HETEROCYCLIC COMPOUNDS FOUND AS SELECTIVE BMP INHIBITORS

专利摘要:
the present invention relates to small molecule inhibitors of bmp signaling which are useful for the treatment of diseases or conditions associated with bmp signaling, including cancers of the central nervous system.
公开号:BR112019014759A2
申请号:R112019014759-4
申请日:2018-01-18
公开日:2020-03-03
发明作者:R. Hopkins Corey；C. Hong Charles；W. Lindsley Craig；W Engers Darren
申请人:Vanderbilt University；
IPC主号:

专利说明:

“HETEROCYCLIC COMPOUNDS FOUND AS SELECTIVE BMP INHIBITORS”
FIELD OF TECHNIQUE [001] This application claims priority benefit for U.S. provisional patent application No. 62 / 447,830, filed on January 18, 2017, which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION [002] Signaling involving the Growth Transforming Factor (TGF-β) superfamily is central to a wide range of cell processes, including cell growth, differentiation and apoptosis. TGF- β signaling involves the binding of a TGF-β ligand to a type II receptor (a serine / threonine kinase), which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates a SMAD regulated by receptor (R-SMAD; for example, SMAD1, SMAD2, SMAD3, SMAD5, SMAD8 or SMAD9), which binds to SMAD4, and the SMAD complex enters the nucleus where it plays a role in transcriptional regulation. The superfamily of TGF ligands includes two main branches, characterized by TGF-β / activin / nodal and Bone Morphogenetic Proteins (BMPs).
[003] Signs mediated by bone morphogenetic protein ligands (BMP) play several roles throughout the life of vertebrates. During embryogenesis, the dorsoventral axis is established by BMP signaling gradients formed by the coordinated expression of ligands, receptors, co-receptors and soluble antagonists. Excess BMP signaling causes ventralization, an expansion of ventral at the expense of back structures, while decreased BMP signaling causes dorsalization, an expansion of the back at the expense of ventral structures. BMPs are key regulators of gastrulation, mesoderm induction, organogenesis and endochondral bone formation, and regulate the fate of multipotent cell populations. BMP signals also play crucial roles
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2/76 in physiology and disease and are involved, for example, in primary pulmonary hypertension, in hereditary hemorrhagic telangiectasia syndrome, in progressive ossifying fibrodysplasia and in juvenile polyposis syndrome, among others.
[004] The BMP signaling family is a diverse subset of the TGF-β superfamily. More than twenty known BMP ligands are recognized by three distinct type II receptors (BMPRII, ActRIla and ActRIlb) and at least three type I receptors (ALK2, ALK3 and ALK6). Dimeric ligands facilitate the assembly of receptor heteromers, allowing constitutively active type II receptor serine / threonine kinases to phosphorylate type I receptor serine / threonine kinases. Activated type I receptors phosphorylate BMP-responsive SMAD effectors (BR-) (SMADs 1.5 and 8) to facilitate nuclear translocation in complex with SMAD4, a co-SMAD that also facilitates TGF signaling. In addition, BMP signals can activate intracellular effectors, such as MAPK p38, independently of SMAD. Soluble BMP antagonists, such as noggin, chordin, gremlin and follistatin, limit BMP signaling by ligand sequestration.
[005] A role for BMP signals in the regulation of the expression of hepcidin, a peptide hormone and central regulator of systemic iron balance, has also been suggested. Hepcidin binds and promotes the degradation of ferroportin, the only exporter of iron in vertebrates. The loss of ferroportin activity prevents the mobilization of iron into the bloodstream from intracellular reserves in enterocytes, macrophages and hepatocytes. The link between BMP signaling and iron metabolism represents a potential target for therapy.
[006] Given the tremendous structural diversity of the BMP and TGFβ superfamily at the level of ligands (> 25 distinct ligands at present) and receptors (three type I receptors and three type II receptors that recognize BMPs), and the heterotetrameric way of connection to the receiver, traditional approaches to inhibit
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BMP via soluble receptors, endogenous inhibitors or neutralizing antibodies are not practical or effective. Endogenous inhibitors, such as noggin and follistatin, have limited specificity for subclasses of ligands. Individual receptors have limited affinity for the ligand, whereas the heterotetramers of the ligands exhibit very precise specificity for particular ligands. Neutralizing antibodies are specific for specific ligands or receptors and are also limited by the structural diversity of this signaling system.
[007] Thus, there is a continuing need for pharmacological agents that antagonize BMP signaling pathways and that can be used to manipulate these pathways in therapeutic or experimental applications.
SUMMARY OF THE INVENTION [008] In one aspect, the invention relates to methods of treating or preventing a disease or condition comprising administering to a subject a compound or a pharmaceutically acceptable salt thereof having the structure represented by Formula I:
where A, D, E, M, G, W, X, Y and Z are defined here.
[009] In some embodiments, the disease is a cancer such as colorectal cancer, sporadic colorectal cancer, acute myeloid leukemia, chronic myeloid leukemia, non-small cell lung cancer (NSCLC), pancreatic cancer, ovarian cancer, cancer of serous ovary, epithelial ovarian cancer, melanoma, or squamous cell carcinoma of the head and neck (HNSCC). In other modalities, the disease is a cancer of the central nervous system such as glioma, astrocytic glioma, diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG),
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4/76 germ cell tumor, glioblastoma multiforme (GBM), oligodendroglioma, pituitary tumor, or ependymoma.
[010] In other modalities, the disease is anemia, iron-deficient anemia refractory to iron (IRIDA), heterotopic ossification, non-hereditary ossifying myositis, traumatic ossifying myositis, or circumscribed ossifying myositis.
[011] In certain embodiments, the compound is administered in a pharmaceutical composition with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION [012] The present invention can be more readily understood with reference to the following detailed description of the invention and the Examples included therein.
[013] Before the present compounds, compositions, articles, systems, devices and / or methods are described, it should be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise indicated. on the contrary, as such it can, of course, vary. It should also be understood that the terminology used here is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described.
[014] All publications mentioned here are hereby incorporated by reference to describe the methods and / or materials together with which the publications are cited. The publications discussed here are provided for your description only prior to the filing date of this application. Nothing here is to be construed as an admission that the present invention has no right to predate such publication by virtue of the previous invention. In addition, the publication dates provided here may differ from the actual publication dates, which
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5/76 need to be confirmed independently.
A. Definitions [015] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbilC (O) preferably alkyl C (O) -.
[016] The term "acylamino" is recognized in the art and refers to an amino group substituted by an acyl group and can be represented, for example, by the hydrocarbilC (0) NH- formula.
[017] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbilC (0) 0-, preferably C (O) O- alkyl.
[018] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached to it. Representative alkoxy groups include methoxy, -OCF3, ethoxy, propoxy, tert-butoxy and the like.
[019] The term "cycloalkyloxy" refers to a cycloalkyl group having an oxygen attached to it.
[020] The term "alkoxyalkyl" refers to an alkyl group substituted by an alkoxy group and can be represented by the general formula alkyl-O-alkyl.
[021] The term "alkylaminoalkyl" refers to an alkyl group substituted by an alkylamino group.
[022] The term "alkenyl", as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents can occur on one or more carbons that are included or not included in one or more double bonds. In addition, such substituents include all those considered for alkyl groups, as discussed below, except when stability is prohibitive. For example, replacing alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl or
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6/76 heteroaryl is considered.
[023] An "alkyl" or "alkane" group is a straight or branched chain non-aromatic hydrocarbon that is completely saturated. Typically, a straight or branched chain alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10, unless otherwise defined. Examples of straight and branched chain alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A straight or branched chain C 1 -C alkyl group is also called a "lower alkyl" group.
[024] In addition, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to to alkyl moieties with substituents replacing a hydrogen in one or more carbons of the hydrocarbon structure. Such substituents, if not otherwise specified, may include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl or an acyl), a thiocarbonyl (such as a thioester, a thioacetate , or a thiophormate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, a starch, an amidine, an imine, a cyan, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate , a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the substituted portions in the hydrocarbon chain can themselves be replaced, if appropriate. For example, substituents on a substituted alkyl may include substituted and unsubstituted forms of amino groups, azido, imino, starch, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate) and silyl, as well as such as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can
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7/76 still be substituted by alkyls, alkenyls, alkoxys, alkylthio, aminoalkyls, alkyls substituted with carbonyl, -CF3, -CN and the like.
[025] The term "Cx- _y ", when used in conjunction with a chemical moiety, such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is intended to include groups containing _{x and y} carbons in the chain. For example, the term "Cx- _y alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including single and branched chain alkyl groups that contain _{x and y} carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2, 2,2-trifluoroethyl, etc. Alkyl indicates a hydrogen where the group is at a terminal position, an internal bond. The terms "C2- _y alkenyl" and "C2- _y alkynyl" refer to unsaturated aliphatic groups substituted or unsubstituted in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.
[026] The term "alkylamino", as used herein, refers to an amino group substituted by at least one alkyl group.
[027] The term "alkylthio", as used herein, refers to a thiol group substituted by an alkyl group and can be represented by the general formula S- alkyl.
[028] The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents can occur on one or more carbons that are included or not included in one or more triple bonds. In addition, such substituents include all those considered for alkyl groups, as discussed above, except when stability is prohibitive. For example, substitution of alkynyl groups for one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups is considered.
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8/76 [029] The term “amide”, as used here, refers to a group o
II R ^{10 10} [030] where each R ¹⁰ independently represents a hydrogen or a hydrocarbyl group, or two R ¹⁰ are considered together with the N atom to which they are attached and complete a heterocycle having 4 to 8 atoms in ring structure.
