Pyrrolo-dipyridine compound

Abstract

In one aspect, the present invention provides compounds of Formula I, Formula Ia, Formula Ib, Formula Ic, and Formula Id, and salts, hydrates, and isomers thereof. In another aspect, the present invention provides methods for promoting bone formation in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of Formula I, Formula Ia, Formula Ib, Formula Ic, or Formula Id. The present invention also provides orthopedic and periodontal devices and methods for treating kidney disease, diabetes, bone loss, and cancer using the compounds of Formula I, Formula Ia, Formula Ib, Formula Ic, and Formula Id. TIFF2022504011000048.tif30151

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority under 35 U.S.C.§119(e) of U.S. Provisional Application Serial No. 62 / 718,612, filed on August 14, 2018, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] Statement Regarding Rights to Inventions Made Under Federally Sponsored Research and Development Not applicable

[0003] Reference to a “Sequence Listing,” Table, or Computer Program List Appendix Submitted on a Compact Disk Not applicable

Background Art

[0004] Bone homeostasis involves a balanced process of bone formation and bone resorption. Increased bone resorption and loss of bone homeostasis are associated with many diseases and disorders such as osteoporosis and Paget's disease. All FDA - approved low - bone - density therapeutics except Teriparatide treat by stopping bone resorption and are thus bone resorption inhibitors. Bone resorption inhibitors act on osteoclasts by preventing them from resorbing bone.

[0005] It is known in the art that bone can be formed by two processes. One is mediated through a chondrocyte cartilage intermediate (endochondral), and the other is a direct process that stimulates osteoblasts (intramembranous). The endochondral process involves chondrocytes (chondrocyte / cartilage cell) dying and leaving voids that become occupied by calcified osteoblasts on the surface of chondrocyte cartilage calcification. During the resorption process, osteoclasts resorb this cartilage calcification, leaving clean non-cartilaginous bone mineral. The endochondral process exists during the basic formation and growth period of long bones, and during the cartilage callus process period of fractures. The endochondral process begins when mesenchymal stem cells differentiate into chondrocytes to form cartilage. On the other hand, the intramembranous process occurs during the new bone growth stage of fractures and during the formation of the bones of the head. The intramembranous process occurs when mesenchymal stem cells differentiate into osteoblasts. Unlike cartilage, which is an elastic tissue, bone is hard and lacks flexibility. Two very different cell processes (osteoblasts vs chondrocytes) involving different molecules (WNT (Wingless and Int-1) vs BMP (bone morphogenetic protein)) and cell mechanisms (osteoblasts vs chondrocytes).

[0006] It is well understood that osteoblasts are involved in the secretion of bone mineral that causes an increase in bone density. To date, only teriparatide has been known to stimulate osteoblasts to increase mineral deposition, albeit indirectly via the Wnt pathway.

[0007] For the treatment of a variety of disorders such as simple aging, bone degeneration and osteoporosis, fracture healing, osteogenesis imperfecta, HPP, the healing of two bones or arthrodesis across a joint, low bone density disorders in mammals, and for the successful placement of various medical orthopedic implants and periodontal implants such as screws, rods, spinal fixation titanium cages, hip joints, knee joints, ankle joints, shoulder joints, dental implants, bone grafts, plates and rods, it is desirable to cause mineral deposition (bone formation) of osteoblasts.

[0008] For treating subjects in a low bone density state, but not limited to, the use of cathepsin K inhibitors, RankL inhibitors, denosumab, Prolia®, osteoprotegerin (OPG) inhibitors, alendronate, selective estrogen receptor modulators (SERMs), bisphosphonates and other bone resorption inhibitors has resulted in a very small initial increase in bone mineral deposition of less than 6% in the first year, and a slight increase in subsequent years. The overall increase in bone density due to bone resorption inhibition therapy (cessation of bone loss) has been reported to be 9.4% over three years. Such treatable conditions may include osteopenia, osteoporosis, arthritis, tumor metastasis, osteogenesis imperfecta, Paget's disease, secondary low bone density disorders / diseases, and other metabolic bone disorders.

[0009] The use of parathyroid hormone and analogs, prostaglandin agonists, PDGE2, PDGE, Forteo®, osteoprotegerin (OPG) inhibitors, teriparatide, BMP2, BMP7, BMP4, EP4 agonists and the like can be used to cause a desirable increase in bone mineral in subjects with the following low bone density states. Such states may include osteopenia, osteoporosis, arthritis, tumor metastasis, osteogenesis imperfecta, Paget's disease, secondary low bone density disorders, bone healing, spinal fusion, arthrodesis, and other metabolic bone disorders. However, the use of BMP agonists for treating systemic diseases has not progressed beyond Phase I clinical trials by the FDA.

[0010] Furthermore, the use of PTH, TGFβ binding proteins, etc. for increased bone mineralization to treat conditions that can be partially characterized by an increased risk of fractures such as osteopenia, degenerative disc disease, fractures, osteoporosis, arthritis, tumor metastasis, osteogenesis imperfecta, Paget's disease, and other metabolic bone disorders is known in the art. It is also known that demineralized bone matrix can partially promote a small amount of new bone growth by endogenous growth factors (TGFβ binding proteins (BMP)) that survive after the sterilization procedure of cadaver bone. However, demineralized bone matrix is usually supplied from a donor cadaver bank and is associated with certain risks such as disease transmission and bacterial contamination. Other versions of demineralized bone matrix are more severely processed and have fewer disease risks. The currently unmet medical needs using currently approved treatments in the field of nonunion fractures (pseudoarthrosis) require improvement of the poor healing observed in large defects of long bones consisting of large gaps between fracture ends. The use of demineralized bone or similar osteoconductive materials known in the art has not resulted in the desired effect of fusing long bones.

[0011] Accordingly, there remains a need in the art for new methods of treating bone disorders, fractures, and related problems. The present invention meets these and other needs. SUMMARY OF THE INVENTION

[0012] In one aspect, the present invention provides compounds and compositions, and methods of using such compounds and compositions. In a first aspect, the present invention provides a compound of formula I:

[0013]

Chemical formula

[0014] or a salt, hydrate, prodrug, or isomer thereof, wherein X is selected from CR 3b and N, where N is optionally oxidized to the corresponding N-oxide, Y is CR 3cand selected from N, where N is optionally oxidized to the corresponding N-oxide, Z is CR 3d and selected from N, where N is optionally oxidized to the corresponding N-oxide, provided that at least one of X, Y, and Z is N or the corresponding N-oxide, A is,

[0015] [Chemical formula]

[0016] and R N is selected from the group consisting of heterocyclyl and heteroaryl, the heterocyclyl moiety is selected from monocyclic, fused bicyclic, and bridged cyclic heterocyclyls, the monocyclic heterocyclyl contains 4 to 7 ring members, the fused bicyclic heterocyclyl and the bridged bicyclic heterocyclyl contain 7 to 10 ring members, each heterocyclyl moiety has 1 to 3 heteroatoms as ring members selected from nitrogen (N), oxygen (O), and sulfur (S), each heterocyclyl moiety contains at least one nitrogen atom as a ring member, and optionally 1 to 3 R 6 moieties are substituted, the heteroaryl moiety contains 5 to 10 ring members, at least one ring member is a nitrogen atom, and optionally 1 to 3 R 6 moieties are substituted, R 2 R 3b R 3c and R 3d are each, independently, H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-OH, -O-C 1-6 alkyl-OH, C 3-6 cycloalkyl-C 1-4selected from the group consisting of an alkoxy and a hydroxyl group (-OH), and R 6 is a hydroxyl group (-OH), C 1-3 alkyl, C 1-3 alkyl-OH, -O-C 1-3 alkyl, C 3-4 heteroalkyl, C 1-3 haloalkyl, -O-C 1-3 haloalkyl, a halogen, and oxo, and provides the said compound.

[0017] In a second embodiment, the present invention provides a method for promoting bone formation and bone healing in a subject in need thereof. The method includes promoting bone formation in the subject by administering to the subject a therapeutically effective amount of a compound of formula I, formula Ia, formula Ib, formula Ic, or formula Id described herein. The bone formation can be systemic or local. For local bone formation, in some embodiments, the compound can be administered with a bone-conductive agent, such as a bone-conductive matrix.

[0018] In a third embodiment, the present invention provides a method for treating kidney disorders. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, formula Ia, formula Ib, formula Ic, or formula Id.

[0019] In a fourth embodiment, the present invention provides a method for treating diabetes. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, formula Ia, formula Ib, formula Ic, or formula Id.

[0020] In a fifth embodiment, the present invention provides a method for treating cancer. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, formula Ia, formula Ib, formula Ic, or formula Id.

[0021] In a sixth embodiment, the present invention provides a medical device, for example, an orthopedic or periodontal medical device. The medical device includes a structural support, and a transplantable portion of the structural support is adapted to be permanently implanted within a subject. The transplantable portion adheres to bone, and the structural support has at least a partial outer coating comprising a compound of Formula I, Formula Ia, Formula Ib, Formula Ic, or Formula Id.

[0022] In a seventh embodiment, the present invention provides a compound or composition (e.g., a compound or composition of Formula I, Formula Ia, Formula Ib, Formula Ic, or Formula Id) as described herein for use in the preparation of a medicament for the treatment of a disease or condition as described herein. In some embodiments, the disease or condition is damaged bone, a fracture, weakened bone, osteogenesis imperfecta, hypophosphatasia (HPP), osteopenia, osteoporosis, arthrodesis, or a condition characterized by low bone mass or low bone density. Also contemplated herein is the use of a compound or composition as described herein in a periodontal implant or a medical orthopedic implant. Orthopedic implants include screws, rods, titanium cages used in spinal fixation, etc.

[0023] In an eighth embodiment, the present invention provides an orthobiologic, for example, a bone formation inducer, for surgical implantation with or without a bone grafting device. The medical device includes a structural support, and a transplantable portion of the structural support is adapted to be permanently implanted within a subject. The transplantable portion adheres to bone, and the structural support has at least a partial outer coating comprising a compound of Formula I, Formula Ia, Formula Ib, Formula Ic, or Formula Id.

[0024] In a ninth embodiment, the present invention provides a method for treating bone loss. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, Formula Ia, Formula Ib, Formula Ic, or Formula Id either continuously or in combination with an antiresorptive agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0025]

Figure 1

Mode for Carrying Out the Invention

[0026] I. First Bone mass homeostasis and bone remodeling involve the balanced processes of bone formation (osteoblast deposition of mineral, an anabolic process) and bone resorption (osteoclast absorption of mineral, bone loss, a catabolic process). These two processes are paired in healthy bone. See Figure 1. In bone formation, osteoblasts synthesize bone matrix and regulate mineralization, ultimately differentiating into osteocytes or bone lining cells. In bone resorption, another cell type, osteoclasts, remove mineralized bone matrix, break down organic bone, and release calcium into the serum. See, for example, Kular et al., Clinical Biochemistry 45:863 - 873 (2012).

[0027] Osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells) are controlled by various mechanisms. The differentiation of osteoclasts is controlled or regulated by osteoblasts (Glass et al., Dev Cell 8:751-764 (2005)) or other hormones such as PTH, calcitonin, and IL6. In contrast, the differentiation or activity of osteoblasts is not controlled or regulated by osteoclasts, but rather by various signals such as CPFA, Hedgehog, WNT / LRP, and sclerostin. Bone formation can occur via endochondral ossification or intramembranous ossification (sclerostin). In intramembranous ossification, bone is formed directly by the stimulation of osteoblasts / osteocytes. In endochondral ossification, bone formation occurs via a cartilage template, and the time until bone is formed is longer. BMP signaling is involved in endochondral ossification, whereas Wnt signaling has been shown to be involved in both endochondral and intramembranous ossification.

[0028] In a normal healthy state, bone remodeling (or bone homeostasis) involves the breakdown of old bone (by osteoclasts) and the repair or replacement of old bone with new bone (by osteoblasts). When this homeostasis is disrupted and bone resorption exceeds bone formation, i.e., in a diseased bone state, as a result, bone resorption becomes decoupled from bone formation. An increase in bone resorption leads to bone loss (trabecular bone loss) and an increase in bone fragility (decrease in bone strength). Many diseases and conditions are associated with an increase in bone resorption, including osteoporosis, osteogenesis imperfecta, Paget's disease of bone, metabolic bone diseases, bone changes secondary to cancer, and other diseases characterized by or associated with low bone density.

[0029] Diseases caused by increased bone resorption are associated with decreased bone mass and increased bone fragility. To name just a few, they are often treated with bone resorption inhibitors such as bisphosphonates, denosumab, Prolia® (prolia), alendronate, cathepsin K modulators, RankL inhibitors, estrogen, cathepsin K inhibitors, and selective estrogen receptor modulators. These agents function by directly or indirectly preventing or inhibiting osteoclastic bone resorption. See Figure 1. However, these agents do not promote new bone formation (i.e., anabolic bone formation) by osteoblasts. In contrast, administration of a single dose of an anabolic agent usually results in a >8% annual cumulative increase from baseline in bone formation in the human lumbar spine. Administration of bone resorption inhibitors results in a slight increase in bone density of <7% in the first year, but subsequent increases in bone density are <3.5%, resulting in an annual cumulative increase of <10%. Therefore, bones with osteoporotic fragility treated with bone resorption inhibitors do not become more brittle, but since the bone resorption inhibitors increase bone density by depositing more bone mineral and do not promote the growth of new bone, the fragile bones do not become stronger or increase in strength. In contrast, for example, agents that promote anabolic bone growth by stimulating osteoblast activity either promote the deposition of more bone matrix or, when proliferation is stimulated, the agent results in more osteoblasts and thus more bone cells to bridge the gap and fuse the two bones. Therefore, bones with osteoporotic fragility treated with anabolic bone formation agents prevent the bones from becoming more fragile and also enable the bones to have greater strength due to increased bone formation.

[0030] Referring to FIG. 1, without being bound by a particular theory, if bone is considered as a bathtub, the drain would be associated with bone loss or resorption, and the faucet would be associated with added bone or bone formation. Due to aging or disease, both the faucet and the drain are added and removed at the same rate (in pairs) until the faucet bends or the size of the drain increases. Such perturbations cause an imbalance (dissociation) in formation / resorption, leading to a decrease in bone density. For example, imagine a sponge with an outer core and fibers extending from one end to the other on the inside. During bone resorption, these fibers are removed, and if bone resorption occurs at a faster rate than bone construction or formation, these fibers become fewer, and the bone becomes brittle. It doesn't take much force to break a sponge with fewer inner fibers compared to a sponge with more inner fibers. Since the process of bone resorption is well understood, many commercially available therapeutic agents act on osteoclasts to stop bone resorption. These include cathepsin K inhibitors, RankL inhibitors, denosumab, Prolia® (prolia), Fosamax® (fosamax), EVISTA® (evista), Premarin® (premarin), osteoprotegerin (OPG) inhibitors, alendronic acid, selective estrogen receptor modulators (SERMs), bisphosphonates, and other agents that act to stop the activity of osteoclasts.

[0031] Based on the sponge example, to increase bone strength, the number of fibers inside the bone increases bone strength. However, it is not possible to increase bone strength by acting on osteoclasts, which are bone resorbing cells. Therefore, it is necessary to focus on the bone that forms osteoblasts. Unlike bone resorption, bone formation is not well understood, and until recently, only one systemic therapeutic agent (teriparatide) and one surgical implant (injection of BMP protein) have been commercially available to promote bone formation. However, BMP products act to increase chondrocytes and promote cartilage production. In this process, chondrocytes may be replaced by osteoblasts.

[0032] Intermittent administration of teriparatide globally increases bone density by activation of PKA, followed by phosphorylation of LRP and activation of the WNT pathway (Wan et al., Genes Dev. 22(21): 2968-2979 (2008)). This increase in bone density occurs along the trabeculae already laid down within the bone matrix. Osteoblasts that reinforce the trabeculae secrete minerals onto the existing trabecular bone and thus increase the amount and density of minerals in the trabeculae.

[0033] When there are bone voids, whereby most of the bone is removed, causing non-union or a defect of significant size of the bone. The bone cannot heal itself across a large gap. Addition of BMP to this site causes pluripotent cells to differentiate into chondrocytes / cartilage and generates a cartilage callus. The ability of bone to fill the gap instead of cartilage is thought to require that osteoblasts and osteocytes proliferate to fill the gap and then deposit minerals to fill the void.

[0034] Without being bound by a particular theory, the compounds of the present invention are thought to be SOST (sclerostin) antagonists and / or WISE antagonists that function by modulating the Wnt / LRP and / or BMP signaling pathways. SOST and WISE are proteins thought to regulate bone formation by binding to the Wnt receptor LRP to inhibit the Wnt signaling pathway or by binding to BMP and inhibiting BMP activity via different amino acid sequences or domains. By neutralizing the inhibitory effects of SOST protein and / or WISE protein on the Wnt pathway, the compounds and compositions of the present invention restore Wnt signaling and promote bone formation / growth. Thus, in one aspect, the present invention provides compounds, compositions, and methods for promoting bone formation in a subject. Bone formation can be systemic or local. The compounds and compositions of the present invention can be administered locally and / or systemically and, if desired, continuously and in combination with one or more other therapeutic agents. In another aspect, the present invention provides a device transplantable as a structural scaffold for promoting osteoblast / osteocyte migration to a scaffold and depositing bone mineral and for delivering the compounds and compositions of the present invention, for example, for promoting bone formation at a transplant site. In another aspect, the compounds and compositions of the present invention can be used to treat kidney disorders, diabetes, osteopenia, and cancer.

[0035] II. Definitions As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and its absorption by the subject. Pharmaceutically acceptable excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, and colorants. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0036] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic radical having the indicated number of carbon atoms. For example, C1-C6 alkyl (or C 1-6Examples of (alkyl) include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, and the like.

[0037] Alkylene represents either a straight-chain or branched alkylene having 1 to 7 carbon atoms, that is, a divalent hydrocarbon radical having 1 to 7 carbon atoms. For example, the straight-chain alkylene is a divalent radical of the formula -(CH2) n -, where n is 1, 2, 3, 4, 5, 6, or 7. Preferably, alkylene represents a straight-chain alkylene having 1 to 4 carbon atoms. For example, methylene, ethylene, propylene, or butylene chain, or methylene, ethylene, propylene, or butylene chain mono-substituted with C1-C3 alkyl (preferably methyl) or di-substituted with C1-C3 alkyl (preferably methyl) at the same or different carbon atoms, and the total number of carbon atoms is 7 or less. Those skilled in the art will understand that a single carbon of alkylene can be divalent as in -CH((CH2) n CH3)-(n = 0 to 5).

[0038] As used herein, the term "alkoxy" or "-O-alkyl" refers to an alkyl containing an oxygen atom, such as methoxy, ethoxy, and the like. "Haloalkoxy" is as defined for alkoxy, and some or all of the hydrogen atoms are replaced by halogen atoms. For example, halo-substituted alkoxy includes trifluoromethoxy and the like.

[0039] The term "hydroxyalkyl" or "alkyl-OH (hydroxyl group)" refers to an alkyl group in which at least one of the hydrogen atoms is replaced by a hydroxy group, as defined above. With respect to the alkyl group, the hydroxyalkyl group may have any suitable number of carbon atoms such as 1-6 C. Exemplary hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (when hydroxy is in the 1- or 2-position), hydroxypropyl (when hydroxy is in the 1-, 2-, or 3-position).

[0040] As used herein, the term "alkenyl" refers to any straight or branched hydrocarbon having from 2 to 6 carbon atoms and having at least one double bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl, pentenyl, or hexadienyl.

