Alkyl-amine harmine derivatives for promoting bone growth

0001Cross-reference of related applications This application claims the priority benefit of US Provisional Patent Application Nos. 61/785, 306 filed on March 14, 2013, the entire contents of which are incorporated herein by reference.

0002Statement on Rights to Inventions Made under Federal Government-Supported Research and Development Not applicable

0003Background of the invention Bone homeostasis involves an offsetting process of bone formation and bone resorption. Increased bone resorption and loss of bone homeostasis are associated with many diseases and disorders, including osteoporosis and Paget's disease.

0004Treatment of a wide variety of heterogeneous diseases in mammals, including simple aging, bone degeneration and osteoporosis, fracture healing, fusion or joint fixation, osteodysplasia, as well as screws, rods, titanium cages for spinal fixation, hip joints, knee joints, etc. It is well understood that bone formation is required for successful placement of various medical orthopedic and periodontal implants such as ankle joints, shoulder joints, dental plates and rods.

0005For example, to treat conditions that can at least partially be characterized by increased bone resorption, such as bone loss, osteoporosis, arthritis, tumor metastasis, osteodysplasia, Paget's disease and other metabolic bone disorders. , The use of catepsin K inhibitors, selective estrogen receptor modulators (SERMs), bisphosphonates, etc. for treating low bone density subjects is well known in the art.

0006In addition, conditions that can be partially characterized by an increased risk of fractures such as osteopenia, degenerative disc disease, fractures, osteoporosis, arthritis, tumor metastasis, osteogenesis imperfecta, Paget's disease and other metabolic bone disorders. It is known in the art to use PTH, TGFβ binding protein, etc. to increase bone mineralization to treat bone. The decalcified bone matrix is also known to have the potential to contribute to a small increase in new bone growth due to the endogenous TGFβ-binding protein (BMP) that survives the sterilization procedure of carcass bone. However, decalcified bone matrices are generally sourced from donor carcass banks and carry certain risks such as disease transmission or bacterial contamination.

<p num="0007"> Therefore, as mentioned above, new methods and other needs for treating bone disorders by fusing bones across the critical size gap and for treating fractures remain in the art. There is. The present invention meets these and other needs.</p>

<p num="0008">Brief gist of the invention In one embodiment, the invention provides compounds and compositions, as well as methods of using such compounds and compositions. In a first embodiment, the present invention provides a compound of formula I, a salt, a hydrate or an isomer thereof.</p><p num="0009"><chemistry num="1"><img id="000003" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0010">(In the above formula, W is CR^3aAnd N, where N may optionally be oxidized to the corresponding N-oxide. X is CR^3bAnd N, where N may optionally be oxidized to the corresponding N-oxide. Y is CR^3cAnd N, where N may optionally be oxidized to the corresponding N-oxide. Z is CR^3dAnd N, where N may optionally be oxidized to the corresponding N-oxide. R^NIs NR⁶R⁷, Heterocyclyl and heteroaryl, where heterocyclyl and heteroaryl contain from about 5 to about 10 ring atoms, at least one of which is nitrogen, and R.^NThe N in it may optionally be oxidized to the corresponding N-oxide, Each R^1a, R^1bAnd R^1cIs independently selected from H, methyl and ethyl, where -C (R)^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-The total number of carbon atoms in the group does not exceed 6, Each R², R^3a, R^3b, R^3cAnd R^3dIndependently, H, Halogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Alkenyl, C_2-6Alkyne, C_1-6Alkoxy, C_1-6Haloalkoxy, aryloxy, C_1-6Alkyl-OH, -OR⁴, -C_0-6Alkyl-NR⁴R⁵, -SR⁴, -C (O) R⁴, -C_0-6Alkyl-C (O) OR⁴, -C (O) NR⁴R⁵, -N (R)⁴) C (O) R⁵, -N (R)⁴) C (O) OR⁵, -N (R)⁴) C (O) NR⁴R⁵, -OP (O) (OR⁴)₂, -S (O)₂OR⁴, -S (O)₂NR⁴R⁵, -CN, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, selected from the group Alternatively, two Rs on adjacent atoms²Groups can be combined with the atoms to which they are attached to form elements selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and Each R⁴, R⁵, R⁶And R⁷Independently, H, C_1-6Alkyl and C_1-6Selected from the group consisting of alkyl-OH, The sign q is an integer from 0 to 4, and The sign t is an integer from 0 to 4 and However, more than one of W, X, Y and Z is not N or the corresponding N-oxide, However, a) The sum of q and t is 1, and b) R, if present⁶Or R⁷Either H or C_1-6When it is alkyl, R^1aAnd R^1bAt least one of them is other than H, However, When the sum of q and t is 2, a) R²Is other than H, and b) R, if present⁶And R⁷At least one of them is other than H or methyl).</p><p num="0011"> In some embodiments, the compounds of formula I are as described above, but not: 1-Amino-3- (3,6-dibromo-9H-carbazole-9-yl) propan-2-ol, 1- (3,6-dibromo-9H-pyrido [3,4-b] indole-9-yl) -3-((3-methoxyphenyl) amino) propan-2-ol, 9-(2- (Piperidin-1-yl) ethyl) -9H-pyrido [3,4-b] indole-3-carboxamide, Methyl 9- (4- (dimethylamino) butyl) -9H-pyrido [3,4-b] indole-3-carboxylate, N, N-dimethyl-4- (9H-pyrido [3,4-b] indole-9-yl) butane-1-amine, N-Ethyl-N-Methyl-4- (9H-pyrido [3,4-b] indole-9-yl) butane-1-amine, 2- [4- [7-Hydroxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl] butyl] -1H-isoindole-1,3 (2H) -dione , 2- [4- [7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl] butyl] -1H-isoindole-1,3 (2H) -dione , 2- [4- (7-Hydroxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) butyl] -1H-isoindole-1,3 (2H) -dione, 2- [3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl] -1H-isoindole-1,3 (2H) -dione, 9- (4-Aminobutyl) -1- (Trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol, 7-Methoxy-N, N, 1-trimethyl-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-N, 1-dimethyl-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-butaneamine, 9- (4-Aminobutyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol, 7-Methoxy-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-propaneamine, N, N-dimethyl-N- [3- (7-methoxy-1-methyl-9H-b-carboline-9-yl) -propyl] amine, N, N, 1,3-tetramethyl-9H-pyrido [3,4-b] indole-9-ethaneamine, N, N-diethyl-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-ethaneamine, 7-Methoxy-N, N, 1-trimethyl-9H-pyrido [3,4-b] indole-9-ethaneamine, 4- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylbutane-1-amine, 4- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N-methylbutane-1-amine, 4- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) butane-1-amine, 1- (9H-carbazole-9-yl) -N, N-dimethylpropan-2-amine, or 2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylethaneamine.</p><p num="0012"> In a second embodiment, the present invention provides a compound of formula III, a salt, a hydrate or an isomer thereof.</p><p num="0013"><chemistry num="2"><img id="000004" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0014">(In the above formula, R¹Is H or C_1-6Alkyl W is CR^3aAnd N, where N may optionally be oxidized to the corresponding N-oxide. X is CR^3bAnd N, where N may optionally be oxidized to the corresponding N-oxide. Y is CR^3cAnd Z is CR^3dAnd N, where N may optionally be oxidized to the corresponding N-oxide. Each R², R^3a, R^3b, R^3cAnd R^3dIndependently, H, Halogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Alkenyl, C_2-6Alkyne, C_1-6Alkoxy, C_1-6Haloalkoxy, aryloxy, C_1-6Alkyl-OH, -OR⁴, -C_0-6Alkyl-NR⁴R⁵, -SR⁴, -C (O) R⁴, -C_0-6Alkyl-C (O) OR⁴, -C (O) NR⁴R⁵, -N (R)⁴) C (O) R⁵, -N (R)⁴) C (O) OR⁵, -N (R)⁴) C (O) NR⁴R⁵, -OP (O) (OR⁴)₂, -S (O)₂OR⁴, -S (O)₂NR⁴R⁵, -CN, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, selected from the group Alternatively, two Rs on adjacent atoms²Groups can be combined with the atoms to which they are attached to form elements selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and Each R⁴, R⁵, R⁶And R⁷Independently, H, C_1-6Alkyl and C_1-6Selected from the group consisting of alkyl-OH).</p><p num="0015"> In a third embodiment, the present invention provides a method of promoting bone formation in a subject in need of bone formation. The method administers to a subject a therapeutically effective amount of a compound of formula I, formula IA, formula IB, formula IC, formula II or formula III as described herein, thereby in the subject. Includes promoting bone formation. Bone formation may be systemic or local. In local bone formation, in some embodiments, the compound is administered with a bone conduction agent, eg, a bone conduction matrix.</p><p num="0016"> In a fourth embodiment, the present invention provides a method for treating renal disorders. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, formula IA, formula IB, formula IC, formula II or formula III.</p><p num="0017"> In a fifth embodiment, the present invention provides a method of treating cancer. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, formula IA, formula IB, formula IC, formula II or formula III.</p><p num="0018"> In a sixth embodiment, the invention provides a medical device, such as an orthopedic or periodontal medical device. The device includes a structural support, where the implantable portion of the structural support is adapted to be permanently implanted inside the subject. The implantable portion binds to the bone, and the structural support has at least a partial external coating containing a compound of formula I, formula IA, formula IB, formula IC, formula II or formula III.</p><p num="0019"> In a seventh embodiment, the invention is a compound or composition as described herein (eg, the compound or composition as described herein, used in the preparation of a pharmaceutical product for treating a disease or condition as described herein. , Formula I, Formula IA, Formula IB, Formula IC, Compounds of formula II or Formula III). In some embodiments, the disease or condition is a condition characterized by damaged bone, fractures, weakened bone, or low bone mass.</p>

0020<figref num="1">Bone mass homeostasis is regulated by a combined process of bone formation (increasing bone mass) and resorption of bone (decreasing bone mass). Bone formation is positively promoted by exercise, activities and agents that act on osteoblast-forming cells such as PTH (teriparatide) or BMP (TGFβ-binding protein), or by sclerostin inhibitors such as the compounds of the invention. be able to. Bone resorption is inhibited by anti-absorption agents such as RANKL inhibitors, selective estrogen receptor modulators (SERMs), calcium, estrogens, bisphosphonates, calcitonin and other agents that act to arrest the activity of osteoclasts. Can be done.</figref>

0021Detailed description of the invention 1. Introduction Bone mass homeostasis and bone remodeling involve the offsetting process of bone formation (bone building, assimilation process) and bone resorption (bone loss, catabolism process). See Figure 1. In bone formation, osteoblasts synthesize bone matrix, regulate calcification, and then differentiate into terminal bone cells or bone lining cells. In bone resorption, different cell types-osteoclasts-remove the calcified bone matrix, destroy organic bone and release calcium into the serum. See, for example, Kular et al., Clinical Biochemistry 45: 863-873 (2012).

0022Osteoblasts (bone-forming cells) and osteoclasts (bone resorption cells) are regulated by different mechanisms. Osteoclast cell differentiation is regulated or regulated by osteoblasts (Glass et al., Dev Cell 8: 751-764 (2005)) or other hormones such as PTH, calcitonin or IL6. In contrast, osteoblast differentiation or activity is not regulated or regulated by osteoclasts, but rather by different signals such as CPFA, hedgehog, and BMP / Wnt. Bone formation can occur via endochondral or intramembranous ossification. In intramembranous ossification, bone forms directly through osteoblast / osteocytic stimulation. In endochondral ossification, bone formation occurs through cartilage templates that increase the amount of time it takes for bone to form. BMP signaling has been shown to be involved in endochondral ossification, while Wnt signaling has been shown to be involved in both endochondral and intramembranous ossification.

0023Under normal conditions, bone remodeling (or bone homeostasis) involves the breakdown of old bone (by osteoclasts) and the repair and replacement of old bone by new bone (by osteoblasts). When this homeostasis is disturbed and bone resorption exceeds bone formation, it results in decreased bone mass (loss of trabecular bone) and increased bone fragility (lower bone strength). Many diseases and conditions are associated with increased bone resorption, such diseases and conditions include osteoporosis, osteogenesis imperfecta, Paget's disease of bone, paget's disease of metabolism, metabolic bone disease, bone changes following cancer, and low bone density. Other characteristic diseases include.

0024Diseases associated with reduced bone mass and greater bone fragility are often treated with anti-absorbants such as bisphosphonates, RankL inhibitors, estrogens, cathepsin K inhibitors and selective estrogen receptor modulators. These agents function by directly or indirectly preventing or inhibiting bone resorption. See Figure 1. However, these agents do not promote new bone formation (ie, anabolic bone formation), in contrast, administration of a single dose of the anabolic usually increases bone formation in humans by more than 3% per year). Bring. Therefore, fragile osteoporotic bone treated with anti-absorbents will prevent fragile bone from becoming more fragile, but fragile bone will not become stronger or increase in strength. This is because anti-absorbents do not promote new bone growth by depositing more bone minerals and increasing bone density. In contrast, if an agent that promotes anabolic bone growth, such as by stimulating the activity of osteoblasts, promotes the deposition of more bone matrix or stimulates proliferation, the agent will produce more. It gives rise to osteoblasts and becomes more bone cells that fill the gap to fuse the two bones. Thus, fragile osteoporotic bone treated with anabolic bone-forming agents will not become more fragile and will become stronger due to increased bone deposition.

0025Without being bound by any particular theory, the compounds of the invention are believed to be SOST (sclerostin) and / or WISE antagonists that promote anabolic bone formation by regulating the Wnt and BMP signaling pathways. SOST and WISE either bind to the Wnt co-receptor LRP, thereby inhibiting the Wnt signaling pathway, or bind to BMP and inhibit BMP activity via another amino acid sequence or domain. It is a protein that is thought to regulate bone formation. By neutralizing the inhibitory effects of SOST and / or WISE proteins on the Wnt pathway, the compounds and compositions of the invention restore Wnt signaling and promote bone growth. Thus, in one embodiment, the invention provides compounds, compositions and methods for promoting bone formation in a subject. Bone formation can be systemic or local. The compounds and compositions of the present invention can be administered topically and / or systemically, and in some cases can be administered sequentially or in combination with one or more other therapeutic agents. In another embodiment, the invention is an implantable device as a structural scaffold capable of transferring osteoblasts / osteoocytes to a structural scaffold and depositing bone minerals, and also, for example, at the site of implantation. Provided is an implantable device device as a structural scaffold for delivering the compounds and compositions of the present invention to promote bone formation in the body. In another embodiment, the compounds and compositions of the present invention can be used to treat nephropathy and cancer.

0026II. Definition As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that assists in the administration and absorption of an activator by a subject. Pharmaceutically acceptable excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents and colorants. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

0027As used herein, the term "alkyl" refers to a linear or branched saturated aliphatic group with the indicated number of carbon atoms. For example, C₁-C₆Alkyl includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl and the like.

0028The alkylene represents a linear or branched alkylene of 1 to 7 carbon atoms, that is, a divalent hydrocarbon of 1 to 7 carbon atoms, for example, the linear alkylene represents the formula (CH).₂)_n(In the formula, n is 1, 2, 3, 4, 5, 6 or 7). Preferably, the alkylene is a linear alkylene with 1 to 4 carbon atoms, eg, a methylene, ethylene, propylene or butylene chain, or C.₁-C₃Substituted with alkyl (preferably methyl) or C₁-C₃A methylene, ethylene, propylene or butylene chain disubstituted on the same or different carbon atoms with alkyl (preferably methyl), with a total carbon atom number of 7 or less and including 7. Those skilled in the art can allow one carbon of the alkylene to be divalent, eg, CH ((CH).₂)_nCH₃) (In the equation, n = 0 ~ 5).

0029As used herein, the term "alkoxy" refers to alkyl having an oxygen atom, such as methoxy, ethoxy, and the like. "Haloalkoxy" is defined as an alkoxy in which some or all of the hydrogen atoms are replaced by halogen atoms. For example, examples of the halo-substituted alkoxy include trifluoromethoxy and the like.

0030As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon having 2 to 6 carbon atoms and having at least one double bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl, pentenyl or hexadienyl.

0031As used herein, the term "alkynyl" refers to a linear 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, acetylenyl, propynyl or butynyl.

0032As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

0033As used herein, the term "haloalkyl" refers to the above alkyl in which some or all of the hydrogen atoms are replaced by halogen atoms. The halogen (halo) preferably represents chloro or fluoro, but can also be bromo or iodine. For example, examples of haloalkyl include trifluoromethyl and fluoromethyl. The term "perfluoro" defines a compound or group in which at least two available hydrogens have been replaced by fluorine. For example, perfluoromethane refers to 1,1,1-trifluoromethyl, and perfluoromethoxy refers to 1,1,1-trifluoromethoxy.

0034As used herein, the term "heteroalkyl" refers to an alkyl group having 1-3 heteroatoms, such as N, O and S. Additional heteroatoms are also useful and include, but are not limited to, B, Al, Si and P. Heteroatoms may also be oxidized, eg, but not limited to, S (O) and S (O).₂Can be mentioned. For example, heteroalkyls include ethers, thioethers and alkylamines.

0035As used herein, the term "cycloalkyl" is a saturated or partially unsaturated monocyclic, fused bicyclic containing 3-12 ring atoms, or the indicated ring atoms. Refers to a formula or bridging polycyclic ring structure. For example, C₃-C₈Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and even cyclooctyl.

0036As used herein, the terms "heterocycle" and "heterocycloalkyl" refer to 3 ring elements to about 20 ring elements and 1 to about 5 heteroatoms, such as N, Refers to a ring system with O and S. Additional heteroatoms can also be useful and include, but are not limited to, B, Al, Si and P. Heteroatoms may also be oxidized, eg, but not limited to, S (O) and S (O).₂Can be mentioned. For example, heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl, 1,4-dioxa-8. -Azaspiro [4,5] Death-8-Il.

0037As used herein, a group "bonded via a carbon atom" refers to the bond between the carbon atom of the referenced group and the rest of the molecule. A group "bonded via a nitrogen atom" refers to the bond between the nitrogen atom of the referenced group and the rest of the molecule. As a mere example, a heterocyclyl group bonded via a carbon atom

0038<chemistry num="3"><img id="000005" he="36" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0039(In the equation, the wavy line points to the point of attachment to the rest of the molecule). As a mere example, a heterocyclyl group bonded via a carbon atom

0040<chemistry num="4"><img id="000006" he="29" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0041(In the equation, the wavy line points to the point of attachment to the rest of the molecule).

0042As used herein, if the referenced compound is an N-oxide, it contains a NO bond with three additional bonds to nitrogen, i.e. the N-oxide is a group R.₃N⁺Refers to -O-. As a mere example, as N-oxide,

0043<chemistry num="5"><img id="000007" he="36" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0044And so on.

0045As used herein, the term "aryl" refers to a monocyclic or condensed bicyclic, tricyclic or more polycyclic aromatic ring system containing 6 to 16 ring carbon atoms. .. For example, the aryl can be phenyl, benzyl or naphthyl, preferably phenyl. "Arylene" means a divalent group derived from an aryl group. Aryl groups include alkyl, alkoxy, aryl, hydroxy, halogen, cyano, amino, aminoalkyl, trifluoromethyl, alkylenedioxy and oxy-C.₂-C₃-Alkylenes (all of which may optionally be further substituted as described above) or 1, 2 or 3 selected from 1- or 2-naphthyl, or 1- or 2-phenanthrenyl). It may be mono- or di- or tri-substituted by the number of groups. The alkylenedioxy is a divalent substituent attached to two adjacent carbon atoms of phenyl, such as methylenedioxy or ethylenedioxy. Oxy-C₂-C₃-Alkylene is a divalent substituent attached to two adjacent carbon atoms of phenyl, such as oxyethylene or oxypropylene. Oxy-C₂-C₃An example of -alkylene phenyl is 2,3-dihydrobenzofuran-5-yl.

0046Preferred aryls are naphthyl, phenyl, or phenyl mono- or di-substituted with alkoxy, phenyl, halogen, alkyl or trifluoromethyl, particularly one with phenyl or alkoxy, halogen or trifluoromethyl. Substituted or disubstituted phenyl, especially phenyl.

0047Examples of substituted phenyl groups as R, such as 4-chlorophen-1-yl, 3,4-dichlorophen-1-yl, 4-methoxyphen-1-yl, 4-methylphen-1-yl, 4 -Aminomethylphen-1-yl, 4-methoxyethylaminomethylphen-1-yl, 4-hydroxyethylaminomethylphen-1-yl, 4-hydroxyethyl- (methyl) -aminomethylphen-1-yl, 3-Aminomethylphen-1-yl, 4-N-Acetylaminomethylphen-1-yl, 4-Aminophen-1-yl, 3-Aminophen-1-yl, 2-Aminophen-1-yl, 4-Phenyl-phen-1-yl, 4- (imidazol-1-yl) -phenyl, 4- (imidazol-1-ylmethyl) -phen-1-yl, 4- (morpholin-1-yl) -phen- 1-yl, 4- (morpholin-1-ylmethyl) -phen-1-yl, 4- (2-methoxyethylaminomethyl) -phen-1-yl and 4- (pyrrolidin-1-ylmethyl) -phen-1 -Il, 4- (thiophenyl) -fen-1-yl, 4- (3-thiophenyl) -fen-1-yl, 4- (4-methylpiperazin-1-yl) -fen-1-yl and 4- They are (piperidinyl) -phenyl and 4- (pyridinyl) -phenyl and may optionally be substituted in the heterocycle.

0048As used herein, the term "heteroaryl" is a monocycle containing 5 to 16 ring atoms, each of which is an N, O or S heteroatom. Formula or fused Bicyclic or tricyclic aromatic ring system. For example, heteroaryls include pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, furanyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isooxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or alkyl. Included are any other groups substituted, such as with nitro or halogen, particularly mono- or di-substituted. Pyridil represents 2-, 3- or 4-pyridyl, preferably 2- or 3-pyridyl. Thienyl represents 2- or 3-thienyl. Kinolinyl preferably represents 2-, 3- or 4-quinolinyl. Isoquinolinyl preferably represents 1-, 3- or 4-isoquinolinyl. Benzopyranyl and benzothiopyranyl preferably represent 3-benzopyranyl or 3-benzothiopyranyl, respectively. Thiazolyl preferably represents 2- or 4-thiazolyl, with 4-thiazolyl being most preferred. The triazolyl is preferably 1-, 2- or 5- (1,2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl.

0049Preferably, the heteroaryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isooxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, benzothiazolyl, benzofuranyl, isoquinolinyl, benzothienyl, oxazolyl, indazolyl, or is particularly substituted. , Mono- or di-substituted arbitrary groups.

0050Aryl and heteroaryl group substituents vary and are 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 (NH)₂) = NH, -NR'C (NH)₂) = 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 (C)₁-C₄) Alkyl, which is a number in the range of 0 to the total open valence of the aromatic ring system, where R', R "and R"'are independently hydrogen, (C.₁-C₈) Alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C₁-C₄) Alkyl and (unsubstituted aryl) oxy- (C₁-C₄) Selected from alkyl.

0051As used herein, the term "salt" refers to a salt or base salt of a compound used in the methods of the invention. Examples of pharmaceutically acceptable salts are salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamate, citric acid, etc.), and quaternary ammonium (iodized). It is a salt of methyl, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Additional 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.

0052The pharmaceutically acceptable salt of the acidic compound of the present invention is a salt formed with a base, that is, alkali metal and alkaline earth metal salts such as sodium, lithium, potassium, calcium and magnesium, as well as ammonium and trimethylammonium. , Diethylammonium and cation salts such as ammonium salts such as tris (hydroxymethyl) methylammonium salts.

0053Similarly, mineral acids such as hydrochloric acid, methanesulfonic acid and maleic acid, and acid addition salts such as organic carboxylic acid and organic sulfonic acid are also possible, provided that basic groups such as pyridyl are part of the structure. ..

0054The neutral form of the compound can be regenerated in the conventional manner by contacting the salt with a base or acid and separating the parent compound. The parent form of the compound differs from various salt forms in certain physical properties such as solubility in a polar solvent, but otherwise the salt is equivalent to the parent form of the compound of interest of the present invention.

0055As 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 arsenic, calcium borate, calcium bromide, calcium carbide, calcium carbonate, calcium chlorate, calcium chloride, Calcium citrate, calcium malate citrate, calcium cyanamide, calcium dihydrogen phosphate, calcium fluoride, calcium formate, calcium grubionate, calcium glucoheptate, calcium gluconate, calcium glyceryl phosphate, calcium hexaborate, calcium hydride, Calcium hydroxide, calcium hypochlorite, calcium inosinate, calcium iodide, calcium iodide, calcium lactate, calcium lactate gluconate, calcium magnesium acetate, calcium malate, calcium nitrate, calcium nitride, calcium oxalate, calcium oxide , Calcium Pangamate, Calcium Peroxide, Calcium Phosphate, Calcium Phosphate, Calcium Propionate, Calcium Pyrophosphate, Calcium Silica, Calcium , Calcium Sorbate, Calcium Stearate, Calcium Sulfate, Calcium Sulfide, Calcium Tartrate, Calcium Chloride (I) , Dicalcium Citrate, Dicalcium Phosphate, Twelve Calcium Heptaluminate, Tricalcium Aluminate, Tricalcium Phosphate and Lime Triperphosphate. Those skilled in the art will appreciate that other calcium salts are useful in the present invention.

0056As used herein, the term "hydrate" refers to a compound complexed into at least one water molecule. The compounds of the present invention can be complexed with 1-10 water molecules.

0057Certain compounds of the invention have asymmetric carbon atoms (optical centers) or double bonds, and racemic mixtures, diastereomers, geometric isomers and individual isomers are all included within the scope of the invention. Is intended.