[031] The terms "amine" and "amino" are recognized in the art and refer to both unsubstituted amines and substituted amines and their salts, for example, a portion that can be represented by
R ¹⁰ R / I / _in | - NN ⁺ —R ¹⁰ s10 s10 laugh OR where each R ¹⁰ independently represents a hydrogen or a hydrocarbyl group, or two R ¹⁰ are taken together with the N atom to which they are attached, and complete a heterocycle with 4 to 8 atoms in the ring structure.
[032] The term "aminoalkyl", as used herein, refers to an alkyl group substituted by an amino group.
[033] The term "aralkyl", as used herein, refers to an alkyl group substituted by an aryl group.
[034] The term "aryl", as used herein, includes substituted or unsubstituted single-ring aromatic groups in which each ring atom is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably, a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings in which at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalquinyls, aryls, heteroaryls
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9/76 and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline and the like.
[035] The term “carbamate” is recognized in the art and refers to a group oo p 10 Up 10 ^r _or
R ⁹ R where R ⁹ and R ¹⁰ independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R ⁹ and R ¹⁰ taken together with the intervening atom (s) complete a heterocycle with 4 to 8 atoms in the ring structure.
[036] The terms "carbocycle" and "carbocyclic", as used here, refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond. “Carbocycle” includes 5- to 7-membered monocyclic rings as well as 8 to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated and aromatic rings. Carbocycles include bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a molten carbocycle can be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, for example, phenyl, can be fused to a saturated or unsaturated ring, for example, cyclohexane, cyclopentane or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence allows, is included in the definition of carbocyclic. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo [2.2.1] heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo [4.2.0] oct-3-ene, naphthalene and adamantane. Molten carbocycles
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Exemplary 10/76 include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicycles [4,2,0] octane, 4,5,6,7-tetrahydro-1 H-indene and bicycles [ 4.1.0] hept-3-ene. "Carbocycles" can be replaced in any one or more positions capable of supporting a hydrogen atom.
[037] A “cycloalkyl” group is a completely saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically from 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from saturated, unsaturated and aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.
[038] The term "carbocyclylalkyl", as used herein, refers to an alkyl group substituted by a carbocycle group.
[039] The term "carbonate" is recognized in the art and refers to an OCO2-R ^{10 group} , where R ¹⁰ represents a hydrocarbyl group.
[040] The term "carboxy", as used herein, refers to a group represented by the formula CO2H.
[041] The term "ester", as used herein, refers to a -C (O) OR ^{10 group} where R ¹⁰ represents a hydrocarbyl group.
[042] The term "ether", as used herein, refers to a hydrocarbyl group attached via oxygen to another hydrocarbyl group. Therefore, an ether substituent on a hydrocarbyl group can be hydrocarbyl-O-. Ethers can
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11/76 be either symmetrical or asymmetric. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. The ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.
[043] The terms "halo" and "halogen", as used herein, mean halogen and include chlorine, fluorine, bromine and iodine.
[044] The terms "heteroalkyl" and "heteroaralkyl", as used herein, refer to an alkyl group substituted by a heteroaryl group.
[045] The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, in which there are not two adjacent heteroatoms.
[046] The term "heteroalkylamino", as used herein, refers to an amino group substituted by a heteroalkyl group.
[047] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic single ring structures, preferably 5 to 7 membered rings, more preferably 5 to 6 membered rings, whose ring structures include at least one heteroatom, preferably one to four hetero atoms, more preferably one or two hetero atoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings in which at least one of the rings is heteroaromatic, for example, the other cyclic rings they may be cycloalkyls, cycloalkenyls, cycloalkylyls, aryls, heteroaryl and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyridone, benzimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, indole, isoindole, indazole, benzoxazole, pyrazine, purine, pyrine, purine pyrimidine, and the like.
[048] The term "heteroatom", as used herein, means an atom of any element other than carbon or hydrogen. Preferred heteroatoms
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12/76 are nitrogen, oxygen and sulfur.
[049] The terms "heterocyclyl", "heterocycle" and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3 to 10 member rings, more preferably 3 to 7 member rings, whose structures of ring include at least one hetero atom, preferably one to four hetero atoms, more preferably one or two hetero atoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings in which at least one of the rings is heterocyclic, for example, the other cyclic rings they may be cycloalkyls, cycloalkenyls, cycloalkylyls, aryls, heteroaryl and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholino, lactones, lactams and the like. Heterocyclyl groups can also be replaced by oxo groups. For example, "heterocyclyl" includes pyrrolidine and pyrrolidinone.
[050] The term "heterocycloalkyl", as used herein, refers to an alkyl group substituted by a heterocycle group.
[051] The term "heterocycloalkylamino", as used herein, refers to an amino group substituted by a heterocycloalkyl group.
[052] The term "hydrocarbyl", as used herein, refers to a group that is attached through a carbon atom that has no substituent = 0 or = S, and typically has at least one carbon-hydrogen bond and mainly a carbon structure, but can optionally include heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl and trifluoromethyl are considered hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a substituent = 0 in the bonding carbon) and ethoxy (which is linked via oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl and combinations
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13/76 of them.
[053] The term "hydroxyalkyl", as used herein, refers to an alkyl group substituted by a hydroxyl group.
[054] The term "lower" when used in conjunction with a chemical moiety, such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups where there are ten or less non-hydrogen atoms in the substituent, preferably six or less. A "lower alkyl", for example, refers to an alkyl group that contains ten or less carbon atoms, preferably six or less. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy, whether they appear alone or in combination with other substituents, such as in hydroxyalkyl and aralkyl citations (in which case, for example, the atoms in the aryl group are not counted when the carbon atoms in the alkyl substituent are counted).
[055] As used herein, the term "oxo" refers to a carbonyl group. When an oxo substituent occurs in an otherwise saturated group, such as with an oxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl), the substituted group is further destined to be a saturated group. When a group is referred to as being replaced by an "oxo" group, this may mean that a carbonyl moiety (i.e., -C (= O) -) replaces a methylene moiety (i.e., -CH2-).
[056] The terms "polycyclic", "polycyclic" and "polycyclic" refer to two or more rings (for example, cycloalkyls, cycloalkenyls, cycloalkylyls, aryls, heteroaryl and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, for example, the rings are "fused rings". Each of the rings on the polyicycle can be replaced or not replaced. In certain embodiments, each ring of the polyicycle contains 3 to 10 ring atoms, preferably 5 to 7.
[057] The term “silyl” refers to a portion of silicon with three portions
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14/76 hydrocarbyl attached to it.
[058] The term "substituted" refers to portions with substituents replacing a hydrogen in one or more carbons in the main chain. It is understood that "substitution" or "substituted by" includes the implicit condition that such substitution is in accordance with the allowed valence of the substituted atom and the substituent, and that the substitution results in a stable compound, for example, that does not suffer spontaneously transformation such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is considered to include all permitted substituents on organic compounds. In a broad sense, admissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. Permissible substituents can be one or more and the same or different for appropriate organic compounds. For the purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any permitted substituents on organic compounds described herein that satisfy the heteroatoms' valences. Substituents may include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl or an acyl), a thiocarbonyl (such as a thioester, a thioacetate or a thiooformate) , an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, a starch, an amidine, an imine, a cyan, a nitro, an azide, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically indicated as "unsubstituted", references to chemical moieties included herein comprise substituted variants. For example, reference to a “aryl” group or portion includes
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15/76 implicitly both substituted and unsubstituted variants.
[059] The term "sulfate" is recognized in the art and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.
[060] The term "sulfonamide" is recognized in the art and refers to the group represented by the general formulas
OR ¹⁰ O. / ¹ ° ^or f- € ° r where R ⁹ and R ¹⁰ independently represent hydrogen or hydrocarbyl, such as alkyl, or R ⁹ and R ¹⁰ taken together with the atom (s) intervener (s) complete a heterocycle with 4 to 8 atoms in the ring structure.
[061] The term "sulfoxide" is recognized in the art and refers to the group S (O) R ¹⁰ , where R ¹⁰ represents a hydrocarbyl.
[062] The term "sulfonate" is recognized in the art and refers to the SO3H group, or a pharmaceutically acceptable salt thereof.
[063] The term "sulfone" is recognized in the art and refers to the group S (O) 2R ¹⁰ , where R ¹⁰ represents a hydrocarbyl.
[064] The term "thioalkyl", as used herein, refers to an alkyl group substituted by a thiol group.
[065] The term "thioester", as used herein, refers to a group -C (O) SR ¹⁰ or SC (O) R ¹⁰ where R ¹⁰ represents a hydrocarbyl.
[066] The term "thioether", as used herein, is equivalent to an ether, in which oxygen is replaced by a sulfur.
[067] The term “urea” is recognized in the art and can be represented by the general formula
R ⁹ R ⁹ [068] where R ⁹ and R ¹⁰ independently represent hydrogen or a
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16/76 hydrocarbyl, such as alkyl, or any occurrence of R ⁹ taken together with R ¹⁰ and the intervening atom (s) complete a 4- to 8-membered heterocycle in the ring structure.
