Pyrrolodipyridine compounds

Abstract

On one hand, the present invention provides compounds of formulas I, Ia, Ib, Ic, and Id, as well as their salts, hydrates, and isomers. On the other hand, the present invention provides a method for promoting bone formation by administering a therapeutically effective amount of a compound of formula I, Ia, Ib, Ic, or Id to a subject in need. The present invention also provides orthopedic and periodontal devices using compounds of formulas I, Ia, Ib, Ic, or Id, and methods for treating kidney disease, diabetes, bone loss, and cancer.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 718,612, filed August 14, 2018, pursuant to 35 USC §119(e), the contents of which are incorporated herein by reference in their entirety.

[0003] Declaration of Invention Rights for Federally Sponsored Research and Development

[0004] not applicable.

[0005] Refer to the "Sequence List," table, or computer program list appendix submitted on the CD.

[0006] not applicable. Background of the Invention

[0008] Bone homeostasis involves the balance between bone formation and bone resorption. Increased bone resorption and loss of bone homeostasis are associated with a variety of diseases and conditions, such as osteoporosis and Paget's disease. Except for teriparatide, all FDA-approved therapies for low bone mineral density work by stopping bone resorption and are therefore anti-resorption drugs. Anti-resorption drugs act on osteoclasts by preventing them from absorbing bone.

[0009] It is well known in the art that bone formation can occur through two processes; one is mediated by chondrocyte-chondrocyte intermediates (intrachondral), and the other is a direct process stimulating osteoblasts (intramembrane). The intrachondral process involves chondrocytes / cartilage cells dying and leaving gaps that are occupied by osteoblasts, which calcify on the calcified surface of the chondrocytes. During resorption, osteoclasts absorb the calcified cartilage material, leaving behind clean, non-cartilaginous bone minerals. The intrachondral process occurs during the basic formation and growth of long bones, as well as during the cartilage callus formation process after fractures. The intrachondral process begins when mesenchymal stem cells differentiate into chondrocytes and form cartilage. The intramembrane process, on the other hand, occurs during the new bone growth phase after fractures and during bone formation in the head. The intramembrane process occurs when mesenchymal stem cells differentiate into osteoblasts. Unlike cartilage, which is elastic tissue, bone is hard and rigid. Two distinct cellular processes (osteoblasts and chondrocytes) involve different molecules (WNT and BMP) and cellular mechanisms (osteoblasts and chondrocytes).

[0010] It is well known that osteoblasts are responsible for secreting bone minerals that increase bone density. To date, only teriparatide is known to stimulate osteoblasts to increase mineral deposition, although this occurs indirectly through the Wnt pathway.

[0011] The aim is to induce osteoblast mineral deposition (bone formation) to treat a wide variety of diseases in mammals, including simple aging, bone degeneration and osteoporosis, fracture healing, osteogenesis imperfecta, HPP, fusion of two bones or joint fixation across joints, any low bone density disease, and successful implantation of various medical orthopedic and periodontal implants, such as screws, rods, titanium cages for spinal fusion, hip, knee, ankle, and shoulder joint implants, dental implants, bone grafts, plates, and rods.

[0012] Anti-resorption agents, such as, but not limited to, cathepsin K inhibitors, Rank ligand inhibitors, denosumab, Prolia, osteoprotegerin (OPG) inhibitors, alendronate, selective estrogen receptor modulators (SERMs), and bisphosphonates, have been used to treat at least a portion of conditions with low bone mineral density. Initial increases in mineral deposition are small, less than 6%, in the first year, with even smaller increases in subsequent years. Overall, bone mineral density has been reported to improve by 9.4% over three years through anti-resorption therapy (preventing bone loss). These treatable conditions may include osteopenia, osteoporosis, arthritis, metastatic tumors, osteogenesis imperfecta, Paget's disease, secondary low bone mineral density disorders / diseases, and other metabolic bone diseases.

[0013] The use of parathyroid hormone and analogues, prostaglandin agonists, PDGE2, PDGE, Forteo, osteoprotective protein (OPG) inhibitors, teriparatide, BMP2, BMP7, BMP4, EP4 agonists, etc., can be used to induce the required increase in bone mineral density in subjects with conditions that may include osteopenia, osteoporosis, arthritis, metastatic tumors, osteogenesis imperfecta, Paget's disease, secondary low bone density disorders, bone fusion, spinal fusion, joint fixation, and other metabolic bone diseases. However, following the FDA's Phase I clinical trials, BMP agonists have not been sought for the treatment of systemic diseases.

[0014] Furthermore, it is known in the art to use PTH, TGFβ-binding proteins, etc., to increase bone mineralization in order to treat conditions that may be partially characterized by an increased risk of fracture, such as osteoporosis, intervertebral disc degeneration, fractures, osteoporosis, arthritis, tumor metastasis, osteogenesis imperfecta, Paget's disease, and other metabolic bone diseases. Since endogenous growth factors (TGFβ-binding proteins (BMPs)) can survive the sterilization process of cadaveric bones, demineralized bone matrix can also partially promote the growth of a small amount of new bone. However, demineralized bone matrix is ​​usually derived from cadaver banks and carries certain risks, such as disease transmission or bacterial contamination. Other versions of demineralized bone matrix handle larger volumes and have lower disease risks. In the field of nonunion fractures, the current unmet medical need using currently approved therapies is to improve poor healing observed in long, large defects consisting of large gaps between fracture ends. The use of demineralized bone or similar bone-guiding materials known in the prior art has not produced the desired effect of fusing long bones.

[0015] Therefore, there remains a need in the art for novel methods to treat bone diseases, fractures, and related problems. This invention addresses these and other needs. Summary of the Invention

[0016] On one hand, the present invention provides compounds and compositions, as well as methods of using these compounds and compositions. In a first embodiment, the present invention provides compounds of formula I:

[0017]

[0018] or its salt, hydrate, prodrug or isomer, wherein

[0019] X is selected from CR 3b and N, wherein N is optionally oxidized to the corresponding N-oxide;

[0020] Y is selected from CR 3c and N, wherein N is optionally oxidized to the corresponding N-oxide;

[0021] Z is selected from CR 3d and N, wherein N is optionally oxidized to the corresponding N-oxide,

[0022] The additional condition is that at least one of X, Y, and Z is N or a corresponding N-oxide;

[0023] A is

[0024] R N Selected from the following group: heterocyclic and heteroaryl, wherein

[0025] The heterocyclic moiety is selected from monocyclic, fused bicyclic, and bridged rings. The monocyclic heterocyclic moiety contains 4 to 7 ring members, while the fused bicyclic and bridged bicyclic heterocyclic moiety contains 7 to 10 ring members. Each heterocyclic moiety has 1 to 3 heteroatoms selected from N, O, and S as ring members, wherein each heterocyclic moiety contains at least one nitrogen atom as a ring member and is optionally surrounded by 1-3 R atoms. 6 Partial replacement,

[0026] The heteroaryl moiety contains 5 to 10 ring members, wherein at least one ring member is a nitrogen atom and optionally surrounded by 1 to 3 R atoms. 6 Partial replacement,

[0027] Each R 2 R 3b R 3c and R 3d Independently selected from the group consisting of: H, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkoxy, C1-6 alkane-OH, -O-C1-6 alkane-OH, C 3-6 cycloalkyl-C 1-4 Alkyl groups and –OH groups; and

[0028] R 6 Selected from the following group: –OH, C 1-3 Alkyl, C1-3 alkyl -OH, -OC 1-3 Alkyl, C 3-4 Heteroalkyl, C 1-3 Halogenated alkyl, -O-C1-3 halogenated alkyl, halogen and oxo.

[0029] In a second embodiment, the present invention provides a method for promoting bone formation and fusion in a subject in need of it. The method comprises administering to the subject a therapeutically effective amount of a compound of formula I, Ia, Ib, Ic, or Id as described herein, thereby promoting bone formation in the subject. Bone formation may be systemic or localized. For localized bone formation, in some embodiments, the compound may be administered together with a bone-guiding agent, such as a bone-guiding matrix.

[0030] In a third embodiment, the present invention provides a method for treating kidney injury. The method comprises administering to a subject in need a therapeutically effective amount of a compound of formula I, Ia, Ib, Ic, or Id.

[0031] In a fourth embodiment, the present invention provides a method for treating diabetes. The method comprises administering to a subject in need a therapeutically effective amount of a compound of formula I, Ia, Ib, Ic, or Id.

[0032] In a fifth embodiment, the present invention provides a method for treating cancer. The method comprises administering to a subject in need a therapeutically effective amount of a compound of formula I, Ia, Ib, Ic, or Id.

[0033] In a sixth embodiment, the present invention provides a medical device, such as an orthopedic or periodontal medical device. The device includes a structural support, wherein an implantable portion of the structural support is adapted for permanent implantation into a subject. The implantable portion is attached to bone, and the structural support has at least a partial external coating comprising a compound of formula I, Ia, Ib, Ic, or Id.

[0034] In a seventh embodiment, the present invention provides compounds or compositions described herein (e.g., compounds or compositions of formula I, Ia, or Ib, Ic, or Id) for use in the preparation of a medicament for treating diseases or conditions as described herein. In some embodiments, said diseases or conditions are injured bones, fractures, osteoporosis, osteogenesis imperfecta, hypophospholipase syndrome (HPP), osteopenia, osteoporosis, arthroplasty, or conditions characterized by low bone mass or low bone mineral density. The use of the compounds or compositions described herein in periodontal implants or medical orthopedic implants is also contemplated herein. Orthopedic implants include screws, rods, and titanium cages for use, for example, in spinal fusion.

[0035] In an eighth embodiment, the present invention provides a bone biology, such as a bone formation inducing agent, for surgical implantation with or without a bone graft device. The device includes a structural support, wherein an implantable portion of the structural support is adapted for permanent implantation in a subject. The implantable portion is attached to bone, and the structural support has at least a partial external coating comprising a compound of formula I, Ia, Ib, Ic, or Id.

[0036] In a ninth embodiment, the present invention provides a method for treating bone loss. The method comprises administering, sequentially or in combination with an anti-resorption agent, a therapeutically effective amount of a compound of formula I, Ia, Ib, Ic, or Id to a subject in need.

[0037] Brief description of the attached figures

[0038] Figure 1Bone homeostasis is regulated through a coupled process of bone formation (increasing bone mineral deposition) and bone resorption (decreasing bone mineral deposition). Bone formation can be actively promoted (e.g., by movement) through actions and agents acting on osteoblasts and bone blast cells, and can also be indirectly promoted by PTH (teriparatide) or sclerosing protein inhibitors (e.g., the compounds of this invention). Bone resorption can be inhibited by anti-resorption agents, such as RankL inhibitors, selective estrogen receptor modulators (SERMs), calcium, estrogen, alendronate, fosamax, denosumab, Prolia, cathepsin K modulators, bisphosphonates, calcitonin, and other agents that inhibit osteoclast activity. Invention Details

[0040] I. Introduction

[0041] Bone homeostasis and bone remodeling involve a balance between bone formation (osteoblasts depositing minerals, anabolic processes) and bone resorption (osteoclasts reabsorbing minerals, leading to bone loss, catabolic processes). These two processes combine in healthy bone. See also Figure 1 In bone formation, osteoblasts synthesize the bone matrix and regulate mineralization before eventually differentiating into osteocytes or bone lining cells. In bone resorption, another cell type—osteoclasts—removes the mineralized bone matrix and breaks down organic bone to release calcium from the serum. See, for example, Kular et al., Clinical Biochemistry 45:863-873 (2012).

[0042] Osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells) are regulated by different mechanisms. Osteoclast differentiation is regulated or controlled by osteoblasts (Glass et al., Developmental Cells (DevCell), 8:751-764 (2005)) or other hormones such as PTH, calcitonin, or IL6. Conversely, osteoblast differentiation or activity is not regulated or controlled by osteoclasts, but rather by different signals (e.g., CPFA, hedgehog, WNT / LRP, and sclerosing proteins). Bone formation can occur through endochondrial ossification or intramembranous ossification (sclerosing proteins). In intramembranous ossification, bone is formed directly by stimulating osteoblasts / skeleton cells. In endochondrial ossification, bone formation occurs via a cartilage template, which increases the time required for bone formation. BMP signaling is associated with endochondrial ossification, while Wnt signaling has been shown to be associated with both endochondrial and intramembranous ossification.

[0043] In a normal, healthy state, bone remodeling (or skeletal homeostasis) involves the degradation of old bone (through osteoclasts) and the repair or replacement of old bone by new bone (through osteoblasts). When this homeostasis is disrupted and bone resorption exceeds bone formation—a diseased bone state—the result is a decoupling of bone resorption from bone formation. Increased bone resorption leads to decreased bone mass (trabecular bone loss) and greater bone fragility (reduced bone strength). Many diseases and conditions are associated with increased bone resorption, including osteoporosis, osteogenesis imperfecta, Paget's disease, metabolic bone diseases, bone changes secondary to cancer, and other diseases characterized by or related to low bone mineral density.

[0044] Diseases caused by increased bone resorption are associated with decreased bone mass and greater bone fragility, and are frequently treated with anti-resorption agents such as bisphosphonates, denosumab, proteolytics, alendronate, cathepsin K modulators, RankL inhibitors, estrogens, cathepsin K inhibitors, and selective estrogen receptor modulators, to name just a few. These agents work by directly or indirectly preventing or inhibiting osteoclast-mediated bone resorption. See also Figure 1 However, these agents do not promote the formation of new bone by osteoblasts (i.e., the formation of anabolic bone); in contrast, a single dose of anabolic agents typically results in an annual cumulative increase of >8% from the baseline in bone formation in the lumbar spine. Taking anti-resorption agents does result in a modest increase in bone mineral density (<7%) in the first year, but thereafter an increase of <3.5%, with an annual cumulative increase of <10%. Therefore, while brittle osteoporotic bone treated with anti-resorption agents will result in the bone no longer being more fragile, it will not become stronger or more robust because the anti-resorption agents do not promote new bone growth by depositing more bone mineral to increase bone density. Conversely, agents that promote anabolic bone growth, such as by stimulating osteoblast activity, promoting more bone matrix deposition, or, if stimulating proliferation, will result in more osteoblasts, leading to more bone cells bridging gaps to fuse two bones. Therefore, brittle osteoporotic bone treated with anabolic bone morphogenetic agents will not become more fragile and will have greater strength due to increased bone formation.

[0045] Reference Figure 1And not bound by any particular theory, if we consider bone as a bathtub, the drain evokes bone loss or resorption, while the faucet evokes the addition of bone or bone formation. The faucet and drain are added and removed at the same rate (coupling) until an age or disease event causes the faucet to be reduced or the drain to be enlarged. Such disturbances lead to an imbalance in formation / resorption (decoupling), resulting in decreased bone density. For example, imagine a sponge with an outer core and an interior made of fibers extending from one end to the other. During bone resorption, these fibers are removed, and if bone resorption occurs faster than bone formation or building up, these fibers will be scarce and the bone will become brittle. It takes much less force to break down a sponge with fewer internal fibers than a sponge with more internal fibers. Because the process of bone resorption is well-known, many commercially available treatments stop bone resorption by acting on osteoclasts. These include anti-reabsorption drugs, such as cathepsin K inhibitors, Rank ligand inhibitors, denosumab, prolifia, Fosamax, raloxifene (Evista), premarin, osteoprotegerin (OPG) inhibitors, alendronate, selective estrogen receptor modulators (SERMs), bisphosphonates, and other agents that inhibit osteoclast activity.

[0046] The analogy of a sponge is still being considered; to increase bone strength, the number of fibers within the bone needs to be increased. However, it's impossible to increase bone strength by acting on bone resorption cells (osteoclasts). Therefore, the focus needs to be on osteoblasts, the cells that form bone. Unlike bone resorption, bone formation is not well understood; until recently, only one systemic treatment (teriparatide) and one surgical implant (injected BMP protein) promoted bone formation. However, BMP products can increase chondrocytes and promote cartilage formation. This process sometimes leads to chondrocytes being replaced by osteoblasts.

[0047] Intermittent administration of teriparatide increases bone mineral density systemically by activating PKA, which in turn phosphorylates LRP and activates the WNT pathway (Wan et al., Genes Dev. 22(21):2968-2979, (2008)). This increase in bone mineral density occurs along the trabeculae already stored within the bone matrix. Osteoblasts in the trabecular lining secrete minerals into the existing trabecular bone, thereby increasing the mineral content and density of the trabeculae.

[0048] When bone voids exist, most of the bone is removed, leading to nonunion or severe dimensional defects. Bone cannot heal itself along large voids. Adding BMP to the site causes pluripotent cells to differentiate into chondrocytes / cartilage and produce cartilaginous callus tissue. The ability of the void to be filled by bone rather than cartilage will require osteoblasts to undergo proliferation to fill the void, followed by mineral deposition to fill the vacancy.

[0049] Unbound by any particular theory, the compounds of the present invention are believed to be SOST (sclerosing protein) and / or WISE antagonists that act by modulating the Wnt / LRP and / or BMP signaling pathways. SOST and WISE are proteins believed to regulate bone formation by binding to the Wnt co-receptor LRP, thereby inhibiting the Wnt signaling pathway, or by binding to BMP via different amino acid sequences or domains and inhibiting BMP activity. By neutralizing the inhibitory effect of SOST and / or WISE proteins on the Wnt pathway, the compounds and compositions of the present invention restore Wnt signaling and promote bone formation / growth. Therefore, in one aspect, the present invention provides compounds, compositions, and methods for promoting bone formation in subjects. Bone formation can be systemic or local. The compounds and compositions of the present invention can be administered locally and / or systemically, and optionally sequentially or in combination with one or more other therapeutic agents. In another aspect, the present invention provides implantable devices as structural scaffolds for allowing osteoblasts / bone cells to migrate into the scaffold and deposit bone minerals, and also for delivering the compounds and compositions of the present invention, for example, for promoting bone formation at the implantation site. In another respect, the compounds and compositions of the present invention can be used to treat kidney damage, diabetes, bone loss and cancer.