[0041] As used herein, the term "alkynyl" refers to any straight or branched hydrocarbon having from 2 to 6 carbon atoms and having at least one triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, or butynyl.

[0042] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0043] As used herein, the term "haloalkyl" refers to alkyl as defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. Halogen (halo) preferably represents chloro or fluoro, but may also be bromo or iodo. For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. The term "perfluoro" defines a compound or radical having at least two available hydrogens replaced by fluorine. For example, perfluoromethane refers to 1,1,1-trifluoromethyl, and perfluoromethoxy refers to 1,1,1-trifluoromethoxy.

[0044] As used herein, the term "heteroalkyl" refers to an alkyl group having from 1 to 3 heteroatoms such as N, O, and S. The heteroalkyl group has the indicated number of carbon atoms and at least one non-terminal carbon substituted with a heteroatom. Additional heteroatoms including, but not limited to, B, Al, Si, and P may also be useful. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. For example, heteroalkyls include ethers, thioethers, and alkylamines. The heteroalkyl group does not include peroxides (-O-O-) or other continuously bonded heteroatoms.

[0045] As used herein, the term "oxo" refers to a double-bonded oxygen (=O).

[0046] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, from 3 to 8, from 3 to 6, or the indicated number of atoms. For example, C 3-8 Cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and up to cyclooctyl. The cycloalkyl groups of the present invention are optionally substituted as defined below.

[0047] As used herein, the terms "heterocyclic ring", "heterocycloalkyl", and "heterocyclyl" refer to ring systems having from 3 to about 20 ring members and from 1 to about 5 heteroatoms such as N, O, and S. Additional heteroatoms including, but not limited to, B, Al, Si, and P may also be useful. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. The term heterocyclic ring includes monocyclic, fused bicyclic, and bridged cyclic moieties. For example, heterocyclic rings include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl hexahydro-1H-furo[3,4-c]pyrrolyl, and 1,4-dioxa-8-aza-spiro[4.5]deca-8-yl. The heterocycloalkyl groups of the present invention are optionally substituted as defined below.

[0048] The substituents of the cycloalkyl group and the heterocyclyl group are diverse and are independently selected from: the number of halogens within the range of 0 to the total number of open valences of the ring system, C 1-8 alkyl, -OR’, -OC(O)R’, -NR’R”, -SR’, -R’, -CN, -NO2, -CO2R’, -CONR’R”, -C(O)R’, -OC(O)NR’R”, -NR”C(O)R’, -NR”C(O)2R’, -NR’-C(O)NR”R”’, -S(O)R’, -S(O)2R’, -S(O)2NR’R”, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl (R’, R”, and R”’ are independently selected from hydrogen, (C1-C8)alkyl, and C 3-8 heteroalkyl, and phenyl.

[0049] As used herein, a "linked through a carbon atom" group refers to a linkage between a carbon atom of the referenced group and the remainder of the molecule. A "linked through a nitrogen atom" group refers to a linkage between a nitrogen atom of the referenced group and the remainder of the molecule. By way of example only, a heterocyclyl group linked through a carbon atom is

[0050]

Chem.

[0051] may also be (the wavy line indicates the attachment point to the rest of the molecule). Merely by way of example, a heterocyclyl group linked via a nitrogen atom may be

[0052]

Chem.

[0053] may also be (the wavy line indicates the attachment point to the rest of the molecule).

[0054] As used herein, when the compound referred to is an N-oxide, it contains an N—O bond having three additional bonds to nitrogen, i.e., the N-oxide is R3N + -O - and refers to a group. Merely by way of example, N-oxides may include

[0055]

Chem.

[0056] and the like may be included.

[0057] As used herein, the term "aryl" refers to a monocyclic or fused bicyclic, tricyclic or higher aromatic ring assembly containing 6 to 16 ring carbon atoms. For example, aryl may be phenyl, benzyl, or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group. An aryl group may be mono-substituted, di-substituted, or tri-substituted with one, two, or three radicals as described below.

[0058] The substituents of the aryl group are diverse and are selected from the following: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R"', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", alkylenedioxy, heteroaryl, -C 1-2 alkylene-heteroaryl, heterocyclyl, C 1-2 alkylene-heterocyclyl, phenyl, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, (R', R", and R"' are independently selected from hydrogen, (C1-C8)alkyl, and C 3-8 heteroalkyl, and phenyl). Alkylenedioxy is a divalent substituent bonded to two adjacent carbon atoms of phenyl, such as methylenedioxy or ethylenedioxy. Oxy-C2-C3-alkylene is also a divalent substituent bonded to two adjacent carbon atoms of phenyl, such as oxyethylene or oxypropylene.

[0059] Examples of substituted phenyl groups include 4-chlorophen-1-yl, 3,4-dichlorophen-1-yl, 4-methoxyphen-1-yl, 4-methylphen-1-yl, 4-aminomethylphen-1-yl, 4-methoxyethylaminomethylphen-1-yl, 4-hydroxyethylaminomethylphen-1-yl, 4-hydroxyethyl-(methyl)-aminomethylphen-1-yl, 3-aminomethylphen-1-yl, 4-N-acetylaminomethylphen-1-yl, 4-aminophen-1-yl, 3-aminophen-1-yl, 2-aminophen-1-yl, 4-phenyl-phen-1-yl, 4-(imidazol-1-yl)-phenyl, 4-(imidazol-1-ylmethyl)-phen-1-yl, 4-(morpholin-1-yl)-phen-1-yl, 4-(morpholin-1-ylmethyl)-phen-1-yl, 4-(2-methoxyethylaminomethyl)-phen-1-yl, and 4-(pyrrolidin-1-ylmethyl)-phen-1-yl, 4-(thiophenyl)-phen-1-yl, 4-(3-thiophenyl)-phen-1-yl, 4-(4-methylpiperazin-1-yl)-phen-1-yl, and 4-(piperidinyl)-phenyl and 4-(pyridinyl)-phenyl, but are not limited thereto.

[0060] As used herein, the term "heteroaryl" refers to a monocyclic, fused bicyclic, or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, wherein 1 to 4 of the ring atoms are each a heteroatom of N, O, or S. For example, heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, furanyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or other radicals substituted, particularly mono- or disubstituted, for example by alkyl, nitro, or halogen. Pyridyl represents 2-, 3-, or 4-pyridyl. Thienyl represents 2- or 3-thienyl. Quinolinyl preferably represents 2-, 3-, or 4-quinolinyl. Isoquinolinyl preferably represents 1-, 3-, or 4-isoquinolinyl. Benzopyranyl and benzothiopyranyl each preferably represent 3-benzopyranyl or 3-benzothiopyranyl, respectively. Thiazolyl preferably represents 2- or 4-thiazolyl, most preferably 4-thiazolyl. Triazolyl is preferably 1-, 2-, or 5-(1,2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl. As defined below, the heteroaryl moiety may be optionally substituted as desired.

[0061] Preferably, heteroaryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, benzothiazolyl, benzofuranyl, isoquinolinyl, benzothienyl, oxazolyl, indazolyl, or any other radical that is substituted, particularly mono- or disubstituted.

[0062] The substituents of the heteroaryl group are diverse and are selected from the following: halogen in an amount within the range of 0 to the total number of open valences of the aromatic ring system, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R"', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl (R', R", and R"' are independently selected from hydrogen, (C1-C8)alkyl, C 3-8 heteroalkyl, and phenyl).

[0063] As used herein, "C 3-6 cycloalkyl-C 1-4 alkoxy" refers to an alkoxy group in which one hydrogen atom is substituted with a C 3-6 cycloalkyl group.

[0064] As used herein, the term "salt" refers to an acidic or basic salt of a compound used in the methods of the present invention. Exemplary examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. Pharmaceutically acceptable salts are understood to be non-toxic. Additional information regarding suitable pharmaceutically acceptable salts is described in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0065] The pharmaceutically acceptable salts of the acidic compounds of the present invention are salts formed with bases, i.e., cationic salts such as alkali and alkaline earth metal salts like sodium, lithium, potassium, calcium, magnesium, and ammonium salts such as ammonium, trimethylammonium, diethylammonium, tris(hydroxymethyl)-methyl-ammonium salts.

[0066] Similarly, acid addition salts such as mineral acids, organic carboxylic acids, and organic sulfonic acids, for example hydrochloric acid, methanesulfonic acid, maleic acid, etc., can also be provided, and basic groups such as pyridyl form part of the structure.

[0067] The neutral form of the compound can be regenerated by contacting the salt with a base or an acid and isolating the parent compound by conventional methods. The parent form of the compound differs from the various salt forms in certain physical properties such as solubility in polar solvents, but otherwise, the salts are equivalent to the parent form of the compound for the purposes of the present invention.

[0068] As used herein, the term "calcium salt" refers to a salt containing calcium. Examples of calcium salts include, but are not limited to, calcium acetate, calcium aluminate, calcium aluminate, calcium arsenide, calcium borate, calcium bromide, calcium carbide, calcium carbonate, calcium chloride, calcium chloride, calcium citrate, calcium citrate malate, calcium cyanamide, calcium dihydrogen phosphate, calcium fluoride, calcium formate, calcium gluceptate, calcium glucoheptonate, calcium gluconate, calcium glycerophosphate, calcium hexaborate, calcium hydride, calcium hydroxide, calcium hypochlorite, calcium inosinate, calcium iodate, calcium iodide, calcium lactate, calcium lactate gluconate, calcium magnesium acetate, calcium malate, calcium nitrate, calcium nitride, calcium oxalate, calcium oxide, calcium pangamate, calcium peroxide, calcium phosphate, calcium phosphide, calcium propionate, calcium pyrophosphate, calcium silicate, calcium silicide, calcium sorbate, calcium stearate, calcium sulfate, calcium sulfide, calcium tartrate, calcium chloride (I), dicalcium citrate, dicalcium phosphate, dodecacalcium hepta-aluminate, tricalcium aluminate, tricalcium phosphate, and triple superphosphate. Those skilled in the art will understand that other calcium salts may be useful in the present invention.

[0069] As used herein, the term "hydrate" refers to a compound that forms a complex with at least one water molecule. The compounds of the present invention can form complexes with 1 to 10 water molecules. The term "hydrate" also includes hemihydrates in which there are two compounds for each water molecule of the complex.

[0070] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds, and it is intended that all racemates, diastereomers, geometric isomers, and individual isomers are included within the scope of the present invention.

[0071] As used herein, the term "subject" refers to an animal, such as a mammal including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0072] As used herein, the terms "therapeutically effective amount or dose", "therapeutically sufficient amount or dose", or "effective or sufficient amount or dose" refer to an amount or dose that produces a therapeutic effect upon administration. The exact amount is determined by the purpose of the treatment and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999), Pickar, Dosage Calculations (1999), and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective amount is often lower than the conventional therapeutically effective amount for non-sensitized cells.

[0073] As used herein, the term "site of injury or local condition" refers to a specific location within the body of a subject in need of treatment by the methods of the present invention. For example, the injury may be a fracture, and the local condition may be a medical condition (such as osteoporosis) limited to a specific location of the subject's body, such as a specific bone, joint, finger, hand, foot, limb, spine, head, torso, etc. In some embodiments, the site of injury or local condition is a surgical implantation site.

[0074] As used herein, the term "promotion of bone formation" refers to the stimulation of new bone formation, bone growth across joints or gaps, enhancement or facilitation of bone formation, and / or an increase in bone density or bone mineral content. In some embodiments, a compound promotes bone formation if it increases the amount of bone in a sample by at least 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% or more compared to a control sample (e.g., a sample not in contact with the compound).

[0075] As used herein, the term "arthrodesis" often refers to the artificial induction of joint ossification across two bones and / or joints, often via surgery. Arthrodesis can be achieved, inter alia, via the use of bone grafts, metal implants, or artificial bone substitutes.

[0076] As used herein, the term "bone autograft" refers to the transplantation of a subject's own bone.

[0077] As used herein, the term "bone allograft" refers to the transplantation of bone from one person to another.

[0078] As used herein, the term "bone resorption inhibitor" refers to a drug that delays or blocks bone resorption and / or acts on osteoclasts.

[0079] As used herein, the term "bone-related disease characterized by low bone mass" refers to bone with a T-score of less than -0.5. Other methods of determining low bone mass are known to those of skill in the art.

[0080] As used herein, the term "fracture" refers to a crack, break, or damaged bone at one or more locations along the bone. In some embodiments, the term "fracture" also includes segments of missing connection.

[0081] As used herein, the term "spinal arthrodesis" refers to a surgical procedure for joining or fusing two or more vertebrae.

[0082] As used herein, the term "structural support" refers to a segment (transplantable portion) of a device that can be implanted into a subject. The structural support can be prepared from a variety of different materials, including metals, ceramics, polymers, and inorganic materials as described below. The structural support may be coated with a variety of materials that promote bone growth. In some embodiments, the entire device includes a structural support that is implantable. For example, in some embodiments, the entire device described herein can be implanted into a surgical site and the surgical site can be closed over the device.

[0083] As used herein, the term "outer coating" refers to a coating of the structural support that can cover only a portion of the structural support (partial outer coating) or can cover the entire structural support. For example, a partial outer coating can completely cover only the implantable portion of the structural support.

[0084] As used herein, the terms "weakened bone", "low bone density", or "low bone mass" refer to bone having a T-score of less than -0.5 (less than 0.9 g / cm 2 ).

[0085] As used herein, the term "demineralized bone" refers to bone from which inorganic minerals have been removed. The remaining organic collagen material may contain bone-inductive growth factors. These growth factors include bone morphogenetic proteins that induce cartilage, which ossifies via endochondral ossification to generate new bone formation. Demineralized bone is often provided in the form of "demineralized bone matrix (DBM)". DBM can be made from fresh frozen or lyophilized bulk bone allografts or by gentle acid extraction of cadaver bone that removes the mineral phase leaving collagen, growth factors, and non-collagenous proteins that provide the inherent properties of osteoconduction. DBM may be processed in various ways and ultimately the powder is mixed with a carrier to provide optimal handling properties desirable for the surgeon. DBM is clinically available in gels, pastes, putties, and fabrics tailored to meet the needs of surgical procedures. Some DBMs are mixed with antibiotics prior to surgical procedures.

[0086] As used herein, the term "kidney disorder" refers to the inability of the kidneys to excrete waste products and to help maintain the body's electrolyte balance. Kidney disorders are characterized by some of the following: high blood pressure, accumulation of urea and formation of urea frost, accumulation of potassium in the blood, decreased erythropoietin synthesis, increased body fluid volume, hyperphosphatemia, and metabolic acidosis, among others.

[0087] As used herein, the term "diabetes" refers primarily to a condition characterized by the inability to produce a sufficient amount of insulin, a hormone produced by the pancreas. When insulin is released into the bloodstream, it induces glucose uptake by cells. Therefore, when the amount of insulin is insufficient, the blood glucose level of the affected individual rises. Those skilled in the art will recognize that the inability of the body to produce a sufficient amount of insulin can be a feature of both type 1 and type 2 diabetes.

[0088] As used herein, the term "osteoconductive matrix" refers to a material having a scaffold structure that can act as an osteoconductive substrate (i.e., enable bone growth), to which infiltrating cells can attach, proliferate, and participate in the process of generating osteoid (the organic phase of bone) leading to bone neogenesis or new bone formation. The terms "matrix" and "scaffold" are used interchangeably to refer to a structural component or substrate that essentially has a three-dimensional form in which specific cellular events involved in bone formation occur. The osteoconductive matrix enables the ingrowth of host capillaries, perivascular tissue, and bone progenitor cells. In some embodiments, the osteoconductive matrix contains an "osteogenic agent" for providing osteogenic ability. As used herein, an osteogenic agent is an agent that stimulates the host to proliferate bone cells, thereby producing more bone osteoid.

[0089] As used herein, the terms "treat", "treating", and "treatment" refer to signs of success in the treatment or amelioration of an injury, condition, state, or symptom (e.g., pain) that include the following objective or subjective parameters: reduction of symptoms, remission, alleviation, or making the symptom, injury, condition, or state more tolerable to the patient, reducing the frequency or duration of the symptom or condition, or, depending on the situation, preventing the onset of the symptom or condition. Treatment or amelioration of a symptom can be based on objective or subjective parameters including, for example, the results of a physical examination.

[0090] As used herein, the term "RankL inhibitor" refers to a compound or agent that inhibits the activity of RankL. RankL (receptor activator of nuclear factor κB ligand) is important for bone metabolism by activating osteoclasts. RankL inhibitors include, but are not limited to, denosumab, a human monoclonal antibody. Those skilled in the art will understand that other RankL inhibitors are useful in the present invention.

[0091] As used herein, the terms "parathyroid hormone" or "PTH" refer to a compound or agent that acts on the PTH receptor to activate the pathway. PTH is important for bone metabolism by activating osteoblasts. PTH includes, but is not limited to, teriparatide, Forteo® (forteo), and abaloparatide-SC. Those skilled in the art will understand that other PTHs may be useful in the present invention.

[0092] As used herein, the term "combination therapy" is the use of the compounds of the present invention together, or sequentially, before or after administration of the compounds of the present invention.

[0093] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds, and racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separate enantiomers) are all intended to be included within the scope of the present invention. In some embodiments, the compounds of the present invention are specific enantiomers or diastereomers that are substantially free of other forms. The compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms that make up such compounds. For example, the compound may be radiolabeled with radioactive or non-radioactive isotopes such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variants of the compounds of the present invention are intended to be included within the scope of the present invention, whether radioactive or not.

[0094] III. Compounds and Compositions In some embodiments, the present invention provides a compound according to the following formula I:

[0095]

Chemical formula

[0096] or a salt, hydrate, prodrug, or isomer thereof, provided that X is CR 3b and N, where N is optionally oxidized to the corresponding N-oxide, Y is CR 3c and N, where N is optionally oxidized to the corresponding N-oxide, Z is CR 3d and N, where N is optionally oxidized to the corresponding N-oxide, provided that at least one of X, Y, and Z is N or the corresponding N-oxide, A is

[0097]

Chemical formula

[0098] where R N is selected from the group consisting of heterocyclyl and heteroaryl, the heterocyclyl moiety is selected from monocyclic, fused bicyclic, and bridged bicyclic heterocyclyls, the monocyclic heterocyclyl contains 4 to 7 ring members, the fused bicyclic heterocyclyl and the bridged bicyclic heterocyclyl contain 7 to 10 ring members, each heterocyclyl moiety has 1 to 3 heteroatoms selected from ring members nitrogen (N), oxygen (O), and sulfur (S), each heterocyclyl moiety contains at least one nitrogen atom as a ring member, and optionally 1 to 3 R 6 moieties, the heteroaryl moiety contains 5 to 10 ring members, at least one ring member is a nitrogen atom, and optionally 1 to 3 R 6 moieties, R 2 R 3b R 3c and R 3d are each, independently, H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-OH, -O-C 1-6 Alkyl-OH, C 3-6 Cycloalkyl-C 1-4 Selected from the group consisting of alkoxy and hydroxyl group (-OH), and R 6 is hydroxyl group (-OH), C 1-3 alkyl, C 1-3 alkyl-OH, -O-C 1-3 alkyl, C 3-4 heteroalkyl, C 1-3 haloalkyl, -O-C 1-3 haloalkyl, halogen, and oxo.

[0099] In some embodiments, the present invention provides a compound according to formula Ia:

[0100]

Chemical formula

[0101] wherein each variable position is as defined in formula I.

[0102] In some embodiments, the present invention provides a compound according to formula Ib:

[0103]

Chemical formula

[0104] wherein each variable position is as defined in formula I.

