US20110269244A1 - Ligand-directed covalent modification of protein - Google Patents

Ligand-directed covalent modification of protein Download PDF

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US20110269244A1
US20110269244A1 US12/982,352 US98235210A US2011269244A1 US 20110269244 A1 US20110269244 A1 US 20110269244A1 US 98235210 A US98235210 A US 98235210A US 2011269244 A1 US2011269244 A1 US 2011269244A1
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independently
alkyl
formula
integer
compound
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Russell C. Petter
Charles F. Jewell
Kwangho Lee
Aravind Prasad Medikonda
Deqiang Niu
Lixin Qiao
Juswinder Singh
Zhendong Zhu
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Celgene CAR LLC
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Avila Therapeutics Inc
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Assigned to AVILA THERAPEUTICS, INC. reassignment AVILA THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JEWELL, CHARLES F., LEE, KWANGHO, MEDIKONDA, ARAVIND PRASAD, NU, DEQIANG, PETTER, RUSSELL C., QIAO, LIXIN, SINGH, JUSWINDER, ZHU, ZHENDONG
Assigned to AVILA THERAPEUTICS, INC. reassignment AVILA THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JEWELL, CHARLES F., LEE, KWANGHO, MEDIKONDA, ARAVIND PRASAD, NIU, DEQIANG, PETTER, RUSSELL C., QIAO, LIXIN, SINGH, JUSWINDER, ZHU, ZHENDONG
Publication of US20110269244A1 publication Critical patent/US20110269244A1/en
Assigned to CELGENE AVILOMICS RESEARCH, INC. reassignment CELGENE AVILOMICS RESEARCH, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: AVILA THERAPEUTICS, INC.
Priority to US15/423,115 priority patent/US11542492B2/en
Assigned to CELGENE CAR LLC reassignment CELGENE CAR LLC MERGER (SEE DOCUMENT FOR DETAILS). Assignors: CELGENE AVILOMICS RESEARCH, INC.
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Definitions

  • the present invention relates to enzyme inhibitors. More specifically, the present invention relates to ligand-directed covalent modification of lysine-containing proteins.
  • reversible inhibitors have been developed that are efficacious therapeutic agents, reversible inhibitors have certain disadvantages. For example, many reversible inhibitors of kinases interact with the ATP-binding site. Because the structure of the ATP-binding site is highly conserved among kinases, it has been very challenging to develop reversible inhibitors that selectively inhibit one or more desired kinases. In addition, because reversible inhibitors dissociate from their target protein, the duration of inhibition may be shorter than desired. Thus, when reversible inhibitors are used as therapeutic agents higher quantities and/or more frequent dosing than is desired may be required in order to achieve the intended biological effect. This dosing requirement may produce toxicity or result in other undesirable effects.
  • Covalent irreversible inhibitors of drug targets have a number of important advantages over their reversible counterparts as therapeutics. Prolonged suppression of the drug targets may be necessary for maximum pharmacodynamic effect and an irreversible inhibitor can provide this advantage by permanently eliminating existing drug target activity, which will return only when new target protein is synthesized.
  • an irreversible inhibitor is administered, the therapeutic plasma concentration of the irreversible inhibitor would need to be attained only long enough to briefly expose the target protein to the inhibitor, which would irreversibly suppress activity of the target and plasma levels could then rapidly decline while the target protein would remain inactivated.
  • This irreversible binding has the potential advantage of lowering the minimal blood plasma concentration at which therapeutic activity occurs, minimizing multiple dosing requirements and eliminating the requirement for long plasma half-lives without compromising efficacy. All of these considerations could reduce toxicity due to any nonspecific off-target interactions that may occur at high or prolonged blood plasma levels. Irreversible inhibitors also likely have advantages in overcoming drug resistance requirements in two ways. First, irreversible inhibitors eliminate the requirement for long blood plasma half-lives without compromising efficacy. Second, because resistance mutations may compromise non-covalent binding, but even in the face of reduced non-covalent affinity, the inactivation mechanism will often, nonetheless, lead to protein target modification and irreversible inhibition.
  • reversible inhibitors of proteins are presently known, as are many of their binding sites in the proteins to which the reversible inhibitors bind.
  • the binding sites of these reversible inhibitors are sometimes populated with amino acids that are capable of covalent modification with suitably reactive ligands.
  • amino acids are located near the binding sites of reversible inhibitors that are capable of covalent modification with suitably reactive ligands.
  • Amino acids capable of covalent modification are typically those which have a heteroatom such as O, S, or N in the side chain, such as threonine, cysteine, histidine, serine, tyrosine, and lysine.
  • Sulfur is amenable to covalent modification due to the nucleophilicty of sulfur, and as such there are examples of ligands that modify cysteine in proteins of interest.
  • amino acids such as lysine are usually sufficiently unreactive that ligands do not react in vivo with lysine.
  • highly reactive indiscriminate reagents are usually employed for lysine modification.
  • ligand-directed modification of lysine has heretofore remained unrealized. For this reason and others, there is a need for irreversible inhibitors of proteins of medicinal interest, which inhibitors exert their biological influence through a ligand-directed modification of lysine.
  • the invention provides a method for designing a ligand that covalently binds a target protein.
  • the method comprises (a) providing a structural model of a reversible ligand docked within, or in proximity to, a ligand-binding site in a target protein, (b) identifying a lysine residue of the target protein in, or in proximity to, the ligand-binding site that is less than about 15 ⁇ from the reversible ligand when the reversible ligand is docked in, or in proximity to, the ligand-binding site, (c) producing at least a structural model of at least one ligand-warhead compound docked within, or in proximity to, the ligand-binding site wherein the ligand-warhead compound comprises the reversible ligand in step (b) or a portion thereof, a warhead comprising a reactive chemical moiety, and optionally a Tether, and (d) identifying a ligand-war
  • the invention provides a method for designing a ligand that covalently binds a lysine residue of a target protein.
  • the method comprises (a) providing a structural model of a reversible ligand docked in, or in proximity to, a ligand-binding site in a target protein, wherein the reversible ligand makes at least one non-covalent contact with the ligand-binding site; (b) identifying a lysine residue in, or in proximity to, the ligand-binding site of the target protein that is adjacent to the reversible ligand when the reversible ligand is docked in, or in proximity to, the ligand-binding site; (c) producing structural models of a plurality of ligand-warhead compounds docked in, or in proximity to, the ligand-binding site wherein each ligand-warhead compound comprises a warhead covalently attached to a substitutable position of the reversible ligand
  • the invention provides a method for identifying at least one lysine residue within at least one protein that can be modified covalently.
  • the method comprises (a) identifying at least one protein having a ligand-binding site, (b) providing a three-dimensional structural model for the identified protein, (c) docking a reversible ligand in, or in proximity to, the identified protein's ligand-binding site in the structural model, wherein the reversible ligand makes at least one non-covalent contact with the ligand-binding site, thereby creating a structural model of a reversible ligand bound to, or in proximity to, an identified protein's ligand-binding site; and (d) identifying in the structural model of a reversible ligand bound to, or in proximity to, an identified protein's ligand-binding site one or more lysine residues in, or in proximity to, the ligand-binding site of the identified protein which is less than about 15 ⁇ from
  • the invention provides a method of covalently modifying a lysine residue in, or in proximity to, a ligand-binding site of a protein, comprising contacting a compound of Formula I:
  • the protein containing a lysine residue in, or in proximity to, the ligand-binding site of the protein and forming a covalent bond between the side chain primary amine group of the lysine residue and the Warhead of the compound.
  • the invention provides compounds of Formula I:
  • Scaffold, Warhead, Tether, x and y are as defined herein.
  • the invention provides protein-modifier-ligand conjugates of Formula XIII:
  • Scaffold, Polypeptide, Tether, M, Y 1 , x and y are as defined herein.
  • a method for selecting a warhead that binds to a target lysine within a ligand binding site of a protein comprises (a) identifying at least one protein having a ligand-binding site, (b) providing a three-dimensional structural model for the identified protein, (c) identifying the locations of at least one lysine in, or in proximity to, the ligand-binding site of step (a); (d) providing at least one warhead in proximity to the at least one identified lysine; (e) aligning the electrophilic atom of the warhead within bonding distance of the primary amine of the at least one identified lysine; (f) forming a covalent bond between the electrophilic atom of the warhead and the primary amine of the at least one lysine; (g) docking a reversible ligand in the identified protein's ligand-binding site within 15 ⁇ of the covalently attached warhead of step (f),
  • FIG. 1 shows the X-ray co-crystal structure (2JK7) with key lysines in XIAP proximal to bound Smac-mimetic ligand.
  • FIG. 2 depicts non-limiting examples of weaponizing the Smac-mimetic ligand.
  • FIG. 3 depicts the mass spectrometric analysis of Compound XVI-26 contacted with HCV NS3 Protease.
  • FIG. 4 depicts the mass spectrometric analysis of Compound XVI-26 treated with HCV NS3 Protease (WT); HCV NS3 Protease (C159S); and HCV NS3 protease (C159S/K136A).
  • FIG. 5 depicts the mass spectrometric analysis of compound XVI-1 treated with HCV NS3 Protease (WT1b).
  • FIG. 6 depicts the mass spectrometric analysis of compound VII-1 contacted with XIAP.
  • FIG. 7 depicts the mass spectrometric analysis of chymotrypsin digestion of XIAP (top) and XIAP contacted with compound VII-1 (bottom).
  • FIG. 8 depicts the mass spectrometric analysis of compound VII-21 contacted with XIAP.
  • FIG. 9 depicts the mass spectrometric analysis of chymotrypsin digestion of XIAP (top) and XIAP contacted with compound VII-21 (bottom).
  • FIG. 10 depicts that the probe compound XVI-27 modifies NS3/4A C159S.
  • FIG. 11 depicts the prolonged duration of action of XVI-26.
  • FIG. 12 depicts the mass spectrometric analysis of Compound XI-27 contacted with PDPK-1 (whole protein).
  • FIG. 13 depicts the mass spectrometric analysis of the trypsin digestion of PDPK-1 (whole protein) contacted with Compound XI-27 identifying the peptide 164 NGELLKYIR 172 (SEQ ID NO.:1).
  • FIG. 14 depicts the MSMS analysis of the peptide 164 NGELLKYIR 172 (SEQ ID NO.:1) modified by XI-27 from the digest depicted in FIG. 13 and identifying K169 as the lysine modified by XI-27.
  • FIG. 15 depicts the mass spectrometric analysis of Compound XI-21 contacted with PDPK-1 (whole protein).
  • FIG. 16 depicts the mass spectrometric analysis of the trypsin digestion of PDPK-1 (whole protein) contacted with Compound XI-21 identifying three peptides 164 NGELLKYIR 172 (SEQ ID NO.:1), 173 KIGSFDETCTR 183 (SEQ ID NO.:2), and 84 FGKILGEGSFSTVVLAR 100 (SEQ ID NO.:3).
  • FIG. 17 depicts the MSMS analysis of the peptide 164 NGELLKYIR 172 (SEQ ID NO.:1) from the digest depicted in FIG. 16 and identifying K169 as the lysine modified by XI-21.
  • FIG. 18 depicts the MSMS analysis of the peptide 173 KIGSFDETCTR 183 (SEQ ID NO.:2) from the digest depicted in FIG. 16 and identifying K173 as the lysine modified by XI-21.
  • FIG. 19 depicts the MSMS analysis of the peptide 84 FGKILGEGSFSTVVLAR 100 (SEQ ID NO.:3) from the digest depicted in FIG. 16 and identifying K86 as the lysine modified by XI-21.
  • FIG. 20 depicts the mass spectrometric analysis of Compound XXXVI-2 contacted with PDPK-1 (whole protein).
  • FIG. 21 depicts the mass spectrometric analysis of Compound XXXVI-1 contacted with PDPK-1 (whole protein).
  • FIG. 22 depicts the mass spectrometric analysis of Compound XXII-33 contacted with PI3K ⁇ (whole protein).
  • protein means linear polymers made up of the 20 different naturally occurring L- ⁇ -amino acids, as well as other less common amino acids. The amino acids in a polymer are joined together by peptide bonds between the carboxyl and amino groups of adjacent amino acid residues.
  • polypeptide can be used interchangeably herein with the term protein. Polypeptides can be full length proteins, as well as any portion of a protein.
  • protein and polypeptide are used to describe proteins containing ligand binding sites. Any protein or polypeptide contemplated herein will be large enough to fold and constitute a ligand binding site.
  • aliphatic or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “carbocyclic,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-8 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “carbocyclic” refers to a monocyclic C 3 -C 8 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bridged bicyclic refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an optionally substituted chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7- to 12-ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group or the bridge is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bridged bicyclics include:
  • lower alkyl refers to a C 1-4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated means that a moiety has one or more units of unsaturation.
  • bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., —(CH 2 ) n —, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure:
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-,” as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH 2 ) 0-4 R o ; —(CH 2 ) 0-4 OR o ; —O(CH 2 ) 0-4 R o , —O—(CH 2 ) 0-4 C(O)OR o ; —(CH 2 ) 0-4 CH(OR o ) 2 ; —(CH 2 ) 0-4 SR o ; —(CH 2 ) 0-4 Ph, which may be substituted with R o ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph which may be substituted with R o ; —CH ⁇ CHPh, which may be substituted with R o ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl which may be substituted with R o ; —NO 2 ; —CN;
  • Suitable monovalent substituents on R o are independently halogen, —(CH 2 ) 0-2 R • , -(haloR • ), —(CH 2 ) 0-2 OR • , —(CH 2 ) 0-2 OR • , —(CH 2 ) 0-2 CH(OR • ) 2 ; —O(haloR • ), —CN, —N 3 , —(CH 2 ) 0-2 C(O)R • , —(CH 2 ) 0-2 C(O)OH, —(CH 2 ) 0-2 C(O)OR • , —(CH 2 ) 0-2 SR • , —(CH 2 ) 0-2 SH, —(CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-2 NHR • , —(CH 2 ) 0-2 NR •
  • Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ⁇ O (“oxo”), ⁇ S, ⁇ NNR* 2 , ⁇ NNHC(O)R*, ⁇ NNHC(O)OR*, ⁇ NNHS(O) 2 R*, ⁇ NR*, ⁇ NOR*, —O(C(R* 2 )) 2-3 O—, or —S(C(R* 2 )) 2-3 S—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR* 2 ) 2-3 O—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R • include halogen, —R • , -(haloR • ), —OH, —OR • , —O(haloR • ), —CN, —C(O)OH, —C(O)OR • , —NH 2 , —NHR • , —NR • 2 , or —NO 2 , wherein each R • is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R ⁇ , —C(O)R ⁇ 2 , —C(O)R ⁇ , —C(O)C(O)R ⁇ , —C(O)CH 2 C(O)R ⁇ , —S(O) 2 R ⁇ , —S(O) 2 NR ⁇ 2 , —C(S)NR ⁇ 2 , —C(NH)NR ⁇ 2 , or —N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ ,
  • Suitable substituents on the aliphatic group of R • are independently halogen, —R • , -(haloR • ), —OH, —OR • , —O(haloR • ), —CN, —C(O)OH, —C(O)OR • , —NH 2 , —NHR • , —NR • 2 , or —NO 2 , wherein each R • is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66, 1-19 (1977), incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • the term “irreversible” or “irreversible inhibitor” refers to an inhibitor (i.e., a compound) that is able to covalently binds to an enzyme, or portion thereof in a substantially non-reversible manner. That is, whereas a reversible inhibitor is able to bind to (but is generally unable to form a covalent bond with) an enzyme, and therefore can become dissociated from the enzyme an irreversible inhibitor will remain substantially bound to an enzyme once covalent bond formation has occurred.
  • Irreversible inhibitors usually display time dependency, whereby the degree of inhibition increases with the length of time with which the inhibitor is in contact with the enzyme. In certain embodiments, an irreversible inhibitor will remain substantially bound to an enzyme once covalent bond formation has occurred and will remain bound for a time period that is longer than the life of the enzyme.
  • Such methods include, but are not limited to, enzyme kinetic analysis of the inhibition profile of the compound with the enzyme, the use of mass spectrometry of the protein drug target modified in the presence of the inhibitor compound, discontinuous exposure, also known as “washout,” experiments, and the use of labeling, such as radiolabelled inhibitor, to show covalent modification of the enzyme, as well as other methods known to one of skill in the art.
  • warheads refers to a functional group present on a compound of the present invention wherein that functional group is capable of covalently binding to lysine, present in or near the binding pocket of a target protein, thereby irreversibly inhibiting the protein.
  • Tether-Warhead group as defined and described herein, provides such warhead groups for covalently, and irreversibly, inhibiting the protein.
  • an inhibitor is defined as a compound that binds to and/or inhibits an enzyme with measurable affinity.
  • an inhibitor has an IC 50 and/or binding constant of less about 10 ⁇ M, less than about 1 ⁇ M, less than about 100 nM, or less than about 10 nM.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change in any lysing-containing protein, such as, e.g., XIAP, PI3K ⁇ / ⁇ , PDPK1 and HCV-NS3 protease activity between a sample comprising a compound of the present invention, or composition thereof, and at least one of XIAP, PI3K ⁇ / ⁇ , PDPK1 and HCV-NS3 protease, and an equivalent sample comprising at least one of XIAP, PI3K ⁇ / ⁇ , PDPK1 and HCV-NS3 protease, in the absence of said compound, or composition thereof.
  • XIAP e.g., XIAP, PI3K ⁇ / ⁇ , PDPK1 and HCV-NS3 protease activity between a sample comprising a compound of the present invention, or composition thereof, and at least one of XIAP, PI3K ⁇ / ⁇ , PDPK1 and HCV-NS
  • lysine residues located in, or in proximity to, a ligand binding site in any targeted family of proteins can be targeted for ligand-directed lysine modification.
  • lysine residues of protein family members targeted for ligand-directed modification by irreversible inhibitors include, without limitation, those summarized in Table 1, below, where “Family” column refers to a family of proteins of interest; the “UniProtAC” column refers to the accession number identifier of a particular protein in accordance with UniProt Knowledgebase (UniProtKB) accession numbers (www.uniprot.org); the “Sequence” column refers to an identifying fragment of the Family member protein's amino acid sequence which includes the lysine of interest; and the “Residue Number” column refers to the lysine residue number as set forth in the sequence.
  • antibodies as a family of proteins, are not contemplated within the present invention and therefore are excluded.
  • the family of proteins having targetable lysine residues according to the present invention is BCL-2.
  • the family of proteins is Calpains.
  • the family of proteins is Caspases.
  • the family of proteins is Cathepsins.
  • the family of proteins is HCV.
  • the family of proteins is HDAC.
  • the family of proteins is HSP70.
  • the family of proteins is HSP90.
  • the family of proteins is IAP.
  • the family of proteins is Kinase.
  • the family of proteins is MDM2.
  • the family of proteins is MMP.
  • the family of proteins is NHR. In other embodiments, the family of proteins is PI3K. In other embodiments, the family of proteins is Phosphatase. In other embodiments, the family of proteins is Transthyretin. In other embodiments, the family of proteins is PARP. In other embodiments, the family of proteins is HIV Protease.
  • the members of the BCL-2 family of proteins comprise Bcl-2-like protein 13, Bcl-2-related protein A1, and Bcl-2-related ovarian killer protein.
  • the target lysines are K110, K121, and K152 in Bcl-2-like protein 13; K046, K050, K077, and K147 in Bcl-2-related protein A1; and K122 in Bcl-2-related ovarian killer protein.
  • the members of the Calpains family of proteins comprise Calpain-3, Calpain-5, Calpain-6, and Calpain-9.
  • the target lysines are K220, and K410 in Calpain 3; K233 in Calpain-5; K081 and K336 in Calpain-6; and K188 and K330 in Calpain-9.
  • the members of the Caspases family of proteins comprises Caspase-2, Caspase-3, Caspase-6, Caspase-8, Caspase-9, Caspase-10, Caspase-14, and Mucosa-associated lymphoid tissue lymphoma translocation protein 1.
  • the target lysines are K381 in Caspase-2; K210 in Caspase-3; K265 in Caspase-6; K253, K453, K456, and K457 in Caspase-8; K358 and K394 in Caspase-9; K298 in Caspase-10; K096 in Caspase-14, and K358, K360, K466, and K513 in Mucosa-associated lymphoid tissue lymphoma translocation protein 1.
  • the members of the Cathepsin family of proteins comprise Cathepsin F, Cathepsin H, and Cathepsin W.
  • the target lysines are K238, K331, and K374 in Cathepsin F; K278 in Cathepsin H; and K267 in Cathepsin W.
  • the members of the HCV family of proteins comprises Genome polyprotein (NS3), Genome polyprotein (NS5A), and Genome polyprotein (NS5B).
  • the target lysines are K1236 in Genome polyprotein (NS3); K2016 in Genome polyprotein (NS5A); and K2560 in Genome polyprotein (NS5B).
  • the members of the HCV family of proteins comprises HCV-NS3, HCV-NS5A, and HCV-NS5B.
  • the members of the HDAC family of proteins comprise Histone deacetylase 1, Histone deacetylase 11, Histone deacetylase 2, Histone deacetylase 3, Histone deacetylase 6, and Histone deacetylase 8.
  • the target lysines are K031 in Histone deacetylase 1; K306 in Histone deacetylase 11; K032 in Histone deacetylase 2; K025 in Histone deacetylase 3; K353 in Histone deacetylase 6; and K033 in Histone deacetylase 8.
  • the members of the HSP70 family of proteins comprise Heat shock 70 kDa protein 6, and Heat shock cognate 71 kDa protein.
  • the target lysines are K058, K073, and K273 in Heat shock 70 kDa protein 6; and K061, K071, and K271 in Heat shock cognate 71 kDa protein.
  • the members of the HSP90 family of proteins comprise Heat shock protein HSP 90-alpha, and Heat shock protein HSP 90-beta.
  • the target lysines are K058 in Heat shock protein HSP 90-alpha; and K053 in Heat shock protein HSP 90-beta.
  • the members of the IAP family of proteins comprise Baculoviral IAP repeat-containing protein 1 (NAIP aka BIRC1), Baculoviral IAP repeat-containing protein 2 (BIRC2 aka C-IAP1 aka API1 aka IAP2 aka MIHB), Baculoviral IAP repeat-containing protein 3 (BIRC3 aka C-IAP2 aka API2 aka IAP1 aka MIHC), Baculoviral IAP repeat-containing protein 4 (XIAP aka ILP1 aka HILP aka API3 aka BIRC4 aka IAP3), Baculoviral IAP repeat-containing protein 5 (BIRC5 aka Survivin aka API4 aka IAP4), Baculoviral IAP repeat-containing protein 7 (BIRC7 aka ML-IAP aka livin aka K-IAP), and Baculoviral IAP repeat-containing protein 8 (BIRC8 aka ILP2 aka TsIAP).
  • NAIP aka BIRC1
  • BIOS Baculoviral
  • the target lysines are K191 and K199 in Baculoviral IAP repeat-containing protein 1; K305 in Baculoviral IAP repeat-containing protein 2; K291 in Baculoviral IAP repeat-containing protein 3; K297, K299, and K311 in Baculoviral IAP repeat-containing protein 4; K062 and K079 in Baculoviral IAP repeat-containing protein 5; K121, K135, and K146 in Baculoviral IAP repeat-containing protein 7; and K036, K050, and K061 in Baculoviral IAP repeat-containing protein 8.
  • the members of the IAP family of proteins comprises XIAP, cIAP1, cIAP2, and ML-IAP.
  • the members of the Kinases family of proteins comprise B-Raf proto-oncogene serine/threonine-protein kinase, Serine/threonine-protein kinase Chk2, Epidermal growth factor receptor, Hepatocyte growth factor receptor, 3-phosphoinositide-dependent protein kinase 1 (PDPK1), Proto-oncogene serine/threonine-protein kinase Pim-1.
  • FGFR1 Basic fibroblast growth factor receptor 1
  • FGFR2 Fibroblast growth factor receptor 2
  • FGFR3 Fibroblast growth factor receptor 3
  • FGFR4 Fibroblast growth factor receptor 4
  • PDPK1 3-phosphoinositide-dependent protein kinase 1
  • b-RAF Serine/threonine-protein kinase B-raf
  • RAF1 RAF proto-oncogene serine/threonine-protein kinase
  • Tyrosine-protein kinase SYK 3-phosphoinositide-dependent protein kinase 1
  • b-RAF Serine/threonine-protein kinase B-raf
  • RAF1 RAF proto-oncogene serine/threonine-protein kinase
  • Tyrosine-protein kinase SYK Tyrosine-protein kinase SYK
  • the target lysines are K483 in B-Raf proto-oncogene serine/threonine-protein kinase; K224, K245, K252, and K349 in Serine/threonine-protein kinase Chk2; K716, K728, and K745 in Epidermal growth factor receptor; K1110 and K1161 in Hepatocyte growth factor receptor; K086, K163, K169, and K207 in PDPK1; K260 in Proto-oncogene serine/threonine-protein kinase Pim-1; K514, K566 in basic fibroblast growth factor receptor 1 (FGFR1), K517, K569 in basic fibroblast growth factor receptor 2 (FGFR2); K560, K508 in basic fibroblast growth factor receptor 3 (FGFR3); K503, K555 in basic fibroblast growth factor receptor 4 (FGFR4); K173 in 3-phosphoinositide-dependent protein kinase 1 (PD
  • the members of the PDK family of proteins comprises PDPK1.
  • the members of the MDM2 family of proteins comprise E3 ubiquitin-protein ligase Mdm2, Protein Mdm4, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2, and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3.
  • the target lysines are K051 and K094 in E3 ubiquitin-protein ligase Mdm2; K050 and K093 in Protein Mdm4; K327 in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1; K301 in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2; and K302 in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3.
  • the members of the MMP family of proteins comprise Macrophage metalloelastase, Collagenase 3, Matrix metalloproteinase-14, Matrix metalloproteinase-15, and Matrix metalloproteinase-20.
  • the target lysines are K233 and K241 in Macrophage metalloelastase; K150 and K249 in Collagenase 3; K146 in Matrix metalloproteinase-14; K284 in Matrix metalloproteinase-15; and K251 in Matrix metalloproteinase-20.
  • the members of the NHR family of proteins comprise Estrogen receptor, Estrogen receptor beta, Peroxisome proliferator-activated receptor alpha, and Progesterone receptor.
  • the target lysines are K529 in Estrogen receptor; K314 in Estrogen receptor beta; K252 and K358 in Peroxisome proliferator-activated receptor alpha; and K919 in Progesterone receptor.
  • the members of the PI3K protein family comprise Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PI3K-alpha aka PIK3CA), Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta isoform (PI3K-beta aka PIK3CB aka PIK3C1), and Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PI3K gamma aka PIK3CG).