[0050] II. Definition

[0051] As used herein, the term "pharmaceuticalally acceptable excipient" refers to a substance that facilitates administration of the active agent to a subject and its absorption therein. Pharmaceutically acceptable excipients that can be used in this invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and colorings. Those skilled in the art will recognize that other pharmaceutical excipients can be used in this invention.

[0052] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic group having a specified number of carbon atoms. For example, C1-C6 alkyl (or C 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.

[0053] Alkylenes represent straight-chain or branched alkylenes with 1 to 7 carbon atoms, i.e., divalent hydrocarbon groups with 1 to 7 carbon atoms; for example, a straight-chain alkylene is of the formula -(CH2). n- a divalent group, wherein n is 1, 2, 3, 4, 5, 6, or 7. Preferably, the alkylene represents a straight-chain alkylene having 1 to 4 carbon atoms, such as methylene, ethylene, propylene, or butylene, or mono-substituted with a C1-C3 alkyl (preferably methyl) or C1-C3 alkyl group on the same or different carbon atoms. 1- C3-alkyl (preferably methyl) disubstituted methylene, ethylene, propylene, or butylene, with a total carbon number of up to 7 and containing 7. Those skilled in the art will understand that a single carbon atom in the alkylene group can be divalent, for example, in -CH((CH2)). n In CH3)-, where n=0-5.

[0054] As used herein, the term "alkoxy" or "-O-alkyl" refers to an alkyl group containing an oxygen atom, such as methoxy, ethoxy, etc. "Haloalkoxy" is defined as an alkoxy group in which some or all of its hydrogen atoms are replaced by halogen atoms. For example, haloalkoxy groups include trifluoromethoxy, etc.

[0055] The term "hydroxyalkyl" or "alkyl-OH" refers to an alkyl group as defined above, wherein at least one hydrogen atom is replaced by a hydroxyl group. As for alkyl groups, hydroxyalkyl groups can have any suitable number of carbon atoms, such as C1-6. Exemplary hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (wherein the hydroxyl group is located at the 1- or 2-position), hydroxypropyl (wherein the hydroxyl group is located at the 1-, 2-, or 3-position), etc.

[0056] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon having 2 to 6 carbon atoms having at least one double bond. Examples of alkenyl include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl, pentenyl, or hexadienyl.

[0057] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon having 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.

[0058] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0059] As used herein, the term "haloalkyl" refers to an alkyl group as defined above, in which some or all of its hydrogen atoms are replaced by halogen atoms. Halogen (halogenated) preferably represents chlorine or fluorine, but can also be bromine or iodine. For example, haloalkyl groups include trifluoromethyl, fluoromethyl, etc. The term "perfluorinated" defines a compound or group having at least two available hydrogen atoms replaced by fluorine. For example, perfluoromethane refers to 1,1,1-trifluoromethoxy, while perfluoromethoxy refers to 1,1,1-trifluoromethoxy.

[0060] As used herein, the term "heteroalkyl" refers to an alkyl group having 1 to 3 heteroatoms such as N, O, and S. Heteroalkyl groups have a specified number of carbon atoms, wherein at least one non-terminal carbon is replaced by a heteroatom. Other heteroatoms may also be useful, including but not limited to B, Al, Si, and P. Heteroatoms may also be oxidized, for example, but not limited to -S(O)- and -S(O)2-. For example, heteroalkyl groups may include ethers, thioethers, and alkyl-amines. Heteroalkyl groups do not include peroxides (-OO-) or other continuously linked heteroatoms.

[0061] As used in this article, the term "oxo" refers to double-bonded oxygen (=O).

[0062] As used herein, the term "cycloalkyl" refers to a monocyclic, fused bicyclic, or bridged polycyclic assembly containing 3 to 12 ring atoms, 3 to 8, 3 to 6, or the specified number of atoms, and is either saturated or partially unsaturated. For example, C 3-8 The cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and at most cyclooctyl. The cycloalkyl groups of this invention may optionally be substituted as defined below.

[0063] As used herein, the terms "heterocyclic," "heterocyclic alkyl," and "heterocyclic group" refer to a ring system having 3 to about 20 ring members and 1 to about 5 heteroatoms such as N, O, and S. Other heteroatoms can also be useful, including but not limited to B, Al, Si, and P. Heteroatoms can also be oxidized, for example, but not limited to -S(O)- and -S(O). 2- The term heterocyclic includes monocyclic, fused bicyclic, and bridged ring moieties. For example, heterocyclic compounds include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, pyrrolyl, pyrrololinyl, imidazoalkyl, imidazolinyl, pyrazolyl, pyrazolyl, piperazinyl, piperidinyl, indolyl, quinolinyl hexahydro-1H-furano[3,4-c], and 1,4-dioxo-8-aza-spiro[4.5]decane-8-yl. The heterocyclic alkyl groups of the present invention may optionally be substituted as defined below.

[0064] The substituents of cycloalkyl and heterocyclic groups are diverse and independently selected from: -halogen, 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, the number of which ranges from zero to the total number of open valences of the ring system; and wherein R', R” and R”' are independently selected from hydrogen, (C1-C8)alkyl and C3-8 heteroalkyl and phenyl.

[0065] As used herein, "linked via a carbon atom" refers to the connection between the carbon atom of the mentioned group and the rest of the molecule. "Linked via a nitrogen atom" refers to the connection between the nitrogen atom of the mentioned group and the rest of the molecule. As an example only, a heterocyclic group linked via a carbon atom could be:

[0066] The wavy lines represent connection points with the rest of the molecule. As an example only, a heterocyclic group connected via a nitrogen atom could be:

[0067] The wavy lines represent the connection points with the rest of the molecule.

[0068] As used herein, when the reference compound is an N-oxide, it contains a NO bond with three additional bonds to nitrogen; that is, an N-oxide refers to the group R3N. + -O - By way of example only, N-oxides may include:

[0069] wait wait.

[0070] As used herein, the term "aryl" refers to a monocyclic or fused bicyclic, tricyclic, or larger aromatic ring assembly containing 6 to 16 ring carbon atoms. For example, an aryl group can be phenyl, benzyl, or naphthyl, preferably phenyl. "Arylidene" refers to a divalent group derived from an aryl group. An aryl group can be mono-, di-, or tri-substituted by one, two, or three groups as described below.

[0071] The substituents of the aryl group are variable and selected from: -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'

[0072] C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R”, alkylene dioxy, heteroaryl, -C 1-2 alkylene-heteroaryl, heterocyclic, C 1-2Alkylene-heterocyclic groups, phenyl groups, perfluoro(C1-C4)alkoxy groups, and perfluoro(C1-C4)alkyl groups, ranging from zero to the total number of open valences of the ring system; and wherein R', R”, and R”’ are independently selected from hydrogen, (C1-C8)alkyl and C3-8 heteroalkyl groups, and phenyl. Alkylene dioxy groups are divalent substituents attached to two adjacent carbon atoms of the phenyl group, such as methylenedioxy or ethylenedioxy. Oxygen-C 2- C3-alkylene groups are also divalent substituents attached to two adjacent carbon atoms of a phenyl group, such as oxoethylene or oxopropylene.

[0073] Examples of substituted phenyl groups include, but are not limited to, 4-chlorophenyl-1-yl, 3,4-dichlorophenyl-1-yl, 4-methoxyphenyl-1-yl, 4-methylphenyl-1-yl, 4-aminomethylphenyl-1-yl, 4-methoxyethylaminomethylphenyl-1-yl, 4-hydroxyethylaminomethylphenyl-1-yl, 4-hydroxyethyl-(methyl)-aminomethylphenyl-1-yl, 3-aminomethylphenyl-1-yl, 4-N-acetamidomethylphenyl-1-yl, 4-aminophenyl-1-yl, 3-aminophenyl-1-yl, 2-aminophenyl-1-yl, 4-phenylphenyl-1-yl, 4-(imidazolium- 1-yl)-phenyl, 4-(imidazol-1-ylmethyl)-phenyl-1-yl, 4-(morpholin-1-yl)-phenyl-1-yl, 4-(morpholin-1-ylmethyl)-phenyl-1-yl, 4-(2-methoxyethylaminomethyl)-phenyl-1-yl and 4-(pyrrolidinyl-1-ylmethyl)-phenyl-1-yl, 4-(thiophenyl)-phenyl-1-yl, 4-(3-thiophenyl)-phenyl-1-yl, 4-(4-methylpiperazin-1-yl)-phenyl-1-yl and 4-(piperidinyl)-phenyl and 4-(pyridinyl)-phenyl, which are optionally substituted in a heterocyclic or heteroaryl ring.

[0074] As used herein, the term "heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, wherein 1 to 4 ring atoms are heteroatoms of N, O, or S. For example, heteroaryl includes pyridinyl, indolyl, indazole, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiopheneyl, benzofuranyl, furanyl, pyrroleyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiopheneyl, or any other group, especially mono- or di-substituted, substituted with, for example, an alkyl, nitro, or halogen. Pyridinyl represents 2-, 3-, or 4-pyridinyl. Thiopheneyl represents 2- or 3-thiopheneyl. Quinolinyl preferably represents 2-, 3-, or 4-quinolinyl. Isoquinolinyl preferably represents 1-, 3-, or 4-isoquinolinyl. Benzopyranyl and benzothiaranyl preferably represent 3-benzopyranyl or 3-benzothiaranyl, respectively. Thiazolyl preferably represents 2- or 4-thiazolyl, and most preferably 4-thiazolyl. Triazolyl is preferably 1-, 2-, or 5-(1,2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl. The heteroaryl moiety may optionally be substituted, as defined below.

[0075] Preferably, the heteroaryl group is pyridyl, indolyl, quinolinyl, pyrroleyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiophenyl, furanyl, benzothiazolyl, benzofuranyl, isoquinolinyl, benzothiaphenyl, oxazolyl, indazoleyl, or any other substituted group, especially mono- or di-substituted groups.

[0076] The substituents of heteroaryl groups are diverse and selected from: -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'

[0077] 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, the number of which ranges from zero to the total number of open valences of the ring system; and wherein R', R” and R”' are independently selected from hydrogen, (C1-C8)alkyl and C3-8 heteroalkyl, and phenyl.

[0078] As used herein, the terms "ring member" and "ring vertex" are intended to have the same meaning. For example, a six-membered ring has six ring vertices.

[0079] As used herein, the term "salt" refers to an acidic or basic salt of a compound used in the methods of this invention. Illustrative examples of pharmaceutically acceptable salts are salts of inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium compounds (methyl iodide, iodoethane, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.

[0080] The pharmaceutically acceptable salts of the acidic compounds of the present invention are salts formed with bases, i.e., cationic salts, such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, and ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tri-(hydroxymethyl)-methyl-ammonium salts.

[0081] Similarly, acid addition salts, such as inorganic acids, organic carboxylic acids, and organic sulfonic acids, such as hydrochloric acid, methanesulfonic acid, and maleic acid, are also possible, provided that a basic group, such as a pyridyl group, forms part of the structure.

[0082] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from its various salt forms in some physical properties, such as solubility in polar solvents, but in other respects the salts are equivalent to the parent form of the compound for the purposes of this invention.

[0083] 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 aluminosilicate, calcium arsenate, calcium borate, calcium bromide, calcium carbide, calcium carbonate, calcium chlorate, calcium chloride, calcium citrate, calcium citrate malate, calcicyanamide, calcium dihydrogen phosphate, calcium fluoride, calcium formate, calcium gluconate, calcium glucoheptonate, calcium gluconate, calcium glycerophosphate, calcium hexaborate, calcium hydride, calcium hydroxide, calcium hypochlorite, calcium inosine, calcium iodate, calcium iodide, calcium lactate, calcium lactate gluconate, calcium magnesium acetate, calcium malate, calcium nitrate, calcium nitride, calcium oxalate, calcium oxide, and calcium panthenium sulfate. (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 heptaaluminate, tricalcium aluminate, tricalcium phosphate, and triple superphosphate. Those skilled in the art will understand that other calcium salts can be used in this invention.

[0084] As used herein, the term "hydrate" refers to a compound that is complexed with at least one water molecule. The compounds of the present invention can be complexed with 1 to 10 water molecules. The term "hydrate" also includes hemihydrates, wherein the revitalized compound contains two compounds for each water molecule.

[0085] Some compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers and monomeric isomers are all intended to be included within the scope of the present invention.

[0086] As used herein, the term "object" refers to animals such as mammals, including but not limited to: primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the object is a human.

[0087] As used herein, the terms “therapeutic effective dose” or “therapeutic adequate dose” or “effective or adequate dose” refer to the dose that produces a therapeutic effect on the subject to which the drug is administered. The precise dose will depend on the purpose of treatment and is determined by a person skilled in the art using known techniques (see, for example, 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, edited by Gennaro, Lippincott, Williams, and Wilkins). In sensitized cells, the therapeutic effective dose may generally be lower than the conventional therapeutic effective dose in unsensitized cells.

[0088] As used herein, the term "injured site or local condition" refers to a specific location within a subject's body that requires treatment by the methods of the present invention. For example, an injury may be a fracture, and a local condition may be a disease state (e.g., osteoporosis), limited to a specific location within the subject's body, such as a particular bone, joint, finger, hand, foot, limb, spine, head, trunk, etc. In some embodiments, the injured site or local condition is a surgical implantation site.

[0089] As used herein, the term "promotes bone formation" refers to stimulating new bone formation, bone growth through joints or spaces, enhancing or accelerating bone formation, and / or increasing bone density or bone mineral content. In some embodiments, a compound promotes bone formation if, relative to a control sample (a sample not exposed to the compound), it increases the amount of bone in the sample by at least 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more.

[0090] As used in this article, the term "arthrodesis" refers to the surgical placement of arthroplasty between two bones.

[0091] Artificial ossification of the joint can be induced across the joint. Joint fixation can be achieved through bone grafting, metal implants, or the use of synthetic bone substitutes.

[0092] As used in this article, the term "autograft" refers to the transplantation of the subject's own bone.

[0093] As used in this article, the term "allogeneic bone graft" refers to bone transplantation from one person to another.

[0094] As used in this article, the term "anti-resorption drug" refers to drugs that slow down or prevent bone resorption and / or act on osteoclasts.

[0095] As used herein, the term "bone-related disease characterized by low bone mass" refers to bone with a T-score less than -0.5. Other methods for determining low bone mass are known to those skilled in the art.

[0096] As used herein, the term "fracture" refers to bone that has broken, fractured, or snapped at one or more locations along the bone. In some embodiments, the term "fracture" also includes a missing portion of bone.

[0097] As used in this article, the term "spinal fusion" refers to a surgical technique used to combine or fuse two or more vertebrae.

[0098] As used herein, the term "structural support" refers to a portion of a device that can be implanted into a subject (the implantable portion). Structural supports can be made from a variety of different materials, including metals, ceramics, polymers, and inorganic materials, as described below. Structural supports can be coated with a variety of materials that promote bone growth. In some embodiments, the entire device includes the implantable structural support. For example, in some embodiments, the entire device, as described herein, can be implanted at a surgical site, and the surgical site can be closed over the device.

[0099] As used herein, the term "external coating" refers to a coating on a structural support that may cover only a portion of the structural support (partial external coating) or cover the entire structural support. For example, a partial external coating may cover only the implantable portion of the structural scaffold.

[0100] As used in this article, the terms “weak bone,” “low bone mineral density,” or “low bone mass” refer to bone with a T score of less than -0.5 (less than 0.9 g / cm2).

[0101] As used herein, the term "demineralized bone" refers to bone from which inorganic minerals have been removed. The remaining organic gelling material may contain bone-inducing growth factors. These growth factors include bone morphogenetic proteins, which induce cartilage to ossify through endochondral ossification to generate new bone. Demineralized bone is often found in the form of "demineralized bone matrix (DBM)." DBM can be made from large blocks of fresh, frozen, or freeze-dried allogeneic bone, or from mild acid extraction of cadaveric bone to remove the mineral phase, leaving collagen, growth factors, and non-collagenous proteins, thus providing the intrinsic properties for bone guidance. DBM can also be processed in various ways to ultimately produce a powder that is mixed with a carrier to provide the optimal handling properties required by the surgeon. Clinically, DBM is available in gels, pastes, putties, and fabrics, which are customized to meet the needs of surgical procedures. Some DBM is mixed with antibiotics prior to surgery.

[0102] As used in this article, the term "kidney damage" refers to the kidneys' inability to excrete waste products and help maintain the body's electrolyte balance. Kidney damage is characterized by some of the following: high blood pressure, urea buildup and uremic frost formation, potassium buildup in the blood, decreased erythropoietin synthesis, increased fluid volume, hyperphosphatemia, and metabolic acidosis.

[0103] As used herein, the term "diabetes" refers primarily to a condition characterized by the body's inability to produce sufficient amounts of insulin (a hormone produced in the pancreas). When released into the bloodstream, insulin induces cells to take up glucose. Therefore, insufficient insulin leads to elevated blood sugar levels in affected individuals. Those skilled in the art will recognize that the body's inability to produce sufficient amounts of insulin can be a characteristic feature of both type 1 and type 2 diabetes.