[0105] In some embodiments, the present invention provides a compound according to formula Ic:

[0106]

Chemical formula

[0107] Provide a compound according to, where each variable position is as defined in formula I.

[0108] In some embodiments, the present invention is a compound of formula Id:

[0109]

Chemical formula

[0110] Provide a compound according to, where each variable position is as defined in formula I.

[0111] In some embodiments, R of formula I, Ia, Ib, Ic, or Id 2 are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy. In some embodiments, R of formula I, Ia, Ib, Ic, or Id 2 is C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, R of formula I, Ia, Ib, Ic, or Id 2 is CH3 or CF3. In some embodiments, R of formula I, Ia, Ib, Ic, or Id 2 is CF3.

[0112] In some embodiments, R 3b , R 3c , and R 3d are each, when present in formula I, Ia, Ib, Ic, or Id, H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy. In some embodiments, R 3b , R 3c , and R 3d are each, when present in formula I, Ia, Ib, Ic, or Id, H, halogen, and C 1-6is an alkoxy group. In some embodiments, R 3b , R 3c , and R 3d are each H, F, and methoxy when present in Formula I, Ia, Ib, Ic, or Id. In some embodiments, at least one of R 3b , R 3c , and R 3d is F when present in Formula I, Ia, Ib, Ic, or Id. In some embodiments, at least one of R 3b , R 3c , and R 3d is methoxy when present in Formula I, Ia, Ib, Ic, or Id. In some embodiments, at least one of R 3b , R 3c , and R 3d is F and at least one of R 3b , R 3c , and R 3d is methoxy when present in Formula I, Ia, Ib, Ic, or Id.

[0113] In some embodiments, R N of Formula I, Ia, Ib, Ic, or Id is heteroaryl. In some embodiments, the heteroaryl moiety contains 4 to 8 ring members, at least one ring member is a nitrogen atom, and is optionally substituted with 1 to 3 R 6 moieties.

[0114] In some embodiments, R N of Formula I, Ia, Ib, Ic, or Id is monocyclic heterocyclyl.

[0115] In some embodiments, R N of Formula I, Ia, Ib, Ic, or Id is

[0116]

Chemical formula

[0117] is.

[0118] In some embodiments, R of formula I, Ia, Ib, Ic, or Id 6 is selected from the group consisting of a hydroxyl group (-OH), C 1-3 alkyl, C 1-3 alkyl-OH, -O-C 1-3 alkyl, C 1-3 haloalkyl, -O-C 1-3 haloalkyl, halogen, and oxo. In some embodiments, R of formula I, Ia, Ib, Ic, or Id 6 is selected from the group consisting of C 1-3 alkyl, -O-C 1-3 alkyl, C 1-3 haloalkyl, -O-C 1-3 haloalkyl, and halogen. In some embodiments, R 5 is a hydroxyl group (-OH), C 1-3 alkyl, or -O-C 1-3 alkyl.

[0119] In some embodiments, the present invention provides a compound of formula I below:

[0120]

Chemical formula

[0121] or a salt, hydrate, prodrug, or isomer thereof, wherein R 2 is selected from the group consisting of hydrogen (H), halogen, C 1-6 alkyl, and C 1-6 haloalkyl, R 3c when present, is independently H or C 1-6 alkoxy, R 3b or R 3d when present, is H or halogen, and A is

[0122]

Chemical formula

[0123] and R N is a heterocyclyl or heteroaryl, and herein X, Y, and Z and A are as defined in Formula I and the sub - embodiments described herein.

[0124] In some embodiments, the present invention provides a compound of Formula I below:

[0125]

Chemical formula

[0126] or a salt, hydrate, prodrug, or isomer thereof, wherein R 2 is H, C 1-6 haloalkyl or C 1-6 alkyl, R 3c when present, is C1 - 6 alkoxy, R 3b or R 3d when present, is H, or halogen, A is

[0127]

Chemical formula

[0128] and R N is

[0129]

Chemical formula

[0130] and X, Y, and Z are as defined above.

[0131] In some embodiments of the compounds of Formula Ia, Ib, Ic, or Id, R 2 is C 1-6 alkyl or C 1-6 haloalkyl, R 3b when present, is H or halogen, R 3c is C 1-6 alkoxy, and R N is heterocyclyl or heteroaryl.

[0132] In some embodiments of the compounds of Formula Ia, Ib, Ic, or Id, R 2 is C 1-6 haloalkyl, R 3b when present, is H or halogen, R 3c is C 1-6 alkoxy, and A is

[0133]

Chem.

[0134] and R N is

[0135]

Chem.

[0136] as such.

[0137] In some embodiments of the compounds of Formula Ia, Ib, Ic, or Id, R 2 is CF3, R 3b when present, is H or halogen, R 3c is methoxy, and A is

[0138]

Chem.

[0139] and R N is as defined in Formula I and the sub - embodiments described herein.

[0140] In one group of embodiments, the compounds of Formula I have a structure selected from:

[0141]

Chem.

[0142] In some embodiments, the present invention provides formates of the compounds with any of the above - mentioned compounds. In some embodiments, the present invention provides citrates of the compounds with any of the above - mentioned compounds. In some embodiments, the present invention provides hydrochlorides of the compounds with any of the above - mentioned compounds.

[0143] The compounds and compositions of the present invention may also include hydrates, solvates, and prodrug forms. The compounds and compositions of the present invention may also include isomers and metabolites of the compounds of Formula I, Ia, Ib, Ic, or Id.

[0144] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound according to Formula I, Ia, Ib, Ic, or Id and a pharmaceutically acceptable excipient.

[0145] The compounds of the present invention can be in the form of salts. Salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, phosphonic acid, isonicotinate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts. Other salts include, but are not limited to, salts with inorganic bases such as alkali metal salts like sodium salts and potassium salts, alkaline earth metal salts like calcium salts and magnesium salts, aluminum salts, and ammonium salts. Other salts containing organic bases include salts containing diethylamine, diethanolamine, meglumine, and N,N'-dibenzylethylenediamine. In some embodiments, the present invention provides the hydrochloride salt.

[0146] In some embodiments, the compounds of the present invention contain a nitrogen atom that is further oxidized as desired, i.e., the compound is an N-oxide. By way of mere example, as an example, the nitrogen atom of the pyrido-indolyl ring system in a compound of formula I, Ia, Ib, Ic, or Id is oxidized to the corresponding N-oxide.

[0147] In some embodiments, the compounds described herein are delivered and / or formulated as prodrugs. In one embodiment, any compound described herein is an ester prodrug. In another embodiment, any compound described herein is an amide prodrug. In further embodiments, the prodrug moiety includes a conjugate group that enables selective targeting at the bone structure. Examples of such motifs are described in Erez et al., Bioorg. Med. Chem. Lett. 2008, 18, 816-820 and Neale et al., Bioorg. Med. Chem. Lett. 2009, 19, 680-683, which are incorporated herein by reference. Accordingly, within the scope of the embodiments presented herein are estradiol conjugates and / or bisphosphonate conjugates of the compounds of Formula I.

[0148] The compounds of the present invention can be made by various methods known to those of skill in the art (see Comprehensive Organic Transformations Richard C. Larock, 1989). Those of skill in the art will understand that other methods of making the compounds will be useful in the present invention. Exemplary methods for synthesizing the compounds of Formula I are described in the Examples section and in Scheme 1 below. Scheme 1

[0149]

Chemical formula

[0150] Starting from Compound 1, the reaction with Compound 2 containing a leaving group (LG) provides the compound of Formula I. Halo, activated ester, mesylate, triflate, or a group at the 9-position of the core ring system

[0151]

Chemical formula

[0152] A variety of leaving groups are suitable, including but not limited to any other suitable leaving group that enables the linkage of 3c When R 3c is methoxy, it may be converted to a hydroxy group by the described procedures, for example, demethylation using HBr in acetic acid, boron tribromide, or any other suitable procedure. Optionally, the compounds of formula I include N-oxides prepared by oxidation, for example, using m-chloroperbenzoic acid.

[0153] IV. Method for Promoting Bone Formation In another aspect, the present invention provides a method for promoting bone formation and bone healing in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention (for example, a compound or composition of formula I, formula Ia, formula Ib, formula Ic, or formula Id as described in section III above).

[0154] In some aspects, the present invention is a method for promoting in a subject in need of bone formation, comprising administering to the subject a therapeutically effective amount of a compound of the following formula I:

[0155]

Chemical formula

[0156] or a salt, hydrate, prodrug, or isomer thereof, comprising X is selected from CR 3b and N, where N is optionally oxidized to the corresponding N-oxide, 3b Y is selected from CR 3c and N, where N is optionally oxidized to the corresponding N-oxide, Y is selected from CR 3c and N, where N is optionally oxidized to the corresponding N-oxide, 3c Z is selected from CR 3d and N, where N is optionally oxidized to the corresponding N-oxide, Z is selected from CR 3d and N, where N is optionally oxidized to the corresponding N-oxide, 3d Z is selected from CR 3d and N, where N is optionally oxidized to the corresponding N-oxide, provided that at least one of X, Y, and Z is N or the corresponding N-oxide, A is

[0157]

Chemical formula

[0158] and R N is selected from the group consisting of heterocyclyl and heteroaryl, the heterocyclyl moiety is selected from monocyclic, fused bicyclic, and bridged bicyclic heterocyclyls, the monocyclic heterocyclyl contains 4 to 7 ring members, the fused bicyclic heterocyclyl and the bridged bicyclic heterocyclyl contain 7 to 10 ring members, each heterocyclyl moiety has 1 to 3 heteroatoms as ring members selected from nitrogen (N), oxygen (O), and sulfur (S), each heterocyclyl moiety contains at least one nitrogen atom as a ring member, and optionally 1 to 3 R 6 moieties are substituted, the heteroaryl moiety contains 5 to 10 ring members, at least one ring member is a nitrogen atom, and optionally 1 to 3 R 6 moieties are substituted, each R 2 、R 3b 、R 3c 、and R 3d is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-OH, -O-C 1-6 alkyl-OH, C 3-6 cycloalkyl-C 1-4 alkoxy, and -OH, R 6 is selected from the group consisting of -OH, C 1-3 alkyl, C 1-3 alkyl-OH, -O-C 1-3 alkyl, C 3-4 heteroalkyl, C 1-3 haloalkyl, -O-C 1-3 haloalkyl, halogen, and oxo, and provides the method.

[0159] In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a hydrochloride, sulfate, formate, or citrate salt of a compound of Formula I, Ia, Ib, Ic, or Id, as described above.

[0160] One of ordinary skill in the art will understand that mineral deposition (bone formation) by osteoblasts can be achieved by local administration, systemic administration, or both local and systemic administration. In some embodiments, the bone formation is local. A subject in need of local bone formation can have any of a variety of diseases or conditions, including, but not limited to, those characterized by weakened bone, fractures, or low bone mass or insufficient mineralization, as described herein. In some embodiments, the subject is in need of spinal fusion, bone healing, arthrodesis, or orthopedic, dental, or periodontal synthetic bone grafts or implants. In some embodiments, the invention provides a method for promoting bone formation at the site of an injury or local condition. In some embodiments, the invention includes a method for fusing bone (e.g., at the site of an injury). In some embodiments, the site of injury is a surgical site. In other embodiments, the injury is a fracture or weakened bone or periodontal disease.

[0161] In some embodiments, bone formation is systemic. Systemic bone formation refers to the formation of bone throughout the subject and can affect all the bones in the subject's body. Subjects in need of systemic bone formation may be suffering from any of a variety of diseases or conditions. In some embodiments, the subject is suffering from low bone mass / density condition / disease (either primary or secondary), fractures, periodontal disease / condition, or a disease / condition that causes insufficient bone mineralization (e.g., osteogenesis imperfecta or HPP). Low bone mass can be determined by a variety of methods known to those of skill in the art. For example, low bone mass / density can be characterized by a T-score of less than about -0.5. Diseases / conditions of low bone mass / density include, but are not limited to, osteoporosis, osteopenia, and osteopetrosis-pseudoglioma syndrome (OPPG), glucocorticoid-induced low bone mass / density, osteogenesis imperfecta. In some other embodiments, the low bone mass condition / disease can be osteopenia or osteopetrosis-pseudoglioma syndrome (OPPG), HPP, or glucocorticoid-induced low bone mass / density or other diseases that result in secondary low bone density conditions.

[0162] Local and / or systemic bone formation using the compounds or compositions of the invention can be achieved according to any of a variety of methods. Methods of formulating and administering the compounds and compositions of the invention (e.g., compounds or compositions of Formula I) are described in Section VII below. In some embodiments, a method of promoting bone formation includes implanting a medical device as described herein (e.g., in Section VIII below) into a subject in need thereof.

[0163] Methods that promote mineral deposition in osteoblasts and ultimately increase bone mineralization or density can be used in the treatment of diseases characterized by secondary osteoporosis (low bone mass). Such diseases include osteomalacia, polyostotic fibrous dysplasia, osteogenesis imperfecta, Paget's disease, rheumatoid arthritis, microgravity, osteoarthritis, prolonged inactivity or immobility, joint immobilization, osteomyelitis, celiac disease, Crohn's disease, ulcerative colitis, inflammatory bowel disease, gastrectomy, secondary osteoporosis, amenorrhea, Cushing's disease, Cushing's syndrome, type 2 diabetes, diabetes, eating disorders, hyperparathyroidism, hyperthyroidism, hypophosphatasia (HPP), hyperprolactinemia, Klinefelter syndrome, thyroid disorders, Turner syndrome, steroid-induced osteoporosis, seizure- or depression-induced osteoporosis, immobility, arthritis, cancer-induced secondary osteoporosis, gonadotropin-releasing hormone agonist-induced low bone mass, thyroid medication-induced low bone mass, Dilantin (phenytoin)-induced low bone mass, Depakote-induced low bone mass, chemotherapy-induced low bone mass, immunosuppressant-induced low bone mass, anticoagulant-induced low bone mass, Graves' disease, juvenile rheumatoid arthritis, malabsorption syndrome, anorexia nervosa, kidney disease, antiepileptic drug treatment (e.g., for epilepsy), corticosteroid treatment (e.g., for rheumatoid arthritis, asthma), immunosuppressive treatment (e.g., for cancer), inadequate nutrition (especially calcium, vitamin D), excessive exercise leading to amenorrhea (absence of menstruation), smoking and alcohol abuse, pregnancy-related osteoporosis, copper deficiency, type 2 aminoaciduria, Werner syndrome, Hallermann-Streiff syndrome, juvenile cortical hyperostosis deformansjuvenilis), type 2 methylmalonic aciduria, cystathionine beta synthase deficiency, exemestane, hyper-IgE syndrome, hemochromatosis, Singleton-Merten syndrome, beta-thalassemia (homozygous), reflex sympathetic dystrophy, sarcoidosis, Winchester syndrome, Hallermann-Streiff syndrome (HSS), cyproterone, glycerol kinase deficiency, Bonnet-Dechaume-Blanc syndrome, prednisolone, heparin, cutis laxa osteodysplasia of the elderly, Torg osteolysis syndrome, orchidectomy, Fabry disease, pseudo-progeria syndrome, Wolcott-Rallison syndrome, ankylosing spondylitis, myeloma, systemic infantile hyalinosis, Albright hereditary osteodystrophy, anorexia nervosa, autoimmune lymphoproliferative syndrome, Brown-Séquard syndrome, Diamond-Blackfan anemia, eating disorders, galactorrhea, hyperprolactinemia, ovarian dysgenesis, kidney diseases, Menkes disease, menopausal disorders, neuritis, ovarian insufficiency due to FSH resistance, familial ovarian insufficiency, premature aging, primary biliary cirrhosis, prolactinoma, familial prolactinoma, renal osteodystrophy, ulcerative colitis, weight loss, Werner syndrome, bone tumors, bone cancer, brittle bone diseases, osteonecrosis, congenital osteogenesis imperfecta, late-onset osteogenesis imperfecta, osteogenesis imperfecta, glucocorticoid-induced osteoporosis / osteopenia, and periodontal diseases are included, but not limited to these. Those skilled in the art will understand that other types of conditions, diseases, and treatments may also lead to osteoporosis.

[0164] Bone formation can be measured according to any of a variety of methods known to those skilled in the art. Methods for measuring bone formation include, but are not limited to, μCT (micro-CT), dual-energy X-ray absorptiometry (bone density), ultrasound, QCT, SPA, DPA, DXR, SEXA, QUS, X-ray, performed visually during surgery, alizarin red S, serum osteocalcin, serum alkaline phosphatase, serum bone Gla-protein (BGP), bone mineral content, bone ash weight, serum calcium, serum phosphorus, tartrate markers, and serum IGF-1.

[0165] Using many indicators of bone formation, the amount of bone formation, including bone density, can be measured and / or quantified. In some embodiments, bone formation is indicated by a 0.1% increase in bone density. In other embodiments, bone growth is indicated by an increase in bone density of 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% or more. Bone density can be measured in various ways, such as T-score and Z-score. The Z-score is the number of standard deviations above or below the average for the patient's age and gender. The T-score is the number of standard deviations above or below the average for a healthy 30-year-old adult of the same sex as the patient. Low bone mass is characterized by a T-score between -1 and -2.5. Osteoporosis is characterized by a T-score less than -2.5. An improvement in the T-score or Z-score indicates bone growth. Bone density can be measured at various locations on the skeleton, such as the spine and hip. Those skilled in the art will understand that other methods of determining bone density are useful in the present invention.

[0166] V. Methods for Treating Kidney Disorders In another aspect, the present invention provides a method for treating kidney disorders in a subject suffering from kidney disorders by administering a therapeutically effective amount of a compound of the present invention (e.g., a compound or composition of Formula I as described in Section III above).

[0167] Kidney disorders can be caused by various diseases known to those skilled in the art. In some embodiments, kidney disorders are caused by infection, radiation, toxins, dehydration, or trauma. Toxins that cause kidney disorders include, but are not limited to, chemicals, poisons, and chemotherapeutic agents. Those skilled in the art will understand that other causes of kidney disorders can be treated by the methods of the present invention.

[0168] Kidney disorders treatable by the compounds of the present invention include acute kidney injury. Acute kidney injury is also known as acute renal failure or acute renal injury. Acute kidney injury usually leads to the retention of nitrogenous (urea and creatinine) and non-nitrogenous waste products that are normally excreted by the kidneys. Depending on the severity and duration of kidney dysfunction, this accumulation is accompanied by metabolic disorders such as metabolic acidosis (acidification of the blood) and hyperkalemia (elevated potassium levels), changes in fluid balance, and effects on other organ systems. Acute kidney injury may be characterized by oliguria or anuria (decreased or absent urine production), although non-oliguric acute kidney injury can also occur.

[0169] Subjects may be characterized by (1) risk of acute injury, (2) kidney injury resulting in harm, (3) acute kidney injury, and (4) loss of kidney function. The risk of acute kidney injury is characterized by a 1.5-fold increase in serum creatinine or urine output less than 0.5 mL / kg body weight over 6 hours. Injury occurs when serum creatinine doubles to 2.0-fold or urine production is less than 0.5 mL / kg over 12 hours. Renal failure occurs when serum creatinine triples or creatinine increases to >355 μM (>44-fold increase), or when urine output is less than 0.3 mL / kg over 24 hours. Loss of kidney function occurs when the subject has persistent acute kidney injury or complete loss of kidney function for more than 4 weeks.

[0170] Renal biopsy can be performed in the setting of acute kidney injury to provide a definitive diagnosis and, in some cases, an idea of the prognosis, provided that the cause is not clearly established and appropriate screening tests are definitely negative.