  • PI3K-alpha aka PIK3CA Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
  • PI3K-beta aka PIK3CB aka PIK3C1
  • the target lysines are K776 and K802 in Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform; K777 and K805 in Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta isoform; and K802, K807, K833, K883, and K890 in Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform.
  • the members of the PI3K family of proteins comprises PI3K ⁇ , PI3K ⁇ and PI3K ⁇ .
  • PI3K refers to PI3K ⁇ and PI3K ⁇ interchangeably as the ligand-directed warhead of the present invention, directed to PI3K will modify both PI3K ⁇ as well as PI3K ⁇ .
  • the members of the Phosphatase family of proteins comprise Leukocyte common antigen, Tyrosine-protein phosphatase non-receptor type 1, Tyrosine-protein phosphatase non-receptor type 11, Tyrosine-protein phosphatase non-receptor type 13, Tyrosine-protein phosphatase non-receptor type 14, Tyrosine-protein phosphatase non-receptor type 18, Tyrosine-protein phosphatase non-receptor type 2, Tyrosine-protein phosphatase non-receptor type 22, Tyrosine-protein phosphatase non-receptor type 3, Tyrosine-protein phosphatase non-receptor type 4, Tyrosine-protein phosphatase non-receptor type 5, Tyrosine-protein phosphatase non-receptor type 6, Tyrosine-protein phosphatase non-receptor type 7, Tyrosine-protein phosphatase non-receptor type 9, and Receptor-type
  • the target lysines are K623 and K759 in Leukocyte common antigen; K120 in Tyrosine-protein phosphatase non-receptor type 1; K260, K280, K364, K366 in Tyrosine-protein phosphatase non-receptor type 11; K2224, K2244, K2316, and K2318 in Tyrosine-protein phosphatase non-receptor type 13; K918, K919, and K1018 in Tyrosine-protein phosphatase non-receptor type 14; K041 and K063 in Tyrosine-protein phosphatase non-receptor type 18; K038 in Tyrosine-protein phosphatase non-receptor type 2; K032, K039, K136, and K138 in Tyrosine-protein phosphatase non-receptor type 22, K656, K666, K677, and K753 in Tyrosine-protein phosphatase non-receptor type 3;
  • the member of the Transthyretin family of proteins comprises Transthyretin (Prealbumin aka TBPA aka TTR aka ATTR aka PALB).
  • the target lysine is K035 in Transthyretin.
  • the members of the PARP family of proteins comprise Poly [ADP-ribose] polymerase 1 (PARP1 aka ADPRT aka PPOL aka ADPRT), Poly [ADP-ribose] polymerase 3 (PARP3 aka ADPRT3 aka ADPRTL3 aka IRT1), Poly [ADP-ribose] polymerase 10 (PARP10), Poly [ADP-ribose] polymerase 12 (PARP12 aka ZC3HDC1), Poly [ADP-ribose] polymerase 15 (PARP15 aka BAL3), and Tankyrase-1 (TNKS aka PARPSA, PARPL aka TIN1 aka TINF1 aka TNKS1).
  • PARP1 ADPRT aka PPOL aka ADPRT
  • PARP3 Poly [ADP-ribose] polymerase 3
  • PARP10 Poly [ADP-ribose] polymerase 10
  • PARP12 Poly [ADP-ribose]
  • the target lysines are K903 in Poly [ADP-ribose] polymerase 1; K421 in Poly [ADP-ribose] polymerase 3; K941 in Poly [ADP-ribose] polymerase 10; K609 in Poly [ADP-ribose] polymerase 12; K566, K579 and K636 in Poly [ADP-ribose] polymerase 15; and K1220 and K1269 in Tankyrase-1.
  • the member of the HIV Protease family of proteins comprises Gag-Pol polyprotein (HIV protease aka Retropepsin aka PR).
  • the target lysine is K535 in Gag-Pol polyprotein.
  • One aspect of the present disclosure is a method for designing a ligand that covalently binds a target protein.
  • the method comprises (a) providing a structural model of a reversible ligand docked within, or in proximity to, a ligand-binding site in a target protein, (b) identifying a lysine residue of the target protein in, or in proximity to, the ligand-binding site that is less than about 15A from the reversible ligand when the reversible ligand is docked in, or in proximity to, the ligand-binding site, (c) producing at least a structural model of at least one ligand-warhead compound docked within, or in proximity to, the ligand-binding site wherein the ligand-warhead compound comprises the reversible ligand in step (b) or a portion thereof, a warhead comprising a reactive chemical moiety, and optionally a Tether, and (d) identifying a ligand
  • FIG. 1 shows X-ray co-crystal structure (2JK7) showing key lysines in XIAP proximal to bound Smac-mimetic ligand.
  • 2JK7 X-ray co-crystal structure
  • step (b) depicts non-limiting lysine-targeted warheads installed on scaffolds such that they are directed toward the targeted lysines positioned strategically at portions of compounds based on the pharmacophore of the Smac-mimetic ligand which are in proximity to the identified lysines, above.
  • the reactive warheads (along with a Tether when required) are positioned in silico such that docking of a modified pharmacophore of the ligand in the structural model of the protein binding site (provided in step (a) above), as described in step (c) above, allows for determination of the spatial arrangement of the reactive warhead vis a vis the identified lysine of step (b).
  • the method further comprises step (e): forming, for the ligand-warhead compound identified in step (d), a ligand-protein, covalent adduct by forming a covalent bond between the side chain primary amine group of the lysine residue identified in step (b) and the warhead electrophile in ligand-warhead compound identified in step (d) while maintaining the binding elements of the pharmacophore required for non-covalent binding to the ligand's target protein.
  • the method further comprises step (f): evaluating the conformation of the resulting ligand-protein covalent adduct formed in step (e) by analyzing the global energy of the resulting conformation, or by analyzing the energy of the conformation of the Tether.
  • the method comprises alternate step (f): determining whether the ligand-binding site is occluded when the covalent bond is formed between the side chain primary amine group of the lysine residue in, or in proximity to, the ligand-binding site and the warhead electrophile.
  • the method comprising steps (a)-(f) is iterated with changes to the Tether and the global energy of the resulting conformation is less than the previous iteration.
  • the covalent bond formed in step (e) is formed using a computational method in which the warhead and the side chain of the lysine residue are flexible and the remainder of the structures of the ligand-warhead compound and the ligand-binding site are fixed.
  • each of the lysine residues in, or in proximity to, the ligand-binding site of the target protein which is less than about 15 ⁇ from the reversible ligand, when the reversible ligand is docked in, or in proximity to, the ligand-binding site, is identified.
  • step (c) of the method further comprises providing a plurality of models of the ligand-warhead compound, wherein the warhead is bonded to a different substitutable position of the ligand or a portion of the ligand in each model of the ligand-warhead compound, optionally with the Tether in between the warhead and the substitutable position.
  • the target protein is an identified member of an identified protein family and the lysine residue is not conserved across the identified members of the protein family.
  • the target protein is an identified member of an identified protein family and the lysine residue is conserved among more than one identified member of the identified protein family.
  • the lysine residue is conserved across identified members of the protein family.
  • the target protein has catalytic activity.
  • the target protein family is selected from the group consisting of BCL-2, Calpains, Caspases, Cathepsins, HCV, HDAC, HSP70, HSP90, IAP, Kinase, MDM2, MMP, NHR, PI3K ⁇ / ⁇ , Phosphatase, Transthyretin, PARP, and HIV Protease.
  • the target family of proteins is selected from the group consisting of IAP, PI3K, PDPK1, and HCV.
  • the target protein is selected from the group consisting of XIAP, PI3K ⁇ / ⁇ , PDPK1, and HCV.
  • the ligand-binding site is a ligand-binding site for a substrate or cofactor.
  • the lysine residue for covalent modification is not a catalytic residue.
  • the disclosure provides a method for designing a ligand that covalently binds a lysine residue of a target protein.
  • the method comprises (a) providing a structural model of a reversible ligand docked in, or in proximity to, a ligand-binding site in a target protein, wherein the reversible ligand makes at least one non-covalent contact with the ligand-binding site, (b) identifying a lysine residue in, or in proximity to, the ligand-binding site of the target protein that is adjacent to the reversible ligand when the reversible ligand is docked in, or in proximity to, the ligand-binding site, (c) producing one or more structural models of a plurality of ligand-warhead compounds docked in, or in proximity to, the ligand-binding site wherein each ligand-warhead compound comprises a warhead covalently attached to a substitutable position of the reversible
  • the hydrogen-bond donor amino acid can participate in the chemical reaction between the warhead of the ligand-warhead and the targeted lysine of the protein.
  • the hydrogen bond donating amino acid is either lysine or arginine
  • the interaction between lysine and lysine or lysine and arginine are repulsive interactions that lower the pKa of the targeted lysine, thus enhancing its nucleophilicity.
  • hydrogen bond donation either by a sidechain, or even a mainchain amide can, in many cases, enhance the electrophilicity of a warhead.
  • the warhead of the ligand-warhead comprises an acrylamide
  • the warhead requires a hydrogen bond donor amino acid residue in, or in proximity to, the ligand-binding site, wherein the hydrogen-bond donor group is within hydrogen-bonding distance of the warhead comprising acrylamide.
  • the method further comprises step (f) forming, for the ligand-warhead compound identified in step (e), a ligand-protein covalent adduct by forming a covalent bond between the side chain primary amine group of the lysine residue identified in step (b) and the warhead electrophile; and also forming a hydrogen bond between the hydrogen-bond donor moiety and the warhead electrophile; or a hydrogen bond between the hydrogen-bond donor moiety and the side chain primary amine group of the lysine residue identified in step (d) while substantially maintaining the non-covalent interactions between the pharmacophore of the ligand and the ligand-binding site.
  • the method further comprises step (g) evaluating a resulting conformation of the ligand-protein covalent adduct by analyzing the global energy of the resulting conformation.
  • steps (a) through (g) are iterated with changes to the linker and the global energy of the resulting conformation is less than the previous iteration.
  • the hydrogen-bond donor-containing amino acid residue is any amino acid residue that is capable of acting as a hydrogen bond donor.
  • the hydrogen-bond donor-containing amino acid residue is selected from the group consisting of arginine, lysine, threonine, serine, histidine, and tyrosine.
  • the target protein is selected from the group consisting of XIAP, PDPK1, PI3K ⁇ / ⁇ , and HCV.
  • the warhead when the warhead comprises an acrylamide moiety, the warhead requires a hydrogen-bond donor-containing amino acid residue in, or in proximity to, the ligand-binding site, wherein the hydrogen-bond donor group is within hydrogen-bonding distance of the warhead comprising acrylamide to facilitate the warhead covalently binding to the target lysine.
  • the hydrogen-bond donor-containing amino acid residue is lysine.
  • a method for identifying at least one lysine residue within at least one protein that can be modified covalently comprises (a) identifying at least one protein having a ligand-binding site, (b) providing a three-dimensional structural model for the identified protein, (c) docking a reversible ligand in, or in proximity to, the identified protein's ligand-binding site in the structural model, wherein the reversible ligand makes at least one non-covalent contact with the ligand-binding site, thereby creating a structural model of a reversible ligand bound to, or in proximity to, an identified protein's ligand-binding site; and (d) identifying in the structural model of the reversible ligand bound to, or in proximity to, an identified protein's ligand-binding site one or more lysine residues in, or in proximity to, the ligand-binding site of the identified protein which is less than about 15 ⁇ from the
  • the method further comprises identifying a plurality of proteins having ligand-binding sites that are structurally homologous.
  • the method further comprises (a) providing a three-dimensional structural model for at least one of the identified proteins, (b) docking a reversible ligand in, or in proximity to, the structural model of the ligand-binding site of at least one of the identified proteins, wherein the reversible ligand makes at least one non-covalent interaction with the ligand-binding site, thereby creating a structural model of a reversible ligand bound to, or in proximity to, the identified protein's ligand-binding site; and (c) identifying in the structural model of a reversible ligand bound to, or in proximity to, the identified protein's ligand-binding site one or more lysine residues in, or in proximity to, the ligand-binding site of the identified protein which is less than about 15 ⁇ from the reversible ligand.
  • the method comprises comparing the three-dimensionally equivalent amino acid positions of the homologous ligand-binding sites of more than one of the plurality of identified proteins and determining the prevalence of lysine residues in, or in proximity to, the ligand binding sites of the identified proteins.
  • the prevalence of lysine residues in, or in proximity to, the ligand binding sites of the identified proteins is in only one of the identified proteins.
  • the prevalence of lysine residues in, or in proximity to, the ligand binding sites of the identified proteins are in more than one of the identified proteins.
  • the prevalence of lysine residues in, or in proximity to, the ligand binding sites of the identified proteins is in less than 10% of the identified proteins of a family at the ligand binding site position. In other embodiments, the prevalence of lysine residues in, or in proximity to, the ligand binding sites of the identified proteins is in less than or greater than 50% of the identified proteins. More than 50%, in some embodiments, the prevalence of lysine residues in, or in proximity to, the ligand binding sites of the identified proteins is in more than 75% of the identified proteins, while in other embodiments, the prevalence of lysine residues in, or in proximity to, the ligand binding sites of the identified proteins is in all of the identified proteins.
  • the protein is selected from the group consisting of BCL-2, Calpains, Caspases, Cathepsins, HCV, HDAC, HSP70, HSP90, IAP, Kinase, MDM2, MMP, NHR, PI3K ⁇ / ⁇ , Phosphatase, Transthyretin, PARP, and HIV Protease.
  • the protein is selected from the group consisting of XIAP, PI3K ⁇ / ⁇ , PDPK1, and HCV.