0058As used herein, the term "subject" refers to, but is not limited to, animals such as mammals, primates (eg, humans), cows, sheep, goats, horses, dogs, cats. , Rabbits, rats, mice and the like. In certain embodiments, the subject is a human.

0059As used herein, the terms "therapeutic effective amount or dose" or "therapeutically sufficient amount or dose" or "effective or sufficient amount or dose" produce a therapeutic effect when administered. Refers to the dose. The exact dose will depend on the purpose of treatment and will be confirmed by those skilled in the art using known techniques (eg Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, See Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams &amp; Wilkins). In sensitized cells, the therapeutically effective dose can often be lower than the traditional therapeutically effective dose of unsensitized cells.

0060As used herein, the term "site of injury or localization" refers to a particular location on the body of a subject in need of treatment by the methods of the invention. For example, the injury can be a contusion and the localized condition is a disease condition that is confined to a specific part of the subject's body, such as a specific bone, joint, finger, hand, foot, limb, spine, head, torso It can be (eg, osteoporosis, etc.). In some embodiments, the site of injury or localization is a surgical implant site.

0061As used herein, the term "promoting bone formation" stimulates new bone formation, grows bone across joints or gaps, and / or contains bone density or bone minerals. Refers to increasing the minutes. In some embodiments, the compound compares the amount of bone in the sample to a control sample (eg, a sample that is not in contact with the compound) at least 5%, 6%, 7%, 8%, 9%, 10 If increased by%, 15% or more, the compound promotes bone formation.

0062As used herein, the term "joint fixation" refers to the artificial induction of joint ossification between or across two bones, often through surgery. Joint fixation can be achieved, among other things, by the use of bone grafts, metal implants or synthetic bone substitutes.

0063As used herein, the term "bone autotransplantation" refers to the subject's own bone transplantation.

0064As used herein, the term "bone allogeneic transplant" refers to a bone transplant from one person to another.

0065As used herein, the term "anti-bone resorbent" refers to an agent that slows or blocks bone resorption and / or acts on osteoclasts.

0066As used herein, the term "bone-related disease characterized by low bone mass" refers to bone with a T-score of less than -0.5. Other methods of determining low bone mass are known to those of skill in the art.

0067As used herein, the term "fracture" refers to a broken or damaged bone.

0068As used herein, the term "spine fusion" refers to a surgical technique that combines two or more spines.

0069As used herein, the term "structural support" refers to a portion of a device that can be implanted in a subject (implantable portion). Structural supports can be prepared from a variety of different materials, including metals, ceramics, polymers and inorganic materials as described below. The structural support can be coated with a variety of materials that promote bone growth. In some embodiments, the entire device constitutes an implantable structural support. For example, in some embodiments, the entire device as described herein can be implanted at the surgical site and the surgical site can be closed on the device.

0070As used herein, the term "external coating" refers to a structural support that can cover only a portion of the structural support (partial external coating) or the entire structural support. Refers to the coating. For example, the partial exterior coating can completely cover only the implantable portion of the structural support.

0071As used herein, the term "embrittled bone" has a t-score of less than -0.5 (0.9 g / cm).²Refers to bones with (less than).

0072As used herein, the term "decalcified bone" refers to bone from which inorganic minerals have been removed. The remaining organic collagen material can contain bone-induced growth factors. These growth factors include bone morphogenesis proteins that induce cartilage ossification via endochondral ossification to produce new bone formation. Decalcified bone often takes the form of a "decalcified bone matrix (DBM)". DBMs can be made from fresh, frozen or lyophilized bulk bone allogeneic grafts, or are non-collagenal, removing the mineral phase to provide essential properties of collagen, growth factors, and bone conduction. It can be produced from mild acid extraction of carcass bone, leaving the protein behind. DBM can also be processed in a variety of ways to finally obtain a powder mixed with the carrier to provide the optimum handling properties desired by the surgeon. DBM is clinically available in gels, pastes, putties and fabrics designed to meet the needs of the surgical procedure. Some DBMs are mixed with antibiotics prior to the surgical procedure.

0073As used herein, the term "kidney injury" refers to the inability of the kidney to excrete excrement and maintain the body's electrolyte balance. Renal injury is characterized by several features: hypertension, urea accumulation and formation of crystalline urinary sweat disease, potassium accumulation in the blood, decreased erythropoietin synthesis, increased fluid volume, hyperphosphatemia and Metabolic acidosis.

0074As used herein, the term "bone conduction matrix" can act as a bone conduction substrate (ie, allows bone growth), and infiltrative cells bind and proliferate. And refers to materials with a scaffold structure that participates in the process of producing osteoid, the organic phase of bone, and maximizes osteogenesis or new bone formation. The terms "matrix" and "scaffold" refer interchangeably to structural parts or substrates that inherently have a three-dimensional shape in which certain cellular events involved in bone formation occur. The bone conduction matrix allows internal growth of host capillaries, perivascular tissue and bone progenitor cells. In some embodiments, the bone conduction matrix comprises a "bone inducer" to provide bone forming ability. Bone inducers, when used herein, are agents that stimulate the host to proliferate bone cells, thereby producing osteoid.

0075As used herein, the terms "treat," "treating," and "treatment" refer to the treatment or amelioration of an injury, condition, condition or symptomatology (eg, pain). Refers to any sign of success, including objective or subjective parameters, eg, reducing, reducing, reducing, or making the subject more tolerable of symptoms, injuries, medical conditions or conditions, symptoms Alternatively, the frequency or duration of the condition may be reduced, or, in some cases, the prevention of the onset of the symptomatology or condition. Treatment or amelioration of symptoms can be based on any objective or subjective parameters, including, for example, the results of physical examination.

0076As used herein, the term "RankL inhibitor" refers to a compound or agent that inhibits the activity of RankL. Rank L (receptor activator of nuclear factor κB ligand) is important for bone metabolism by activating osteoclasts. RankL inhibitors include, but are not limited to, the human monoclonal antibody denosumab. Those skilled in the art will appreciate that other RankL inhibitors are useful in the present invention.

0077III. Compounds and compositions Examples of compounds useful for the method of the present invention include harmine and harmine derivatives. Therefore, some embodiments of the present invention provide compounds according to formula I, or salts, hydrates or isomers thereof.

0078<chemistry num="6"><img id="000008" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0079(In the above formula, W is CR^3aAnd N, where N may optionally be oxidized to the corresponding N-oxide. X is CR^3bAnd N, where N may optionally be oxidized to the corresponding N-oxide. Y is CR^3cAnd N, where N may optionally be oxidized to the corresponding N-oxide. Z is CR^3dAnd N, where N may optionally be oxidized to the corresponding N-oxide. R^NIs NR⁶R⁷, Heterocyclyl and heteroaryl, where heterocyclyl and heteroaryl contain from about 5 to about 10 ring atoms, at least one of which is nitrogen, and R.^NThe N in it may optionally be oxidized to the corresponding N-oxide, Each R^1a, R^1bAnd R^1cIs independently selected from H, methyl and ethyl, where -C (R)^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-The total number of carbon atoms in the group does not exceed 6, Each R², R^3a, R^3b, R^3cAnd R^3dIndependently, H, Halogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Alkenyl, C_2-6Alkyne, C_1-6Alkoxy, C_1-6Haloalkoxy, aryloxy, C_1-6Alkyl-OH, -OR⁴, -C_0-6Alkyl-NR⁴R⁵, -SR⁴, -C (O) R⁴, -C_0-6Alkyl-C (O) OR⁴, -C (O) NR⁴R⁵, -N (R)⁴) C (O) R⁵, -N (R)⁴) C (O) OR⁵, -N (R)⁴) C (O) NR⁴R⁵, -OP (O) (OR⁴)₂, -S (O)₂OR⁴, -S (O)₂NR⁴R⁵, -CN, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, selected from the group Alternatively, two Rs on adjacent atoms²Groups can be combined with the atoms to which they are attached to form elements selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and Each R⁴, R⁵, R⁶And R⁷Independently, H, C_1-6Alkyl and C_1-6Selected from the group consisting of alkyl-OH, The sign q is an integer from 0 to 4, and The sign t is an integer from 0 to 4 and However, more than one of W, X, Y and Z is not N or the corresponding N-oxide, However, a) The sum of q and t is 1, and b) R, if present⁶Or R⁷Either H or C_1-6When it is alkyl R^1aAnd R^1bAt least one of them is other than H, However, When the sum of q and t is 2, a) R²Is other than H, and b) R, if present⁶And R⁷At least one of them is other than H or methyl).

0080In some embodiments, the present invention provides a compound according to formula I, or a salt, hydrate or isomer thereof.

0081<chemistry num="7"><img id="000009" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0082(In the above formula, W is CR^3aAnd N, where N may optionally be oxidized to the corresponding N-oxide. X is CR^3bAnd N, where N may optionally be oxidized to the corresponding N-oxide. Y is CR^3cAnd N, where N may optionally be oxidized to the corresponding N-oxide. Z is CR^3dAnd N, where N may optionally be oxidized to the corresponding N-oxide. R^NIs NR⁶R⁷, Heterocyclyl and heteroaryl, where heterocyclyl and heteroaryl contain from about 5 to about 10 ring atoms, at least one of which is nitrogen, R.^NThe N in it may optionally be oxidized to the corresponding N-oxide, Each R^1a, R^1bAnd R^1cIs independently selected from H, methyl and ethyl, where the group-C (R)^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-The total number of carbon atoms in it does not exceed 6, Each R², R^3a, R^3b, R^3cAnd R^3dIndependently, H, Halogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Alkenyl, C_2-6Alkyne, C_1-6Alkoxy, C_1-6Haloalkoxy, aryloxy, C_1-6Alkyl-OH, -OR⁴, -C_0-6Alkyl-NR⁴R⁵, -SR⁴, -C (O) R⁴, -C_0-6Alkyl-C (O) OR⁴, -C (O) NR⁴R⁵, -N (R)⁴) C (O) R⁵, -N (R)⁴) C (O) OR⁵, -N (R)⁴) C (O) NR⁴R⁵, -OP (O) (OR⁴)₂, -S (O)₂OR⁴, -S (O)₂NR⁴R⁵, -CN, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, selected from the group Alternatively, two Rs on adjacent atoms²Groups can be combined with the atoms to which they are attached to form elements selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl. Each R⁴, R⁵, R⁶And R⁷Independently, H, C_1-6Alkyl, C_1-6Alkyl-OH and C_1-6Alkyl-OC_1-6Selected from the group consisting of alkyl The sign q is an integer from 0 to 4, and The sign t is an integer from 0 to 4 and However, more than one of W, X, Y and Z is not N or the corresponding N-oxide, However, a) The sum of q and t is 1, and b) R, if present⁶Or R⁷Either H or C_1-6When it is alkyl R^1aAnd R^1bAt least one of is non-H, and However, a) The sum of q and t is 1, and b) R^NBut when it is a heterocycle At least one R²Is other than H, and However, When the sum of q and t is 2. a) At least one is other than H, b) R^NIs not phthalimide, and c) If it exists, R⁶And R⁷At least one of is non-H or methyl, and However, a) The sum of q and t is 3, and b) Each R^1a, R^1bAnd R^1cWhen is H R^NIs not a phthalimide, and if present, R⁶And R⁷At least one of them is other than H, methyl and ethyl).

0083In certain embodiments, the present invention provides a compound of formula I as described above, provided that the compound is not: 1-Amino-3- (3,6-dibromo-9H-carbazole-9-yl) propan-2-ol, 1- (3,6-dibromo-9H-pyrido [3,4-b] indole-9-yl) -3-((3-methoxyphenyl) amino) propan-2-ol, 9-(2- (Piperidin-1-yl) ethyl) -9H-pyrido [3,4-b] indole-3-carboxamide, Methyl 9- (4- (dimethylamino) butyl) -9H-pyrido [3,4-b] indole-3-carboxylate, N, N-dimethyl-4- (9H-pyrido [3,4-b] indole-9-yl) butane-1-amine, N-Ethyl-N-Methyl-4- (9H-pyrido [3,4-b] indole-9-yl) butane-1-amine, 2- [4- [7-Hydroxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl] butyl] -1H-isoindole-1,3 (2H) -dione , 2- [4- [7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl] butyl] -1H-isoindole-1,3 (2H) -dione , 2- [4- (7-Hydroxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) butyl] -1H-isoindole-1,3 (2H) -dione, 2- [3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl] -1H-isoindole-1,3 (2H) -dione, 9- (4-Aminobutyl) -1- (Trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol, 7-Methoxy-N, N, 1-trimethyl-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-N, 1-dimethyl-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-butaneamine, 9- (4-Aminobutyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol, 7-Methoxy-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-propaneamine, N, N-dimethyl-N- [3- (7-methoxy-1-methyl-9H-b-carboline-9-yl) -propyl] amine, N, N, 1,3-tetramethyl-9H-pyrido [3,4-b] indole-9-ethaneamine, N, N-diethyl-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-ethaneamine, 7-Methoxy-N, N, 1-trimethyl-9H-pyrido [3,4-b] indole-9-ethaneamine, 4- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylbutane-1-amine, 4- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N-methylbutane-1-amine, 4- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) butane-1-amine, 1- (9H-carbazole-9-yl) -N, N-dimethylpropan-2-amine, or 2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylethaneamine.

0084In certain embodiments, the compound is not a dihydro β-carboline derivative or a tetrahydroγ-carboline derivative.

0085Some additional embodiments of the invention provide compounds according to formula IA, or salts, hydrates or isomers thereof.

0086<chemistry num="8"><img id="000010" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0087(In the above formula, W is CR^3aAnd N, where N may optionally be oxidized to the corresponding N-oxide. X is CR^3bAnd N, where N may optionally be oxidized to the corresponding N-oxide. Y is CR^3cAnd N, where N may optionally be oxidized to the corresponding N-oxide. Z is CR^3dAnd N, where N may optionally be oxidized to the corresponding N-oxide. R^NIs NR⁶R⁷, Heterocyclyl and heteroaryl, where heterocyclyl and heteroaryl contain from about 5 to about 10 ring atoms, at least one of which is nitrogen, where R.^NThe N in it may optionally be oxidized to the corresponding N-oxide, Each R^1a, R^1bAnd R^1cIs independently selected from H, methyl and ethyl, where the group-C (R)^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-The total number of carbon atoms in it does not exceed 6, Each R², R^3a, R^3b, R^3cAnd R^3dIndependently, H, Halogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Alkenyl, C_2-6Alkyne, C_1-6Alkoxy, C_1-6Haloalkoxy, aryloxy, C_1-6Alkyl-OH, -OR⁴, -C_0-6Alkyl-NR⁴R⁵, -SR⁴, -C (O) R⁴, -C_0-6Alkyl-C (O) OR⁴, -C (O) NR⁴R⁵, -N (R)⁴) C (O) R⁵, -N (R)⁴) C (O) OR⁵, -N (R)⁴) C (O) NR⁴R⁵, -OP (O) (OR⁴)₂, -S (O)₂OR⁴, -S (O)₂NR⁴R⁵, -CN, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, selected from the group Alternatively, two Rs on adjacent atoms²Groups can be combined with the atoms to which they are attached to form elements selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl. Each R⁴, R⁵, R⁶And R⁷Independently, H, C_1-6Alkyl and C_1-6Selected from the group consisting of alkyl-OH, The sign q is an integer from 0 to 4, and The sign t is an integer from 0 to 4, and However, more than one of W, X, Y and Z cannot be N or the corresponding N-oxide).

0088In some embodiments, the present invention provides a compound of formula I having the following structure, or a salt, hydrate or isomer thereof.

0089<chemistry num="9"><img id="000011" he="65" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0090(In the above formula, R²Is H, C_1-6Alkoxy, -OH and C_1-6Selected from the group consisting of alkyl-OH, R^3aAnd R^3bIndependently, H, Halo, C_1-6Selected from the group consisting of alkoxy, -OH, and R^3dIs H, C_1-6Alkyl and C_1-6Selected from the group consisting of haloalkyl).

0091In some embodiments, the present invention provides a compound of formula I having the following structure, or a salt, hydrate or isomer thereof.

0092<chemistry num="10"><img id="000012" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0093(In the above formula, R²Is H, C_1-6Alkoxy, -OH and C_1-6Selected from the group consisting of alkyl-OH, R^3bH, halo, C_1-6Selected from the group consisting of alkoxy, -OH, and R^3dIs H, C_1-6Alkyl and C_1-6Selected from the group consisting of haloalkyl).

0094In some embodiments, the compound of formula (I) is one of the following compounds: (A) In some embodiments, the present invention R²Is selected from the group consisting of OH and methoxy, and R^3a, R^3bAnd R^3dIs H, Provided is a compound or a salt, hydrate or isomer thereof. (B) In some embodiments, the present invention R²Is selected from the group consisting of methoxy and -OH, R^3aAnd R^3bIs H, and R^3dIs selected from the group consisting of methyl, methoxy and trifluoromethyl, preferably R^3dIs methyl or trifluoromethyl, Provided is a compound or a salt, hydrate or isomer thereof. (C) In some embodiments, the present invention R²Is selected from the group consisting of methoxy and -OH, R^3aAnd R^3dIs H, and R^3bIs selected from the group consisting of F, Cl, Br and I, preferably R.^3bIs F, Provided is a compound or a salt, hydrate or isomer thereof. (D) In some embodiments, the present invention R²Is selected from the group consisting of methoxy and -OH, R^3aIs H, and R^3bIs selected from the group consisting of F, -OH and methoxy, Provided is a compound or a salt, hydrate or isomer thereof. (E) In some embodiments, the present invention R²Is selected from the group consisting of methoxy and -OH, and R^3aAnd R^3bIs H, Provided is a compound or a salt, hydrate or isomer thereof. (F) In some embodiments, the present invention R²Is selected from the group consisting of H and methoxy, and R^3aIs H, R^3bIs F, Cl, Br or I, preferably R^3bIs F, and R^3dIs methyl, Provided is a compound or a salt, hydrate or isomer thereof.

0095In any of the above embodiments (A), (B), (C), (D), (E) or (F), in one group of embodiments, R²Is OH, and R^3a, R^3bAnd R^3dIs as above. In any of the above embodiments (A), (B), (C), (D), (E) or (F), in the second group of embodiments, R²Is methoxy, and R^3a, R^3bAnd R^3dIs as above. In any of the above embodiments (A), (B), (C), (D), (E) or (F), in one group of embodiments, the nitrogen at position Z is oxidized to N-oxides. ing.

0096Compounds of formula (I) having a structure selected from the following are included in one group of embodiments.

0097<chemistry num="11"><img id="000013" he="157" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0098In each of the above structures, in one group of embodiments,<chemistry num="12"><img id="000014" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0099Is selected from the following.

0100<chemistry num="13"><img id="000015" he="87" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0101In some embodiments, the invention provides a compound in which N at the Z position is oxidized to the corresponding N-oxide, or a salt, hydrate or isomer thereof.

0102In some embodiments, the present invention is R.^3aIs selected from the group consisting of F and -OH, and R^3bProvided is a compound in which H is, or a salt, hydrate or isomer thereof.

0103In some embodiments, the present invention has the following structure:

0104<chemistry num="14"><img id="000016" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0105(In the above formula, R²Is H, C_1-6Alkoxy, -OH and C_1-6Selected from the group consisting of alkyl-OH, R^3bAnd R^3cIndependently, H, Halo, C_1-6Selected from the group consisting of alkoxy, -OH, and R^3dIs H, C_1-6Alkyl and C_1-6(Selected from the group consisting of haloalkyl) Provided is a compound having the above, or a salt, hydrate or isomer thereof.

0106In some embodiments, the present invention R²Is methoxy, R^3dIs methyl, and R^3bAnd R^3cIs H, Provided is a compound or a salt, hydrate or isomer thereof.

0107In some embodiments, the present invention has the following structure:

0108<chemistry num="15"><img id="000017" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0109(In the above formula, R²Is H, C_1-6Alkoxy, -OH and C_1-6Selected from the group consisting of alkyl-OH, R^3aAnd R^3cIndependently, H, Halo, C_1-6Selected from the group consisting of alkoxy, -OH, and R^3dIs H, C_1-6Alkyl and C_1-6(Selected from the group consisting of haloalkyl) Provided is a compound having the above, or a salt, hydrate or isomer thereof.

0110In some embodiments, the present invention R²Is methoxy, R^3dIs methyl, and R^3aAnd R^3cIs H, Provided is a compound or a salt, hydrate or isomer thereof.

0111In some embodiments, the present invention has the following structure:

0112<chemistry num="16"><img id="000018" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0113(In the above formula, Z is selected from CH and N, R²Is selected from the group consisting of H and methoxy, and R^3a, R^3bAnd R^3cIs H) Provided is a compound having the above, or a salt, hydrate or isomer thereof.

0114In some embodiments, the present invention has Z of N and R.²Provided is a compound in which H is, or a salt, hydrate or isomer thereof.

0115In some embodiments, the present invention has the following structure:

0116<chemistry num="17"><img id="000019" he="65" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0117(In the above formula, W is CR^3aAnd N, where N may optionally be oxidized to the corresponding N-oxide. X is CR^3bAnd N, where N may optionally be oxidized to the corresponding N-oxide. Y is CR^3cAnd N, where N may optionally be oxidized to the corresponding N-oxide. Z is CR^3dAnd N, where N may optionally be oxidized to the corresponding N-oxide. R^NIs selected from the group consisting of heterocyclyls and heteroaryls, where heterocyclyls and heteroaryls contain from about 5 to about 10 ring atoms, at least one of which is nitrogen, and R.^NThe N in it may optionally be oxidized to the corresponding N-oxide, Each R^1a, R^1bAnd R^1cIs independently selected from H, methyl and ethyl, with the group -C (R).^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-The total number of carbon atoms in it does not exceed 6, Each R², R^3a, R^3b, R^3cAnd R^3dIndependently, H, Halogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Alkenyl, C_2-6Alkyne, C_1-6Alkoxy, C_1-6Haloalkoxy, aryloxy, C_1-6Alkyl-OH, -OR⁴, -C_0-6Alkyl-NR⁴R⁵, -SR⁴, -C (O) R⁴, -C_0-6Alkyl-C (O) OR⁴, -C (O) NR⁴R⁵, -N (R)⁴) C (O) R⁵, -N (R)⁴) C (O) OR⁵, -N (R)⁴) C (O) NR⁴R⁵, -OP (O) (OR⁴)₂, -S (O)₂OR⁴, -S (O)₂NR⁴R⁵, -CN, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, selected from the group Alternatively, two Rs on adjacent atoms²Groups can be combined with the atoms to which they are attached to form elements selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl. Each R⁴, R⁵, R⁶And R⁷Independently, H, C_1-6Alkyl and C_1-6Selected from the group consisting of alkyl-OH, The sign q is an integer from 0 to 4 and The sign t is an integer from 0 to 4, and However, more than one of W, X, Y and Z cannot be N or the corresponding N-oxide) Provided is a compound having the above, or a salt, hydrate or isomer thereof.

0118In one group of embodiments, R^NIs a heterocyclyl group. In another group of embodiments, R^NIs a heteroaryl group. In an additional set of embodiments, R^NIs a piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, morpholinyl, pyrrolidinyl or azetidinyl group. In a further embodiment, R^NIs a triazolyl, tetrazolyl, imidazolyl or pyridinyl group.

0119In some embodiments, the present invention has the following structure:

0120<chemistry num="18"><img id="000020" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0121(In the above formula, R²Is -OH, C_1-6Selected from the group consisting of alkoxy and aryloxy, and R^3dIs C_1-6(Selected from the group consisting of alkyl, aryl and heteroaryl) Provided is a compound having the above, or a salt, hydrate or isomer thereof.

0122In some embodiments, the present invention R²Is selected from -OH and methoxy, and R^3dIs selected from the group consisting of 4-methoxyphenyl, 1,2,3-triazolyl, 1,2,4-oxadizaolyl and 1,3,4-oxadiazolyl. Provided is a compound or a salt, hydrate or isomer thereof.

0123In some embodiments, the present invention R²Is selected from the group consisting of phenoxy, (4-methyl) phenoxy, (4-methoxy) phenoxy, (4-chloro) phenoxy and (3,4-dichloro) phenoxy, and R^3dIs methyl, Provided is a compound or a salt, hydrate or isomer thereof.

0124In some embodiments, the present invention has the following structure:

0125<chemistry num="19"><img id="000021" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0126(During the above ceremony, R²H, Halogen, -OH and C_1-6Selected from alkoxy, R^3dH, halogen, C_1-6Alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, C_1-6Haloalkoxy and C_1-6Selected from alkyl-OH, R^NIs selected from the group consisting of heterocyclyls and heteroaryls, where heterocyclyls and heteroaryls contain from about 5 to about 10 ring atoms, at least one of which is nitrogen, and R.^NThe N in it may optionally be oxidized to the corresponding N-oxide, Each R^1a, R^1bAnd R^1cIs independently selected from H, methyl and ethyl, with the group -C (R).^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-The total number of carbon atoms in it does not exceed 6, The sign q is an integer from 0 to 4, and The sign t is an integer from 0 to 4) Provided is a compound having the above, or a salt, hydrate or isomer thereof.

0127In one group of embodiments of compounds of formula (IC), R²Is selected from fluoro, -OH, methoxy, ethoxy, isopropoxy or isobutoxy. In one group of embodiments of compounds of formula (IC), R^3dIs selected from fluoro, chloro, methoxy, ethoxy, methyl, ethyl or trifluoromethyl.