[069] "Protection group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or impede the reactivity of the functional group. Typically, a protecting group can be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 ^to Ed., 1999, John Wiley & Sons, NY and Harrison and others, Compendium of Synthetic Organic Methods, Vols. 1 to 8, 1971 to 1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), ter-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2trimethylsilyl-ethanesulfonyl (“ TES ”), trityl and substituted trityl groups, allyloxycarbonyl, 9fluorenylmethylxicarbonyl (“ FMOC ”), nitro-veratryloxycarbonyl (“ NVOC ”) and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g. TMS or TIPS), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
[070] As used here, a therapeutic that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample compared to an untreated control sample, it either delays the onset or reduces the severity of one or more symptoms of the disorder or condition in relation to the untreated control sample.
[071] The term "treat" includes prophylactic and / or therapeutic treatments. The term “prophylactic or therapeutic” treatment is recognized in the art and includes
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17/76 administration to the host of one or more of the compositions in question. If it is administered prior to the clinical manifestation of the unwanted condition (for example, disease or other unwanted state of the host animal), then treatment is prophylactic (that is, it protects the host against the development of the unwanted condition), whereas if it is administered after the manifestation of the unwanted condition, the treatment is therapeutic (that is, it aims to reduce, improve or stabilize the existing unwanted condition or its side effects).
[072] The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention (for example, a compound of formula I). A common method for producing a prodrug is to include one or more selected portions that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, esters or carbonates (for example, esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of formula I in a formulation shown above can be replaced with the corresponding suitable prodrug, for example, in which a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound it is presented as an ester.
[073] The compounds described herein may contain one or more double bonds and thus potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless otherwise stated, the invention includes all of these possible isomers, as well as mixtures of these isomers.
[074] Unless otherwise stated, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines considers each possible isomer, for example, each enantiomer and diastereomer, and
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18/76 a mixture of isomers, such as a racemic or scalemic mixture. The compounds described herein can contain one or more asymmetric centers and thus potentially give rise to diastereomers and optical isomers. Unless otherwise indicated, the present invention includes all of these possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. Mixtures of stereoisomers are also included, as well as specific isolated stereoisomers. During the course of the synthetic procedures used to prepare these compounds, or in the use of racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
[075] Naturally, when a variable is present in more than one occurrence, it can be the same or different in each occurrence. In other words, each variable is independent of the other. In some ways, a compound's structure can be represented by a formula:
which is understood as equivalent to a formula: Rn (a)
Rn (d) where n is typically an integer. That is, R ⁿ is understood to represent five independent substituents, R ^{n (a)} , R ^{n (b)} , R ^{n (c)} , R ^{n (d)} , R ^{n (e)} . “Independent substituents” means that each substituent R can be defined
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19/76 independently. For example, if in an occurrence R ^{n (a)} is halogen, then R ^{n (b)} is not necessarily halogen in that occurrence. Likewise, when a group R is defined as four substituents, R is understood to represent four independent substituents, R ^a , R ^b , R ^c and R ^d . Unless otherwise indicated, the substituents are not limited to any particular order or arrangement.
[076] The following abbreviations are used here. DMF: dimethylformamide. EtOAc: ethyl acetate. THF: tetrahydrofuran. DIPEA or DIEA: diisopropylethylamine. HOBt:
1- hydroxybenzotriazole. EDC: 1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride. DMSO: dimethyl sulfoxide. DMAP: 4-Dimethylaminopyridine. RT: room temperature. H: hours: Min: DCM minutes: dichloromethane. MeCN: acetonitrile. MeOH: methanol. iPrOH:
2- propanol. n-BuOH: 1-butanol.
B. Compounds [077] In one aspect, the invention relates to compounds, or pharmaceutically acceptable salts thereof, useful as BMP inhibitors. For example, compounds of Formula I, II or III can be used to treat or prevent a disease or condition. In general, it is considered that each derivative described can be optionally additionally substituted. It is also considered that any one or more derivatives can be optionally omitted from the invention. It is understood that a described compound can be provided by the described methods. It is also understood that the described compounds can be employed in the described methods of use.
[078] In certain modalities of the methods described here, the compound has the structure represented by Formula I:
(D
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20/76 where:
W, X, Y and Z are independently N or CH;
A is cycloalkyl, heterocyclyl, aryl or optionally substituted heteroaryl;
G is selected from CF3, halogen, CN, alkyl, aryl, heteroaryl, NR1R2, CHR ³ R ⁴ , S (O) NR ¹ R ² , S (O) ₂ NR ¹ R ² , SR ¹ , SOR ¹ or SO2R ¹ ;
M is aryl or optionally substituted heteroaryl;
D is selected from a bond, O, CR ³ R ⁴ , NR ¹ , NR ¹ R ² , SR ¹ , SOR ¹ or SO2R ¹ ;
E is absent or selected from H, CF3, halogen, CN, alkyl, aryl, heteroaryl, C3-C12 cycloalkyl or C3-C12 heterocyclyl or C3-C12 cycloalkylalkyl or C3-C12 heterocyclylalkyl;
R ¹ is absent or is selected from H, alkyl, aryl or heteroaryl;
R ² is selected from H, alkyl, aryl, heteroaryl, or COR ¹ , or
R ¹ and R ² form a C3-C12 cycloalkyl or C3-C12 heterocyclyl containing O, N and / or S;
R ³ is selected from H, alkyl, aryl or heteroaryl; and
R ⁴ is selected from H, alkyl, aryl, heteroaryl or COR ¹ , or
R ³ and R ⁴ form a C3-C12 cycloalkyl or a C3-C12 heterocyclyl containing O, N and / or S;
or a pharmaceutically acceptable salt thereof.
[079] In some modalities, W is CH. In some embodiments, Z is CH. In some modalities, Z is N. In some modalities, X is N. In some modalities, Y is N.
C 7 θ (0-2) [080] In some modalities, 'e:
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wherein Ai is independently O, CR ³ R ⁴ , NH or NR ¹ , or it can join with another Ai to form C3-Cy2cycloalkyl, C3-Cy2cycloalkenyl, aryl, heteroaryl or C3Ci2heterocyclyl.
[081] In some modalities, A is chosen from the following:
* *<3 — í- --G * μ _ΝΗ *<Ij ^ - NH OG XQ s-4 * ^G —r 1 o— ⁽ *G — í- - ^ 1 - G *G — í- JT -j - ( G —-- ⁽ * ^G- O G cw ^g 45 *v ^ NG — k 1 -f— ( *OH */* laughs ν ^α * Λ* * V ^NH / ύ V ^N H * ^S ^ N * ^G ~ cS < ^N
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plus G e is selected from aryl or heteroaryl. For example, in some embodiments, M is optionally substituted phenyl or pyridine.
[083] Also described are compounds of formula I, where M, D and E together form:
T TIJ * J HN ^^ IXXJ 0 νΔJ Cf'V |* J h ₂ n. ^. xX XXJ HCT ^XXJ * J 90 ^^XXJ -O XXJ X ^f XX * J the ^N Uk J c ° xxJ ^ xxJ
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[084] Also described are compounds of formula (I), having a structure selected from:
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or a pharmaceutically acceptable salt thereof.
[085] In certain modalities of the methods described here, the compound has the structure represented by Formula II:
on what:
X ¹ is N or CR ⁵ ;
X ² and X ⁴ are independently N or CR ⁵ ;
Y ¹ , Y ² and Y ³ are independently N or CR ⁵ ;
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D is C or N;
W is N or Ο;
W ¹ is N, O or C;
Cy is replaced by one or more G ¹ , and is selected from C3-C12 cycloalkyl, C3-Ci2cycloalkenyl, aryl, heteroaryl, or C3-Ci2heterocyclyl.
G ¹ - G ⁵ are absent or are independently selected from H, halogen, CN, CF3, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl optionally substituted by a 3-8 membered ring containing C, O , S or N, optionally substituted by one or more R ⁶ , NR ⁶ Ci-w alkyl optionally substituted by or a 3- to 8-membered ring containing C, O, S or N, optionally substituted by one or more R ⁶ ;
R ⁵ and R ⁶ are independently selected from H, halogen, CN, CF3, C1-10 alkyl, C3-10 cycloalkyl, C1-10 alkyl optionally substituted by a 3 to 8 membered ring containing C, O, S or N ;
Z is optionally substituted by one or more R ⁵ , and is selected from C3-C12 cycloalkyl, C3-Cy2cycloalkenyl, aryl, heteroaryl or C3-Cy2heterocyclyl; in is 1 or 2.
[086] In some modalities, D is C and m is 2. In some modalities, W is N.
[087] In some modalities,
'' A-i (o-i)
D
is ^A i / _G ^ü ( ⁰ - ² ), where A1 is independently O, CR ¹ R ² or NH or NR ¹ or
NR ¹ R ² , or can join with another A1 to form C3-C12 cycloalkyl, C3-C12
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31/76 cycloalkenyl, aryl, heteroaryl, or C3-C12 heterocyclyl.
[088] In certain embodiments of the methods described here, the compound has a structure represented by Formula III:
on what:
X ¹ , X ² and X ⁴ are independently N or CR ⁵ ;
Y ¹ , Y ² and Y ³ are independently N or CR ⁵ ;
G ¹ -G ⁵ are absent or are independently selected from H, halogen, CN, CF3, C1-10 alkyl, C3-10 cycloalkyl, C1-10 alkyl optionally substituted by a 3-8 membered ring containing C, O , S or N, optionally replaced by one or more R ⁶ ,
R ⁵ and R ⁶ are independently selected from H, halogen, CN, CF3, C1-10 alkyl, C3-10 cycloalkyl and C1-10 alkyl optionally substituted by a 3-8 membered ring containing C, O, S or N; and
Z is optionally substituted by one or more G ⁵ , and is selected from C3-C12 cycloalkyl, C3-C12 cycloalkenyl, aryl, heteroaryl or C3-C12 heterocyclyl.
