Diaminomethylene-containing agonists of the parathyroid hormone 1 receptor

Abstract

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

Description

[0001]GPX-02325 DIAMINOMETHYLENE-CONTAINING AGONISTS OF THE PARATHYROID HORMONE 1 RECEPTOR CROSS-REFERENCE TO A RELATED APPLICATION This application claims the benefit of priority to U.S. Provisional Patent Application No.63 / 686,933, filed August 26, 2024. BACKGROUND Regulation of calcium concentration is important to normal function of the gastrointestinal tract, skeletal system, nervous system, muscular nervous system and cardiovascular system. Parathyroid hormone (PTH) synthesis and release is primarily controlled by serum calcium levels. Osteoporosis is characterized by bone loss resulting in an increased incidence of fracture. This condition, which is most prevalent in the spine and hip, affects 1 in 3 postmenopausal women, a lesser but significant number of aging men, and is also caused by other conditions including hypogonadism and prolonged glucocorticoid use. Current therapies to treat osteoporosis, such as bisphosphonates, hormone replacement therapy, SERMs and calcitonin, serve to arrest further bone loss by inhibiting bone resorption. Although these treatments may slow or even prevent continued bone loss, new bone formation leading to increased bone mass and strength, does not occur. Consequently, there is still a need for a therapeutic agent capable of stimulating bone formation. Such a therapeutic agent would be beneficial both to patients who are at risk of developing osteoporosis or who present with established osteoporosis. Parathyroid hormone (PTH) is a significant regulator of calcium homeostasis and acts, in part, by mobilizing calcium from the skeleton through increased bone resorption. Additionally, pulsatile administration of PTH can stimulate new bone formation, both in laboratory animals and in humans. Thus, there is evidence to suggest that targeting of the receptor for PTH with a small molecule agonist mimicking the actions of PTH, would be a suitable approach for generating an anabolic response in bone. PTH elicits its effects by binding and activating a class B, G protein-coupled receptor of the 7 transmembrane superfamily, designated PTH1R. PTH1R activates multiple signaling pathways, but predominantly the adenylyl cyclase / cyclic AMP and the phospholipase C / calcium mobilization pathways. - 1 - FH13029825.4 GPX-02325 Accordingly, there is a need in the art to provide small molecule therapeutics that treat or prevent hypoparathyroidism, osteoporosis and related conditions. In particular, there is a need for providing compounds that act as PTH1R agonists. SUMMARY The present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: R1and R2are independently hydrogen or (C1-C6)alkyl, provided that at least one of R1and R2is hydrogen; and R3is (C1-C6)fluoroalkyl. The present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen or (C1-C6)alkyl; R5is (C1-C6)alkyl; and R6is (C1-C6)fluoroalkyl. Other aspects of the disclosure provide a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. - 2 - FH13029825.4 GPX-02325 In still other aspects, provided herein is a method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. BRIEF DESCRIPTION OF THE FIGURES Figure 1 tabulates exemplary compounds of the invention, and their characterization data and biological activity. DETAILED DESCRIPTION Definitions For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. - 3 - FH13029825.4 GPX-02325 The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in some embodiments, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in some embodiments, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and - 4 - FH13029825.4 GPX-02325 optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an - 5 - FH13029825.4 GPX-02325 isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in - 6 - FH13029825.4 GPX-02325 which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms. Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C- enriched carbon are within the scope of this invention. The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a - 7 - FH13029825.4 GPX-02325 purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.) In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra). The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule. A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). - 8 - FH13029825.4 GPX-02325 The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human. An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl groups may be substituted or unsubstituted. As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen. As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein substituted with at least one halogen atom. For example, haloalkoxy groups include fluoroalkoxy groups, such as trifluoromethoxy, difluoromethoxy, and the like. As used herein, the term “hydroxyalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl. As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic - 9 - FH13029825.4 GPX-02325 or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents. "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. “1,2-Disubstituted cyclohexyl” as used herein refers to a cyclohexane ring that contains points of attachment at the 1 and 2 positions of the cyclohexane ring to the rest of the compound. Similarly, “1,2-disubstituted cyclopentyl” as used herein refers to a cyclopentane ring that contains points of attachment at the 1 and 2 positions of the cyclopentane ring to the rest of the compound.1,2-Disubstituted cyclohexyl and 1,2- disubstituted cyclopentyl can also be referred to as 1,2-cyclohexylene and 1,2- cyclopentylene, respectively. As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen. "Cycloheteroalkyl" refers to a cycloalkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted. Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl. “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located - 10 - FH13029825.4 GPX-02325 anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety. The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, indazole, quinoline, benzofuran, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic. The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo. The terms “heterocyclyl” or “heterocyclic group” or “heterocycloalkyl” refer to 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. Heterocycloalkyl groups can - 11 - FH13029825.4 GPX-02325 be fully saturated or partially saturated. Heterocycloalkyl groups include, for example, bicyclic ring systems having either or both constituent rings saturated (e.g., 2,3-dihydroindole, 4,5,6,7- tetrahydro-benzofuran, decahydroquinoline, and the like) or partially saturated (e.g., octahydroquinoline and the like). The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood - 12 - FH13029825.4 GPX-02325 to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. As used herein, “small molecules” refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da). The small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da). In some embodiments, a “small molecule” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound, with a size on the order of 1 nm. In some embodiments, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000. An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments. The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” - 13 - FH13029825.4 GPX-02325 typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter as compared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment. The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response. A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and / or therapy of various diseases. The radiolabeled pharmaceutical agent, for example, a radiolabeled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. - 14 - FH13029825.4 GPX-02325 Compounds of the Invention The present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: R1and R2are independently hydrogen or (C1-C6)alkyl, provided that at least one of R1and R2is hydrogen; and R3is (C1-C6)fluoroalkyl. In some embodiments, a compound has the structure of Formula (Ia): or a pharmaceutically acceptable salt thereof. In other embodiments, a compound has the structure of Formula (Ib): or a pharmaceutically acceptable salt thereof. In some embodiments, R1is (C1-C6)alkyl, preferably methyl, and R2is hydrogen. In other embodiments, R2is (C1-C6)alkyl, preferably methyl, and R1is hydrogen. In still other embodiments, R1and R2are each hydrogen. In some embodiments, R3is (C1-C6)trifluoroalkyl, preferably 4,4,4-trifluorobutyl. In some embodiments, provided herein is a compound of Formula (II): - 15 - FH13029825.4 GPX-02325 or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen or (C1-C6)alkyl; R5is (C1-C6)alkyl; and R6is (C1-C6)fluoroalkyl. In some embodiments, a compound has the structure of Formula (IIa): or a pharmaceutically acceptable salt thereof. In some embodiments, a compound has the structure of Formula (IIb): , or a pharmaceutically acceptable salt thereof. In some embodiments, R4is hydrogen. In other embodiments, R4is (C1-C6)alkyl, preferably R4is methyl. In some preferred embodiments, embodiments, R5is methyl. In some embodiments, R6is (C1-C6)trifluoroalkyl. In some preferred embodiments, R6is 4,4,4-trifluorobutyl. In some embodiments, a compound of the invention is: - 16 - FH13029825.4 GPX-02325 pharmaceutically acceptable salt thereof. Methods of Treatment - 17 - FH13029825.4 GPX-02325 Provided herein is a method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. Also provided herein is a method for preventing or treating a condition mediated by PTH which comprises administering to a mammal in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, either alone or in admixture with a pharmaceutically acceptable excipient. Another aspect of the invention includes compounds of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment and prevention of diseases and conditions characterized by loss of bone mineral density, mass, or strength, as well as in conditions wherein PTH would have a beneficial pharmacological effect. The invention includes administering compounds of formula (I) or (II) for use as a PTH mimetic. Another aspect of the invention includes use of the compounds of the present invention in the manufacture of a medicament for use in the treatment of osteopenia and osteoporosis in men and women for reduction in the risk of fractures, both vertebral and nonvertebral. In certain embodiments, the compound is administered orally to the subject. In certain embodiments, the compound is administered parenterally to the subject. In certain embodiments, the disease is prevented. In other embodiments, the disease is treated. Pharmaceutical Compositions, Routes of Administration, and Dosing In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention, and a pharmaceutically acceptable carrier. In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents. As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by - 18 - FH13029825.4 GPX-02325 choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein. In certain embodiments, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 20 mg / kg / day. In some embodiments, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 2 mg / kg / day. In some embodiments, intravenous administration of a compound may typically be from 0.5 mg / kg / day to 5 mg / kg / day. In some embodiments, intravenous administration of a compound may typically be from 1 mg / kg / day to 20 mg / kg / day. In some embodiments, intravenous administration of a compound may typically be from 1 mg / kg / day to 10 mg / kg / day. Generally, daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams / kg per day to 1000 milligrams / kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound. For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for - 19 - FH13029825.4 GPX-02325 compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan. The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical. For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration. For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may - 20 - FH13029825.4 GPX-02325 also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers. Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp.367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable. For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine. To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films. A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used. - 21 - FH13029825.4 GPX-02325 The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used. The therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression. Colorants and flavoring agents may all be included. For example, the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents. One may dilute or increase the volume of the therapeutic with an inert material. These diluents could include carbohydrates, especially mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell. Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants. Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic. An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, - 22 - FH13029825.4 GPX-02325 vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000. Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate. To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios. Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For topical administration, the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration. For administration by inhalation, compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from - 23 - FH13029825.4 GPX-02325 pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (α1- antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Pat. No.5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No.5,451,569 (incorporated by reference), issued Sep.19, 1995 to Wong et al. Contemplated for use in the practice of this invention are mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art. Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass. All such devices require the use of formulations suitable for the dispensing of the compounds of the invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Also, the use of liposomes, - 24 - FH13029825.4 GPX-02325 microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed. Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol. Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant. Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing a compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers (μm), most preferably 0.5 to 5 μm, for most effective delivery to the deep lung. Nasal delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran. For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In some embodiments, the metered dose is delivered by drawing the - 25 - FH13029825.4 GPX-02325 pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available. Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug. The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described above, a compound may also be formulated as a depot preparation. Such long-acting formulations may be formulated with suitable - 26 - FH13029825.4 GPX-02325 polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990). The compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicine the salts or cocrystals should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group. Suitable buffering agents include: acetic acid and a salt (1-2% w / v); citric acid and a salt (1-3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphoric acid and a salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v) and thimerosal (0.004-0.02% w / v). Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means - 27 - FH13029825.4 GPX-02325 one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency. The therapeutic agent(s), including specifically but not limited to a compound of the invention, may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state. The particles may be of virtually any shape. Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate). - 28 - FH13029825.4 GPX-02325 The therapeutic agent(s) may be contained in controlled release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.” Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above. It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention. EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Abbreviations: - 29 - FH13029825.4 GPX-02325 Examples 1 and 2. 5-(Diaminomethylene)-1-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (1) and 5-(Diaminomethylene)-1-((5R,7r,10R)-3-methyl-2,4- - 30 - FH13029825.4 GPX-02325 dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (2) 2-(2-Trimethylsilylethoxymethyl)-11,14-dioxa-2,4- diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione - 31 - FH13029825.4 GPX-02325 To a solution of 11,14-dioxa-2,4-diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione (1.35 g, 5.07 mmol) in DCM (30 mL) was added SEMCl (2.54 g, 15.2 mmol) and DIPEA (3.28 g, 25.4 mmol). After stirring at 25 °C for 12 h, the reaction was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 20: 1 to 1: 1) to provide the title compound (1.1 g, 55%) as a yellow solid. MS (ESI): mass calcd. for C19H32N2O5Si: 396.21, found: 369.2 [M-28+H]+. 2-(2-Trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecane-1,3,10-trione To a solution of 2-(2-trimethylsilylethoxymethyl)-11,14-dioxa-2,4- diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione (6 g, 15.1 mmol) in acetone (60 mL) and H2O (30 mL) was added TsOH.H2O (5.76 g, 30.3 mmol). The mixture was stirred at 60 °C for 2 h. The reaction was adjusted to pH = 6 with NaHCO3 and extracted with DCM (50 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 1: 1) to provide the title compound (4.5 g, 84.4%) as a white solid. MS (ESI): mass calcd. for C17H28N2O4Si: 352.18, found: 375.2 [M+Na]+. 