[0104] As used herein, the term "bone-guided matrix" refers to a material that can act as a bone-guided matrix (i.e., allows bone growth) and has a scaffold structure on which infiltrating cells can attach, proliferate, and participate in the production of osteoid (the organic phase of bone), ultimately leading to bone formation or new bone formation. The terms "matrix" and "scaffold" are interchangeable and refer to structural components or matrices that are inherently three-dimensional in form, on which specific cellular events involving bone formation will occur. The bone-guided matrix allows host capillaries, perivascular tissue, and osteoprogenitor cells to grow inward. In some embodiments, the bone-guided matrix includes a "bone inducer" for providing osteogenic potential. As used herein, a bone inducer is an agent that stimulates the proliferation of host osteocytes to produce more osteoid.

[0105] As used herein, the terms “treatment,” “therapeutic,” and “treatment” refer to any indicator of success in treating or alleviating an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameters such as the elimination of symptoms; relief; reduction or making the symptoms, injury, pathology, or condition more tolerable for the patient; reduction of the frequency or duration of symptoms or condition; or, in some cases, prevention of the onset of symptoms or condition. Treatment or relief of symptoms can be based on any objective or subjective parameters, including, for example, the results of a physical examination.

[0106] As used herein, the term "RankL inhibitor" refers to a compound or agent that inhibits RankL activity. RankL (a receptor activator of nuclear factor κB ligand) plays an important role in bone metabolism by activating osteoclasts. RankL inhibitors include, but are not limited to, the human monoclonal antibody denosumab. Those skilled in the art will understand that other RankL inhibitors may be used in this invention.

[0107] As used herein, the term "parathyroid hormone" or "PTH" refers to compounds or agents that act on PTH receptors to activate the pathway. PTH plays an important role in bone metabolism by activating osteoblasts. PTH includes, but is not limited to, teriparatide, Forteo, and abaloparatide-SC. Those skilled in the art will understand that other PTHs may be used in this invention.

[0108] As used herein, the term "combination therapy" refers to the combination of the invention used together with the compounds of the invention, either before or after administration.

[0109] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and monomeric isomers (e.g., single enantiomers) are all intended to be included within the scope of the present invention. In some embodiments, the compounds of the present invention are substantially free of other forms of specific enantiomers or diastereomers. The compounds of the present invention may also contain atomic isotopes in non-natural proportions on one or more atoms constituting these compounds. For example, the compounds may be radiolabeled with radioactive or non-radioactive isotopes, such as deuterium (…). 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variants of the compounds of this invention, whether radioactive or not, are intended to be included within the scope of this invention.

[0110] III. Compounds and Compositions

[0111] In some embodiments, the present invention provides compounds according to Formula I:

[0112]

[0113] or its salt, hydrate, prodrug or isomer, wherein

[0114] X is selected from CR 3b and N, wherein N is optionally oxidized to the corresponding N-oxide;

[0115] Y is selected from CR 3c and N, wherein N is optionally oxidized to the corresponding N-oxide;

[0116] Z is selected from CR 3d and N, wherein N is optionally oxidized to the corresponding N-oxide,

[0117] The additional condition is that at least one of X, Y, and Z is N or a corresponding N-oxide;

[0118] A is

[0119] R N Selected from heterocyclic and heteroaryl groups, wherein

[0120] The heterocyclic moiety is selected from monocyclic, fused bicyclic, and bridged rings. The monocyclic heterocyclic moiety contains 4 to 7 ring members, while the fused bicyclic and bridged bicyclic heterocyclic moiety contains 7 to 10 ring members. Each heterocyclic moiety has 1 to 3 heteroatoms selected from N, O, and S as ring members, wherein each heterocyclic moiety contains at least one nitrogen atom as a ring member and is optionally surrounded by 1-3 R atoms. 6 Partial replacement,

[0121] The heteroaryl moiety contains 5 to 10 ring members, wherein at least one ring member is a nitrogen atom and optionally surrounded by 1 to 3 R atoms. 6 Partial replacement,

[0122] Each R 2 R 3b R 3c and R 3d Independently selected from the group consisting of: H, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl-OH, -O-C1-6 alkane-OH, C 3-6 cycloalkyl-C 1-4 Alkyl groups and –OH groups;

[0123] R 6 Selected from the following group: –OH, C 1-3 Alkyl, C1-3 alkyl -OH, -OC 1-3Alkyl, C 3-4 Heteroalkyl, C 1-3 Halogenated alkyl, -O-C1-3 halogenated alkyl, halogen and oxo.

[0124] In some embodiments, the present invention provides compounds according to formula Ia:

[0125]

[0126] Each of the variable positions is defined as in Equation I.

[0127] In some embodiments, the present invention provides compounds according to formula Ib:

[0128]

[0129] Each of the variable positions is defined as in Equation I.

[0130] In some embodiments, the present invention provides compounds according to formula Ic:

[0131]

[0132] Each of the variable positions is defined as in Equation I.

[0133] In some embodiments, the present invention provides compounds according to formula Id:

[0134]

[0135] Each of the variable positions is defined as in Equation I.

[0136] In some embodiments, each R2 in formula I, Ia, Ib, Ic, or Id is independently selected from the group consisting of halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, and C1-6 alkoxy groups. In some embodiments, R in formula I, Ia, Ib, Ic, or Id... 2 C 1-6 Alkyl or C1-6 haloalkyl. In some embodiments, R in formula I, Ia, Ib, Ic, or Id 2 It is CH3 or CF3. In some embodiments, R in formula I, Ia, Ib, Ic or Id 2 It is CF3.

[0137] In some implementations, when one of formulas I, Ia, Ib, Ic, or Id is present, each R 3b R 3c and R 3dIndependently selected from the group consisting of: H, halogens, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. In some embodiments, when present in formula I, Ia, Ib, Ic, or Id, each R 3b R 3c and R 3d Independently, it is H, halogen, and C1-6 alkoxy. In some embodiments, when present in formula I, Ia, Ib, Ic, or Id, each R 3b R 3c and R 3d It is H, F, and methoxy. In some embodiments, when present in formula I, Ia, Ib, Ic, or Id, R 3b R 3c and R 3d At least one of them is F. In some embodiments, when one of formulas I, Ia, Ib, Ic or Id is present, R 3b R 3c and R 3d At least one of them is a methoxy group. In some embodiments, when present in formula I, Ia, Ib, Ic or Id, R 3b R 3c and R 3d At least one of them is F, and R 3b R 3c and R 3d At least one of them is a methoxy group.

[0138] In some implementations, R in formula I, Ia, Ib, Ic, or Id N It is a heteroaryl group. In some embodiments, the heteroaryl moiety comprises 4 to 8 ring members, wherein at least one ring member is a nitrogen atom and optionally surrounded by 1 to 3 R atoms. 6 Partial replacement.

[0139] In some implementations, R in formula I, Ia, Ib, Ic, or Id N It is a monocyclic heterocyclic group.

[0140] In some implementations, R in formula I, Ia, Ib, Ic, or Id N for

[0141]

[0142] In some implementations, R in formula I, Ia, Ib, Ic, or Id 6 Selected from the following groups: -OH, C 1-3 Alkyl, C1-3 alkyl -OH, -OC 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OC 1-3Halogenated alkyl groups, halogens, and oxo groups. In some embodiments, R in formula I, Ia, Ib, Ic, or Id... 6 Selected from the following group: C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl groups and halogens. In some embodiments, R 5 For –OH, C 1-3 Alkyl or –OC 1-3 alkyl.

[0143] In some embodiments, the present invention provides compounds of formula I, wherein,

[0144]

[0145] or its salt, hydrate, prodrug or isomer, wherein

[0146] R 2 Selected from the following groups: H, C 1-6 Alkyl and C1-6 haloalkyl,

[0147] R 3c If present, it is an H or C1-6 alkoxy group;

[0148] R 3b Or R 3d If present, it is H or a halogen; and

[0149] A is

[0150] R N It is a heterocyclic or heteroaryl group, and in which

[0151] X, Y, and Z, as well as A, are defined as in Formula I and the sub-implementations described herein.

[0152] In some embodiments, the present invention provides compounds of formula I, wherein

[0153]

[0154] or its salt, hydrate, prodrug or isomer, wherein

[0155] R2 is H, a C1-6 haloalkyl, or a C1-6 alkyl;

[0156] R 3c If present, it is a C1-6 alkoxy group;

[0157] R 3b Or R 3d If present, it is H or a halogen;

[0158] A is and

[0159] R N for and

[0160] X, Y, and Z are defined as above.

[0161] In some embodiments of compounds of formula Ia, Ib, Ic or Id

[0162] R 2 It is a C1-6 alkyl or a C1-6 haloalkyl;

[0163] R 3b If present, it is either hydrogen or halogen;

[0164] R 3c It is a C1-6 alkoxy group; and

[0165] R N It is a heterocyclic group or a heteroaryl group.

[0166] In some embodiments of compounds of formula Ia, Ib, Ic or Id

[0167] R 2 It is a C1-6 haloalkyl group;

[0168] R 3b If present, it is either hydrogen or halogen;

[0169] R 3c It is a C1-6 alkoxy group;

[0170] A is and

[0171] R N for

[0172] In some embodiments of compounds of formula Ia, Ib, Ic or Id

[0173] R 2 It's CF3; and

[0174] R 3b If present, it is either hydrogen or halogen;

[0175] R 3c It is a methoxy group; and among them

[0176] A is and

[0177] R N As defined in Formula I and the sub-implementations described herein.

[0178] In one set of embodiments, the compound of formula I has a structure selected from the following:

[0179]

[0180] In some embodiments, the present invention provides formate salts of compounds according to any of the above-described compounds. In some embodiments, the present invention provides citrate salts of compounds according to any of the above-described compounds. In some embodiments, the present invention provides hydrochloride salts of compounds according to any of the above-described compounds.

[0181] 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 compounds of formula I, Ia, Ib, Ic, or Id.

[0182] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound according to formula I, Ia, Ib, Ic or Id and a pharmaceutically acceptable excipient.

[0183] The compounds of this invention can be in salt form. Salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, phosphonates, isonicotinates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and dihydroxynaphthyl acid (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthylcarboxylic acid)) salts. Other salts include, but are not limited to, salts formed with inorganic bases, including alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; aluminum salts; and ammonium salts. Other salts with organic bases include salts with diethylamine, diethanolamine, meglumine, and N,N'-dibenzylethylenediamine. In some embodiments, the present invention provides hydrochloride salts.

[0184] In some embodiments, the compounds of the present invention contain nitrogen atoms that are optionally further oxidized, i.e., the compound is an N-oxide. By way of example only, in one case, the nitrogen atom in the pyridyl-indolyl ring system of the compound of formula I, Ia, Ib, Ic or Id is oxidized to the corresponding N-oxide.

[0185] 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 a further embodiment, the prodrug moiety comprises a conjugating group that allows selective targeting of bone structures. Examples of such modifications have been described in Erez et al., Bioorganic and Medicinal Chemistry Letters, 2008, 18, 816-820 and Neale et al., Bioorganic and Medicinal Chemistry Letters, 2009, 19, 680-683, which are incorporated herein by reference. Therefore, estradiol conjugates and / or bisphosphonate conjugates of Formula I compounds are contemplated within the scope of the embodiments presented herein.

[0186] The compounds of this invention can be prepared by a variety of methods known to those skilled in the art (see Comprehensive Organic Transformations, Richard C. Larock, 1989). Those skilled in the art will understand that other methods for preparing the compounds can be used in this invention. Exemplary synthetic methods for the compounds of Formula I are described in the following Examples section and in Scheme 1.

[0187] Option 1

[0188]

[0189] Starting with compound 1, reacting it with compound 2 containing a leaving group (LG) yields compound I. Various leaving groups are applicable, including but not limited to halogens, activated esters, methanesulfonates, trifluoromethanesulfonates, or any other suitable leaving group that allows attachment of the following group at the 9-position of the core ring system.

[0190] Optionally, in R 3c In the case of a methoxy group, it can be converted to a hydroxyl group by demethylation using the methods described, such as HBr in acetic acid, or boron tribromide, or any other suitable method. Optionally, the compound of formula I contains an N-oxide, which is prepared by oxidation using, for example, chloroperbenzoic acid.

[0191] IV. Methods to promote bone formation

[0192] In another aspect, the present invention provides a method for promoting bone formation and fusion in a subject in need by administering a therapeutically effective amount of a compound of the present invention (e.g., a compound or composition of formula I, Ia, Ib, Ic or Id, as described in Section III above).

[0193] In some embodiments, the present invention provides a method for promoting bone formation in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I:

[0194]

[0195] or its salt, hydrate, prodrug or isomer, wherein

[0196] X is selected from CR 3b and N, wherein N is optionally oxidized to the corresponding N-oxide;

[0197] Y is selected from CR 3c and N, wherein N is optionally oxidized to the corresponding N-oxide;

[0198] Z is selected from CR 3d and N, wherein N is optionally oxidized to the corresponding N-oxide,

[0199] An additional condition is that at least one of X, Y, and Z is N or a corresponding N-oxide;

[0200] A is

[0201] R N Selected from the following group: heterocyclic and heteroaryl, wherein

[0202] The heterocyclic moiety is selected from monocyclic, fused bicyclic, and bridged rings. The monocyclic heterocyclic moiety contains 4 to 7 ring members, while the fused bicyclic and bridged bicyclic heterocyclic moiety contains 7 to 10 ring members. Each heterocyclic moiety has 1 to 3 heteroatoms selected from N, O, and S as ring members, wherein each heterocyclic moiety contains at least one nitrogen atom as a ring member and is optionally surrounded by 1-3 R atoms. 6 Partial replacement,

[0203] The heteroaryl moiety contains 5 to 10 ring members, wherein at least one ring member is a nitrogen atom and optionally surrounded by 1 to 3 R atoms. 6 Partial replacement,

[0204] Each R 2 R 3b R 3c and R 3d Independently selected from the group consisting of: H, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl-OH, -O-C1-6 alkyl-OH, C 3-6 cycloalkyl-C 1-4 Alkyl groups and –OH groups;

[0205] R 6Selected from the following group: –OH, C 1-3 Alkyl, C1-3 alkyl -OH, -OC 1-3 Alkyl, C 3-4 Heteroalkyl, C 1-3 Halogenated alkyl, -O-C1-3 halogenated alkyl, halogen and oxo.

[0206] In some embodiments, the method includes administering to a subject a therapeutically effective amount of the hydrochloride, sulfate, formate, or citrate of a compound of formula I, Ia, Ib, Ic, or Id.

[0207] Those skilled in the art will recognize that osteoblast mineral deposition (bone formation) can be achieved through local, systemic, or a combination of local and systemic administration. In some embodiments, bone formation is localized. Subjects requiring localized bone formation may have any of a variety of diseases or conditions (including, but not limited to, osteoporosis, fractures, or diseases or conditions characterized by low bone mass or poor mineralization as described herein). In some embodiments, subjects require spinal fusion, bone fusion, arthroplasty, or orthopedic, dental, or periodontal synthetic bone grafts or implants. In some embodiments, the invention provides methods for promoting bone formation at the site of injury or in the presence of a localized condition. In some embodiments, the invention includes methods for fusing bone (e.g., at the site of injury). In some embodiments, the site of injury is a surgical site. In other embodiments, the injury is a fracture, osteoporosis, or periodontal disease.

[0208] In some embodiments, bone formation is systemic. Systemic bone formation refers to the formation of the entire skeleton of the subject and affects all bones in the subject's body. Subjects requiring systemic bone formation may have any of a variety of diseases or disease states. In some embodiments, the subject has a low bone mass / density condition / disease (primary or secondary), fracture, periodontal disease / condition, or a disease / condition that leads to poor bone mineralization (e.g., osteogenesis imperfecta or HPP). Low bone mass can be determined by a variety of methods known to those skilled in the art. For example, low bone mass / density can be characterized by a T-score of less than about -0.5. Low bone mass / density conditions / diseases include, but are not limited to, osteoporosis, osteopenia and osteoporotic pseudoglioma syndrome (OPPG), glucocorticoid-induced low bone mass / density, and osteogenesis imperfecta. In some other embodiments, a low bone mass condition / disease may be osteopenia or osteoporotic pseudoglioma syndrome (OPPG), HPP, or glucocorticoid-induced low bone mass / density, or other diseases that lead to secondary low bone density conditions.

[0209] Local and / or systemic bone formation using the compounds or compositions of the present invention can be achieved according to any of a variety of methods. Methods for formulating and administering the compounds and compositions of the present invention (e.g., compounds or compositions of Formula I) are described in Section VII below. In some embodiments, methods for promoting bone formation include implanting a medical device described herein (e.g., in Section VIII below) into a subject in need of this procedure.