[0171] The renal therapeutic agent of the present invention can be used for a subject suffering from renal impairment or at risk of chronic renal failure. As used herein, a subject is considered to have chronic renal failure or be at risk thereof, or be said to be at risk of the need for renal replacement therapy (i.e., chronic hemodialysis, continuous peritoneal dialysis, or kidney transplantation) if it is reasonably expected that the subject suffers from a progressive loss of renal function associated with a progressive loss of functioning nephron units. Whether a particular subject has chronic renal failure or is at risk thereof is a determination that can be routinely made by a person skilled in the relevant medical or veterinary art. Subjects with chronic renal failure or at risk thereof, or at risk of the need for renal replacement therapy, include, but are not limited to: subjects with chronic renal failure, end-stage renal disease, chronic diabetic nephropathy, hypertensive nephrosclerosis, chronic glomerulonephritis, hereditary nephritis, and / or subjects who can be considered to have renal dysplasia; subjects with a biopsy showing glomerular hypertrophy, tubular hypertrophy, chronic glomerulosclerosis, renal cell carcinoma, and / or chronic tubulointerstitial sclerosis; subjects undergoing ultrasound, MRI, CAT scan, or other non-invasive tests showing renal fibrosis; subjects with an abnormal number of casts in the urine sediment; subjects with a GFR that is chronically less than about 50% of the predicted GFR of the subject, more specifically less than about 40%, 30%, or 20%; human male subjects weighing at least about 50 kg and having a GFR that is chronically less than about 50 mL / min, more specifically less than about 40 mL / min, 30 mL / min, or 20 mL / min; human female subjects weighing at least about 40 kg and having a GFR that is chronically less than about 40 mL / min, more specifically less than about 30 mL / min, 20 mL / min, or 10 mL / min; subjects having a number of functioning nephron units that is less than about 50% of the number of functioning nephron units possessed by a healthy but otherwise similar subject, more specifically less than about 40%, 30%, or 20%; subjects with only one kidney; and subjects who are kidney transplant recipients.

[0172] VI. Method for treating diabetes The compounds and compositions of the present invention are also useful in the treatment of diabetes. Accordingly, some embodiments of the present invention provide a method for treating diabetes. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention (e.g., a compound or composition of Formula I, Formula Ia, Formula Ib, Formula Ic, or Formula Id as described in Section III above).

[0173] Diabetes is a disease in which the body cannot produce insulin at all or sufficiently, causing an increase in blood glucose levels in the affected individual. Without being bound by a particular theory, the compounds and compositions of the present invention are thought to be useful in treating diabetes by regenerating pancreatic cells. In some embodiments, the compounds of the present invention are thought to induce the regeneration of β cells in the pancreas. See, for example, Wang P. et al., Nat Med., 21(4):383-388 (2015).

[0174] The diabetes therapeutics of the present invention can be used in subjects with pancreatic injury, in a prediabetic state, or with diabetes. As used herein, a subject with pancreatic injury is a subject in which the natural production of insulin has decreased, been impaired, or is absent. Whether a subject is considered prediabetic or diabetic is determined by many factors, including fasting blood glucose levels. A subject is considered prediabetic if their fasting blood glucose level exceeds 100 mg / dL. If a subject's fasting blood glucose level exceeds 125 mg / dL, the subject is considered diabetic.

[0175] Pancreatic injury can be caused by various diseases known to those skilled in the art. In some embodiments, pancreatic injury is caused by an infectious disease, an autoimmune disease, radiation, a toxin, or trauma. Toxins that cause pancreatic injury include, but are not limited to, chemicals, poisons, and chemotherapeutic agents. Those skilled in the art will understand that other causes of pancreatic injury can be treated by the methods of the present invention.

[0176] In some embodiments, the disease to be treated is type 1 diabetes. In some embodiments, the disease to be treated is type 2 diabetes.

[0177] The compounds of the present invention can be administered continuously or in combination with other therapeutic agents useful for the treatment of diabetes. In some embodiments, the other therapeutic agent is an antidiabetic agent. Antidiabetic agents include, but are not limited to, lipid-lowering agents / lipid-regulating agents, agents for treating diabetic complications, anti-obesity agents, antihypertensive agents, SGLT1 inhibitors, SGLT2 inhibitors, anti-hyperuricemia agents, and agents for treating chronic heart failure, atherosclerosis, or related disorders.

[0178] VII. Treatment methods for osteopenia In another aspect, the present invention provides a method for treating osteopenia in a subject suffering from osteopenia by administering a therapeutically effective amount of a compound of the present invention (e.g., a compound or composition of formula I, formula Ia, formula Ib, formula Ic, or formula Id as described in Section III above).

[0179] As shown in Figure 1, the bone density of an individual can be explained by the net loss (bone resorption) and increase (bone formation) of bone mass. In an individual with osteopenia, the net bone resorption is greater than bone formation, causing a decrease in osteopenia. In certain embodiments of the present invention, it is believed that osteopenia can be treated by inhibiting or reducing bone resorption while stimulating or promoting bone formation.

[0180] Bone resorption inhibitors are compounds that slow down the process of bone resorption. Bone resorption inhibitors include, but are not limited to, RankL inhibitors, denosumab, Prolia, cathepsin K modulators, alendronic acid, Fosamax, selective estrogen receptor modulators (SERMs), calcium, estrogen, bisphosphonates, and calcitonin.

[0181] The compounds and compositions of the present invention treat bone loss by promoting bone formation. When the compounds of the present invention are administered continuously or in combination with one or more bone resorption inhibitors, the rate of bone resorption is inhibited or reduced and the rate of bone formation is stimulated.

[0182] The compounds and compositions of the present invention and the bone resorption inhibitors described herein can be administered continuously or in combination. Details of the combination therapy are described in Section IX.C below.

[0183] The compounds and compositions of the present invention treat bone loss by promoting bone formation. In some embodiments, when the compounds of the present invention are administered continuously with one or more bone resorption inhibitors, the rate of bone resorption is inhibited or reduced and the amount of bone formation is maintained.

[0184] The compounds and compositions of the present invention can be administered to a patient who is a bone resorption inhibitor and thus has been administered continuously, or the patient can be administered one or more bone resorption inhibitors continuously, whereby the rate of bone resorption is inhibited or reduced and the amount of bone formation is maintained.

[0185] VIII. Cancer Therapy The compounds and compositions of the present invention are also useful in the treatment of cancer. Accordingly, some embodiments of the present invention provide a method of treating cancer. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention (e.g., a compound or composition of Formula I, Formula Ia, Formula Ib, Formula Ic, or Formula Id as described in Section III above).

[0186] In some embodiments, the compounds of the present invention are useful for the treatment of proliferative disorders such as cancer and leukemia, and other disorders associated with uncontrolled cell proliferation such as psoriasis and restenosis. As defined herein, the anti-proliferative effects within the scope of the present invention can be demonstrated, for example, by using any of the A549, HT29, Saos-2, HeLa, or MCF-7 cell lines, or by showing inhibition of CDK enzymes (such as CDK2 or CDK4), MTT, or BRDU in an appropriate assay, in an in vitro whole cell assay by the ability to inhibit cell proliferation. Such cell lines and enzyme assays can be used to determine whether a compound is anti-proliferative in light of the present invention.

[0187] As used herein, the term "cancer" includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver and biliary tract cancer, kidney cancer, myeloid disorders, lymphatic disorders, Hodgkin's disease, hairy cell leukemia, oral and pharyngeal (oral) cancer, lip cancer, tongue cancer, oral cavity cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, brain and central nervous system tumors, and leukemia. Those skilled in the art will understand that other cancers and proliferative disorders can be treated by the compounds and compositions of the present invention.

[0188] In some embodiments, the cancer is bone cancer, colon cancer, multiple myeloma, gastric cancer, colorectal cancer, prostate cancer, cervical cancer, lung cancer, pancreatic cancer, medulloblastoma, liver cancer, parathyroid cancer, endometrial cancer, or breast cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is a cancer characterized by secondary low bone mass including, but not limited to, breast cancer and prostate cancer. In some embodiments, the cancer is a cancer that has metastasized to the bone.

[0189] IX. Formulation and Administration In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I or a composition as described in Section III above) and a pharmaceutically acceptable excipient. In other embodiments, the composition further comprises a bone-conductive matrix.

[0190] The composition of the present invention can be in the form of a pharmaceutical composition comprising the antagonist and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include physiologically buffered saline solutions, other buffers, solvents, vehicles such as glycols and glycerols, oils such as olive oil, or aqueous solutions such as injectable organic esters. The selection of a pharmaceutically acceptable carrier will depend, in part, on the chemical nature of the compound.

[0191] The compounds of the present invention can be formulated in a variety of different ways known to those skilled in the art. The pharmaceutically acceptable carrier is determined in part by the particular composition being administered and the particular method used to administer the composition. Thus, there are a variety of suitable formulations for the pharmaceutical compositions of the present invention (see, e.g., Remington’s Pharmaceutical Sciences, 20 th ed., 2003, supra).

[0192] The pharmaceutically acceptable carrier can include, for example, a physiologically acceptable compound that acts to stabilize the composition or increase its absorption, or other excipients as needed. Physiologically acceptable compounds include, for example, carbohydrates such as glucose, sucrose, dextran, dextrin, cyclodextrin, or captisol, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. Those skilled in the art will know that the selection of a pharmaceutically acceptable carrier containing a physiologically acceptable compound is determined, for example, by the route of administration and its particular physicochemical properties.

[0193] Typically, such carriers must be non-toxic to the recipient at the dosages and concentrations used. Generally, the preparation of such compositions involves combining the therapeutic agent with buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, maltose, sucrose, dextran, dextrin, cyclodextrin, or captisol, chelating agents such as EDTA, glutathione, and other stabilizers and excipients. Neutral buffered saline or saline mixed with non-specific serum albumin are exemplary suitable diluents.

[0194] The amount of the compound or composition of the invention (e.g., a compound or composition of formula I described herein) to be administered to an individual will be determined, in part, by the degree of the disease and / or injury. Methods for determining an effective amount of a drug to be administered for diagnostic or therapeutic procedures are well known in the art and include Phase I, Phase II, and Phase III clinical trials, or pilot and pivotal trials (US Food and Drug Administration (FDA) device approval pathways). Generally, the drug is administered at a dosage of about 0.0001 - 500 mg / kg body weight when administered systemically and at a concentration of about 0.1 nM - 1000 μM when administered directly to the site of injury.

[0195] The total amount of the compound or composition can be administered to the subject as a bolus, or by relatively short infusions, as a single administration, or using a divided treatment protocol in which multiple administrations are carried out over a longer period. One of ordinary skill in the art will know that the concentration of a particular compound or composition required to provide an effective amount to one or more regions of injury is determined by many factors including the age and general health of the subject as well as the route of administration, the number of administrations, and the nature of the compound. Taking these factors into account, one of ordinary skill in the art will adjust the specific dosage to obtain an effective amount to effectively promote bone formation for therapeutic purposes.

[0196] The pharmaceutical preparation is preferably in unit dosage form. In such a form, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation, and the package can contain individually dosed preparations such as packeted tablets, capsules, transdermal patches, ampoules, and powders in vials or ampoules or on osteoconductive matrices. Also, the unit dosage form can be a capsule, tablet, cachet, or troche itself, or an appropriate number of packaged forms thereof. The composition can optionally also contain other compatible therapeutic agents. Preferred pharmaceutical preparations are capable of delivering the compounds of the present invention in sustained release formulations.

[0197] In some embodiments, the methods of the present invention include the application of the compounds described herein in cocktails containing other agents such as antibiotics, bactericides, bone anabolic agents, bone resorption inhibitors, and / or anti-inflammatory agents. Alternatively, the methods can include the sequential administration of the compounds described herein and one or more additional agents to an affected individual to optimize a treatment regimen. In such optimized regimens, the agents containing the compounds of the present invention can be applied in any order and in any combination.

[0198] Individuals to be treated with the compounds and compositions of the present invention can be any mammal, such as a human or non-human mammal, such as a primate, dog, cat, horse, cow, goat, sheep, pig, mouse, or rat, or a commercially important animal or livestock.

[0199] In some embodiments, the individual being treated according to the methods of the invention is an individual who has been administered, or is being administered, an antiresorptive agent. For example, in some embodiments, the antiresorptive therapy may be concurrent with the administration of the compounds or compositions of the invention. In some embodiments, the antiresorptive therapy and treatment with the compounds or compositions of the invention are sequential (either antiresorptive therapy preceding treatment with the compounds or compositions of the invention, or treatment with the compounds or compositions of the invention preceding antiresorptive therapy). In some embodiments, the individual may have been previously treated with an antiresorptive agent. In some embodiments, the individual may be co-treated with an antiresorptive agent during the first part of the treatment course with the compounds or compositions of the invention, but treatment with the antiresorptive agent may be discontinued during the second part of the treatment course. In some embodiments, the individual being treated according to the methods of the invention has not been treated with an antiresorptive agent. In some embodiments, the individual is treated with an antiresorptive agent after treatment with the compounds or compositions of the invention.

[0200] In some embodiments, the individual being treated according to the methods of the invention is, or has been, an individual who has received, or is receiving, a combination of an antiresorptive agent and / or an anabolic agent. For example, in some embodiments, the antiresorptive and / or anabolic therapy may be concurrent with the administration of the compounds or compositions of the invention. In some embodiments, the antiresorptive and / or anabolic therapy and treatment with the compounds or compositions of the invention are administered sequentially (either antiresorptive therapy preceding treatment with the compounds or compositions of the invention, or treatment with the compounds or compositions of the invention preceding antiresorptive therapy). In some embodiments, the individual may have been previously treated with an antiresorptive agent and / or an anabolic agent. In some embodiments, the individual may be treated concurrently with an antiresorptive agent and / or an anabolic agent during the first part of the treatment course with the compounds or compositions of the invention, but treatment with the antiresorptive agent and / or an anabolic agent may be discontinued during the second part of the treatment course. In some embodiments, the individual being treated according to the methods of the invention has not been treated with an antiresorptive agent and / or an anabolic agent. In some embodiments, the individual is treated with an antiresorptive agent and / or an anabolic agent after treatment with the compounds or compositions of the invention.

[0201] In some embodiments, the compounds and compositions of the invention are administered systemically. In some embodiments, the compounds and compositions of the invention are administered locally.

[0202] A. Systemic Delivery In some embodiments, the compounds and compositions of the invention are administered systemically. Systemic administration of the compounds and compositions of the invention can be used, for example, for the treatment of systemic diseases or conditions characterized by systemic effects, i.e., low bone mass (e.g., osteoporosis), diabetes, cancer, or renal disease.

[0203] The pharmaceutical composition of the present invention can be prepared for administration by various different routes. Usually, the type of carrier is selected based on the administration method. The pharmaceutical composition can be formulated for any suitable administration method including, for example, topical, oral, nasal, intrathecal, rectal, vaginal, sublingual, or parenteral administration, including injection or infusion subcutaneously, intravenously, intramuscularly, intracostally, transdermally, intracorporally, intrameatally, or intraurethrally. The pharmaceutical composition (for delivery, for example, by oral administration or injection) can be in the form of a liquid (for example, elixir, syrup, solution, emulsion, or suspension). The liquid pharmaceutical composition can include, for example, one or more of the following: water for injection, physiological saline, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oil that can serve as a solvent or suspension medium, polyethylene glycol, glycerin, propylene glycol, or other solvents, such as a sterile diluent; antibacterial agents; antioxidants; chelating agents; buffers such as acetate, citrate, phosphate; and agents for adjusting the osmotic pressure such as sodium chloride and dextrose. The parenteral preparation may be placed in an ampoule, disposable syringe, or multiple-dose vial made of glass or plastic. The use of physiological saline is preferred, and the injectable pharmaceutical composition is preferably sterile.

[0204] The formulations of the present invention are also suitable for administration into all body spaces / cavities including, but not limited to, the pleura, peritoneum, skull, mediastinum, pericardium, synovial sheath or bursa, epidural, intrathecal, intraocular, intra-articular, intradiscal, intramedullary, perispinal.

[0205] Formulations suitable for oral administration may be (a) liquid solutions such as an effective amount of a compound of the present invention suspended in a diluent such as water, physiological saline or PEG400, (b) capsules, sachets, depots, or tablets, each containing a predetermined amount of the active ingredient as a liquid, solid, granule, or gelatin, (c) suspensions in a suitable liquid, (d) suitable emulsions, and (e) patches. The dosage form may contain one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, dextran, dextrin, cyclodextrin, captisol, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffers, wetting agents, preservatives, fragrances, dyes, disintegrants, pharmaceutically acceptable carriers, and other components classified as inactive ingredients by the FDA. The lozenge form may include a lozenge containing the active ingredient in an inert base including, in addition to the active ingredient and carriers known in the art, the active ingredient in a flavor, such as sucrose, and gelatin and glycerin or sucrose and acacia emulsion, gel, and the like.

[0206] Specific oral formulations suitable for the present invention include, but are not limited to: buffered aqueous solutions with a pH of 4 to 10; non-buffered aqueous systems with a pH of 2 to 10; co-solvent aqueous solutions containing propylene glycol, glycerol, ethanol, or combinations thereof; aqueous solutions containing one or more emulsifiers such as one or more saturated polyglyceride saccharides (e.g., Gelucire®); aqueous suspensions containing methylcellulose (optionally containing sodium dodecyl sulfate, sodium lauryl sulfate, docusate, or polysorbate 80 at sub-critical micelle concentration (CMC)); aqueous solutions containing cyclodextrin (e.g., hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin); solutions containing one or more vegetable oils (e.g., safflower oil, soybean oil, oleic acid, etc.); non-aqueous solutions with or without emulsifiers such as PEG400 or 600, soybean oil / polysorbate 80 / sorbitan fatty acid ester (Span 80), mono / diglyceride or capric acid / caprylic acid (IMWITOR 742) / polysorbate 80 (70:30), polyethoxylated palm kernel oil / polyethylene glycol (PEG) 400 or 600 / water; surfactant aqueous solutions containing polysorbate 80 and SDS or SLS; oily suspensions containing soybean oil and safflower oil; and the preparation of the compounds or compositions of the present invention in nanoparticles.

[0207] Formulations suitable for intravenous bolus injection of the compound or composition include, but are not limited to: aqueous solutions containing buffered or unbuffered saline, optionally containing dextrose; co-solvent systems containing glycerin, ethanol, propylene glycol, PEG 300 or 400, glycofural, N-methylpyrrolidone (NMP), dimethylacetamide (DMA), dimethylformamide (DMF), dimethylisosorbide (DMI), dimethyl sulfoxide (DMSO), or combinations thereof in water; aqueous surfactant solutions containing polysorbate 80; aqueous solutions containing cyclodextrin (e.g., hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin); oily emulsions; plasma; and, optionally, aqueous suspensions containing methylcellulose and / or sodium dodecyl sulfate, sodium lauryl sulfate, docusate, or polysorbate 80 at sub-critical micelle concentration (CMC).

[0208] Formulations suitable for intravenous infusion of the compound or composition include, but are not limited to, aqueous solutions containing buffered or unbuffered saline, optionally containing dextrose, mannitol, or lactose, or any of the above formulations for intravenous bolus injection.

[0209] Formulations suitable for intramuscular, subcutaneous, or intraperitoneal administration include, but are not limited to: solutions in oil containing soybean oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, polysorbate 80, or sorbitan fatty acid esters; aqueous suspensions containing water, buffered or unbuffered saline, or dextrose (in water); or any of the above formulations for intravenous bolus injection.

[0210] Formulations suitable for intraocular administration include, but are not limited to: buffered or unbuffered aqueous solutions of pH 4 to 9 such as saline, optionally containing hydroxyethylcellulose; aqueous suspensions; or oily emulsions containing, for example, mineral oil, peanut oil, or petrolatum.