10-Amino-2-(2-trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecane-1,3- dione A solution of 2-(2-trimethylsilylethoxymethyl)-2,4-diazadispiro[4.1.57.15]tridecane- 1,3,10-trione (4.5 g, 12.77 mmol) in NH3 / MeOH (60 mL) was stirred at 20 °C for 2 h. Raney Ni (1.09 g) was added under N2. The suspension was degassed and purged with H23x and stirred under H2(15 Psi) at 25 °C for 4 h. The reaction was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to provide the title compound (3.5 g, 77.6%) as a green solid. MS (ESI): mass calcd. for C17H31N3O3Si: 353.21, found: 354.1 [M+H]+. - 32 - FH13029825.4 GPX-02325 1-(2,4-Dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)-3-(4,4,4-trifluorobutyl)urea To a solution of 10-amino-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3- diazadispiro[4.1.57.15]tridecane-2,4-dione (800 mg, 2.26 mmol) in DCM (5 mL) was added TEA (458 mg, 4.53 mmol). The reaction was degassed and purged with N23x. (4- Nitrophenyl) N-(4,4,4-trifluorobutyl)carbamate (793.5 mg, 2.72 mmol) was added and stirred at 15 °C for 1 h under N2. After completion, the reaction was quenched with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 1 to 0 : 1) to provide the title compound (830 mg, 72.4%) as a yellow oil. MS (ESI): mass calcd. for C22H37F3N4O4Si: 506.25, found: 507.1 [M+H]+. 1-(2,4-Dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (1H,3H,5H)-trione To a solution of 1-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)urea (830 mg, 1.64 mmol) in AcOH (8.5 mL) was added malonic acid (70.5 mg, 1.64 mmol). The mixture was degassed and purged with N23x. Ac2O (1.17 g, 11.47 mmol) was added and stirred at 80 °C for 4 h under N2. After completion, the reaction was quenched with H2O (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 1 to 0 : 1) to provide the title compound (540 mg, 57.4%) as a white solid. MS (ESI): mass calcd. for C25H37F3N4O6Si: 574.24, found: 547.1 [M-28+H]+. - 33 - FH13029825.4 GPX-02325 5-(Diaminomethylene)-1-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione To a solution of 1-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)- trione (540 mg, 939.68 μmol) in THF (6 mL) was added cyanamide (395 mg, 9.4 mmol). The mixture was degassed and purged with N23x. Ni(acac)2 (72.4 mg, 282 μmol) was added, and the reaction was heated at 80 °C for 20 h under N2. After completion, the reaction was filtered through a celite pad. The filtrate was diluted with H2O (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to provide the title compound (400 mg, 69%) as a white solid. MS (ESI): mass calcd. for C26H39F3N6O6Si: 616.27, found: 589.5 [M-28+H]+. 5-(Diaminomethylene)-1-(2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4- trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione A solution of 5-(diaminomethylene)-1-(2,4-dioxo-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4- trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (400 mg, 648.6 μmol) in TFA (5 mL) and H2O (1 mL) was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure. The crude product was dissolved in MeOH (5 mL), adjusted to pH = 9 with solid K2CO3 and stirred at 25 °C for 1 h. After completion, the reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified - 34 - FH13029825.4 GPX-02325 by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to provide the title compound (200 mg, 63.4%) as a white solid. MS (ESI): mass calcd. C20H25F3N6O5: 486.18, found: 487.0 [M+H]+. 5-(Diaminomethylene)-1-(2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4- trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 5-(diaminomethylene)-1-(2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)- trione (150 mg, 308 μmol) in DMF (2 mL) was added Cs2CO3 (110.5 mg, 339 μmol). The mixture was degassed and purged with N23x. MeI (43.77 mg, 308 μmol) was added, and the reaction was stirred at 25°C for 1 h under N2. After completion, the reaction was diluted with saturated NH4Cl (20 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (mobile phase: H2O (0.2% FA)-ACN; gradient: 15%-45% over 8.0 min) to provide the title compound (65 mg, 42%) as a white solid. MS (ESI): mass calcd. C21H27F3N6O5: 500.20, found: 501.1 [M+H]+. 5-(Diaminomethylene)-1-((5S,7s,10S)-3-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (1) and 5-(Diaminomethylene)-1-((5R,7r,10R)-3-methyl-2,4- dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (2) 5-(Diaminomethylene)-1-(2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3- (4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (65 mg, 130 μmol) was separated by chiral SFC (column: DAICEL CHIRALCEL OZ, (250 mm*25 mm, 10 um); mobile phase: CO2-MeOH (0.1% NH3H2O); with 40% B isocratic elution) to provide the title compound (1) - 35 - FH13029825.4 GPX-02325 (20.4 mg, 32%) as a white solid and to provide the title compound (2) (18.7 mg, 31%) as a white solid. 1: MS (ESI): mass calcd. C21H27F3N6O5: 500.20, found: 501.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.51 (s, 2H), 8.66 (s, 1H), 7.33 (s, 2H), 4.56-4.68 (m, 1H), 3.81 (t, J = 7.2 Hz, 2H), 2.81 (s, 3H), 2.18-2.34 (m, 7H), 1.99 (t, J = 13.2 Hz, 2H), 1.88 (br d, J = 10.4 Hz, 1H), 1.70-1.73 (m, 2H), 1.34-1.45 (m, 3H), 1.20-1.32 (m, 1H). 2: MS (ESI): mass calcd. C21H27F3N6O5: 500.20, found: 501.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.51 (s, 2H), 8.67 (s, 1H), 7.34 (s, 2H), 4.59-4.64 (m, 1H), 3.82 (t, J = 7.2 Hz, 2H), 2.81 (s, 3H), 2.18-2.34 (m, 7H), 1.99 (t, J = 13.2 Hz, 2H), 1.88 (br d, J = 10.4 Hz, 1H), 1.70-1.73 (m, 2H), 1.34-1.45 (m, 3H), 1.21-1.32 (m, 1H). Examples 3 and 4. 5-(Diaminomethylene)-1-((5S,7s,10S)-2,4-dimethyl-3-oxo-1,4- diazadispiro[4.1.57.15]tridec-1-en-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (3) and 5-(Diaminomethylene)-1-((5R,7r,10R)-2,4-dimethyl-3- oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (4) Synthetic scheme: - 36 - FH13029825.4 GPX-02325 1,3-Dimethyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadecan-2-one To a solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (3 g, 15.3 mmol), 2- amino-N-methyl-propanamide hydrochloride (2.77 g, 20 mmol) in MeOH (30 mL) was added TEA (1.55 g, 15.3 mmol). The mixture was stirred at 80 °C for 16 h under N2. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 1 to 0 : 1) to provide the title compound (2.3 g, 53.7%) as a yellow oil. MS (ESI): mass calcd. for C15H24N2O3: 280.18, found: 281.0 [M+H]+. 1,3-Dimethyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadec-3-en-2-one - 37 - FH13029825.4 GPX-02325 To a solution of 1,3-dimethyl-11,14-dioxa-1,4- diazatrispiro[4.1.2.410.27.15]heptadecan-2-one (1 g, 3.57 mmol) in DCE (10 mL) was added MnO2 (6.2 g, 71.34 mmol). The reaction was degassed and purged with N23x. After heating at 80 °C for 16 h under N2, the reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to provide the title compound (782 mg, 78.8%) as a white solid. MS (ESI): mass calcd. for C15H22N2O3: 278.16, found: 279.0 [M+H]+. 