0128In some embodiments, the present invention describes the formula ID:

0129<chemistry num="20"><img id="000022" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0130(In the above formula, W is CR^3aAnd N, where N may optionally be oxidized to the corresponding N-oxide. X is CR^3bAnd N, where N may optionally be oxidized to the corresponding N-oxide. Y is CR^3cAnd N, where N may optionally be oxidized to the corresponding N-oxide. Z is CR^3dAnd N, where N may optionally be oxidized to the corresponding N-oxide. R^NIs NR⁶R⁷, Heterocyclyl and heteroaryl selected from the group consisting of heterocyclyl and heteroaryl containing from about 5 to about 10 ring atoms, at least one of which is nitrogen, and R.^NThe N in it may optionally be oxidized to the corresponding N-oxide, Each R^1a, R^1bAnd R^1cIs independently selected from H, methyl and ethyl, where the group-C (R)^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-The total number of carbon atoms in it does not exceed 6, Each R², R^3a, R^3b, R^3cAnd R^3dIndependently, H, Halogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Alkenyl, C_2-6Alkyne, C_1-6Alkoxy, C_1-6Haloalkoxy, aryloxy, C_1-6Alkyl-OH, -OR⁴, -C_0-6Alkyl-NR⁴R⁵, -SR⁴, -C (O) R⁴, -C_0-6Alkyl-C (O) OR⁴, -C (O) NR⁴R⁵, -N (R)⁴) C (O) R⁵, -N (R)⁴) C (O) OR⁵, -N (R)⁴) C (O) NR⁴R⁵, -OP (O) (OR⁴)₂, -S (O)₂OR⁴, -S (O)₂NR⁴R⁵, -CN, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, selected from the group Alternatively, two Rs on adjacent atoms²Groups can be combined with the atoms to which they are attached to form elements selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl. Each R⁴, R⁵, R⁶And R⁷Independently, H, C_1-6Alkyl, C_1-6Alkyl-OH and C_1-6Alkyl-OC_1-6Selected from the group consisting of alkyl The sign q is an integer from 0 to 4, and The sign t is an integer from 0 to 4 and However, No more than one of W, X, Y and Z is N or the corresponding N-oxide) The compound of, or a salt, hydrate or isomer thereof is provided.

0131In some embodiments, the invention provides a compound of formula ID, wherein a) The sum of q and t is 1, and b) R, if present⁶And R⁷Both are H or C_1-6When it is alkyl R^1aAnd R^1bAt least one of is non-H, and When the sum of Q and t is 2, a) R²Is other than H, and b) R, if present⁶And R⁷At least one of is other than H or methyl.

0132In some embodiments, the present invention provides a compound of formula ID, wherein. a) The sum of q and t is 1, and b) R, if present⁶And R⁷Both are H or C_1-6When it is alkyl R^1aAnd R^1bAt least one of is non-H, and a) The sum of q and t is 1, and b) R^NWhen is a heterocyclist At least one R²Is other than H, and When the sum of q and t is 2. a) At least one R²Is other than H, b) R^NIs not phthalimide, and c) If it exists, R⁶And R⁷At least one of is non-H or methyl, and a) The sum of q and t is 3, and b) Each R^1a, R^1bAnd R^1cWhen is H R^NIs not a phthalimide, and if present, R⁶And R⁷At least one of is other than H, methyl and ethyl.

0133In certain embodiments, the present invention provides a compound of formula ID as described above, provided that the compound is not: 1-Amino-3- (3,6-dibromo-9H-carbazole-9-yl) propan-2-ol, 1- (3,6-dibromo-9H-pyrido [3,4-b] indole-9-yl) -3-((3-methoxyphenyl) amino) propan-2-ol, 9-(2- (Piperidin-1-yl) ethyl) -9H-pyrido [3,4-b] indole-3-carboxamide, Methyl 9- (4- (dimethylamino) butyl) -9H-pyrido [3,4-b] indole-3-carboxylate, N, N-dimethyl-4- (9H-pyrido [3,4-b] indole-9-yl) butane-1-amine, N-Ethyl-N-Methyl-4- (9H-pyrido [3,4-b] indole-9-yl) butane-1-amine, 2- [4- [7-Hydroxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl] butyl] -1H-isoindole-1,3 (2H) -dione , 2- [4- [7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl] butyl] -1H-isoindole-1,3 (2H) -dione , 2- [4- (7-Hydroxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) butyl] -1H-isoindole-1,3 (2H) -dione, 2- [3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl] -1H-isoindole-1,3 (2H) -dione, 9- (4-Aminobutyl) -1- (Trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol, 7-Methoxy-N, N, 1-trimethyl-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-N, 1-dimethyl-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-butaneamine, 9- (4-Aminobutyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol, 7-Methoxy-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-butaneamine, 7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-propaneamine, N, N-dimethyl-N- [3- (7-methoxy-1-methyl-9H-b-carboline-9-yl) -propyl] amine, N, N, 1,3-tetramethyl-9H-pyrido [3,4-b] indole-9-ethaneamine, N, N-diethyl-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-ethaneamine, 7-Methoxy-N, N, 1-trimethyl-9H-pyrido [3,4-b] indole-9-ethaneamine, 4- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylbutane-1-amine, 4- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N-methylbutane-1-amine, 4- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) butane-1-amine, 1- (9H-carbazole-9-yl) -N, N-dimethylpropan-2-amine, or 2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylethaneamine.

0134In some embodiments, the present invention has the following structure:

0135<chemistry num="21"><img id="000023" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0136(During the above ceremony, R²Is selected from -OH and methoxy, R^3dIs selected from methyl or trifluoromethyl, and

0137<chemistry num="22"><img id="000024" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0138Is below,

0139<chemistry num="23"><img id="000025" he="115" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0140(Selected from), or salts, hydrates or isomers thereof.

0141In some embodiments, the present invention is structured.

0142<chemistry num="24"><img id="000026" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0143(In the above formula, R²Is selected from -OH and methoxy, R^3dIs selected from methyl or trifluoromethyl, and

0144<chemistry num="25"><img id="000027" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0145Is below

0146<chemistry num="26"><img id="000028" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0147Provided are compounds having (selected from), or salts, hydrates or isomers thereof.

0148In some embodiments, the present invention is structural

0149<chemistry num="27"><img id="000029" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0150(In the above formula, R²Is selected from -OH and methoxy, R^3dIs selected from methyl or trifluoromethyl, and

0151<chemistry num="28"><img id="000030" he="45" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0152Is below

0153<chemistry num="29"><img id="000031" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0154Provided are compounds having (selected from), or salts, hydrates or isomers thereof.

0155In any of the above embodiments, in some cases the nitrogen in Z is oxidized to N-oxides.

0156In some embodiments, the present invention provides compounds having a sign q and a sign t of 0.

0157In some embodiments, the present invention provides compounds having a sign q of 0 and a sign t of 1.

0158In some embodiments, the present invention provides compounds having a sign q of 1 and a sign t of 0.

0159In some embodiments, the present invention provides compounds of reference numeral q and reference numeral t.

0160In some embodiments of the compounds provided herein, group-C (R).^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-Is a linear alkyl group. In other embodiments, the group-C (R)^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-Is a branched alkyl group. In some embodiments, the base R^NIs a dialkylamino group, where alkyl is a linear alkyl or a branched alkyl group. In additional embodiments, the alkyl moiety in the dialkylamino moiety may optionally be substituted with a hydroxyl group. In a further embodiment, the base R^NIs a heterocyclyl or heteroaryl group. R^NIf is a heterocyclyl or heteroaryl group, then R^NIs attached to the rest of the molecule via either a carbon atom or a nitrogen atom. R^NIn a further embodiment where is a heterocyclyl or heteroaryl group, R^NIs attached to the rest of the molecule via either a carbon atom or a nitrogen atom, and R^NThe nitrogen atom in it may optionally be oxidized to the corresponding N-oxide.

0161In some embodiments, the present invention is based on the basis-C (R).^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-But

0162<chemistry num="30"><img id="000032" he="32" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0163Provided is a compound selected from the group consisting of, or a salt, hydrate or isomer thereof.

0164In some embodiments, the present invention is based on the basis-C (R).^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-But

0165<chemistry num="31"><img id="000033" he="74" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0166Provided is a compound selected from the group consisting of, or a salt, hydrate or isomer thereof.

0167In some embodiments, the present invention is based on the basis-C (R).^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-But

0168<chemistry num="32"><img id="000034" he="70" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0169Provided is a compound selected from the group consisting of, or a salt, hydrate or isomer thereof.

0170In some embodiments, the present invention provides a compound selected from the group consisting of the following, or a salt, hydrate or isomer thereof. 9-(2- (Dimethylamino) propyl) -9H-pyrido [3,4-b] indole-7-ol, 9-(2- (Dimethylamino) propyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol, N, N-dimethyl-1-(9H-pyrido [3,4-b] indole-9-yl) propan-2-amine, 1- (7-Methoxy-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-2-amine, 1- (2-Methoxy-9H-carbazole-9-yl) -N, N-dimethylpropan-2-amine, 4- (3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine, N, N-diethyl-3- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-1-amine, 7-Methoxy-1-methyl-9-(3- (piperazin-1-yl) propyl) -9H-pyrido [3,4-b] indole, 2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-1-amine, N, N-diethyl-2- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-1-amine, 7-Methoxy-1-methyl-9- (2- (piperazin-1-yl) ethyl) -9H-pyrido [3,4-b] indole, 4- (2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) morpholine, 4- (2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine, 7-Methoxy-1-methyl-9-(1- (piperidine-1-yl) propan-2-yl) -9H-pyrido [3,4-b] indole, 9-(2- (4H-1,2,4-triazole-3-yl) ethyl) -7-methoxy-1-methyl-9H-pyrido [3,4-b] indole, 2- (2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) -1,3,4-oxadiazole, 5- (2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) -1,2,4-oxadiazole, 9-(2- (1H-1,2,4-triazole-1-yl) ethyl) -7-methoxy-1-methyl-9H-pyrido [3,4-b] indole, 9-(3- (4H-1,2,4-triazole-3-yl) propyl) -7-methoxy-1-methyl-9H-pyrido [3,4-b] indole, 2- (3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) -1,3,4-oxadiazole, 5- (3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) -1,2,4-oxadiazole, and 9-(3- (1H-1,2,4-triazole-1-yl) propyl) -7-methoxy-1-methyl-9H-pyrido [3,4-b] indole.

0171In some embodiments, the present invention 1- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-2-aminium formate, N, N-dimethyl-1-(9H-pyrido [2,3-b] indole-9-yl) propan-2-amine, 1- (9H-carbazole-9-yl) -N, N-dimethylpropan-2-amine, and 9-(2- (Dimethylamino) propyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol Provided are compounds of formula I or formula II selected from the group consisting of.

0172In some embodiments, the present invention 7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-3-ol, 1-Methyl-9H-pyrido [3,4-b] indole-3,7-diol, 7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole, 3-Fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole, and 3,7-Dimethoxy-1-methyl-9H-pyrido [3,4-b] indole Provided are compounds selected from the group consisting of.

0173In some embodiments, the present invention 7-Methoxy-4-methyl-5H-pyrido [3,2-b] indole and 7-Methoxy-4-methyl-5H-pyrido [4,3-b] indole Provided are compounds of formula III selected from the group consisting of.

0174In a further embodiment, the invention provides a compound having any of the following structures:

0175<chemistry num="33"><img id="000035" he="83" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0176In a further embodiment, the above compounds are described using the procedures described herein above.

0177<chemistry num="34"><img id="000036" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0178It is further modified to bind to the group of.

0179Therefore, further provided herein are the following compounds:

0180<chemistry num="35"><img id="000037" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9- (2- (dimethylamino) propyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0181<chemistry num="36"><img id="000038" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (Dimethylamino) propyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0182<chemistry num="37"><img id="000039" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (Dimethylamino) propyl) -3-fluoro-1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0183<chemistry num="38"><img id="000040" he="45" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-(7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-2-amine,

0184<chemistry num="39"><img id="000041" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-2-amine,

0185<chemistry num="40"><img id="000042" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1- (3-Fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-2-amine,

0186<chemistry num="41"><img id="000043" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(1- (dimethylamino) propan-2-yl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0187<chemistry num="42"><img id="000044" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(1- (dimethylamino) propan-2-yl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0188<chemistry num="43"><img id="000045" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(1- (Dimethylamino) propan-2-yl) -3-fluoro-1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0189<chemistry num="44"><img id="000046" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-1-amine,

0190<chemistry num="45"><img id="000047" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-1-amine,

0191<chemistry num="46"><img id="000048" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2- (3-Fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-1-amine,

0192<chemistry num="47"><img id="000049" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2-((2-Hydroxyethyl) (methyl) amino) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0193<chemistry num="48"><img id="000050" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2-((2-Hydroxyethyl) (methyl) amino) ethyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0194<chemistry num="49"><img id="000051" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-9-(2-((2-Hydroxyethyl) (methyl) amino) ethyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0195<chemistry num="50"><img id="000052" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2-((2- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) (methyl) amino) ethanol,

0196<chemistry num="51"><img id="000053" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2-((2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) (methyl) amino) ethanol,<chemistry num="52"><img id="000054" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2-((2- (3-Fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) (methyl) amino) ethanol,

0197<chemistry num="53"><img id="000055" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9- (2- (dimethylamino) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0198<chemistry num="54"><img id="000056" he="45" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9- (2- (dimethylamino) ethyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0199<chemistry num="55"><img id="000057" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (Dimethylamino) ethyl) -3-fluoro-1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0200<chemistry num="56"><img id="000058" he="45" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2- (7-menu butoxy-1- (trifluoromethyl) -9H- pyrido [3,4-b] indol-9-yl) -N, N-dimethyl ethane amine,

0201<chemistry num="57"><img id="000059" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylethaneamine,

0202<chemistry num="58"><img id="000060" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2- (3-Fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylethaneamine,

0203<chemistry num="59"><img id="000061" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (Piperidin-1-yl) propyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0204<chemistry num="60"><img id="000062" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-Methyl-9- (2- (piperidin-1-yl) propyl) -9H-pyrido [3,4-b] indole-7-ol,

0205<chemistry num="61"><img id="000063" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-1-methyl-9-(2- (piperidine-1-yl) propyl) -9H-pyrido [3,4-b] indole-7-ol,

0206<chemistry num="62"><img id="000064" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>7-Methoxy-9- (2- (piperidin-1-yl) propyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole,

0207<chemistry num="63"><img id="000065" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>7-Methoxy-1-methyl-9- (2- (piperidine-1-yl) propyl) -9H-pyrido [3,4-b] indole,

0208<chemistry num="64"><img id="000066" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-7-Methoxy-1-methyl-9-(2- (piperidin-1-yl) propyl) -9H-pyrido [3,4-b] indole,

0209<chemistry num="65"><img id="000067" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (Piperidin-1-yl) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0210<chemistry num="66"><img id="000068" he="52" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-Methyl-9-(2- (piperidine-1-yl) ethyl) -9H-pyrido [3,4-b] indole-7-ol,

0211<chemistry num="67"><img id="000069" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-1-methyl-9-(2- (piperidine-1-yl) ethyl) -9H-pyrido [3,4-b] indole-7-ol,

0212<chemistry num="68"><img id="000070" he="52" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>7-Methoxy-9- (2- (piperidine-1-yl) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole,

0213<chemistry num="69"><img id="000071" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>7-Methoxy-1-methyl-9-(2- (piperidine-1-yl) ethyl) -9H-pyrido [3,4-b] indole,

0214<chemistry num="70"><img id="000072" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-7-methoxy-1-methyl-9-(2- (piperidine-1-yl) ethyl) -9H-pyrido [3,4-b] indole,

0215<chemistry num="71"><img id="000073" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9- (2-morpholinoethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0216<chemistry num="72"><img id="000074" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-Methyl-9- (2-morpholinoethyl) -9H-pyrido [3,4-b] indole-7-ol,

0217<chemistry num="73"><img id="000075" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3,4-b] indole-7-ol,

0218<chemistry num="74"><img id="000076" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (2- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) morpholine,

0219<chemistry num="75"><img id="000077" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) morpholine,

0220<chemistry num="76"><img id="000078" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (2- (3-Fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) morpholine,

0221<chemistry num="77"><img id="000079" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9- (2-morpholinopropyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0222<chemistry num="78"><img id="000080" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-Methyl-9- (2-morpholinopropyl) -9H-pyrido [3,4-b] indole-7-ol,

0223<chemistry num="79"><img id="000081" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-1-methyl-9- (2-morpholinopropyl) -9H-pyrido [3,4-b] indole-7-ol,

0224<chemistry num="80"><img id="000082" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (1- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) propan-2-yl) morpholine,

0225<chemistry num="81"><img id="000083" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (1- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-2-yl) morpholine,

0226<chemistry num="82"><img id="000084" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (1- (3-Fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-2-yl) morpholine,

0227<chemistry num="83"><img id="000085" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (Piperazine-1-yl) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0228<chemistry num="84"><img id="000086" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (2- (7-Hydroxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) piperazine-1-carboxylate,

0229<chemistry num="85"><img id="000087" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>7-Methoxy-9- (2- (piperazin-1-yl) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole,

0230<chemistry num="86"><img id="000088" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (2- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) piperazine-1-carboxylate,

0231<chemistry num="87"><img id="000089" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-Methyl-9- (2- (piperazin-1-yl) ethyl) -9H-pyrido [3,4-b] indole-7-ol,

0232<chemistry num="88"><img id="000090" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>7-Methoxy-1-methyl-9- (2- (piperazin-1-yl) ethyl) -9H-pyrido [3,4-b] indole,

0233<chemistry num="89"><img id="000091" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (2- (7-Hydroxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) piperazine-1-carboxylate,

0234<chemistry num="90"><img id="000092" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (2- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) piperazine-1-carboxylate,

0235<chemistry num="91"><img id="000093" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-1-methyl-9-(2- (piperazin-1-yl) ethyl) -9H-pyrido [3,4-b] indole-7-ol,

0236<chemistry num="92"><img id="000094" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-7-Methoxy-1-methyl-9-(2- (piperazin-1-yl) ethyl) -9H-pyrido [3,4-b] indole,

0237<chemistry num="93"><img id="000095" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (2- (3-fluoro-7-hydroxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) piperazine-1-carboxylate,

0238<chemistry num="94"><img id="000096" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (2- (3-fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) piperazine-1-carboxylate,

0239<chemistry num="95"><img id="000097" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(3- (Piperazine-1-yl) propyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0240<chemistry num="96"><img id="000098" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>7-Methoxy-9- (3- (piperazin-1-yl) propyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole,

0241<chemistry num="97"><img id="000099" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (3- (7-Hydroxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) propyl) piperazine-1-carboxylate,

0242<chemistry num="98"><img id="000100" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (3- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) propyl) piperazine-1-carboxylate,

0243<chemistry num="99"><img id="000101" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-Methyl-9- (3- (piperazin-1-yl) propyl) -9H-pyrido [3,4-b] indole-7-ol,

0244<chemistry num="100"><img id="000102" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>7-Methoxy-1-methyl-9-(3- (piperazin-1-yl) propyl) -9H-pyrido [3,4-b] indole,

0245<chemistry num="101"><img id="000103" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (3- (7-Hydroxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) piperazine-1-carboxylate,

0246<chemistry num="102"><img id="000104" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (3- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) piperazine-1-carboxylate,

0247<chemistry num="103"><img id="000105" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-1-methyl-9-(3- (piperazin-1-yl) propyl) -9H-pyrido [3,4-b] indole-7-ol,

0248<chemistry num="104"><img id="000106" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-7-Methoxy-1-methyl-9-(3- (piperazin-1-yl) propyl) -9H-pyrido [3,4-b] indole,

0249<chemistry num="105"><img id="000107" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (3- (3-fluoro-7-hydroxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) piperazine-1-carboxylate,

0250<chemistry num="106"><img id="000108" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>tert-Butyl 4- (3- (3-fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) piperazine-1-carboxylate,

0251<chemistry num="107"><img id="000109" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9- (3-morpholinopropyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0252<chemistry num="108"><img id="000110" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (3- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine,

0253<chemistry num="109"><img id="000111" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-Methyl-9- (3-morpholinopropyl) -9H-pyrido [3,4-b] indole-7-ol,

0254<chemistry num="110"><img id="000112" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine,

0255<chemistry num="111"><img id="000113" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-1-methyl-9- (3-morpholinopropyl) -9H-pyrido [3,4-b] indole-7-ol,

0256<chemistry num="112"><img id="000114" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (3- (3-Fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine,

0257<chemistry num="113"><img id="000115" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9- (4-morpholinobutyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0258<chemistry num="114"><img id="000116" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (4- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) butyl) morpholine,

0259<chemistry num="115"><img id="000117" he="59" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-Methyl-9- (4-morpholinobutyl) -9H-pyrido [3,4-b] indole-7-ol,

0260<chemistry num="116"><img id="000118" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (4- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) butyl) morpholine,

0261<chemistry num="117"><img id="000119" he="64" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-1-methyl-9- (4-morpholinobutyl) -9H-pyrido [3,4-b] indole-7-ol,

0262<chemistry num="118"><img id="000120" he="61" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (4- (3-Fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) butyl) morpholine,

0263<chemistry num="119"><img id="000121" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (1H-1,2,4-triazole-1-yl) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0264<chemistry num="120"><img id="000122" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (1H-1,2,4-triazole-1-yl) ethyl) -7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole,

0265<chemistry num="121"><img id="000123" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (1H-1,2,4-triazole-1-yl) ethyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0266<chemistry num="122"><img id="000124" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (1H-1,2,4-triazole-1-yl) ethyl) -7-methoxy-1-methyl-9H-pyrido [3,4-b] indole,

0267<chemistry num="123"><img id="000125" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (1H-1,2,4-triazole-1-yl) ethyl) -3-fluoro-1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0268<chemistry num="124"><img id="000126" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (1H-1,2,4-triazole-1-yl) ethyl) -3-fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole,

0269<chemistry num="125"><img id="000127" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(1- (piperidine-1-yl) propan-2-yl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0270<chemistry num="126"><img id="000128" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>7-Methoxy-9- (1- (piperidine-1-yl) propan-2-yl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole,

0271<chemistry num="127"><img id="000129" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-Methyl-9-(1- (piperidine-1-yl) propan-2-yl) -9H-pyrido [3,4-b] indole-7-ol,

0272<chemistry num="128"><img id="000130" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>7-Methoxy-1-methyl-9-(1- (piperidine-1-yl) propan-2-yl) -9H-pyrido [3,4-b] indole,

0273<chemistry num="129"><img id="000131" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-1-methyl-9-(1- (piperidine-1-yl) propan-2-yl) -9H-pyrido [3,4-b] indole-7-ol,

0274<chemistry num="130"><img id="000132" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-7-methoxy-1-methyl-9-(1- (piperidine-1-yl) propan-2-yl) -9H-pyrido [3,4-b] indole,

0275<chemistry num="131"><img id="000133" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9- (1-morpholinopropan-2-yl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0276<chemistry num="132"><img id="000134" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (2- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine,

0277<chemistry num="133"><img id="000135" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1-Methyl-9- (1-morpholinopropan-2-yl) -9H-pyrido [3,4-b] indole-7-ol,

0278<chemistry num="134"><img id="000136" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine,

0279<chemistry num="135"><img id="000137" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>3-Fluoro-1-methyl-9- (1-morpholinopropan-2-yl) -9H-pyrido [3,4-b] indole-7-ol,

0280<chemistry num="136"><img id="000138" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (2- (3-Fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine,

0281<chemistry num="137"><img id="000139" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(1- (diethylamino) propan-2-yl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0282<chemistry num="138"><img id="000140" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>N, N-diethyl-2- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) propan-1-amine,

0283<chemistry num="139"><img id="000141" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(1- (diethylamino) propan-2-yl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0284<chemistry num="140"><img id="000142" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>N, N-diethyl-2- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-1-amine,

0285<chemistry num="141"><img id="000143" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(1- (diethylamino) propan-2-yl) -3-fluoro-1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0286<chemistry num="142"><img id="000144" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>N, N-diethyl-2- (3-fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-1-amine,

0287<chemistry num="143"><img id="000145" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(3- (diethylamino) propyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0288<chemistry num="144"><img id="000146" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>N, N-diethyl-3- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) propan-1-amine,

0289<chemistry num="145"><img id="000147" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(3- (diethylamino) propyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0290<chemistry num="146"><img id="000148" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>N, N-diethyl-3- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-1-amine,

0291<chemistry num="147"><img id="000149" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(3- (diethylamino) propyl) -3-fluoro-1-methyl-9H-pyrido [3,4-b] indole-7-ol,

0292<chemistry num="148"><img id="000150" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>N, N-diethyl-3- (3-fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-1-amine,

0293<chemistry num="149"><img id="000151" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2-((2- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) amino) ethanol,

0294<chemistry num="150"><img id="000152" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2,2'-((2- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) azandiyl) diethanol,

0295<chemistry num="151"><img id="000153" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>2,2'-((2- (7-Hydroxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) azandyl) diethanol,

0296<chemistry num="152"><img id="000154" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>4- (2- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) -3-methylmorpholine,

0297<chemistry num="153"><img id="000155" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (3-Methylmorpholino) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0298<chemistry num="154"><img id="000156" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (2,6-dimethylmorpholino) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0299<chemistry num="155"><img id="000157" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>9-(2- (3,3-dimethylmorpholino) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol,

0300<chemistry num="156"><img id="000158" he="45" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>N, N-dimethyl-1-(9H-pyrido [2,3-b] indole-9-yl) propan-2-amine,

0301<chemistry num="157"><img id="000159" he="45" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>1- (9H-carbazole-9-yl) -N, N-dimethylpropan-2-amine.

0302In some embodiments, the invention provides formate for a compound according to any of the above compounds. In some embodiments, the invention provides a citrate of a compound according to any of the above compounds. In some embodiments, the present invention provides hydrochlorides of compounds according to any of the above compounds.

