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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Definitions

• the complement system is a branch of an organism’s immune system that enhances the ability of antibodies and phagocytic cells to destroy and remove foreign particles (eg., pathogens) from the organism.
• the complement system comprises a set of plasma proteins that act together to attack extracellular forms of pathogens and induce a series of inflammatory responses to help fight infection.
• Complement activation can occur through several pathways. For example, complement activation can occur spontaneously in response to certain pathogens or by antibody binding to a pathogen. When complement proteins are activated a cascade is triggered by which one complement protein induces the activation of the next protein in the sequence.
• complement proteins When activated, complement proteins can bind to a pathogen, opsonizing them for engulftnent by phagocytes bearing receptors for complement. Then, small fragments of some complement proteins act as chemoattractants to recruit more phagocytes to the site of complement activation, and also to activate these phagocytes. Next, the complement proteins create holes or pores in the invading organisms, leading to their destruction. While complement plays an important role in protecting the body from foreign organisms, it can also destroy healthy cells and tissue. The inappropriate activation of complement is implicated in a long list of disease pathologies (Morgan, B. EurJClin Invest 1994, Vol. 24, pages 219-228) affecting the immune, renal, cardiovascular, and neurological systems. Accordingly, there exists a need to develop further complement inhibitors, which have therapeutic potential in the treatment of numerous disorders.
• the invention provides compounds having the structure of formula (I), and pharmaceutically acceptable salts thereof: wherein, independently for each occurrence: X is a bond or C(R X )2;
• V is a bond, C(R Y ) 2 , or -N(R b K
• G is S or C(R 3 )z
• R a and R b are each independently H or (Ci-C6)alkyl
• R 1 represents optionally substituted aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, or cycloalkenyl;
• R 2 represents optionally substituted bicyclic or tricyclic heteroaryl
• R 3 is independently for each occurrence H, halogen, -CN, -Ntfc, -CH2NH2, (Ci- Ce)alkoxy or (Ci-Ce)alkyl; or two vicinal occurrences of R 3 taken together with the carbon atoms to which they are bonded form an optionally substituted fused (C3-C7)cycloalkyl or (Ce)aryl; or two geminal occurrences of R 3 taken together with the carbon atom to which they are bonded form an optionally substituted spiro (C.3-C7)cycloalkyl; or two hominal occurrences of R 3 taken together with the carbon atoms to which they are bonded form an optionally substituted bridged (C3-C7)cycloalkyl;
• R x is independently for each occurrence H, (Ci-Ce)alkyl, or (C3-C7)cycloalkyl;
• R Y is independently for each occurrence H, (Ci-Ce)alkyl, or (C3-C?)c>'cloalkyl; or an occurrence of R Y and a substituent on R 2 taken together with the intervening atoms form a ring; optional substituents on R 1 or R 2 each independently represent halogen, -CN, -NO2, -OR 13 , -NR 13 R 14 , -C(0)R 13 , -C(0)0R 13 , -C(0)NR 13 R 14 , -0C(0)R 13 , -NR 13 C(0)R 14 , -0C(0)NR 13 R 14 , -0C(0)NR 13 R 14 , -0C(0)NR 13 R 14 , -0C(0)0R 13 , -NR 13 C(0)0R 14 , -NR 13 C(0)NR !3 R 14 , -0S(0)p(R 13 ), -SR 13 ,-NR 13 S(0)p(R 14 ), or optionally substituted
• R 13 and R 14 independently for each occurrence, represent H or optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, aryl, or heteroaiyl; and p is 0, 1, or 2.
• the invention provides a pharmaceutical composition, comprising a compound of the invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
• the invention provides methods of treating a disease or condition characterized by aberrant complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound the invention, or a pharmaceutically acceptable salt thereof.
• the disease or condition characterized by aberrant complement system activity is an immunological disorder.
• the disease or condition characterized by aberrant complement system activity is a disease of the central nervous system.