1,3-Dimethyl-1,4-diazadispiro[4.1.57.15]tridec-3-ene-2,10-dione To a solution of 1,3-dimethyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadec- 3-en-2-one (0.2 g, 719 μmol) in THF (2 mL) was added HCl (1 N, 2 mL). The reaction was stirred at 60 °C for 0.5 h. After completion, the reaction was quenched with aq. Na2CO3, diluted with H2O (10 mL) and extracted with DCM : i-PrOH (3 : 1) (15 mL x 2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to provide the title compound (120 mg, 71%) as a white solid. MS (ESI): mass calcd. for C13H18N2O2: 234.14, found: 234.9 [M+H]+. 10-Amino-1,3-dimethyl-1,4-diazadispiro[4.1.57.15]tridec-3-en-2-one A solution of 1,3-dimethyl-1,4-diazadispiro[4.1.57.15]tridec-3-ene-2,10-dione (150 mg, 640 μmol) in NH3 / MeOH (7 M, 1.50 mL) was stirred at 25 °C for 3 h. To the mixture was added Raney-Ni (11 mg) in one portion at 25 °C under Ar. The mixture was degassed with H23x. The reaction was stirred under H2(15 psi) at 25 °C for 13 h and was filtered through a celite pad. The filtrate was concentrated under reduced pressure to provide the title compound (150 mg, 99.6%) as a green oil. MS (ESI): mass calcd. C13H21N3O: 235.17, found: 235.9 [M+H]+. - 38 - FH13029825.4 GPX-02325 1-(2,4-Dimethyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en-10-yl)-3-(4,4,4- trifluorobutyl)urea A solution of 10-amino-1,3-dimethyl-1,4-diazadispiro[4.1.57.15]tridec-3-en-2-one (150 mg, 637 μmol) and TEA (129 mg, 1.27 mmol) in DCM (2 mL) was degassed and purged with N23x. (4-Nitrophenyl) N-(4,4,4-trifluorobutyl)carbamate (279 mg, 956 μmol) was added and the reaction was stirred at 20 °C for 2 h under N2. After completion, the mixture was adjusted to pH = 4 with AcOH, diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to provide the title compound (150 mg, 61%) as a white solid. MS (ESI): mass calcd. C18H27F3N4O2: 388.21, found: 389.3 [M+H]+. 1-(2,4-Dimethyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en-10-yl)-3-(4,4,4- trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione A solution of 1-(2,4-dimethyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en-10-yl)-3- (4,4,4-trifluorobutyl)urea (150 mg, 386 μmol) and malonic acid (40 mg, 386 μmol) in AcOH (1.5 mL) was degassed and purged with N23x. Ac2O (276 mg, 2.7 mmol) was added and stirred at 80 °C for 4 h under N2. After completion, the reaction was quenched with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether : ethyl acetate = 0 : 1) to provide the title compound (110 mg, 62.4%) as a yellow solid. MS (ESI): mass calcd. C21H27F3N4O4: 456.20, found: 457.1 [M+H]+. 5-(Diaminomethylene)-1-(2,4-dimethyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en-10- yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione - 39 - FH13029825.4 GPX-02325 To a solution of 1-(2,4-dimethyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en-10-yl)- 3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (110 mg, 241 μmol) in THF (2 mL) was added cyanamide (202.6 mg, 4.82 mmol) and Ni(acac)2(18.6 mg, 72 μmol). The mixture was degassed and purged with N23x and stirred at 80 °C for 16 h under N2. After completion, the reaction was filtered through a celite pad. The residue was purified by prep- HPLC (mobile phase: H2O (10 mM NH4HCO3)-ACN; gradient: 25%-50% B over 8.0 min) to provide the title compound (42 mg, 34.6%) as a white solid. MS (ESI): mass calcd. C22H29F3N6O4: 498.22, found: 499.2 [M+H]+. 5-(Diaminomethylene)-1-((5S,7s,10S)-2,4-dimethyl-3-oxo-1,4- diazadispiro[4.1.57.15]tridec-1-en-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (3) and 5-(Diaminomethylene)-1-((5R,7r,10R)-2,4-dimethyl-3- oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (4) 5-(Diaminomethylene)-1-(2,4-dimethyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en- 10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (42 mg, 83.4 μmol) was separated by chiral SFC (column: DAICEL CHIRALPAK IK, (250 mm*25 mm, 10 um); mobile phase: CO2-IPA (0.1% NH3H2O); with 35% B isocratic elution) to provide the title compound (3) (13 mg, 36%) as a white solid and the title compound (4) (13 mg, 35.8%) as a white solid. 3: MS (ESI): mass calcd. C22H29F3N6O4: 498.22, found: 499.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.51 (s, 2H), 7.36 (s, 2H), 4.63-4.70 (m, 1H), 3.82 (t, J = 7.2 Hz, 2H), 2.98 (s, 3H), 2.39-2.47 (m, 2H), 2.21-2.38 (m, 5H), 2.05-2.12 (m, 4H), 1.96 (dd, J = 4.0, 12.4 Hz, 1H), 1.81 (dd, J = 1.6, 12.8 Hz, 1H), 1.71 (quin, J = 7.6 Hz, 2H), 1.38-1.54 (m, 4H). - 40 - FH13029825.4 GPX-02325 4: MS (ESI): mass calcd. C22H29F3N6O4: 498.22, found: 499.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.51 (s, 2H), 7.35 (s, 2H), 4.63-4.70 (m, 1H), 3.82 (t, J = 7.2 Hz, 2H), 2.96 (s, 3H), 2.39-2.47 (m, 2H), 2.21-2.38 (m, 5H), 2.05-2.12 (m, 4H), 1.96 (dd, J = 4.0, 12.4 Hz, 1H), 1.81 (dd, J = 1.6, 12.8 Hz, 1H), 1.71 (quin, J = 7.6 Hz, 2H), 1.38-1.54 (m, 4H). Examples 5 and 6. 5-(Diaminomethylene)-1-((5R,7r,10R)-2-methyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec- 1-en-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (5) and 5- (Diaminomethylene)-1-((5S,7s,10S)-2-methyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1- en-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (6) - 41 - FH13029825.4 GPX-02325 Synthetic scheme: 2-Methyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadecan-3-one To a solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (6.5 g, 33.1 mmol) in MeOH (50 mL) was added 2-aminopropanamide hydrochloride (4.95 g, 39.8 mmol) and TEA (3.35 g, 33.1 mmol). The reaction was stirred at 80 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 1 to 0 : 1) to provide the title compound (6.13 g, 70%) as a colorless oil. MS (ESI): mass calcd. for C14H22N2O3: 266.16, found: 267.3 [M+H]+. 3-Methyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadec-3-en-2-one - 42 - FH13029825.4 GPX-02325 To a solution of 2-methyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadecan-3- one (5.93 g, 22.3 mmol) in DCE (60 mL) was added MnO2(38.7 g, 445 mmol) under N2. After heating at 80 °C for 16 h, the reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to provide the title compound (4 g, 68%) as a colorless oil. MS (ESI): mass calcd. for C14H20N2O3: 264.15, found: 264.9 [M+H]+. 