0303In some embodiments, the invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising compounds of formula IA or formula IB or formula IC are further provided herein. Pharmaceutical compositions comprising compounds of formula ID are further provided herein.

0304In a further aspect, the invention provides a compound of formula III, a salt, a hydrate or an isomer thereof.

0305<chemistry num="158"><img id="000160" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0306(In the above formula, R¹Is H or C_1-6Alkyl W is CR^3aAnd N, where N may optionally be oxidized to the corresponding N-oxide. X is CR^3bAnd N, where N may optionally be oxidized to the corresponding N-oxide. Y is CR^3cAnd Z is CR^3dAnd N, where N may optionally be oxidized to the corresponding N-oxide. Each R², R^3a, R^3b, R^3cAnd R^3dIndependently, H, Halogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Alkenyl, C_2-6Alkyne, C_1-6Alkoxy, C_1-6Haloalkoxy, aryloxy, C_1-6Alkyl-OH, -OR⁴, -C_0-6Alkyl-NR⁴R⁵, -SR⁴, -C (O) R⁴, -C_0-6Alkyl-C (O) OR⁴, -C (O) NR⁴R⁵, -N (R)⁴) C (O) R⁵, -N (R)⁴) C (O) OR⁵, -N (R)⁴) C (O) NR⁴R⁵, -OP (O) (OR⁴)₂, -S (O)₂OR⁴, -S (O)₂NR⁴R⁵, -CN, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, selected from the group Alternatively, two Rs on adjacent atoms²Groups can be combined with the atoms to which they are attached to form elements selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and Each R⁴, R⁵, R⁶And R⁷Independently, H, C_1-6Alkyl and C_1-6Selected from the group consisting of alkyl-OH).

0307In one group of embodiments of formula (III) R¹Is H or C_1-6Alkyl W is CR^3aAnd X is CR^3bAnd Y is CR^3cAnd Z is N, where N may optionally be oxidized to the corresponding N-oxide.

0308In another group of embodiments of formula (III), R¹Is H or C_1-6Alkyl W is CR^3aAnd X is N, where N may optionally be oxidized to the corresponding N-oxide, Y is CR^3cAnd Z is CR^3dIs.

0309In yet another group of embodiments of formula (III), R¹Is H or C_1-6Alkyl W is N, where N may optionally be oxidized to the corresponding N-oxide, X is CR^3aAnd Y is CR^3cAnd Z is CR^3dIs.

0310In some embodiments of formula (III), its salts, hydrates or isomers, R¹Is a compound in which is H.

0311In some embodiments of formula (III), its salts, hydrates or isomers, R¹Is C_1-6It is a compound that is alkyl.

0312In some embodiments, the compound of formula (III) is 1- (9H-carbazole-9-yl) -N, N-dimethylpropan-2-amine or 1-amino-3- (3,6-dibromo). -9H-carbazole-9-yl) Propane-2-ol is not.

0313In one embodiment, the formate of the compound of formula (III) is provided.

0314In one embodiment, the citrate of the compound of formula (III) is provided.

0315In one embodiment, hydrochloride of the compound of formula (III) is provided.

0316In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (III).

0317The compounds and compositions of the present invention can also include salts, hydrates, solvates and prodrug forms. The compounds and compositions of the present invention may also include isomers and metabolites of compounds of formulas I, IA, IB, IC, ID, II and / or III.

0318The compounds of the present invention can be in salt form. The salt is not limited, but is not limited to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bicarbonate, phosphate, acid phosphate, phosphonic acid. Salt, isonicotate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentidic acid Salts, fumarates, gluconates, glucurates, saccharides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates and pamoic acids Salts (ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthate)) salts can be mentioned. Other salts containing organic bases include salts containing diethylamine, diethanolamine, meglumine and N, N'-dibenzylethylenediamine. In some embodiments, the present invention provides hydrochloride.

0319In some embodiments, it comprises a compound of the invention, optionally a further oxidized nitrogen atom, i.e. the compound is an N-oxide. As just one example, in some cases the nitrogen atom in the pyridoindrill ring system in the compound of formula (I) has been oxidized to the corresponding N-oxide.

0320In 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 conjugated group capable of selectively targeting bone structure. Examples of such motifs are described in Erez et al., Bioorg.Med.Chem.Lett.2008, 18, 816-820 and Neale et al., Bioorg.Med.Chem.Lett.2009, 19, 680-683. Incorporated herein by reference. Therefore, within the scope of the embodiments presented herein, estradiol conjugates and / or bisphosphonate conjugates of compounds of formula (I), formula (II) and / or (III) are conceivable.

0321The compounds of the present invention can be prepared by a variety of methods known to those of skill in the art (see Comprehensive Organic Transformations Richard C. Larock, 1989). Those skilled in the art will appreciate that other methods for producing compounds are useful in the present invention. Illustrative methods for the synthesis of compounds of formula I, formula II and formula III are described in the Examples section and Scheme 1 below.

0322<chemistry num="159"><img id="000161" he="70" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0323Starting from compound 1, reaction with compound 2 containing a leaving group (LG) provides a compound of formula I or formula II. The various leaving groups are suitable and, but not limited to, halos, activated esters, mesylates, triflate, or any other suitable leaving group at the 9-position of the core ring system. To the base

0324<chemistry num="160"><img id="000162" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0325There are those that enable the combination of. Optionally, a compound of formula III is converted to a compound of formula I or II. In some cases, R²If is methoxy, it can be converted to a hydroxyl group by demethylation using the described procedure, eg, HBr or boron tribromide in acetic acid, or any other suitable procedure. Optionally, the compound of formula I or formula II comprises an N-oxide prepared by oxidation with chloroperbenzoic acid or the like.

0326How to promote bone formation In another embodiment, the invention is the treatment of a compound of the invention (eg, a compound or composition of formula I, formula IA, formula IB, formula IC, formula II or formula III as described in Section III above). Provided is a method for promoting bone formation in a subject in need of bone formation by administering an effective amount to the subject.

0327In some embodiments, the present invention relates to Formula II.

0328<chemistry num="161"><img id="000163" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0329(In the above formula, W is CR^3aAnd N, where N may optionally be oxidized to the corresponding N-oxide. X is CR^3bAnd N, where N may optionally be oxidized to the corresponding N-oxide. Y is CR^3cAnd N, where N may optionally be oxidized to the corresponding N-oxide. Z is CR^3dAnd N, where N may optionally be oxidized to the corresponding N-oxide. R^NIs NR⁶R⁷, Heterocyclyl and heteroaryl, where heterocyclyl and heteroaryl contain from about 5 to about 10 ring atoms, at least one of which is nitrogen, and R.^NThe N in it may optionally be oxidized to the corresponding N-oxide, R¹Is -C_1-6Alkyl Each R², R^3a, R^3b, R^3cAnd R^3dIndependently, H, Halogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Alkenyl, C_2-6Alkyne, C_1-6Alkoxy, C_1-6Haloalkoxy, C_1-6Alkyl-OH, -OR⁴, -C_0-6Alkyl-NR⁴R⁵, -SR⁴, -C (O) R⁴, -C_0-6Alkyl-C (O) OR⁴, -C (O) NR⁴R⁵, -N (R)⁴) C (O) R⁵, -N (R)⁴) C (O) OR⁵, -N (R)⁴) C (O) NR⁴R⁵, -OP (O) (OR⁴)₂, -S (O)₂OR⁴, -S (O)₂NR⁴R⁵, -CN, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, selected from the group Alternatively, two Rs on adjacent atoms²Groups can be combined with the atoms to which they are attached to form elements selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and Each R⁴, R⁵, R⁶And R⁷Independently, H, C_1-6Alkyl and C_1-6A therapeutically effective amount of a compound (selected from the group consisting of alkyl-OH) or salts, hydrates or isomers thereof may be administered to a subject to promote bone formation in the subject. Provided is a method of promoting bone formation in a required subject.

0330In some embodiments R¹Is -C (R^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-And here, each R^1a, R^1bAnd R^1cAre independently selected from H, methyl and ethyl, and the group-C (R)^1a)₂-[C (R)^1b)₂]_q-[C (R)^1c)₂]_t-The total number of carbon atoms in it does not exceed 6, The sign q is an integer from 0 to 4, and The sign t is an integer from 0 to 4 and However, a) The sum of q and t is 1, and b) R, if present⁶Or R⁷Either H or C_1-6When it is alkyl R^1aAnd R^1bAt least one of is non-H, and However, when the sum of q and t is 2. a) R²Is other than H, and b) R, if present⁶And R⁷At least one of is other than H or methyl.

0331In some embodiments, the compound is selected from the group consisting of: 9-(2- (Dimethylamino) propyl) -9H-pyrido [3,4-b] indole-7-ol, 9-(2- (Dimethylamino) propyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol, N, N-dimethyl-1-(9H-pyrido [2,3-b] indole-9-yl) propan-2-amine, N, N-dimethyl-1-(9H-pyrido [3,4-b] indole-9-yl) propan-2-amine, 1- (9H-carbazole-9-yl) -N, N-dimethylpropan-2-amine, 1- (7-Methoxy-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-2-amine, 1- (2-Methoxy-9H-carbazole-9-yl) -N, N-dimethylpropan-2-amine, 4- (3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine, N, N-diethyl-3- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-1-amine, 7-Methoxy-1-methyl-9-(3- (piperazin-1-yl) propyl) -9H-pyrido [3,4-b] indole, 2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-1-amine, N, N-diethyl-2- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-1-amine, 7-Methoxy-1-methyl-9- (2- (piperazin-1-yl) ethyl) -9H-pyrido [3,4-b] indole, 4- (2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) morpholine, 4- (2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine, 7-Methoxy-1-methyl-9-(1- (piperidine-1-yl) propan-2-yl) -9H-pyrido [3,4-b] indole, 9-(2- (4H-1,2,4-triazole-3-yl) ethyl) -7-methoxy-1-methyl-9H-pyrido [3,4-b] indole, 2- (2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) -1,3,4-oxadiazole, 5- (2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) -1,2,4-oxadiazole, 9-(2- (1H-1,2,4-triazole-1-yl) ethyl) -7-methoxy-1-methyl-9H-pyrido [3,4-b] indole, 9-(3- (4H-1,2,4-triazole-3-yl) propyl) -7-methoxy-1-methyl-9H-pyrido [3,4-b] indole, 2- (3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) -1,3,4-oxadiazole, 5- (3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) -1,2,4-oxadiazole, 9-(3- (1H-1,2,4-triazole-1-yl) propyl) -7-methoxy-1-methyl-9H-pyrido [3,4-b] indole, and 2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylethaneamine, or a salt, hydrate or isomer thereof.

0332In some embodiments, the method comprises administering to the subject a therapeutically effective amount of formate or citrate of the compound of formula II.

0333Those skilled in the art will appreciate that bone formation can be local, systemic, or both local and systemic. In some embodiments, bone formation is local. Subjects in need of local bone formation are characterized by a variety of diseases or conditions (but not limited to, embrittled bone, fractured bone, or low bone mass as described herein. Can have any of the diseases or conditions). In some embodiments, the subject requires spinal fusion, joint fixation, or orthopedic, dental or periodontal synthetic bone graft or implant. In some embodiments, the present invention provides a method of promoting bone formation at the site of injury or local symptoms. In some embodiments, the invention includes a method of fusing bone (eg, at the site of injury). In some embodiments, the site of injury is a surgical site. In other embodiments, the injury is a fractured or embrittled bone or periodontal disease.

0334In some embodiments, bone formation is systemic. Systemic bone formation refers to the formation of bone throughout the subject and can affect all bones within the subject's body. Subjects requiring systemic bone formation can suffer from any of a variety of diseases or conditions. In some embodiments, the subject suffers from a low bone mass phenotypic disease, fracture or periodontal disease. In some embodiments, the subject suffers from a low bone mass phenotypic disease. Low bone mass can be determined by various methods known to those of skill in the art. For example, low bone mass can be characterized by a T-score of less than about -0.5. Low bone mass phenotypic disorders include osteoporosis, osteopenia and osteoporosis pseudoretinal glioma syndrome (OPPG). In some other embodiments, the low bone mass phenotypic disease can be osteopenia or osteoporosis pseudoretinal glioma syndrome (OPPG).

0335Topical and / or systemic bone formation using the compounds or compositions of the present invention can be achieved by any of a variety of methods. Methods for formulating and administering the compounds and compositions of the invention (eg, compounds or compositions of formula I, formula IA, formula IB, formula IC, formula II or formula III) are described in Section VII below. .. In some embodiments, the method of promoting bone formation comprises implanting the medical device described herein (eg, section VIII below) into a subject requiring it.

0336Syndrome), prednisolone, heparin, senile skin atrophic osteogenesis imperfecta, ridge osteolysis syndrome, nephrectomy, Fabry's disease, Pseudoprogeria syndrome, Wolcott-Rallison syndrome, Tonic spondylitis, myeloma, systemic infantile hyalinosis, all-bright hereditary osteogenesis imperfecta, neuropathic anorexia, autoimmune lymphocyte proliferative syndrome, Brown-Sekar syndrome, Diamond-Blackfan anemia, feeding Disorders, lactation-hyperprolactinemia, osteogenesis imperfecta, renal symptoms, Menquez's disease, menopause, neuritis, ovarian dysfunction due to FSH resistance, familial ovarian dysfunction, premature aging, primary biliary cirrhosis, prolactinoma, family Sexual prolactinoma, renal bone dysplasia, ulcerative colitis, low body weight, Werner syndrome, bone tumor, bone cancer, brittle bone disease, osteolysis, congenital osteogenesis imperfecta, delayed osteogenesis imperfecta and periodontal Illness is mentioned. Those skilled in the art will appreciate that other types of symptoms, diseases, and treatments result in osteoporosis. osteolysis) syndrome, nephrectomy, Fabry's disease, Pseudoprogeria syndrome, Wolcott-Rallison syndrome, tonic spondylitis, myeloma, systemic infantile hyalinosis, all-bright hereditary osteogenesis imperfecta , Nervous anorexia, autoimmune lymphocyte proliferation syndrome, Brown-Sekar syndrome, Diamond-Blackfan anemia, feeding disorders, lactation-hyperprolactinemia, osteogenesis imperfecta, renal symptoms, Menquez's disease, menopause , Nervitis, ovarian dysfunction due to FSH resistance, familial ovarian dysfunction, premature aging, primary biliary cirrhosis, prolactinoma, familial prolactinoma, renal bone dysplasia, ulcerative colitis, low body weight, Werner syndrome, bone tumor , Bone cancer, brittle bone disease, osteonecrosis, congenital osteogenesis imperfecta, delayed osteogenesis imperfecta and periodontal disease. Those skilled in the art will appreciate that other types of symptoms, diseases, and treatments result in osteoporosis. osteolysis) syndrome, nephrectomy, Fabry's disease, Pseudoprogeria syndrome, Wolcott-Rallison syndrome, tonic spondylitis, myeloma, systemic infantile hyalinosis, all-bright hereditary osteogenesis imperfecta , Nervous anorexia, autoimmune lymphocyte proliferation syndrome, Brown-Sekar syndrome, Diamond-Blackfan anemia, feeding disorders, lactation-hyperprolactinemia, osteogenesis imperfecta, renal symptoms, Menquez's disease, menopause , Nervitis, ovarian dysfunction due to FSH resistance, familial ovarian dysfunction, premature aging, primary biliary cirrhosis, prolactinoma, familial prolactinoma, renal bone dysplasia, ulcerative colitis, low body weight, Werner syndrome, bone tumor , Bone cancer, brittle bone disease, osteonecrosis, congenital osteogenesis imperfecta, delayed osteogenesis imperfecta and periodontal disease. Those skilled in the art will appreciate that other types of symptoms, diseases, and treatments result in osteoporosis.

0337Bone formation can be measured by any of a variety of methods known to those of skill in the art. Methods for measuring bone formation are not limited, but are limited to Uct (micro CT), dual X-ray resorption (bone density), ultrasound, QCT, SPA, DPA, DXR, SEXA, QUS, X-ray, surgery. Human eye use during manipulation, Alizarin Red S, serum osteocalcin, serum alkaline phosphatase, serum bone Gla protein (BGP), bone mineral content, serum calcium, serum phosphorus, tantalum markers and serum IGF-1. ..

0338Many indicators of bone formation can be used to measure and / or quantify the amount of bone formation, including bone density. In some embodiments, bone formation can be indicated by a 0.1% increase in bone density. In other embodiments, bone growth is 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5 of bone density. %, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, It can be indicated by an increase of 800%, 900% or 1000% or more. Bone density can be measured by a variety of different methods, including T-score and Z-score. The Z-score is the number of standard deviations above or below average for a patient's age and gender. The T-score is the number of standard deviations above or below mean for a healthy 30-year-old adult of the same gender as the patient. Low bone mass is characterized by a T-score of -1 to -2.15. Osteoporosis is characterized by a T-score of less than -2.15. Improvements in T-score or Z-score suggest bone growth. Bone density can be measured at various locations in the skeleton, such as the spine or hip joint. Those skilled in the art will appreciate that other methods of determining bone density are useful in the present invention.

0339V. How to treat kidney injury In another embodiment, the invention is a therapeutically effective amount of a compound of the invention (eg, a compound or composition of formula I, formula IA, formula IB, formula IC, formula II or formula III as described in Section III above. To provide a method for treating renal injury by administering the substance) to a subject suffering from renal injury.

0340Kidney injury can be caused by a variety of illnesses known to those of skill in the art. In some embodiments, renal injury is caused by infection, radiation, toxins, dehydration or injury. Toxic substances that cause kidney injury include, but are not limited to, chemicals, poisons and chemotherapeutic agents. Those skilled in the art will appreciate that other causes of renal injury can be treated by the methods of the invention.

0341Acute renal failure can be mentioned as a renal injury that can be treated with the compound of the present invention. 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 non-nitrogen waste products that are normally excreted by the kidneys. Depending on the severity and duration of renal dysfunction, this accumulation is associated with metabolic disorders such as metabolic acidosis (acidification of blood) and hyperkalemia (increased potassium concentration), altering fluid balance, and Affects other organ systems. Acute renal failure is characterized by oliguria or anuria (decreased or interrupted urine production), but non-oliguric acute renal failure can also occur.

0342Subjects are characterized by (1) risk of acute injury, (2) renal injury due to injury, (3) acute renal failure, and (4) impaired renal function. Can be done. The risk of acute kidney injury is characterized by a 1.5-fold increase in serum creatinine or a urine production of &lt;0.5 ml / kg body weight over 6 hours. Damage is reached when serum creatinine is increased 2.0-fold or when urine production is &lt;0.5 ml / kg body weight over 12 hours. Insufficiency is reached if serum creatinine is increased 3.0-fold, or if creatinine is&gt; 355 μM (&gt; 44 increase), or if urine output is less than 0.3 ml / kg over a 24-hour period. Subjects reach loss of renal function if acute renal failure persists or if there is a complete loss of renal function for more than 4 weeks.

0343Renal biopsy is performed in the context of acute renal failure when the cause is unclear and appropriate screening studies are definitely not negative, which can provide a clear diagnosis and, occasionally, a prognostic view. Can be provided.

0344The renal therapeutic agent of the present invention can be used in a subject who has suffered renal injury or who is at risk of chronic renal failure. As used herein, a subject is chronic renal failure, is at risk thereof, or suffers from progressive loss of renal function associated with progressive loss of nephron units in which the subject functions. Those at risk of needing renal replacement therapy (ie, chronic hemodialysis, continuous peritoneal dialysis, or kidney transplantation) when reasonably expected. The determination of whether a particular subject has or is at risk for chronic renal failure can be routinely made by one of ordinary skill in the art or veterinary field concerned. Targets who have or are at risk of chronic renal failure or who are at risk of requiring renal replacement therapy include, but are not limited to:

0345VI. How to treat cancer The compounds and compositions of the present invention are also useful in the treatment of cancer. Therefore, some embodiments of the present invention provide a method of treating cancer. The method, for a subject in need thereof, a compound of the invention (eg, a compound of formula I, formula IA, formula IB, formula IC, formula II or formula III as described in Section III above. Or it comprises administering a therapeutically effective amount of the composition).

0346In some embodiments, the compounds of the invention are useful in treating proliferative disorders such as cancer, leukemia, and other disorders associated with uncontrolled cell proliferation such as psoriasis and restenosis. As defined herein, antiproliferative effects within the scope of the invention are total, eg, in vitro, using any of the cell lines A549, HT29, Saos-2, HeLa or MCF-7. It can be demonstrated by the ability to inhibit cell proliferation in cell assays, or by showing inhibition of CDK enzymes (eg, CDK2 or CDK4) in appropriate assays. Such cell lines and enzyme assays can be used to determine if a compound is antiproliferative in the context of the present invention.

0347As used herein, the term "cancer" includes, but is not limited to, cancers: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, urogenital tract cancer. , Esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratinized spinal cell tumor, lung cancer, epidermoid cancer, large cell cancer, small cell cancer, lung adenocarcinoma, bone cancer, colon Cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular cancer, undifferentiated cancer, papillary cancer, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, myeloid disorder, lymph system disorder , Hodgkin's disease, hairy cell cancer, oral vestibular cancer and pharyngeal (oral) cancer, lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, small bowel cancer, colon-rectal cancer, colon cancer, rectal cancer, brain cancer and central nervous system Cancer, as well as leukemia. Those skilled in the art will appreciate that other cancers and proliferative disorders can be treated with the compounds and compositions of the present invention.

0348In some embodiments, the cancer is bone cancer, colon cancer, multiple myeloma, gastric cancer, colonic rectal cancer, prostate cancer, cervical cancer, lung cancer, pancreatic cancer, myelblastoma, 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, such cancers include, but are not limited to, breast and prostate cancers. In some embodiments, the cancer is a metastatic cancer to the bone.

0349Formulation and administration In some embodiments, the invention is of a compound as described herein (eg, of Formula I, Formula IA, Formula IB, Formula IC, Formula II or Formula III as described in Section III above. Compounds or compositions) and pharmaceutical compositions containing pharmaceutically acceptable excipients. In other embodiments, the composition further comprises a bone conduction matrix.

0350The compositions of the present invention can be in the form of pharmaceutical compositions containing antagonists and pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers are well known in the art and are either aqueous solutions such as physiologically buffered saline or oils such as glycols, glycerol, olive oil, or other buffers such as injectable organic esters. Examples include agents or solvents or vehicles. The choice of pharmaceutically acceptable carrier will depend, in part, on the chemical nature of the compound.

0351The compounds of the present invention can be formulated by various different methods known to those skilled in the art. The pharmaceutically acceptable carrier is determined, in part, by the particular composition administered and by the particular method used to administer the composition. Therefore, there is a wide range of suitable formulations of the pharmaceutical compositions of the present invention (see, eg, Remington's Pharmaceutical Sciences, 20th ed., 2003 above).

0352Pharmaceutically acceptable carriers include, for example, physiologically acceptable compounds that act to stabilize the compound or increase its absorption, or, if desired, other excipients. be able to. Physiologically acceptable compounds include, for example, carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. .. Those skilled in the art will know that the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable compound, depends, for example, on the route of administration and its particular physiochemical properties.

0353In general, such carriers should be non-toxic to the recipient at the dose and concentration used. Typically, the preparation of such compositions includes therapeutic agents, buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, glucose, maltose, sucrose or dextrin. It is necessary to combine with carbohydrates, chelating agents such as EDTA, glutathione, and other stabilizers and excipients. Neutral buffered saline or saline mixed with non-specific serum albumin is an exemplary suitable diluent.

0354The amount of a compound or composition of the invention administered to an individual (eg, a compound or composition of formula I, formula IA, formula IB, formula IC, formula II or formula III as described herein) is: In part, it will depend on the severity and / or degree of injury. Methods for determining the amount of drug administered for a diagnostic or therapeutic procedure are well known in the art and are Phase I, Phase II and Phase III clinical trials or pilot and pivotal trials (FDA device acceptable). Route) is included. Generally, the drug is administered at a dose of about 0.01-200 mg / kg body weight for systemic administration and at a concentration of about 0.1-100 μM for direct administration to the wound site.

0355The total amount of the compound or composition can be administered to the subject as a single dose, either as a bolus or by infusion, over a relatively short period of time, or may be administered using a divided therapeutic protocol. Multiple doses are given over a longer period of time. Those skilled in the art will appreciate that the concentration of a particular compound or composition required to provide an effective amount to the injured area depends on the age and overall health of the subject, as well as the route of administration, the number of treatments administered and the compound. You will know that it depends on many factors such as the nature of. With these factors in mind, one of ordinary skill in the art will adjust a particular dose for therapeutic purposes to obtain an effective amount to effectively promote bone formation.

0356The pharmaceutical product is preferably in the unit dosage form. In such a form, the pharmaceutical product is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged formulation, the package containing a defined amount of formulation such as packetized tablets, capsules, and powder in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cashier or lozenge itself, or it can be in any number of any of these packaged forms. The composition also comprises other compatible therapeutic agents, if desired. The preferred pharmaceutical formulation is a sustained release formulation capable of delivering the compounds of the invention.

0357In some embodiments, the method of the invention comprises administering a compound as described herein in a cocktail comprising other pharmaceuticals such as antibiotics, fungicides and anti-inflammatory agents. Alternatively, the method can include sequential administration to affected individuals using the compounds as described herein and one or more additional medicinal products to optimize the therapeutic regimen. In such an optimized regimen, the drug containing the granulation inhibitor can be administered in any order and in any combination.

0358The individual treated using the compounds and methods of the invention may be any mammal, eg, human or primate, dog, cat, horse, cow, goat, sheep, pig, mouse or rat. , Or any non-human mammal such as a commercially important animal or domestic animal.