[089] In certain modalities of the methods described here, the compound has the
[090] In some modalities,
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i. X ¹ is N, X ⁴ is N and X ² , X ⁴ , Y ¹ , Y ² and Y ³ are independently C or CR ⁵ ;
ii. X ¹ is N, X ² is N, Y ¹ is N and X ⁴ , Y ² and Y ³ are independently CR ⁵ ;
iii. X ¹ is N, X ² is N, Y ² is N and X ⁴ , Y ² and Y ³ are independently CR ⁵ ; or iv. X ¹ is N and X ² , X ⁴ , Y ¹ , Y ² and Y ³ are independently CR ⁵ ;
Y ¹ , Y ² and Y ³ are independently N or CR ¹ .
[091] In some modalities, X ¹ is N, X ⁴ is N and X ² , X ⁴ , Y ¹ , Y ² and Y ³ are CH. In some embodiments, X ¹ , X ⁴ and Y ¹ are N and X ² , X ⁴ , Y ² and Y ³ are CH. In some embodiments, X ¹ , X ⁴ and Y ² are N, and X ² , X ⁴ , Y ¹ and Y ³ are CH.
[092] In some modalities, G ² is absent. In some modalities, G ³ is absent.
[093] The compounds described herein can include all forms of salt, for example, salts of both basic groups, among others, amines, as well as salts of acid groups, among others, carboxylic acids. The following are non-limiting examples of anions that can form salts with basic protonated groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, format, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate , succinate, tartrate, fumarate, citrate and the like. The following are non-limiting examples of cations that can form salts of acidic groups: ammonium, sodium, lithium, potassium, calcium, magnesium, bismuth, lysine and the like.
C. Pharmaceutical Compositions [094] In one aspect, the invention relates to methods for treating a disease or condition by administering a compound of Formula I, II or III in a pharmaceutical composition. That is, a pharmaceutical composition can be provided comprising a therapeutically effective amount of at least one described compound or at least one product of a described method and a pharmaceutically acceptable carrier.
[095] The compositions and methods of the present invention can be used
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33/76 to treat an individual in need of it. In certain embodiments, the individual is a mammal such as a human or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e. routes, such as injection or implantation, which bypass transport or diffusion through an epithelial barrier), the aqueous solution is free of pyrogens, or substantially pyrogen-free. Excipients can be chosen, for example, to effect the delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in unit dosage form such as a tablet, capsule (including "spinkle" and gelatin capsule), granule, lyophilisate for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, for example, a skin patch. The composition can also be present in a solution suitable for topical administration, such as eye drops.
[096] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as acid
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34/76 ascorbic or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The pharmaceutical preparation or composition can be a self-emulsifying drug delivery system or an auto-emulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymeric matrix, which can incorporate, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are non-toxic, physiologically acceptable and metabolizable carriers that are relatively simple to manufacture and administer.
[097] The phrase “pharmaceutically acceptable” is used here to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problem or complication, proportional to a reasonable risk / benefit ratio.
[098] The phrase "pharmaceutically acceptable carrier", as used herein, means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or packaging material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil,
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35/76 cotton, safflower oil, sesame oil, olive oil, corn oil and soy oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar;
(14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
(15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.
[099] A pharmaceutical composition (preparation) can be administered to an individual through any one of several routes of administration including, for example, orally (for example, greases as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules) and gelatin capsules), boluses, powders, granules, pastes for application on the tongue); absorption through the oral mucosa (for example, sublingually); anal, rectal or vaginal (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally such as, for example, a sterile solution or suspension); nasally; intraperitoneal; subcutaneous; transdermal (for example as an adhesive applied to the skin); and topical (for example, as a cream, ointment or spray applied to the skin or as eye drops). The compound can also be formulated for inhalation. In certain embodiments, a compound can be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for them can be found, for example, in Patents 6,117,973, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in the cited patents .
[0100] Formulations can conveniently be presented in unit dosage form and can be prepared by any method well known in the pharmacy art. The amount of active ingredient that can be combined with a carrier material to produce an individual dosage form will vary
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36/76 depending on the host to be treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce an individual dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, at one hundred percent, this amount varies between about 1 percent and about ninety-nine percent of the active ingredient, preferably between about 5 percent and about 70 percent, more preferably between about 10 percent one hundred and about 30 percent.
[0101] Methods for preparing these formulations or compositions include the step of associating an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately associating a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
[0102] The formulations of the invention suitable for oral administration can be in the form of capsules (including sprinkle capsules and gelatin capsules), pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilization, powders, granules or as a solution or suspension in an aqueous or non-aqueous liquid, or as an aqueous or non-aqueous liquid emulsion, oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as lozenges (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds can also be administered as a bolus, electuary or paste.
[0103] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, pills, powders, granules and the like), the active ingredient is mixed with one or more
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37/76 pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarding agents such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
[0104] A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Pressed tablets can be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactant or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
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38/76 [0105] Tablets and other solid dosage forms of pharmaceutical compositions, such as pills, capsules (including sprinkle capsules and gelatin capsules), pills and granules, can be optionally classified or prepared with coatings and wrappings, such as enteric coatings and other coatings well known in the pharmaceutical formulations art. They can also be formulated to provide slow or controlled release of the active ingredient using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymeric matrices, liposomes and / or microspheres. They can be sterilized, for example, filtration through a bacteria retention filter, or incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient (s) only, or preferably, in a certain part of the gastrointestinal tract, optionally, in a delayed manner. Examples of incorporated compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the excipients described above.
[0106] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilisates for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and their derivatives, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate , ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3butylene glycol, oils (in particular, cottonseeds, peanuts, corn, germ, olive, castor and sesame), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and esters
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39/76 of sorbitan fatty acid, and mixtures thereof.
[0107] In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying agents and suspending agents, sweeteners, flavorings, dyes, perfuming agents and preservatives.
[0108] The suspensions, in addition to the active compounds, may contain suspending agents such as, for example, isostearyl ethoxylated alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum meta-hydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
[0109] Formulations of pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as a suppository, which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter , polyethylene glycol, a suppository wax or a salicylate, which is solid at room temperature, but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.
[0110] The formulations of pharmaceutical compositions for administration in the mouth can be presented as a mouthwash, or an oral spray, or an oral ointment.
[0111] Alternatively or in addition, the compositions can be formulated for delivery via a catheter, stent, wire or other intraluminal device. Delivery via such devices can be especially useful for delivery to the bladder, urethra, ureter, rectum or intestine.
[0112] Formulations that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers known in the art to be suitable.
[0113] Dosage forms for topical or transdermal administration
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40/76 include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, plasters and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that may be required.
[0114] Ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
[0115] Powders and sprays may contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain usual propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
[0116] Transdermal patches have the additional advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate of such flow can be controlled either by providing a rate control membrane or by dispersing the compound in a polymeric matrix or gel.
[0117] Ophthalmic formulations, eye ointments, powders, solutions and the like are also considered to be within the scope of this invention. Exemplary ophthalmic formulations are described in US Publications. We. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and in the US Patent. No. 6,583,124, the contents of which are hereby incorporated by reference. If desired, liquid ophthalmic formulations have properties similar to those of tear fluids, aqueous humor or vitreous humor or are compatible with those fluids. One way
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Preferred administration is local administration (for example, topical administration, such as eye drops, or administration via an implant).
[0118] The phrases “parenteral administration” and “administered parenterally”, as used herein, mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial injection, intrathecal, intracapsular, intraorbital, intracardiac, intradermal intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal and infusion.
[0119] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable stable isotonic aqueous or non-aqueous solutions, dispersions, emulsions, or sterile powders that can be made up into injectable solutions or dispersions sterile immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that make the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
[0120] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils, such as such as olive oil, and injectable organic esters, such as ethyl oleate. Adequate fluidity can be maintained, for example, by using coating materials, such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.
[0121] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be ensured by the inclusion of several
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42/76 antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.
[0122] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor solubility in water. The rate of absorption of the drug then depends on its rate of dissolution, which, in turn, may depend on the size of the crystal and the crystalline shape. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle.
[0123] Injectable deposit forms are made by forming microencapsulated matrices of the compounds in question in biodegradable polymers, such as polylactia-polyglycolide. Depending on the relationship between the drug and the polymer, and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissue.
[0124] For use in the methods of this invention, the active compounds can be given by themselves or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of ingredient active in combination with a pharmaceutically acceptable carrier.
[0125] The methods of introduction can also be provided by rechargeable or biodegradable devices. Various polymeric devices of
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43/76 slow release have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a given target site.
[0126] The actual dosage levels of the active ingredients in pharmaceutical compositions can be varied in order to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient.
[0127] The dosage level selected will depend on a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound (s) to be used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound (s) used ( s), age, sex, weight, condition, general health and previous medical history of the patient to be treated, and similar factors well known in medical techniques.
[0128] A doctor or veterinarian with general knowledge in the art can readily determine and prescribe the therapeutically effective amount of the required pharmaceutical composition. For example, the doctor or veterinarian may initiate doses of the pharmaceutical composition or compound at levels below those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of a compound that is sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the individual's weight, sex, age and medical history. Other factors that influence the effective amount may include, but are not
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44/76 limited to the severity of the patient's condition, the disorder to be treated, the stability of the compound and, if desired, another type of therapeutic agent to be administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al (1996) Harrison's Principles of Internal Medicine 13th Ed. 1814 to 1882 are incorporated herein by reference).