2-Methyl-4-(2-trimethylsilylethoxymethyl)-11,14-dioxa-1,4- diazatrispiro[4.1.2.410.27.15]heptadec-1-en-3-one To a solution of 3-methyl-11,14-dioxa-1,4-diazatrispiro[4.1.2.410.27.15]heptadec-3-en- 2-one (4 g, 15.1 mmol) in THF (40 mL) was added NaH (726 mg, 18.2 mmol, 60% in mineral oil) at 0 °C and the reaction was stirred at 20 °C for 0.5 h. SEMCl (4.54 g, 27.2 mmol) was added at 0 °C. After stirring at 20 °C for 2 h, the reaction was quenched with saturated NH4Cl (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 0 : 1) to provide the title compound (4.2 g, 70%) as a colorless oil. MS (ESI): mass calcd. for C20H34N2O4Si: 394.23, found: 395.3 [M+H]+. 2-Methyl-4-(2-trimethylsilylethoxymethyl)-1,4-diazadispiro[4.1.57.15]tridec-1-ene-3,10- dione To a solution of 2-methyl-4-(2-trimethylsilylethoxymethyl)-11,14-dioxa-1,4- diazatrispiro[4.1.2.410.27.15]heptadec-1-en-3-one (4.08 g, 10.34 mmol) in acetone (30 mL) - 43 - FH13029825.4 GPX-02325 and H2O (15 mL) was added TsOH.H2O (3.93 g, 20.68 mmol). The mixture was stirred at 25 °C for 4 h. After completion, the reaction was quenched with H2O (50 mL) and extracted with DCM (50 mL x 2). The combined organic layer was washed with saturated NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (3.78 g, crude) as a colorless oil, which was used directly in the next step without further purification. MS (ESI): mass calcd. C18H30N2O3Si: 350.20, found: 351.3 [M+H]+. 10-Amino-2-methyl-4-(2-trimethylsilylethoxymethyl)-1,4-diazadispiro[4.1.57.15]tridec-1- en-3-one A mixture of 2-methyl-4-(2-trimethylsilylethoxymethyl)-1,4- diazadispiro[4.1.57.15]tridec-1-ene-3,10-dione (2 g, 5.71 mmol) and NH3 / MeOH (7 M, 8.15 mL) in MeOH (10 mL) was degassed and purged with N23x. The mixture was stirred at 20 °C for 2 h under N2. Raney-Ni (2.44 g) was added, and the reaction was degassed and purged with H23x. The reaction was stirred at 20°C for 2 h under H2 (15 psi). After completion, the reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure to provide the title compound (2 g, 99.7%) as a colorless oil, which was used directly in the next step without further purification. MS (ESI): mass calcd. C18H33N3O2Si: 351.23, found: 352.3 [M+H]+. 1-[2-Methyl-3-oxo-4-(2-trimethylsilylethoxymethyl)-1,4-diazadispiro[4.1.57.15]tridec-1- en-10-yl]-3-(4,4,4-trifluorobutyl)urea To a solution of 10-amino-2-methyl-4-(2-trimethylsilylethoxymethyl)-1,4- diazadispiro[4.1.57.15]tridec-1-en-3-one (1 g, 2.84 mmol) and TEA (1.15 g, 11.4 mmol) in DCM (10 mL) was added (4-nitrophenyl) N-(4,4,4-trifluorobutyl)carbamate (914 mg, 3.13 mmol) at 0~5 °C under N2. The mixture was stirred at 10 - 20 °C for 1 h. The reaction was quenched with H2O (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum - 44 - FH13029825.4 GPX-02325 ether : ethyl acetate = 10 : 1 to 1 : 1) to provide the title compound (0.645 g, 45%) as a colorless oil. MS (ESI): mass calcd. C23H39F3N4O3Si: 504.27, found: 505.3 [M+H]+. 1-[2-Methyl-3-oxo-4-(2-trimethylsilylethoxymethyl)-1,4-diazadispiro[4.1.57.15]tridec-1- en-10-yl]-3-(4,4,4-trifluorobutyl)hexahydropyrimidine-2,4,6-trione A mixture of 1-[2-methyl-3-oxo-4-(2-trimethylsilylethoxymethyl)-1,4- diazadispiro[4.1.57.15]tridec-1-en-10-yl]-3-(4,4,4-trifluorobutyl)urea (0.645 g, 1.28 mmol), acetyl acetate (913 mg, 9.0 mmol) and malonic acid (133 mg, 1.28 mmol) in AcOH (7 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 80 °C for 5 h under N2. After completion, the reaction was quenched with H2O (20 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with saturated NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 1 : 0 to 1 : 1) to provide the title compound (377 mg, 51.5%) as a colorless oil. MS (ESI): mass calcd. C26H39F3N4O5Si: 572.26, found: 573.3 [M+H]+. 5-(Diaminomethylene)-1-[2-methyl-3-oxo-4-(2-trimethylsilylethoxymethyl)-1,4- diazadispiro[4.1.57.15]tridec-1-en-10-yl]-3-(4,4,4-trifluorobutyl)hexahydropyrimidine- 2,4,6-trione To a solution of 1-[2-methyl-3-oxo-4-(2-trimethylsilylethoxymethyl)-1,4- diazadispiro[4.1.57.15]tridec-1-en-10-yl]-3-(4,4,4-trifluorobutyl)hexahydropyrimidine-2,4,6- trione (377 mg, 658 μmol) in THF (4 mL) was added cyanamide (277 mg, 6.58 mmol) and Ni(acac)2 (50.7 mg, 198 μmol). The reaction was heated at 80 °C for 16 h. After completion, the reaction was quenched with H2O (20 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with saturated NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, - 45 - FH13029825.4 GPX-02325 petroleum ether : ethyl acetate = 1 : 1) to provide the title compound (240 mg, 59.3%) as a colorless oil. MS (ESI): mass calcd. C27H41F3N6O5Si: 614.29, found: 615.3 [M+H]+. 5-(Diaminomethylene)-1-(2-methyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en-10-yl)-3- (4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione To a solution of 5-(diaminomethylene)-1-[2-methyl-3-oxo-4-(2- trimethylsilylethoxymethyl)-1,4-diazadispiro[4.1.57.15]tridec-1-en-10-yl]-3-(4,4,4- trifluorobutyl)hexahydropyrimidine-2,4,6-trione (0.2 g, 325 μmol) in H2O (0.4 mL) was added TFA (2 mL). The reaction was stirred at 25 °C for 1 h. The residue was diluted with MeOH (2 mL), adjusted to pH = 8 with saturated K2CO3and stirred at 25 °C for 1 h. Then the reaction was adjusted to pH = 5 with saturated citric acid and extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (mobile phase: H2O (10 mM NH4HCO3)-ACN; gradient: 20%-55% B over 8.0 min) to provide the title compound (20 mg, 12.7%) as a white solid. MS (ESI): mass calcd. C21H27F3N6O4: 484.20, found: 485.1 [M+H]+. 5-(Diaminomethylene)-1-((5R,7r,10R)-2-methyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec- 1-en-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (5) and 5- (Diaminomethylene)-1-((5S,7s,10S)-2-methyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1- en-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (6) 5-(Diaminomethylene)-1-(2-methyl-3-oxo-1,4-diazadispiro[4.1.57.15]tridec-1-en-10- yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (85 mg, 175 μmol) was separated by chiral SFC (column: Daicel ChiralPak IM, (250 mm*25 mm, 10 um); mobile phase: CO2-EtOH (0.1% NH3H2O); with 25% B isocratic elution) to provide the title - 46 - FH13029825.4 GPX-02325 compound (5) (25.8 mg, 30.4%) as a white solid and the title compound (6) (27.4 mg, 32.2%) as a white solid. 