein R 2 is optionally (C 1- C6) alkoxy substituted (C 1- C6) alkyl.

27. The compound of claim 26, wherein R 2 It is a methyl group.

28. The compound of claim 26, wherein R 2 It is methoxymethyl.

29. The compound of claim 23, wherein R 1 for and R 2 It is -CH3 or -CH2-OCH3.

30. The compound of claim 23, wherein R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 9-membered heterocycloalkyl, wherein the 4- to 9-membered heterocycloalkyl is optionally replaced by (C 1- C6) alkyl, wherein said (C 1- C6) alkyl is further optionally substituted with one or more substituents independently selected from the group consisting of: (C 3- C8) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, hydroxy, halo, (C 1- C6) alkoxy, cyano, carboxyl, -CONR a R b and-SO2R a .

31. The compound of claim 30, wherein R 1 and R 2 Together with the atoms to which they are attached, they form: where R 1g and R 1h are each independently hydrogen or (C 1- C6) alkyl, wherein said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: (C 3- C8) cycloalkyl, 4 to 7 membered heterocyclylalkyl, hydroxy, halo, (C 1- C6) alkoxy, cyano, carboxyl, -CONR a R b and-SO2R a .

32. The compound of claim 31, wherein R 1h is ethyl, methyl, ethyl, isopropyl or tert-butyl, each of which is optionally substituted by hydroxy, methoxy, cyclopropyl, oxetanyl, tetrahydrofuranyl, phenyl, cyano, carboxyl, hydroxy, -CONR a R b 、-SO2R a or one to three fluorine atoms.

33. The compound of claim 32, wherein R 1h It is trifluoromethyl.

34. A compound as described in any one of claims 31 to 33, wherein R 1g is hydrogen, methyl or ethyl, wherein the methyl or ethyl group is optionally substituted by a cyano group.

35. A compound as described in any one of claims 1 to 34, wherein R a It is a methyl group.

36. A compound as described in any one of claims 1 to 35, wherein R b It is a methyl group.

37. The compound of claim 30, wherein R 1 and R 2 Together with the atoms to which they are attached, they form:

38. The compound of claim 30, wherein R 1 and R 2 Together with the atoms to which they are attached, they form:

39. The compound of claim 30, wherein R 1 and R 2 Together with the atoms to which they are attached, they form:

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

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

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

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

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

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

46. A compound as described in any one of claims 1 to 5 and 7 to 45, wherein q is 1.

47. A compound as described in any one of claims 1 to 5 and 7 to 45, wherein q is 0.

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

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

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

51. A compound as claimed in any one of claims 1 to 3 and 6 to 20, wherein B represents cyclohexyl or cyclopentyl.

52. A compound as claimed in any one of claims 1 to 3 and 6 to 20, wherein B represents phenyl, tolyl or pyridyl.

53. A compound as claimed in any one of claims 1 to 3 and 6 to 20, wherein B represents a 4 to 7 membered heterocycloalkyl group.

54. A compound as described in any one of claims 1, 2 and 5 to 17, wherein B represents:

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

56. A compound as described in any one of claims 1 to 55, wherein R 5a 、R 5b 、R 6a and R 6b Each is hydrogen.

57. A compound as described in any one of claims 1 to 55, wherein R 5a 、R 5b 、R 6a and R 6b Each is a methyl group.

58. A compound as described in any one of claims 1 to 55, wherein R 5a is methyl and R 5b 、R 6a and R 6b Each is hydrogen.

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

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

61. The compound of claim 60, wherein R A It is a methyl group.

62. The compound of claim 1, wherein the compound has the structure of Formula (Ic): or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from (C 1- C6) alkyl, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, NR a R b or Among them (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl and (C 1- C6) alkoxy.

63. The compound of claim 1, wherein the compound has the structure of Formula (Id): or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R b , (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or wherein each of the 4 to 7 membered heterocycloalkyl groups is optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamide, sulfonamide, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, (C 1- C6) alkoxy and (C 1- C6) hydroxyalkyl, R 1a is hydrogen or (C 1- C6) alkyl; R 2 Selected from hydrogen, cyano, hydroxy, NH2, NHCOCH3, NHR a 、(C 1- C6) alkoxy, -CONR a R b or (C 1- C6) alkyl, said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy and NR a R b .

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

65. The compound of any one of claims 1 to 64, wherein R 3 Methyl, n-propyl, n-butyl, 66. A compound as described in any one of claims 1 to 64, wherein R 3 Methyl, n-butyl, 67. The compound of any one of claims 1 to 66, wherein the compound is represented by Formula Ia.

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

69. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

70. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

71. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

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

73. A compound of formula (IIa) or (IIb): or a pharmaceutically acceptable salt thereof; in: Y means: X is N or CR 2 ; L is -(C1-C6)alkylene-; B represents (C3-C8) cycloalkyl, (C6-C 10 )aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy or Among them (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy and 4 to 7 membered heterocycloalkyl are each optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, and (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl and Or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is or (C1-C6) alkylene, then R 1 Not hydrogen; R 1a 、R 1b and R 1c is independently hydrogen or (C 1- C6) alkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group; R 2 For hydrogen, fluorine, chlorine, -CONR a R b or (C 1- C6) alkyl, said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, and (C 1- C6) alkoxy; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 7-membered heterocycloalkyl group; R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, carboxamido, amino, cyano, carboxyl and alkoxycarbonyl; R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group; n, m and p are independently 0 or 1; q is 0, 1, or 2; The condition is that the sum of p and q is equal to 0, 1 or 2; Z is S or O; R 4 H、-C(O)NH2、(C 1- C6) alkyl, -NHSO2Me or -N(R 4a )2; and R 4a is independently hydrogen or (C 1- C6) alkyl.