[0129] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above.
[0130] If desired, the effective daily dose of the active compound can be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound can be administered two or three times a day. In preferred modalities, the active compound will be administered once a day.
[0131] The patient receiving this treatment is any animal in need of it, including primates, in particular humans, and other mammals such as horses, cattle, pigs and sheep; and birds and pets in general.
[0132] This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. The term "pharmaceutically acceptable salt", as used herein, includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic,
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45/76 benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic and other acids. Pharmaceutically acceptable salt forms can include forms in which the ratio of molecules comprising the salt is not 1: 1. For example, the salt may comprise more than one molecule of inorganic or organic acid per base molecule, such as two hydrochloric acid molecules per molecule of Formula I or Formula II compound. As another example, the salt may comprise less than one molecule of inorganic or organic acid per base molecule, such as two molecules of Formula I or Formula II compound per molecule of tartaric acid.
[0133] In other embodiments, the salts considered of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, the salts considered of the invention include, but are not limited to, L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4- (2-hydroxyethyl) morpholino, piperazine, potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium, triethanolamine, tromethamine and zinc salts. In certain embodiments, the salts considered of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
[0134] Pharmaceutically acceptable acid-added salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide and the like. Mixtures of such solvates can also be prepared. The source of such a solvate may be the crystallization solvent, inherent in the preparation or crystallization solvent, or accidental to such solvent.
[0135] Wetting, emulsifying and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring and perfuming agents, preservatives and antioxidants may also be present in the compositions .
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46/76 [0136] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gaiate, alpha-tocopherol and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
[0137] In such combinations, the compound of the present invention and other active agents can be administered separately or together. In addition, the administration of one element can be prior, simultaneous or subsequent to the administration of other agent (s).
[0138] Consequently, the compounds in question can be used alone or in combination with other agents that are known to be beneficial in the indications in question or other drugs that affect receptors or enzymes that either increase efficacy, safety, convenience or reduce side effects unwanted effects or toxicity of the described compounds. The compound in question and the other agent can be co-administered, either in simultaneous therapy or in a fixed combination.
[0139] In one aspect, the compound can be employed in combination with a second compound with the known side effect of modulating BMP signaling pathways.
D. Uses of Compounds and Compositions [0140] In certain respects, methods of treating or preventing a disease or condition comprising administering to a subject a compound having the structure represented by Formula I, II or III are provided herein.
[0141] In certain modalities, the disease is a cancer. In certain modalities, the disease is colorectal cancer, juvenile polyposis syndrome, cancer
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Sporadic colorectal 47/76, leukemia, acute myeloid leukemia, acute megacarioblastic leukemia (AMKL), AMKL non Down syndrome, AMKL Down syndrome, chronic myeloid leukemia, lung cancer, non-small cell lung cancer (NSCLC), cancer of pancreas, ovarian cancer, serous ovarian cancer, epithelial ovarian cancer, osteosarcoma, prostate cancer, bone cancer, kidney cell cancer, breast cancer, melanoma or squamous cell carcinoma of the head and neck (HNSCC).
[0142] In certain modalities, cancer is a cancer of the central nervous system. In certain modalities, cancer is a glioma, astrocytic glioma, diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), germ cell tumor, glioblastoma multiforme (GBM), oligodendroglioma, pituitary tumor, or ependymoma.
[0143] In other modalities, the disease is anemia, iron-refractory iron deficiency anemia (IRIDA), heterotopic ossification, non-hereditary ossifying myositis, traumatic ossifying myositis, or circumscribed ossifying myositis.
[0144] In certain embodiments, the compound or pharmaceutical composition is administered other than directly to the central nervous system, for example, topically, orally, nasal, intravenously, intramuscularly, intra-arterial, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal , transmucosa, transdermal, anal, rectal, vaginal, transtracheal, subcutaneous, subcuticular, intra-articular or subcapsular.
E. Manufacture of a Medicament [0145] In one aspect, the invention relates to methods for the manufacture of a medicament to treat or prevent a disease in an individual in need thereof, comprising combining a compound of formula I, II or II with a pharmaceutical carrier.
[0146] The present invention is now being described in general, it will be more easily understood by reference to the following examples which are
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48/76 included solely for the purpose of illustrating certain aspects and modalities of the present invention, and are not intended to limit the invention.
F. Experimental [0147] The following examples are presented in order to provide those skilled in the art with a complete description and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended for be purely exemplary of the invention and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to numbers (eg quantities, temperature, etc.), but some errors and deviations must be accounted for. Unless otherwise stated, the parts are parts by weight, the temperature is at ⁰ C or is at room temperature and the pressure is at or near atmospheric pressure.
Example 1: Chemical Synthesis [0148] General. All NMR spectra were recorded on a 400 MHz AMR Bruker NMR spectrometer. Chemical deviations ¹ H are reported at δ values in ppm with the deuterated solvent as an internal standard. The data are presented as follows: chemical deviation, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), integration, coupling constant (Hz). The low resolution mass spectra were obtained on an Agilent 1200 series 6130 mass spectrometer with electrospray ionization. The high resolution mass spectra were recorded on a Waters Q-TOF API-US system plus Acquity with electrospray ionization (see Table 1, below). Analytical thin layer chromatography was performed on 60-F silica gel plates with 0.25 mm EM reagent. Analytical HPLC was performed on an Agilent 1200 series with UV detection at 215 nm and 254 nm, along with ELSD detection. LC / MS: (Phenomenex-C18, 2.1 x 30 mm, 1 min gradient, 7% [0.1% TFA / CH3CN]: 93%
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49/76 [0.1% TFA / H2O] 95% [0.1% TFA / CH3CN]. Preparative purification was performed in a personalized HP1100 purification system (reference 16) with collection triggered by mass detection. The solvents for extraction, washing and chromatography were HPLC grade. All reagents were purchased from Aldrich Chemical Co. and were used without purification.
General Scheme I
1.1 1.2 1.3
Xi = haloaenium
AB (OH) ₂ , metal (Pd), base, solvent, gW
MB (OH) ₂ , metal (Pd),
1.4 base, solvent, gW
1. unprotect
2. D-X1, base, solvent
7-chloroimidazo [1,2-a] pyridine.
[0149] To a mixture of 4-chloropyridin-2-amine (1.0 g, 7.78 mmol, 1.0 eq) and NaHCOs (1.31 g, 15.56 mmol, 2.0 eq) in EtOH (18 ml) chloroacetaldehyde, 50% by weight in water (1.48 ml, 11.67 mmol, 1.5 eq) was added. The reaction mixture was heated to reflux. After 10 h, the solvent was removed under reduced pressure and the residue was partitioned between EtOAc: H2O (1: 1, 100 ml). The organic layer was washed with brine (50 ml), dried (MgSO4), filtered and concentrated. The material was removed without further purification.
LCMS: Rt = 0.123 min,> 98% @ 215 and 254 nM, m / z = 153.0 [M + H] ⁺ .
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7-chloro-3-iodoimidazo [1,2-a] pyridine.
[0150] To a solution of 7-chloroimidazo [1,2-a] pyridine (7.78 mmol, 1.0 eq) in DMF (12 mL) in rt was added N-iodosucinimide (1.84 g, 8, 17 mmol, 1.05 eq). After 16 h, the brown suspension was diluted with H2O (100 ml) and brine (15 ml). The mixture was extracted with EtOAc (100 ml). The aqueous layer was re-extracted with EtOAc (100 mL) and the collected organic layers were washed with H2O (2 x 20 mL), 10% sodium thiosulfate (20 mL), saline (20 mL) and dried (MgSCU ). After filtration, the solution was concentrated. The residue was triturated with diethyl ether (15 ml) and filtered to provide an off-white solid (1.58 g, 73% yield over 2 steps).
LCMS: RT = 0.265 min,> 98% @ 215 and 254 nM, m / z = 279.0 [M + H] ⁺ .
7-chloro-3-phenylimidazo [1,2-a] pyridine.
[0151] In a pwave flask, 7-chloro-3-iodoimidazo [1,2-a] pyridine (0.39 g, 1.38 mmol, 1.0 eq), phenyl boronic acid (0.18 g, 1 , 45 mmol, 1.05 eq) and Pd (dppf) Cl2 (50.5 mg, 0.07 mmol, 0.05 eq) were added. The solid mixture was evacuated under vacuum and purged with argon (3x). To the mixture, 1,4-dioxane (6 ml) was added, followed by a solution of K3PO4 (0.59 g, 2.76 mmol, 2.0 eq) in H2O (2.5 ml). The reaction was heated to 120 ^Q C for 30 min under microwave irradiation. The reaction was added to EtOAc: H2O (1: 1,120 ml). The organic layer was separated, washed with H2O (2 x 25 ml), brine (25 ml), dried (MgSO4), filtered and concentrated. The material
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51/76 was purified by reverse phase HPLC (15-40% acetonitrile: H2O with 0.1% TFA) to provide 7-chloro-3-phenylimidazo [1,2-a] pyridine (0.30 g, 96% yield).
LCMS: Rt = 0.458 min,> 98% @ 215 and 254 nM, m / z = 229.0 [M + H] ⁺ .