• the disease or condition characterized by aberrant complement system activity is a neurodegenerative disease or neurological disease.
• the disease or condition characterized by aberrant complement system activity is a renal disease.
• the disease or condition characterized by aberrant complement system activity is a cardiovascular disease.
• the disease or condition characterized by aberrant complement system activity is a cardiometabolic disease.
• the disease or condition characterized by aberrant complement system activity is selected from the group consisting of paroxysmal noctural hemoglobinuria, atypical hemolytic membranoproliferative glomerulonephritis, dense-deposit disease, cold agglutinin disease, and catastrophic antiphospholipid syndrome.
• the disease or condition characterized by aberrant complement system activity is selected from the group consisting of adult respiratory distress syndrome, myocardial infarct, lung inflammation, sepsis, cardiopulmonary bypass, bums, asthma, restenosis, multiple organ dysfunction, Guillain-Barre syndrome, hemorrhagic shock, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer’s disease, multiple sclerosis, platelet storage, and hemodialysis.
• the disease or condition characterized by aberrant complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis.
• ANCA antineutrophil cytoplasmic antibody
• AAV antigen-associated vasculitis
• warm autoimmune hemolytic anemia IgA nephropathy
• C3 glomerulonephritis C3 glomerulonephritis
• focal segmental glomerulosclerosis a hematological disorder.
• the disease or condition characterized by aberrant complement system activity is an ocular disorder or an eye disorder.
• the disease or condition characterized by aberrant complement system activity is macular degeneration, age-related macular degeneration (AMD), wet AMD, geographic atrophy, macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet’s uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, a comeal neovascularization disease, post-comeal transplant rejection, a comeal dystrophic disease, an autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren’s syndrome, an environmental dry eye disease, Fuchs’ endothelial dystrophy, retinal vein occlusion, or postoperative inflammation.
• AMD age-related macular degeneration
• CNV choroidal neovascularization
• Behcet’s uveitis proliferative diabetic retinopathy, non-prolife
• the disease or condition characterized by aberrant complement system activity is selected from the group consisting of obesity, insulin resistance, diabetes, dyslipidemia, nephropathy, neuropathy, angioedema, e.g., hereditary angioedema or acquired angioedema, thrombotic microangiopathy, Parkinson’s disease, schizophrenia, periodontitis, Crohn’s disease, C3 glomerulopathy, membranous nephropathy, osteoarthritis, bullous pemphigoid, psoriasis, hidradenitis suppurativa, of ischemia/reperfusion injury, acute kidney injury, and organ transplantation, e.g., kidney transplant, systemic inflammatory response syndrome, septic shock, trauma, cancer, antibody-mediated rejection, Berger’s disease, delayed graft function, granulomatosis with polyangiitis, graft versus host disease, hematopoietic stem cell transplant-related thrombotic microangiopathy immune
• Inhibitors of the complement system are useful in therapeutic methods and compositions suitable for use in treating disorders of the immune, renal, cardiovascular, and neurological systems.
• compounds of formula (I) and pharmaceutically acceptable salts thereof that are useful in treating or preventing a disease or condition characterized by aberrant activity of the complement system.
• an element means one element or more than one element.
• heteroatom refers to an atom of any element other than carbon or hydrogen.
• Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alteratively oxygen, nitrogen or sulfur.
• alkyl as used herein is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
• a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alteratively, about 20 or fewer, or 10 or fewer.
• the term “alkyl” refers to a C1-C10 alkyl group.
• alkyl refers to a Ci-Ce alkyl group, for example a Ci-Ce straight-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-C12 branched-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-C8 branched-chain alkyl group.
• alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
• cycloalkyl means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5-12 carbon atoms in their ring structure, and may have 6-10 carbons in the ring structure. Preferably, cycloalkyl is (C C )cycloalk>'l which represents a monocyclic saturated carbocyclic ring having from 3 to 7 carbon atoms.
• monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
• Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (/. ⁇ ?
• bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
• Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
• the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
• Cycloalkyl groups are optionally substituted.