5: MS (ESI): mass calcd. C21H27F3N6O4: 484.20, found: 485.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.81 (s, 1H), 9.51 (s, 2H), 7.34 (s, 2H), 4.60-4.67 (m, 1H), 3.82 (t, J = 7.2 Hz, 2H), 2.22-2.38 (m, 6H), 2.09-2.19 (m, 3H), 2.02 (s, 3H), 1.65-1.80 (m, 3H), 1.36-1.51 (m, 4H). 6: MS (ESI): mass calcd. C21H27F3N6O4: 484.2, found: 485.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.82 (s, 1H), 9.52 (s, 2H), 7.34 (s, 2H), 4.62-4.68 (m, 1H), 3.83 (t, J = 7.2 Hz, 2H), 2.23-2.37 (m, 6H), 2.10-2.20 (m, 3H), 2.03 (s, 3H), 1.68-1.80 (m, 3H), 1.38-1.52 (m, 4H). Examples 7 and 8 were prepared through chiral SFC separation of step 7 product (5- (diaminomethylene)-1-(2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4- trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione) in Examples 1 and 2. Column: DAICEL CHIRALCEL OD, (250mm * 30mm, 10 um); mobile phase: CO2-MeOH (0.1% NH3H2O); gradient: 30% B with isocratic elution. Examples 9 and 10. 5-(Diaminomethylene)-1-((5S,7s,10S)-1-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (9) & 5-(Diaminomethylene)-1-((5R,7r,10R)-1-methyl-2,4-dioxo- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (10) - 47 - FH13029825.4 GPX-02325 Synthetic scheme: 1-Methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-11,14-dioxa-1,3- diazatrispiro[4.1.2.410.27.15]heptadecane-2,4-dione To a solution of 2-(2-trimethylsilylethoxymethyl)-11,14-dioxa-2,4- diazatrispiro[4.1.2.410.27.15]heptadecane-1,3-dione (See Example 1 for synthesis, 1 g, 2.52 mmol) in DMF (10 mL) was added K2CO3 (697 mg, 5.04 mmol) and CH3I (716 mg, 5.04 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. After completion, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1 g, 96.58%) as a white solid. MS (ESI): mass calcd. for C20H34N2O5Si: 410.22, found: 433.3 [M+Na]+. - 48 - FH13029825.4 GPX-02325 5-(Diaminomethylene)-1-((5S,7s,10S)-1-methyl-2,4-dioxo-1,3- diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (9) & 5-(Diaminomethylene)-1-((5R,7r,10R)-1-methyl-2,4-dioxo- 1,3-diazadispiro[4.1.57.15]tridecan-10-yl)-3-(4,4,4-trifluorobutyl)pyrimidine- 2,4,6(1H,3H,5H)-trione (10) 5-(Diaminomethylene)-1-(1-methyl-2,4-dioxo-1,3-diazadispiro[4.1.57.15]tridecan-10- yl)-3-(4,4,4-trifluorobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione was synthesized from 1- Methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-11,14-dioxa-1,3- diazatrispiro[4.1.2.410.27.15]heptadecane-2,4-dione following the synthetic route of Example 1. The racemic material was separated through chiral SFC purification (column: ChiralPak IH, (250mm * 30mm, 10 um); mobile phase: CO2-EtOH (0.1% NH3H2O); gradient: 30% B with isocratic elution) to provide the title compounds. Example 9: MS (ESI): mass calcd. for C21H27F3N6O5: 500.20, found: 501.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 10.50-10.84 (m, 1H), 9.50 (s, 2H), 7.40 (s, 2H), 4.52- 4.72 (m, 1H), 3.82 (t, J = 6.8 Hz, 2H), 2.88 (s, 3H), 2.24-2.43 (m, 5H), 2.18-2.23 (m, 2H), 2.03-2.18 (m, 2H), 1.80 (d, J = 11.6 Hz, 1H), 1.65-1.76 m, 2H), 1.35-1.47 (m, 3H), 1.18-1.27 (m, 1H). Example 10: MS (ESI): mass calcd. for C21H27F3N6O5: 500.20, found: 501.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 10.49-10.88 (m, 1H), 9.51 (s, 2H), 7.38 (s, 2H), 4.53- 4.71 (m, 1H), 3.81 (t, J = 7.2 Hz, 2H), 2.88 (s, 3H), 2.24-2.41 (m, 5H), 2.19-2.24 (m, 2H), 2.04-2.18 (m, 2H), 1.80 (d, J = 10.8 Hz, 1H), 1.64-1.76 (m, 2H), 1.40 (t, J = 11.6 Hz, 3H), 1.17-1.28 (m, 1H). Biological Assay procedure Assays were performed using Expi293F Inducible cells (Invitrogen) stably expressing hPTH1R via a pcZeo TetO DNA plasmid. Cell lines were maintained in suspension in Expi293 Expression Medium (ThermoFisher Scientific) supplemented with 10 μg / mL Blasticidin and 10 μg / mL Zeocin and incubated at 37°C, 8% CO2, with shaking. To induce receptor expression, hPTH1R cells were incubated in induction medium (Expi293 Expression Medium with 4 μg / mL Doxycycline (Millipore Sigma), 5 mM sodium butyrate (Millipore Sigma) and 100 ng / mL Pertussis toxin (Millipore Sigma)) for 24 hours at 32°C, 5% CO2, with shaking. Assay-ready aliquots were prepared by harvesting cells 24-hour post-induction. - 49 - FH13029825.4 GPX-02325 Cells were pelleted at 4°C, resuspended in Expi293 Expression medium + 10% DMSO, aliquoted, and kept frozen at -80°C until ready for use. For the assay, concentration-response curves of test and reference compounds were added to 384-well plates using an Apricot liquid handler (SPT Labtech) and backfilled with DMSO to a final concentration of 0.3%. cAMP was measured using the cisbio cAMP Gs dynamic HTRF kit (PerkinElmer) according to manufacturer instructions. Aliquots of frozen hPTH1R cells were quickly thawed and washed with phosphate-buffered saline (Sigma- Aldrich) to remove media and DMSO. The cells were resuspended in kit-supplied Stimulation Buffer at 0.2 x 106cells / mL.10 μl of the hPTH1R cell dilution were added to each well of the assay plate and incubated with the compounds for 1 hour in a 37°C, 0% CO2 incubator. Following this incubation, the cells were lysed and accumulated cAMP was detected through the addition of kit-supplied lysis buffer containing d2-reagent and Eu- cryptate antibody. The HTRF signal was quantified using a BMG PHERAstar FSX plate reader optimized for HTRF assays. The HTRF ratio was determined by dividing the signal output at 665 nm by that at 620 nm. Data were normalized to the signal produced by 1 μM PTH(1-34) (100% activation) and vehicle (0% activation). A complete listing of the compounds, characterization data, and assay data for the exemplary compounds is set forth in the table in Figure 1 (pEC50 >7: +++; pEC50 between 6 and 7: ++; and pEC50 <6: +). INCORPORATION BY REFERENCE All of the U.S. patents and U.S. and PCT patent application publications cited herein are hereby incorporated by reference. EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. - 50 - FH13029825.4