7- (4-isopropoxyphenyl) -3-phenylimidazo [1,2-a] pyridine
N [0152] In a pwave flask, 7-chloro-3-phenylimidazo [1,2-a] pyridine (5) (25.0 mg, 0.11 mmol, 1.0 eq), boronic acid 6 (22, 0 mg, 0.121 mmol, 1.1 eq) and Pd (dppf) Cl2 (4.0 mg, 0.006 mmol, 0.05 eq) were added. The solid mixture was evacuated under vacuum and purged with argon (3x). To the mixture, 1,4-dioxane (2 ml) was added, followed by a solution of K2CO3 (30.0 mg, 0.22 mmol, 2.0 eq) in H2O (1.0 ml). The reaction was heated to 150 ^Q C for 30 min under microwave irradiation. The reaction was added to EtOAc: H2O (1: 1.20 mL). The organic layer was separated, washed with H2O (5 ml), brine (5 ml), dried (MgSCM), filtered and concentrated. The material was purified by reverse phase HPLC (30-65% acetonitrile: H2O with 0.1% TFA) to provide 7- (4-isopropoxyphenyl) -3-phenylimidazo [1,2-a] pyridine (5, 30 mg, 15% yield).
LCMS: Rt = 0.714 min,> 98% @ 215 and 254 nM, m / z = 329.0 [M + H] ⁺ . 7-chloro-3- (pyridin-4-yl) imidazo [1,2-a] pyridine.
[0153] In a pwave flask, 7-chloro-3-iodoimidazo [1,2-a] pyridine (3) (0.31 g, 1.13 mmol, 1.0 eq), 4-pyridyl boronic acid (0 , 15 g, 1.24 mmol, 1.1 eq), and Pd (dppf) Cl2 (41.0 mg, 0.06 mmol, 0.05 eq) were added. The solid mixture was evacuated under
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52/76 vacuum and purged with argon (3x). To the mixture, 1,4-dioxane (5 ml) was added, followed by a solution of K3PO4 (0.48 g, 2.26 mmol, 2.0 eq) in H2O (2.0 ml). The reaction was heated to 120 ^Q C for 30 min under microwave irradiation. The reaction was added to EtOAc: H2O (1: 1, 120 ml). The organic layer was separated, washed with H2O (2 x 25 ml), brine (25 ml), dried (MgSCM), filtered and concentrated. The material was removed without further purification.
LCMS: Rt = 0.147 min,> 98% @ 215 and 254 nM, m / z = 230.0 [M + H] ⁺ .
4- (3- (pyridin-4-yl) imidazo [1,2-a] pyridin-7-yl) phenol. hcx
N [0154] In a pwave flask, 7-chloro-3- (pyridin-4-yl) imidazo [1,2-a] pyridine (0.28 g, 1.23 mmol, 1.0 eq), acid 4 boronic hydroxyphenyl (0.19 g, 1.35 mmol, 1.1 eq) and Pd (dppf) Cl2 (45.0 mg, 0.06 mmol, 0.05 eq) were added. The solid mixture was evacuated under vacuum and purged with argon (3x). To the mixture, 1,4-dioxane (5 mL) was added, followed by a solution of K2CO3 (0.34 g, 2.46 mmol, 2.0 eq) in H2O (2.0 mL). The reaction was heated to 150 ^Q C for 30 min under microwave irradiation. The reaction was added to EtOAc: H2O (1: 1, 20 ml). The organic layer was separated, washed with H2O (5 ml), brine (5 ml), dried (MgSO4), filtered and concentrated. The material was purified by reverse phase HPLC (5-35% acetonitrile: H2O with 0.1% TFA) to provide 4- (3- (pyridin-4-yl) imidazo [1,2-a] pyridin- 7-yl) phenol (53.0 mg, 15% yield).
LCMS: Rt = 0.343 min,> 98% @ 215 and 254 nM, m / z = 288.0 [M + H] ⁺ .
7- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -3- (pyridin-4-yl) imidazo [1,2-a] pyridine.
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[0155] To a pwave flask were added 4- (3- (pyridin-4-yl) imidazo [1,2a] pyridin-7-yl) phenol (29.5 mg, 0.10 mmol, 1.0 eq) , CS2CO3 (134.0 mg, 0.411 mmol, 4.0 eq), Kl (16.6 mg, 0.10 mmol, 1.0 eq), 1- (2-chloroethyl) piperidine hydrochloride (20.3 mg , 0.11 mmol, 1.1 eq) and DMF (1.5 mL). The rxn was subjected to microwave irradiation for 10 min at 120 ° C. The reaction was filtered through a Celite buffer and the solution was purified by reverse phase HPLC (5-35% acetonitrile: H2O with TFA a 0.1%) to produce 7- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -3- (pyridin-4-yl) imidazo [1,2a] pyridine (15.02 mg, 38 % of yield).
LCMS: Rt = 0.404 min,> 98% @ 215 and 254 nM, m / z = 399.0 [M + H] ⁺ .
General Scheme II
1.1 gw
Xi = halogen
2.2
A-X-i, metal (Pd), base, solvent, heat Xi = halogen
THE
2.3
4- (4- (4-methylpiperazin-1-yl) phenyl) pyridin-2-amine.
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54/76 [0156] In a pwave flask, 4-bromopyridin-2-amine (0.50 g, 2.89 mmol, 1.0 eq), boronic ester (0.92 g, 3.03 mmol, 1, 05 eq) and Pd (dppf) Cl2 (106 mg, 0.15 mmol, 0.05 eq) were added. The solid mixture was evacuated under vacuum and purged with argon (3x). To the mixture, 1,4-dioxane (12 ml) was added, followed by a solution of K3PO4 (1.23 g, 5.78 mmol, 2.0 eq) in H2O (5.0 ml). The reaction was heated to 120 ^Q C for 30 min under microwave irradiation. To the reaction, EtOAc (15 mL) was added and 0 ml was filtered. The solid was rinsed with cold EtOAc (2 ml). The material was removed without further purification.
LCMS: Rt = 0.285 min,> 98% @ 215 nM and ELSD, m / z = 269.1 [M + H] ⁺ .
7- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine.
, N
N Ί [0157] To a mixture of 4- (4- (4-methylpiperazin-1-yl) phenyl) pyridin-2-amine (2.89 mmol, 1.0 eq) and NaHCOs (0.49 g, 5 , 78 mmol, 2.0 eq) in EtOH (30 ml) was added chloroacetaldehyde, 50% by weight in water (0.56 ml, 4.34 mmol, 1.5 eq). The reaction mixture was heated to reflux. After 18 h, the solvent was removed under reduced pressure and the residue was partitioned between EtOAc: H2O (1: 1, 100 ml). The organic layer was washed with brine (50 ml), dried (MgSO4), filtered and concentrated. The material was removed without further purification.
LCMS: Rt = 0.343 min,> 90% @ 215 nM and ELSD, m / z = 293.1 [M + H] ⁺ .
7- (7- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-3-yl) thieno [3,2-b] pyridine.
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[0158] In a pwave flask, 7- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridine (23 mg, 0.08 mmol, 1.1 eq), 7- chlorothieno [3,2-b] pyridine (8 mL, 0.071 mmol, 1.0 eq), KOAc (14.0 mg, 0.143 mmol, 2.0 eq) and Pd (0Ac) 2 (~ 1 mg, 0.001 eq ) were added, followed by the addition of DMA (1.5 ml). The reaction was heated to 200 ^Q C for 30 min under microwave irradiation. To the reaction, DMSO (0.5 ml) was added and after filtration through a Celite buffer, the solution was purified by reverse phase HPLC (20-55% acetonitrile: H2O with 0.1% TFA) to obtain 7 - (7- (4) (4-methylpiperazin-1-yl) phenyl) imidazo [1,2-a] pyridin-3-yl) thieno [3,2-b] pyridine (14.0 mg, 47% Yield).
LCMS: Rt = 0.361 min,> 98% @ 215 nM and ELSD, m / z = 370.1 [M + H] ⁺ .
7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridine.
N [0159] The compound 7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridine was prepared in a similar manner to 7- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2 -a] pyridine.
LCMS: Rt = 0.578 min,> 98% @ 220 and 254 nM, m / z = 253.1 [M + H] ⁺ .
3-iodo-7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridine.
N
I [0160] To a solution of compound 7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridine (2.89 mmol, 1.0 eq) in DMF (20 mL) in rt was added N-iodosuccinimide
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56/76 (0.68 g, 3.03 mmol, 1.05 eq). After 16 h, the brown suspension was diluted with H2O (100 ml) and brine (15 ml). The mixture was extracted with EtOAc (100 ml). The aqueous layer was re-extracted with EtOAc (100 mL) and the collected organic layers were washed with H2O (2 x 20 mL), 10% sodium thiosulfate (20 mL), saline (20 mL) and dried (MgSOd ). After filtration, the solution was concentrated and the material was obtained without further purification.
LCMS: Rt = 0.640 min,> 95% @ 220 nM and ELSD, m / z = 378.9 [M + H] ⁺ .
7- (4-isopropoxyphenyl) -3- (2-methylpyridin-4-yl) imidazo [1,2-a] pyridine.