0359In some embodiments, the individual treated by the method of the invention is an individual who has received or has received an anti-absorbable therapeutic agent. For example, in some embodiments, the anti-absorbable therapeutic agent can be administered simultaneously with the compounds and compositions of the invention. In some embodiments, the anti-absorbable therapeutic agent and the therapeutic agent comprising the compound and composition of the present invention are administered sequentially (the anti-absorbable therapeutic agent prior to the therapeutic agent containing the compound and composition of the present invention). , Or any therapeutic agent containing the compounds and compositions of the present invention prior to the anti-absorbable therapeutic agent). In some embodiments, the individual may be pre-treated with an anti-absorbing agent. In some embodiments, the individual is simultaneously treated with an anti-absorbing agent during the first part of the course of treatment of the compounds and compositions of the invention, but treated with an anti-absorbing agent during the second part of the course of treatment. Can be stopped. In some embodiments, the individuals treated by the methods of the invention are not treated with anti-absorbing agents. In some embodiments, it is treated with an anti-absorbing agent after being treated with the compounds and compositions of the present invention.

0360In some embodiments, the compounds and compositions of the invention are administered systemically. In some embodiments, the compounds and compositions of the invention are administered topically.

0361A. Systemic administration In some embodiments, the compounds and compositions of the invention are administered systemically. Systemic administration of the compounds and compositions of the present invention can be used for the treatment of diseases or conditions characterized by low bone mass, such as osteoporosis.

0362The pharmaceutical compositions of the present invention can be prepared for administration by a variety of different routes. Generally, the type of carrier is selected based on the mode of administration. The pharmaceutical composition can be formulated for any suitable mode of administration, including, for example, topical, oral, nasal, intrathecal, transrectal, vaginal, sublingual or parenteral administration. For example, there are injections or injections subcutaneously, intravenously, intramuscularly, intracorporeally, intracavitarily, intraductally, or intraurethrally. The pharmaceutical composition (eg, for oral administration or delivery by injection) can be in liquid form (eg, elixir, syrup, solution, emulsion or suspension). The liquid pharmaceutical composition may include, for example, one or more of the following, which can function as water for injection, saline, preferably saline, Ringer's solution, isotonic sodium chloride, solvent or suspension medium. Aseptic diluents such as oils, polyethylene glycols, glycerins, propylene glycols or other solvents, antibacterial agents, antioxidants, chelating agents, acetates, buffers such as citrates or phosphates, and sodium chloride or It is an osmotic pressure regulator such as dextrose. The parenteral preparation may be encapsulated in glass or plastic ampoules, disposable syringes or multi-dose vials. The use of saline is preferred and the pharmaceutical composition for injection is preferably sterile.

0363The formulations of the present invention are also suitable for administration into all body spaces / cavities, and are not limited to, but not limited to, pleura, peritoneum, skull, mediastinum, pericardium, sac or bursa, epidura, and spinal cord cavity. Intraocular, intraocular, internal joint, intradiscal, internal medulla or pericardial and the like.

0364Suitable formulations for oral administration are (a) liquid solutions such as water, saline, or effective amounts of compounds of the invention suspended in diluents such as PEG400, (b) liquids, solids, granules or gelatin. Consists of capsules, sachets, depots or tablets, (c) suspensions in suitable liquids, (d) suitable emulsions and (e) patches, each containing a predetermined amount of active ingredient. be able to. Pharmaceutical forms include one or more lactose, sucrose, mannitol, sorbitol, calcium phosphate, cornstarch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid and other excipients, coloring. It can include agents, fillers, binders, diluents, buffers, wetting agents, preservatives, flavoring agents, pigments, disintegrants and pharmaceutically compatible carriers. The troche form can contain the active ingredient in a fragrance such as sucrose and is known to those skilled in the art in addition to the active ingredient and the active ingredient in an inert base such as gelatin and glycerin or sucrose. Can contain sucrose containing acacia emulsions, gels and the like that can contain the carriers of sucrose.

0365The compounds of the present invention may be included in a delayed release preparation for continuous treatment after a single dose. In one embodiment, the formulation is prepared in the form of microspheres. The microspheres can be prepared as a homogeneous matrix of compounds, along with biodegradable controlled release materials, and optionally with additional pharmaceuticals used, upon treatment request. Microspheres are preferably prepared in a size suitable for infiltration and / or infusion and injected systemically or directly into the treatment site.

0366Some delayed release agent embodiments include polymeric substances that are biodegradable and / or slowly dissolve. Examples of such polymer substances include polyvinylpyrrolidone, low molecular weight and medium molecular weight hydroxypropyl cellulose and hydroxypropyl methyl cellulose, crosslinked sodium carboxymethyl cellulose, carboxymethyl starch, potassium divinyl methacrylate copolymer, polyvinyl alcohol, starch, starch derivative, and microcrystalline cellulose. , Ethyl cellulose, methyl cellulose and cellulose derivatives, β-cyclodextrin, poly (methyl vinyl ether / maleic anhydride), glucan, cierozlucans, mannan, xanthan, alzinic acid and its derivatives, dextrin derivatives, glycerin monostearate , Semi-synthetic glyceride, glycerin palmitostearate, glycerin behate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, sodium stearate, talc, sodium benzoate, boric acid and colloidal silica.

0367The delayed release agent of the present invention includes starch, pregelatinized starch, calcium phosphate, mannitol, lactose, saccharose, glucose, sorbitol, microcrystalline cellulose, gelatin, polyvinylpyrrolidone, methylcellulose, starch solution, ethyl cellulose, arabic rubber, tragacanth rubber, magnesium stearate. , Stealic acid, colloidal silica, glycerin monostearate, hydrogenated castor oil, wax and mono- and mono-substituted, di- and tri-substituted glycerides can also be included. Delayed release agents can also be prepared as commonly described in WO 94/06416.

0368B. Local delivery In some embodiments, the compounds and compositions of the invention are administered topically. Topical administration of the compounds and compositions of the present invention can be used, for example, for fracture healing, fusion (joint fixation), orthopedic reconstruction and periodontal repair. In some embodiments, topical administration administers the compound and composition in combination with a suitable carrier material capable of maintaining the compound at an in vivo site of administration or providing a structural load. Including. In some embodiments, the carrier is a biocompatible or biodegradable and / or porous matrix sufficiently in vivo to allow cell infiltration. In some embodiments, the compounds and compositions of the invention (eg, compounds and compositions of formula I, formula IA, formula IB, formula IC, formula II or formula III) are topical via an implantable medical device. Is administered.

0369The compounds and compositions of the present invention are useful in clinical applications in combination with suitable delivery or support devices (eg, scaffolds or matrices as described herein). As disclosed herein, the matrix is reliable and reliable in the mammalian body in combination with compounds and compositions of formula I, formula IA, formula IB, formula IC, formula II or formula III. Reproducible bone formation can be induced. The matrix preferably contains particles of a porous material. The pores are preferably sized to allow the migration of progenitor cells into the matrix and subsequent differentiation and proliferation. In some embodiments, the pore size of the matrix is at least 5 μm, eg, at least 5, 10, 20, 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 or 1000 μm. The matrix is by densely filling the shape over the bone defect, or otherwise as a "temporary scaffold" and as a basis for the replacement of migrating progenitor cells, and subsequently for anchoring and proliferation. It can be produced by constructing a biocompatible, preferably biodegradable or in vivo absorbable material, which serves as the basis for the above, as desired. In some embodiments, the scaffold or matrix comprises a mesh structure, a foam structure, a sponge structure or a fibrous structure.

0370The scaffolding or matrix used to deliver the compounds of the invention can include synthetic and / or biological materials. In some embodiments, the scaffold or matrix comprises a naturally occurring polymer, a synthetic biodegradable polymer, a non-biodegradable synthetic polymer, a bioceramic, a bioglass or a combination thereof. Natural and synthetic polymers, bioceramics and bioglasses for use in scaffolding are known in the art, eg, Dhandayuthapani et al., International Journal of Polymer Science, volume 2011, article ID. 290602 (2011), incorporated herein by reference. Natural polymers include, but are not limited to, proteins (eg, silk, collagen, gelatin, fibrinogen, elastin, keratin, actin and myosin), polysaccharides (eg, cellulose, amylose, dextran, chitin, chitosan and glycosami). Noglycans) and polynucleotides (eg, DNA and RNA). Synthetic polymers include, but are not limited to, PLA, PGA, PLLA, PLGA, PCL, PLDLA, PDS, PGCL, PEA, PCA, PDLLA, PEU and PBT. Bioceramics and bioglasses include, but are not limited to, HAP, TCP, CP ceramics, BCP and TCP. In some embodiments, the scaffold or matrix is a hydrogel scaffold, a fibrous scaffold, a microsphere scaffold, a polymer-bioceramic composite scaffold or a cell-free scaffold.

0371In some embodiments, the scaffold or matrix is a bone conduction matrix. Non-limiting examples of suitable osteoconducting matrix materials include, for example, collagen; homopolymers or copolymers of glycolic acid, lactic acid and butyric acid (including derivatives thereof); ceramics, hydroxyapatite, tricalcium phosphate and other calcium phosphates. , And calcium sulfate. Other matrices useful in the present invention include, but are not limited to, kryptonite bone cement (Doctors Research). Group, Oxford, CT) and Genex bone grafts (Biocomposites, WilmingtoN, NC). Combinations of these matrix materials can also be useful. The osteoconductive matrix is also calcium salt, calcium sulfate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-based hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, calcined gypsum, Structural supports such as phosphophorin, borosilicates, biocompatible ceramics, calcium phosphate ceramics, polytetrafluoroethylene, sulfates or hydrogels can be included.

0372In some embodiments, the bone conduction matrix comprises a bone inducer and optionally a structural support. Bone inducers can be any agent that promotes bone formation. In some embodiments, the bone inducer is a bone allogeneic graft, a bone autograft, a decalcified bone, or a periodontal ligament cell.

0373C. Combination therapy In practicing the methods of the invention, the pharmaceutical composition can be used alone or in combination with other therapeutic or diagnostic agents. The additional agents used in the combination procedure of the present invention may be administered separately, or one or more agents used in the combination procedure may be administered together, for example in a mixture. When one or more drugs are administered separately, the timing and schedule of administration of each drug can be changed. Other therapeutic or diagnostic agents may be administered simultaneously with the compounds of the invention or separately at different times.

0374In some embodiments, a compound or composition as described herein (eg, a compound or composition of formula I, formula IA, formula IB, formula IC, formula II or formula III) is one or more. It is administered in combination with other therapeutic agents. When the compounds of the invention are combined with other agents, the two may be co-administered or administered separately. Co-administration includes administration of other agents within 0.5, 1,2,4,6,8,10,12,16,20 or 24 hours and also for 1-7 days (eg, 1, 2, 3, 4, 5, 6 or 7 days), 1 to 4 weeks (eg 1, 2, 3 or 4 weeks), or 1 or 6 months (eg 1, 2, 3, 4, 5) Or, it comprises administering the compound of the present invention within 6 months). Co-administration may also be co-administration of other agents and compounds of the invention at the same time, approximately simultaneously (eg, within about 1, 5, 10, 15, 20 or 30 minutes of each other, or on the same day), or in any order. Includes sequential administration. In some embodiments, co-administration administers another agent (eg, an anti-absorbing agent) for a period of time (eg, weeks, months, or years) and then for a period of time (eg, weeks). , Months or years) to administer a compound or composition of formula I, formula IA, formula IB, formula IC, formula II or formula III, followed by other agents (eg, anti-absorbants) alone. , Or in combination with a compound or composition of formula I, formula IA, formula IB, formula IC, formula II or formula III. In some embodiments, the other agent and the compounds of the invention are administered once daily, or twice, three or more times daily, respectively, to provide a preferred dose level per day. Can be done.

0375In some embodiments, co-administration is obtained by co-formulation, i.e. by preparing a single pharmaceutical composition comprising both the compounds of the invention and a second therapeutic agent (eg, an anti-absorbing agent). can get. In other embodiments, the compound of the invention and the second therapeutic agent are formulated separately.

0376One or more other therapeutic agents may be delivered by any suitable means. .. The pharmaceutical product is preferably in the unit dosage form. In such a form, the pharmaceutical product is subdivided into unit doses containing appropriate amounts of anti-absorbents and / or compounds of the invention. The unit dosage form can be a packaged formulation, the package containing a defined amount of formulation such as packetized tablets, capsules, and powder in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cashier or lozenge itself, or it can be in any number of any of these packaged forms.

0377One or more other therapeutic agents can be present in any suitable amount and can depend on many factors, the factors including, but not limited to, the body weight and age of the subject. And the state of the disease. Suitable dose ranges for one or more other therapeutic agents in combination with the compounds and compositions of the present invention range from about 0.1 μg to about 10,000 mg, or about 0.1 μg to about 1000 mg, or about 0.1 μg to. About 500 mg, or about 0.1 μg to about 1000 μg, or about 1 μg to about 1000 mg, or about 1 μg to about 500 mg, or about 1 μg to about 50 mg, or about 1 μg to about 1000 ug, or about 10 ug to about 1000 mg, or about 10 μg to about 500 mg, or about 10 μg to about 50 mg, or about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about Examples thereof include 500 mg, or about 50 mg to about 250 mg. Suitable doses of one or more other therapeutic agents used in combination with the compounds or compositions of the invention are approximately 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100. , 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg.

0378One or more other therapeutic agents and compounds or compositions of the invention can be present in any suitable ratio in the compositions of the invention, eg, from 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). Anti-absorbents and other doses and dose ratios of the compounds of the invention are appropriate in the compositions and methods of the invention.

0379The composition can also include other compatible therapeutic agents. The compounds described herein can be used in combination with other activators or auxiliaries that are not effective on their own but can contribute to the efficacy of the activators.

0380In some embodiments, the individual treated by the methods of the invention is a compound or composition as described herein (eg, Formula I, Formula IA, Formula IB, Formula IC, Formula II or Formula. A compound or composition of III) is administered in combination with or sequentially with an anti-absorbing agent. Anti-absorbing agents include agents that slow or block bone resorption. Administration of compounds or compositions and anti-absorbents as described herein promotes local bone growth and / or systemic bone growth. In some embodiments, administration of the compounds or compositions and anti-absorbing agents as described herein promotes systemic bone growth. Bone growth can be achieved by increasing the mineral cancer content of bone, increasing bone density and / or increasing the growth of new bone. In other embodiments, topical administration of compounds or compositions and anti-absorbents as described herein achieves systemic bone growth.

0381Antiabsorbants useful in the methods of the invention include, but are not limited to, denosumab, RankL inhibitors, bisphosphonates (eg, fosamax, actonel or recrust), selective estrogen receptor modulators (SERMs) or analogs. (Eg, Evista), calcitonin, calcitonin analogs (eg, Miacalcic), vitamin D or vitamin D analogs, CatK inhibitors, prostaglandin inhibitors or phosphodiesterase inhibitors type E.

0382In some embodiments, the anti-absorbing agent is denosumab.

0383The bisphosphonates useful in the methods of the invention can be any suitable bisphosphonates. In some embodiments, the bisphosphonates are nitrogen-based, such as pamidronate (APD, aredia), neridronate, olpadronate, alendronate (phosamax), ibandronate (bonia), lysedronate (actonel) and zoledronic acid (zometa). is there. In other embodiments, the bisphosphonate is a non-nitrogen system such as etidronate (dydronel), clodronate (bonephos, loron) and chilldronate (skelelide). Those skilled in the art will appreciate that other bisphosphonates are useful in the present invention.

0384The SERM useful in the methods of the invention can be any suitable SERM. In some embodiments, the SERM can be clomiphene, raloxifene, tamoxifen, toremifene, bazedoxifene, lasofoxyfene or ormeloxifene. Those skilled in the art will appreciate that other SERMs are useful in the present invention.

0385The anti-absorbing agent can also be any suitable calcitonin analog or cathepsin K inhibitor. In some embodiments, calcitonin analogs useful in the methods of the invention include, but are not limited to, miacalcic. Those skilled in the art will appreciate that other calcitonin analogs are useful in the present invention.

0386Vitamin D analogs useful in the methods of the invention can be any suitable vitamin D analog. In some embodiments, vitamin D analogs useful in the methods of the invention include, but are not limited to, vitamin D1 (molecular compounds of lumisterol and ergocalciferol, 1: 1), vitamin D2 (ergo). Calciferol or calciferol), vitamin D3 (choleciferol), vitamin D4 (22-dihydroergocalciferol) and vitamin D5 (citocarciferol). Those skilled in the art will appreciate that other vitamin D analogs are useful in the present invention.

0387RankL inhibitors useful in the present invention include any compound that inhibits RankL activity. For example, RankL inhibitors include, but are not limited to, the human monoclonal antibody denosumab. Those skilled in the art will appreciate that other RankL inhibitors are useful in the present invention.

0388In some embodiments, individuals treated by the methods of the invention are compounded or composed as described herein (eg, Formula I, in combination with or in sequence with anabolic agents. Formula IA, Formula IB, Formula IC, Formula II or Formula III compounds or compositions) are administered. In some embodiments, the anabolic is parathyroid hormone (PTH) or an analog thereof (eg, teriparatide (forteo). In some embodiments, the anabolic is a sclerostin antibody (Mab) inhibitor or formula. A compound of formula I, formula IA, formula IB, formula IC, formula II or formula III.

0389VIII. Medical device In some embodiments, the invention provides a medical device formed from a structural support, wherein the implantable portion of the structural support is adapted to be permanently implanted inside the subject. The implantable part is attached to the bone and the structural support is at least partially containing a compound of formula I, formula IA, formula IB, formula IC, formula II or formula III as described herein. Has a coating. In some embodiments, the medical device is an orthopedic or periodontal medical device device.

0390Another aspect of the invention relates to a medical implant. Examples of such a medical device and a graft include an osteogenesis device for repairing endochondral bone and osteochondral defects and a method of using the same, which are taught in the following documents. David Rueger et al. Published US Patent Application Publication No. 20060177475 and patented US Patents Nos. 6,190,880, 5,344,654, 5,324,819, 5,468,845, 6,949,251 and 6,949,251. No. 6,426,332 and No. 5,656,593 and No. 2002/0169122, No. 2002/0187104, No. 2006/0252724 and No. 2007/0172479, the subject matter of which is incorporated herein by reference. ..

0391These medical devices generally have a structural support with implantable portions that are preferentially adapted to mechanically engage bone and / or cartilage, eg, on August 10, 2006. As taught in Published US Patent Publication No. 2006/0178752 by Joseph Vaccarino III et al., The subject matter of which is incorporated herein by reference. These bone grafts preferably contain an activator on at least a portion thereof. Activators are preferred, as set forth in U.S. Patent Publication No. 2006/0188542 by John Dennis Bobyn et al., Published August 24, 2006, the subject of which is incorporated herein by reference. Is formulated for local delivery to bone in the vicinity of the implant in a sustained release or at least two-phase release scheme. In the latter case, the first phase releases the first amount of activator rapidly, and the second subsequent phase gradually releases the second amount of activator, thereby the activator. Bone formation stimulated by is regulated.

0392Medical devices such as bone implants feature implantable moieties having the compounds or compositions of the invention (eg, compounds or compositions of formula I, formula IA, formula IB, formula IC, formula II or formula III). Make bone formation faster and more complete on the fly. It may be desirable that the implantable portion of the medical device is at least partially or completely covered with the compounds and compositions of the invention. In some embodiments, the medical device is externally coated with a compound or composition described herein. In some embodiments, the outer coating completely covers the implantable portion of the structural support. In some embodiments, the structural support (eg, matrix or scaffold) comprises, i.e., internally, a compound or composition as described herein. In some embodiments, the structural support (eg, matrix or scaffold) comprises an external coating of the compound or composition as described herein and also in the support, i.e. internally, the compound. Or contains a composition.

0393In some other embodiments, the implantable portion of the structural support comprises an osteoconducting matrix. Matrix material can promote bone growth. This may be desirable for materials such as teeth and artificial bone graft sections. Alternatively, it may be desirable when the implantable portion is load-bearing, formed from stainless steel or the like, and the implantable portion is formed with a coating of a compound or composition of the invention. In that case, it is also desirable to provide a separate matrix material that promotes the formation of new bone growth.

0394In some embodiments, the matrix comprises particles of porous material. The pores are preferably sized to allow the migration of progenitor cells into the matrix and subsequent differentiation and proliferation. In some embodiments, the pore size of the matrix is at least 5 μm, eg, at least 5, 10, 20, 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 or 1000 μm. In some embodiments, the scaffold or matrix comprises a mesh structure, a foam structure, a sponge structure or a fibrous structure.

0395Scaffolds or matrices for use in devices as described herein can include synthetic and / or biological materials. In some embodiments, the scaffold or matrix comprises a naturally occurring polymer, a synthetic biodegradable polymer, a non-biodegradable synthetic polymer, a bioceramic, a bioglass or a combination thereof. Natural and synthetic polymers, bioceramics and bioglasses for use in scaffolding are known in the art, eg, Dhandayuthapani et al., International Journal of Polymer Science, volume 2011, article ID. See 290602 (2011), which is incorporated herein by reference. Natural polymers include, but are not limited to, proteins (eg, silk, collagen, gelatin, fibrinogen, elastin, keratin, actin and myosin), polysaccharides (eg, cellulose, amylose, dextran, chitin, chitosan and glycosami). Noglycans) and polynucleotides (eg, DNA and RNA). Synthetic polymers include, but are not limited to, PLA, PGA, PLLA, PLGA, PCL, PLDLA, PDS, PGCL, PEA, PCA, PDLLA, PEU and PBT. Bioceramics and bioglasses include, but are not limited to, HAP, TCP, CP ceramics, BCP and TCP. In some embodiments, the scaffold or matrix is a hydrogel scaffold, a fibrous scaffold, a microsphere scaffold, a polymer-bioceramic composite scaffold or a cell-free scaffold.

0396In some embodiments, a suitable matrix is as taught in Takashi Saito's US Publication No. 2006/0188544, published August 24, 2006 (incorporated herein by reference). , Fluorophorin and / or those containing a composite biomaterial having a sponge-like structure, such as containing collagen. Such coatings include, for example, US Publication No. 2006/0204542 of Zongtao Zhang et al. Published September 14, 2006, and US Pat. Nos. 6,949,251, 5,298, Single and multi-layer coatings as taught in 852, 5, 939, 039 and 7, 189, 263 are mentioned and by conventional methods, including those taught therein. It can be manufactured and its subject matter is incorporated herein by reference.

0397In some embodiments, the matrix is a bone conduction matrix. In some embodiments, the bone conduction matrix comprises a bone inducer such as bone allogeneic graft, autologous bone graft, decalcified bone, or periodontal ligament cells. In some embodiments, the bone conduction matrix material is calcium salt, calcium sulfate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-based hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate. , Collagen, calcined gypsum, phosphophorin, borosilicate, biocompatible ceramic, calcium phosphate ceramic, polytetrafluoroethylene, sulfate, borosilicate or hydrogel. Those skilled in the art will appreciate that other bone conduction matrices and bone inducers are useful in the present invention.

0398IX. Assay for identification of therapeutic compounds for bone loss Compounds useful in the methods of the invention can be identified by various methods known to those of skill in the art. Several exemplary methods for identifying such antagonists are described herein and are cell-based in vitro techniques (Journal of Bone and Mineral Research 2006, 21 (11), 1738- 1749). Common methods for identifying compounds include assessing the effect of candidate antagonists on bone formation under controlled conditions. Preferably, bone formation is determined using micro-CT technology in living animals. Rodents are preferred animals, and primates are more preferred. The femur, tibia and vertebrae are particularly useful subjects for such studies.

0399Simply put, test animals are treated with a predetermined dose of candidate compound. Control animals are treated with control solution, preferably non-irritating buffer or other carrier. When the candidate compound is delivered in the carrier, the control solution is ideally a carrier in which no candidate compound is present. Multiple doses of the candidate compound can preferably be given to the test animal according to a predetermined dosing schedule. The dosing schedule may be, for example, over several days, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 days or more, for several weeks, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more, or for several months, for example 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10 months or more.

0400In an exemplary embodiment, in-situ topical administration of the candidate compound can be made to the test animal and the control animal receives the same volume of control solution without the candidate compound. The appropriate dose depends on the nature of the particular candidate compound being tested. As an example, it should be noted that systemic administration (eg, oral or injectable, eg, intravenous, subcutaneous or intramuscular) can also be used for administration. Administrations made by spray inhalation, eye drops or oral ingestion should be in sufficient quantity to result in blood levels of candidate compounds similar to those reached using systemic infusion. The amount of candidate compound that can be delivered by spray inhalation, eye drops or oral ingestion to achieve these levels depends on the nature of the inhibitor used and can be determined by routine experimentation.

0401Once the dosing schedule is complete, both test and control animals will be examined to determine the amount of bone formation present. This can be done by any suitable method, but preferably by analyzing the bone mineral content in live animals. Micro-CT examination methods for bone in animals are well known in the art. Candidate compounds suitable for use in promoting bone formation are identified by observing significant bone formation in test animals when compared to control animals. In some embodiments, the candidate compound is at least 0.5%, 1, 5, 10, 20, 30, 40, 50, 60, if the amount of bone formation in the test bone of the test animal is at least 0.5% compared to the control animal. If it is 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000% or more, it is identified as suitable for use in promoting bone formation. .. In some embodiments, bone formation is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50% or more as compared to the control animal. If desired, the level of bone formation can be calculated by determining the volume of bone formation present in each animal. The calculation can be done by constructing a three-dimensional image of bone formation and calculating the volume from the image with the help of tissue morphometry and the like.