Claims

GPX-02325 CLAIMS We Claim:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: R1and R2are independently hydrogen or (C1-C6)alkyl, provided that at least one of R1and R2is hydrogen; and R3is (C1-C6)fluoroalkyl.

2. The compound of claim 1, having the structure of Formula (Ia):or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, having the structure of Formula (Ib):or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein R1is (C1-C6)alkyl.

5. The compound of claim 4, wherein R1is methyl. - 51 - FH13029825.4GPX-02325 6. The compound of any one of claims 1-3, wherein R1is hydrogen.

7. The compound of any one of claims 1-3 and 6, wherein R2is (C1-C6)alkyl.

8. The compound of claim 7, wherein R2is methyl.

9. The compound of any one of claims 1-6, wherein R2is hydrogen.

10. The compound of any one of claims 1-9, wherein R3is (C1-C6)trifluoroalkyl.

11. The compound of claim 10, wherein R3is 4,4,4-trifluorobutyl.

12. A compound of Formula (II):or a pharmaceutically acceptable salt thereof; wherein: R4is hydrogen or (C1-C6)alkyl; R5is (C1-C6)alkyl; and R6is (C1-C6)fluoroalkyl.

13. The compound of claim 12, having the structure of Formula (IIa):or a pharmaceutically acceptable salt thereof. - 52 - FH13029825.4GPX-02325 14. The compound of claim 12, having the structure of Formula (IIb):or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 12-14, wherein R4is hydrogen.

16. The compound of any one of claims 12-14, wherein R4is (C1-C6)alkyl.

17. The compound of claim 16, wherein R4is methyl.

18. The compound of any one of claims 12-17, wherein R5is methyl.

19. The compound of any one of claims 12-18, wherein R6is (C1-C6)trifluoroalkyl.

20. The compound of claim 19, wherein R6is 4,4,4-trifluorobutyl.

21. A compound having the structure:- 53 - FH13029825.4GPX-02325pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition, comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

23. A method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof. - 54 - FH13029825.4

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