  • a method for selecting a warhead that binds to a target lysine within a ligand binding site of a protein comprises (a) identifying at least one protein having a ligand-binding site, (b) providing a three-dimensional structural model for the identified protein, (c) identifying the location of at least one lysine in, or in proximity to, the ligand-binding site of step (a); (d) providing at least one warhead in proximity to the at least one identified lysine; (e) aligning the electrophilic atom of the warhead within bonding distance of the primary amine of the at least one identified lysine; (f) forming a covalent bond between the electrophilic atom of the warhead and the primary amine of the at least one lysine; (g) docking a reversible ligand in the identified protein's ligand-binding site within 15 ⁇ of the covalently attached warhead of step (f),
  • the method comprises contacting a compound of Formula I with a protein containing a lysine residue in, or in proximity to, a ligand-binding site of a protein and forming a covalent bond between the side chain primary amine group of the lysine residue and Warhead of the compound.
  • the method encompasses compounds of Formula I:
  • Warhead is an organic moiety optionally containing one or more heteroatoms selected from O, N, and S, and has a molecular weight of about 14 daltons to about 200 daltons, the Warhead is capable of reacting with a side chain primary amine group of a lysine residue and attaches to the Scaffold through the Tether;
  • Tether is null, a bond, or a bivalent C 1 -C 15 saturated, unsaturated, straight, branched, cyclic, bicyclic, tricyclic alkyl, alkenyl, alkynyl; bridged bicyclic, heterocycle, heteroaryl, or aryl moiety; wherein optionally one or more methylene units of the hydrocarbon chain are independently replaced by —O—, —C(O)—, —S—, —SO—, —C( ⁇ S)—, or C( ⁇ NR 1 )—; optionally, one or more hydrogens are independently replaced by heteroatoms, and optionally, one or more methine groups of the C 1 -C 15 alkyl, when present, are independently replaced by
  • x 0, 1, or 2;
  • y is 1, 2, or 3;
  • R 1 is hydrogen or C 1 -C 8 alkyl.
  • the compound of Formula I is a compound of Formula I′,
  • suicide inhibitors such as, for example Vigabatrin, or carbaglucose-6-phosphate (pseudo-DL-glucose, C-6-P) are not contemplated in the present invention.
  • Vigabatrin or carbaglucose-6-phosphate (pseudo-DL-glucose, C-6-P) are not contemplated in the present invention.
  • C-6-P carbaglucose-6-phosphate
  • wortmannin is known to covalently modify lysine in the protein phosphatidylinositol 3-kinase (PI3K).
  • PI3K protein phosphatidylinositol 3-kinase
  • wortmannin is a naturally occurring compound known to covalently modify lysine and exert its biological effects through its inherent ability to covalently bind to lysine.
  • Known analogues of wortmannin that covalently modify lysine through substantially the same mechanism as wortmannin are also excluded from the present invention. Examples of such wortmannin analogues include, without limitation:
  • Liphagal Another example of a naturally occurring compound that is believed to covalently modify lysine and is not encompassed within the present invention is Liphagal:
  • Nucleoside/nucleotide derived drugs such as, for example, those disclosed in Statsuk, A. V., et al., JACS, 130, 17568, (2008) and Guillerm, G., et al., J. Med. Chem., 49, 1223, (2006), and the like, are also not contemplated in the present invention.
  • manolide and its analogues which are believed to covalently modify lysine, such as manoalogue (Reynolds, L. J., et al., J. Am. Chem. Soc., 1988, 110, 5172-5177):
  • neratinib aka HKI-272
  • HKI-272 which covalently modify lysine in intact proteins
  • azaphilone and its analogues which are believed to covalently modify lysine.
  • Non limiting illustrative examples of azaphilone cores are described below:
  • the Warhead of Formula I is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
  • each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
  • each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
  • each X 9 is independently
  • each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • a and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl;
  • n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond.
  • At least one of R 2 and R 3 of the compounds of Formula I-b and I-c is hydrogen.
  • the compound of Formula I-a, I-d, I-e, I-j, I-k, or I-l is a compound of Formula II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-j, II-k, II-l, II-m, II-n, II-o, II-p, II-q, II-r, II-s, II-t, II-u, II-v, II-w, II-x, II-y, II-z, II-aa, II-bb, II-cc, II-dd, II-ee, II-ff, II-gg, II-hh, II-jj, II-kk, II-ll, II-mm, II-nn, II-oo, or II-pp:
  • each m is independently an integer from 0-4;
  • each m 5 is independently an integer from 0-3;
  • each m 4 is independently an integer from 0-5;
  • each n 2 is independently an integer from 0-2;
  • each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 is independently hydrogen or C 1 -C 6 alkyl and R 1 is hydrogen, C 1 -C 6 alkyl, halogen, CF 3 , or nitro, wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —SO—, —SO 2 —, or —C( ⁇ S)—, one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 when taken together, form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group.
  • the compound of Formula I-d, or I-h is a compound of Formula III-a, III-b, III-h, or III-i:
  • n 3 is an integer from 0-2;
  • each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl
  • each B 1 , B 2 , B 4 , and B 5 is independently CR 7 or N;
  • each B 3 is NR 7 , O, or S;
  • each R z1 , R z2 , R z3 , R z4 , and R z5 is hydrogen, C 1 -C 6 alkyl, halogen, CF 3 , or nitro, wherein one or more methylene groups of the C 1 -C 6 alkyl can be optionally replaced by —O—, —C(O)—, —SO—, —SO 2 —, or —C( ⁇ S)—, one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • the compound of Formula I-h is a compound of Formula IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g, IV-h, or IV-i:
  • R 1 , R 2 , and R 3 are as defined above for Formula I-h;
  • any of the substitutable hydrogens on the nitrogen heterocycle of the compound can be substituted with alkyl, alkoxy, amido, acyl, acyloxy, oxoacyl, or halogen.
  • the radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-d, I-k, or I-m is a radical of Formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, or V-j:
  • n 1 and m 2 are each independently an integer from 0 to 2;
  • each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is independently hydrogen or C 1 -C 6 alkyl, wherein one or more methylene groups of the C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 when taken together, form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group.
  • the compounds of Formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t are described below:
  • any substitutable hydrogen may be substituted with the substituents as those defined by R 2 -R 8 .
  • the radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-d, I-k, or I-m is a radical of Formula VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-j, VI-k, VI-l, VI-m, VI-n, VI-o, VI-p, VI-q, VI-r, VI-s, or VI-t:
  • R zz is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, —CH 2 OCH 3 , or —CH 2 CH 2 OCH 3 .
  • Tether is null, a bond, or a bivalent C 1 -C 15 saturated, unsaturated, straight, branched, cyclic, bicyclic, tricyclic alkyl, alkenyl, alkynyl; bridged bicyclic, heterocycle, heteroaryl, or aryl moiety; wherein optionally one or more methylene units of the hydrocarbon chain are independently replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, —C( ⁇ S)—, or C( ⁇ NR 1 )—; R 1 is hydrogen or C 1 -C 8 alkyl; and optionally one or more hydrogens are independently replaced by heteroatoms; and optionally one or more methine groups of the C 1 -C 15 alkyl, when present, are independently replaced by
  • the Scaffold is selected from the group consisting of Formulas VII, VIII, IX-a, IX-b, XI, XII, XVI, XVII, XVIII, XIX, XX, XXI, XXIII, XXXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXXVI, and XXXVII.
  • the present disclosure provides compounds capable of covalently binding to lysine residues of a protein thereby inhibiting the function of the protein. Described herein are compounds of the Formula I:
  • azaphilone core analogues such as
  • the compound of Formula I is a compound of Formula I′,
  • the Warhead is a radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t:
  • each X 1 and X 8 is independently —O—, —S—, or —NR 6 —;
  • each X 2 is independently —R 6 , —OR 6 , or —NR 6 R 7 ;
  • each X 9 is independently
  • each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • a and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl;
  • n is an integer from 2-4; each n 1 and n 2 is independently an integer from 0-2; n 3 is an integer from 1-2; n 4 is an integer from 1-3; and each one of n 9 , n 10 , n 11 , and n 12 is an integer from 0-1; and n 13 is an integer from 0-2, wherein when any one of the foregoing n integers is more than 1, the adjacent carbons represented by the integer can form a single or double bond.
  • At least one of R 2 and R 3 of the compounds of Formula I-b and I-c is hydrogen.
  • the compound of Formula I-a, I-d, I-e, I-j, I-k, or I-l is a compound of Formula II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-j, II-k, II-l, II-m, II-II-o, II-p, II-q, II-r, II-s, II-t, II-u, II-v, II-w, II-x, II-y, II-z, II-aa, II-bb, II-cc, II-dd, II-ee, II-ff, II-gg, II-hh, II-jj, II-kk, II-ll, II-mm, II-nn, II-oo, or II-pp.
  • each m is independently an integer from 0-4;
  • each m 5 is independently an integer from 0-3;
  • each m 4 is independently an integer from 0-5;
  • each n 2 is independently an integer from 0-2;
  • each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 is independently hydrogen or C 1 -C 6 alkyl;
  • R 1 is hydrogen, C 1 -C 6 alkyl, halogen, CF 3 , or nitro; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl.
  • the compound of Formula I-d or I-h is a compound of Formula III-a, III-b, III-h, or III-i:
  • n 3 is an integer from 0-2;
  • each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl
  • each B 1 , B 2 , B 4 , and B 5 is independently CR 7 or N and each B 3 is NR S , O, or S;
  • each R z1 , R z2 , R z3 , R z4 , and R z5 is hydrogen, C 1 -C 6 alkyl, halogen, CF 3 , or nitro;
  • one or more methylene groups of the C 1 -C 6 alkyl can be optionally replaced by —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • the compound of Formula I-h is a compound of Formula IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-h, or IV-i:
  • R 2 , R 3 and R 4 are defined above for Formula I-d or I-h; and the hydrogen on the nitrogen heterocycle of the compound of Formula IV-a, IV-b, and IV-c can be substituted with alkyl, alkoxy, amido, acyl, acyloxy, oxoacyl, and halogen.
  • the radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-d, I-k, or I-m is a radical of Formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, or V-j:
  • n 1 and m 2 are each independently an integer from 0 to 2;
  • each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is independently hydrogen or C 1 -C 6 alkyl, wherein one or more methylene groups of the C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 when taken together, form a 3- to 8-membered carbocyclic or heterocyclic ring or an aryl or heteroaryl group.
  • the compounds of Formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, I-s, and I-t are described below:
  • any substitutable hydrogen may be substituted with the substituents as those defined by R 2 -R 8 .
  • the radical resulting from the removal of a hydrogen of a compound of Formula I-a, I-d, I-k, or I-m is a radical of Formula VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-j, VI-k, VI-l, VI-m, VI-n, VI-o, VI-p, or VI-q:
  • R zz is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, —CH 2 OCH 3 , or —CH 2 CH 2 OCH 3 .
  • the Tether is null, a bond, or a bivalent C 1 -C 15 saturated, unsaturated, straight, branched, cyclic, bicyclic, tricyclic alkyl, alkenyl, alkynyl; bridged bicyclic, heterocycle, heteroaryl, or aryl moiety; wherein optionally one or more methylene units of the hydrocarbon chain are independently replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, —C( ⁇ S)—, or C( ⁇ NR 1 )—; optionally, one or more hydrogens are independently replaced by heteroatoms, and optionally, one or more methine groups of the C 1 -C 15 alkyl, when present, are independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl.
  • the Tether is null, a bond, or a bivalent C 1 -C 15 saturated, unsaturated, straight, branched, cyclic, bicyclic, tricyclic alkyl, alkenyl, alkynyl; wherein optionally one or more methylene units of the hydrocarbon chain are independently replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, —C( ⁇ S)—, or C( ⁇ NR 1 )—; optionally, one or more hydrogens are independently replaced by heteroatoms, and optionally, one or more methine groups of the C 1 -C 15 alkyl, when present, are independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl.
  • the Scaffold is selected from the group consisting of Formulas VII, VIII, IX-a, IX-b, XI, XII, XVI, XVII, XVIII, XIX, XX, XXI, XXIII, XXXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXXVI, and XXXVII.
  • the compounds of Formula I are described wherein Scaffold is a radical resulting from the removal of one or more hydrogens of a compound of Formula VII:
  • V and W are each independently —(CR 14 R 15 ) q X 3 (CR 16 R 17 ) r —;
  • q and r are each independently 0, 1, 2, 3, or 4;
  • X 3 is —CR 18 R 19 —, or —NR 20 —;
  • R x , R y , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, —C( ⁇ S)—, optionally substituted aryl or heteroaryl groups; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • Tether and Warhead are as defined above in the embodiments of Formula I.
  • the compound of Formula VII is a compound of Formula VII-a:
  • V and W are each independently —(CR 14 R 15 ) q X 3 (CR 16 R 17 ) r —;
  • q and r are each independently 0, 1, 2, 3, or 4;
  • X 3 is —CR 18 R 19 —, or —NR 20 —;
  • p 0, 1, 2, 3, or 4;
  • R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, —C( ⁇ S)—, optionally substituted aryl or heteroaryl groups; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • R 23 is hydrogen, C 1 -C 6 alkyl, halogen, amino, or nitro; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 21 and R 23 taken together can form a 4- to 8-membered carbocyclic or heterocyclic ring.
  • the compound of Formula I′ is a compound of Formula VII-b:
  • R 12 , R 13 , R 21 , R 22 , R 23 , V, W, p, are as defined above for Formula VII-a and T and R wh are as defined above in the embodiments of Formula I.