0402A typical example of molecular modeling above consists of the CHARMm and QUANTA programs (Polygen Corporation, Waltham, Mass). CHARMm performs energy minimization and molecular dynamics functions. QUANTA performs construction, graphic modeling and molecular structure analysis. QUANTA can perform interaction construction, modification, visualization and analysis of each other's molecular behavior.

0403Compounds can also be identified using a process known as computer or molecular modeling, which allows visualization of the three-dimensional atomic structure of selected molecules and rational design of new compounds that interact with the molecule. .. Three-dimensional structures typically rely on data from X-ray crystallographic analysis or NMR image formation of selected molecules. Molecular dynamics requires force field data. Computer graphics systems can predict what novel compounds will bind to the target molecule, and experimental manipulation of the structure of the compound and target molecule will provide complete binding specificity. Prediction of what a molecule-compound interaction is requires molecular mechanical software and a computationally intensive computer when small changes are made to one or both, and the software and the computer are usually It is linked by a user-friendly menu-driven interface between the molecular design program and the user.

<p num="0404">X. Example<u style="single">Example 1: Synthesis of N, N-dimethyl-1-(9H-pyrido [2,3-b] indole-9-yl) propan-2-amine</u></p><p num="0405"><chemistry num="162"><img id="000164" he="45" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0406"> 2- (Dimethylamino) propan-1-ol (Matrix Catalog No. 032457; 1.0 g, 9.7 mmol) was dissolved in 10 mL DMF and 1 mL (14 mmol) thionyl chloride was added. The reaction mixture was stirred at ambient temperature overnight and monitored by LCMS. After completing the reaction, the solvent was evaporated to dryness and 1.5 g of crude 1-chloro-N, N-dimethylpropan-2-amine HCl salt was further used without purification (yield 94%).</p><p num="0407"> A mixture of α-carboline starting material (Toronto Research Chemicals Catalog No. C176600, 25 mg, 0.1 mmol), anhydrous DMF (3 mL) and anhydrous THF (1 mL) was stirred at ambient temperature until clear. 60% NaH (every 50 mg dose until gas generation stopped) and 1-chloro-N, N-dimethylpropan-2-aminehydrochloride (47 mg, 0.28 mmol) were then added, and at ambient temperature 30 The mixture was stirred for minutes and then the THF was evaporated under reduced pressure. The obtained solution is H₂It was poured into O (10 mL) and extracted with petroleum ether (15 mL). The aqueous phase was concentrated under reduced pressure. Preparative HPLC of the resulting oil (mobile phase A: 0.1% formic acid in water; mobile phase B: MeCN; solvent gradient: 100-50 A / B for 35 minutes, then 50-0 A / B for 5 minutes, then 0 Purification by flow rate: 45 mL / min; column: LunaRP18, 10 mm, 21x250 mm) for 5 minutes at / 100 A / B to give the target product (8 mg, 27% yield).¹H NMR (DMSO-d₆, 400MHz) δ8.53 (dd, 1H, J = 1.6, 6.0Hz), 8.47 (dd, 1H, J = 1.6, 4.8Hz), 8.20 (d, 1H, J = 7.6Hz), 7.66 (d, 1H) , J = 8.4Hz), 7.53 (t, 1H), 7.24 (m, 2H), 4.54 (dd, 1H, J = 6.8, 21Hz), 4.33 (dd, 1H, J = 6.8, 21Hz), 3.48 (m) , 1H), 2.23 (s, 6H), 0.87 (d, 3H, J = 6.4Hz); LCMSm / z254.37 ([M + H]⁺, C₁₆H₂₀N₃Request value 254.17).</p><p num="0408"><u style="single">Example 2: Synthesis of 1: 1- (9H-carbazole-9-yl) -N, N-dimethylpropan-2-amine</u></p><p num="0409"><chemistry num="163"><img id="000165" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0410"> 2- (Dimethylamino) propan-1-ol (Matrix Catalog No. 032457; 1.0 g, 9.7 mmol) was dissolved in 10 mL DMF and 1 mL (14 mmol) thionyl chloride was added. The reaction mixture was stirred at ambient temperature overnight and monitored by LCMS. After the reaction was complete, the solvent was evaporated to dryness to provide 1.5 g of crude 1-chloro-N, N-dimethylpropan-2-amine HCl salt, which was further used without purification (yield 94%). ).</p><p num="0411"> A mixture of carbazole starting material (Aldrich Catalog No. C5132, 40 mg, 0.23 mmol), anhydrous DMF (3 mL) and anhydrous THF (1 mL) was stirred at ambient temperature until clear. 60% NaH (every 50 mg dose until gas generation stopped) and 1-chloro-N, N-dimethylpropan-2-aminehydrochloride (75 mg, 0.46 mmol) were then added, and at ambient temperature 30 The mixture was stirred for minutes and then the THF was evaporated under reduced pressure. The obtained solution is H₂It was poured into O (10 mL) and extracted with petroleum ether (15 mL). The aqueous phase was condensed under reduced pressure. Preparative HPLC of the resulting oil (mobile phase A: 0.1% formic acid in water; mobile phase B: MeCN; solvent gradient: 100-50 A / B for 35 minutes, then 50-0 A / B for 5 minutes, then 0 Purification by flow rate: 45 mL / min; column: LunaRP18, 10 mm, 21x250 mm) for 5 minutes at / 100 A / B to provide the target product (9 mg, 20% yield).¹H NMR (DMSO-d₆, 400MHz) δ8.14 (d, 2H, J = 7.6Hz), 7.58 (d, 2H, J = 8.0Hz), 7.45 (t, 2H, J = 7.2Hz), 7.20 (t, 2H, J = 7.2 Hz), 4.45 (dd, 1H, J = 6.0, 14.8Hz), 4.33 (dd, 1H, J = 8.0, 14.6Hz), 3.15 (m, 1H), 2.27 (s, 6H), 0.85 (d, 3H) , J = 6.8Hz).</p><p num="0412"><u style="single">Example 3: Synthesis of 3- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-2-aminium format</u></p><p num="0413"><chemistry num="164"><img id="000166" he="45" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0414"> 2- (Dimethylamino) propan-1-ol (Matrix Catalog No. 032457; 1.0 g, 9.7 mmol) was dissolved in 10 mL DMF and 1 mL (14 mmol) thionyl chloride was added. The reaction mixture was stirred at ambient temperature overnight and monitored by LCMS. After completing the reaction, the solvent was evaporated to dryness to provide 1.5 g of crude 1-chloro-N, N-dimethylpropan-2-amine HCl salt, which was further used without purification. (Yield 94%).</p><p num="0415"> A mixture of β-carboline starting material (TCI Catalog No. H0001, 20 mg, 0.1 mmol), anhydrous DMF (1 mL) and anhydrous THF (1 mL) was stirred at ambient temperature until clear. 60% NaH (10 mg) and 1-chloro-N, N-dimethylpropan-2-amine hydrochloride (30 mg, 0.2 mmol) are then added and stirred at ambient temperature for 30 minutes, after which THF is depressurized. Evaporated down. The obtained solution is H₂It was poured into O (10 mL) and extracted with ethyl acetate (15 mL). The organic phase was washed with water and brine, dried over sodium sulphate, filtered and evaporated. Preparative HPLC of the resulting oil (mobile phase A: 0.1% formic acid in water; mobile phase B: MeCN; solvent gradient: 100-50 A / B for 35 minutes, then 50-0 A / B for 5 minutes, then 0 Purification by / 100 A / B for 5 minutes, flow rate: 45 mL / min; column: Luna RP18, 10 mm, 21x250 mm) to give the target product (17 mg, 62% yield).¹H NMR (DMSO-d₆, 300MHz) δ11.86 (bs, 1H), 8.54 (d, 1H, J = 6.0Hz), 8.45 (m, 2H), 7.71 (d, 1H, J = 1.8Hz), 7.11 (dd, 1H, J = 1.8, 8.7Hz), 5.28 (m, 1H), 4.99 (m, 1H), 4.02 (s, 3H), 3.92 (m, 1H), 3.26 (s, 3H), 2.87 (bs, 6H), 0.99 (d, 3H, J = 6.6Hz); LCMSm / z298.54 ([M + H]⁺, C₁₈H₂₄N₃O Request value 298.19).</p><p num="0416"> The β-carboline starting material of Example 3 (TCI Catalog No. H0001) can also be converted to a compound of Formula I or Formula II using the procedures described in Example 3 and Scheme 1.</p><p num="0417"><u style="single">Example 4: Synthesis of 9- (2- (dimethylamino) propyl) -1-methyl-9H-pyrido [3,4-b] indole-7-ol</u></p><p num="0418"><chemistry num="165"><img id="000167" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0419"> 1- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-2-aminium formate (150 mg, 0.5 mmol) in 5 mL It was dissolved in acetic acid and 5 mL of concentrated HBr was carefully added. The solution was refluxed overnight and monitored by LCMS. After the reaction is complete, the reaction mixture is evaporated and the crude product is RPHPLC (mobile phase A: 0.1% formic acid in water; mobile phase B: MeCN; solvent gradient: 100-50 A / B for 35 minutes, then 50- Purification by 0 A / B for 5 minutes, then 0/100 A / B for 5 minutes, flow rate: 45 mL / min; column: LunaRP18, 10 mm, 21x250 mm) to give the target product (85 mg, 61% yield). ..¹H NMR (DMSO-d₆, 400MHz) δ8.26 (s, 1H), 8.15 (d, 1H, J = 6.0Hz), 8.01 (d, 1H, J = 11Hz), 7.86 (d, 1H, J = 6.4Hz), 7.01 (s) , 1H), 6.78 (d, 1H, J = 11.2Hz), 4.57 (m, 1H), 4.48 (m, 1H), 3.19 (m, 1H), 2.95 (s, 3H), 2.39 (s, 6H) , 0.78 (d, 3H, J = 8.8Hz); LCMSm / z284.37 ([M + H]⁺, C₁₇H₂₂N₃O Request value 284.18).</p><p num="0420"> The β-carboline starting material of Example 3 (TCI Catalog No. H0001) can also be converted to a compound of Formula I or Formula II using the procedures described in Example 3 and Example 4 as well as Scheme 1.</p><p num="0421"><u style="single">Example 5: 2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-1-amine</u></p><p num="0422"><chemistry num="166"><img id="000168" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0423">¹H NMR (DMSO-d₆, 400MHz) δ8.16 (d, 1H, J = 5.2Hz), 8.12 (d, 1H, J = 8.8Hz), 7.87 (d, 1H, J = 5.2Hz), 7.11 (d, 1H, J = 2.4) Hz), 6.88 (dd, 1H, J = 8.8, 2.0Hz), 5.35 (m, 1H), 3.89 (s, 3H), 3.01 (dd, 1H, J = 12.5, 8.0Hz), 2.97 (s, 3H) ), 2.83 (dd, 1H, J = 12.8, 6.4Hz), 2.07 (s, 6H), 1.64 (d, 1H, J = 6.8Hz); LCMSm / z298.19 ([M + H]⁺, C₁₈H₂₄N₃O Request value 298.19).</p><p num="0424"><u style="single">Example 6: N, N-diethyl-3- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-1-amine</u></p><p num="0425"><chemistry num="167"><img id="000169" he="48" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0426">¹H NMR (DMSO-d₆, 400MHz) δ8.15 (d, 1H, J = 5.2Hz), 8.07 (d, 1H, J = 8.8Hz), 7.85 (d, 1H, J = 5.2Hz), 7.15 (d, 1H, J = 2.0) Hz), 6.87 (dd, 1H, J = 8.4, 2.0Hz), 4.55 (m, 2H), 3.89 (s, 3H), 2.95 (s, 3H), 2.42 (m, 6H), 1.79 (m, 2H) ), 0.92 (t, 6H, J = 6.8Hz); LCMSm / z326.22 ([M + H]⁺, C₂₀H₂₈N₃O request value 326.22)</p><p num="0427"><u style="single">Example 7: 2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylethaneamine</u></p><p num="0428"><chemistry num="168"><img id="000170" he="45" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0429">¹H NMR (DMSO-d₆, 400MHz) δ8.16 (d, 1H, J = 5.2Hz), 8.08 (d, 1H, J = 8.4Hz), 7.86 (d, 1H, J = 5.2Hz), 7.12 (d, 1H, J = 2.0) Hz), 6.87 (dd, 1H, J = 8.4, 2.0Hz), 4.64 (t, 2H, J = 7.2Hz), 3.90 (s, 3H), 2.95 (s, 3H), 2.57 (t, 2H, J = 7.2Hz), 2.23 (s, 6H).</p><p num="0430"><u style="single">Example 8: 4- (1- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propan-2-yl) morpholine</u></p><p num="0431"><chemistry num="169"><img id="000171" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0432">¹H NMR (DMSO-d₆, 400MHz) δ8.18 (d, 1H, J = 5.2Hz), 8.08 (d, 1H, J = 8.8Hz), 7.87 (d, 1H, J = 5.2Hz), 7.19 (d, 1H, J = 2.0) Hz), 6.86 (dd, 1H, J = 8.4, 2.0Hz), 4.61 (dd, 1H, J = 15.2,6.4Hz), 4.47 (dd, 1H, J = 15.2,6.4Hz), 3.89 (s, 3H) ), 3.39 (m, 4H), 2.97 (m, 1H), 2.93 (s, 3H), 2.65 (m, 2H), 2.31 (m, 2H), 0.82 (d, 3H, J = 6.4Hz).</p><p num="0433"><u style="single">Example 9: 7-Methoxy-1-methyl-9-(2- (piperidin-1-yl) propyl) -9H-pyrido [3,4-b] indole</u></p><p num="0434"><chemistry num="170"><img id="000172" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0435">¹H NMR (DMSO-d₆, 400MHz) δ8.17 (d, 1H, J = 5.2Hz), 8.06 (d, 1H, J = 8.4Hz), 7.86 (d, 1H, J = 5.2Hz), 7.17 (d, 1H, J = 2.0) Hz), 6.84 (dd, 1H, J = 8.4, 2.0Hz), 4.56 (dd, 1H, J = 14.8, 6.4Hz), 4.46 (dd, 1H, J = 14.8, 6.4Hz), 3.89 (s, 3H) ), 2.97 (m, 1H), 2.92 (s, 3H), 2.61 (m, 2H), 2.25 (m, 2H), 1.32 (m, 6H), 0.80 (d, 3H, J = 6.8Hz).</p><p num="0436"><u style="single">Example 10: 7-Methoxy-1-methyl-9-(2- (piperidin-1-yl) ethyl) -9H-pyrido [3,4-b] indole</u></p><p num="0437"><chemistry num="171"><img id="000173" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0438">¹H NMR (DMSO-d₆, 400MHz) δ8.16 (d, 1H, J = 5.2Hz), 8.08 (d, 1H, J = 8.4Hz), 7.86 (d, 1H, J = 5.2Hz), 7.14 (d, 1H, J = 2.4) Hz), 6.86 (dd, 1H, J = 8.8, 2.4Hz), 4.65 (t, 2H, J = 7.2Hz), 3.90 (s, 3H), 2.97 (s, 3H), 2.62 (t, 2H, J = 7.2Hz), 2.40 (m, 4H), 1.45 (m, 4H), 1.35 (m, 2H).</p><p num="0439"><u style="single">Example 11: 4- (3- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) morpholine formate</u></p><p num="0440"><chemistry num="172"><img id="000174" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0441">¹H NMR (DMSO-d₆, 400MHz) δ8.17 (d, 1H, J = 5.2Hz), 8.15 (formate), 8.10 (d, 1H, J = 8.4Hz), 7.89 (d, 1H, J = 5.6Hz), 7.18 (d, 1H, J = 2.4Hz), 6.88 (dd, 1H, J = 8.8, 2.4Hz), 4.62 (t, 1H, J = 7.6Hz), 3.90 (s, 3H), 3.53 (t, 1H, J = 4.8) Hz), 2.97 (s, 3H), 2.31 (m, 6H), 1.89 (m, 2H).</p><p num="0442"><u style="single">Example 12: 4- (2- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) morpholine</u></p><p num="0443"><chemistry num="173"><img id="000175" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0444">¹H NMR (DMSO-d₆, 400MHz) δ8.16 (d, 1H, J = 5.2Hz), 8.08 (d, 1H, J = 8.8Hz), 7.87 (d, 1H, J = 5.2Hz), 7.15 (d, 1H, J = 2.4) Hz), 6.87 (dd, 1H, J = 8.8, 2.4Hz), 4.67 (t, 2H, J = 7.2Hz), 3.90 (s, 3H), 3.52 (t, 4H, J = 4.8Hz), 2.97 ( s, 3H), 2.65 (m, 2H), 2.44 (m, 4H).</p><p num="0445"><u style="single">Example 13: 1-Methyl-9- (2-morpholinoethyl) -9H-pyrido [3,4-b] Indole-7-ol</u></p><p num="0446"><chemistry num="174"><img id="000176" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0447">¹H NMR (DMSO-d₆, 400MHz) δ8.15 (d, 1H, J = 5.2Hz), 8.00 (d, 1H, J = 8.4Hz), 7.85 (d, 1H, J = 5.2Hz), 6.95 (d, 1H, J = 2.0) Hz), 6.76 (dd, 1H, J = 8.4, 2.0Hz), 4.58 (t, 2H, J = 7.2Hz), 3.56 (t, 4H, J = 4.4Hz), 2.97 (s, 3H), 2.66 ( m, 2H), 2.48 (m, 4H).</p><p num="0448"><u style="single">Example 14: t-Butyl 4- (2- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) piperazine-1-carboxylate</u></p><p num="0449"><chemistry num="175"><img id="000177" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0450">¹H NMR (DMSO-d₆, 400MHz) δ8.16 (d, 1H, J = 5.2Hz), 8.09 (d, 1H, J = 8.8Hz), 7.87 (d, 1H, J = 5.2Hz), 7.16 (d, 1H, J = 2.0) Hz), 6.87 (dd, 1H, J = 8.6, 2.0Hz), 4.67 (t, 2H, J = 7.2Hz), 3.90 (s, 3H), 3.24 (m, 4H), 2.97 (s, 3H), 2.68 (t, 2H, J = 7.2Hz), 2.42 (m, 4H), 1.38 (s, 9H).</p><p num="0451"><u style="single">Example 15: t-Butyl 4- (3- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) propyl) piperazine-1-carboxylate</u></p><p num="0452"><chemistry num="176"><img id="000178" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0453">¹H NMR (DMSO-d₆, 400MHz) δ8.15 (d, 1H, J = 4.8Hz), 8.07 (d, 1H, J = 8.8Hz), 7.85 (d, 1H, J = 5.2Hz), 7.14 (d, 1H, J = 2.0) Hz), 6.85 (dd, 1H, J = 8.8, 2.0Hz), 4.58 (t, 2H, J = 7.2Hz), 3.89 (s, 3H), 3.25 (m, 4H), 2.94 (s, 3H), 2.29 (t, 4H, J = 6.4Hz), 1.86 (m, 2H), 1.37 (s, 9H); LCMSm / z439.27 ([M + H]⁺, C₂₅H₃₅N₄O₃Request value 439.27).</p><p num="0454"><u style="single">Example 16: 7-Methoxy-1-methyl-9-(2- (piperazin-1-yl) ethyl) -9H-pyrido [3,4-b] indole</u></p><p num="0455"><chemistry num="177"><img id="000179" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0456"> Tert-butyl 4- (2- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indol-9-yl) ethyl) piperazin-1-carboxylate (.1 g, 0.236 mmol), It was dissolved in a 1/3 mixture of trifluoroacetic acid (Sigma Aldrich, 299537) and dichloromethane. The sample was stirred to completion. The sample was concentrated in vacuo and then purified by reverse phase chromatography (pH = 9 water, acetonitrile) to 7-methoxy-1-methyl-9- (2- (piperazine-1-yl) ethyl)-. 9H-pyrido [3,4-b] indol (.074 g, 0.228 mmol, 97% yield) was provided.¹1 H NMR (CDCl_3,400MHz) δ8.28 (d, 1H, J = 5.2Hz), 7.97 (d, 1H, J = 8.4Hz), 7.72 (d, 1H, J = 5.2Hz), 6.91 (d, 1H, J = 2.0Hz) ), 6.90 (d, 1H, J = 2.0Hz), 6.88 (d, 1H, J = 2.0Hz), 4.62 (t, 2H, J = 8.0Hz), 3.94 (s, 3H), 3.04 (s, 1H) ), 2.90 (t, 4H, J = 4.8Hz), 2.73 (t, 2H, J = 7.6Hz), 2.52 (m, 4H); LCMSm / z325.20 ([M + H]⁺, C₁₉H₂₅N₄O Request value 325.20).</p><p num="0457"><u style="single">Example 17: 7-Methoxy-1-methyl-9-(3- (piperazin-1-yl) propyl) -9H-pyrido [3,4-b] indole trifluoroacetate</u></p><p num="0458"><chemistry num="178"><img id="000180" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0459"> Example 17 was synthesized from Example 15 using the procedure of Example 16.¹H NMR (DMSO-d₆, 400MHz) δ9.56 (bs, 1H), 8.53 (d, 1H, J = 6.0Hz), 8.45 (d, 1H, J = 6.0Hz), 8.39 (d, 1H, J = 8.8Hz), 7.40 ( d, 1H, J = 2.0Hz), 7.08 (dd, 1H, J = 8.8, 2.0Hz), 4.72 (t, 2H, J = 7.2Hz), 3.98 (s, 3H), 3.40-3.31 (m, 10H) ), 3.19 (s, 3H), 2.21 (m, 2H); LCMSm / z339.22 ([M + H]⁺, C₂₀H₂₇N₄O Request value 339.22).</p><p num="0460"><u style="single">Example 18: 2-((2- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) ethyl) (methyl) amino) ethanol</u></p><p num="0461"><chemistry num="179"><img id="000181" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0462"> 7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole hydrochloride (.15 g, 0.603 mmol)) was dissolved in 3 mL DMF and 3 mL THF, and a 10 mL round bottom containing a stir bar. Transferred to flask. Sodium hydride (0.096 g, 2.412 mmol) was added slowly to the reaction flask and then stirred under argon for 30 minutes. tert-Butyl (2-chloroethyl) (methyl) carbamate (0.234 g, 1.206 mmol) was then added as a 1 mL solution of a 1: 1 mixture of DMF and THF. The reaction was then heated to 60 ° C until completion. The reaction was quenched with water and then extracted 3 times with ethyl acetate. The organic phase was washed 3 times with water and then once with brine. The organic phase was then dried over sodium sulphate and then concentrated in vacuo. The crude residue was purified by positive phase and then reverse phase chromatography to tert-butyl (2- (7-methoxy-1-methyl-9H-pyrido [3,4-b] indol-9-yl) ethyl). (Methyl) carbamate (.065 g, 0.176 mmol, 29.2% yield) was provided. The product was then dissolved in a 1: 3 mixture of trifluoroacetic acid: dichloromethane until the reaction was complete. The reaction mixture is concentrated in vacuo, dissolved in dichloromethane, washed with sodium bicarbonate, dried over sodium sulphate, then concentrated in vacuo and 2- (7-methoxy-1-methyl-9H-pyrido). [3,4-b] Indol-9-yl) -N-methylethaneamine was provided in&gt; 95% yield.</p><p num="0463"> 2- (7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-9-yl) -N-methylethaneamine (.04 g, 0.149 mmol) in 3 mL DMF and 3 mL THF It was dissolved and transferred to a 10 mL round bottom flask containing a stir bar. Sodium hydride (0.024 g, 0.594 mmol) was added slowly to the reaction flask and then stirred under argon for 30 minutes. 2-Bromoethanol (0.032 ml, 0.446 mmol) was then added as a 1 mL solution in a 1: 1 mixture of DMF and THF. The reaction was then heated to 60 ° C until completion. The reaction was quenched with water and then extracted 3 times with ethyl acetate. The organic phase was washed 3 times with water and then once with brine. The organic phase was then dried over sodium sulfate and then concentrated in vacuo. The crude residue is positive phase, then the crude residue is positive phase, then purified by reverse phase chromatography and 2-((2- (7-methoxy-1-methyl-9H-pyrido] [3,4-b ] Indole-9-yl) ethyl) (methyl) amino) ethanol (.038 g, 0.121 mmol, 82% yield) was provided.¹H NMR (DMSO-d₆, 400MHz) δ8.16 (d, 1H, J = 5.2Hz), 8.08 (d, 1H, J = 8.4Hz), 7.87 (d, 1H, J = 4.8Hz), 7.15 (d, 1H, J = 2.0) Hz), 6.86 (dd, 1H, J = 8.4, 2.0Hz), 4.63 (t, 2H, J = 7.6Hz), 4.37 (bs, 1H), 3.90 (s, 3H), 3.40 (m, 2H), 2.96 (s, 3H), 2.73 (t, 1H, J = 7.6Hz), 2.50 (m, 2H), 2.32 (s, 3H); LCMSm / z314.19 ([M + H]⁺, C₁₈H₂₄N₃O₂Request value 314.19).</p><p num="0464"><u style="single">Example 19: Synthesis of 7-methoxy-1-methyl-9H-pyrido [3,4-b] indole-3-ol</u></p><p num="0465"><chemistry num="180"><img id="000182" he="35" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0466"> 6- (benzyloxy) -3-bromo-2-methylpyridine (ArkPharm Catalog No. AK-27978, 0.1g, 0.360 mmol), 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i -Propyl-1,1'-biphenyl (Chemimpex catalog number 27675, 0.013 g, 0.027 mmol), cesium carbonate (0.141 g, 0.431 mmol) and palladium (II) acetate (4.04 mg, 0.018 mmol) in a stir bar and 5 mL. It was added to a microwave vial containing anhydrous toluene. Then 2-chloro-5-methoxyaniline (Chemimpex Catalog No. 27675, 0.059 g, 0.378 mmol) was added. The solvent was degassed twice with argon. The reaction was heated on a heating block at 100 ° C. for 15 hours. The crude reaction mixture was cooled to room temperature and then filtered through Celite. Celite was repeatedly rinsed with ethyl acetate to recover the crude product mixture. A positive phase ethyl acetate / hexane column was run against the crude mixture to provide 6- (benzyloxy) -N- (2-chloro-5-methoxyphenyl) -2-methylpyridine-3-amine (0.1195 g). , 94% yield).