[0161] In a pwave bottle, 3-iodo-7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridine (35 mg, 0.093 mmol, 1.0 eq), acid (2-methylpyridin-4-yl ) boronic acid (15 mg, 0.11 mmol, 1.2 eq) and Pd (dppf) Cl2 (4.0 mg, 0.005 mmol, 0.05 eq) were added. The solid mixture was evacuated under vacuum and purged with argon (3x). To the mixture, 1,4-dioxane (2 ml) was added, followed by a solution of K3PO4 (40 mg, 0.19 mmol, 2.0 eq) in H2O (0.5 ml). The reaction was heated to 120 ^Q C for 30 min under microwave irradiation. The reaction was added to EtOAc: H2O (1: 1, 20 ml). The organic layer was separated, washed with H2O (2 x 25 ml), brine (25 ml), dried (MgSO4), filtered and concentrated. The residue was purified by reverse phase HPLC (20-55% acetonitrile: H2O with 0.1% TFA) to provide 7- (4-isopropoxyphenyl) -3- (2-methylpyridin4-yl) imidazo [1,2 - a] pyridine (4.3 mg, 14% yield).
LCMS: Rt = 0.544 min,> 98% @ 215 nM and ELSD, m / z = 344.1 [M + H] ⁺ .
_______Table 1: Mass Spectrum Data________________________________ Example Compound Name ,, ⁺
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4- (2- (4- (3- (quinolin-4-yl) imidazo [1,2-a] pyridin-7yl) phenoxy) ethyl) morpholine
5- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) isoquinoline
4- (2- (4- (3- (pyridin-4-yl) imidazo [1,2-a] pyridin-7yl) phenoxy) ethyl) morpholine
7- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -3- (pyridin-4yl) imidazo [1,2-a] pyridine
4- (7- (2,3-dihydrobenzo [b] [1,4] dioxin-6yl) imidazo [1,2-a] pyridin-3-yl) quinoline
7- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -3 (pyridin-4-yl) imidazo [1,2-a] pyridine
7- (4- (ter-butyl) phenyl) -3- (pyridin-4-yl) imidazo [1,2a] pyridine
7- (4-isopropoxyphenyl) -3- (pyridin-4-yl) imidazo [1,2a] pyridine
7- (4-phenoxyphenyl) -3- (pyridin-4-yl) imidazo [1,2a] pyridine
5- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) quinoline
451
380
401
399
380
330
328
330
364
380
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8- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) quinoline
7- (4-isopropoxyphenyl) -3- (naphthalen-1yl) imidazo [1,2-a] pyridine
6- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) quinoxaline
3- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) quinoline
4- (3-phenylimidazo [1,2-a] pyridin-7-yl) anilino
6- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) isoquinoline
7- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) isoquinoline
4- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) isoquinoline
4- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) quinoline
380
379
381
380
286
380
380
380
380
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N- (4- (3-phenylimidazo [1,2-a] pyridin-7yl) phenyl) picolinamide
391
4- (7- (4- (4-methylpiperazin-1-yl) phenyl) im idazo [1,2a] pyridin-3-yl) quinoline
420
4- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) phenol
4- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) -N, N-dimethylaniline
6- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) quinoline
3- (2-chloropyridin-4-yl) -7- (4isopropoxyphenyl) imidazo [1,2-a] pyridine
3- (2-fluoropyridin-4-yl) -7- (4isopropoxyphenyl) imidazo [1,2-a] pyridine
7-chloro-4- (7- (4-isopropoxyphenyl) imidazo [1,2a] pyridin-3-yl) quinoline
3- (2'-chloro- [2,4'-bipyridin] -4-yl) -7- (4isopropoxyphenyl) imidazo [1,2-a] pyridine
345
372
380
364
348
414
441
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7- (4-isopropoxyphenyl) -3- (pyrimidin-5yl) imidazo [1,2-a] pyridine no
4- (2- (4- (3-phenylimidazo [1,2-a] pyridin-7yl) phenoxy) ethyl) morpholino
4- (3-phenylimidazo [1,2-a] pyridin-7-yl) phenol 287
7- (4-phenoxyphenyl) -3-phenylimidazo [1,2-a] pyridine 363
7- (6-methoxypyridin-3-yl) -3-phenylimidazo [1,2a] pyridine
3-phenyl-7- (4- (2- (piperid in-1 yl) ethoxy) phenyl) imidazo [1,2-a] pyridine
3-phenyl-7- (4-propoxyphenyl) imidazo [1,2-a] pyridine 329
7- (4-isopropoxyphenyl) -3-phenylimidazo [1,2a] pyridine
3-phenyl-7- (4- (trifluoromethoxy) phenyl) imidazo [1,2a] pyridine
7- (4-isopropoxyphenyl) -3-phenylimidazo [1,2a] pyridine
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3- (1,5-dimethyl-1 H-pyrazol-4-yl) -7- (4isopropoxyphenyl) imidazo [1,2-a] pyridine
3- (3,5-dimethyl-1 H-pyrazol-4-yl) -7- (4isopropoxyphenyl) imidazo [1,2-a] pyridine
4- (7- (4-isopropoxyphenyl) imidazo [1,2-c] pyrimidin3-yl) quinoline
7- (4-isopropoxyphenyl) -3- (1 H-pyrazol-4yl) imidazo [1,2-a] pyridine
3- (1 - (4-fluorophenyl) -1 H-pi razol-4-i 1) -7- (4isopropoxyphenyl) imidazo [1,2-a] pyridine
7- (4-isopropoxyphenyl) -3- (3-methyl-1 H-pyrazol-4yl) imidazo [1,2-a] pyridine
7- (4-isopropoxyphenyl) -3- (2-methylpyridin-4yl) imidazo [1,2-a] pyridine
3- (3-bromo-2-fluoropyridin-4-yl) -7- (4isopropoxyphenyl) imidazo [1,2-a] pyridine
4- (7- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2a] pyridin-3-yl) -7- (trifluoromethyl) quinoline
347
347
381
319
413
333
344
427
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7- (4- (4-methylpiperazin-1-yl) phenyl) -3- (3methylpyridin-4-yl) imidazo [1,2-a] pyridine
7- (4- (4-methylpiperazin-1-yl) phenyl) -3- (thiophen-3yl) imidazo [1,2-a] pyridine
4- (7- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2a] pyridin-3-yl) -2- (trifluoromethyl) quinoline
2-methyl-4- (7- (4- (4-methylpiperazin-1yl) phenyl) imidazo [1,2-a] pyridin-3-yl) quinoline
5- (7- (4-isopropoxyphenyl) imidazo [1,2-a] pyridin-3yl) thiazole
7- (4-isopropoxyphenyl) -3- (thiophen-3-yl) imidazo [1,2a] pyridine
7- (4-isopropoxyphenyl) -3- (3-methylpyridin-4yl) imidazo [1,2-a] pyridine
7- (4-isopropoxyphenyl) -3- (thiophen-2-yl) imidazo [1,2a] pyridine
3- (4-fluorophenyl) -7- (4- (4-methylpiperazin-1yl) phenyl) imidazo [1,2-a] pyridine
384
375
488
434
336
335
344
335
387
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3- (benzo [b] thiophen-2-yl) -7- (4- (4-methylpiperazin1-yl) phenyl 1) imidazo [1,2-a] pyridine
4- (7- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2a] pyridin-3-yl) benzonitrile
5- (7- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2a] pyridin-3-yl) benzo [d] thiazole
7- (7- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2a] pyridin-3-yl) thieno [2,3-b] pyrazine
-methyl-5- (7- (4- (4-methylpiperazin-1 yl) pheni l) imidazo [1,2-a] pyridin-3-yl) -1 H- 423 benzo [d] imidazole
7- (7- (4- (4-methylpiperazin-1-yl) phenyl) imidazo [1,2a] pyridin-3-yl) thieno [3,2-b] pyridine
3-fluoro-5- (7- (4- (4-methylpiperazin-1yl) phenyl) imidazo [1,2-a] pyridin-3-yl) benzonitrile
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5- (7- (4- (4-methylpiperazi n-1-yl) phenyl) im idazo [1,2 a] pyridin-3-yl) benzo [c] [1,2,5] thiadiazole
7- (4- (4-methylpiperazin-1-yl) phenyl) -3phenylimidazo [1,2-a] pyridine
7- (4- (4-methylpiperazin-1-yl) phenyl) -3- (pyridin-4yl) imidazo [1,2-a] pyridine
7- (4- (4-methylpiperazin-1-yl) phenyl) -3- (2methylpyridin-4-yl) imidazo [1,2-a] pyridine
3- (2-chloropyridin-4-yl) -7- (4- (4-methylpiperazin-1 yl) phenyl) imidazo [1,2-a] pyridine
7- (4- (4-methylpiperazin-1-yl) phenyl) -3- (pyridin-3yl) imidazo [1,2-a] pyridine
4- (7- (4- (4-methylpiperazin-1-yl) phenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl) quinoline
4- (2- (4- (3- (quinolin-4-yl) - [1,2,4] triazolo [4,3a] pyridin-7-yl) phenoxy) ethyl) morpholine
427
369
370
384
404
370
421
452
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N, N-dimethyl-2- (4- (3- (quinolin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-7-yl) phenoxy) propan1-amine
4- (7- (4- (2- (piperidin-1-yl) ethoxy) phenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl) quinoline
4- (7- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl) quinoline
N, N-dimethyl-1 - (4- (3- (quinolin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-7-yl) phenoxy) propan2-amine
4- (3- (quinolin-4-yl) - [1,2,4] triazolo [4,3-a] pyridin7-yl) phenol
4- (7- (4-methoxyphenyl) - [1,2,4] triazolo [4,3a] pyridin-3-yl) quinoline
4- (7- (4-propoxyphenyl) - [1,2,4] triazolo [4,3a] pyridin-3-yl) quinoline
4- (3- (quinolin-4-yl) - [1,2,4] triazolo [4,3-a] pyridin7-yl) phenyl acetate
4- (7- (4-butoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridin3-yl) quinoline
424
450
436
424
339
353
381
381
395
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4- (3- (quinolin-4-yl) - [1,2,4] triazolo [4,3-a] pyridin7-yl) phenyl benzoate
4- (7- (4- (cyclopentyloxy) phenyl) - [1,2,4] triazolo [4,3a] pyridin-3-yl) quinoline
4- (7- (4-isopropoxyphenyl) - [1,2,4] triazolo [4,3a] pyridin-3-yl) quinoline
4- (7- (4-ethoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridin3-yl) quinoline
443
407
381
367
4- (7- (4- (allyloxy) phenyl) - [1,2,4] triazolo [4,3a] pyridin-3-yl) quinoline
4- (7- (4- (sec-butoxy) phenyl) - [1,2,4] triazolo [4,3a] pyridin-3-yl) quinoline
-cyclopentyl-4- (3- (quinolin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-7-yl) pyrid in-2 (1 H) one
-ethyl-4- (3- (cholinolin-4-yl) - [1,2,4] triazolo [4,3a] pyridin-7-yl) pyridin-2 (1 H) -one
-isopropyl-4- (3- (quinolin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-7-yl) pyrid in-2 (1 H) one
379
395
408
368
382
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-methyl-4- (3- (quinoli n-4-yl) - [1,2,4] triazolo [4,3a] pyridin-7-yl) pyridin-2 (1 H) -one
-butyl-4- (3- (quinol n-4-yl) - [1,2,4] triazolo [4,3a] pyridin-7-yl) pyridin-2 (1 H) -one
-propyl-4- (3- (quinol n-4-yl) - [1,2,4] triazolo [4,3a] pyridin-7-yl) pyridin-2 (1 H) -one
-allyl-4- (3- (quinolin-4-yl) - [1,2,4] triazolo [4,3a] pyridin-7-yl) pyridin-2 (1 H) -one
4- (3- (quinolin-4-yl) - [1,2,4] triazolo [4,3-a] pyridin7-yl) pyridin-2 (1 H) -one
1- (sec-butyl) -4- (3- (quinolin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-7-yl) pyrid in-2 (1 H) - 396 ona
Example 2: Biological Tests [0162] Tables 2-4 summarize the results of the tests used to identify and evaluate the modalities of the present invention.