[0211] Typical formulations for topical / transdermal administration include creams, ointments, sprays, lotions, and patches. The topical / transdermal formulations of the present disclosure include propylene glycol, isopropyl myristate, PEG300, PEG400, petrolatum, or mixtures thereof, and may optionally also include ethanol or isopropanol.

[0212] The compounds of the present invention may also be included in sustained-release formulations for long-term treatment after a single administration. In one embodiment, the formulation is prepared in the form of microspheres. The nanoparticles / microspheres can be prepared using the desired additional agents required for treatment as a homogeneous matrix of the compound containing a biodegradable controlled-release material. The nanoparticles / microspheres are preferably prepared in a size suitable for penetration and / or injection and are administered systemically or directly injected into the treatment site.

[0213] Some sustained-release embodiments include biodegradable and / or slowly dissolving polymeric substances. Such polymeric substances include polyvinylpyrrolidone, low molecular weight and medium molecular weight hydroxypropyl cellulose and hydroxypropyl methylcellulose, cross-linked sodium carboxymethyl cellulose, carboxymethyl starch, potassium methacrylate / divinylbenzene copolymer, polyvinyl alcohol, starch, starch derivatives, microcrystalline cellulose, ethyl cellulose, methyl cellulose, and cellulose derivatives, β-cyclodextrin, captisol, poly(methyl vinyl ether / maleic anhydride), glucan, scierozlucan, mannan, xanthan, alzinic acid and its derivatives, dextrin derivatives, glyceryl monostearate, semi-synthetic glycerides, glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, sodium stearate, talc, sodium benzoate, boric acid, and colloidal silica.

[0214] The sustained-release agent of the present invention may also contain adjuvants such as starch, pregelatinized starch, calcium phosphate, mannitol, lactose, sucrose, glucose, sorbitol, microcrystalline cellulose, gelatin, polyvinylpyrrolidone, methylcellulose, starch solution, ethylcellulose, gum arabic, tragacanth gum, magnesium stearate, stearic acid, colloidal silica, glyceryl monostearate, hydrogenated castor oil, wax, and mono-substituted, di-substituted, and tri-substituted glycerides. The sustained-release agent can also be prepared as usually described in WO 94 / 06416 pamphlet.

[0215] B. Local delivery In some embodiments, the compounds and compositions of the present invention are administered locally. Local administration of the compounds and compositions of the present invention can be used, for example, for fracture healing, bone union (e.g., arthrodesis), orthopedic reconstruction, and periodontal repair. In some embodiments, local administration involves administering the compound or composition in combination with a suitable carrier material that can maintain the compound at the in vivo application site or provide a structural load. In some embodiments, the carrier is biocompatible, a matrix, biodegradable or absorbable in vivo, and / or porous enough to allow cell infiltration. In some embodiments, the compound or composition of the present invention (e.g., a compound or composition of formula I) is administered locally via an implantable (embedded) medical device.

[0216] The compounds and compositions of the present invention are useful in clinical applications in combination with suitable delivery or support systems (e.g., scaffolds or matrices described herein). As disclosed herein, the matrix may be combined with a compound or composition of Formula I to reliably and reproducibly induce bone formation in a mammalian body. The matrix preferably comprises particles of a porous material. The pores are preferably of a size that allows migration of progenitor cells into the matrix and subsequent differentiation and proliferation. In some embodiments, the pore size of the matrix is at least 5 μm, e.g., at least 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1500, 1700, or 2000 μm. The matrix can be produced by tightly packing particulate materials into a shape spanning a bone defect or, as needed, structuring a material that is biocompatible, preferably biodegradable or absorbable in vivo, and functions as a "temporary scaffold" and a substrate for mobilization of migratory progenitor cells and as a substrate for subsequent anchorage and proliferation. In some embodiments, the scaffold or matrix consists of a mesh structure, a foam structure, a sponge structure, or a fibrous structure.

[0217] The scaffold or matrix for use in delivering the compounds of the present invention may include synthetic substances, biological materials, or combinations thereof. In some embodiments, the scaffold or matrix includes naturally occurring polymers, synthetic biodegradable polymers, synthetic non-biodegradable polymers, bioceramics, bioglasses, or combinations thereof. Natural polymers and synthetic polymers, bioceramics, and bioglasses for use in scaffolds are known in the art. See, for example, Dhandayuthapani et al., International Journal of Polymer Science, volume 2011, article ID 290602 (2011), which is incorporated herein by reference. Natural polymers include, but are not limited to, proteins (e.g., silk, collagen, gelatin, fibrinogen, elastin, keratin, actin, and myosin), polysaccharides (e.g., cellulose, amylose, dextran, chitin, chitosan, and glycosaminoglycans), and polynucleotides (e.g., DNA and RNA). Synthetic polymers include, but are not limited to, PLA, PGA, PLLA, PLGA, PCL, PLDLA, PDS, PGCL, PEA, PCA, PDLLA, PEU, and PBT. Bioceramics and bioglasses include, but are not limited to, HAP, TCP, CP ceramics, BCP, and TCP. In some embodiments, the scaffold or matrix is a hydrogel scaffold, a fibrous scaffold, a microsphere scaffold, a polymer-bioceramic composite scaffold, or a cell-free scaffold.

[0218] In some embodiments, the scaffold or matrix is a bone-conductive matrix. Non-limiting examples of suitable bone-conductive matrix materials include, for example: collagen; homopolymers or copolymers of glycolic acid, lactic acid, and butyric acid (including their derivatives); and ceramics, hydroxyapatite, tricalcium phosphate, biphasic calcium phosphate and other calcium phosphates, and calcium sulfate, or combinations thereof. Typically, the bone-conductive matrix contemplated herein includes at least one of the materials listed above. Other matrices useful in the present invention include, but are not limited to, biocomposite bone grafts, Kryptonite Bone Cement™ (Doctors Research Group, Oxford, Connecticut), Vitoss®, Vitoss® BA, Grafton® Orthoblend, Arthrex® allografts, cadaver bone, OSTEOSET®, NovaBone®, AUGMATRIX®, Mastergraft®, HydroSet®, PRO-DENSE™, PRO-STIM™, (porous) tantalum bone grafts, titanium mesh, titanium bone grafts, and genex® bone grafts. Combinations of these matrix materials may also be useful. The bone-conductive matrix can also include calcium salts, calcium sulfate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-derived hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, plaster of paris, phosphopholine, borosilicate, bioactive glass, biocompatible ceramics, calcium phosphate ceramics, polytetrafluoroethylene, sulfates, collagen, and homopolymers or copolymers of glycolic acid, lactic acid, butyric acid (including their derivatives), and structural supports such as ceramics, hydroxyapatite, tricalcium phosphate, biphasic calcium phosphate and other calcium phosphates, and calcium sulfate.Other matrices useful in the present invention include, but are not limited to, biocomposite bone grafts, Kryptonite Bone Cement™ (Doctors Research Group, Oxford, Connecticut), Vitoss®, Vitoss® BA, Grafton® Orthoblend, Arthrex® allografts, cadaver bone, OSTEOSET®, NovaBone®, AUGMATRIX®, Mastergraft®, HydroSet®, PRO-DENSE™, PRO-STIM™, (porous) tantalum bone grafts, titanium mesh, titanium bone grafts, and genex® bone grafts or hydrogels.

[0219] In some embodiments, the osteoconductive matrix comprises an osteoinductive agent and, optionally, a structural support. The osteoinductive agent can be any agent that promotes bone formation. In some embodiments, the osteoinductive agent is an allograft, autograft, demineralized bone, or periodontal ligament cells.

[0220] C. Combination Therapy When practicing the methods of the present invention, the pharmaceutical compositions can be used alone or in combination with other therapeutic or diagnostic agents. Further, the medical devices described herein include using the compounds of Formula I alone or in combination with other therapeutic or diagnostic agents. Additional drugs used in the combination protocols of the present invention may be administered separately or one or more of the drugs used in the combination protocol may be administered together, such as in a mixture. When administering one or more agents separately, the timing and schedule of administration of each agent can be different. The other therapeutic or diagnostic agents may be administered simultaneously with, separately from, or at different times from the compounds of the present invention.

[0221] In some embodiments, the compounds or compositions described herein (e.g., compounds or compositions of Formula I) are administered in combination with one or more other therapeutic agents. When the compounds of the invention are combined with another agent, the two may be administered simultaneously or separately. Simultaneous administration means that within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours after administering the compound of the invention, and within 1 to 7 days (e.g., 1, 2, 3, 4, 5, 6, or 7 days), within 1 to 4 weeks (e.g., 1, 2, 3, or 4 weeks), or within 1 to 18 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months), the other agent is administered. Simultaneous administration also includes administering the other agent and the compound of the invention simultaneously, substantially simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other, or on the same day, in the same week, or in the same month), or in any order in sequence. In some embodiments, simultaneous administration involves administering another agent (e.g., an antiresorptive agent) for a period of time (e.g., several weeks, months, or years), then administering the compound or composition of Formula I for a period of time (e.g., several days, weeks, months, or years), and then administering the other agent (e.g., an antiresorptive agent) alone or in combination with the compound or composition of Formula I. In some embodiments, the other agents and compounds of the invention are each administered once, twice, three times, or more times a day, and can provide a preferred dosage level per day.

[0222] In some embodiments, simultaneous administration can be achieved by preparing a simultaneous formulation, i.e., a single pharmaceutical composition containing both the compound of the invention and a second therapeutic agent (e.g., an antiresorptive agent). In other embodiments, the compound of the invention and the second therapeutic agent are formulated separately.

[0223] One or more other therapeutic agents can be delivered by any suitable means. The pharmaceutical formulation is preferably in unit dosage form. In such form, the formulation is subdivided into unit doses containing an appropriate amount of the bone resorption inhibitor and / or the compound of the present invention. The unit dosage form can be a packaged formulation, and the package can include individual amounts of the formulation such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, patch, or troche itself, or an appropriate number of any of these in packaged form.

[0224] One or more other therapeutic agents may be present in any suitable amount and can be determined by various factors including, but not limited to, the weight and age of the subject, the state of the disease, etc. Suitable dosage ranges for one or more other therapeutic agents in combination with the compound or composition of the present invention include from about 0.0001 μg to about 10,000 mg, from about 0.0001 μg to about 1000 mg, from about 0.0001 μg to about 500 mg, from about 0.0001 μg to about 1000 μg, from 0.1 μg to about 10,000 mg, from about 0.1 μg to about 1000 mg, from about 0.1 μg to about 500 mg, from about 0.1 μg to about 1000 μg, from about 1 μg to about 1000 mg, from about 1 μg to about 500 mg, from about 1 μg to about 50 mg, from about 1 μg to about 1000 μg, from about 10 μg to about 1000 mg, from about 10 μg to about 500 mg, from about 10 μg to about 50 mg, from about 0.1 mg to about 10,000 mg, from about 1 mg to about 1000 mg, from about 10 mg to about 750 mg, from about 25 mg to about 500 mg, or from about 50 mg to about 250 mg. Suitable dosages for one or more other therapeutic agents in combination with the compound or composition of the present invention include about 0.01, 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1250, 1500, 1750, or 2000 mg.

[0225] One or more other therapeutic agents and the compounds or compositions of the present invention may be present in the compositions of the present invention at any suitable weight ratio, such as from about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:10 to about 10:1, about 1:5 to about 5:1 (w / w), or about 1:1 (w / w). Other dosages and dosage ratios of the bone resorption inhibitors and compounds of the present invention are suitable for the compositions and methods of the present invention.

[0226] The compositions may also include other compatible therapeutic agents. The compounds described herein may be used in combination with each other, with other active agents, or with adjuvants that are not effective alone but may contribute to the effectiveness of the active agents.

[0227] In some embodiments, the compounds or compositions described herein (e.g., compounds or compositions of Formula I, Formula Ia, Formula Ib, Formula Ic, or Formula Id described herein) are administered to an individual being treated according to the methods of the present invention, in combination with, or sequentially to, a bone resorption inhibitor. Bone resorption inhibitors include agents that slow or block bone resorption. Administration of the compounds or compositions described herein and the bone resorption inhibitor may promote local and / or systemic bone growth. In some embodiments, administration of the compounds or compositions described herein and the bone resorption inhibitor promotes systemic bone growth. Bone growth can be achieved by an increase in bone mineral content, an increase in bone density, and / or the growth of new bone. In other embodiments, local application of the compounds or compositions described herein and the bone resorption inhibitor achieves systemic bone growth.

[0228] Bone resorption inhibitors useful in the method of the present invention include, but are not limited to, denosumab, Prolia (registered trademark), RankL inhibitor, bisphosphonates (e.g., Fosamax (registered trademark), denosumab, Prolia (registered trademark), Actonel (registered trademark), Reclast (registered trademark), alendronic acid, Bonviva (trademark), Zometa (trademark), olpadronate, neridronate, Skelid (registered trademark), Bonefos (registered trademark)), selective estrogen receptor modulators (SERMs) or analogs (e.g., Evista (registered trademark)), calcitonin, calcitonin analogs (e.g., Miacalcic (registered trademark)), parathyroid hormone, calcium degrading agents, calcium mimetics (e.g., cinacalcet), statins, anabolic steroids, lanthanum and strontium salts, and sodium fluoride, vitamin D or vitamin D analogs, cathepsin K (CatK) inhibitors, prostaglandin inhibitors, or phosphodiesterase inhibitors (type E).

[0229] In some embodiments, the bone resorption inhibitor is denosumab.

[0230] The bisphosphonates useful in the method of the present invention can be any suitable bisphosphonates. In some embodiments, the bisphosphonates are nitrogen-containing compounds such as pamidronic acid (APD, Aredia®), neridronate, olpadronate, alendronic acid (Fosamax®), ibandronic acid (Bonviva™), risedronic acid (Actonel®), and zoledronic acid (Zometa™). In other embodiments, the bisphosphonates are non-nitrogen-containing compounds such as etidronic acid (Didronel®), clodronic acid (Bonefos®, Loron®), and tiludronic acid (Skelid®). Those skilled in the art will understand that other bisphosphonates are useful in the present invention.

[0231] The SERMs useful in the method of the present invention can be any suitable SERMs. In some embodiments, the SERMs can be clomiphene, raloxifene, tamoxifen, toremifene, bazedoxifene, lasofoxifene, or ormeloxifene. Those skilled in the art will understand that other SERMs are useful in the present invention.

[0232] The bone resorption inhibitor can also be any suitable calcitonin analog or cathepsin K inhibitor. In some embodiments, the calcitonin analogs useful in the method of the present invention include, but are not limited to, Miacalcic®. Those skilled in the art will understand that other calcitonin analogs are useful in the present invention.

[0233] The vitamin D analogs useful in the method of the present invention can be any suitable vitamin D analog. In some embodiments, the vitamin D analogs useful in the method of the present invention include, but are not limited to, vitamin D1 (a molecular compound of ergocalciferol and lumisterol, 1:1), vitamin D2 (ergocalciferol or calciferol), vitamin D3 (cholecalciferol), vitamin D4 (22-dihydroergocalciferol), and vitamin D5 (sitocalciferol). Those skilled in the art will understand that other vitamin D analogs are useful in the present invention.

[0234] The RankL inhibitors useful in the present invention include any compound that inhibits RankL activity. For example, the RankL inhibitors include, but are not limited to, denosumab or Prolia® (Prolia), a human monoclonal antibody. Those skilled in the art will understand that other RankL inhibitors are useful in the present invention.

[0235] In some embodiments, the individuals treated according to the method of the present invention are administered the compounds or compositions described herein (e.g., the compounds or compositions of formula I, formula Ia, formula Ib, formula Ic, or formula Id described herein) in combination with, or sequentially with, an osteoanabolic agent. Osteoanabolic agents include, but are not limited to, parathyroid hormone (PTH) or an analog thereof, a sclerostin inhibitor, a bone morphogenetic protein (BMP) or a BMP agonist, a population of bone marrow stem cells, or a population of mesenchymal stem cells.

[0236] In some embodiments, the bone anabolic agent is parathyroid hormone (PTH) or an analogue thereof (e.g., teriparatide (Forteo®)). In some embodiments, the bone anabolic agent is a sclerostin antibody (Mab) inhibitor. In some embodiments, the BMP is selected from the group consisting of BMP2, BMP7, and BMP4. In some embodiments, the BMP agonist is a compound described in Vrijens K, et al. PLoS One. 2013;8(3):e59045, the content of which is incorporated herein by reference. In some embodiments, the bone anabolic agent is a population of bone marrow stem cells. In some embodiments, the bone anabolic agent is a population of mesenchymal stem cells.

[0237] X. Medical Devices In some embodiments, the invention is a medical device formed from a structural support, wherein the implantable portion of the structural support is adapted to be permanently implanted within a subject, the implantable portion adheres to bone, and the structural support carries at least a partial coating comprising the compound of claim 1 (comprising a compound of formula I as described herein (e.g., in section III above)). In some embodiments, the medical device is an orthopedic or periodontal medical device.

[0238] Another aspect of the invention is directed to medical implants. Such medical devices and implants include, for example, bone forming devices and methods of using the same for repairing endochondral bone and osteochondral defects, as taught in U.S. Patent Application Publication No. 20060177475 to David Rueger et al. (issued August 10, 2006), the subject matter of which is incorporated herein by reference, and as disclosed in U.S. Patent Nos. 6,190,880, 5,344,654, 5,324,819, 5,468,845, 6,949,251, 6,426,332, and 5,656,593, and U.S. Patent Application Publications Nos. 2002 / 0169122, 2002 / 0187104, 2006 / 0252724, and 2007 / 0172479.

[0239] These medical devices typically provide a structural support having a transplantable portion that is preferentially adapted to mechanically engage bone and / or cartilage, for example, as taught in U.S. Patent Application Publication No. 2006 / 0178752 to Joseph Vaccarino III, et al. (issued Aug. 10, 2006), the subject matter of which is incorporated herein by reference. These bone implants preferably contain an active agent in at least a portion thereof. As shown in U.S. Patent Application Publication No. 2006 / 0188542 to John Dennis Bobyn, et al. (issued Aug. 24, 2006), the subject matter of which is incorporated herein by reference, the active agent is preferably formulated to be locally deliverable to bone adjacent the implant in a sustained release or at least biphasic release scheme. In the latter case, a first phase rapidly releases a first amount of the active agent and a second and subsequent phases gradually release a second amount of the active agent, thereby regulating bone formation stimulated by the active agent.

[0240] Medical devices such as bone implants feature a transplantable portion having the compound or composition of the present invention (e.g., a compound or composition of formula I) and promote more rapid and complete bone formation in situ. The transplantable portion of the medical device may desirably be at least partially or completely covered or impregnated with the compound or composition of the present invention. In some embodiments, the medical device is externally coated with the compound or composition described herein. In some embodiments, the external coating completely coats the transplantable portion of the structural support. In some embodiments, the structural support (e.g., a matrix or scaffold) contains the compound or composition described herein within the support, i.e., internally. In some embodiments, the structural support (e.g., a matrix or scaffold) includes an external coating of the compound or composition described herein and also contains the compound or composition within the support, i.e., internally.

[0241] The medical devices of the present invention include pins, rods, screws, plates, and orthopedic implants or dental implants. In some embodiments, the medical devices are made from materials including metals, polymers, ceramics, or combinations thereof. Metals useful for manufacturing the medical devices of the present invention include, but are not limited to, cobalt, chromium, chromium, stainless steel, titanium, titanium alloys, tantalum, Trabecular Metal (trademark). Polymers useful for manufacturing the medical devices of the present invention include, but are not limited to, ultra-high molecular weight polyethylene or high density polyethylene. In some embodiments, carbon fibers are combined with polyethylene. Additional useful polymers are described below. Ceramics useful for manufacturing the medical devices of the present invention include, but are not limited to, aluminum oxide, calcium phosphate, hydroxyapatite, zirconium oxide, silicon oxide.