¹1 H NMR (CDCl 3,400MHz) δ7.39 (m, 6H), 7.20 (d, 1H, J = 8.8Hz), 6.67 (d, 1H, J = 8.4Hz), 6.26 (dd, 1H, J = 2.8, 8.8Hz), 6.01 (d, 1H, J = 2.8Hz), 5.65 (s, 1H), 5.37 (s, 2H), 3.65 (s, 3H), 2.38 (s, 3H).</p><p num="0467"> 6- (benzyloxy) -N- (2-chloro-5-methoxyphenyl) -2-methylpyridine-3-amine (0.1195 g, 0.337 mmol), N, N-dimethylacetamide (5 mL), tri-t- Butylphosphonium tetrafluoroborate (0.020 g, 0.067 mmol), potassium carbonate (0.093 g, 0.674 mmol) and palladium (II) acetate (7.56 mg, 0.034 mmol) were added to the microwave sample vessel. The solvent was degassed twice with argon. The microwave vial was heated at 150 ° C. for 3 hours in a microwave device. The crude reaction mixture was filtered through Celite. Celite was repeatedly washed with ethyl acetate. The combined organic moieties were washed twice with water, twice with brine, dried over sodium sulphate and then concentrated in vacuo. Positive phase chromatography (methanol / DCM) followed by reverse phase chromatography (water / acetonitrile), 3- (benzyloxy) -7-methoxy-1-methyl-9H-pyrido [3,4-b ] Indole (0.135 g, 75% yield) was provided.¹1 H NMR (CDCl 3,400MHz) δ8.98 (bs, 1H), 7.69 (d, 1H, J = 8.4Hz), 7.42 (d, 1H, J = 7.2Hz), 7.25 (m, 3H), 6.90 (s , 1H), 6.84 (s, 1H), 6.69 (d, 1H, J = 8.4Hz), 5.22 (s, 2H), 3.65 (s, 3H), 2.73 (s, 3H). LCMSm / z319.15 ([M + H]⁺, C₂₀H₁₉N₂O₂, Request value 319.14).</p><p num="0468"> 3- (benzyloxy) -7-methoxy-1-methyl-9H-pyrido [3,4-b] indole (0.07 g, .220 mmol) in THF (10 mL) in a round bottom flask equipped with a stir bar and rubber septum. Dissolved in. 10% palladium on carbon (0.014 g, 0.132 mmol) was added slowly. The reaction chamber was repeatedly purged with hydrogen gas (double balloon pressure). Then, the reaction was allowed to stand under balloon-filled hydrogen gas pressure for 3 hours. The crude reaction mixture was then filtered through Celite. Celite was washed repeatedly with ethyl acetate, then the combined wash was concentrated in vacuo. The residue was purified by positive phase chromatography (methanol / dichloromethane) followed by reverse phase chromatography (water, acetonitrile) and 7-methoxy-1-methyl-9H-pyrido [3,4-b] indol-3- All provided (.046 g, 92% yield).¹H NMR (DMSO-d₆, 500MHz) δ10.69 (bs, 2H), 7.87 (d, 1H, J = 8.5Hz), 6.80 (d, 1H, J = 2.0Hz), 6.73 (s, 1H), 6.66 (dd, 1H, J = 2.0, 8.5Hz), 3.83 (s, 3H), 2.50 (s, 3H). LCMSm / z229.09 ([M + H]⁺, C₁₃H₁₃N₂O₂Request value 229.10).</p><p num="0469"> The compound of Example 19 is subjected to the procedure described in Example 3 and Scheme 1 and then the corresponding 3- (benzyloxy) -7-methoxy using the debenzylation procedure described in Example 19. It can be converted to a compound of formula I or formula II through a -1-methyl-9H-pyrido [3,4-b] indole intermediate.</p><p num="0470"><u style="single">Example 20: Synthesis of 1-methyl-9H-pyrido [3,4-b] indole-3,7-diol</u></p><p num="0471"><chemistry num="181"><img id="000183" he="35" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0472"> 7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole-3-ol (0.013 g, 0.057 mmol) was dissolved in THF and then cooled to -78 ° C. Then, boron tribromide (1N solution in dichloromethane) (0.285 mL, 0.285 mmol) was added dropwise. The reactants were slowly warmed to room temperature as determined by UPLC until the reaction was complete. The reaction was then cooled to -78 ° C and then quenched by the addition of methanol dropwise. The reaction mixture was concentrated in vacuo and then purified by positive phase chromatography to provide 1-methyl-9H-pyrido [3,4-b] indole-3,7-diol (0.0058 g, 47% yield). rate).¹H NMR (DMSO-d₆, 500MHz) δ10.35 (s, 1H), 7.69 (d, 1H, J = 8.5Hz), 6.62 (d, 1H, J = 2.0Hz), 6.57 (s, 1H), 6.48 (dd, 1H, J = 2.0, 8.5Hz), 2.45 (s, 3H). LCMSm / z215.08 ([M + H]⁺, C₁₂H₁₁N₂O₂Request value 215.08).</p><p num="0473"> The compound of Example 20 was subjected to the corresponding 3- (benzyloxy) using the procedure described in Example 3 and Scheme 1, followed by the debenzylation procedure described in Example 19 and the demethylation of Example 20. It can be converted to a compound of formula I or II through a -7-methoxy-1-methyl-9H-pyrido [3,4-b] indol intermediate.</p><p num="0474"><u style="single">Example 21: Synthesis of 7-methoxy-1-methyl-9H-pyrido [3,4-b] indole pyridine N-oxide</u></p><p num="0475"><chemistry num="182"><img id="000184" he="36" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0476"> 7-Methoxy-1-methyl-9H-pyrido [3,4-b] indole (Chemimpex catalog number 21756, 0.1 g, 0.471 mmol), 5 mL chloroform and 5 mL ethanol and m-chloroper benzoic acid (0.317) g, 1.413 mmol) dissolved in the mixture. The reaction mixture was refluxed for 2 hours, then cooled to room temperature, then 3 mL of 0.1 M NaOH was added and stirring was continued for 30 minutes. Organic layer Na₂SO₄It was dried in and the solvent was evaporated. The residue was purified by positive phase chromatography (ethyl acetate / MeOH) to provide the product (0.087 g, 81% yield).¹H NMR (DMSO-d₆, 400MHz) δ11.60 (s, 1H), 8.05 (d, 1H, J = 6.8Hz), 8.00 (d, 1H, J = 8.8Hz), 7.86 (d, 1H, J = 6.4Hz), 6.98 ( d, 1H, J = 2.4Hz), 6.86 (dd, 1H, J = 2.0, 8.6Hz), 3.85 (s, 3H), 2.63 (s, 3H). LCMSm / z229.09 ([M + H]⁺, C₁₃H₁₃N₂O₂Request value 229.10).</p><p num="0477"> The compound of Example 21 can then be converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0478"><u style="single">Example 22: Synthesis of 7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole</u></p><p num="0479"><chemistry num="183"><img id="000185" he="35" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0480"> 3-Bromo-2- (trifluoromethyl) pyridine (Matrix Catalog No. 032388, 0.2 g, 0.885 mmol), toluene anhydrous (5 mL), 2- (dicyclohexylphosphino) -2', 4', 6'-tri- i-propyl-1,1'-biphenyl (0.032 g, 0.066 mmol), cesium carbonate (0.346 g, 1.062 mmol) and palladium (II) acetate (9.93 mg, 0.044 mmol) were added to the microwave vial. Then 2-chloro-5-methoxyaniline (Chemimpex Catalog No. 27675, 0.146 g, 0.929 mmol) was added. The solvent was degassed twice with argon. The reaction was heated to 100 ° C. for 15 hours on a heating block. The crude reaction mixture was cooled to room temperature and then filtered through Celite. Celite was repeatedly rinsed with ethyl acetate to recover the crude product mixture. A positive phase ethyl acetate / hexane column was applied to the crude mixture to provide N- (2-chloro-5-methoxyphenyl) -2- (trifluoromethyl) pyridine-3-amine (0.1182 g, 44% yield). ..¹1 H NMR (CDCl_3,400MHz) δ8.28 (dd, 1H, J = 0.6, 4.4Hz), 7.74 (d, 1H, J = 8.4Hz), 7.37 (m, 2H), 6.76 (d, 1H, J = 2.8Hz), 6.56 (dd, 1H, J = 2.8, 8.8Hz), 6.46 (s, 1H), 3.76 (s, 3H).</p><p num="0481"> N- (2-chloro-5-methoxyphenyl) -2- (trifluoromethyl) pyridine-3-amine (0.110 g, 0.364 mmol), N, N-dimethylacetamide (5 mL), tri-t-butylphosphonium tetra Fluorobolate (0.053 g, 0.182 mmol), potassium carbonate (0.101 g, 0.728 mmol) and palladium (II) acetate (16 mg, 0.073 mmol) were added to the microwave sample vessel. The solvent was degassed twice with argon. The microwave vial was heated in a microwave device at 150 ° C for 3 hours. The crude reaction mixture was filtered through Celite. Celite was repeatedly washed with ethyl acetate. The combined organic fractions were washed twice with water, dried over sodium sulfate and then concentrated in vacuo. Positive phase chromatography (methanol / DCM) followed by reverse phase chromatography (water / acetonitrile) 7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indol ( 0.067 g, 69% yield) was provided.¹1 H NMR (CDCl_3,400MHz) δ8.631 (s, 1H), 8.49 (d, 1H, J = 5.2Hz), 8.01 (d, 1H, J = 8.4Hz), 7.99 (d, 1H, J = 5.6Hz), 6.99 (d , 1H, J = 2.4Hz), 6.95 (dd, 1H, J = 2.4, 8.4Hz), 3.92 (s, 3H). LCMSm / z267.07 ([M + H]⁺, C₁₃H₁₀F₃N₂O Request value 267.07).</p><p num="0482"> The compound of Example 22 is then converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0483"><u style="single">Example 23: 1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol</u></p><p num="0484"><chemistry num="184"><img id="000186" he="35" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0485"> 3-Bromo-2- (trifluoromethyl) pyridine (.4 g, 1.770 mmol), 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl-1,1'-biphenyl ( 0.063 g, 0.133 mmol), cesium carbonate (0.692 g, 2.124 mmol) and palladium (II) acetate (0.020 g, 0.088 mmol) were added to the microwave vial. Then 2-chloro-5-methoxyaniline (0.293 g, 1.858 mmol) was added. Vials were repeatedly purged with argon. Dry toluene was added. The reaction was heated to 100 ° C for 15 hours. The reaction mixture was filtered through Celite and concentrated in vacuo. The crude material was purified using positive phase chromatography (ethyl acetate / hexane) and N- (2-chloro-5-methoxyphenyl) -2- (trifluoromethyl) pyridine-3-amine (.376 g, 1.242 mmol). , 70.2% yield).</p><p num="0486"> N- (2-Chloro-5-methoxyphenyl) -2- (trifluoromethyl) pyridine-3-amine (.2382 g, 0.787 mmol) was dissolved in DMA and then placed in a 5 mL microwave reaction tube. The solution was degassed with argon. Next, palladium (II) acetate (0.035 g, 0.157 mmol), tri-t-butylphosphonium tetrafluoroborate (0.114 g, 0.393 mmol) and potassium carbonate (0.218 g, 1.574 mmol) were added. The headspace was purged with argon and then the microwave tube was resealed. The reaction vessel was heated in a reaction microwave device at 150 ° C. for 3.5 hours. The crude reaction mixture was filtered through Celite. Ethyl acetate was added to the filtrate, then washed 3 times with water, 1 time with brine, dried over sodium sulfate and then concentrated in vacuo. The crude reaction mixture is purified by positive phase (MeOH / DCM) and then reverse phase chromatography to 7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indol (.067g, 0.252). mmol, 32.0% yield) was provided. The product was dissolved in 1 mL of dichloromethane and then cooled to -78 ° C in acetone / dry dry ice. Then 3 mL of 1NBBr3 / DCM was added slowly. The reaction was stirred until the reaction was complete. The reaction was quenched with a few drops of methanol and then concentrated in vacuo. The crude reaction mixture was purified by reverse phase chromatography to provide 1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol (&gt; 95% yield). LCMSm / z253.06 ([M + H]⁺, C₁₂H₈F₃N₂O Request value 253.06).</p><p num="0487"> Derivatives of Example 23 of Formula I or Formula II are obtained through Example 22 using the procedures described in Example 3 and Scheme 1 followed by the demethylation procedure described in Example 23.</p><p num="0488"><u style="single">Example 24: t-Butyl 4-(2- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) piperazine-1-carboxylate</u></p><p num="0489"><chemistry num="185"><img id="000187" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0490">¹H NMR (DMSO-d₆, 400MHz) δδ8.45 (d, 1H, J = 4.8Hz), 8.41 (d, 1H, J = 4.8Hz), 8.25 (d, 1H, J = 8.6Hz), 7.25 (d, 1H, J = 2.1) Hz), 7.01 (dd, 1H, J = 8.6, 2.1Hz), 4.60 (t, 2H, J = 7.6Hz), 3.95 (s, 3H), 3.28 (m, 4H), 2.66-2.58 (m, 2H) ), 2.46-2.34 (m, 4H), 1.39 (s, 9H).</p><p num="0491"><u style="single">Example 25: 4- (2- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) morpholine</u></p><p num="0492"><chemistry num="186"><img id="000188" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0493">¹H NMR (DMSO-d₆, 400MHz) δ8.44 (d, 1H, J = 5.2Hz), 8.41 (d, 1H, J = 5.2Hz), 8.25 (d, 1H, J = 8.8Hz), 7.25 (d, 1H, J = 2.4) Hz), 7.00 (dd, 1H, J = 8.4, 2.0Hz), 4.61 (t, 2H, J = 7.2Hz), 3.94 (s, 3H), 3.53 (t, 4H, J = 4.4Hz), 2.60 ( t, 2H, J = 7.2Hz), 2.44 (m, 4H); LCMSm / z380.16 ([M + H]⁺, C₁₉H₂₁F₃N₃O₂Request value 380.16).</p><p num="0494"><u style="single">Example 26: 9- (2-morpholinoethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol</u></p><p num="0495"><chemistry num="187"><img id="000189" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0496">¹H NMR (DMSO-d₆, 400MHz) δ10.24 (bs, 1H), 8.39 (d, 1H, J = 5.2Hz), 8.33 (d, 1H, J = 5.2Hz), 8.14 (d, 1H, J = 8.5Hz), 7.01 ( d, 1H, J = 2.0Hz), 6.86 (dd, 1H, J = 8.8, 2.0), 4.49 (t, 2H, J = 8Hz), 3.56 (t, 4H, J = 4.4Hz), 2.58 (t, 2H, J = 8.4Hz), 2.46 (t, 2H, J = 4.8Hz); LCMSm / z366.14 ([M + H]⁺, C₁₈H₁₉F₃N₃O₂Request value 366.14).</p><p num="0497"><u style="single">Example 27: 1- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) -N, N-dimethylpropan-2-amine</u></p><p num="0498"><chemistry num="188"><img id="000190" he="42" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0499">¹H NMR (DMSO-d₆, 400MHz) δ8.45 (d, 1H, J = 4.8Hz), 8.41 (d, 1H, J = 5.2Hz), 8.23 (d, 1H, J = 8.8Hz), 7.32 (d, 1H, J = 2.0) Hz), 76.98 (dd, 1H, J = 8.4, 2.0Hz), 4.61 (dd, 1H, J = 15.2,6.8Hz), 4.36 (dd, 1H, J = 15.6, 7.2Hz), 3.93 (s, 3H) ), 3.03 (q, 1H, J = 4.0Hz), 2.15 (s, 1H), 0.65 (d, 3H, J = 6.4Hz).</p><p num="0500"><u style="single">Example 28: 4- (1- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) propan-2-yl) morpholine</u></p><p num="0501"><chemistry num="189"><img id="000191" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0502">¹H NMR (DMSO-d₆, 400MHz) δ8.47 (d, 1H, J = 4.8Hz), 8.41 (d, 1H, J = 4.8Hz), 8.24 (d, 1H, J = 8.4Hz), 7.36 (d, 1H, J = 2.4) Hz), 6.99 (dd, 1H, J = 8.8, 2.0Hz), 4.64 (dd, 1H, J = 15.6, 8.4Hz), 4.36 (dd, 1H, J = 15.6, 6.4Hz), 3.93 (s, 3H) ), 3.15 (m, 4H), 2.94 (s, 1H), 2.58 (m, 2H), 2.05 (m, 2H), 0.78 (d, 3H, J = 6.8Hz); LCMSm / z394.17 ([M) + H]⁺, C₂₀H₂₃F₃N₃O₂Request value 394.17).</p><p num="0503"><u style="single">Example 29: 4- (2- (7-Methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) -3-methylmorpholine</u></p><p num="0504"><chemistry num="190"><img id="000192" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0505">¹1 H NMR (CDCl_3,400MHz) δ8.45 (d, 1H, J = 4.8Hz), 8.05 (d, 1H, J = 4.8Hz), 8.02 (d, 1H, J = 8.4Hz), 7.00 (d, 1H, J = 2.0Hz) ), 6.97 (dd, 1H, J = 8.4, 2.0Hz), 4.64 (m, 1H), 4.49 (m, 1H) 3.96 (s, 3H), 3.83 (m, 1H), 3.68 (m, 2H), 3.23 (m, 1H), 3.12 (m, 1H), 2.90 (m, 1H), 2.51 (m, 3H), 0.95 (d, 3H, J = 6.4Hz).</p><p num="0506"><u style="single">Example 30: 9- (2- (3-methylmorpholino) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol</u></p><p num="0507"><chemistry num="191"><img id="000193" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0508">¹1 H NMR (CDCl_3,400MHz) δ8.45 (d, 1H, J = 4.8Hz), 8.02 (d, 1H, J = 4.8Hz), 7.97 (d, 1H, J = 8.4Hz), 7.06 (d, 1H, J = 2.0Hz) ), 6.91 (dd, 1H, J = 8.4, 2.0Hz), 4.59 (m, 1H), 4.53 (m, 1H), 3.82 (m, 1H), 3.69 (m, 2H), 3.29 (m, 1H) , 3.14 (m, 1H), 2.94 (m, 1H), 2.56 (m, 3H), 0.95 (d, 3H, J = 6.4Hz).</p><p num="0509"><u style="single">Example 31: 9- (2- (2,6-dimethylmorpholino) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol</u></p><p num="0510"><chemistry num="192"><img id="000194" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0511"> From 7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole to 4- (2- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] b] Indole-9-yl) ethyl) -2,6-dimethylmorpholine was synthesized using the procedure in Example 3.¹1 H NMR (CDCl_3,400MHz) δ8.43 (d, 1H, J = 4.8Hz), 8.00 (m, 2H), 7.02 (d, 1H, J = 2.0Hz), 6.95 (dd, 1H, J = 8.4, 2.0Hz), 4.59 (t, 2H, J = 7.6Hz), 3.96 (s, 3H), 3.70 (m, 2H), 2.77 (m, 4H), 2.52 (m, 2H), 1.17 (d, 6H, J = 6.4Hz) ..</p><p num="0512"> From 4- (2- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) -2,6-dimethylmorpholino, 9- (2- (2- (2,6-dimethylmorpholino) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol was synthesized using demethylation in Example 23.¹1 H NMR (CDCl_3,400MHz) δ8.47 (d, 1H, J = 4.8Hz), 8.01 (d, 1H, J = 5.2Hz), 7.96 (d, 1H, J = 8.4Hz), 7.49 (s, 1H), 6.94 (d , 1H, J = 8.4Hz), 4.98 (m, 2H), 4.16 (m, 2H), 3.30 (m, 2H), 3.15 (m, 2H), 2.35 (m, 2H), 1.25 (s, 6H) ..</p><p num="0513"><u style="single">Example 32: 9- (2- (3,3-dimethylmorpholino) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-7-ol</u></p><p num="0514"><chemistry num="193"><img id="000195" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0515">¹1 H NMR (CDCl_3,400MHz) δ8.29 (d, 1H, J = 5.2Hz), 7.92 (d, 1H, J = 8.4Hz), 7.78 (d, 1H, J = 5.2Hz), 6.93 (d, 1H, J = 2.0Hz) ), 6.91 (dd, 1H, J = 8.4, 2.0Hz), 4.46 (t, 2H, J = 7.2Hz), 3.60 (t, 2H, J = 4.8Hz), 3.20 (s, 2H), 2.71 (t) , 2H, J = 7.2Hz), 2.55 (t, 2H, J = 4.8Hz), 0.69 (s, 1H).</p><p num="0516"><u style="single">Example 33: 7-Methoxy-9- (2- (piperidin-1-yl) ethyl) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole</u></p><p num="0517"><chemistry num="194"><img id="000196" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0518">¹H NMR (DMSO-d₆, 400MHz) δ8.45 (d, 1H, J = 5.2Hz), 8.41 (d, 1H, J = 4.8Hz), 8.25 (d, 1H, J = 8.8Hz), 7.25 (d, 1H, J = 2.0) Hz), 7.01 (dd, 1H, J = 8.8, 2.0Hz), 4.58 (t, 2H, J = 7.6Hz), 3.96 (s, 3H), 2.54 (m, 2H), 2.42 (m, 4H), 1.46 (m, 4H), 1.37 (m, 2H).</p><p num="0519"><u style="single">Example 34: 2-((2- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) amino) ethanol</u></p><p num="0520"><chemistry num="195"><img id="000197" he="51" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0521">¹1 H NMR (CDCl_3,400MHz) δ8.45 (d, 1H, J = 5.2Hz), 8.05 (d, 1H, J = 5.2Hz), 8.02 (d, 1H, J = 8.4Hz), 7.03 (d, 1H, J = 2.4Hz) ), 6.97 (dd, 1H, J = 8.8, 2.2Hz), 4.60 (d, 2H, J = 7.2Hz), 4.00 (s, 3H), 3.65 (t, 2H, J = 5.2Hz), 3.06 (t) , 2H, J = 7.6Hz), 2.84 (t, 2H, J = 5.2Hz).</p><p num="0522"> Derivatives of Example 34 of Formula I or II are obtained through Example 22 using the procedures described in Example 18 and Scheme 1. The demethylation procedure described in Example 4 is used to provide additional phenol derivatives.</p><p num="0523"><u style="single">Example 35: 2,2'-((2- (7-methoxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) azandiyl) diethanol</u></p><p num="0524"><chemistry num="196"><img id="000198" he="54" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0525">¹1 H NMR (CDCl_3,400MHz) δ8.46 (d, 1H, J = 5.2Hz), 8.05 (m, 2H), 7.06 (d, 1H, J = 2.4Hz), 6.97 (dd, 1H, J = 8.8, 2.4Hz), 4.63 (d, 2H, J = 8.0Hz), 3.97 (s, 3H), 3.69 (t, 4H, J = 5.2Hz), 2.98 (t, 2H, J = 8.0Hz), 2.84 (t, 4H, J = 5.6Hz).</p><p num="0526"><u style="single">Example 36: 2,2'-((2- (7-Hydroxy-1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) azandiyl) diethanol</u></p><p num="0527"><chemistry num="197"><img id="000199" he="58" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0528">¹H NMR (DMSO-d₆, 400MHz) δ10.30 (s1H), 9.75 (s, 1H), 8.93 (s, 1H), 8.45 (d, 1H, J = 4.8Hz), 8.38 (d, 1H, J = 4.8Hz), 8.20 ( d, 1H, J = 8.4Hz), 7.25 (d, 1H, J = 2.4Hz), 6.94 (dd, 1H, J = 8.4, 2.0Hz), 4.82 (t, 2H, J = 8.4Hz), 3.82 ( t, 4H, J = 5.6Hz), 3.44 (m, 4H), 3.10-2.90 (m, 2H).</p><p num="0529"><u style="single">Example 37: Synthesis of 7-methoxy-4-methyl-5H-pyrido [3,2-b] indole</u></p><p num="0530"><chemistry num="198"><img id="000200" he="35" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0531"> 3-Bromo-4-methylpyridine (Matrix Catalog No. 011246, 0.266g, 1.547 mmol), 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl-1,1'-biphenyl (0.055 g, 0.116 mmol), cesium carbonate (0.605 g, 1.856 mmol) and palladium (II) acetate (0.017 g, 0.077 mmol) were added to the microwave vial. Then 3-methoxyaniline (Aldrich Catalog No. A88204-100G, 0.2 g, 1.624 mmol) was added. The solvent was degassed twice with argon. The reaction was heated to 100 ° C. for 15 hours on a heating block. The crude reaction mixture was cooled to room temperature and then filtered through Celite. Celite was repeatedly rinsed with ethyl acetate to recover the crude product mixture. A positive phase ethyl acetate / hexane column was applied to the crude mixture to provide N- (3-methoxyphenyl) -4-methylpyridine-3-amine (0.246 g, 74% yield).¹1 H NMR (CDCl_3,400MHz) δ8.49 (s, 1H), 8.19 (d, 1H, J = 4.8Hz), 7.18-7.11 (m, 2H), 6.50-6.42 (m, 3H), 5.34 (s, 1H), 3.76 ( s, 1H), 2.25 (s, 1H).</p><p num="0532"> N- (3-Methoxyphenyl) -4-methylpyridine-3-amine (0.245 g, 1.143 mmol) dissolved in trifluoroacetic acid (20 mL) in a round bottom flask equipped with a stirring rod and reflux condenser. did. Then palladium (II) acetate (0.19 g, 0.846 mmol) was added slowly in small increments. The reaction mixture was refluxed for 3 hours. The crude mixture is concentrated in vacuo and then purified by reverse phase chromatography (water (pH = 9.5), acetonitrile) with 7-methoxy-4-methyl-5H-pyrido [3,2-b] indol (0.193). g, 80% yield) was provided.¹H NMR (DMSO-d₆, 400MHz) δ11.31 (s, 1H), 8.25 (d, 1H, J = 4.8Hz), 8.01 (d, 1H, J = 8.8Hz), 7.12 (dd, 1H, J = 0.8, 4.8Hz), 7.00 (d, 1H, J = 2.0Hz), 6.85 (dd, 1H, J = 2.4, 8.6Hz), 3.88 (s, 3H), 2.56 (s, 3H). LCMSm / z213.10 ([M + H]⁺, C₁₃H₁₃N₂O Request value 213.10).