[0210] Methods that promote osteoblast mineral deposition, ultimately increasing bone mineralization or density, can be used to treat diseases characterized by secondary induced osteoporosis (low bone mass), including but not limited to osteomalacia, polyostotic fibrous dysplasia, osteogenesis imperfecta, Paget's disease, rheumatoid arthritis, zero gravity, osteoarthritis, prolonged inactivity or lack of exercise, arthroplasty, osteomyelitis, celiac disease, Crohn's disease, ulcerative colitis, inflammatory bowel disease, gastrectomy, secondary induced osteoporosis, amenorrhea, Cushing's disease, Cushing's syndrome, diabetes mellitus, eating disorders, hyperparathyroidism, hyperthyroidism, hyperphosphatemia (HPP), hyperprolactinemia, and Kleinfelter syndrome. Osteoporosis caused by various factors including: thyroid disease, Turner syndrome, steroid-induced osteoporosis, osteoporosis caused by epilepsy or depression, immobility, arthritis, secondary osteoporosis caused by cancer, low bone mass caused by gonadotropin-releasing hormone agonists, low bone mass caused by thyroid medications, low bone mass caused by phenytoin, depakote, chemotherapy, immunosuppressants, blood thinners, Graves' disease, juvenile rheumatoid arthritis, malabsorption syndrome, anorexia nervosa, kidney disease, anticonvulsant therapy (e.g., for epilepsy), corticosteroid therapy (e.g., for rheumatoid arthritis, asthma), immunosuppressive therapy (e.g., for cancer), malnutrition (especially calcium and vitamin D), excessive exercise leading to amenorrhea, and smoking.Osteoporosis associated with alcoholism and pregnancy, copper deficiency, type 2 diaminouric aciduria, Werner syndrome, Hajdu-Cheney syndrome, juvenile malformation with extraosseous hypertrophy, type 2 methylmalonic aciduria, cystathionine β-synthiasis deficiency, exemestane, hyperimmune globulin E (IgE) syndrome, hemochromatosis, Singleton-Merten syndrome, homozygous β-thalassemia, reflex sympathetic osteodystrophy, sarcoidosis, Winchester syndrome, Hallermann-Streiff syndrome (HSS), cyproterone acetate, glycerol kinase deficiency, Bonnet-Dechaume-Blanc syndrome, prednisolone, heparin, and senile dysplasia of the bone. Osteodysplastica, Torg's osteolysis syndrome, orchiectomy, Fabry's disease, Pseudoprogeria syndrome, Wolcott-Rallison syndrome, ankylosing spondylitis, myeloma, systemic infantile hyaluronic acidemia, Albright's hereditary osteodystrophy, anorexia nervosa, autoimmune lymphoproliferative syndrome, Brown-Sequard syndrome, Diamond-Blackfan anemia, eating disorders, galactorrhea-hyperprolactinemia, gonadal dysgenesis, nephropathy, Menkes disease. Diseases, menopause, neuritis, FSH resistance-induced ovarian insufficiency, familial ovarian insufficiency, premature ovarian failure, primary biliary cirrhosis, prolactinoma, familial prolactinoma, renal osteodystrophy, ulcerative colitis, underweight, Werner syndrome, bone tumors, bone cancer, brittle bone disease, osteonecrosis, congenital osteogenesis imperfecta, late-onset osteogenesis imperfecta, osteogenesis imperfecta, glucocorticoid-induced osteopenia / osteoporosis, and periodontal disease. Those skilled in the art will understand that other types of conditions, diseases, and treatments can also lead to osteoporosis.

[0211] Bone formation can be measured using any of a variety of methods known to those skilled in the art. Methods for measuring bone formation include, but are not limited to, uCT (mini-CT), dual X-ray absorption (bone mineral density), ultrasound, QCT, SPA, DPA, DXR, SEXA, QUS, X-ray, use of the human eye during surgical procedures, Alizarin Red S, serum osteocalcin, serum alkaline phosphatase, serum osteocalcin (BGP), bone mineral content, bone ash weight, serum calcium, serum phosphorus, tantalum markers, and serum IGF-1.

[0212] Many indicators of bone formation can be used to measure and / or quantify the amount of bone formation, including bone mineral density (BMD). In some embodiments, bone formation can be demonstrated by an increase in BMD of 0.1%. In other embodiments, bone growth can be demonstrated by an increase in BMD 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 higher. Bone mineral density can be measured using various methods, including T-score and Z-score. The Z-score is the number of standard deviations above or below the mean for the patient's age and sex. The T-score is the number of standard deviations above or below the mean for healthy 30-year-old adults of the same sex as the patient. Low bone mass is characterized by a T-score of -1 to -2.5. Osteoporosis is characterized by a T-score less than -2.5. Improvement in either the T-score or Z-score indicates bone growth. Bone mineral density can be measured at multiple locations in the bone (e.g., the spine or hip joint). Those skilled in the art will understand that other methods for determining bone mineral density can be used in this invention.

[0213] V. Treatment methods for kidney injury

[0214] In another aspect, the present invention provides a method for treating kidney injury 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) to a subject suffering from kidney injury.

[0215] Kidney injury can be caused by a variety of diseases known to those skilled in the art. In some embodiments, kidney injury is caused by infection, radiation, toxins, dehydration, or trauma. Toxins that cause kidney damage include, but are not limited to, chemicals, poisons, and chemotherapeutic agents. Those skilled in the art will understand that kidney injury from other causes can be treated by the methods of the present invention.

[0216] Kidney injury treatable by the compounds of this invention includes acute renal failure. Acute renal failure is also known as acute kidney failure or acute kidney injury. Acute renal failure results in the retention of nitrogenous (urea and creatinine) and nitrogenless waste products that are normally excreted by the kidneys. Depending on the severity and duration of renal insufficiency, this accumulation is accompanied by metabolic disturbances such as metabolic acidosis (blood acidification) and hyperkalemia (elevated potassium levels), changes in fluid balance, and effects on other organ systems. Acute renal failure is characterized by oliguria or anuria (decreased or stopped urine output), although non-uremia-related acute renal failure can also occur.

[0217] Subjects can be characterized as having (1) the risk of acute injury; (2) kidney injury leading to harm; (3) acute renal failure; or (4) loss of renal function. The risk characteristics of acute kidney injury are a 1.5-fold increase in serum creatinine or a urine output of <0.5 ml / kg body weight over 6 hours. Harm occurs when serum creatinine increases 2.0-fold or urine output is <0.5 ml / kg over 12 hours. Failure is defined as a 3.0-fold increase in serum creatinine or creatinine >355 μM (an increase >44) or urine output less than 0.3 ml / kg over 24 hours. Loss of renal function is defined as a subject experiencing persistent acute renal failure or complete loss of renal function for more than four weeks.

[0218] Kidney biopsy can be performed in cases of acute renal failure to provide a definitive diagnosis and sometimes even a prognostic idea, unless the cause is clear and appropriate screening tests are reliably negative.

[0219] The renal therapeutic agent of the present invention can be used in subjects who have already suffered kidney injury or are at risk of chronic renal failure. As used herein, a subject is considered to have chronic renal failure or be at risk of chronic renal failure, or be at risk of requiring renal replacement therapy (i.e., chronic hemodialysis, continuous peritoneal dialysis, or kidney transplantation), if it is reasonably expected that the subject will suffer progressive renal function loss associated with progressive loss of nephron function. Whether a particular subject has chronic renal failure or is at risk of chronic renal failure can be routinely determined by a person skilled in the art in the relevant medical or veterinary fields. Subjects with chronic renal failure, at risk of chronic renal failure, or at risk of requiring renal replacement therapy include, but are not limited to, the following: subjects who can be considered to have chronic renal failure, end-stage renal disease, chronic diabetic nephropathy, hypertensive nephrosclerosis, chronic glomerulonephritis, hereditary nephritis, and / or renal dysplasia; subjects whose biopsy shows glomerular hypertrophy, tubular hypertrophy, chronic glomerulosclerosis, renal cell carcinoma, and / or chronic tubulointerstitial sclerosis; subjects whose ultrasound, MRI, CAT scan, or other non-invasive examinations show renal fibrosis; subjects with an abnormal number of extensive morphological changes in urinary sediment; and subjects whose GFR is consistently lower than approximately 50% of the subject's expected GFR, especially lower than approximately 40%, 30%, or... 20% of the subjects; human male subjects weighing at least about 50 kg and with a long-term glomerular filtration rate of less than about 50 ml / min, especially less than about 40 ml / min, 30 ml / min or 20 ml / min; human female subjects weighing at least about 40 kg and with a long-term glomerular filtration rate of less than about 40 ml / min, more especially less than about 30 ml / min, 20 ml / min or 10 ml / min; subjects with fewer than about 50% of the number of functional nephrons in healthy but otherwise similar subjects, more especially less than about 40%, 30% or 20% of the number of functional nephrons in subjects; subjects with a single kidney; and subjects who are kidney transplant recipients.

[0220] VI. Treatment methods for diabetes

[0221] The compounds and compositions of the present invention can also be used for the treatment of diabetes. Therefore, some embodiments of the present invention provide a method for treating diabetes. This method comprises administering a therapeutically effective amount of a compound of the present invention (e.g., a compound or composition of formula I, Ia, Ib, Ic, or Id as described in Part III above) to a subject in need.

[0222] Diabetes is a disease in which the body is unable to produce any or enough insulin, resulting in elevated blood sugar levels in the affected individual. Without being bound by any particular theory, the compounds and compositions of the present invention are believed to help treat diabetes by regenerating pancreatic cells. In some embodiments, the compounds of the present invention are believed to induce the regeneration of β cells in the pancreas. See, for example, Wang P. et al., Nat Med., 21(4): 383-388 (2015).

[0223] The diabetes treatment agent of the present invention can be used in subjects who have pancreatic damage, are in a pre-diabetic state, or have diabetes. As used herein, a subject with pancreatic damage is one whose insulin production has decreased, falls below the standard, or is absent. Whether a subject is considered pre-diabetic or diabetic depends on many factors, including the subject's fasting blood glucose level. Patients with fasting blood glucose levels above 100 mg / dL are considered pre-diabetic. If a subject's fasting blood glucose level is above 125 mg / dL, the subject is considered to have diabetes.

[0224] Pancreatic injury can be caused by a variety of diseases known to those skilled in the art. In some embodiments, pancreatic injury is caused by infection, autoimmune disease, radiation, toxins, 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 pancreatic injury caused by other reasons can be treated by the methods of the present invention.

[0225] In some embodiments, the disease being treated is type 1 diabetes. In some embodiments, the disease being treated is type 2 diabetes.

[0226] The compounds of this invention can be administered sequentially or in combination with other therapeutic agents that can be used to treat diabetes. In some embodiments, the other therapeutic agents are antidiabetic drugs. Diabetic drugs include, but are not limited to, lipid-lowering / lipid-regulating agents, drugs for treating diabetic complications, anti-obesity drugs, antihypertensive drugs, SGLT1 inhibitors, SGLT2 inhibitors, anti-hyperuric acid drugs, and drugs for treating chronic heart failure, atherosclerosis, or related diseases.

[0227] VII. Methods for treating bone loss

[0228] In another aspect, the present invention provides a method for treating bone loss by administering a therapeutically effective amount of a compound of the present invention (e.g., a compound or composition of formula I, Ia, Ib, Ic or Id as described in Part III above) to a subject suffering from bone loss.

[0229] like Figure 1As shown, an individual's bone mineral density can be described by net bone loss (bone resorption) and increase (bone formation). In individuals with bone loss, net bone resorption exceeds bone formation, resulting in bone loss and reduction. It is anticipated that, in certain embodiments of the present invention, bone loss can be treated by inhibiting or reducing bone resorption while stimulating or promoting bone formation.

[0230] Anti-resorption drugs are compounds that slow down the process of bone resorption. Anti-resorption drugs include, but are not limited to, RankL inhibitors, denosumab, Prolia, cathepsin K modulators, alendronate, Fosamax, selective estrogen receptor modulators (SERMS), calcium, estrogen, bisphosphonates, and calcitonin.

[0231] The compounds and compositions of the present invention treat bone loss by promoting bone formation. When the compounds of the present invention are administered sequentially or in combination with one or more anti-resorption agents, the rate of bone resorption is inhibited or reduced, and the rate of bone formation is stimulated.

[0232] The compounds and compositions of the present invention, as well as the anti-reabsorption agents described herein, can be administered sequentially or in combination. Further details of combination therapies are discussed in Section IX.C below.

[0233] 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 sequentially with one or more anti-resorption agents, the rate of bone resorption is inhibited or reduced and the amount of bone formation is maintained.

[0234] The compounds and compositions of the present invention can be administered to patients who have been treated with anti-resorption agents, either continuously or sequentially, to inhibit or reduce the rate of bone resorption and maintain the amount of bone formation.

[0235] VIII. Methods of Treating Cancer

[0236] The compounds and compositions of the present invention can also be used to treat cancer. Therefore, some embodiments of the present invention provide a method for treating cancer. This method includes administering a therapeutically effective amount of a compound of the present invention (e.g., a compound or composition of formula I, Ia, Ib, Ic, or Id as described in Part III above) to a subject in need.

[0237] In some embodiments, the compounds of the present invention can be used to treat proliferative diseases such as cancer, leukemia, and other diseases associated with uncontrolled cell proliferation, such as psoriasis and restenosis. As defined herein, antiproliferative activity within the scope of the invention can be demonstrated by the ability to inhibit cell proliferation in in vitro whole-cell assays, for example using any cell line A549, HT29, Saos-2, HeLa, or MCF-7, or by showing inhibition of CDK enzymes (e.g., CDK2 or CDK4), MTT, or BRDU in appropriate assays. Using such cell line and enzyme assays, it can be determined whether a compound is antiproliferative in the context of the present invention.

[0238] As used herein, the term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, malignant glioma, neuroblastoma, stomach, skin, corneal acanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver and biliary tract cancer, kidney cancer, medullary disease, lymphoid disease, Hodgkin's disease, hair cell carcinoma, buccal cavity and pharynx (oral cavity), lips, tongue, mouth, pharynx, small intestine, colon and rectum, large intestine, rectum, brain and central nervous system, and leukemia. Those skilled in the art will understand that other cancers and proliferative diseases can be treated with the compounds and compositions of the present invention.

[0239] In some embodiments, the cancer is bone cancer, colon cancer, multiple myeloma, stomach 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.

[0240] IX. Formulation and Administration

[0241] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein (e.g., a compound or composition of Formula I as described in Section III above) and a pharmaceutically acceptable excipient. In other embodiments, the composition further comprises a bone-guiding matrix.

[0242] The compositions of the present invention can be in the form of a pharmaceutical composition containing an antagonist and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include aqueous solutions, such as physiologically buffered saline, or other buffers, solvents, or mediators, such as ethylene glycol, glycerol, oils such as olive oil, or injectable organic esters. The choice of a pharmaceutically acceptable carrier will depend in part on the chemical properties of the compound.

[0243] The compounds of the present invention can be formulated in a variety of different ways known to those skilled in the art. A pharmaceutically acceptable carrier depends in part on the specific composition being administered and the specific method of administration. Therefore, a variety of suitable formulations of the pharmaceutical compositions of the present invention exist (see, for example, Remington Pharmaceutical Sciences).

[0244] (Remingtons Pharmaceutical Sciences, 20th ed., 2003).

[0245] Pharmaceutically acceptable carriers may include physiologically acceptable compounds, such as those that 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 appreciate that the selection of pharmaceutically acceptable carriers, including physiologically acceptable compounds, depends, for example, on the route of administration and their specific physiological and chemical properties.

[0246] Typically, such carriers are non-toxic to recipients at the doses and concentrations used. The preparation of such compositions usually involves mixing the therapeutic agent with buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) peptides, proteins, amino acids, carbohydrates (including glucose, maltose, sucrose-glucan, dextrin, cyclodextrin, or sulfobutylcyclodextrin), chelating agents such as EDTA, glutathione, and other stabilizers and excipients. Neutral buffered saline or saline mixed with nonspecific serum albumin is an exemplary suitable diluent.

[0247] The amount of the compounds or compositions of the present invention (e.g., compounds or compositions of Formula I as described herein) administered to an individual will depend in part on the severity of the disease and / or injury. Methods for determining the effective amount of the agent for a diagnostic or therapeutic procedure are well known in the art, including Phase I, II, and III clinical trials or pilot and pivotal trials (FDA device approval pathway). Typically, when administered systemically, the agent is given at a dose of about 0.0001 to 500 mg / kg body weight, while when administered directly to a wound site, it is given at a concentration of about 0.1 nM to 1000 μM.

[0248] The total amount of the compound or composition may be administered to the subject as a single dose in a large pellet or by infusion over a relatively short period of time, or it may be administered using a fractionated treatment regimen in which multiple doses are administered over a longer period of time. Those skilled in the art will recognize that the concentration of a particular compound or composition that provides an effective amount to one or more injured areas depends on many factors, including the subject's age and overall health condition, as well as the route of administration, timing, frequency of administration, and the nature of the compound. Taking these factors into account, those skilled in the art will adjust the specific dosage to obtain an effective amount that promotes bone formation for therapeutic purposes.

[0249] The pharmaceutical formulation is preferably a unit dosage form. In this form, the formulation is divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as packaged tablets, capsules, transdermal patches, ampoules, and powder in vials, ampoules, or on a bone-guided matrix. Similarly, the unit dosage form itself can be a capsule, tablet, pouch, or lozenge, or can be any appropriate quantity of these in packaged form. If desired, the composition may also contain other compatible therapeutic agents. Preferred pharmaceutical formulations can deliver the compounds of the invention in the form of sustained-release formulations.

[0250] In some embodiments, the method of the present invention includes the use of the compounds described herein in a mixture comprising other pharmaceuticals, such as antibiotics, antifungals, anabolic osteopathies, antiresorption agents, and / or anti-inflammatory agents. Alternatively, the method may include sequentially administering the compounds described herein and one or more other pharmaceuticals to a patient to optimize the treatment regimen. In such optimization, the pharmaceuticals comprising the compounds of the present invention may be administered in any order and in any combination.

[0251] Individuals treated with the compounds and compositions of the present invention can be any mammal, such as humans or non-human mammals, such as primates, dogs, cats, horses, cattle, goats, sheep, pigs, mice or rats, or any commercially viable or domesticated animal.

[0252] In some embodiments, the individual to be treated by the method according to the invention is an individual who has received or is receiving an anti-reabsorption therapy. For example, in some embodiments, the anti-reabsorption therapy may be administered simultaneously with the compound or composition of the invention. In some embodiments, the anti-reabsorption therapy and the therapy with the compound or composition of the invention are administered sequentially (either the anti-reabsorption therapy is administered before or after the anti-reabsorption therapy). In some embodiments, the individual may have previously been treated with an anti-reabsorption agent. In some embodiments, the individual may be treated with an anti-reabsorption agent concurrently during a first portion of the treatment process with the compound or composition of the invention, but may discontinue the anti-reabsorption agent treatment during a second portion of the treatment process. In some embodiments, the individual to be treated by the method according to the invention has not yet been treated with an anti-reabsorption agent. In some embodiments, the individual is treated with an anti-reabsorption agent after treatment with the compound or composition of the invention.