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

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

76. The compound of any one of claims 73 to 75, wherein R 1 for:

77. The compound of any one of claims 73 to 75, wherein R 1 for:

78. The compound of any one of claims 73 to 77, wherein R 1 for: hydrogen, and R 1d 、R 1e and R 1f is independently selected at each occurrence from hydrogen, (C 1- C6) alkyl, (C 1- C6) haloalkyl and (C 1- C6) alkoxy; or R 1d and R 1e Together with the carbon to which it is attached, it forms a (C3-C8)cycloalkyl or a 3- to 7-membered heterocycloalkyl.

79. The compound of claim 78, wherein R 1 for and R 1d and R 1e Together with the carbon to which it is attached, it forms a morpholine, cyclobutane, oxetane, or cyclohexane.

80. The compound of claim 79, wherein R 1d and R 1e Each is a methyl group.

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

82. The compound of any one of claims 78 to 80, wherein R 1f For (C 1- C6) alkyl.

83. The compound of claim 82, wherein R 1f It is methyl or ethyl.

84. The compound of any one of claims 78 to 80, wherein R 1f For (C 1- C6) fluoroalkyl.

85. The compound of claim 84, wherein R 1f It is 2,2,2-trifluoroethyl.

86. The compound of any one of claims 73 to 77, wherein R 1 for: hydrogen, 87. A compound as described in any one of claims 73 to 86, wherein Y is 88. A compound as described in any one of claims 73 and 74 to 84, wherein X is N.

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

90. The compound of claim 89, wherein R 2 For hydrogen.

91. The compound of claim 89, wherein R 2 For fluorine.

92. The compound of claim 89, wherein R 2 is optionally (C 1- C6) alkoxy substituted (C 1- C6) alkyl.

93. The compound of claim 92, wherein R 2 It is a methyl group.

94. The compound of claim 92, wherein R 2 It is methoxymethyl.

95. The compound of claim 89, wherein R 1 for and R 2 It is -CH3 or -CH2-OCH3.

96. The compound of claim 89, wherein R 1 and R 2 Together with the atoms to which it is attached, it forms a 4- to 7-membered heterocycloalkyl.

97. The compound of claim 96, wherein R 1 and R 2 Together with the atoms to which they are attached, they form:

98. The compound of any one of claims 73 to 97, wherein R 3 For: methyl, 99. The compound of any one of claims 73 to 98, wherein Z is O.

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

101. The compound of any one of claims 73 to 100, wherein R 4 For H.

102. The compound of any one of claims 73 to 100, wherein R 4 is NH2.

103. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

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

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

106. A compound of formula (IIIa), (IIIb), (IIIc) or (IIId): or a pharmaceutically acceptable salt thereof; in: YR 1 express: -(C1-C6)alkylene-R 1 ; X is N or CR 2 ; L is -(C1-C6)alkylene-; B represents (C3-C8) cycloalkyl, (C6-C 10 )aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more instances of (C1-C6)alkyl; R 1 For hydrogen, -CO2R a 、-CONR a R b 、-SO2R a 、-SONR a R b 、-SO2NR a R b 、-NR a R, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy or Among them (C 1- C6) alkyl, (C 3- C8) cycloalkyl, (C 1- C6) alkoxy and 4 to 7 membered heterocycloalkyl are each optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, oxo, cyano, amino, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, carboxamido, sulfonamido, aminoalkyl, (C 1- C6) alkyl, (C3-C8) cycloalkyl, (C 1- C6) haloalkyl, and (C 1- C6) alkoxy, (C 1- C6) hydroxyalkyl and Or when Y represents -LB-, R 1 together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl ring, provided that if Y is (C1-C6) alkylene, then R 1 Not hydrogen; R 1a 、R 1b and R 1c is independently hydrogen or (C 1- C6) alkyl; or R 1a and R 1b Together with the atoms to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group; R 2 For hydrogen, fluorine, chlorine, -CONR a R b or (C 1- C6) alkyl, said (C 1- C6) alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, and (C 1- C6) alkoxy; or R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 7-membered heterocycloalkyl group; R 3 For (C 1- C6) alkyl or (C 3- C8) cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1- C6) alkoxy, (C 3- C8) cycloalkyl, carboxamido, amino, cyano, carboxyl and alkoxycarbonyl; R a and R b is independently hydrogen at each occurrence, (C 1- C6) alkyl or 4 to 7 membered heterocycloalkyl, wherein (C 1- C6) alkyl and 4 to 7 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, (C 1- C6) alkoxy, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group; n, m and p are independently 0 or 1; q is 0, 1, or 2; The condition is that the sum of p and q is equal to 0, 1 or 2; R 4 H or N(R 4a )2; and R 4a is independently hydrogen or (C 1- C6) alkyl.

107. The compound of claim 106, wherein R 1 for: hydrogen, 108. The compound of claim 106, wherein R 1 for and R 2 It is -CH3 or -CH2-OCH3.

109. The compound of claim 106, wherein R 1 for:

110. The compound of claim 106, wherein R 1 for:

111. A compound as described in any one of claims 106 to 110, wherein Y is 112. The compound of any one of claims 106 to 111, wherein R 3 For: methyl, 113. The compound of any one of claims 106 to 110, wherein R 4 For H.

114. The compound of any one of claims 106 to 110, wherein R 4 is NH2.

115. A compound having the following structure: or 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, bone fractures, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumor calcification, comprising administering to a subject in need thereof an effective amount of a compound as described in any one of claims 1 to 115 or a pharmaceutically acceptable salt thereof.

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