[0242] In some other embodiments, the implantable portion of the structural support includes an osteoconductive matrix. The matrix material may promote bone growth. This may be desirable for materials such as teeth and bone grafts. Alternatively, if the implantable piece is load-bearing and formed of, for example, stainless steel, these implantable pieces are considered desirable when formed with a coating of the compounds or compositions of the present invention. In that case, it is also desirable to provide a separate matrix material that helps to form new bone growth.

[0243] In some embodiments, the matrix is composed of particles of a porous material. The pores are preferably of a size that allows the migration of progenitor cells into the matrix and their subsequent differentiation and proliferation. In some embodiments, the pore diameter of the matrix is at least 5 μm, for example, at least 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 115, 120, 125, 150, 175, 200, 250, 300, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, or 2000 μm. In some embodiments, the scaffold or matrix consists of a mesh structure, a foam structure, a sponge structure, or a fiber structure.

[0244] The scaffolds or matrices for use in the devices described herein may include synthetic and / or biological materials. In some embodiments, the scaffold or matrix includes naturally occurring polymers, synthetic biodegradable polymers, synthetic non-biodegradable polymers, bioceramics, bioglasses, bioactive glasses, biocomposites, or combinations thereof. Natural polymers and synthetic polymers, bioceramics, and bioglasses for use in scaffolds are known in the art. See, for example, Dhandayuthapani et al., International Journal of Polymer Science, volume 2011, article ID 290602 (2011), which is incorporated herein by reference. Natural polymers include, but are not limited to, proteins (e.g., silk, collagen, gelatin, fibrinogen, elastin, keratin, actin, and myosin), polysaccharides (e.g., cellulose, amylose, dextran, chitin, chitosan, and glycosaminoglycans), and polynucleotides (e.g., DNA and RNA). Synthetic polymers include, but are not limited to, PLA, PGA, PLLA, PLGA, PCL, PLDLA, PDS, PGCL, PEA, PCA, PDLLA, PEU, and PBT. Bioceramics and bioglasses include, but are not limited to, HAP, TCP, CP ceramics, BCP, and TCP. In some embodiments, the scaffold or matrix is a hydrogel scaffold, a fibrous scaffold, a microsphere scaffold, a polymer-bioceramic composite scaffold, or a cell-free scaffold.

[0245] In some embodiments, suitable matrices include, for example, composite biomaterials having a sponge-like structure such as those containing phosphoholine and / or collagen, as taught by U.S. Patent Application Publication No. 2006 / 0188544 to Takashi Saito, published Aug. 24, 2006, which is incorporated herein by reference. Such coatings include, for example, monolayer and multilayer coatings as taught by U.S. Patent Application Publication Nos. 2006 / 0204542 to Zongtao Zhang et al., published Sep. 14, 2006, which are incorporated herein by reference, and those described in U.S. Pat. Nos. 6,949,251, 5,298,852, 5,939,039, and 7,189,263, and may be made by conventional methods including those taught therein.

[0246] In some embodiments, the matrix is an osteoconductive matrix. In some embodiments, the osteoconductive matrix includes an osteoinductive agent such as an allograft, autograft, demineralized bone or periodontal ligament cells, or combinations thereof. In some other embodiments, the osteoconductive matrix can be a calcium salt, calcium sulfate, biphasic calcium phosphate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-derived hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, plaster of paris, phosphoholine, borosilicate, biocompatible ceramic, calcium phosphate ceramic, polytetrafluoroethylene, sulfate, borosilicate, bioactive glass, Mastergraft™ (Mastergraft) variants, Vitoss™ (Vitoss) variants, cement hydrogel, or combinations thereof. One of ordinary skill in the art will understand that other osteoconductive matrices and osteoinductive agents are useful in the present invention.

[0247] In some embodiments, the medical devices described herein include both a compound of Formula I and an additional therapeutic agent. Suitable additional therapeutic agents include the combinations discussed in Section IX.C herein. For example, the medical device may include a compound of Formula I in combination with an osteoanabolic agent. In some embodiments, the medical devices described herein include a compound of Formula I in combination with a bone morphogenetic protein (BMP) or a BMP agonist. In some embodiments, the BMP is selected from the group consisting of BMP2, BMP7, BMP4. In some embodiments, the BMP agonist is a compound described in Vrijens K, et al. PLoS One. 2013;8(3):e59045, the contents of which are incorporated herein by reference.

[0248] XI. Assays for Identifying Compounds for Treating Osteopenia Compounds useful in the methods of the present invention can be identified via a variety of methods known to those of skill in the art. Some exemplary methods for identifying such antagonists are described herein, including cell-based in vitro techniques (Journal of Bone and Mineral Research 2006, 21(11), 1738-1749). A general method for identifying a compound involves assessing the effect of an antagonist candidate on bone formation under controlled conditions. Preferably, bone formation is determined using dual energy x-ray absorptiometry (DEXA) on a living animal or microCT on an ex vivo sample. Preferred animals include rodents, and more preferably primates. The femur, tibia, and vertebrae are particularly useful subjects for such studies.

[0249] Briefly, the test animals are treated with a predetermined dose of the candidate compound. The control animals are treated with a control solution, preferably a non-irritating buffer or other carrier. When the candidate compound is delivered with a carrier, the control solution is ideally a carrier without the candidate compound. Multiple administrations of the candidate compound can preferably be applied to the test animals according to a predetermined dosing schedule. The dosing schedule can be, for example, over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 days or more, over several weeks, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more, or over other periods of several months, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 months or more.

[0250] In an exemplary embodiment, local in situ administration of the candidate compound may be performed on the test animals, and the control animals are given an equal amount of the control solution without the candidate compound. The appropriate dosage will depend on the nature of the particular candidate compound being tested. Note that as an example, systemic administration (e.g., by oral or injection, e.g., intravenous, subcutaneous, or intramuscular) may also be used in dosing. The dosing performed by aerosol inhalation, eye drops, or oral ingestion must be in an amount sufficient to produce blood levels of the candidate compound similar to those achieved using systemic injection. The amount of the candidate compound that can be delivered by aerosol inhalation, eye drops, or oral ingestion to achieve these levels depends on the nature of the inhibitor used and can be determined by routine experimentation.

[0251] Once the dosing schedule is complete, both the test animals and the control animals are examined to determine the amount of bone formation present. This can be accomplished by any suitable method, but is preferably performed on live animals to analyze bone mineral content. Methods for micro-CT examination of animal bones are well known in the art. Candidate compounds suitable for use in promoting bone formation are identified by noting a significant increase in bone formation in the test animals as compared to the control animals. In some embodiments, the amount of bone formation in the test bone of the test animals is at least 0.5%, 1%, 3%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 22%, 24%, 26%, 28%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% or more compared to the equivalent bone of the control animals, and the candidate compound is identified as being suitable for use in promoting bone formation. In some embodiments, bone formation increases by at least 3%, at least 5%, at least 7%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 30%, at least 40%, or at least 50% or more compared to the control animals. Optionally, the level of bone formation can be calculated by determining the amount of bone formation present in each animal. The calculation can be performed by constructing a three-dimensional image of the bone formation and calculating the volume from the image, for example with the aid of histomorphometry.

[0252] Examples of the above molecular modeling systems consist of the CHARMm program and the QUANTA program (Polygen Corporation, Waltham, Massachusetts). CHARMm performs energy minimization and molecular dynamics functions. QUANTA performs molecular structure construction, graphic modeling, and analysis. QUANTA enables the interactive construction, modification, visualization, and analysis of molecular interactions.

[0253] Compounds may be identified using a process known as computer or molecular modeling. This enables visualization of the three-dimensional atomic structure of the selected molecule and rational design of new compounds that interact with the molecule. The three-dimensional structure is typically determined from data obtained by X-ray crystallography or NMR imaging of the selected molecule. Molecular dynamics requires force field data. A computer graphics system predicts how a new compound will link to a target molecule and experimentally manipulates the structures of the compound and the target molecule to achieve complete binding specificity. Predicting how the molecule-compound interaction will change when small changes are made to one or both requires molecular mechanics software and computers specialized for calculations, usually combined with a user-friendly menu-based interface between the molecular design program and the user.

[0254] XII. Specific Embodiments of the Present Disclosure Embodiment 1. A compound according to the following formula I:

[0255]

Chemical formula

[0256] or a salt, hydrate, prodrug, or isomer thereof, wherein X is selected from CR 3b and N, where N is optionally oxidized to the corresponding N-oxide, Y is selected from CR 3c and N, where N is optionally oxidized to the corresponding N-oxide, Z is selected from CR 3d and N, where N is optionally oxidized to the corresponding N-oxide, provided that at least one of X, Y, and Z is N or the corresponding N-oxide, A is

[0257]

Chemical formula

[0258] and is R N selected from the group consisting of heterocyclyl and heteroaryl, wherein the heterocyclyl moiety is selected from monocyclic, fused bicyclic, and bridged cyclic heterocyclyls, the monocyclic heterocyclyl contains 4 to 7 ring members, the fused bicyclic heterocyclyl and the bridged bicyclic heterocyclyl contain 7 to 10 ring members, each heterocyclyl moiety has 1 to 3 heteroatoms as ring members selected from nitrogen (N), oxygen (O), and sulfur (S), each heterocyclyl moiety contains at least one nitrogen atom as a ring member, and optionally 1 to 3 R 6 moieties are substituted, wherein the heteroaryl moiety contains 5 to 10 ring members, at least one ring member is a nitrogen atom, and optionally 1 to 3 R 6 moieties are substituted, R 2 、R 3b 、R 3c 、and R 3d each of which is independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-OH, -O-C 1-6 alkyl-OH, C 3-6 cycloalkyl-C 1-4 alkoxy, and -OH, R 6 is selected from the group consisting of a hydroxyl group (-OH), C 1-3 alkyl, C 1-3 alkyl-OH, -O-C 1-3 alkyl, C 3-4 heteroalkyl, C 1-3 haloalkyl, -O-C 1-3 haloalkyl, halogen, and oxo, a compound.

[0259] Embodiment 2. A compound according to Embodiment 1, having the formula Ia, Ib, Ic, or Id:

[0260]

Chemical formula

[0261]

[0262] Embodiment 3. R 2 is selected from the group consisting of hydrogen (H), halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy, and is a compound according to Embodiment 1 or 2.

[0263] Embodiment 4. R 2 is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy, and is a compound according to Embodiment 1 or 2.

[0264] Embodiment 5. R 2 is C 1-6 alkyl, or C 1-6 haloalkyl, and is a compound according to Embodiment 4.

[0265] Embodiment 6. R 2 is CH3 or CF3, and is a compound according to Embodiment 5.

[0266] Embodiment 7. R 2 is CH3, and is a compound according to Embodiment 6.

[0267] Embodiment 8. R 2 is CF3, and is a compound according to Embodiment 6. ​

[0268] Embodiment 9. R 3b 、R 3c 、and R 3d each, when present, is independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, the compound according to any one of Embodiments 1 to 8.

[0269] Embodiment 10. R 3b 、R 3c 、and R 3d each, when present, is independently selected from the group consisting of H, halogen, and C 1-6 alkoxy, the compound according to Embodiment 9.

[0270] Embodiment 11. R 3b 、R 3c 、and R 3d each, when present, is independently selected from the group consisting of H, F, and methoxy, the compound according to Embodiment 10.

[0271] Embodiment 12. R 3c is, when present, methoxy, the compound according to any one of Embodiments 1 to 8.

[0272] Embodiment 13. R N is heterocyclyl or heteroaryl, the compound according to any one of Embodiments 1 to 11.

[0273] Embodiment 14. R N is heterocyclyl, the compound according to Embodiment 13.

[0274] Embodiment 15. R N is monocyclic heterocyclyl, the compound according to Embodiment 14.

[0275] Embodiment 16. R N is

[0276]

Chemical formula

[0277] the compound according to Embodiment 13, which is

[0278] Embodiment 18. R 2 is H, or C 1-6 haloalkyl, R 3c when present, is C 1-6 alkoxy, R 3b or R 3d when present, is H or halogen, and R N is

[0279]

Chemical formula

[0280] the compound according to Embodiment 17, which is

[0281] Embodiment 19. R 2 is C 1-6 alkyl, or C 1-6 haloalkyl, R 3b when present, is H or halogen, R 3c is C 1-6 alkoxy, and R N is heterocyclyl or heteroaryl, the compound according to Embodiment 2

[0282] Embodiment 20. R 2 is C 1-6is a haloalkyl, R 3b when present, is H or halogen, R 3c is C 1-6 is an alkoxy, and R N is

[0283]

Chemical formula

[0284] is the compound according to Embodiment 19.

[0285] Embodiment 21. R 2 is CF3, and R 3c is methoxy, is the compound according to Embodiment 20.

[0286] Embodiment 22.

[0287]

Chemical formula

[0288] or a salt, hydrate, or prodrug thereof, is the compound according to Embodiment 1.

[0289] Embodiment 23. The formate salt of the compound according to any one of Embodiments 1 to 22.

[0290] Embodiment 24. The sulfate salt of the compound according to any one of Embodiments 1 to 22.

[0291] Embodiment 25. The citrate salt of the compound according to any one of Embodiments 1 to 22.

[0292] Embodiment 26. The hydrochloride salt of the compound according to any one of Embodiments 1 to 22.

[0293] Embodiment 27. A prodrug of the compound according to any one of Embodiments 1 to 22.

[0294] Embodiment 28. A pharmaceutical composition comprising the compound according to any one of Embodiments 1 to 27 and a pharmaceutically acceptable excipient.

[0295] Embodiment 29. A method for promoting bone formation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of Embodiments 1 to 28, thereby promoting bone formation in the subject.

[0296] Embodiment 30. The method according to Embodiment 29, wherein the bone formation is promoted at a surgical site of an injury or a local condition.

[0297] Embodiment 31. The method according to Embodiment 30, wherein the bone formation is promoted at a surgical site selected from the group consisting of a fracture and weakened bone.

[0298] Embodiment 32. The method according to Embodiment 30, wherein the subject requires spinal fusion, arthrodesis, or synthetic bone grafts or implants in orthopedics or periodontics.

[0299] Embodiment 33. The method according to Embodiment 29, wherein the bone formation is systemic.

[0300] Embodiment 34. The method according to any one of Embodiments 29 to 33, wherein the subject has a low bone mass / density condition, a fracture, or periodontal disease.

[0301] Embodiment 35. The method according to embodiment 34, wherein the low bone mass state is selected from osteoporosis, osteopenia, osteogenesis imperfecta (OI), osteoporosis - pseudoglioma syndrome (OPPG), and secondary low bone mass state.

[0302] Embodiment 36. The method according to embodiment 35, wherein the low bone mass state is selected from the group consisting of osteoporosis, osteopenia, and osteoporosis - pseudoglioma syndrome (OPPG).

[0303] Embodiment 37. The method according to any one of embodiments 29 - 36, further comprising administering a bone - conductive matrix to the subject.

[0304] Embodiment 38. The method according to embodiment 37, wherein the bone - conductive matrix comprises an osteoinductive agent selected from the group consisting of bone allografts, bone autografts, and periodontal ligament cells.

[0305] Embodiment 39. The method according to embodiment 37, wherein the bone - conductive matrix comprises a calcium salt, calcium sulfate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral - derived hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, plaster of paris, phosphopholine, borosilicate, biocompatible ceramic, calcium phosphate ceramic, demineralized bone matrix, biphasic calcium phosphate, biocomposite, tantalum, titanium, polytetrafluoroethylene, sulfate, hydrogel, bio - glass, or a combination thereof.

[0306] Embodiment 40. The osteoconductive matrix is the method according to embodiment 37, comprising calcium salts, calcium sulfate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-derived hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, plaster of Paris, phosphopholine, borosilicate, biocompatible ceramic, calcium phosphate ceramic, demineralized bone matrix, biphasic calcium phosphate, biocomposite, tantalum, titanium, polytetrafluoroethylene, sulfate, or hydrogel.

[0307] Embodiment 41. The method according to any one of embodiments 29 to 40, wherein the compound is administered continuously or in combination with an osteoclast inhibitor.

[0308] Embodiment 42. The method according to embodiment 41, wherein the compound is administered to a patient who has been treated with the osteoclast inhibitor or has previously been treated with an absorption inhibitor.

[0309] Embodiment 43. The method according to embodiment 41, wherein the osteoclast inhibitor is selected from the group consisting of denosumab, Prolia (registered trademark), RankL inhibitor, bisphosphonate, selective estrogen receptor modulator (SERM), calcitonin, calcitonin analog, vitamin D, vitamin D analog, and cathepsin K inhibitor.

[0310] Embodiment 44. The method according to embodiment 41, wherein the osteoclast inhibitor is denosumab.

[0311] Embodiment 45. The method according to embodiment 41, wherein the osteoclast inhibitor is administered systemically.

[0312] Embodiment 46. The method according to embodiment 41, wherein the osteoclast inhibitor is administered locally.

[0313] Embodiment 47. The method according to any one of Embodiments 29 to 46, further comprising administering an osteoanabolic agent.

[0314] Embodiment 48. A medical device comprising a structural support, wherein the implantable portion of the structural support is adapted to be permanently implanted within a subject, the implantable portion adheres to bone, and the structural support carries at least a partial outer coating comprising the compound according to any one of Embodiments 1 to 28.

[0315] Embodiment 49. A method for treating bone loss in a subject in need thereof, by administering to the subject a therapeutically effective amount of the compound according to any one of Embodiments 1 to 28 continuously or in combination with an antiresorptive agent to treat the bone loss in the subject.

Examples

[0316] XIII. Examples Example 1: 4-(2-(1-(Trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride

[0317]

Chemical formula

[0318] Into a round-bottomed flask were placed 3-bromo-2-trifluoromethylpyridine (500 mg, 2.21 mmol) and 3-amino-4-chloropyridine (298 mg, 2.32 mmol). The flask was flushed with Ar and PhMe (5 mL) was added. To the resulting solution were added Cs2CO3 (866 mg, 2.65 mmol), X-Phos (80 mg, 0.16 mmol), and Pd(OAc)2 (25 mg, 0.11 mmol) in this order. The flask was equipped with a Liebig condenser, the mixture was degassed, and stirred at 110 °C overnight under Ar. The mixture was allowed to cool, diluted with EtOAc, washed once with water and once with brine, dried (MgSO4), and evaporated. Flash chromatography on SiO2 (40 g) using 30 - 100% EtOAc - hexane (gradient elution) gave 4-chloro-N-(2-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine (314 mg, 52%).

[0319] Into a flask was placed 4-chloro-N-(2-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine (314 mg, 1.15 mmol), DMA (10 mL) was added, followed by K2CO3 (317 mg, 2.30 mmol). Next, the mixture was degassed and placed under an Ar atmosphere. t-Bu3P-HBF4 (85 mg, 0.30 mmol) was added, followed by Pd(OAc)2 (26 mg, 0.12 mmol), the mixture was degassed again, placed under Ar, and heated at 130 °C overnight. Next, an additional portion of t-Bu3P-HBF4 (85 mg, 0.30 mmol) and Pd(OAc)2 (26 mg, 0.12 mmol) was reinjected into the mixture, and stirred at 130 °C again overnight. The mixture was allowed to cool, diluted with EtOAc, washed once with water and once with brine, dried (MgSO4), and evaporated. Flash chromatography on SiO2 (24 g) using 60 - 100% EtOAc - hexane gave 1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c’]dipyridine (100 mg, 37%).