[0253] In some embodiments, the individual to be treated by the method according to the invention is an individual who has received or is receiving a combination of anti-resorption and / or bone anabolic agents. For example, in some embodiments, anti-resorption and / or bone anabolic therapy may be administered concurrently with the compounds or compositions of the invention. In some embodiments, anti-resorption and / or bone anabolic therapy and the compounds or compositions of the invention are administered sequentially (anti-resorption therapy is administered before or after the anti-resorption therapy). In some embodiments, the individual may have previously been treated with anti-resorption and / or bone anabolic agents. In some embodiments, the individual may be treated with anti-resorption agents / / or bone anabolic agents concurrently during a first portion of the treatment process with the compounds or compositions of the invention, but may discontinue treatment with anti-resorption agents and / or bone anabolic agents during a second portion of the treatment process. In some embodiments, the individual to be treated by the method according to the invention has not yet been treated with anti-resorption agents and / or bone anabolic agents. In some embodiments, the individual is treated with anti-resorption and / or bone anabolic agents after treatment with the compounds or compositions of the invention.

[0254] In some embodiments, the compounds and compositions of the present invention are administered systemically. In some embodiments, the compounds and compositions of the present invention are administered topically.

[0255] A. System delivery

[0256] In some embodiments, the compounds and compositions of the present invention are administered systemically. Systemic administration of the compounds and compositions of the present invention can, for example, be used to treat systemic diseases or conditions characterized by systemic effects, namely, low bone mass (e.g., osteoporosis), diabetes, cancer, or kidney disease.

[0257] The pharmaceutical compositions of the present invention can be prepared for administration via a variety of different routes. Typically, the type of carrier is selected based on the route of administration. The pharmaceutical compositions can be formulated for any suitable route of administration, including, for example, local, oral, nasal, intrathecal, rectal, vaginal, sublingual, or parenteral administration, including subcutaneous, intravenous, intramuscular, intrasternal, transdermal, cavernous sinus, intratracheal, or intraurethral injection or infusion. The pharmaceutical compositions (e.g., for oral administration or delivery by injection) can be in liquid form (e.g., elixirs, syrups, solutions, emulsions, or suspensions). Liquid pharmaceutical compositions may include one or more of, for example, sterile diluents such as water for injection, saline solutions (preferably physiological saline), Ringer's solution, isotonic sodium chloride, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other solvents that can be used as solvents or suspension media; antibacterial agents; antioxidants; chelating agents; buffers such as acetate, citrate, or phosphate; and agents for adjusting tension, such as sodium chloride or glucose. Parenteral preparations can be packaged in glass or plastic ampoules, disposable syringes, or multi-dose vials. Physiological saline is preferred, and the injectable pharmaceutical composition is preferably sterile.

[0258] The formulations of the present invention are also suitable for administration in all body cavities, including but not limited to the pleura, peritoneum, skull, mediastinum, pericardium, bursae or mucous bursae, epidural space, intrathecal space, intraocular space, intra-articular space, intervertebral disc space, intramedullary space, and perispinal space.

[0259] Formulations suitable for oral administration may consist of: (a) a liquid solution, such as a suspension in a diluent, such as water, saline, or PEG400, in an effective amount of the compound of the present invention; (b) capsules, sachets, long-acting formulations, or tablets, each containing a predetermined amount of the active ingredient, in liquid, solid, granule, or gelatin form; (c) a suspension in a suitable liquid; (d) a suitable emulsion; and (e) a patch. Pharmaceutical forms may include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, dextran, dextrin, cyclodextrin, sulfobutyl cyclodextrin, microcrystalline cellulose, gelatin, colloidal silica, talc, magnesium stearate, and stearic acid, as well as other excipients, colorants, fillers, binders, diluents, buffers, humectants, preservatives, flavorings, dyes, disintegrants, pharmaceutically acceptable carriers, and other ingredients classified as inert by the FDA. The tablet form may be an active ingredient contained in a flavoring agent (e.g., sucrose), or an active ingredient contained in an inert matrix, such as gelatin and glycerin or sucrose and gum arabic emulsions, gels, etc., and may also contain a carrier known in the art in addition to the active ingredient.

[0260] Specific oral formulations suitable for use in this invention include, but are not limited to, buffered aqueous solutions with a pH of 4 to 10; and unbuffered aqueous systems with a pH of 2 to 10; aqueous solutions containing propylene glycol, glycerol, ethanol, or combinations thereof as cosolvents; and formulations containing one or more emulsifiers, such as one or more saturated polyglycerol esters (e.g., Aqueous solutions of the present invention include: aqueous solutions of methylcellulose; aqueous suspensions containing methylcellulose (optionally containing sodium dodecyl sulfate, sodium lauryl sulfate, docusate, or polysorbate 80 at a subcritical 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 / span 80, glyceryl mono / diester or capric acid / caprylic acid (IMWITOR 742) / polysorbate 80 (70:30), polyethoxylated palm kernel oil / polyethylene glycol (PEG) 400 or 600 / water; aqueous solutions of surfactants containing polysorbate 80 and SDS or SLS; oil suspensions containing soybean oil and safflower oil; and compounds or compositions of the present invention prepared in nanoparticles.

[0261] Formulations suitable for intravenous bolus administration of compounds or compositions include, but are not limited to, aqueous solutions containing buffered or non-buffered salt solutions, optionally including glucose; cosolvent systems containing glycerol, ethanol, propylene glycol, PEG 300 or 400, glycogen, N-methylpyrrolidone (NMP), dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), or combinations thereof in water; aqueous solutions containing surfactants including polysorbate 80; aqueous solutions containing cyclodextrins (e.g., hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin); oily emulsions; plasmas; and aqueous suspensions of methylcellulose and / or sodium dodecyl sulfate, sodium lauryl sulfate, docusate, or polysorbate 80, optionally containing a subcritical micelle concentration (CMC).

[0262] Formulations suitable for intravenous infusion of compounds or compositions include, but are not limited to, aqueous solutions containing buffered or non-buffered saline, optionally including glucose, mannitol or lactose; or any of the formulations listed above for intravenous bolus injection.

[0263] Preparations suitable for intramuscular, subcutaneous, or intraperitoneal administration include, but are not limited to, solutions in oils, such as 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 glucose (in water); or any of the preparations listed above for intravenous bolus administration.

[0264] Formulations suitable for ocular administration include, but are not limited to, buffered or non-buffered aqueous solutions with a pH of 4 to 9, such as saline, which may include hydroxyethyl cellulose; aqueous suspensions; or oily emulsions containing, for example, mineral oil, peanut oil, or petrolatum.

[0265] Typical formulations for topical / transdermal drug delivery include creams, ointments, sprays, lotions, and patches. The topical / transdermal formulations disclosed herein comprise propylene glycol, isopropyl myristate, PEG 300, PEG 400, paraffin, or mixtures thereof, and optionally may also include ethanol or isopropanol.

[0266] The compounds of the present invention can also be included in sustained-release formulations to prolong the duration of treatment after a single dose. In one embodiment, the formulation is prepared in the form of microspheres. Nanoparticles / microspheres can be prepared as a homogeneous matrix of the compound and a biodegradable controlled-release material, containing other drugs required for treatment. The nanoparticles / microspheres are preferably prepared at a size suitable for penetration and / or injection, and are injected systemically or directly at the treatment site.

[0267] Some sustained-release formulations include biodegradable and / or slowly dissolving polymer matrices. Such polymer matrices include polyvinylpyrrolidone, low and medium molecular weight hydroxypropyl cellulose and hydroxypropyl methyl cellulose, croscarmellose sodium, carboxymethyl starch, potassium methacrylate divinylbenzene copolymer, polyvinyl alcohol, starch, starch derivatives, microcrystalline cellulose, ethyl cellulose, methyl cellulose and cellulose derivatives, β-cyclodextrin, sulfobutyl cyclodextrin, poly(methyl vinyl ether / maleic anhydride), dextran, scierozlucan, mannan, xanthan gum, alginic acid and its derivatives, dextrin derivatives, glyceryl monostearate, semi-synthetic glyceryl monostearate, glyceryl palmitate, glyceryl behenate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, sodium stearate, talc, sodium benzoate, boric acid, and colloidal silica.

[0268] The sustained-release agent of the present invention may also include 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, waxes, and mono-, di-, and tri-substituted glycerides. The sustained-release agent may also be prepared according to the general description in WO94 / 06416.

[0269] B. Local delivery

[0270] In some embodiments, the compounds and compositions of the present invention are administered topically. Topical administration of the compounds and compositions of the present invention can be used for, for example, fracture healing, fusion (e.g., arthroplasty), orthopedic reconstruction, and periodontal restoration. In some embodiments, topical administration includes administering the compound or composition together with a suitable carrier material capable of maintaining the compound at the site of application or capable of providing structural load. In some embodiments, the carrier is a biocompatible, biodegradable or absorbable matrix and / or sufficiently porous to allow cell infiltration. In some embodiments, the compounds or compositions of the present invention (e.g., compounds or compositions of Formula I) are topically administered via an implantable medical device.

[0271] The compounds and compositions of the present invention, in combination with suitable delivery or support systems (e.g., scaffolds or matrices as described herein), can be used for clinical applications. As disclosed herein, the matrix can be combined with compounds or compositions of Formula I to reliably and reproducibly induce bone formation in mammals. The matrix preferably comprises particles of porous material. The pore size preferably allows progenitor cells to migrate into the matrix and subsequently differentiate and proliferate. In some embodiments, the pore size 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, 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 fabricated by tightly packing particulate material into a shape that spans the bone defect, or it can be made by structuring biocompatible materials on demand, preferably biodegradable or absorbable in vivo, to serve as a “temporary scaffold” and basis for recruiting migrating progenitor cells and as a foundation for their subsequent anchoring and proliferation. In some embodiments, the scaffold or matrix includes a mesh structure, a foam structure, a sponge structure, or a fibrous structure.

[0272] Scaffolds or matrices used to deliver the compounds of the present invention may comprise synthetic, biological materials or combinations thereof. In some embodiments, the scaffold or matrix comprises naturally occurring polymers, synthetic biodegradable polymers, synthetic non-biodegradable polymers, bioceramics, bioglasses, or combinations thereof. Natural and synthetic polymers, bioceramics, and bioglasses used for scaffolds are known in the art. See, for example, Dhandayuthapani et al., International Journal of Polymer Science, Vol. 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 fiber scaffold, a microsphere scaffold, a polymer-bioceramic composite scaffold, or a cell-free scaffold.

[0273] In some embodiments, the scaffold or matrix is ​​a bone-guiding matrix. Non-limiting examples of suitable bone-guiding matrix materials include, for example, collagen; homopolymers or copolymers of glycolic acid, lactic acid, and butyric acid, including derivatives thereof; ceramics, hydroxyapatite, tricalcium phosphate, biphasic calcium phosphate and other calcium phosphates, and calcium sulfate, or combinations thereof. Generally, bone-guiding matrices considered herein include at least one of the previously listed materials. Other matrices that can be used in this invention include, but are not limited to, biocomposite bone grafts, Kryptonite bone cement (Doctors Research Group, Oxford, CT), Vitoss, Vitoss BA, Orthoblend, Grafton, Arthrex, allogeneic grafts (Allograft), Cadaverbone, Ostoset, Novabone, Augmatrix, absorbable artificial bone (Mastergraft), Hydroset, Pro-dense, Pro-stim, Hydroset, (porous) tantalum bone grafts, titanium mesh, titanium bone grafts, and Genex bone grafts. Combinations of these matrix materials are also useful. Bone-guiding matrices may also include structural supports such as calcium salts, calcium sulfate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-based hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, calcined gypsum, phosphoproteins, borosilicates, bioactive glass, biocompatible ceramics, calcium phosphate ceramics, polytetrafluoroethylene, sulfates, collagen, glycolic acid, lactic acid, and butyric acid homopolymers or copolymers, including their derivatives; as well as ceramics, hydroxyapatite, tricalcium phosphate, biphasic calcium phosphate, and other calcium phosphates, and calcium sulfate. Other matrices that can be used in this invention include, but are not limited to, biocomposite bone grafts, kryptonite bone cement (Physician Research Group, Oxford, CT), Vitoss, Vitoss BA, Orthoblend, Grafton, Rex, allogeneic grafts, Cadaverbone, Ostoset, Bexon, Augmatrix, absorbable artificial bone, Hydroset, Pro-dense, Pro-stim, Hydroset, (porous) tantalum bone grafts, titanium mesh, titanium bone grafts, and Genex bone graft hydrogel.

[0274] In some embodiments, the bone-guiding matrix comprises a bone-inducing agent and optionally a structural support. The bone-inducing agent can be any agent that promotes bone formation. In some embodiments, the bone-inducing agent is allogeneic bone, autologous bone, demineralized bone, or periodontal ligament cells.

[0275] C. Combination therapy

[0276] In the methods of carrying out the present invention, the pharmaceutical composition may be used alone or in combination with other therapeutic or diagnostic agents. Additionally, the medical devices described herein include compounds of Formula I used alone or in combination with other therapeutic or diagnostic agents. Other drugs used in the combination schemes of the present invention may be administered separately, or one or more drugs used in the combination scheme may be administered together, for example, in the form of a mixture. If one or more drugs are administered separately, the timing and schedule of administration for each drug may differ. Other therapeutic or diagnostic agents may be administered simultaneously, separately, or at different times with the compounds of the present invention.

[0277] 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 present invention are combined with another drug, both may be administered co-administered or separately. Co-administration includes administering other agents within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours, and within 1 to 7 days (e.g., 1, 2, 3, 4, 5, 6, or 7 days), 1 to 4 weeks (e.g., 1, 2, 3, or 4 weeks), or 1 or 18 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months) of administering the compounds of the present invention. Co-administration also includes administering other agents and the compounds of the present invention simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes, or on the same day, in the same week, or in the same month), or in any order. In some embodiments, co-administration includes administering other agents (e.g., anti-reabsorption agents) over a period of time (e.g., weeks, months, or years), followed by administering a compound or composition of Formula I over a period of time (e.g., days, weeks, months, or years), and then administering other drugs (e.g., anti-reabsorption agents) alone or in combination with a compound or composition of Formula I. In some embodiments, the other agents and the compounds of the present invention may be administered once daily, or twice, three times, or more daily to provide a preferred daily dose level.

[0278] In some embodiments, co-administration can be achieved through co-formulation, i.e., preparing a single pharmaceutical composition comprising the compound of the present invention and a second therapeutic agent (e.g., an anti-reabsorption agent). In other embodiments, the compound of the present invention and the second therapeutic agent are formulated separately.

[0279] One or more other therapeutic agents may be delivered by any suitable means. The pharmaceutical formulation is preferably a unit dosage form. In this form, the formulation is further divided into unit doses containing appropriate amounts of the anti-reabsorption agent and / or the compound of the present invention. The unit dosage form may be a packaged formulation containing discrete amounts of the formulation, such as packaged tablets, capsules, and powder in vials or ampoules. Similarly, the unit dosage form itself may be a capsule, tablet, sachets, patch, or lozenge, or may be any suitable quantity of these packaged forms.

[0280] One or more other therapeutic agents may be present in any suitable amount and may depend on various factors, including but not limited to the subject's weight and age, disease state, etc. Suitable dosage ranges for one or more other therapeutic agents in combination with the compounds or compositions of the present invention include about 0.0001 ug to about 10,000 mg, or about 0.0001 ug to about 1000 mg, or about 0.0001 ug to about 500 mg, or about 0.0001 ug to about 1000 ug, 0.1 ug to about 10,000 mg, or about 0.1 ug to about 1000 mg, or about 0.1 ug to about 500 mg, or about 0.1 ug to about 1000 mg. ug or about 1ug to about 1000mg, or about 1ug to about 500mg, or about 1ug to about 50mg, or about 1ug to about 1000ug, or about 10ug to about 1000mg, or about 10ug to about 500mg, or about 10ug to about 50mg, or about 0.1mg to about 10,000mg, or about 1mg to about 1000mg, or about 10mg to about 750mg, or about 25mg to about 500mg, or about 50mg to about 250mg. Suitable doses of one or more other therapeutic agents in combination with the compounds or compositions 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.

[0281] 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 in any suitable weight ratio, for example, about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, or about 1:25 to about 25:1, or about 1:10 to about 10:1, or about 1:5 to about 5:1 (w / w) or about 1:1 (w / w). Other doses and dose ratios of the antiresorption agents and the compounds of the present invention are applicable to the compositions and methods of the present invention.

[0282] The composition may also contain other compatible therapeutic agents. The compounds described herein may be combined with each other, or used in combination with other active agents or adjuvants, which may not be effective on their own but may contribute to the efficacy of the active agents.

[0283] In some embodiments, the compounds or compositions described herein (e.g., compounds or compositions of formula I, Ia, Ib, Ic, or Id as described herein) are administered to an individual treated according to the method of the invention, in combination with or sequentially with an anti-resorption agent. Anti-resorption agents include those that slow or prevent bone resorption. The administration of the compounds or compositions described herein and the anti-resorption agent can promote local bone growth and / or systemic bone growth. In some embodiments, the administration of the compounds or compositions described herein and the anti-resorption agent promotes systemic bone growth. Bone growth can be achieved by increasing bone mineral content, increasing bone density, and / or new bone growth. In other embodiments, systemic bone growth is achieved through the local application of the compounds or compositions described herein and the anti-resorption agent.