  • the compound of Formula VII-b is a compound of Formula VII-h:
  • T, R wh , p, R 12 , R 13 , R 23 , and p are as described above for Formula VII-b.
  • the compound of Formula VII-h is a compound of Formula VII-j, VII-k, VII-l, VII-m, VII-n, or VII-o:
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are as described above for embodiments of Formula I, and R 12 , R 13 , R 23 , and p are as described above for Formulas VII and VII-h.
  • Non-limiting examples of compounds of Formula VII are as set forth below.
  • X 4 is —CR 33 — or —N—;
  • p and s are each independently 0, 1, 2, 3, or 4;
  • R 12 , R 13 , R 21 , R 22 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , and R 33 are each independently hydrogen or C 1 -C 6 alkyl;
  • R 23 is hydrogen, C 1 -C 6 alkyl, halogen, amino, or nitro; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • R 21 and R 23 taken together can form a 4- to 8-membered carbocyclic or heterocyclic ring;
  • Tether and Warhead are as defined above in the embodiments of Formula I.
  • the compound of Formula I is a compound of Formula VIII-a or VIII-b.
  • Non-limiting examples of compounds of Formula VIII are as set forth below.
  • X 5 is —O—, —CR 42 R 43 — or —NR 42 —;
  • R 12 , R 13 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , and R 43 are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—;
  • R 1 is hydrogen or C 1 -C 8 alkyl; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • D, E, F, G, and H are each independently optionally substituted aryl or heteroaryl;
  • Tether and Warhead are as defined above in the embodiments of Formula I.
  • the compound of Formula I′ is a compound of Formula IX-c or IX-d:
  • R 12 , R 13 , R 31 , F, G, and H are as defined above for Formulas IX-a and IX-b, and T and R wh are Tether and Warhead, respectively, and are as defined above in the embodiments of Formula I.
  • compounds of Formula I′ are described by compounds of the Formula XVII:
  • T is Tether and R wh is Warhead and are as defined above in the embodiments of Formula I.
  • Nonlimiting examples of the compounds of Formula XVII are set forth below.
  • compounds of Formula I are described by compounds of the Formula XVIII:
  • T is Tether and R wh is Warhead and are as defined above in the embodiments of Formula I.
  • Nonlimiting examples of the compounds of Formula XVIII are set forth below.
  • compounds of Formula I are described by compounds of Formula XIX:
  • T is Tether and R wh is Warhead and are as defined above in the embodiments of Formula I.
  • Nonlimiting examples of the compounds of Formula XIX are set forth below.
  • compounds of Formula I are described by compounds of Formula XX-a and Formula XX-b:
  • R 1000 is C(H) or N, wherein -T-R wh can be attached to any carbon or the NH of the heteroaryl moiety of Formula XX-a and Formula XX-b;
  • T and R wh are Tether and Warhead, respectively, and are as defined above in the embodiments of Formula I.
  • Nonlimiting examples of the compounds of Formula XX-a and Formula XX-b are set forth below.
  • compounds of Formula I′ are described by compounds of Formula XXI-a, Formula XXI-b, and Formula XXI-c:
  • T and R wh are Tether and Warhead, respectively, and are as defined above in the embodiments of Formula I.
  • Nonlimiting examples of the compounds of Formula XXI-a, Formula XXI-b, and Formula XXI-c are set forth below.
  • compounds of Formula I′ are described by compounds of Formula XI:
  • B 6 and B 7 are each independently CR 7 or N;
  • R 69 is hydrogen, C 1 -C 6 alkyl, halogen, amino, nitro, or —NH(CO)NR 78 R 79 ;
  • R 70 is hydrogen, C 1 -C 6 alkyl, halogen, amino, nitro;
  • R 7 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , and R 79 are each independently hydrogen or C 1 -C 6 alkyl;
  • R 1 is hydrogen or C 1 -C 8 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • p is an integer from 0 to 4
  • u is an integer from 1 to 4
  • T and R wh are Tether and Warhead respectively, and are as defined above in the embodiments of Formula I;
  • the compound of Formula XI is a compound of Formula XI-a, XI-b, or XI-c.
  • the compound of Formula XI-a, XI-b or XI-c is a compound of Formula XI-d, XI-e, XI-f, XI-g, XI-h, XI-i, or XI-j.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 80 , R 81 , R 82 , R 83 , R 84 , R 85 , R 86 , and R 87 are each independently hydrogen or C 1 -C 6 alkyl, wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—, R 1 is hydrogen or C 1 -C 8 alkyl, and one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • the compound of Formula XI-d, XI-e, XI-f, XI-g, XI-h, XI-i, or XI-j is a compound of Formula XI-k, XI-l, XI-m, XI-n, XI-o, XI-p, or XI-q.
  • R 1 -R 8 , R 70 , R 88 , and R 89 are as defined above for Formula XI-a, XI-b or XI-c;
  • X 6 is CH 2 , NH, O, or S
  • n 5 is an integer from 0 to 3.
  • the compound of Formula XI-e or XI-j is a compound of Formula XI-r, XI-s, XI-t, XI-u, XI-v, XI-w, or XI-x:
  • R 2 , R 3 , R 4 , R 5 , and R 6 are as defined above for Formula XI-a, XI-b, and XI-c.
  • the compound of Formula XI-e, XI-h, XI-i, or XI-j is a compound of Formula XI-y, XI-z, XI-aa, or XI-bb.
  • R 2 -R 9 are as defined above for Formula II-a above;
  • X 6 is as defined above for Formula XI-t above.
  • the compound of Formula XI-h or XI-i is a compound of Formula XI-cc, XI-dd, XI-ee, or XI-ff.
  • R 2 -R 7 , R 8 , R 9 are as defined above for Formula II-a.
  • Nonlimiting examples of compounds of the Formula XI are set forth below.
  • compounds of Formula I are described by compounds of Formula XII:
  • T and R wh are Tether and Warhead, respectively, and are as defined above in the embodiments of Formula I;
  • R 1 and R 2 are each independently hydrogen or C 1 -C 8 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • compounds of Formula I are described by compounds of Formula XXXVI:
  • Rv is H, optionally substituted C 1 -C 3 branched or straight chain alkyl, or optionally substituted C 1 -C 3 branched or straight chain acyl;
  • T and R wh are Tether and Warhead, respectively, and are as defined above in the embodiments of Formula I.
  • Nonlimiting examples of compounds of the Formula XXXVI are set forth below:
  • R 90 , R 91 , R 92 , R 93 , R 94 , R 95 , R 96 , R 97 , R 98 , R 99 , R 100 , R 102 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , R 112 , R 113 , and R 114 are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —O—, —C(O)—, —SO—, —SO 2 —, or —C( ⁇ S)—;
  • R 103 is hydrogen, C 1 -C 6 alkyl, or C 2 -C 8 alkenyl
  • one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • each R 101 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, halogen, amino, nitro, optionally substituted aryl or heteroaryl;
  • n 6 and n 7 are each independently integer from 0 to 4; n 8 is an integer from 0 to 2; and
  • Warhead is a radical resulting from the removal of a hydrogen of a compound of Formula I-b, I-c, I-e, I-j, I-k, I-l, I-n, or I-o;
  • each X 1 and X 8 is independently —O—, or —NR 6 —;
  • each X 9 is independently
  • each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—;
  • one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • a and B are each independently an optionally substituted monocyclic, bicyclic, or tricyclic aryl or heteroaryl;
  • n is an integer from 2-4;
  • each n 1 and n 2 are independently an integer from 0-2;
  • n 3 is an integer from 1-2;
  • n 4 is an integer from 1-3;
  • T is Tether and is null, a bond, or a bivalent C 1 -C 15 saturated, unsaturated, straight, branched, cyclic, bicyclic, tricyclic alkyl, alkenyl, alkynyl; bridged bicyclic, heterocycle, heteroaryl, or aryl moiety; wherein optionally one or more methylene units of the hydrocarbon chain are independently replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —C( ⁇ S)—, or C( ⁇ NR 1 )—; optionally, one or more hydrogens are independently replaced by heteroatoms, and optionally, one or more methine groups of the C 1 -C 15 alkyl, when present, are independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl.
  • the compound of Formula I′ is a compound of Formula XVI-d, XVI-e, or XVI-f:
  • R 90 , R 101 , R 114 , n 6 , n 8 , T and R wh are as defined above for Formula XV-a;
  • R 103 is hydrogen or C 2 -C 8 alkenyl.
  • the compound of Formulas XVI-d, XVI-e, or XVI-f is a compound of Formula XVI-g, XVI-h, or XVI-i:
  • R 2 , R 3 , R 4 , R 5 , R 101 , R 114 are as defined above for Formulas XVI-a.
  • Non-limiting examples of compounds of Formula XVI-a, Formula XVI-b, and Formula XVI-c are as set forth below.
  • the compound of Formula I′ is a compound of Formula XXII-a, Formula XXII-b, or Formula XXII-c:
  • n, m, p, and q for Formula XXII-a and Formula XXII-b are each independently 0, 1, 2, 3; provided that n and q are not 0 at the same time, and m and q are not 0 at the same time;
  • T and R wh are as defined in embodiments of Formula I;
  • a 2 is an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-10 membered saturated or partially unsaturated bridged bicyclic heterocyclic ring having at least one nitrogen, at least one oxygen, and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • B′ is an optionally substituted group selected from phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or -T-Rwh; and
  • C 2 is hydrogen or an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Nonlimiting examples of compounds for Formula XXII-a and Formula XXII-b are set forth below.
  • the compound of Formula I is a compound of Formula XXIII:
  • R wh is a warhead group and is as defined above in the embodiments of Formula I;
  • R 201 is hydrogen or C 1-6 alkyl
  • R 202 is hydrogen or an optionally substituted group selected from C 1-6 alkyl, C 1-6 alkoxy, or (C 1-6 alkylene)-R 203 ; or
  • R 201 and R 202 are taken together with the intervening carbon to form an optionally substituted ring selected from a 3- to 7-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • R 203 is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, a 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
  • Ring A 6 is absent or an optionally substituted group selected from a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Non-limiting examples of the compounds of Formula XXIII are listed below:
  • the compound of Formula I is a compound of Formula XXIV-a or XXIV-b:
  • R wh is a warhead group
  • R 204 is an hydrogen or an optionally substituted group selected from C 1-6 aliphatic, —(CH 2 ) m -(3- to 7-membered saturated or partially unsaturated carbocyclic ring), —(CH 2 ) m -(7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring), —(CH 2 ) m -(4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur), —(CH 2 ) m -(7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur), —(CH 2 ) m -phenyl, —(CH 2 ) m -(8- to 10-membered bicyclic aryl ring), —(CH 2 ) m -(5- to 6-membered heteroaryl ring
  • each R 205 and R 206 is independently —R′′, halogen, —NO 2 , —CN, —OR′′, —SR′′, —N(R′′) 2 , —C(O)R′′, —CO 2 R′′, —C(O)C(O)R′′, —C(O)CH 2 C(O)R′′, —S(O)R′′, —S(O) 2 R′′, —C(O)N(R′′) 2 , —SO 2 N(R′′) 2 , —OC(O)R′′, —N(R′′)C(O)R′′, —N(R′′)N(R′′) 2 , —N(R′′)C( ⁇ NR′′)N(R′′) 2 , —C( ⁇ NR′′)N(R′′) 2 , —C ⁇ NOR′′, —N(R′′)C(O)N(R′′) 2 , —N(R′′)SO 2 N(R′′) 2
  • each R′′ is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
  • n is an integer from 0 to 6, inclusive
  • each n for Formula XXIV-a or Formula XXIV-b is independently 0, 1, or 2;
  • Ring A 5 is an optionally substituted 6-membered heterocyclic or heteroaryl ring having 1-2 nitrogens.
  • Non-limiting examples of compounds of Formula XXIV-a and XXIV-b are set forth below:
  • the compound of Formula I′ is a compound of Formula XXV:
  • R wh is a warhead group
  • each R 205 and R 206 is independently —R′′, halogen, —NO 2 , —CN, —OR′′, —SR′′, —N(R′′) 2 , —C(O)R′′, —CO 2 R′′, —C(O)C(O)R′′, —C(O)CH 2 C(O)R′′, —S(O)R′′, —S(O) 2 R′′, —C(O)N(R′′) 2 , —SO 2 N(R′′) 2 , —OC(O)R′′, —N(R′′)C(O)R′′, —N(R′′)N(R′′) 2 , —N(R′′)C( ⁇ NR′′)N(R′′) 2 , —C( ⁇ NR′′)N(R′′) 2 , —C ⁇ NOR′′, —N(R′′)C(O)N(R′′) 2 , —N(R′′)SO 2 N(R′′) 2
  • each R′′ is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
  • R′′ groups on the same nitrogen are taken together with the nitrogen to which they are attached to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • n is an integer from 0 to 6, inclusive
  • each n is independently 0, 1, or 2;
  • Ring A 5 is an optionally substituted 6-membered heterocyclic or heteroaryl ring having 1-2 nitrogens.