• the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.
• (cycloalkyl)alkyr refers to an alkyl group substituted with one or more cycloalkyl groups.
• An example of cycloalkylalkyl is cyclohexylmethyl group.
• 3 ⁇ 4eterocycloalkyl refers to a radical of a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and having 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
• heterocyclic rings aziridinyl, azirinyl, oxiranyl, thiiranyl, thiircnyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3- dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl, dioxalanyl, o
• heterocycloalkylalkyl refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups.
• alkenyl as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
• Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-metiiyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl- 1-heptenyl, and 3-decenyl.
• the unsaturated bond(s) of the alkenyl group can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).
• alkynyl as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
• Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
• alkylene is art-recognized, and as used herein pertains to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above.
• an alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the
• amino is a term of art and as used herein refers to both imsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: wherein Ra Rt> and Rc each independently represent a hydrogen an alkyl an complete a heterocycle having from 4 to 8 atoms in the ring structure; Rd represents an aryl, a heteroaiyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and x is zero or an integer in the range of 1 to 8.
• Ra or Rb may be a carbonyl, e.g., Ra, Rb, and the nitrogen together do not form an imide.
• Ra and Rb (and optionally Rc) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CI1 ⁇ 2)x-Rd.
• Ra and Rb are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaiyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aryl alkyl, heteroarylalkyl, alkoxyalkyl, or haloalkyl, any of which may be further substituted (e.g., by halogen, alkyl, alkoxy, hydroxy, and so forth).
• the term “amino” refers to -NHz.
• alkylamino refers to -NH(alkyl).
• dialkylamino refers to -N(alkyl)z.
• acyl is a term of art and as used herein refers to any group or radical of the form RCO- where R is any organic group, e.g., alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.
• R is any organic group, e.g., alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.
• Representative acyl groups include acetyl, benzoyl, and malonyl.
• aminoalkyl refers to an alkyl group substituted with one or more one amino groups.
• aminoalkyl refers to an aminomethyl group, i.e., -CH2NH2.
• aminoacyl is a term of art and as used herein refers to an acyl group substituted with one or more amino groups.
• aminothionyl refers to an analog of an aminoacyl in which the O ofRC(O)- has been replaced by sulfur, hence is of the form RC(S)-.
• phosphoryl is a term of art and as used herein may in general be represented by the formula:
• O IR59 wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl; for example, -P(0)(0Me)- or -P(0)(0H)2.
• R59 represents hydrogen, a lower alkyl or an aryl; for example, -P(0)(0Me)- or -P(0)(0H)2.
• the phosphoryl group of the phosphorylalkyl may be represented by the general formulas: Q50 Q50
• aminophosphoryl refers to a phosphoryl group substituted with at least one amino group, as defined herein; for example, -P(0)(0H)NMez.
• azide or “azido”, as used herein, means an -Na group.
• alkylphosphoryl refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, -P(0)(0H)Me.
• alkylthio refers to alkyl-S-.
• (alkylthio)alkyl refers to an alkyl group substituted by an alkylthio group.
• aromatic hydrocarbon groups for example, benzene, naphthalene, anthracene, and pyrene.
• an aryl group contains from 6-10 carbon ring atoms (i.e., (C «-Cio)aryl).
• the aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the Uke.
• substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydry
• aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic hydrocarbon, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
• the term “aryl” refers to a phenyl group.
• roarvi is a term of art and as used herein refers to a monocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure.
• heteroaryl may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like.
• substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, im
• heteroaryl also includes polycyclic ring systems having two or more cyclic rings in which two or more atoms are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
• Such heteroaryl groups may be connected to the rest of the molecule through either the aromatic group having one or more heteroatoms in the ring structure or the other cyclic group.
• heteroaryl includes indole, which comprises a benzene ring and a pyrrole ring that are fused together.
• An indole substituent may be attached to a parent structure through either the benzene ring or through the pyrrole ring of the indole.