[0284] Anti-reabsorption agents that can be used in the methods of this invention include, but are not limited to, denosumab, prolifia, RankL inhibitors, bisphosphonates (e.g., fosamax, denosumab, prolifia, Actonel, or zoledronic acid), alendronate, and Bonviva. TM Zometa TM Olpadronate, neridronate, skelid, bonofos, selective estrogen receptor modulators (SERMs) or analogs (e.g., raloxifene), calcitonin, calcitonin analogs (e.g., miacalcic), parathyroid hormone, calcilytics, calcimimetic agents (e.g., cinacalcet), statins, anabolic steroids, lanthanum and strontium salts, sodium fluoride, vitamin D or vitamin D analogs, CatK inhibitors, prostaglandin inhibitors or phosphodiesterase E inhibitors.

[0285] In some implementations, the anti-reabsorption agent is denosumab.

[0286] The bisphosphonate used in the methods of this invention can be any suitable bisphosphonate. In some embodiments, the bisphosphonate is nitrogen-containing, such as pamidronate (APD, Aredia), neridonate, opamidronate, alendronate (Fosamax), ibandronate (Boniva), riseronate (Atrofen), and zoledronic acid (Zometa). In other embodiments, the bisphosphonate is nitrogen-free, such as etidronate (Didronel), clodronate (Bonefos, Loron), and skelid. Those skilled in the art will understand that other bisphosphonates may also be used in this invention.

[0287] The SERM useful in the method of this invention can be any suitable SERM. In some embodiments, the SERM can be clomiphene, raloxifene, tamoxifen, toremifene, basildenafil, lasoxifene, or olmexifen. Those skilled in the art will recognize that other SERMs are useful in this invention.

[0288] The anti-reabsorption agent can also be any suitable calcitonin analog or cathepsin K inhibitor. In some embodiments, calcitonin analogs that can be used in the methods of the present invention include, but are not limited to, miacalcic. Those skilled in the art will understand that other calcitonin analogs can be used in the present invention.

[0289] The vitamin D analogues that can be used in the methods of this invention can be any suitable vitamin D analogue. In some embodiments, vitamin D analogues that can be used in the methods of this 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 (sitosterol). Those skilled in the art will understand that other vitamin D analogues can be used in this invention.

[0290] RankL inhibitors that can be used in this invention include any compound that inhibits RankL activity. For example, RankL inhibitors include, but are not limited to, the human monoclonal antibody denosumab or proglin. Those skilled in the art will understand that other RankL inhibitors can be used in this invention.

[0291] In some embodiments, compounds or compositions described herein (e.g., compounds or compositions of formula I, Ia, Ib, Ic, or Id as described herein) are administered to an individual treated according to the method of the invention in combination with or sequentially with an anabolic agent. Anabolic agents include, but are not limited to, parathyroid hormone (PTH) or analogues thereof, sclerosing protein inhibitors, bone morphogenetic protein (BMP) or BMP agonists, bone marrow stem cell populations, or mesenchymal stem cell populations.

[0292] In some embodiments, the anabolic agent is parathyroid hormone (PTH) or an analogue thereof (e.g., teriparatide (Forteo)). In some embodiments, the anabolic agent is a sclerosing protein antibody (Mab) inhibitor. In some embodiments, 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 contents of which are incorporated herein by reference for all purposes. In some embodiments, the anabolic agent is a bone marrow stem cell population. In some embodiments, the anabolic agent is a mesenchymal stem cell population.

[0293] X. Medical Equipment

[0294] In some embodiments, the present invention provides a medical device formed of a structural support, wherein an implantable portion of the structural support is adapted for permanent implantation into a subject, wherein the implantable portion is attached to bone, and the structural support is loaded with a coating comprising at least a portion of a compound of formula I described herein (e.g., in Part III above). In some embodiments, the medical device is an orthopedic or periodontal medical device.

[0295] Other aspects of the present invention relate to medical implants. Such medical devices and implants include, for example, US Patent Application Publication Serial No. 20060177475 by David Rueger et al., published August 10, 2006, and published US Patent Nos. 6,190,880, 5,344,654, 5,324,819, 5,468,845, 6,949,251, 6,426,332 and 5,656,593, as well as osteogenic devices and methods of repairing endochondral and osteochondral defects using such devices, the subject matter of which is incorporated herein by reference.

[0296] These medical devices typically provide structural support with implantable portions, preferably adapted for mechanical engagement with bone and / or cartilage, for example, as taught in U.S. Publication Serial No. 2006 / 0178752, published August 10, 2006 by Joseph Vaccarino III et al., the subject matter of which is incorporated herein by reference. These bone implants are intended to contain an active agent in at least a portion thereof. As shown in U.S. Publication Serial No. 2006 / 0188542, published August 24, 2006 by John Dennis Bobyn et al., the subject matter of which is incorporated herein by reference, the active agent is preferably formulated to be locally delivered to the bone near the implant for sustained release or at least a two-stage release protocol. In the latter, a first stage rapidly releases a first amount of the active agent, and a second and subsequent stage gradually releases a second amount of the active agent, thereby modulating bone formation stimulated by the active agent.

[0297] Medical devices such as bone implants are characterized in that the implantable portion, loaded with a compound or composition of the present invention (e.g., a compound or composition of Formula I), promotes faster and more complete bone formation in situ. The implantable portion of the medical device is desirably at least partially or completely covered or impregnated with a compound or composition of the present invention. In some embodiments, the medical device is externally coated with a compound or composition described herein. In some embodiments, the external coating completely coats the implantable 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) contains an external coating of the compound or composition described herein, and also contains the compound or composition within the support (i.e., internally).

[0298] The medical device of the present invention includes pins, rods, screws, plates, and orthopedic or dental implants. In some embodiments, the medical device is made of materials including metals, polymers, or ceramics, or combinations thereof. Metals that can be used to manufacture the medical device of the present invention include, but are not limited to, cobalt, chromium, elemental chromium, stainless steel, titanium, titanium alloys, tantalum, and trabecular metals. Polymers that can be used to manufacture the medical device 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. Other useful polymers are described below. Ceramics that can be used to manufacture the medical device of the present invention include, but are not limited to, alumina, calcium phosphate, hydroxyapatite, zirconium oxide, and silicon oxide.

[0299] In some other embodiments, the implantable portion of the structural support includes a bone-guiding matrix. The matrix material can be conducive to bone growth. This may be ideal for materials such as teeth and artificial bone grafts. Alternatively, when the implantable portion is load-bearing and formed of, for example, stainless steel, these implantable portions may be ideal when they are formed together 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 facilitates the formation of new bone growth.

[0300] In some embodiments, the matrix comprises particles of porous material. The pore size preferably allows progenitor cells to migrate into the matrix and subsequently differentiate and proliferate. In some embodiments, the matrix has a pore size of 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 comprises a mesh structure, a foam structure, a sponge structure, or a fibrous structure.

[0301] Scaffolds or matrices used in the devices described herein may comprise synthetic and / or biological materials. In some embodiments, the scaffold or matrix comprises naturally occurring polymers, synthetic biodegradable polymers, synthetic non-biodegradable polymers, bioceramics, bioglasses, bioactive glasses, biocomplexes, or combinations thereof. Natural and synthetic polymers, bioceramics, and bioglasses used in scaffolds are known in the art. See, for example, Dhandayuthapani et al., International Journal of Polymer Science, Vol. 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 fiber scaffold, a microsphere scaffold, a polymer-bioceramic composite scaffold, or a cell-free scaffold.

[0302] In some embodiments, suitable matrices include those comprising composite biomaterials having a sponge-like structure, such as those containing, for example, phosphoproteins and / or collagen, as taught in U.S. Publication Serial No. 2006 / 0188544 by Takashi Saitos, published August 24, 2006, the contents of which are incorporated herein by reference. Such coatings include, for example, single-layer and multi-layer coatings taught in U.S. Publication Serial No. 2006 / 0204542 by Zongtao Zhang et al., published September 14, 2006, and those in U.S. Patent Serial Nos. 6,949,251, 5,298,852, and 5,939,039, and can be manufactured by conventional methods, including those taught herein, the subject of which is incorporated herein by reference.

[0303] In some embodiments, the matrix is ​​a bone-guiding matrix. In some embodiments, the bone-guiding matrix includes bone-inducing agents, such as allogeneic bone, autologous bone, demineralized bone, or periodontal ligament cells, or combinations thereof. In some other embodiments, the bone-guiding matrix may be calcium salts, calcium sulfate, biphasic calcium phosphate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-based hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, calcined plaster, phosphoprotein, borosilicate, biocompatible ceramics, calcium phosphate ceramics, polytetrafluoroethylene, sulfates, borosilicates, bioactive glass, absorbable artificial bone (Mastergraft) variants, Vitoss variants, cement hydrogels, or combinations thereof. Those skilled in the art will understand that other bone-guiding matrices and bone-inducing agents may be used in this invention.

[0304] In some embodiments, the medical device described herein comprises a compound of Formula I and an additional therapeutic agent. Suitable additional therapeutic agents, including combinations, are discussed in Section IX.C. above. For example, a medical device may comprise a compound of Formula I in combination with an anabolic agent. In some embodiments, the medical device described herein comprises a compound of Formula I in combination with bone morphogenetic protein (BMP) or a BMP agonist. In some embodiments, 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 contents of which are incorporated herein by reference for all purposes.

[0305] XI. Determination of compounds for the treatment of bone loss

[0306] Compounds suitable for use in the methods of this invention can be identified using a variety of methods known to those skilled in the art. Several exemplary methods for identifying such antagonists are described herein, including cell-based and in vitro techniques (Journal of Bone and Mineral Research, 2006, 21(11), 1738-1749). A general approach to identifying compounds involves assessing the effect of antagonist candidates on bone formation under controlled conditions. Preferably, bone formation is determined using the Dexa technique on live animals or using uCT on ex vivo samples. Preferred animals include rodents, more preferably primates. The femur, tibia, and vertebrae are particularly useful subjects for this type of study.

[0307] In short, test animals are treated with a predetermined dose of the candidate compound. Control animals are treated with a control solution, preferably a non-irritating buffer solution or other carrier. Ideally, the control solution is a carrier in which the candidate compound is not present when it is delivered to the carrier. Multiple doses of the candidate compound can be administered to test animals, preferably according to a predetermined dosing schedule. The dosing schedule can be over several days, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 days or longer; over several weeks, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or longer; or over several months, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 months or longer.

[0308] In one exemplary embodiment, the candidate compound can be administered topically in situ to test animals, while control animals receive an equal volume of a control solution without the candidate compound. The appropriate dose will depend on the nature of the specific candidate compound being tested. For example, care should be taken when administering the compound to ensure that systemic administration (e.g., by oral or injectable route, such as intravenous, subcutaneous, or intramuscular) is also possible. The dose administered via nebulization, eye drops, or oral intake should be sufficient to produce blood levels of the candidate compound similar to those achieved by systemic injection. The amount of candidate compound that can be achieved via nebulization, eye drops, or oral intake depends on the nature of the inhibitor used and can be determined through routine experiments.

[0309] Once the dosing schedule is completed, the test animals and control animals are examined to determine the amount of bone formation present. This can be done by any suitable method, but is preferably performed on live animals to analyze bone mineral content. Methods for microCT examination of the bones of animals are well known in the art. Candidate compounds suitable for promoting bone formation are identified by noting a significant increase in bone formation in the test animals compared to the control animals. In some embodiments, a candidate compound is identified as suitable for promoting bone formation if the amount of bone formation in the test bones 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 comparable bones of the control animals. In some implementations, bone formation is increased 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%, at least 50%, or more compared to control animals. Where necessary, the level of bone formation can be calculated by determining the amount of bone formation present in each animal. This calculation can be performed by constructing a three-dimensional image of bone formation and calculating the volume from the image using, for example, histomorphometry.

[0310] An example of the molecular modeling system generally described above consists of CHARMm and the QUANTA program (Polygen, Waltham, MA). CHARMm performs energy minimization and molecular dynamics functions.

[0311] QUANTA performs molecular structure construction, graphical modeling, and analysis. QUANTA allows for the construction, modification, visualization, and behavioral analysis of interactions between molecules.

[0312] Compound identification can also be achieved using a process called computer or molecular modeling, which visualizes the three-dimensional atomic structure of a selected molecule and allows for the design of new compounds that will interact with that molecule. The three-dimensional structure typically depends on X-ray crystallographic analysis or NMR imaging data of the selected molecule. Molecular dynamics requires force field data. Computer graphics systems can predict how a new compound will connect with a target molecule and allow for experimental manipulation of the structures of both the compound and the target molecule to achieve perfect binding specificity. Predicting molecule-compound interactions when small changes are made to one or both requires molecular mechanics software and computationally intensive computing, typically coupled between the molecular design program and the user through a user-friendly, menu-driven interface.

[0313] XII. Specific Embodiments of this Disclosure

[0314] Implementation method 1. According to the compound of formula I:

[0315]

[0316] or its salt, hydrate, prodrug or isomer, wherein

[0317] X is selected from CR 3b and N, wherein N is optionally oxidized to the corresponding N-oxide;

[0318] Y is selected from CR 3c and N, wherein N is optionally oxidized to the corresponding N-oxide;

[0319] Z is selected from CR 3d and N, wherein N is optionally oxidized to the corresponding N-oxide,

[0320] An additional condition is that at least one of X, Y, and Z is N or a corresponding N-oxide;

[0321] A is

[0322] R N Selected from heterocyclic and heteroaryl groups, wherein

[0323] The heterocyclic moiety is selected from monocyclic, fused bicyclic, and bridged rings. The monocyclic heterocyclic moiety contains 4 to 7 ring members, while the fused bicyclic and bridged bicyclic heterocyclic moiety contains 7 to 10 ring members. Each heterocyclic moiety has 1 to 3 heteroatoms selected from N, O, and S as ring members, wherein each heterocyclic moiety contains at least one nitrogen atom as a ring member and is optionally surrounded by 1-3 R atoms. 6 Partial replacement,

[0324] The heteroaryl moiety contains 5 to 10 ring members, wherein at least one ring member is a nitrogen atom and optionally surrounded by 1 to 3 R atoms. 6 Partial replacement,

[0325] Each R 2 R 3b R 3c and R 3d Independently selected from the group consisting of: H, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl-OH, -O-C1-6 alkyl-OH, C 3-6 cycloalkyl-C 1-4 Alkyl groups and –OH groups;

[0326] R 6 Selected from the following group: –OH, C 1-3Alkyl, C1-3 alkyl -OH, -OC 1-3 Alkyl, C 3-4 Heteroalkyl, C 1-3 Halogenated alkyl, -O-C1-3 halogenated alkyl, halogen and oxo.

[0327] Implementation Method 2. The compound of Implementation Method 1 has the formula Ia, Ib, Ic or Id:

[0328]

[0329] Implementation Method 3. The compound according to Implementation Method 1 or 2, wherein R 2 Selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0330] Implementation Method 4. The compound according to Implementation Method 1 or 2, wherein R 2 It is selected from halogens, C1-6 alkyl groups, C1-6 haloalkyl groups, and C1-6 alkoxy groups.

[0331] Embodiment 5. The compound according to Embodiment 4, wherein R 2 C 1-6 Alkyl or C1-6 haloalkyl.

[0332] Implementation Method 6. The compound according to Implementation Method 5, wherein R 2 It is CH3 or CF3.

[0333] Embodiment 7. The compound according to Embodiment 6, wherein R 2 It is CH3.

[0334] Implementation Method 8. The compound according to Implementation Method 6, wherein R 2 It is CF3.

[0335] Embodiment 9. A compound according to any one of Embodiments 1 to 8, wherein

[0336] When it exists, each R 3b R 3c and R 3d Independently selected from the group consisting of: H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.

[0337] Embodiment 10. The compound according to Embodiment 9, wherein

[0338] When it exists, each R 3b R 3c and R 3dIt is independently selected from the following group: H, halogens and C1-6 alkoxy groups.

[0339] Embodiment 11. The compound according to Embodiment 10, wherein

[0340] When it exists, each R 3b R 3c and R 3d It is independently selected from the following groups: H, F and methoxy.

[0341] Embodiment 12. A compound according to any one of Embodiments 1 to 8, wherein

[0342] R 3c (If present) is a methoxy group.

[0343] Embodiment 13. A compound according to any one of Embodiments 1 to 11, wherein

[0344] R N It is a heterocyclic group or a heteroaryl group.

[0345] Embodiment 14. The compound according to Embodiment 13, wherein R N It is a heterocyclic group.

[0346] Embodiment 15. The compound according to Embodiment 14, wherein R N It is a monocyclic heterocyclic group.

[0347] Embodiment 16. The compound according to Embodiment 13, wherein R N for

[0348]

[0349] Embodiment 17. The compound according to Embodiment 1, wherein

[0350] R 2 Selected from the following groups: H, C 1-6 Alkyl and C1-6 haloalkyl,

[0351] R 3c (If present) is an H or C1-6 alkoxy group;

[0352] R 3b Or R 3d (If present) is H or a halogen; and

[0353] R N It is a heterocyclic group or a heteroaryl group.

[0354] Embodiment 18. The compound according to Embodiment 17, wherein

[0355] R 2 It is an H or C1-6 haloalkyl group;

[0356] R 3c (If present) is a C1-6 alkoxy group;

[0357] R 3b Or R 3d (If present) is H or a halogen; and

[0358] R N for

[0359] Implementation Method 19. The compound according to Implementation Method 2, wherein

[0360] R 2 C1 - 6-alkyl or C1-6 haloalkyl;

[0361] R 3b (If present) is hydrogen or halogen;

[0362] R 3c It is a C1-6 alkoxy group; and

[0363] R N It is a heterocyclic group or a heteroaryl group.