[0320] To a stirred solution of 1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridine (100 mg, 0.420 mmol) in DMF (5 mL) was added 4-(2-chloroethyl)morpholine HCl (94.1 mg, 0.510 mmol). NaH (60% in oil, 100 mg, 2.52 mmol) was added all at once, the flask was rinsed with Ar, and the mixture was heated at 60 °C overnight with stirring. The mixture was cooled to room temperature, diluted with EtOAc, washed once with water and once with brine, dried (MgSO4), and evaporated. Flash chromatography of the residue on SiO2 (12 g) using 50 - 100% EtOAc - hexane, followed by 50% MeOH - EtOAc gave the compound 4-(2-(1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridin-9-yl)ethyl)morpholine (14 mg, 10%), and the oxidized compound 9-(2-morpholinoethyl)-8-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridine 2-oxide (10 mg, 6%).

[0321] Characterization of 4-(2-(1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridin-9-yl)ethyl)morpholine: 1 H NMR (CDCl3, 400 MHz) δ 9.16 (s, 1H), 8.63 (d, 1H, J = 5.2 Hz), 8.59 (d, 1H, J = 4.8 Hz), 8.25 (d, 1H, J = 5.2 Hz), 8.04 (dd, 1H, J = 5.2, 0.8 Hz), 4.74 (t, 2H, J = 7.6 Hz), 3.69 (t, 4H, J = 4.8 Hz), 2.79 (t, 2H, J = 7.6 Hz), 2.54 (t, 4H, J = 4.8 Hz).

[0322] HCl (2 M in Et2O, 10 equiv) was added via syringe to a stirred solution of 4-(2-(1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridin-9-yl)ethyl)morpholine, or the oxidized compound 9-(2-morpholinoethyl)-8-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridine 2-oxide in HCl (1 mL). After stirring was continued for 5 minutes, the volatiles were removed in vacuo. The residue was purified by trituration using 80% CH2Cl2 - hexane to afford 4-(2-(1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride, or the oxidized compound 9-(2-morpholinoethyl)-8-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridine 2-oxide hydrochloride in quantitative yield.

[0323] Characterization of 4-(2-(1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride: 1 H NMR (DMSO―d6, 400 MHz) δ 12.00 (s, 1H), 9.88 (s, 1H), 8.88 (d, 1H, J = 4.8 Hz), 8.80 (s, 2H), 8.74 (d, 1H, J = 4.8 Hz), 5.15 (t, 2H, J = 8.4 Hz), 4.04 (m, 2H), 3.86 (m, 2H), 3.59 (m, 2H), 3.50 (m, 2H), 3.23 (m, 2H). LCMS m / z 351.2 ([M+H] + , C 17 H 18 F3N4O requires 351.2).

[0324] Example 2: 9-(2-Morpholinoethyl)-8-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridine 2-oxide hydrochloride

[0325]

Chem.

[0326] Free base: 1 1H NMR (CDCl3, 400 MHz) δ 9.94 (s, 1H), 8.54 (d, 1H, J = 5.2 Hz), 8.03 (d, 1H, J = 5.2 Hz), 7.24 (d, 1H, J = 7.2 Hz), 6.93 (d, 1H, J = 7.2 Hz), 4.27 (t, 2H, J = 6.4 Hz), 3.68 (t, 4H, J = 4.4 Hz), 2.78 (t, 2H, J = 6.4 Hz), 2.54 (t, 4H, J = 4.4 Hz).

[0327] HCl salt: 1 1H NMR (DMSO–d6, 400 MHz) δ 12.84 (s, 1H), 10.24 (bs, 1H), 8.48 (d, 1H, J = 5.2 Hz), 8.43 (d, 1H, J = 5.2 Hz), 7.59 (d, 1H, J = 7.2 Hz), 7.28 (d, 1H, J = 7.2 Hz), 4.51 (m, 2H), 3.99 (m, 2H), 3.62 (m, 6H), 3.17 (m, 2H). LCMS m / z 367.2 ([M+H] + , C 17 H 18 F3N4O2requires 367.2).

[0328] Example 3: 4-(2-(2-Methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c’]dipyridin-9-yl)ethyl)morpholine hydrochloride

[0329] [Chemical formula]

[0330] To a solution of 6-methoxypyridin-2-amine (5.0 g, 40 mmol) in CHCl3 (150 mL) at 0 °C was added NCS (5.35 g, 40 mmol) portionwise. The reaction solution was stirred at room temperature for 3 days, then diluted with CH2Cl2, washed with water, NaHCO3 (saturated), brine, dried over MgSO4, and concentrated. The product was purified by silica chromatography using a gradient of 90% hexane / 10% EtOAc to 50% hexane / 50% EtOAc to give 3-chloro-6-methoxypyridin-2-amine (4.8 g, 75%).

[0331] To a dry tube were added 3-bromo-2-(trifluoromethyl)pyridine (500 mg, 2.2 mmol), cesium carbonate (866 mg, 2.7 mmol), X-Phos (80 mg, 0.16 mmol), palladium(II) acetate (Pd(OAc)2) (25 mg, 0.1 mmol), and 3-chloro-6-methoxypyridin-2-amine (370 mg, 2.3 mmol). The reaction solution was diluted with toluene (5 mL), degassed, stirred at 120 °C overnight, then cooled to room temperature, diluted with ethyl acetate (EtOAc), washed with water, brine, dried over magnesium sulfate (MgSO4), and concentrated. The product was purified by silica chromatography using a gradient of 80% hexane / 20% EtOAc to 100% EtOAc to give 3-chloro-6-methoxy-N-(2-(trifluoromethyl)pyridin-3-yl)pyridin-2-amine (588 mg, 88%).

[0332] To a drying tube, 3-chloro-6-methoxy-N-(2-(trifluoromethyl)pyridin-3-yl)pyridine-2-amine (588 mg, 1.49 mmol), potassium carbonate (536 mg, 3.9 mmol), and dimethylacetamide (DMA) (20 mL) were added. The reaction mixture was degassed, and tert-butylphosphonium tetrafluoroborate ((t-Bu3)P HBF4) (113 mg, 0.39 mmol) and Pd(OAc)2 (45 mg, 0.19 mmol) were introduced. The reaction mixture was stirred at 120 °C overnight. An additional aliquot of the catalyst was added, and the reaction mixture was stirred at 120 °C overnight, then cooled to room temperature, diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated. The product was purified by silica chromatography using a gradient of 85% hexane / 15% EtOAc to 50% hexane / 50% EtOAc. The product was re-purified by reverse-phase chromatography on a C 18 column. Since the dichloro substance was still present, the product was further re-purified by HPLC on a C 18 column using a gradient of 10% ACN / 90% water (0.1% FA) to 90% ACN / 10% water (0.1% FA) to obtain 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c’]dipyridine (47 mg, 9%).

[0333] Characterization of 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c’]dipyridine: 1 H NMR (CDCl3, 400 MHz) δ 8.47 (d, 1H, J = 4.8 Hz), 8.23 (dd, 1H, J = 8.4, 0.8 Hz), 7.98 (d, 1H, J = 4.8 Hz), 6.74 (dd, 1H, J = 8.4, 0.8 Hz), 4.76 (t, 2H, J = 7.6 Hz), 4.07 (s, 3H), 3.69 (t, 4H, J = 4.8 Hz), 2.77 (t, 2H, J = 7.6 Hz), 2.60 (t, 4H, J = 4.4 Hz).

[0334] To a solution of 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine (47 mg, 0.18 mmol) in DMF (3 ml) was added 4-(2-chloroethyl)morpholine hydrochloride (66 mg, 0.35 mmol), followed by sodium hydride (60% in oil, 42 mg, 1.1 mmol). The solution was stirred at 60 °C overnight, then cooled to room temperature, quenched with NaHCO3 (saturated), and diluted with EtOAc. The crude product was washed with NaHCO3 (saturated), brine, dried over MgSO4, and concentrated. The product was purified by silica chromatography using a gradient from 70% hexane / 30% EtOAc to 100% EtOAc to give 4-(2-(2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine (42 mg, 63%). This product was then diluted with CH2Cl2, 1 ml of 4 M HCl in dioxane was added, stirred for 10 minutes, and then evaporated to dryness. Trituration from CH2Cl2 / hexane gave 4-(2-(2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride in quantitative yield.

[0335] Characterization of 4-(2-(2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride: 1 H NMR (DMSO―d6, 400 MHz) δ 11.54 (s, 1H), 8.69 (d, 1H, J = 8.4 Hz), 8.53 (d, 1H, J = 5.2 Hz), 8.46 (d, 1H, J = 4.8 Hz), 6.91 (d, 1H, J = 8.4 Hz), 4.98 (m, 2H), 4.09 (s, 3H), 4.02 (d, 2H, J = 12.4 Hz), 3.84 (m, 2H), 3.65 (d, 2H, J = 10.4 Hz), 3.45 (m, 2H), 3.22 (m, 2H). LCMS m / z 381.2 ([M+H] +, C 18 H 20 F3N4O2 requires 381.2).

[0336] Example 4: 4-(2-(3-Methoxy-6-(trifluoromethyl)-5H-pyrrolo[2,3-c:5,4-c']dipyridin-5-yl)ethyl)morpholine hydrochloride

[0337]

Chemical formula

[0338] Into a flask were added 5-chloro-2-methoxypyridin-4-amine HCl salt (0.6065 g, 3.109 mmol), 3-bromo-2-trifluoromethylpyridine (3) (0.77 g, 3.41 mmol), Cs2CO3 (2.53 g, 7.77 mmol), X-Phos ligand (0.22 g, 0.46 mmol), and Pd(OAc)2 (0.14 g, 0.62 mmol). The flask was equipped with a condenser, flushed with Ar, and m-xylene (8.8 mL) was added. The mixture was degassed, placed under Ar, and refluxed overnight with stirring. The mixture was allowed to cool, diluted with water and EtOAc, and filtered through celite (washing the filter cake with EtOAc). The aqueous layer was extracted once with EtOAc, and the combined organic extracts were washed once with water and once with brine, dried (Na2SO4), and evaporated. Purification of the residue by flash chromatography gave an impure substance (a mixture from which the starting aniline and the desired product could not be separated). The mixture was separated by flash chromatography on reverse-phase C-18 silica eluting with 30 - 95% MeCN-H2O (gradient elution) using a Biotage SNAP cartridge KP-C18-HS (60 g) to give N-(5-(5-chloro-2-methoxypyridin-4-yl)-2-(trifluoromethyl)pyridin-3-amine (0.3069 g, 33%).

[0339] A microwave flask was charged with t-Bu3P-HBF4 (59 mg, 0.20 mmol), K2CO3 (0.35 g, 2.5 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), and PivOH (21 mg, 0.20 mmol). The flask was capped, flushed with Ar, and N-(5-chloro-2-methoxypyridin-4-yl)-2-(trifluoromethyl)pyridine-3-amine (0.3069 g, 1.011 mmol) in DMA (4 mL) was added via syringe. While stirring, Ar was bubbled through the solution for 5 minutes, and then the mixture was heated at 164 °C for 2 hours in a microwave. The mixture was allowed to cool, diluted with EtOAc, filtered through celite, and the filter cake was washed with EtOAc. Next, the mixture was washed twice with brine, dried (Na2SO4), and evaporated. Purification of the residue by flash chromatography on SiO2 (40 g) using 5 - 40% EtOAc - hexane (gradient elution) gave 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c’]dipyridine (34.2 mg, 13%). NaH (60% in oil, 30 mg, 0.75 mmol) was added all at once to a stirred solution of 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c’]dipyridine (34.2 mg, 0.127 mmol), 4-(2-chloroethyl)morpholine hydrochloride (48 mg, 0.25 mmol), and TBAI (5 mg, 0.01 mmol) in DMF (1.8 mL). The flask was flushed with N2 and heated at 60 °C overnight with stirring. The next day, the mixture was cooled to room temperature, diluted with EtOAc, washed once with water and once with brine, dried (Na2SO4), and evaporated. Purification of the residue by flash chromatography on SiO2 (12 g) using 20 - 100% EtOAc - hexane (gradient elution) gave 4-(2-(3-methoxy-6-(trifluoromethyl)-5H-pyrrolo[2,3-c:4,5-c’]dipyridin-5-yl)ethyl)morpholine (33 mg, 69%).

[0340] Characterization of 4-(2-(3-methoxy-6-(trifluoromethyl)-5H-pyrrolo[2,3-c:4,5-c’]dipyridin-5-yl)ethyl)morpholine:1 1H NMR (CDCl3, 400 MHz) δ 8.98 (s, 1H), 8.53 (d, 1H, J = 5.2 Hz), 8.11 (d, 1H, J = 5.2 Hz), 6.79 (s, 1H), 4.52 (t, 2H, J = 7.6 Hz), 4.07 (s, 3H), 3.72 (t, 4H, J = 4.4 Hz), 2.72 (t, 2H, J = 7.6 Hz), 2.56 (t, 4H, J = 4.4 Hz).

[0341] HCl (0.2 M in Et2O, 0.42 mL, 0.084 mmol) was added via syringe to 4-(2-(3-methoxy-6-(trifluoromethyl)-5H-pyrrolo[2,3-c:5,4-c']dipyridin-5-yl)ethyl)morpholine (16 mg, 0.042 mmol) in CH2Cl2 (1 mL). The mixture was stirred for 10 minutes and the volatiles were removed in vacuo to afford an off-white solid. The solid was triturated with 1:1 Et2O - hexane (ca. 2 mL) to give 4-(2-(3-methoxy-6-(trifluoromethyl)-5H-pyrrolo[2,3-c:4,5-c']dipyridin-5-yl)ethyl)morpholine hydrochloride (17.5 mg, quantitative) as a white solid.

[0342] Characterization of 4-(2-(3-methoxy-6-(trifluoromethyl)-5H-pyrrolo[2,3-c:4,5-c']dipyridin-5-yl)ethyl)morpholine hydrochloride: 1 1H NMR (DMSO - d6, 400 MHz) δ 11.83 (s, 1H), 9.27 (s, 1H), 8.58 (d, 1H, J = 5.2 Hz), 8.55 (d, 1H, J = 4.8 Hz), 7.43 (s, 1H), 4.88 (t, 2H, J = 8.4 Hz), 4.01 (s, 3H), 3.82 (d, 2H, J = 11.6 Hz), 3.70 (m, 2H), 3.59 (d, 2H, J = 11.2 Hz), 3.35 (m, 2H), 3.18 (m, 2H). LCMS m / z 381.2 ([M+H] + , C18 H 20 F3N4O2 requires 381.2).

[0343] Example 5: 4-(2-(2-Methoxy-8-(trifluoromethyl)-9H-pyrido[4’,3’:4,5]pyrrolo[2,3-d]pyrimidin-9-yl)ethyl)morpholine

[0344]

Chemical formula

[0345] To a stirred solution of 2,5-dichloropyrimidin-4-amine (2 g, 12.2 mmol) in methanol (40 mL) was added MeONa (25% in MeOH, 3.3 mL, 14.6 mmol). The mixture was stirred at 50 °C for 4 h while protecting from moisture. Next, the mixture was cooled to room temperature and quenched by the addition of saturated NH4Cl (aq) and EtOAc was added. The organics were washed once with NaHCO 3(aq) and once with brine, and dried (MgSO4). The solvent was evaporated to give 6-amino-5-chloro-2-methoxypyrimidine without further purification.

[0346] A microwave flask was charged with 6-amino-5-chloro-2-methoxypyrimidine (404 mg, 2.53 mmol) and 3-bromo-2-trifluoromethylpyridine (500 mg, 2.21 mmol). The flask was flushed with Ar, and DMF (3 mL) was added via syringe. Cs2CO3 (866 mg, 2.66 mmol) was then added, followed by the X-Phos ligand (80 mg, 0.16 mmol). After degassing the solution, Pd(OAc)2 (25 mg, 0.11 mmol) was added, and the flask was flushed again with Ar. The mixture was heated in a microwave (Biotage) at 160 °C for 2 h, allowed to cool, then diluted with EtOAc, washed once with water and once with brine, and dried (MgSO4). Flash chromatography on SiO2 (40 g) using 20 - 80% EtOAc - hexane (gradient elution) afforded 5-chloro-2-methoxy-N-(2-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine (120 mg, 18%).

[0347] A microwave flask was charged with 5-chloro-2-methoxy-N-(2-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine (120 mg, 0.394 mmol), and DMA (5 mL) was added, followed by K2CO3 (109 mg, 0.788 mmol). The mixture was then degassed and placed under an Ar atmosphere. t-Bu3P-HBF4 (22.8 mg, 0.0788 mmol) was added, followed by Pd(OAc)2 (8.8 mg, 0.0394 mmol). The mixture was degassed again and placed under Ar, and heated at 130 °C overnight. At this point, the conversion was low (LCMS), so an additional portion of the t-Bu3P-HBF4 ligand (22.8 mg, 0.0788 mmol) and Pd(OAc)2 catalyst (8.8 mg, 0.0394 mmol) were reinjected into the mixture, and heated in a microwave (Biotage) at 160 °C for 1.5 h. At this point, the conversion was approximately 50% (LCMS), so an additional portion of the t-Bu3P-HBF4 ligand (22.8 mg, 0.0788 mmol) and Pd(OAc)2 catalyst (8.8 mg, 0.0394 mmol) were reinjected into the mixture, and heated in a microwave (Biotage) at 160 °C for 2 h. The mixture was allowed to cool, diluted with EtOAc, and saturated NaHCO3(aq) Washed once with brine and once with water, and dried (MgSO4). Flash chromatography on SiO2 (24 g) using 20 - 80% EtOAc - hexane (gradient elution) gave 2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrido[4’,3’:4,5]pyrrolo[2,3 - d]pyrimidine (34 mg, 33%).

[0348] 4 - (2 - chloroethyl)morpholine (0.01 mL, 0.05 mmol), followed by Kuwajima reagent ((cyanomethylene)tributylphosphorane, 15 mg, 0.05 mmol) were added via syringe to a stirred solution of 2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrido[4’,3’:4,5]pyrrolo[2,3 - d]pyrimidine (7 mg, 0.03 mmol) in PhMe (0.8 mL) under N2. The mixture was heated at 100 °C overnight with stirring, allowed to cool, and diluted with EtOAc. The mixture was washed once with water and once with brine, and dried (Na2SO4). Evaporation of the solvent and flash chromatography on SiO2 (0.5×10 cm) in a Pasteur pipette using 60 - 100% EtOAc - hexane gave 4 - (2 - (2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrido[4’,3’:4,5]pyrrolo[2,3 - d]pyrimidin - 9 - yl)ethyl)morpholine (2.8 mg, 28%).

[0349] Characterization of 4 - (2 - (2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrido[4’,3’:4,5]pyrrolo[2,3 - d]pyrimidin - 9 - yl)ethyl)morpholine: 1 H NMR (CDCl3, 400 MHz) δ 9.19 (s, 1H), 8.61 (d, 1H, J = 4.8 Hz), 8.10 (d, 1H, J = 5.2 Hz), 4.74 (t, 2H, J = 7.6 Hz), 4.15 (s, 3H), 3.63 (t, 4H, J = 4.8 Hz), 2.75 (t, 2H, J = 7.6 Hz), 2.57 (t, 4H, J = 4.4 Hz). LCMS m / z 382.2 ([M + H] + , C 17H 19 F3N5O2 requires 382.2).