Example R Laugh IC ₅ of BMP4 Cell (nM)
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1 p N O ^ J * 62 2 * O3 *^ 34*O5 *^ 36* 03 6,100 7 * ^ jO ⁿ 8 * 39 * to10 Vz ^0-3 > 10,000 11 *12 *Ò ~ N Νΐ = Ζ Inactive
Petition 870190067761, of 7/17/2019, p. 78/101
69/76
13* vV ^N v) inactive 14 *Λι Inactive 15 * Λ, ^N Negative 16 * fO Inactive 17*OH Inactive 18 * / ^N Negative 19 *ΛιS3N = Z Negative 20 * 970 21 *O-F 1,250 22 * > 10,000
Petition 870190067761, of 7/17/2019, p. 79/101
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23* Negative 24 * NN ^ = / Power @ 1-1 OuM 25 *^ 3 Power @ 1-1 OuM 26 * Power @ 0.510uM 27 * Negative 28 *Çnh 730 29 * inactive 30 * Ζϊ N ^N H > 10,000 31 ry * z 670 32 * -Y BrC ^ F Negative 33 *s ^ l ^ N > 10,000 34 *O Power @ 0.110uM
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35* í Power @ 1 uM but decreases @ 10 uM 36 jr * <r> Power @ 0.110uM 37 ^F T *^ 3 Power @ 1-1 OuM 38* Power @ 0.510uM 39*^ 3 Power @ 0.110uM 40 fu *^ 3 Negative 41 Çj * 342*43 H *^ 3 The cf__Y> 2890C ° XXO
Petition 870190067761, of 7/17/2019, p. 81/101
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O UÇ ^ N ò Really induces / power at 0.5 -10 uM (5-25-2012)o ^{o =} ZI Really induces / reporter power of BMP (5-31-2012, Sep 9)MycO N 8100
Table 3
Petition 870190067761, of 7/17/2019, p. 82/101
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47 * 5,000 (TFA) 48 * Z ^ NF ₃ C Inhibits 10uM 49 */ ^ N 4.5 50 *F Inhibits 10uM 51 * ^s ZL O No inhibition at 10uM 52 *CN PARTIAL INHIBITION 53 *V-V'N Inhibits 10uM 54 * (V ^s = N 59 55 *fl V-Z ^ N/ No inhibition at 10uM 56 * V / ^S X ^ N ⁷ 11.6
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57 *F 10,000 58 *N-S No inhibition at 10uM. 59 * Induces to 0.1-1 µM. Partially inhibits @ 5uM. KILLS at 10uM 60 * 100 61 *THE 40 62 *CKc.N 58 63 *O Inhibits 10uM, but not 5uM 64 * <10 (TFA) 65 * W ^N CF ₃ Powerful: Inhibits 50% @ 5uM, completely @ 1 OU 66 * Active at 10uM 67 *0 ^ -4 ^ Weakly Potent: Inhibits @ 5uM, completely @ 10uM (# 26. 10-24-2012) 69 *V.N.The j0 ^^ Weakly Potent: Inhibits @ 5uM, completely @ 10uM (# 26. 10-24-2012)
Petition 870190067761, of 7/17/2019, p. 84/101
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69 * 1280 (TFA) 70 ζ ^Ν; = Λ <10 71 * z ^F 16.6 72 Jj 1Z /u 10uM inhibition
Table 4
Input BMP Receiver Type 1 (nM) ALK2 /ACVR1 ALK1 /ACVR1 ALK3 / BMPRR1A ALK4 / ACVR1B ALK5 / TGFBR1 ALK6 / BMPR1B 1 53.1 49.6 52 31,000 23,000 151.2 5 270.021 24.0 6.4 7.9 ND 3960 11 25 155.0 87 118 ND 13,600 340 26 265.0 > 100,00030 645.1 > 100,00042 1970.0 494 92 ND > 100,000 895 45 149.0 349051 26.560 1.340.1 62 14.450.8 66 46.067 20.068 33.240.6
Incorporation by reference [0163] All publications and patents mentioned herein are incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In
Petition 870190067761, of 7/17/2019, p. 85/101
76/76 case of conflict, this request, including any definitions cited herein, will control.
Equivalents [0164] Although specific embodiments of the present invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art after reviewing this specification and claims below. The full scope of the invention must be determined by reference to the claims, along with its full scope of equivalents, and the specification, along with such variations.

权利要求:
Claims (11)
[1]
1. Method to treat or prevent a disease or condition, CHARACTERIZED by the fact that it comprises administering to an individual a compound having the structure represented by Formula I:

[2]
2/14
2. Method, according to claim 1, CHARACTERIZED by the fact that W is CH.
[3]
3. Method, according to any of the preceding claims, CHARACTERIZED by the fact that Z is CH.
[4]
4. Method according to claim 1 or 2, CHARACTERIZED by the fact that Z is N.
[5]
5. Method, according to any of the previous claims, CHARACTERIZED by the fact that X is N.
[6]
6. Method, according to any of the preceding claims, CHARACTERIZED by the fact that Y is N.
[7]
7. Method, according to any of the preceding claims, CHARACTERIZED by the fact that

[8]
8. Method according to any one of claims 1 to 7,
CHARACTERIZED by the fact that A is chosen d among the following: * Q- *O * / —NH *
Petition 870190067761, of 7/17/2019, p. 88/101
3/14
x. _s THEG X * ^G —r I □ - ⁽* *G- 1 z * * ^G- O GCa-n* rfXXX ^G —r 1 - ⁽*OH */ fX * V ^a*X Λ N ^ N <bx * * V ^NH/ Zii V ^N H * * < ^N / ^Br ft ^ N ^{F N} ΪΧ O * - ² / o * ° ^Z o Z./*the o ~ z. ^O J O *S ^ J χχ ο c N-S
[9]
9. Method, according to any of the preceding claims, CHARACTERIZED by the fact that M is optionally substituted by one or more G, and is selected from aryl or heteroaryl.
[10]
10. Method according to claim 9, CHARACTERIZED by the fact that M is optionally substituted phenyl or pyridine.
Petition 870190067761, of 7/17/2019, p. 89/101
4/14
[11]
11 Method, according to any of the preceding claims, CHARACTERIZED by the fact that M, D and E together form: ____________
1 T jlJ J HN ^XXJ 0 grandmaJ Cf'V |0 ^ 9* J XX XXJ HCX ^XXJ XX* J 9XXJ -O XXJ X ^f XX * J the ^N XX J c ° xxJ ^ XXJ *J * *J XXJ ° XX J ΟγγχJ (X XXJ ^ ° xx*J - ° xxJ I XXJ Ζ ^ η 0XJ 0^ xJ
Petition 870190067761, of 7/17/2019, p. 90/101

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法律状态:
2021-05-04| B11A| Dismissal acc. art.33 of ipl - examination not requested within 36 months of filing|

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2021-07-20| B11Y| Definitive dismissal - extension of time limit for request of examination expired [chapter 11.1.1 patent gazette]|

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2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762447830P| true| 2017-01-18|2017-01-18|

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US62/447,830|2017-01-18|

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PCT/US2018/014239|WO2018136634A1|2017-01-18|2018-01-18|Fused heterocyclic compounds as selective bmp inhibitors|

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