[0364] Embodiment 20. The compound according to Embodiment 19, wherein

[0365] R 2 It is a C1-6 haloalkyl group;

[0366] R 3b (If present) is hydrogen or halogen;

[0367] R 3c It is a C1-6 alkoxy group; and

[0368] R N for

[0369] Embodiment 21. The compound according to Embodiment 20, wherein

[0370] R 2 It's CF3; and

[0371] R 3c It is a methoxy group.

[0372] Implementation Method 22. The compound of Implementation Method 1 is selected from the group consisting of:

[0373]

[0374] Or its salt, hydrate, or prodrug.

[0375] Implementation Method 23. Formate salt of any one of Implementation Methods 1 to 22.

[0376] Implementation Method 24. The sulfate of any one of the compounds in Implementation Methods 1 to 22.

[0377] Embodiment 25. Citrate of any one of Embodiments 1 to 22.

[0378] Embodiment 26. The hydrochloride salt of any one of Embodiments 1 to 22.

[0379] Implementation Method 27. A prodrug of any one of the compounds in Implementation Methods 1 to 22.

[0380] Implementation Method 28. A pharmaceutical composition comprising a compound of any one of Implementation Methods 1-27 and a pharmaceutically acceptable excipient.

[0381] Implementation 29. A method for promoting bone formation in a subject in need, comprising administering to the subject a compound of any one of embodiments 1 to 28 that is therapeutically effective, thereby promoting bone formation in the subject.

[0382] Implementation 30. The method according to Example 29, wherein bone formation is promoted at the surgical site of injury or local lesion.

[0383] Implementation 31. The method according to Example 30, wherein bone formation is promoted at a surgical site selected from the group consisting of fractures and osteoporosis.

[0384] Implementation Method 32. The method according to Implementation Method 30, wherein the subject requires spinal fusion, arthroplasty, or orthopedic or periodontal synthetic bone graft or implantation.

[0385] Implementation method 33. The method according to implementation method 29, wherein the bone formation is systemic.

[0386] Implementation Method 34. The method according to any one of Examples 29-33, wherein the subject suffers from low bone mass / density, fracture, or periodontal disease.

[0387] Implementation Method 35. According to the method of Implementation Method 34, the low bone mass condition is selected from osteoporosis, osteopenia, osteogenesis imperfecta (OI), osteoporotic pseudoglioma syndrome (OPPG), and secondary low bone mass condition.

[0388] Implementation Method 36. According to the method of Implementation Method 35, wherein the low bone mass condition is selected from the group consisting of: osteoporosis, osteopenia, and osteoporotic pseudoglioma syndrome (OPPG).

[0389] Implementation Method 37. The method according to any one of Implementation Methods 29-36, the method further comprising applying a bone-guiding matrix to the subject.

[0390] Implementation 38. The method according to Implementation 37, wherein the bone-guiding matrix comprises a bone-inducing agent selected from the group consisting of allogeneic bone grafts, autologous bone grafts, and periodontal ligament cells.

[0391] Implementation Method 39. The method according to Implementation Method 37, wherein the bone-guided matrix comprises calcium salts, calcium sulfate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-based hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, calcined gypsum, phosphoprotein, borosilicate, biocompatible ceramics, calcium phosphate ceramics, demineralized bone matrix, biphasic calcium phosphate, biocomposite materials, tantalum, titanium, polytetrafluoroethylene, sulfates, hydrogels, bioglass, or combinations thereof.

[0392] Implementation 40. The method according to Implementation 37, wherein the bone-guiding matrix comprises calcium salts, calcium sulfate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-based hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, calcined gypsum, phosphoprotein, borosilicate, biocompatible ceramics, calcium phosphate ceramics, demineralized bone matrix, biphasic calcium phosphate, biocomposite materials, tantalum, titanium, polytetrafluoroethylene, sulfates, or hydrogels.

[0393] Implementation Method 41. The method according to any one of Implementation Methods 29-40, wherein the compound is administered sequentially or in combination with the antiresorption agent.

[0394] Implementation 42. The method according to implementation 41, wherein the compound is administered to a patient who is being treated with an antiresorption agent or who has previously been treated with an antiresorption agent.

[0395] Implementation Method 43. According to the method of Implementation Method 41, wherein the anti-reabsorption drug is selected from the group consisting of: denosumab, Prolia, RankL inhibitors, bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin, calcitonin analogs, vitamin D, vitamin D analogs, and cathepsin K inhibitors.

[0396] Implementation Method 44. The method according to Implementation Method 41, wherein the anti-reabsorption drug is denosumab.

[0397] Implementation Method 45. According to the method of Implementation Method 41, wherein the antireabsorption drug is administered systemically.

[0398] Implementation 46. The method according to implementation 41, wherein the antireabsorption drug is applied topically.

[0399] Implementation method 47. The method according to any one of implementation methods 29-46 further includes administering an anabolic agent.

[0400] Embodiment 48. A medical device comprising a structural support, wherein an implantable portion of the structural support is adapted for permanent implantation into a subject, wherein the implantable portion is attached to bone, and the structural support having at least a partial outer coating comprising a compound of any one of Embodiments 1 to 28.

[0401] Implementation 49. A method of treating bone loss in a subject in need, comprising administering to the subject, in connection with or in combination with an anti-reabsorption agent, a therapeutically effective amount of any one of the compounds of Implementation 1-28, thereby treating bone loss in the subject.

[0402] XIII. Example

[0403] Example 1: 4-(2-(1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride

[0404]

[0405] In a round-bottom flask, 3-bromo-2-trifluoromethylpyridine (500 mg, 2.21 mmol) and 3-amino-4-chloropyridine (298 mg, 2.32 mmol) were charged. The flask was rinsed with Ar and PhMe (5 mL) was added. Cs₂CO₃ (866 mg, 2.65 mmol), X-Phos (80 mg, 0.16 mmol), and Pd(OAc)₂ (25 mg, 0.11 mmol) were added sequentially to the resulting solution. The flask was equipped with a Liebig condenser, and the mixture was degassed and stirred overnight at 110 °C under Ar conditions. The mixture was cooled, diluted with EtOAc, washed once with water, washed once with brine, dried (MgSO₄₄), and evaporated. Rapid chromatographic separation (gradient elution) was performed on SiO2 (40 g) using 30-100% EtOAc-hexane to give 4-chloro-N-(2-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine (314 mg, 52%).

[0406] Add 4-chloro-N-(2-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine (314 mg, 1.15 mmol) to a flask and add DMA (10 mL), followed by K₂CO₃ (317 mg, 2.30 mmol). Degas the mixture and place it under an Ar atmosphere. Add t-Bu₃P-HBF₄ (85 mg, 0.30 mmol), followed by Pd(OAc)₂ (26 mg, 0.12 mmol), degas the mixture again, place it under Ar, and heat at 130 °C overnight. Then add another portion of t-Bu₃P-HBF₄ (85 mg, 0.30 mmol) and Pd(OAc)₂ (26 mg, 0.12 mmol) to the mixture and stir again at 130 °C overnight. Cool the mixture, dilute with EtOAc, wash once with water, wash once with brine, dry (MgSO₄₄), and evaporate. Rapid chromatography on SiO2 (24 g) with 60-100% EtOAc-hexane yielded 1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c′]dipyridine (100 mg, 37%).

[0407] 4-(2-chloroethyl)morpholine hydrochloride (94.1 mg, 0.510 mmol) was added 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). NaH (100 mg, 2.52 mmol in 60% oil) was added in one go. The flask was rinsed with Ar and the mixture was heated overnight at 60 °C with stirring. The mixture was allowed to cool to room temperature, diluted with EtOAc, washed once with water, washed once with brine, dried (MgSO4), and evaporated. The residue was rapidly purified by chromatography on SiO2 (12 g) using 50-100% EtOAc-hexane and 50% MeOH-EtOAc to give compound 4-(2-(1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridin-9-yl)ethyl)morpholine (14 mg, 10%) and oxidized compound 9-(2-morpholinoethyl)-8-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c′]dipyridin-2-oxide (10 mg, 6%).

[0408] Characterization of 4-(2-(1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridin-9-yl)ethyl)morpholine: 1H NMR (CDCl3, 400MHz) δ9.16 (s, 1H), 8.63 (d, 1H, J = 5.2Hz), 8.59 (d, 1H, J = 4.8Hz), 8.25 (d, 1H, J = 5.2Hz), 8.04 (dd ,1H,J=5.2,0.8Hz),4.74(t,2H,J=7.6Hz),3.69(t,4H,J=4.8Hz),2.79(t,2H,J=7.6Hz),2.54(t,4H,J=4.8Hz).

[0409] Using a syringe, add HCl (2M, 10 eq in Et₂O) 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']dipyridin-2-oxide in CH₂Cl₂ (1 mL). Continue stirring for 5 min, then remove the volatiles under vacuum. The residue was purified by grinding with 80% CH2Cl2-hexane to give quantitative yields of 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']dipyridin 2-oxide hydrochloride.

[0410] Characterization of 4-(2-(1-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c′]dipyridin-9-yl)ethyl)morpholine hydrochloride: 1 H NMR(DMSO-d6,400MHz)δ12.00(s,1H),9.88(s,1H),8.88(d,1H,J=4.8Hz),8.80(s,2H),8.74(d,1H,J= 4.8Hz),5.15(t,2H,J=8.4Hz),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 a value of 351.2).

[0411] Example 2: 9-(2-morpholinoethyl)-8-(trifluoromethyl)-9H-pyrrolo[2,3-c:5,4-c']dipyridine 2-oxide hydrochloride

[0412]

[0413] Free base: 1 H NMR (CDCl3, 400MHz) δ9.94 (s, 1H), 8.54 (d, 1H, J = 5.2Hz), 8.03 (d, 1H, J = 5.2Hz), 7.24 (d, 1H, J = 7.2Hz), 6.93 (d,1H,J=7.2Hz), 4.27(t,2H,J=6.4Hz), 3.68(t,4H,J=4.4Hz), 2.78(t,2H,J=6.4Hz), 2.54(t,4H,J=4.4Hz).

[0414] HCl salt: 1 H NMR(DMSO-d6,400MHz)δ12.84(s,1H),10.24(bs,1H),8.48(d,1H,J=5.2Hz),8.43(d,1H,J=5.2Hz),7 .59(d,1H,J=7.2Hz),7.28(d,1H,J=7.2Hz),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 F3N4O2 requires a value of 367.2).

[0415] Example 3: 4-(2-(2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride

[0416]

[0417] NCS (5.35 g, 40 mmol) was added fractionally to a CHCl3 (150 mL) solution of 6-methoxypyridine-2-amine (5.0 g, 40 mmol) at 0 °C. The reaction solution was stirred at room temperature for 3 days, then diluted with CH2Cl2, washed with water, saturated NaHCO3, and brine, dried over MgSO4, and concentrated. The product was purified by silica chromatography using a gradient from 90% hexane / 10% EtOAc to 50% hexane / 50% EtOAc to give 3-chloro-6-methoxypyridine-2-amine (4.8 g, 75%).

[0418] 3-Bromo-2-trifluoromethylpyridine (500 mg, 2.2 mmol), cesium carbonate (866 mg, 2.7 mmol), X-Phos (80 mg, 0.16 mmol), Pd(OAc)₂ (25 mg, 0.1 mmol), and 3-chloro-6-methoxypyridin-2-amine (370 mg, 2.3 mmol) were added to a dry test tube. The reaction solution was diluted with toluene (5 mL), degassed, and stirred overnight at 120 °C. The solution was then cooled to room temperature, diluted with EtOAc, washed with water and brine, dried over MgSO₄, and concentrated. The product was purified by silica gel chromatography using a gradient elution from 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%).

[0419] Add 3-chloro-6-methoxy-N-(2-(trifluoromethyl)pyridin-3-yl)pyridine-2-amine (588 mg, 1.9 mmol), potassium carbonate (536 mg, 3.9 mmol), and DMA (20 mL) to a dry test tube. Degas the reactants and introduce (t-Bu3)PHBF4 (113 mg, 0.39 mmol) and Pd(OAc)2 (45 mg, 0.19 mmol). Stir the reaction overnight at 120 °C. Add another equal amount of catalyst, stir the reaction overnight at 120 °C, then cool to room temperature, dilute with EtOAc, wash with water and brine, dry with MgSO4, and concentrate. Purify the product by silica gel chromatography using a gradient elution from 85% hexane / 15% EtOAc to 50% hexane / 50% EtOAc. 18 Reversed-phase column chromatography was used, with gradient elution from 50% ACN / 50% water (0.1% FA) to 90% ACN / 10% water (0.1% FA) to further purify the product. Since dechlorination substances were still present, the product was further purified by HPLC C. 18 The column was eluted with a gradient from 10% ACN / 90% water (0.1% FA) to 90% ACN / 10% water (0.1% FA) to 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine (47 mg, 9%).

[0420] Characterization of 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c′]dipyridine: 1H NMR (CDCl3, 400MHz) δ8.47 (d, 1H, J = 4.8Hz), 8.23 ​​(dd, 1H, J = 8.4, 0.8Hz), 7.98 (d, 1H, J = 4.8Hz), 6.74 (dd, 1H, J = 8. 4,0.8Hz), 4.76(t,2H,J=7.6Hz), 4.07(s,3H), 3.69(t,4H,J=4.8Hz), 2.77(t,2H,J=7.6Hz), 2.60(t,4H,J=4.4Hz).

[0421] Add 4-(2-chloroethyl)morpholine hydrochloride (66 mg, 0.35 mmol) to a DMF (3 mL) solution of 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine (47 mg, 0.18 mmol), followed by sodium hydride (60% in oil, 42 mg, 1.1 mmol). Stir the solution overnight at 60 °C, then cool to room temperature, quench with saturated NaHCO3, and dilute with EtOAc. Wash the crude product with saturated NaHCO3 and brine, dry over MgSO4, and concentrate. The product was purified by silica gel chromatography using a gradient of 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%). The product was then diluted with CH2Cl2, and 1 mL of 4M HCl in dioxane was added. After stirring for 10 min, the mixture was evaporated to dryness. The product was then ground in CH2Cl2 / hexane to give a quantitative yield of 4-(2-(2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride.

[0422] 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, 400MHz) δ 11.54 (s, 1H), 8.69 (d, 1H, J = 8.4Hz), 8.53 (d, 1H, J = 5.2Hz), 8.46 (d, 1H, J = 4.8Hz), 6.91 (d, 1H, J = 8. 4Hz),4.98(m,2H),4.09(s,3H),4.02(d,2H,J=12.4Hz),3.84(m,2H),3.65(d,2H,J=10.4Hz),3.45(m,2H),3.22(m,2H).LCMS m / z 381.2([M+H] + C18 H 20 F3N4O2 requires a value of 381.2).

[0423] Example 4: 4-(2-(3-methoxy-6-(trifluoromethyl)-5H-pyrrolo[2,3-c:4,5-c']dipyridin-5-yl)ethyl)morpholine hydrochloride

[0424]

[0425] A flask was charged with 5-chloro-2-methoxypyridine-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, rinsed 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 cooled, diluted with water and EtOAc, and filtered through diatomaceous earth (the filter cake was washed with EtOAc). The aqueous layer was extracted once with EtOAc, and the combined organic extracts were washed once with water, once with brine, dried (Na₂SO₄), and evaporated. The residue was purified by rapid chromatography to obtain an impure substance (an inseparable mixture of the starting aniline and the desired product). The mixture was rapidly separated by reversed-phase C-18 silica gel using a Biotage SNAP column KP-C18-HS (60 g) and eluted with 30–95% MeCN-H2O (gradient elution) to give N-(5-chloro-2-methoxypyridin-4-yl)-2-(trifluoromethyl)pyridin-3-amine (0.3069 g, 33%).

[0426] In a microwave-safe flask, 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) were charged. The flask was capped, rinsed with Ar, and N-(5-chloro-2-methoxypyridin-4-yl)-2-(trifluoromethyl)pyridin-3-amine (0.3069 g, 1.011 mmol) was added to DMA (4 mL) via a syringe. Argon was bubbled through the solution for 5 minutes with stirring, followed by microwave heating at 164 °C for 2 hours with stirring. The mixture was cooled, diluted with EtOAc, and filtered through diatomaceous earth. The filter cake was washed with EtOAc. The mixture was then washed twice with brine, dried (Na2SO4), and evaporated. The residue was purified by rapid chromatography on SiO2 (40 g) using 5-40% EtOAc-hexane (gradient elution) to give 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine (34.2 mg, 13%).

[0427] NaH (60% from oil, 30 mg, 0.75 mmol) was added in one step to a stirred solution of 2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine (34 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 rinsed with N2 and heated overnight at 60 °C with stirring. The next day, the mixture was cooled to room temperature, diluted with EtOAc, washed once with water, washed once with brine, dried (Na2SO4), and evaporated. The residue was rapidly purified by SiO2 (12 g) chromatography using 20-100% EtOAc-hexane (gradient elution) to give 4-(2-(3-methoxy-6-(trifluoromethyl)-5H-pyrrolo[2,3-c:4,5-c']dipyridin-5-yl)ethylmorpholine (33 mg, 69%).

[0428] Characterization of 4-(2-(3-methoxy-6-(trifluoromethyl)-5H-pyrrolo[2,3-c:4,5-c']dipyridin-5-yl)ethyl)morpholine: 1H NMR (CDCl3, 400MHz) δ8.98 (s, 1H), 8.53 (d, 1H, J = 5.2Hz), 8.11 (d, 1H, J = 5.2Hz), 6.79 (s, 1H), 4.52 (t,2H,J=7.6Hz),4.07(s,3H),3.72(t,4H,J=4.4Hz),2.72(t,2H,J=7.6Hz),2.56(t,4H,J=4.4Hz).