[0350] Example 6: 4-(2-(3-Fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride

[0351]

Chemical formula

[0352] Selectfluor (192 mg, 0.542 mmol) was added all at once to a stirred solution of 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine (96.6 mg, 0.362 mmol) in MeCN (3 mL). The flask was flushed with N2 and heated at 65 °C for 2 days with stirring. Next, the mixture was diluted with EtOAc and dilute NaCl (aq)Washed once with water and once with brine, dried (Na2SO4), and evaporated. The residue was filtered through a plug of SiO2 (2 × 4 cm) using 30% EtOAc - hexane to give a mixture of 2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrrolo[2,3 - b:5,4 - c']dipyridine / 3 - fluoro - 2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrrolo[2,3 - b:5,4 - c']dipyridine (1:2, 75 mg, at 48% base conversion). The 2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrrolo[2,3 - b:5,4 - c']dipyridine / 3 - fluoro - 2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrrolo[2,3 - b:5,4 - c']dipyridine (1:2) mixture was purified by reverse - phase HPLC (using a Puri - Flash system, a Phenomenex Synergi 10u MAX - RP 80A 50×50 mm 10 - micron column, and 10 - 95% MeCN - water containing a 0.1% formic acid gradient elution) to give another fraction of 2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrrolo[2,3 - b:5,4 - c']dipyridine / 3 - fluoro - 2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrrolo[2,3 - b:5,4 - c']dipyridine (3:17) mixture (19.1 mg) and 2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrrolo[2,3 - b:5,4 - c']dipyridine / 3 - fluoro - 2 - methoxy - 8 - (trifluoromethyl) - 9H - pyrrolo[2,3 - b:5,4 - c']dipyridine (7:3) mixture (10.4 mg) for use in the next step.

[0353] A flask was charged with the 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine / 3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine (3:17) mixture (19.1 mg, 0.066 mmol) from the above experiment, 4-(2-chloroethyl)morpholine hydrochloride (25 mg, 0.13 mmol), and TBAI (5 mg, 0.01 mmol). The flask was flushed with N2 and DMF was introduced via syringe while stirring. NaH (60% oil dispersion, 16 mg, 0.40 mmol) was added and stirring was continued for 5 minutes under a N2 stream before removing the N2 exit needle, and the mixture was heated to 60 °C overnight while stirring. The next day, the mixture was diluted with EtOAc, washed twice with water and once with brine, dried (Na2SO4), and evaporated. The residue was crystallized from CH2Cl2-hexane to give partially pure 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine (12 mg). The mixture was further purified using silica chromatography with 30 - 80% EtOAc-hexane and then recrystallized again from CH2Cl2-hexane to give the compound 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine (9 mg).

[0354] Characterization of 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine: 11H NMR (CDCl3, 400 MHz) δ 8.49 (d, 1H, J = 5.2 Hz), 8.01 (d, 1H, J = 9.6 Hz), 7.97 (d, 1H, J = 5.2 Hz), 4.76 (t, 2H, J = 7.6 Hz), 4.18 (s, 3H), 3.69 (t, 4H, J = 4.4 Hz), 2.76 (t, 2H, J = 7.6 Hz), 2.60 (t, 4H, J = 4.4 Hz).

[0355] HCl (0.2 M in Et2O, 0.22 mL, 0.044 mmol) was added via syringe at a fast drip rate to a stirred solution of 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine (9 mg) in CH2Cl2 (0.8 mL). After stirring for 5 minutes at room temperature, the volatiles were removed in vacuo and the resulting solid was washed once with a small amount of 1:1 Et2O - hexane to remove grease. Next, with the aid of sonication, the salt was suspended in water (ca. 2 mL), frozen, and lyophilized to afford 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride (9 mg, quantitative).

[0356] Characterization of 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride: 11H NMR (DMSO―d6, 400 MHz) δ 11.04 (s, 1H), 8.76 (d, 1H, J = 10.4 Hz), 8.54 (d, 1H, J = 5.2 Hz), 8.44 (d, 1H, J = 4.8 Hz), 4.95 (m, 2H), 4.19 (s, 3H), 4.03 (d, 2H, J = 10.8 Hz), 3.79 (m, 2H), 3.65 (d, 2H, J = 10.4 Hz), 3.48 (m, 2H), 3.24 (m, 2H). LCMS m / z 399.2 ([M+H] + , C 18 H 19 F4N4O2requires 399.2).

[0357] Example 7: Modulation of Sclerostin / Wnt Activity The compounds synthesized according to the methods of Examples 1-14 were assayed for their ability to restore Wnt signaling in the presence of sclerostin, a known sclerostin antagonist, sclerostin monoclonal antibody that matches sclerostin. See Ellies et al., J Bone Miner Res 21:1738-1749 (2006). As shown in Table 1 below, sclerostin antagonized Wnt3a signaling in human embryonic cells. The addition of a known sclerostin antagonist inhibited the sclerostin inhibition of Wnt3a signaling, thereby restoring intracellular Wnt3a signaling (IC 100 )(data not shown). The compounds of Examples 1-6 also inhibited the sclerostin inhibition of Wnt3a signaling and restored intracellular Wnt3a signaling.

[0358] Example 8: Bone Formation Assay Mineralization (crystalline calcium phosphate formation) represents an in vitro model of bone formation. Using an assay that quantifies the amount of mineralization by measuring total calcium after solubilization of the deposited crystalline calcium phosphate, it has previously been shown that sclerostin inhibits mineralization of MC3T3-E1 (mouse calvarial) osteoblasts. Li et al., J Bone Miner Res 24:578-588 (2008). Compounds were assayed for their ability to rescue the inhibition of mineralization by sclerostin in MC3T3 osteoblasts according to the protocol described by Li et al. In the presence of sclerostin treatment alone, mineralization was significantly reduced as measured by calcium concentration (Table 1 and data not shown). As reflected by the increase in calcium concentration, the addition of the compounds of Examples 1-6 neutralized the inhibition of mineralization mediated by sclerostin.

[0359] Example 9: Metabolic Stability The compounds of the present invention (0.1 μM) were incubated with microsomes at 37° C. for a total of 60 minutes. The reaction contained human liver microsomal protein (0.1 mg / mL) pooled in potassium phosphate buffer containing NADPH. At the indicated time points (0, 5, 15, 30, and 60 minutes). Samples were analyzed by LC / MS / MS and the remaining parent drug was calculated using Microsoft Excel (2007). Obach RS, Drug Metab Dispos. 27(11):1350-1359 (1999)).

[0360] [Table 1]

[0361] The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, but those skilled in the art will appreciate that certain changes and modifications can be practiced within the scope of the appended claims. Further, each of the prior art documents provided herein is incorporated by reference in its entirety to the same extent as if each document were individually incorporated by reference.

Claims

1. A compound according to the following formula I: 【Chemical Formula 1】 or a salt or hydrate thereof, wherein X is selected from CR 3b and N, Y is selected from CR 3c and N, Z is selected from CR 3d and N, provided that at least one of X, Y, and Z is N, A is 【Chemical Formula 2】 and RN is monocyclic heterocyclyl, said monocyclic heterocyclyl containing 4 to 7 ring members having 1 to 3 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) as ring members, said monocyclic heterocyclyl moiety containing at least one nitrogen atom as a ring member, and each heterocyclyl moiety is optionally substituted with 1 to 3 R 6 moieties, R 2 R 3b R 3c and R 3d are each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1 -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-OH, -O-C 1-6 alkyl-OH, C 3-6 cycloalkyl- C 1-4 alkoxy, and hydroxyl (-OH), R 6 are each hydroxyl (-OH), C 1-3 alkyl, C 1-3 alkyl-OH, -O-C 1-3 alkyl, C 3-4Heteroalkyl, C 1-3 Haloalkyl, -O-C 1-3 A compound selected from the group consisting of haloalkyl, halogen, and oxo. Claim 2 Formula Ia, Ib, Ic, or Id: [Chemical Formula 3] The compound according to claim 1, having Claim 3 R 2 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy, and is selected from the group consisting of, the compound according to claim 1 or 2. Claim 4 R 2 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy, and is selected from the group consisting of, the compound according to claim 1 or 2. Claim 5 R 2 is C 1-6 alkyl, or C 1-6 haloalkyl, the compound according to claim 4. Claim 6 R 2 is CH 3 or CF 3 and is, the compound according to claim 5. Claim 7 R 2 is CH 3 and is, the compound according to claim 6. Claim 8 R 2 is CF 3 and is, the compound according to claim 6. Claim 9 R 3b R 3c and R 3d each, when present, is H, halogen, C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, and C 1-6 The compound according to any one of claims 1 to 8, independently selected from the group consisting of haloalkoxy.

10. R 3b 、R 3c 、and R 3d are each, when present, H, halogen, and C 1-6 The compound according to claim 9, independently selected from the group consisting of alkoxy.

11. R 3b 、R 3c 、and R 3d are each, when present, selected from the group consisting of H, F, and methoxy, the compound according to claim 10.

12. R 3c is, when present, methoxy, the compound according to claim 9.

13. R N is 【Chemical Formula 4】 The compound according to claims 1 to 12.

14. R 2 is H, C 1-6 alkyl, and C 1-6 selected from the group consisting of haloalkyl, R 3c is, when present, H, or C 1-6 alkoxy and R 3b 、or R 3d is, when present, H, or halogen, the compound according to claim 1 or 13.

15. R 2 is H, or C 1-6 haloalkyl, R 3c is, when present, C 1-6 alkoxy, R 3b 、or R 3d is, when present, H, or halogen, and R N is Formula 5 the compound according to claim 14, which is Claim 16 R 2 is C 1-6 alkyl, or C 1-6 haloalkyl, R 3b is, when present, H, or halogen, and R 3c is C 1-6 alkoxy, the compound according to claim 2 or 13. Claim 17 R 2 is C 1-6 haloalkyl, R 3b is, when present, H, or halogen, R 3c is C 1-6 alkoxy, and R N is Formula 6 the compound according to claim 16, which is Claim 18 R 2 is CF 3 and R 3c is methoxy, the compound according to claim 17. Claim 19 Formula 7 the compound according to claim 1, selected from the group consisting of, or a salt or hydrate thereof. Claim 20 The formula: Formula 8 having the compound according to claim 1, or a salt thereof. Claim 21 The formula: Formula 9 The compound according to claim 1, having

22. Formula: 【Chemical Formula 10】 The compound according to claim 1, having, or a salt thereof.

23. Formula: 【Chemical Formula 11】 The compound according to claim 1, having

24. The formate salt of the compound according to any one of claims 1 to 20 or 22.

25. The sulfate salt of the compound according to any one of claims 1 to 20 or 22.

26. The citrate salt of the compound according to any one of claims 1 to 20 or 22.

27. The hydrochloride salt of the compound according to any one of claims 1 to 20 or 22.

28. A pharmaceutical composition comprising the compound according to any one of claims 1 to 27 and a pharmaceutically acceptable excipient.

29. A composition for promoting bone formation in a subject in need of bone formation, comprising a therapeutically effective amount of the compound according to any one of claims 1 to 27.

30. The composition according to claim 29, wherein the bone formation is promoted at a surgical site of an injury or a local condition.

31. The composition according to claim 30, wherein the bone formation is promoted at a surgical site selected from the group consisting of a fracture and weakened bone.

32. The composition according to claim 30, wherein the subject requires spinal fusion, arthrodesis, or synthetic bone grafts or implants for orthopedics or periodontics.

33. whether the bone formation is promoted at the surgical site, or the subject has periodontal disease, osteoporosis, osteopenia, pseudoglioblastoma syndrome (OPPG), or rheumatoid arthritis, long-term immobility or immobilization arthropathy, osteomyelitis, celiac disease, Crohn's disease, ulcerative colitis, inflammatory bowel disease, gastrectomy, amenorrhea, Cushing's disease, Cushing's syndrome, eating disorder, hyperparathyroidism, hyperthyroidism, hyperprolactinemia, Klinefelter syndrome, thyroid disease, Turner syndrome, steroid-induced osteoporosis, seizure or depression-induced osteoporosis, immobility, arthritis, gonadotropin-releasing hormone agonist-induced low bone mass, thyroid drug-induced low bone mass, dilantin (phenytoin)-induced low bone mass, Depakote-induced low bone mass, chemotherapy-induced low bone mass, immunosuppressant-induced low bone mass, anticoagulant-induced low bone mass, Graves' disease, juvenile rheumatoid arthritis, malabsorption syndrome, anorexia nervosa, kidney disease, antiepileptic drug treatment, corticosteroid treatment, immunosuppressive treatment, inadequate nutrition, smoking, alcohol abuse, pregnancy-related osteoporosis, copper deficiency, type 2 aminoaciduria, Werner syndrome, Hallermann-Streiff syndrome, juvenile cortical hyperostosis, type 2 methylmalonic aciduria, cystathionine beta synthase deficiency, exemestane, hyper IgE syndrome, hemochromatosis, Singleton-Merten syndrome, beta thalassemia, reflex sympathetic dystrophy, sarcoidosis, Winchester syndrome, Hallermann-Streiff syndrome (HSS), cyproterone, glycerol kinase deficiency, Bonnet-Dechaume-Blanc syndrome, prednisone use, heparin use, osteodystrophy cutis atrophicans senilis, Torg osteolysis syndrome, orchidectomy, Fabry disease, pseudoprogeria syndrome, Wolcott-Rallison syndrome, ankylosing spondylitis, multiple myeloma, systemic hyalinosis of infancy, Albright hereditary osteodystrophy, anorexia nervosa, autoimmune lymphoproliferative syndrome, Brown-Séquard syndrome, Diamond-Blackfan anemia, galactorrhea, hyperprolactinemia, ovarian dysgenesis, kidney disease, Menkes disease, menopause, neuritis, ovarian insufficiency due to FSH resistance, familial ovarian insufficiency, premature aging, primary biliary cirrhosis, prolactinoma, familial prolactinoma, renal osteodystrophy, underweight, Werner syndrome, bone cancer, brittle bone disease, osteonecrosis, osteomalacia, polyfibrous dysplasia, osteogenesis imperfecta, Paget's disease, The composition according to claim 29, having a secondary low bone mass disease selected from the group consisting of osteoarthritis, osteomyelitis, late-onset osteogenesis imperfecta, and congenital osteogenesis imperfecta.

34. The composition according to claim 29, wherein the subject has a low bone mass / density state, a fracture, or periodontal disease.

35. The composition according to claim 34, wherein the low bone mass state is selected from osteoporosis, osteopenia, osteogenesis imperfecta (OI), osteoporosis-pseudoglioma syndrome (OPPG), and secondary low bone mass state.

36. The low bone mass state is selected from the group consisting of osteoporosis, osteopenia, and osteoporosis-pseudoglioma syndrome (OPPG

37. The composition according to any one of claims 29 to 36, further comprising an osteoconductive matrix.

38. The composition according to claim 37, wherein the osteoconductive matrix comprises an osteoinductive agent selected from the group consisting of allograft bone, autograft bone, and periodontal ligament cells.

39. The composition according to claim 37, wherein the osteoconductive matrix comprises a calcium salt, calcium sulfate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-derived hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, plaster of Paris, phosphopholine, borosilicate, biocompatible ceramic, calcium phosphate ceramic, demineralized bone matrix, biphasic calcium phosphate, biocomposite, tantalum, titanium, polytetrafluoroethylene, sulfate, hydrogel, bioglass, or a combination thereof.

40. The composition according to any one of claims 29 to 36, further comprising an antiresorptive agent.

41. The composition according to claim 40, wherein the bone resorption inhibitor is selected from the group consisting of denosumab, Prolia, RankL inhibitor, bisphosphonate selective estrogen receptor modulator or analog, calcitonin, calcitonin analog, parathyroid hormone, calcium degrading agent, calcium mimetic, statin, anabolic steroid, lanthanum and strontium salts, and sodium fluoride, vitamin D or vitamin D analog, cathepsin K (CatK) inhibitor, prostaglandin inhibitor, or phosphodiesterase inhibitor (type E).

42. A medical device comprising a structural support, wherein the implantable portion of the structural support is adapted to be permanently implanted within a subject, the implantable portion adheres to bone, and the structural support carries at least a partial external coating, a partial internal coating, or both, at least one of which contains the compound according to claim 1, the medical device.

43. The medical device according to claim 42, wherein osteoblasts / osteocytes are capable of migrating to the structural support by the structural support and depositing bone mineral.

44. The medical device according to claim 42, wherein the structural support has at least a partial external coating, at least a partial internal coating, or at least a partial external and internal coating.

45. The medical device according to claim 42, wherein the structural support has at least a partial internal coating.

46. The medical device according to any one of claims 42 to 45, wherein the structural support is a pin, rod, screw, plate, orthopedic implant, or dental implant.

47. The medical device according to claim 46, wherein the structural support contains a substance selected from metal, polymer, ceramic, or a combination thereof.

48. The medical device according to claim 46, wherein the structural support includes a polymer.

49. The medical device according to claim 47, wherein the metal includes stainless steel, cobalt, chromium, titanium alloy, titanium, tantalum, or Trabecular Metal (registered trademark).

50. The medical device according to any one of claims 42 to 45, wherein the structural support is a titanium cage.

51. The medical device according to claim 42, wherein the structural support is used for hip joint, knee joint, ankle joint, shoulder joint, dental implant, or spinal fixation.

52. The medical device according to claim 47, wherein the ceramic is calcium phosphate, aluminum oxide, zirconium oxide, silicon oxide, or hydroxyapatite.

53. The medical device according to claim 42, wherein the structural support is a scaffold and matrix including synthetic materials, biological materials, biocomposites, naturally occurring polymers, synthetic biodegradable polymers, synthetic non-biodegradable polymers, bioceramics, bioglass, or combinations thereof.

54. The medical device according to claim 53, wherein the structural support is a scaffold or matrix including a synthetic non-biodegradable polymer.

55. The medical device according to claim 42, wherein the structural support is a scaffold or matrix including silk, collagen, gelatin, fibrinogen, elastin, keratin, actin, myosin, cellulose, amylose, dextran, chitin, chitosan, glycosaminoglycan, DNA, or RNA.

56. The medical device according to claim 42, wherein the structural support is a scaffold or matrix comprising PLA, PGA, PLLA, PLGA, PCL, PLDLA, PDS, PGCL, PEA, PCA, PDLLA, PEU, PBT, HAP, CP ceramic, BCP, or TCP.

57. The medical device according to claim 42, wherein the structural support is a matrix comprising particles of a porous material.

58. The medical device according to claim 57, wherein the pore diameter of the matrix is at least 5 μm.

59. The medical device according to any one of claims 42 to 58, further comprising an anabolic agent.

60. The medical device according to claim 59, wherein the anabolic agent is selected from the group consisting of parathyroid hormone (PTH) or an analogue thereof, a sclerostin antibody inhibitor, a sclerostin inhibitor, BMP, a BMP agonist, a population of bone marrow stem cells, and a population of mesenchymal stem cells.

61. The medical device according to any one of claims 42 to 58, further comprising an antiresorptive agent.

62. The medical device according to claim 61, wherein the antiresorptive agent is selected from the group consisting of denosumab, Prolia, a RankL inhibitor, a bisphosphonate selective estrogen receptor modulator or analogue, calcitonin, a calcitonin analogue, parathyroid hormone, a calcium degrading agent, a calcium mimetic, a statin, an anabolic steroid, lanthanum and strontium salts, and sodium fluoride, vitamin D or a vitamin D analogue, a cathepsin K (CatK) inhibitor, a prostaglandin inhibitor, or a phosphodiesterase inhibitor (type E).

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