  • the compound of Formula I is a compound of Formula XXVI:
  • R wh is a warhead group and is as defined above in the embodiments of Formula I;
  • Ring A 7 is an optionally substituted ring selected from a 4- to 8-membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-10 membered saturated or partially unsaturated bridged bicyclic heterocyclic ring having at least one nitrogen, at least one oxygen, and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • R 207 is R′′′, halogen, —OR′′ —CN, —NO 2 , —SO 2 R′′′, —SOR′′′, —C(O)R′′′, —CO 2 R′′′, —C(O)N(R′′′) 2 , —NRC(O)R′′′, —NR′′′C(O)N(R′′′) 2 , —NRSO 2 R′′′, or —N(R′′′) 2 ;
  • each R′′′ is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, aryl, a 4- to 7-membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • R′′′ groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ring B 7 is an optionally substituted group selected from phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • T 7 is a covalent bond or a bivalent straight or branched, saturated or unsaturated C 1-6 hydrocarbon chain wherein one or more methylene units of T 7 are optionally replaced by —O—, —S—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R′′′)—, —N(R′′′)C(O)—, —N(R′′′)C(O)N(R′′′)—, —SO 2 —, —SO 2 N(R′′′)—, —N(R′′′)SO 2 —, or —N(R′′′)SO 2 N(R′′′)—;
  • Ring C 7 is an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 7- to 12-membered saturated or partially unsaturated bridged bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen
  • Ring D 7 is absent or an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 7- to 12-membered saturated or partially unsaturated bridged bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen
  • Nonlimiting examples of the compounds of Formula XXVI are set forth below.
  • the compound of Formula I is a compound of Formula XXVII:
  • T and R wh are as defined above in the embodiments of Formula I.
  • R is H, alkyl, or alkoxy.
  • Nonlimiting examples of the compounds of the Formula XXVII are set forth below.
  • the compound of Formula I is a compound of Formula XXVIII:
  • Non-limiting examples of the compounds of Formula XXVIII are set forth below:
  • the compound of Formula I is a compound of Formula XXIX:
  • T and R wh are Tether and Warhead, respectively, and are as defined as above for Formula I;
  • a 8 is an optionally substituted aryl, biaryl, or heteroaryl.
  • Non-limiting examples of the compounds of Formula XXIX are set forth below:
  • the compound of Formula I is a compound of Formula XXXVII:
  • T and R wh are Tether and Warhead, respectively, and are as defined as above for Formula I.
  • Non-limiting examples of the compounds of Formula XXXVII are set forth below:
  • warhead groups are suitable for covalent bonding to lysine.
  • R wh groups include, but are not limited to, those described herein and depicted in Formulas VI-a-VI-t, and aa-ooo, inclusive, supra. That these warheads are suitable for covalent bonding to the primary amine of a lysine residue was determined by performing mass spectrometric experiments using the protocol described in detail in Examples 50-54, 88, 163-164, and 174-175, infra, the results of which are depicted in FIGS. 3-9 , and 12 - 22 . These experiments show that the compounds described herein covalently modify a target lysine residue in HCV-NS3 protease, XIAP, PDPK-1, and PI3K ⁇ / ⁇ .
  • Warhead is an organic moiety optionally containing one or more heteroatoms selected from O, N, and S; the organic moiety having a molecular weight of about 14 daltons to about 200 daltons; Warhead being capable of reaction with a side chain primary amine group of a lysine residue; and Warhead being attached to Scaffold through Tether; and
  • Tether is null, a bond, or a bivalent C 1 -C 15 saturated, unsaturated, straight, branched, cyclic, bicyclic, tricyclic alkyl, alkenyl, alkynyl; bridged bicyclic, heterocycle, heteroaryl, or aryl moiety; wherein optionally one or more methylene units of the hydrocarbon chain are independently replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —C( ⁇ S)—, or C( ⁇ NR 1 )—; optionally, one or more hydrogens are independently replaced by heteroatoms, and optionally, one or more methine groups of the C 1 -C 6 alkyl, when present, are independently replaced by
  • x 0, 1, or 2;
  • y is 1, 2, or 3;
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • Y 1 is a bivalent or trivalent moiety resulting from the removal of a hydrogen of a radical of Formula XIV-a, XIV-b, XIV-c, XIV-d, XIV-e, XIV-f, XIV-g, XIV-h, or XIV-i,
  • each X 1 and X 2 is independently —CR 2 R 3 R 4 , —OR 2 , or —NR 2 R 3 ;
  • each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently hydrogen or C 1 -C 6 alkyl
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 can be linked together to form a 3- to 8-membered carbocyclic or heterocyclic ring;
  • one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by and
  • n is an integer from 2-4, m 4 is an integer from 1 to 2;
  • A is an optionally substituted aryl or heteroaryl
  • a hydrogen of a radical of Formula XIV-a, XIV-b, XIV-c, XIV-d, XIV-e, XIV-f, XIV-g, XIV-h, or XIV-i, is substituted by Tether-Scaffold;
  • M is connected to the position labeled as “*” and is —NH— or ⁇ N—, the nitrogen atom of M being a nitrogen from the side chain primary amine group of the lysine residue of the protein.
  • the conjugate of Formula XIII is a conjugate of Formula XIII′,
  • the Scaffold is selected from the group consisting of Formulas VII, VIII, IX-a, IX-b, XI, XII, XVI, XVII, XVIII, XIX, XX, XXI, XXIII, XXXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXXVI, and XXXVII.
  • M(CH 2 ) 4 -Protein is selected from the group consisting of M(CH 2 ) 4 -K1236-HCV-NS3 ⁇ M(CH 2 ) 4 -K2016-HCV-NS3, M(CH 2 ) 4 -K2560-HCV-NS3, M(CH 2 ) 4 -K191-(Baculoviral IAP repeat-containing protein 1), M(CH 2 ) 4 -K199-(Baculoviral IAP repeat-containing protein 1), M(CH 2 ) 4 -K305-(Baculoviral IAP repeat-containing protein 2), M(CH 2 ) 4 -K291-(Baculoviral IAP repeat-containing protein 3), M(CH 2 ) 4 -K297-(Baculoviral IAP repeat-containing protein 4), M(CH 2 ) 4 -K299-(Baculoviral IAP repeat-containing protein 4), M(CH 2 ) 4 -K311-(Baculoviral IAP repeat
  • the bivalent or trivalent moiety resulting from the removal of a hydrogen of a radical of Formula XIV-a, XIV-d, XIV-h, or XIV-i is a moiety of Formula XV-a, XV-b, XV-c, XV-d, XV-e, XV-f, or XV-g;
  • n 4 is an integer from 1 to 2;
  • each R 2 , R 3 , R 4 , R 5 and R 6 is independently hydrogen or C 1 -C 6 alkyl;
  • the bivalent moiety of Formula XV-a, XV-b, XV-c, XV-d, XV-e, XV-f, or XV-g is a bivalent moiety of Formula XV-h, XV-i, XV-j, XV-k, XV-1, XV-m, XV-n, XV-o, XV-p, XV-q, XV-r, XV-s, or XV-t;
  • M is connected to the position of Y 1 labeled as “*”;
  • Tether is connected to the position of Y 1 labeled as “**”.
  • R wh is a warhead group.
  • R wh groups i.e. warhead groups
  • XIAP XIAP
  • PDPK-1 PDPK-1
  • HCV protease PI3K
  • mutants thereof have at least one lysine residue in the binding domain of each protein.
  • compounds of the present invention have a warhead group characterized in that inventive compounds may target the K297 lysine residue of XIAP. In certain embodiments, compounds of the present invention have a warhead group characterized in that inventive compounds target the K86 lysine residue of PDPK-1. In certain embodiments, compounds of the present invention have a warhead group characterized in that inventive compounds target the K169 lysine residue of PDPK-1. In certain embodiments, compounds of the present invention have a warhead group characterized in that inventive compounds target the K173 lysine residue of PDPK-1. In other embodiments, compounds of the present invention have a warhead group characterized in that inventive compounds target the K136 lysine residue of HCV protease.
  • compounds of the present invention have a warhead group characterized in that inventive compounds target the K777 lysine residue of PI3K ⁇ . In other embodiments, compounds of the present invention have a warhead group characterized in that inventive compounds target the K802 lysine residue of PI3K ⁇ . In other embodiments, compounds of the present invention have a warhead group characterized in that inventive compounds target the K890 lysine residue of PI3K ⁇ .
  • R wh is characterized in that the -T-R wh moiety is capable of covalently binding to a lysine residue thereby irreversibly inhibiting the enzyme.
  • the present invention provides a conjugate comprising XIAP, or a mutant thereof, covalently bonded to an inhibitor at K297.
  • the inhibitor moiety is bonded via a linker moiety.
  • the present invention provides a conjugate of the Formula K297-linker-inhibitor moiety.
  • the “linker” group corresponds to a -T-R wh as described herein. Accordingly, in certain embodiments, the linker group is as defined for -T-R wh was defined above and described in classes and subclasses herein. It will be appreciated, however, that the linker group is bivalent and, therefore, the corresponding -T-R wh group is also intended to be bivalent resulting from the reaction of the warhead with the K297 of XIAP, or a mutant thereof.
  • the inhibitor moiety is a compound of Formula A:
  • V and W are each independently —(CR 14 R 15 ) q X 3 (CR 16 R 17 ) r ;
  • p, q and r are each independently 0, 1, 2, 3, or 4;
  • X 3 is —CR 18 R 19 —, or —NR 20 —;
  • R 21 and R 22 are each independently hydrogen or C 1 -C 6 alkyl
  • R 23 is hydrogen, C 1 -C 6 alkyl, halogen, amino, or nitro; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • R 21 and R 23 taken together can form a 4- to 8-membered carbocyclic or heterocyclic ring.
  • the present invention provides a conjugate of the formula:
  • R 12 , R 13 , R 21 , R 22 , R 23 , V, W, and p are as defined above for formula A.
  • the inhibitor moiety is a compound of formula B:
  • X 4 is —CR 33 — or —N—;
  • p and s are each independently 0, 1, 2, 3, or 4;
  • R 12 , R 13 , R 21 , R 22 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , and R 33 are each independently hydrogen or C 1 -C 6 alkyl;
  • R 23 is hydrogen, C 1 -C 6 alkyl, halogen, amino, or nitro; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —O—, —C(O)—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • R 21 and R 23 taken together can form a 4- to 8-membered carbocyclic or heterocyclic ring.
  • the present invention provides a conjugate of the formula:
  • compounds of the present invention have a warhead group characterized in that inventive compounds target the K86 lysine residue of PDPK-1. In certain embodiments, compounds of the present invention have a warhead group characterized in that inventive compounds target the K169 lysine residue of PDPK-1. In certain embodiments, compounds of the present invention have a warhead group characterized in that inventive compounds target the K173 lysine residue of PDPK-1.
  • R wh is characterized in that the -T-R wh moiety is capable of covalently binding to a lysine residue thereby irreversibly inhibiting the enzyme.
  • the lysine residue is K86 lysine residue of PDPK-1, or a mutant thereof.
  • the present invention provides a conjugate comprising PDPK-1, or a mutant thereof, covalently bonded to an inhibitor at K86.
  • the inhibitor is covalently bonded via a linker moiety.
  • the present invention provides a conjugate of the formula K86-linker-inhibitor moiety. In certain embodiments, the present invention provides a conjugate of the formula K169-linker-inhibitor moiety. In certain embodiments, the present invention provides a conjugate of the formula K173-linker-inhibitor moiety.
  • the “linker” group corresponds to a -T-R wh as described herein. Accordingly, in certain embodiments, the linker group is as defined for -T-R wh was defined above and described in classes and subclasses herein.
  • linker group is bivalent and, therefore, the corresponding -T-R wh group is also intended to be bivalent resulting from the reaction of the warhead with the K86, K169, or K173 of PDPK-1, or a mutant thereof.
  • the inhibitor moiety is a compound of Formula C:
  • B 6 and B 7 are each independently CR 7 or N;
  • R 69 is hydrogen, C 1 -C 6 alkyl, halogen, amino, nitro, or —NH(CO)NR 78 R 79 ;
  • R 70 is hydrogen, C 1 -C 6 alkyl, halogen, amino, nitro;
  • R 7 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , and R 79 are each independently hydrogen or C 1 -C 6 alkyl;
  • R 1 is hydrogen or C 1 -C 8 alkyl; wherein one or more methylene groups of the C 1 -C 6 alkyl can be replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—; one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • p is an integer from 0 to 4
  • u is an integer from 1 to 4.
  • the present invention provides a conjugate of the formula:
  • B 6 , B 7 , R 69 , R 70 , R 7 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , R 79 , R 1 and p are as defined above for Formula C and Kxxx is K86, K169, or K173.
  • Kxxx is K86 of PDPK-1.
  • Kxxx is K169 of PDPK-1.
  • Kxxx is K173 of PDPK-1.
  • the inhibitor moiety is a compound of Formula D:
  • R v is H, optionally substituted C 1 -C 3 branched or straight chain alkyl, or optionally substituted C 1 -C 3 branched or straight chain acyl.
  • the present invention provides a conjugate of the formula:
  • R v is as defined above for Formula D.
  • the present invention provides a conjugate of the formula:
  • R v is as defined above for Formula D.
  • the present invention provides a conjugate of the formula:
  • R v is as defined above for Formula D.
  • compounds of the present invention have a warhead group characterized in that inventive compounds target the K136 lysine residue of HCV protease.
  • R wh is characterized in that the -T-R wh moiety is capable of covalently binding to a lysine residue thereby irreversibly inhibiting the enzyme.
  • the lysine residue is K136 lysine residue of HCV protease, or a mutant thereof.
  • the present invention provides a conjugate comprising HCV protease, or a mutant thereof, covalently bonded to an inhibitor at K136.
  • the inhibitor is covalently bonded via a linker moiety.
  • the present invention provides a conjugate of the formula K136-linker-inhibitor moiety.