• aralkyl or “arylalkyl” is a term of art and as used herein refers to an alkyl group substituted with an aryl group, wherein the moiety is appended to the parent molecule through the alkyl group.
• heteroarylalkyl is a term of art and as used herein refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through the alkyl group.
• alkoxy as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
• Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
• alkoxyalkyl refers to an alkyl group substituted by an alkoxy group.
• alkoxycarbonyl means an alkoxy group as defined herein appended to herein.
• Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxy carbonyl, and te/7-butoxy carbonyl .
• alkylcarbonyl means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
• Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- 1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
• arylcarbonyl means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
• Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2- pyridinyl)carbonyl .
• alkylcarbonyloxy and “arylcarbonyloxy”, as used herein, means an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
• Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, elhylcarbonyloxy, and ter/-butylcarbonyloxy.
• Representative examples of arylcarbonyloxy include, but are not limited to phenylcarbonyloxy.
• alkenoxy or “alkenoxyl” means an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
• aryloxy as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
• heteroaryloxy as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
• Carbocyclyl as used herein means a monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl).
• carbocyclyl groups include 1 -cyclopropyl, 1 -cyclobutyl, 2-cyclopentyl, 1- cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl.
• cyano is a term of art and as used herein refers to -CN.
• halo is a term of art and as used herein refers to -F, -Cl, -Br, or -I.
• haloalkyl refers to an alkyl group, as defined herein, wherein some or all of the hydrogens are replaced with halogen atoms
• 3 ⁇ 4ydroxyalkyl means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein.
• Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4- hydroxyheptyl.
• silyl includes hydrocarbyl derivatives of the silyl (EbSi-) group (i.e., (hydrocarbyl)3Si-), wherein a hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl.
• the hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert- butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS), and [2- (trimethylsilyl)ethoxy]methyl (SEM).
• TMS trimethylsilyl
• TDPS tert-butyldiphenylsilyl
• TIPS triisopropylsilyl
• SEM [2- (trimethylsilyl)ethoxy]methyl
• silyloxy means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom.
• compositions of the present invention may exist in particular geometric or stereoisomeric forms.
• compounds of the present invention may also be optically active.
• the present invention contemplates all such compounds, including cis- and tram- isomers, (/?)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
• Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
• a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary', where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
• the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
• substitution ' or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound e g which does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.
• substituted is also contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
• Illustrative substituents include, for example, those described herein above.
• the permissible substituents may be one or more and the same or different for appropriate organic compounds.
• the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
• the optional substituents contemplated in this invention include halogen, azide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, hydroxyl, alkoxyl, amino, aminoalkyl, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether (e.g., -alkylene-0(alkyl)), alkylthio, sulfonyl, sulfonamido, ketone (e.g., - CO(alkyl)), aldehyde (-C(O)H), ester (e.g., -COO(alkyl)), haloalkyl, hydroxy
• the term “optionally substituted” or “substituted or unsubstituted” when it precedes a list of chemical moieties means that the list of chemical moieities that follow are each substituted or unsubstituted.
• “substituted or unsubstituted aryl, heteroaryl, and cycloalkyl” or “optionally substituted aryl, heteroaryl, and cycloalkyl” means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl.
• vicinal describes the positional relationship between two substituents, moieties, or functional groups each of which is bonded to one of two adjacent carbon atoms that are bonded to each other (i.e., the two substituents, moieties, or functional groups are in a 1,2-relationship).
• the methyl groups in 3,4-dimethylheptane are vicinal.
• the term “geminal” describes the positional relationship between two substituents, moieties, or functional groups bonded to the same carbon atom (i.e., the two substituents, moieties, or functional groups are in a 1,1-relationship).
• the methyl groups in 3,3- dimethylheptane are geminal
• the term “hominal” describes the positional relationship between two substituents, moieties, or functional groups each of which is bonded to one of two carbon atoms that themselves are each bonded to a single carbon atom (i.e., the two substituents, moieties, or functional groups are in a 1,3-relationship).