[0429] HCl (0.2 M in Et2O, 0.42 mL, 0.084 mmol) was added via syringe to a stirred CH2Cl2 (1 mL) solution of 4-(2-(3-methoxy-6-(trifluoromethyl)-5H-pyrrolidine[2,3-c:4,5-c']dipyridin-5-yl)ethyl)morpholine (16 mg, 0.042 mmol). The mixture was stirred for 10 min and the volatiles were removed under vacuum to obtain a grayish-white solid. The solid was ground together with 1:1 Et2O-hexane (approximately 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, quantified), a white solid.

[0430] Characterization of 4-(2-(3-methoxy-6-(trifluoromethyl)-5H-pyrrolo[2,3-c:4,5-c']dipyridin-5-yl)ethyl)morpholine hydrochloride: 1 H NMR(DMSO-d6,400MHz)δ11.83(s,1H),9.27(s,1H),8.58(d,1H,J=5.2Hz),8.55(d,1H,J=4.8Hz),7.43(s,1H),4.88(t, 2H,J=8.4Hz),4.01(s,3H),3.82(d,2H,J=11.6Hz),3.70(m,2H),3.59(d,2H,J=11.2Hz),3.35(m,2H),3.18(m,2H).LCMS m / z381.2([M+H] + C 18 H 20 F3N4O2 requires a value of 381.2).

[0431] Example 5: 4-(2-(2-methoxy-8-(trifluoromethyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)ethyl)morpholine

[0432]

[0433] MeONa (25% MeOH solution, 3.3 mL, 114.6 mmol) was added to a stirred solution of 2,5-dichloropyrimidin-4-amine (2 g, 12.2 mmol) in methanol (40 mL). The mixture was stirred at 50 °C for 4 h while protecting it from moisture. The mixture was then cooled to room temperature and thawed by adding saturated NH4Cl. (水溶液) Quenching. Add EtOAc, and wash the organic matter once with NaHCO3 (aqueous solution), once with brine, and dry (MgSO4). Evaporate the solvent to give 6-amino-5-chloro-2-methoxypyrimidine, which requires no further purification.

[0434] In a microwave-safe flask, 6-amino-5-chloro-2-methoxypyrimidine (404 mg, 2.53 mmol) and 3-bromo-2-trifluoromethylpyridine (500 mg, 2.21 mmol) were added. The flask was rinsed with Ar and DMF (3 mL) was added via syringe. Cs₂CO₃ (866 mg, 2.66 mmol) was added, followed by X-Phos ligand (80 mg, 0.16 mmol). The solution was degassed, and then Pd(OAc)₂ (25 mg, 0.11 mmol) was added. The flask was rinsed again with Ar. The mixture was heated in a microwave (Biotage) at 160 °C for 2 hours, cooled, diluted with EtOAc, washed once with water, washed once with brine, and dried (MgSO₄⁻). Rapid chromatographic separation was performed on SiO2 (40 g) using 20-80% EtOAc-hexane (gradient elution) to obtain 5-chloro-2-methoxy-N-(2-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine (120 mg, 18%).

[0435] In a microwave-safe flask, 120 mg (0.394 mmol) of 5-chloro-2-methoxy-N-(2-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine was added, followed by 5 mL of DMA and then 109 mg (0.788 mmol) of K₂CO₃. The mixture was then degassed and placed under an Ar atmosphere. 22.8 mg (0.0788 mmol) of t-Bu₃P-HBF₄ was added, followed by 8.8 mg (0.0394 mmol) of Pd(OAc)₂. The mixture was degassed again, placed under Ar, and heated overnight at 130 °C. The conversion rate was low at this point (LCMS), so another portion of t-Bu3P-HBF4 ligand (22.8 mg, 0.0788 mmol) and Pd(OAc)2 catalyst (8.8 mg, 0.0394 mmol) were added to the mixture, and it was heated in a microwave oven (Biotage) at 160 s °C for 1.5 h. The conversion rate was approximately 50% at this point (LCMS). Another portion of t-Bu3P-HBF4 ligand (22.8 mg, 0.0788 mmol) and Pd(OAc)2 catalyst (8.8 mg, 0.0394 mmol) were added to the mixture, and it was heated in a microwave oven (Biotage) at 160 °C for 2 h. The mixture was cooled, diluted with EtOAc, washed once with saturated NaHCO3 (aqueous solution), washed once with brine, and dried (MgSO4). Rapid chromatographic purification was performed on SiO2 (24 g) using 20-80% EtOAc-hexane (gradient elution) to obtain 2-methoxy-8-(trifluoromethyl)-9H-pyridyl[4',3':4,5]pyrrolo[2,3-d]pyrimidine (34 mg, 33%).

[0436] 4-(2-chloroethyl)morpholine (0.01 mL, 0.05 mmol) was added via syringe, followed by Tsunoda's reagent ((cyanomethylene)tributylphosphine, 15 mg, 0.05 mmol) to a phMe (0.8 mL) solution of 2-methoxy-8-(trifluoromethyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine (7 mg, 0.03 mmol) stirred under N2. The mixture was heated overnight at 100 °C with stirring, allowed to cool, and diluted with EtOAc. The mixture was washed once with water, once with brine, and dried (Na2SO4). The solvent was evaporated and the mixture was rapidly purified by chromatography on SiO2 (0.5 x 10 cm) in a Pasteur pipette using 60-100% EtOAc-hexane to give 4-(2-(2-methoxy-8-(trifluoromethyl)-9H-pyridyl[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)ethylmorpholine (2.8 mg, 28%).

[0437] 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, 400MHz) δ9.19 (s, 1H), 8.61 (d, 1H, J = 4.8Hz), 8.10 (d, 1H, J = 5.2Hz), 4.74 (t, 2H, J = 7.6Hz), 4.15 (s, 3H), 3.63 (t, 4H, J = 4.8Hz), 2.75 (t, 2H, J = 7.6Hz), 2.57 (t, 4H, J = 4.4Hz).LCMS m / z 382.2([M+H] + C 17 H 19 F3N5O2 requires a value of 382.2).

[0438] Example 6: 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride.

[0439]

[0440] Selectfluor (192 mg, 0.542 mmol) was added in a single addition 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 3 mL of MeCN. The flask was rinsed with N2 and heated to 65 °C with stirring for 2 days. The mixture was then diluted with EtOAc and dilute with dilute NaCl. (水溶液)Wash once, wash once with brine, dry (Na2SO4), and evaporate. Filter the residue through a SiO2 plug (2×4 cm) using 30% EtOAc-hexane to give 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, based on 48% conversion). 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) was subjected to reversed-phase HPLC (Puri-Flash system, using Phenomenex Synergi 10u MAX-RP 80A 50x50mm) The fraction was eluted with a 10-micron column and a gradient of 10-95% MeCN-water containing 0.1% formic acid to give a mixture (19.1 mg) 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) for the next step, and another fraction consisting of a mixture (10.4 mg) 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 (7:3).

[0441] To a flask, add 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 (3:17) (19 mg, 0.066 mmol), 4-(2-chloroethyl)morpholine hydrochloride (25 mg, 0.13 mmol), and TBAI (5 mg, 0.01 mmol). Rinse the flask with N2 and introduce DMF via a syringe with stirring. Add NaH (60% oil dispersion, 16 mg, 0.40 mmol) and stir continuously under a stream of N2 for 5 minutes before removing the N2 outlet needle. Heat the mixture to 60°C with stirring overnight. The next day, the mixture was diluted with EtOAc, washed twice with water, 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 with 30-80% EtOAc-hexane by silica gel chromatography, and then crystallized again from CH2Cl2-hexane to give compound 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethylmorpholine (9 mg).

[0442] Characterization of 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine: 1 H NMR (CDCl3, 400MHz) δ8.49 (d, 1H, J = 5.2Hz), 8.01 (d, 1H, J = 9.6Hz), 7.97 (d, 1H, J = 5.2Hz), 4.76 (t ,2H,J=7.6Hz),4.18(s,3H),3.69(t,4H,J=4.4Hz),2.76(t,2H,J=7.6Hz),2.60(t,4H,J=4.4Hz).

[0443] HCl (0.2 M, 0.22 mL, 0.044 mmol in Et2O) was added to a stirred CH2Cl2 (0.8 mL) solution of 9 mg of 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethylmorpholine (0.9 mg) at a rapid dropping rate using a syringe. After stirring for 5 min at room temperature, the volatiles were removed under vacuum. The resulting solid was washed once with a small amount of 1:1 Et2O-hexane to remove oils. The salt was then suspended in water (approximately 2 mL) under ultrasonic assistance, frozen, and lyophilized to obtain 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).

[0444] Characterization of 4-(2-(3-fluoro-2-methoxy-8-(trifluoromethyl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)ethyl)morpholine hydrochloride: 1 H NMR (DMSO-d6, 400MHz) δ11.04 (s, 1H), 8.76 (d, 1H, J = 10.4Hz), 8.54 (d, 1H, J = 5.2Hz), 8.44 (d, 1H, J = 4.8Hz), 4.95 (m,2H),4.19(s,3H),4.03(d,2H,J=10.8Hz),3.79(m,2H),3.65(d,2H,J=10.4Hz),3.48(m,2H),3.24(m,2H).LCMS m / z 399.2([M+H] + C 18 H 19 F4N4O2 requires a value of 399.2).

[0445] Example 7: Regulation of Sclerosing Protein / Wnt Activity

[0446] The ability of compounds synthesized according to the methods of Examples 1-6 to restore Wnt signaling was determined in the presence of sclerosing proteins consistent with the known sclerosing protein antagonist, sclerosing protein Mab. See, Ellies et al., Journal of Bone and Mineral Metabolism (J Bone Miner Res) 21: 1738-1749 (2006). See below.

[0447] As shown in Table 1, scleroprotein antagonizes Wnt3a signaling in human embryonic cells. The addition of known scleroprotein antagonists inhibited the scleroprotein's inhibition of Wnt3a signaling, thereby restoring Wnt3a signaling in cells (IC100: 10 μM) (data not shown). The compounds of Examples 1-6 also inhibited the scleroprotein's inhibition of Wnt3a signaling and restored Wnt3a signaling in cells.

[0448] Example 8: Bone Formation Analysis

[0449] Mineralization (formation of crystalline calcium phosphate) represents an in vitro model of bone formation. Using an assay in which the amount of mineralization is quantified by measuring the total calcium content after the dissolution of deposited crystalline calcium phosphate, sclerosing proteins have previously been shown to inhibit mineralization in MC3T3-E1 (mouse calcaneal) osteoblasts. (Li et al., Journal of Bone and Mineral Metabolism, 24: 578-588 (2008)). Following the method described by Li et al., the ability of compounds to rescue the inhibitory effect of sclerosing proteins on mineralization in MC3T3 osteoblasts was analyzed. Treatment with sclerosing proteins alone resulted in a significant reduction in mineralization, as measured by calcium concentration (…).

[0450] Table 1 (data not shown). The addition of the compounds in Examples 1-6 neutralized the inhibition of sclerosing proteins mediated by mineralization, as reflected in the increase in calcium concentration.

[0451] Example 9: Metabolic stability

[0452] The compound of the present invention (0.1 μM) was co-incubated with microsomes at 37 °C for 60 min. The reaction was carried out in potassium phosphate buffer containing conjugated human liver microsomal protein (0.1 mg / mL) at indicated time points (0, 5, 15, 30, and 60 min). The samples were analyzed by LC / MS / MS, and the remaining parent drug was calculated using Microsoft Excel (2007). Obach RS, Drug Metab Disposal 27(11):1350-1359 (1999).

[0453] Table 1. Activities of compounds that regulate the activity of sclerosing protein / Wnt, and the inhibition of mineralization and metabolic stability by sclerosing protein.

[0454]

[0455]

[0456] - Indicates no improvement compared to sclerotic protein alone.

[0457] + indicates IC100 > 10μM

[0458] ++ indicates IC100 < 10μM

[0459] + indicates stability <1x

[0460] ++ indicates stability > 1 times

[0461] Although the foregoing invention has been described in detail by way of illustration and examples for purposes of clarity, those skilled in the art will understand that certain changes and modifications may be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated herein by reference in its entirety as if it were incorporated separately by reference.

Claims

1. Compounds of formulas Ia, Ib and Ic: (Ia), (Ib), or (Ic), or its salt, wherein A is ; R N for ; R 2 is C 1-6 haloalkyl; R 3c is C 1-6 alkoxy; and When it exists, R 3b It is H or halogen.

2. The compound according to claim 1, characterized in that, It has formula Ia.

3. The compound according to claim 2, characterized in that, Having the formula Id: (Id)。 4. The compound according to claim 1, characterized in that, R 2 is CF3.

5. The compound according to claim 1, characterized in that, When it exists, R 3b It can be H or F.

6. The compound according to claim 1, characterized in that, R 3c It is a methoxy group.

7. The compound according to claim 1, characterized in that, R 2 It's CF3; and R 3c It is a methoxy group.

8. The compound according to claim 1, selected from the group consisting of: , , and , Or its salt.

9. A formate, sulfate, citrate, or hydrochloride salt of the compound according to claim 1.

10. A pharmaceutical composition comprising the compound of claim 1 or a salt thereof, and a pharmaceutically acceptable excipient.

11. A medical device comprising a structural support, wherein, The implantable portion of the structural support is adapted for permanent implantation in a subject, the implantable portion being attached to bone, and the structural support having at least a partial external or internal coating comprising compounds selected from the group consisting of: , , , , and ; Or its salt.

12. The medical device according to claim 11, characterized in that, The structural support has at least a partial external coating including the compound, or the compound is located inside the support, or the structural support has both an external coating including the compound and the compound located inside the support.

13. The medical device as claimed in claim 11, characterized in that, The compound is located inside the support.

14. The medical device as claimed in claim 11, characterized in that, The structural support is a titanium cage, pin, rod, screw, plate, orthopedic implant or dental implant.

15. The medical device of claim 11, characterized in that, The structural support is made of materials including metals, polymers, ceramics, or combinations thereof.

16. The medical device of claim 15, characterized in that, The metal is cobalt, chromium, stainless steel, titanium, or tantalum.

17. The medical device of claim 15, characterized in that, The metal is chromium, titanium alloy, or slab metal.

18. The medical device as claimed in claim 11, characterized in that, The structural support is a titanium cage.

19. The medical device as claimed in claim 15, characterized in that, The ceramic is alumina, calcium phosphate, hydroxyapatite, zirconium oxide, or silicon oxide.

20. The medical device as claimed in claim 11, characterized in that, The structural support is a scaffold or matrix comprising synthetic materials, biological materials, or combinations thereof.

21. The medical device as claimed in claim 11, characterized in that, The structural support is a scaffold or matrix comprising naturally occurring polymers, synthetic biodegradable polymers, synthetic non-biodegradable polymers, bioceramics, or combinations thereof.

22. The medical device as claimed in claim 11, characterized in that, The structural support is a scaffold or matrix comprising bioactive glass.

23. The medical device as claimed in claim 11, characterized in that, The structural support is a scaffold or matrix comprising filaments, collagen, gelatin, fibrinogen, elastin, keratin, actin, myosin, cellulose, amylose, dextran, chitin, chitosan, glycosaminoglycans, DNA, or RNA.

24. Use of the medical device of claim 11 in the preparation of a medical device for promoting bone formation.

25. Use of a compound in the preparation of a pharmaceutical composition that promotes bone formation, wherein, The compounds are selected from the group consisting of: , , , , and , Or its salt.

26. The use as described in claim 25, characterized in that, The bone formation refers to promoting bone formation at the site of injury or local lesion.

27. The use as described in claim 26, characterized in that, The injured areas are selected from fractures and areas of bone weakness.

28. The use as described in claim 25, characterized in that, The bone formation refers to bone formation in patients requiring spinal fusion, arthroplasty, or orthopedic surgery, or periodontal synthetic bone grafting or implantation.

29. The use according to claim 25, characterized in that, The pharmaceutical composition is applied to individuals suffering from low bone mass, fractures, or periodontal disease.

30. The use according to claim 29, characterized in that, The low bone mass syndromes are selected from osteoporosis, osteopenia, osteogenesis imperfecta, osteoporotic pseudoglioma syndrome, and secondary low bone mass syndromes.

31. The use according to claim 25, characterized in that, The drug composition is administered to individuals suffering from osteogenesis imperfecta.

32. The use according to claim 25, characterized in that, The drug composition is administered to individuals suffering from osteoporosis and / or osteopenia.

33. The use as described in claim 25, characterized in that, The pharmaceutical composition further comprises a bone guiding matrix.

34. The use as described in claim 33, characterized in that, The bone guiding matrix includes a bone inducing agent selected from the group consisting of allogeneic bone, autologous bone, or periodontal ligament cells.

35. The use as described in claim 33, characterized in that, The bone guiding matrix includes calcium salts, collagen, phosphoproteins, borosilicates, biocompatible ceramics, demineralized bone matrix, tantalum, titanium, polytetrafluoroethylene, hydrogels, or combinations thereof.

36. The use as described in claim 33, characterized in that, The bone guiding matrix is ​​hydroxyapatite or bioglass.

37. The use as described in claim 33, characterized in that, The bone guiding matrix includes calcium sulfate, calcium phosphate, coral-based hydroxyapatite, dicalcium phosphate, tricalcium phosphate, or calcium carbonate.

38. The use as described in claim 33, characterized in that, The bone guiding matrix includes calcium phosphate cement or biphasic calcium phosphate.

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