  • the “linker” group corresponds to a -T-R wh as described herein. Accordingly, in certain embodiments, the linker group is as defined for -T-R wh was defined above and described in classes and subclasses herein. It will be appreciated, however, that the linker group is bivalent and, therefore, the corresponding -T-R wh group is also intended to be bivalent resulting from the reaction of the warhead with the K136 of HCV protease, or a mutant thereof.
  • the inhibitor moiety is a compound of E, F, or G:
  • R 90 , R 94 , R 95 , R 96 , R 97 , R 98 , R 99 , R 100 , R 102 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , R 112 , R 113 , and R 114 are each independently hydrogen or C 1 -C 6 alkyl; wherein one or more methylene groups of C 1 -C 6 alkyl can be optionally replaced by —NR 1 —, —O—, —C(O)—, —S—, —SO—, —SO 2 —, or —C( ⁇ S)—;
  • R 103 is hydrogen, C 1 -C 6 alkyl, or C 2 -C 8 alkenyl
  • one or more methine groups of the C 1 -C 6 alkyl, when present, can be independently replaced by
  • R 1 is hydrogen or C 1 -C 8 alkyl
  • each R 101 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, halogen, amino, nitro, optionally substituted aryl or heteroaryl; n 6 is an integer from 0 to 4; and n 8 is an integer from 0 to 2.
  • the present invention provides a conjugate of the formula:
  • R 1 , R 90 , R 94 , R 95 , R 96 , R 97 , R 98 , R 99 , R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , R 112 , R 113 , R 114 , n 6 , and n 8 are as defined above for Formula E.
  • the present invention provides a conjugate of the formula:
  • R 1 , R 90 , R 94 , R 95 , R 96 , R 97 , R 98 , R 99 , R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , R 112 , R 113 , R 114 , n 6 , and n 8 are as defined above for Formula F.
  • the present invention provides a conjugate of the formula:
  • R 1 , R 90 , R 94 , R 95 , R 96 , R 97 , R 98 , R 99 , R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , R 112 , R 113 , R 114 , n 6 , and n 8 are as defined above for Formula G.
  • compounds of the present invention have a warhead group characterized in that inventive compounds target the K777 lysine residue of PI3K ⁇ . In certain embodiments, compounds of the present invention have a warhead group characterized in that inventive compounds target the K802 lysine residue of PI3K ⁇ . In certain embodiments, compounds of the present invention have a warhead group characterized in that inventive compounds target the K890 lysine residue of PI3K ⁇ .
  • R wh is characterized in that the -T-R wh moiety is capable of covalently binding to a lysine residue thereby irreversibly inhibiting the enzyme.
  • the lysine residue is K777 lysine residue of PI3K ⁇ , or a mutant thereof.
  • the present invention provides a conjugate comprising PI3K ⁇ , or a mutant thereof, covalently bonded to an inhibitor at K777.
  • the inhibitor is covalently bonded via a linker moiety.
  • the present invention provides a conjugate of the formula K777-linker-inhibitor moiety. In certain embodiments, the present invention provides a conjugate of the formula K802-linker-inhibitor moiety. In certain embodiments, the present invention provides a conjugate of the formula K890-linker-inhibitor moiety.
  • the “linker” group corresponds to a -T-R wh as described herein. Accordingly, in certain embodiments, the linker group is as defined for -T-R wh was defined above and described in classes and subclasses herein.
  • the linker group is bivalent and, therefore, the corresponding -T-R wh group is also intended to be bivalent resulting from the reaction of the warhead with the K777 of PI3K ⁇ , or from the reaction of the warhead with the K802 or K890 of PI3K ⁇ , or a mutant thereof.
  • the inhibitor moiety is a compound of Formula H, J or K:
  • n, m, p, and q are each independently 0, 1, 2, 3; provided that n and q are not 0 at the same time, and m and q are not 0 at the same time;
  • a 2 is an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-10 membered saturated or partially unsaturated bridged bicyclic heterocyclic ring having at least one nitrogen, at least one oxygen, and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • B′ is an optionally substituted group selected from phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or -T-Rwh; and
  • C 2 is hydrogen or an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the present invention provides a conjugate of the formula:
  • Kxxx is K777 of PI3K ⁇ , or K802 or K890 of PI3K ⁇ .
  • Kxxx is K777 of PI3K ⁇ .
  • Kxxx is K802 of PI3K ⁇ .
  • Kxxx is K890 of PI3K ⁇ .
  • the present invention provides a conjugate of the formula:
  • K xxx is K777 of PI3K ⁇ , or K802 or K890 of PI3K ⁇ .
  • Kxxx is K777 of PI3K ⁇ .
  • Kxxx is K802 of PI3K ⁇ .
  • Kxxx is K890 of PI3K ⁇ .
  • the present invention provides a conjugate of the formula:
  • K xxx is K777 of PI3K ⁇ , or K802 or K890 of PI3K ⁇ .
  • Kxxx is K777 of PI3K ⁇ .
  • Kxxx is K802 of PI3K ⁇ .
  • Kxxx is K890 of PI3K ⁇ .
  • the inhibitor moiety is a compound of Formula L or M:
  • R 204 is an hydrogen or an optionally substituted group selected from C 1-6 aliphatic, —(CH 2 ) m -(3- to 7-membered saturated or partially unsaturated carbocyclic ring), —(CH 2 ) m -(7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring), —(CH 2 ) m -(4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur), —(CH 2 ) m -(7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur), —(CH 2 ) m -phenyl, —(CH 2 ) m -(8- to 10-membered bicyclic aryl ring), —(CH 2 ) m -(5- to 6-membered heteroaryl ring
  • each R 205 and R 206 is independently —R′′, halogen, —NO 2 , —CN, —OR′′, —SR′′, —N(R′′) 2 , —C(O)R′′, —CO 2 R′′, —C(O)C(O)R′′, —C(O)CH 2 C(O)R′′, —S(O)R′′, —S(O) 2 R′′, —C(O)N(R′′) 2 , —SO 2 N(R′′) 2 , —OC(O)R′′, —N(R′′)C(O)R′′, —N(R′′)N(R′′) 2 , —N(R′′)C( ⁇ NR′′)N(R′′) 2 , —C( ⁇ NR′′)N(R′′) 2 , —C ⁇ NOR′′, —N(R′′)C(O)N(R′′) 2 , —N(R′′)SO 2 N(R′′) 2
  • each R′′ is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
  • n is an integer from 0 to 6, inclusive
  • each n is independently 0, 1, or 2;
  • Ring A 5 is an optionally substituted 6-membered heterocyclic or heteroaryl ring having 1-2 nitrogens.
  • the present invention provides a conjugate of the formula:
  • R 204 , R 205 , R 206 , n, and A 5 defined as above for Formula L and K xxx is K777 of PI3K ⁇ , or K802 or K890 of PI3K ⁇ .
  • K xxx is K777 of PI3K ⁇ .
  • K xxx is K802 of PI3K ⁇ .
  • K xxx is K890 of PI3K ⁇ .
  • the present invention provides a conjugate of the formula:
  • R 204 , R 205 , R 206 , n, and A 5 defined as above for Formula M and K xxx is K777 of PI3K ⁇ , or K802 or K890 of PI3K ⁇ .
  • Kxxx is K777 of PI3K ⁇ .
  • Kxxx is K802 of PI3K ⁇ .
  • Kxxx is K890 of PI3K ⁇ .
  • the inhibitor moiety is a compound of Formula N:
  • R 201 is hydrogen or C 1-6 alkyl
  • R 202 is hydrogen or an optionally substituted group selected from C 1-6 alkyl, C 1-6 alkoxy, or (C 1-6 alkylene)-R 203 ; or
  • R 201 and R 202 are taken together with the intervening carbon to form an optionally substituted ring selected from a 3- to 7-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • R 203 is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, a 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
  • Ring A 6 is absent or an optionally substituted group selected from a 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the present invention provides a conjugate of the formula:
  • R 201 , R 202 , R 203 and A 6 are as defined above for Formula N, and Kxxx is K777 of PI3K ⁇ , or K802 or K890 of PI3K ⁇ .
  • Kxxx is K777 of PI3K ⁇ .
  • Kxxx is K802 of PI3K ⁇ .
  • Kxxx is K890 of PI3K ⁇ .
  • the inhibitor moiety is a compound of Formula O:
  • each R 205 and R 206 is independently —R′′, halogen, —NO 2 , —CN, —OR′′, —SR′′, —N(R′′) 2 , —C(O)R′′, —CO 2 R′′, —C(O)C(O)R′′, —C(O)CH 2 C(O)R′′, —S(O)R′′, —S(O) 2 R′′, —C(O)N(R′′) 2 , —SO 2 N(R′′) 2 , —OC(O)R′′, —N(R′′)C(O)R′′, —N(R′′)N(R′′) 2 , —N(R′′)C( ⁇ NR′′)N(R′′) 2 , —C( ⁇ NR′′)N(R′′) 2 , —C ⁇ NOR′′, —N(R′′)C(O)N(R′′) 2 , —N(R′′)SO 2 N(R′′) 2
  • each R′′ is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
  • R′′ groups on the same nitrogen are taken together with the nitrogen to which they are attached to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • n is an integer from 0 to 6, inclusive
  • each n is independently 0, 1, or 2;
  • Ring A 5 is an optionally substituted 6-membered heterocyclic or heteroaryl ring having 1-2 nitrogens.
  • the present invention provides a conjugate of the formula:
  • R 205 , R 206 , n and A 5 are as defined above for formula O, and Kxxx is K777 of PI3K ⁇ , or K802 or K890 of PI3K ⁇ .
  • Kxxx is K777 of PI3K ⁇ .
  • Kxxx is K802 of PI3K ⁇ .
  • Kxxx is K890 of PI3K ⁇ .
  • the inhibitor moiety is a compound of Formula P:
  • the present invention provides a conjugate of the formula:
  • K xxx is K777 of PI3K ⁇ , or K802 or K890 of PI3K ⁇ .
  • Kxxx is K777 of PI3K ⁇ .
  • Kxxx is K802 of PI3K ⁇ .
  • Kxxx is K890 of PI3K ⁇ .
  • the term “inhibitor moiety” refers to a Scaffold group that binds in the active site of a protein.
  • Scaffold groups are well known in the art and include those described in, for example, but not limited to, Formulae VII, VIII, IX-a, IX-b, XI, XII, XVI, XVII, XVIII, XIX, XX, XXI, XXIII, XXXIV, XXV, XVI, XXVII, XXVIII, XXIX, XXVI, and XXXVII.
  • certain compounds described herein are reversible inhibitors.
  • such compounds are useful as assay comparator compounds.
  • such reversible compounds are useful as inhibitors of the proteins disclosed herein, or a mutants thereof, and are therefore useful for treating one or more disorders as described herein.
  • provided compounds are reversible counterparts of provided irreversible inhibitors.
  • the key elements of the pharmacophore required for non-covalent binding to the target protein are retained. Whether the key elements of the pharmacophore are retained for binding is demonstrated when the non-covalent affinity conferred by the Scaffold is sufficient to further confer selective binding of the ligand and also covalent bonding.
  • the Pharmacophore is GDC-0941
  • Non-limiting examples of Scaffolds derived from the truncation of a pharmacophore, as described in the present disclosure, are set forth below in Formulas XXX, XXXI, XXXII, XXXIII, XXXIV, and XXXV.
  • R 200 is located at the site of truncation and is -Tether-R wh , where Tether and R wh are as defined for Formula I;
  • Ring B is an optionally substituted group selected from phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 200 is located at the site of truncation and is -Tether-R WH , where Tether and R wh are as defined in Formula I;
  • Ring B is an optionally substituted group selected from phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 200 is at the site of truncation and is -Tether-R WH , where Tether and R wh are as defined above in the embodiments of Formula I;
  • T 2 is a covalent bond or a bivalent straight or branched, saturated or unsaturated C 1-6 hydrocarbon chain wherein one or more methylene units of T 2 are optionally replaced by —O—, —S, —N(R 1 )—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R 1 )—, —N(R 1 )C(O)—, —N(R 1 )C(O)N(R 1 )—, —SO 2 —, —SO 2 N(R 1 )—, —N(R 1 )SO 2 —, or —N(R 1 )SO 2 N(R 1 )—;
  • C 2 is hydrogen or an optionally substituted ring selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
  • B′ is an optionally substituted group selected from phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Non-limiting examples of Scaffolds of the Formula XXXII above include:
  • the Scaffolds described by Formula XXXIII are based on truncating the pharmacophore dihydroimidazoquinazoline:
  • R 200 is at the site of truncation and is -Tether-R WH , where Tether and R wh are as defined previously;
  • X 10 is hydrogen, alkoxy, heterocycloalkyl, heterocycloalkoxy
  • X 11 is an optionally substituted group selected from phenyl, an 8- to 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the Scaffolds described by Formula XXXIV and Formula XXXV are based on truncating the pharmacophore SM ⁇ 337 and SM ⁇ 122.
  • R** is phenylacetamide
  • R** is phenylacetamide and the arrow denotes the site of attachment for T-R WH , both of which are as described herein.
  • X-linked Inhibitor of Apoptosis Protein is a member of the inhibitor of apoptosis family of proteins (IAP).
  • IAP apoptosis family of proteins
  • Other family members of IAP include cIAP1, cIAP2 and ML-IAP.
  • IAPs were initially identified in baculoviruses, but XIAP is one of the homologous proteins found in mammals. It is so called because it was first discovered by a 273 base pair site on the X chromosome.