• the methyl groups in 3,5-dimethylheptane are hominal.
• protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
• protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
• the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.
• 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, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids.
• Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1.
• the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula I.
• the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula I per molecule of tartaric acid.
• prodrug refers to a compound that can be metabolized in vivo to provide a compound of formula I
• prodrugs include compounds that can be a corresponding compound that can be metabolized in vivo to provide a compound of formula I.
• modifications are known in the art.
• Prodrug forms of a compound beating various nitrogen-containing functional groups may include the following types of derivatives, where each Rp group individually may be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, a!kynyl, heterocycle, alksiarsi, aryl alkyl, ara!kenyl, aralkynyl, cycloalkyl or cycloalkenyl.
• Prodrug forms of carboxyl-bearing compounds include esters ( — COaRm), where the Rm group corresponds to any alcohol whose release m the body through enzymatic or hydrolytic processes would be at pharmaceutically acceptable levels.
• Another prodrug derived from a carboxylic acid form of the disclosure may ⁇ be a quaternary salt type of structure described by Bodor et al., J. Med. Chem. 1980, 23, 469.
• carrier' * and “pharmaceutically acceptable carrier” as used herein refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration.
• pharmaceutically acceptable carriers include liquids, such as water, saline, and oils; and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
• auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used.
• suitable pharmaceutical carriers are described in Remington 's Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety.
• treat means prevent, halt or slow the progression of, or eliminate a disease or condition in a subject
• “treat” means halt or slow “treat” means reduce at least one objective manifestation of a disease or condition in a subject.
• an effective amount refers to an amount that is sufficient to bring about a desired biological effect.
• terapéuticaally effective amount refers to an amount that is sufficient to bring about a desired therapeutic effect.
• inhibitor means decrease by an objectively measurable amount or extent. In various embodiments “inhibit” means decrease by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to relevant control. In one embodiment “inhibit” means decrease 100 percent, i.e., halt or eliminate.
• a subject refers to a mammal.
• a subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate.
• a subject is a human.
• the present invention provides compounds having the structure of Formula (I), and pharmaceutically acceptable salts thereof: wherein, independently for each occurrence:
• X is a bond or C(R X )J
• V is a bond, C(R Y ) 2 , or -N(R b K G is S or C(R 3 )z;
• R a and R b are each independently H or (Ci-Cejalkyl
• R 1 represents optionally substituted aryl, heteroaiyl, alkyl, cycloalkyl, alkenyl, or cycloalkenyl;
• R 2 represents optionally substituted bicyclic or tricyclic heteroaryl
• R 3 is independently for each occurrence H, halogen, -CN, -NHz, -CH2NH2, (Ci- Ce)alkoxy or (Ci-Ce)alkyl; or two vicinal occurrences of R 3 taken together with the carbon atoms to which they are bonded form an optionally substituted fused (C3-C7)cycloalkyl or (Ce)aiyl; or two geminal occurrences of R 3 taken together with the carbon atom to which they are bonded form an optionally substituted spiro (C3-C7)cycloalkyl; or two hominal occurrences of R 3 taken together with the carbon atoms to which they are bonded form an optionally substituted bridged (C3-C?)cycloalk>'l;
• R x is independently for each occurrence H, (Ci-C6)alkyl, or (C3-C7)cycloalkyl;
• R Y is independently for each occurrence H, (Ci-Ce)alkyl, or (C3-C7)cycloalkyl; or an occurrence of R Y and a substituent on R 2 taken together with the intervening atoms form a ring; optional substituents on R 1 or R 2 each independently represent halogen, -CN, -NO2, -OR 13 , -NR 13 R 14 , -C(0)R 13 , -C(0)0R 13 , -C(0)NR 13 R 14 , -0C(0)R 13 , -NR 13 C(0)R 14 , -OC(0)NR 13 R 14 , -0C(0)0R 13 , -NR 13 C(0)0R 14 , -NR 13 C(0)NR 13 R 14 , -0S(0)p(R 13 ), -SR 13 , -NR 13 S(0)p(R 14 ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalky
• R 13 and R 14 independently for each occurrence, represent H or optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, aryl, or heteroaryl; and p is 0, l, or 2.