</p><p num="0533"> The compound of Example 37 can be converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0534"><u style="single">Example 38: Synthesis of 3-fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indole</u></p><p num="0535"><chemistry num="199"><img id="000201" he="39" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0536"> 3-Bromo-6-fluoro-2-methylpyridine (Matrix Catalog No. 024607, 0.230g, 1.209 mmol), 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl-1, 1'-biphenyl (0.043 g, 0.091 mmol), cesium carbonate (0.473 g, 1.450 mmol) and palladium (II) acetate (0.014 g, 0.060 mmol) were added to the microwave vial. Then 2-chloro-5-methoxyaniline (0.2 g, 1.269 mmol) was added. The solvent was degassed twice with argon. The reaction was heated to 100 ° C. for 15 hours on a heating block. The crude reaction mixture was cooled to room temperature and then filtered through Celite. Celite was repeatedly rinsed with ethyl acetate to provide a crude product mixture. A reverse phase column was applied (water, acetonitrile) to provide N- (2-chloro-5-methoxyphenyl) -6-fluoro-2-methylpyridine-3-amine (0.246 g, 76% yield).¹1 H NMR (CDCl_3,400MHz) δ7.65 (t, 1H, J = 8.4Hz), 7.24 (s, 1H), 6.79 (dd, 1H, J = 3.6, 8.4Hz), 6.35 (dd, 1H, J = 2.8, 8.8Hz) , 6.15 (d, 1H, J = 2.8Hz), 5.71 (s, 1H), 3.69 (s, 3H), 2.44 (s, 3H).</p><p num="0537"> N- (2-Chloro-5-methoxyphenyl) -6-fluoro-2-methylpyridine-3-amine (0.217 g, 0.812 mmol), N, N-dimethylacetamide (5 ml), tri-t-butylphosphonium tetra Fluoroborate (0.118 g, 0.406 mmol), potassium carbonate (0.224 g, 1.624 mmol) and palladium (II) acetate (0.036 mg, 0.162 mmol) were added to the microwave sample vessel. The solvent was degassed twice with argon. The microwave vial was heated in a microwave device at 150 ° C. for 3 hours. The crude reaction mixture was filtered through Celite. Celite was washed repeatedly with ethyl acetate. The combined organic fractions were washed twice with water, dried over sodium sulfate and then concentrated in vacuo. Positive phase chromatography (methanol / DCM) followed by reverse phase chromatography (water / acetonitrile), 3-fluoro-7-methoxy-1-methyl-9H-pyrido [3,4-b] indol ( 0.11 g, 58% yield) was provided.¹H NMR (DMSO-d₆, 400MHz) δ11.45 (s, 1H), 8.07 (d, 1H, J = 8.8Hz), 7.51 (d, 1H, J = 2.0Hz), 6.98 (d, 1H, J = 2.4Hz), 6.84 ( dd, 1H, J = 2.4, 8.4Hz), 3.88 (s, 3H), 2.67 (s, 3H) .LCMSm / z231.09 ([M + H]⁺, C₁₃H₁₂FN₂O Request value 231.09).</p><p num="0538"> The compound of Example 38 is then converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0539"><u style="single">Example 39: 3-Fluoro-7-Methoxy-1-methyl-9-(2- (piperidin-1-yl) ethyl) -9H-pyrido [3,4-b] indole</u></p><p num="0540"><chemistry num="200"><img id="000202" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0541">¹H NMR (DMSO-d₆, 400MHz) δδ8.10 (d, 1H, J = 8.6Hz), 7.59 (d, 1H, J = 2.6Hz), 7.13 (d, 1H, J = 2.2Hz), 6.86 (dd, 1H, J = 8.7) , 2.2Hz), 4.61 (t, 2H, J = 7.1Hz), 3.92 (s, 3H), 2.90 (s, 3H), 2.60 (t, 2H, J = 7.0Hz), 2.43-2.32 (m, 4H) ), 1.42 (m, 4H), 1.34 (m, 2H).</p><p num="0542"><u style="single">Example 40: Synthesis of 3,7-dimethoxy-1-methyl-9H-pyrido [3,4-b] indole</u></p><p num="0543"><chemistry num="201"><img id="000203" he="39" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0544"> 3-Bromo-6-methoxy-2-methylpyridine (Aldrich Catalog No. 758911-1G, 0.3g, 1.485 mmol), 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl- 1,1'-biphenyl (0.053 g, 0.111 mmol), cesium carbonate (0.581 g, 1.782 mmol) and palladium (II) acetate (0.017 g, 0.074 mmol) were added to the microwave vial. Then 2-chloro-5-methoxyaniline (Chemimpex Catalog No. 27675, 0.246 g, 1.559 mmol) was added. The solvent was degassed twice with argon. The reaction was heated to 100 ° C. for 15 hours on a heating block. The crude reaction mixture was cooled to room temperature and then filtered through Celite. Celite was repeatedly rinsed with ethyl acetate to recover the crude product mixture. A reverse phase column was applied (water, acetonitrile) to provide N- (2-chloro-5-methoxyphenyl) -6-methoxy-2-methylpyridine-3-amine (0.286 g, 69% yield).¹1 H NMR (CDCl_3,400MHz) δ7.42 (d, 1H, J = 8.4Hz), 7.20 (d, 1H, J = 8.4Hz), 6.60 (d, 1H, J = 8.4Hz), 6.26 (dd, 1H, J = 2.8, 8.8Hz), 6.00 (d, 1H, J = 2.8Hz), 5.65 (s, 1H), 3.93 (s, 3H), 3.66 (s, 3H), 2.37 (s, 3H).</p><p num="0545"> N- (2-Chloro-5-methoxyphenyl) -6-methoxy-2-methylpyridine-3-amine (0.1697 g, .609 mmol), N, N-dimethylacetamide (5 mL), tri-t-butylphosphonium tetra Fluoroborate (0.035 g, 0.122 mmol), potassium carbonate (0.168 g, 1.218 mmol) and palladium (II) acetate (14 mg, 0.061 mmol) were added to the microwave sample vessel. The solvent was degassed twice with argon. The microwave vial was heated in a microwave device at 150 ° C. for 3 hours. The crude reaction mixture was filtered through Celite. Celite was washed repeatedly with ethyl acetate. The combined organic fractions were washed twice with water, dried over sodium sulphate, and concentrated in a vacuum. Positive phase chromatography (methanol / DCM) followed by reverse phase chromatography (water / acetonitrile), 3,7-dimethoxy-1-methyl-9H-pyrido [3,4-b] indole (0.115g) , 78% yield).¹H NMR (DMSO-d₆, 400MHz) δ11.03 (s, 1H), 7.99 (d, 1H, J = 8.8Hz), 7.18 (s, 1H), 6.92 (d, 1H, J = 2.0Hz), 6.76 (dd, 1H, J = 2.4, 8.4Hz), 3.87 (s, 3H), 3.86 (s, 3H), 2.65 (s, 3H). LCMSm / z243.11 ([M + H]⁺, C₁₄H₁₅N₂O₂Request value 243.11).</p><p num="0546"> The compound of Example 40 can be converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0547"><u style="single">Example 41: Synthesis of 7-methoxy-4-methyl-5H-pyrido [4,3-b] indole</u></p><p num="0548"><chemistry num="202"><img id="000204" he="35" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0549"> 4-Bromo-3-methylpyridine (Astatech Catalog No. 56516, 0.3 g, 1.744 mmol), 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl-1,1'-biphenyl (0.062 g, 0.131 mmol), cesium carbonate (0.682 g, 2.093 mmol), toluene anhydrous (5 mL) and palladium (II) acetate (0.020 g, 0.087 mmol) were added to the microwave vial. Then 2-chloro-5-methoxyaniline (0.289 g, 1.831 mmol) was added. The vial was purged with argon twice. The reaction was heated to 100 ° C. for 16 hours. The crude reaction mixture was filtered through Celite. Celite was repeatedly rinsed with ethyl acetate to recover the crude product mixture. A positive phase column was applied (ethyl acetate / hexane) to provide N- (2-chloro-5-methoxyphenyl) -6-methoxy-2-methylpyridine-3-amine (0.41 g, 95% yield).</p><p num="0550"> N- (2-Chloro-5-methoxyphenyl) -3-methylpyridine-4-amine (.1572g, .632 mmol), N, N-dimethylacetamide (5ml, Aldrich, 271012-100ML), tri-t-butyl Phenyltetrafluoroborate (.037 g, .126 mmol), potassium carbonate (.175 g, 1.264 mmol) and palladium (II) acetate (II) (14 mg, .063 mmol, Aldrich, 520764-1G) were added to the microwave sample vessel. The solvent was degassed twice with argon. The microwave vial was heated in a microwave device at 150 ° C. for 3 hours. The crude reaction mixture was filtered through Celite. Celite was washed repeatedly with ethyl acetate. The combined organic fractions were washed twice with water and twice with brine, dried over sodium sulphate and concentrated in vacuo. Positive phase chromatography (methanol / DCM) followed by reverse phase chromatography (water / acetonitrile) 7-methoxy-4-methyl-5H-pyrido [4,3-b] indol (.089g, 67) % Yield) was provided.¹H NMR (DMSO-d₆, 400MHz) δ11.56 (s, 1H), 9.05 (s, 1H), 8.17 (s, 1H), 8.05 (d, 1H, J = 8.4Hz), 7.02 (d, 1H, J = 2.4Hz), 6.86 (dd, 1H, J = 2.4, 8.4Hz), 3.85 (s, 3H), 2.50 (s, 3H). LCMSm / z213.10 ([M + H]⁺, C₁₃H₁₃N₂O Request value 213.10).</p><p num="0551"> The compound of Example 41 can be converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0552"><u style="single">Example 42: 7-Cyclopropoxy-1-methyl-9H-pyrido [3,4-b] indole</u></p><p num="0553"><chemistry num="203"><img id="000205" he="39" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0554"> 1-Methyl-9H-pyrido [3,4-b] indole-7-ol (.2 g, 1.009 mmol) was dissolved in DMF. Then cesium carbonate (0.329 g, 1.009 mmol) and sodium hydride (0.089 g, 2.220 mmol) were added slowly. Bromocyclopropane (0.122 g, 1.009 mmol) was added to the reaction mixture. The reaction was heated to 80 ° C until the starting material was no longer detected by the UPLC. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed 3 times with water, 1 time with brine, dried over sodium sulphate and then concentrated in vacuo. The crude residue was purified by positive phase chromatography (ethyl acetate / hexane) and then by reverse phase chromatography to 7-cyclopropoxy-1-methyl-9H-pyrido [3,4-b] indole (. 067 g, 0.281 mmol, 27.9% yield).¹H NMR (DMSO-d₆, 400MHz) δ10.91 (s, 1H), 8.65 (d, 1H, J = 5.2Hz), 8.48 (d, 1H, J = 8.8Hz), 8.22 (d, 1H, J = 5.2Hz), 7.73 ( d, 1H, J = 2.0Hz), 7.36 (dd, 1H, J = 8.8, 2.4Hz), 4.34 (m, 1H), 3.19 (s, 3H), 1.29 (m, 2H), 1.18 (m, 2H) ).</p><p num="0555"> The compound of Example 42 can be converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0556"><u style="single">Example 43: 7- (1,1-difluoroethoxy) -1-methyl-9H-pyrido [3,4-b] indole</u></p><p num="0557"><chemistry num="204"><img id="000206" he="35" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0558"> In a reaction flask, 1-methyl-9H-pyrido [3,4-b] indole-7-ol (.24 g, 1.211 mmol), stir bar, acetonitrile (7.5 mL), water (0.5 mL) and potassium hydroxide (. 0.075 g, 1.332 mmol) was added. The reaction mixture was stirred for 2 minutes and 2-bromo-1,1-difluoroethylene (0.095 ml, 1.211 mmol) in acetonitrile was added. The reaction mixture was heated to 65 ° C for up to 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite and then concentrated in vacuo. The crude residue was purified by positive phase chromatography (ethyl acetate / hexane) and 7- (2-bromo-1,1-difluoroethoxy) -1-methyl-9H-pyrido [3,4-b] indole ( .331 g, 0.970 mmol, 80% yield) was provided.</p><p num="0559"> A par bottle is loaded with 7- (2-bromo-1,1-difluoroethoxy) -1-methyl-9H-pyrido [3,4-b] indole (.331 g, 0.970 mmol) and ethanol (10 mL) in 2 mL. 10% palladium (on activated carbon) (0.103 g, 0.970 mmol) was added as a slurry in ethanol. The reaction was hydrogenated at 45 psi for 20 hours. Upon completion detected by UPLC, the mixture was filtered and concentrated in vacuo. The crude residue was purified by positive phase chromatography (ethyl acetate / hexane) and then by reverse phase chromatography to 7- (1,1-difluoroethoxy) -1-methyl-9H-pyrido [3,4-b]. ] Indole (.216 g, 0.824 mmol, 85% yield) was provided.</p><p num="0560">¹HNMR (DMSO-d₆, 400MHz) δ8.22 (m, 2H), 7.92 (d, 1H, J = 5.2Hz), 7.38 (s, 1H), 7.06 (dd, 1H, J = 8.4, 2.0Hz), 2.76 (s, 3H) ), 2.01 (t, 3H, J = 14Hz).</p><p num="0561"> The compound of Example 43 can be converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0562"><u style="single">Example 44: 7-Chloro-1-methyl-9H-pyrido [3,4-b] indole</u></p><p num="0563"><chemistry num="205"><img id="000207" he="32" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0564"> 1-Methyl-9H-pyrido [3,4-b] indole-7-ol (.122 g, 0.615 mmol) was dissolved in pyridine (0.487 g, 6.15 mmol) in a round bottom flask equipped with a stirring rod. .. The reaction mixture was cooled to 0 ° C. Then, trifluoromethanesulfonic anhydride (0.114 ml, 0.677 mmol) was added dropwise. The reaction was slowly warmed to room temperature and stirred overnight. Water was added to the reaction mixture and then extracted with ethyl acetate. The organic phase was washed 3 times with water and 2 times with copper sulphate solution with brine, dried over sodium sulphate and then concentrated in vacuo. The crude residue was purified by positive phase chromatography (ethyl acetate / hexane) and 1-methyl-9H-pyrido [3,4-b] indole-7-yltrifluoromethanesulfonate (.103 g, 0.312 mmol, 50.7% yield). Rate) provided.</p><p num="0565"> Potassium chloride (0.035 g, 0.472 mmol)), potassium fluoride (6.86 mg, 0.118 mmol) and 1-methyl-9H-pyrido [3,4-b] indol-in a screw cap test tube equipped with a magnetic stir bar. 7-Iltrifluoromethanesulfonate (.078 g, 0.236 mmol)) was added. The tubes were sealed with Teflon-lined septum, evacuated, and backfilled with argon (this process was repeated a total of 3 times).</p><p num="0566"> Tris (dibenzylideneacetone) dipalladium (0) (3.24 mg, 3.54 μmol) and 2- (di-tert-butylphosphino) -2', 4'in another screw cap test tube equipped with a magnetic stir bar. , 6'-Triisopropyl-3,6-dimethoxy-1,1'-biphenyl (5.15 mg, 10.63 μmol) was added. Sealed with tube Teflon-lined septum, evacuated, and backfilled with argon (this process was repeated a total of 3 times). 1,4-Dioxane (1 mL) was added via syringe and the mixture was heated at 120 ° C. in a preheated oil bath for 3 minutes. After cooling the catalytic solution to room temperature, it was added via syringe to a reaction tube containing KCl, KF and ArOTf, followed by dioxane (3 mL). The resulting mixture was vigorously stirred in a preheated oil bath at 130 ° C. for 16 hours, then cooled to room temperature, filtered through a silica gel pad (eluted with EtOAc) and concentrated under reduced pressure. The crude material was purified by positive phase chromatography (ethyl acetate / hexane) to provide 7-chloro-1-methyl-9H-pyrido [3,4-b] indole (.035 g, 0.162 mmol, 68.4% yield). did.¹H NMR (DMSO-d₆, 400MHz) δ11.72 (s, 1H), 8.23 (d, 1H, J = 1.2Hz), 8.21 (d, 1H, J = 1.6Hz), 7.93 (d, 1H, J = 5.6Hz), 7.59 ( d, 1H, J = 2.0Hz), 7.24 (dd, 1H, J = 8.4, 2.0Hz), 2.75 (s, 3H); LCMSm / z217.05 ([M + H]⁺, C₁₂H₁₀ClN₂Required value 217.05).</p><p num="0567"> The compound of Example 44 can be converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0568"><u style="single">Example 45: 7- (difluoromethoxy) -1-methyl-9H-pyrido [3,4-b] indole</u></p><p num="0569"><chemistry num="206"><img id="000208" he="35" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0570"> In a solution of 1-methyl-9H-pyrido [3,4-b] indole-7-ol (.1 g, 0.504 mmol) and potassium hydroxide (0.283 g, 5.04 mmol), acetonitrile (2 mL) and water (2 mL) , Bromodifluoromethyldiethylphosphonate (0.099 ml, 0.555 mmol) was added at -15 ° C. After 30 minutes, the mixture is warmed to room temperature, stirred for an additional 30 minutes, then treated with 1 M aqueous HCl, and Et.₂Extracted with O. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The crude residue was purified by positive phase chromatography (ethyl acetate / hexane) and 7- (difluoromethoxy) -1-methyl-9H-pyrido [3,4-b] indole (.075 g, 0.302 mmol, 59.9% yield). Rate) provided.¹H NMR (DMSO-d₆, 400MHz) δ11.70 (s, 1H), 8.24 (d, 1H, J = 8.4Hz), 8.20 (d, 1H, J = 5.2Hz), 7.91 (d, 1H, J = 5.2Hz), 7.35 ( t, 1H, J = 74Hz, F-splitting), 7.30 (d, 1H, J = 2.0Hz), 7.05 (dd, 1H, J = 8.4, 2.0Hz), 2.71 (s, 3H); LCMSm / z249. 08 ([M + H]⁺, C₁₃H₁₁F₂N₂O Request value 249.08).</p><p num="0571"> The compound of Example 45 can be converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0572"><u style="single">Example 46: 7- (cyclopropylmethoxy) -1-methyl-9H-pyrido [3,4-b] indole</u></p><p num="0573"><chemistry num="207"><img id="000209" he="35" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0574"> 1-Methyl-9H-pyrido [3,4-b] indole-7-ol (.1 g, 0.504 mmol) was dissolved in DMF (3 mL) and then added to a 10 mL round bottom flask equipped with a stir bar. .. Sodium hydride (0.020 g, 0.504 mmol) was added slowly and the reaction mixture was stirred at room temperature for 30 minutes. Then (bromomethyl) cyclopropane (0.047 ml, 0.504 mmol) was added slowly. The reaction was heated to 80 ° C until completion. The reaction was quenched with water and then extracted with ethyl acetate. The organic phase was washed 3 times with water, 1 time with brine, dried over sodium sulphate and then concentrated in vacuo. The crude residue was purified by positive phase chromatography (ethyl acetate / hexane) and then by reverse phase chromatography to give 7- (cyclopropylmethoxy) -1-methyl-9H-pyrido [3,4-b] indol. Provided.¹H NMR (DMSO-d₆, 400MHz) δ11.37 (s, 1H), 8.13 (d, 1H, J = 5.6Hz), 8.03 (d, 1H, J = 8.8Hz), 7.78 (d, 1H, J = 5.2Hz), 6.96 ( d, 1H, J = 2.0Hz), 6.83 (dd, 1H, J = 8.8, 2.0Hz), 3.93 (d, 2H, J = 7.2Hz), 2.71 (s, 3H), 1.27 (m, 1H), 0.60 (m, 2H), 0.38 (m, 2H).</p><p num="0575"> The compound of Example 46 can be converted to a compound of formula I or II using the procedures described in Example 3 and Scheme 1.</p><p num="0576"><u style="single">Example 47: 4- (2- (7- (cyclopropylmethoxy) -1- (trifluoromethyl) -9H-pyrido [3,4-b] indole-9-yl) ethyl) morpholine</u></p><p num="0577"><chemistry num="208"><img id="000210" he="55" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry></p><p num="0578">¹H NMR (DMSO-d₆, 400MHz) δ8.44 (d, 2H, J = 5.4Hz), 8.40 (d, 2H, J = 4.8Hz), 8.23 (d, 1H, J = 5.4Hz), 7.24 (d, 1H, J = 2.0) Hz), 7.00 (dd, 1H, J = 8.4, 2.0Hz), 4.58 (t, 2H, J = 7.2Hz), 4.01 (d, 2H, J = 6.8Hz), 3.53 (d, 4H, J = 4.4) Hz), 2.59 (d, 2H, J = 7.2Hz), 2.44 (m, 4H), 1.33-1.28 (m, 1H), 0.65-0.60 (m, 2H), 0.41-0.37 (m, 2H).</p><p num="0579"><u style="single">Example 48: Denaturation of screostin / Wnt activity</u> Compounds synthesized by the methods of Examples 1-46 were evaluated for their ability to restore Wnt signaling in the presence of screostin, which is consistent with the known screostin antagonist screostin Mab. See Ellies et al., J Bone Miner Res 21: 1738-1749 (2006). As shown in Table 1 below, screostin antagonized Wnt3a signaling in human germ cells. Addition of a known screostin antagonist inhibited the screostin inhibition of Wnt3a signaling and thus restored intracellular Wnt3a signaling (IC100 at 10 μM) (data not shown). The compounds of Examples 1-46 also inhibited the inhibition of Wnt3a signaling and restored Wnt3a signaling in cells.</p><p num="0580"><u style="single">Example 49: Bone formation assay</u> Calcification (crystalline calcium phosphate production) represents an in vivo model of bone formation. Sculeostin inhibits calcification in MC3T3-E1 (mouse calvaria) osteoblasts using an assay that quantifies the amount of calcification by measuring the total calcium after solubilization of deposited crystalline calcium phosphate. It was previously shown to do. Li et al., J Bone Miner Res 24: 578-588 (2008). Compounds were evaluated for their ability to restore inhibition of screostine calcification in MC3T3 osteoblasts according to the protocol described by Li et al. Treatment with screostin alone resulted in a significant reduction in calcification as measured by calcium concentration (Table 1 and data not shown). Addition of the compounds of Examples 1-46 neutralized the sculeostin-mediated inhibition of calcification as reflected by the increased calcium concentration.</p><p num="0581"> Bone formation can also be assessed in vitro or in vivo using osteocalcin (OCN) available from Biomedical Tecnhnologies, Inc. (Stoughton, MA), a serum marker for bone formation. Bone formation in MC3T3 osteoblasts was assessed by measuring OCN concentrations according to the manufacturer's protocol for the mouse osteocalcin EIA kit (listed on the website www.btiinc.com/page/cata2.html#mouse_osteocalcin). Secreted from cells treated with screostin alone or in combination with compounds of Examples 1-46 using an ELISA assay and then a spectrophotometer optical density (OD) reading to measure the concentration of OCN. OCN level detected. Treatment of cells with screostin inhibited OCN expression and resulted in a near complete loss of OCN secretion (Table 1 and data not shown). In contrast, treatment with screostin and the compounds of Examples 1-46 was shown to neutralize the inhibitory effect of screostin on OCN secretion and thus form bone.</p><p num="0582"><tables num="1"><img id="000211" he="229" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0583"><u style="single">Example 50: hERG assay</u> One major type of drug-related cardiovascular toxicity results from drug effects on cardiac ion channels such as hERG. Drug-induced inhibition of hERG results in long-term QT intervals, which can lead to life-threatening ventricular arrhythmias. Therefore, the inhibitory effect of the compounds described in Examples 1-46 on the hERG potassium channel is automated as described in Mathes, C. (2006)-Expert Opin.Ther.Targets, 10 (2): 319-327. It was evaluated using a patch clamp assay. CHO-K1 cells that stably express hERG channels were used. As shown in Table 2 below, cells were incubated with the compounds of Examples 1-46 at a concentration of 1 μM for 5 minutes at room temperature, after which inhibition of hERG tail current was measured. Table 2 shows that many of the compounds tested have less than 50% inhibition of hERG.<tables num="2"><img id="000212" he="144" wi="167" file="JP2016519082A_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0584"> Although the above inventions have been described in some detail by way of example and examples for the purpose of clarifying understanding, one of ordinary skill in the art understands that certain modifications and modifications can be made within the scope of the appended claims. Will do. Moreover, each document provided herein is incorporated by reference in its entirety as if each document were incorporated by reference.</p>