• Y represents C(R Y )2, preferably CHz.
• X represents a bond. Alteratively, X may represent CH2.
• R 1 represents optionally substituted aryl or heteroaryl. In some embodiments, R 1 is optionally substituted heteroaryl. Exemplary embodiments of R 1 include optionally substituted phenyl (e.g., 3-halophenyl, or 2,3-dihalophenyl), (C3- C6)cycloalkyl, alkenyl, pyridinyl (e.g., 6-halopyridin-2-yl), orpyrazinyl (e.g., 6-halopyrazin-
• R 1 is mono-, di-, ortri- substituted.
• R 1 represents optionally substituted pyridinyl, preferably optionally substituted 2-pyridinyl.
• R 1 may represent
• R 1 represents optionally substituted phenyl.
• R 1 may represent
• R 2 represents *
• Z 1 represents N or CR 1Z ;
• Z 2 represents N or CR 2Z ;
• Z 3 represents N or C;
• Z 4 represents N or CR 4Z ;
• Z 5 represents N or CR 5Z ;
• Z 6 represents N or CR 6Z ;
• Z 8 represents C;
• Z 9 represents N or C; k is an integer from 1-4; m is an integer from 1-3; and each occurrence of R 1Z , R 2Z , R 4Z , R 5Z , R 6Z , R 7Z , R M independently represents H, halogen, -CN, -NO2, -OR 13 , -NR 13 R 14 , -C(0)R 13 , -C(0)0R 13 , -C(0)NR 13 R 14 , -0C(0)R 13 , -NR !3 C(0)R 14 , -0C(0)NR 13 R 14 , -0C(0)0R 13 , -NR 13 C(0)0R 14 , -NR 13 C(0)NR 13 R 14 , -0S(0)p(R 13 ), -SR 13 , -NR 13 S(0)p(R 14 ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy alkyl,
• Z 2 , Z 3 , Z 4 , and Z 6 represent N.
• Z 3 , Z 4 , and Z 6 represent N.
• Z 9 , Z 4 , and Z 6 represent N.
• Z 3 and Z 4 represent N.
• Z 1 , Z 3 , Z 4 , and Z 6 represent N.
• R 2 represents .
• R 2 may represent .
• k is 2.
• R 2 represents
• R 2 represents R 7Z R 1Z
• R 2 represents R 7Z , for example
• R 2 represents
• R 2 represents R 72 R1Z , for example
• R 7Z represents -NR 13 R 14 , for example -NH2.
• R 6Z represents -C(0)R 13 , -C(0)0R 13 , -C(0)NR 13 R 14 , or hydroxyalkyl.
• R 5Z represents alkyl, halo, or -NR 13 R 14 .
• R 1Z represents -CN, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, -C(0)R 13 , -SR 13 , -NR 13 R 14 , -OR 13 , -C(0)0R 13 , -C(0)NR 13 R 14 , or -NR 13 C(0)R 14 .
• each occurrence of R 2A independently represents -CN, -NO2, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted hydroxyalkyl, -C(0)NR 13 R 1
• G is C(R 3 )z.
• the compound of the invention has the structure of formula
• two vicinal occurrences of R 3 taken together with the carbon atoms to which they are bonded form an optionally substituted fused C3 -cycloalkyl.
• At least one occurrence of R 3 is halo, preferably fluoro.
• At least one occurrence of R 3 is methyl.
• two vicinal occurrences of R 3 taken together with the carbon atoms to which they are bonded form an optionally substituted fused C3 -cycloalkyl and another occurrence of R 3 is methyl.
• the compound of formula (I) is selected from the following table of compounds, and pharmaceutically acceptable salts thereof: 75d 24a
• N TT N o ⁇ 6 ,Na- ,N,

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