  • XIAP Deregulation of XIAP can result in cancer, neurodegenerative disorders, and autoimmunity. High proportions of XIAP may function as a tumor marker. In the development of lung cancer NCI-H460, the overexpression of XIAP not only inhibits caspase, but also stops the apoptotic activity of cytochrome c (Apoptosis). In developing prostate cancer, XIAP is one of four IAPs overexpressed in the prostatic epithelium, indicating that a molecule that inhibits all IAPs may be necessary for effective treatment.
  • AML acute myelogenous leukemia
  • ALD adrenoleukodystrophy
  • ALD adrenoleukodystrophy
  • Alexander's disease alopecia greata
  • Alper's disease Alzheimer's disease
  • amyotrophic lateral sclerosis Lou Gehrig's Disease
  • angiitis ankylosing spondylitis
  • antiphospholipid syndrome ataxia telangiectasia
  • autism autoimmune haemolytic anaemia
  • Batten disease also known as Spielmeyer-Vogt-Sjögren-Batten disease
  • Behcet's syndrome Behcet's syndrome
  • Berger's disease bovine spongiform encephalopathy
  • BSE bovine spongiform encephalopathy
  • Canavan disease cardiomyopathy
  • Chagas disease chronic fatigue syndrome
  • CFS chronic fatigue syndrome
  • CFIDS chronic inflammatory polyneuropathy
  • the invention provides compositions useful for treating or preventing a proliferative disorder or an autoimmune disease.
  • the compositions are suitable for internal use and comprise an effective amount of a IAP inhibitor and a physiologically acceptable carrier or vehicle, useful for treating or preventing cancer, neurodegenerative disorders, and autoimmunity.
  • a XIAP inhibitor can be administered in amounts that are effective to treat or prevent or reduce the severity of a proliferative disorder in a subject.
  • Proliferative disorders include, but are not limited to, solid tumor cancers such as malignant lymphoma, malignant gliomas, X-linked lymphoproliferative disease (XLP), acute myelogenous leukemia (AML), fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, Leiomyosarcoma, rhabdomyosarcoma, brain cancer, colon cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer
  • the invention provides compositions of a IAP inhibitor useful for treating or preventing an autoimmune disease.
  • Autoimmune diseases include, but are not limited to, autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, acute pancreatitis, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy).
  • a XIAP inhibitor can be administered in amounts that are effective to treat or prevent an autoimmune disease in a subject.
  • Neurodegenerative disease which can be treated according to the methods of this invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.
  • a cIAP inhibitor can be administered in amounts that are effective to treat or prevent or reduce the severity of a proliferative disorder in a subject.
  • Proliferative disorders include, but are not limited to, mucosa associated lymphoid tissue lymphoma (MALT lymphoma) which is a subset of non-Hodgkin's lymphoma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, malignant gliomas, and acute myelogenous leukemia (AML).
  • MALT lymphoma mucosa associated lymphoid tissue lymphoma
  • AML acute myelogenous leukemia
  • PI3K ⁇ / ⁇ The phosphatidylinositol 3-kinase (“PI3K ⁇ / ⁇ ”) pathway is a central signaling pathway that exerts its effect on numerous cellular functions including cell cycle progression, proliferation, motility, metabolism and survival (Marone, et al. Biochim. Biophys. Acta (2008) 1784: 159-185).
  • Activation of receptor tyrosine kinases in the case of Class IA PI3Ks, or G-proteins in the case of Class IB PI3K ⁇ causes phosphorylation of phosphatidylinositol-(4,5)-diphosphate, resulting in membrane-bound phosphatidylinositol-(3,4,5)-triphosphate.
  • the latter promotes the transfer of a variety of protein kinases from the cytoplasm to the plasma membrane by binding of phosphatidylinositol-(3,4,5)-triphosphate to the pleckstrin-homology (PH) domain of the kinase.
  • PH pleckstrin-homology
  • PI3K phosphatidylinositide-dependent kinase 1
  • Akt also known as Protein Kinase B or PKB
  • Phosphorylation of such kinases then allows for the activation or deactivation of numerous other pathways, involving mediators such as GSK3, mTOR, PRAS40, FKHD, NF- ⁇ B, BAD, Caspase-9, and others. These pathways are involved in many cellular processes, such as cell cycle progression, cell survival and apoptosis, cell growth, transcription, translation, metabolism, degranulation, and cell motility.
  • PTEN a phosphatase that catalyzes the dephosphorylation of phosphatidylinositol-(3,4,5)-triphosphate to phosphatidylinositol-(4,5)-diphosphate.
  • PTEN is mutated into an inactive form, permitting a constitutive activation of the PI3K pathway.
  • a targeting of PI3K itself or individual downstream kinases in the PI3K pathway provide a promising approach to mitigate or even abolish the disregulation in many cancers and thus restore normal cell function and behavior.
  • Diseases and disorders treatable by regulating the function of PI3K include, but are not limited to, cancer, neurofibromatosis, ocular angiogenesis, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, angiogenic disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, and CNS disorders in a patient.
  • cancer cancer
  • neurofibromatosis ocular angiogenesis
  • stroke e.g., stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, at
  • proliferative diseases/disorders include, but are not limited to, solid tumor cancers such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, Leiomyosarcoma, rhabdomyosarcoma, brain cancer, colon cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, head and neck cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adeno
  • a PI3K inhibitor can be administered in amounts that are effective to treat or prevent or reduce the severity of a proliferative disorder in a subject. More specifically, compounds of the current invention are useful in the treatment of a proliferative disease selected from a benign or malignant tumor, carcinoma of the brain, kidney, liver, bile duct, adrenal gland, bladder, breast, esophagus, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer), stomach, vagina, endometrial, uterus, cervix and vulva, testes, genitourinary tract, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma and lymphomas, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, a cancer of the central nervous system
  • a PI3K inhibitor can be administered in amounts that are effective to treat or prevent or reduce the severity of a neurodegenerative disease/disorder in a subject.
  • Neurodegenerative disease which can be treated according to the methods of this invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.
  • a PI3K inhibitor can be administered in amounts that are effective to treat or prevent an autoimmune disease in a subject.
  • Autoimmune diseases include, but are not limited to, autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, acute pancreatitis, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy).
  • the present invention provides a method of using the disclosed compounds to prevent, treat, or reduce the severity of neurofibromatosis type I (NF1), neurofibromatosis type II (NF2) Schwann cell neoplasms (e.g. MPNST's), or Schwannomas.
  • NF1 neurofibromatosis type I
  • NF2 neurofibromatosis type II
  • MPNST's Schwann cell neoplasms
  • Schwannomas e.g. MPNST's
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as “whez infants”, an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to “morning dipping.” “Morning dipping” is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
  • compounds of the current invention can be used to prevent, treat, or reduce the severity of other inflammatory or obstructive airways diseases and conditions associated with PI3K including, but not limited to, acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • ALI acute lung injury
  • ARDS adult/acute respiratory distress syndrome
  • COAD chronic obstructive pulmonary, airways or lung disease
  • COAD chronic obstructive pulmonary, airways or lung disease
  • exacerbation of airways hyperreactivity consequent to other drug therapy in particular other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
  • the methods disclosed herein may be used to treat eosinophil related disorders associated with PI3K, e.g. eosinsophilia, in particular eosinophil related disorders of the airways (e.g.
  • eosinophilic infiltration of pulmonary tissues including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
  • eosinophil-related disorders of the airways consequential or concomitant to Loffler's syndrome
  • eosinophilic pneumonia including parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg
  • the methods disclosed herein are also useful to prevent, treat, or reduce the severity of psoriasis, contact dermatitis, atopic dermatitis, alopecia greata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, systemic lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.
  • diseases or conditions having an inflammatory component caused by aberrant PI3K may also be prevented, treated, or used to reduce the severity by the methods disclosed herein.
  • diseases and disorders include, but are not limited to, diseases and conditions of the eye such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g.
  • hemolytic anemia aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, acute pancreatitis, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy).
  • Cardiovascular diseases which can be prevent, treated, or used to reduce the severity according to the methods of this invention include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure.
  • the invention provides compositions useful for treating or preventing cancer, neurofibromatosis, ocular angiogenesis, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, angiogenic disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, and CNS disorders in a patient.
  • CML chronic myelogenous leukemia
  • the methods of the present invention may be advantageous for inhibiting angiogenesis, for example, to treat eye disease associated with ocular angiogenesis, such as by topical administration of the subject compounds.
  • Compounds according to the invention can be formulated for topical administration.
  • the irreversible inhibitor can be formulated for topical delivery to the lung (e.g., as an aerosol, such as a dry powder or liquid formulation) to treat asthma, as a cream, ointment, lotion or the like for topical application to the skin to treat psoriasis, or as an ocular formulation for topical application to the eye to treat an ocular disease.
  • Such a formulation will contain a subject inhibitor and a pharmaceutically acceptable carrier. Additional components, such as preservatives, and agents to increase viscosity of the formulation such as natural or synthetic polymers may also be present.
  • the ocular formulation can be in any suitable form, such as a liquid, an ointment, a hydrogel or a powder.
  • Compounds of the current invention can be administered together with another therapeutic agent, such as an anti-VEGF agent, for example ranibizumab a Fab fragment of an antibody that binds VEGFA, or another anti-angiogenic compound as described further below.
  • 3-Phosphoinositide-dependent kinase 1 phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), serum and glucocorticoid-induced kinase, protein kinase C isoforms, and the p70 ribosomal S6 kinase.
  • PPK1 protein kinase B
  • Akt protein kinase B
  • serum and glucocorticoid-induced kinase protein kinase C isoforms
  • the phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDPK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anti-cancer drugs.
  • a proliferative disorder can be prevented, treated, or reduce the severity of by administration of an effective amount of a PDPK1 inhibitor to a subject in need thereof.
  • Proliferative disorders that can be prevented, treated, or reduce the severity of by administering an effective amount of a PDPK1 inhibitor include, but are not limited to, cancer, uterine fibroids, benign prostatic hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, an inflammatory bowel disease, transplantation rejection, endotoxic shock, a fungal infection, a defective apoptosis-associated condition, or a proliferative disease that is dependent on PDPK1 activity.
  • diseases and disorders that are regulated by PI3K are also implicated in aberrant PDPK1 function.
  • diseases treatable by regulating PDPK1 activity include, but are not limited to, cancer, neurofibromatosis, ocular angiogenesis, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, angiogenic disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, and CNS disorders in a patient.
  • CML chronic myelogenous leukemia
  • proliferative diseases/disorders include, but are not limited to, solid tumor cancers such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, Leiomyosarcoma, rhabdomyosarcoma, brain cancer, colon cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, head and neck cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adeno
  • a PDPK1 inhibitor can be administered in amounts that are effective to treat or prevent or reduce the severity of a proliferative disorder in a subject. More specifically, compounds of the current invention are useful in the treatment of a proliferative disease selected from a benign or malignant tumor, carcinoma of the brain, kidney, liver, bile duct, adrenal gland, bladder, breast, esophagus, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer), stomach, vagina, endometrial, uterus, cervix and vulva, testes, genitourinary tract, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma and lymphomas, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, a cancer of the central nervous system
  • a PDPK1 inhibitor can be administered in amounts that are effective to treat or prevent or reduce the severity of a neurodegenerative disease/disorder in a subject.
  • Neurodegenerative disease which can be treated according to the methods of this invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.
  • a PDPK1 inhibitor can be administered in amounts that are effective to treat or prevent an autoimmune disease in a subject.
  • Autoimmune diseases include, but are not limited to, autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, acute pancreatitis, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy).
  • Blood-borne cancers implicated in aberrant PDPK1 expression include, but are not limited to, acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia (“CML”), chronic lymphocytic leukemia (“CLL”), hairy cell leukemia, and myeloma.
  • acute lymphoblastic leukemia acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythrole
  • Lymphomas where PDPK1 is implicated include, but are not limited to, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and polycythemia vera.
  • CNS and brain cancers where aberrant PDPK1 expression include, but not limited to, glioma, pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, vestibular schwannoma, adenoma, metastatic brain tumor, and meningioma.
  • Virally-mediated cancers have also been implicated in overexpression of PDPK1.
  • viruses include human papilloma virus, which can lead to cervical cancer (see, e.g., Hernandez-Avila et al., Archives of Medical Research (1997) 28:265-271); Epstein-Barr virus (EBV), which can lead to lymphoma (see, e.g., Herrmann et al., J Pathol (2003) 199(2):140-5); hepatitis B or C virus, which can lead to liver carcinoma (see, e.g., El-Serag, J Clin Gastroenterol (2002) 35(5 Suppl 2):572-8); human T cell leukemia virus (HTLV)-I, which can lead to T-cell leukemia (see e.g., Mortreux et al., Leukemia (2003) 17(1):26-38); human herpesvirus-8 infection, which can lead to Kaposi's sarcoma (see, e.g., Kadow
  • the invention provides methods for treating or preventing these aforementioned cancers, disorders and diseases, comprising administering to a subject in need of such treatment or prevention an effective amount of a PDPK1 inhibitor.
  • HCV is a positive-stranded RNA virus whose genome encodes a polyprotein of approximately 3000 amino acids. This precursor protein is processed into at least 10 viral structural and nonstructural proteins: C, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B (Blight, K. J., et al., Antiviral Ther. 3, Suppl. 3: 71-81, 1998). HCV nonstructural (NS) proteins are derived by proteolytic cleavage of the polyprotein and are presumed to provide the essential catalytic machinery for viral replication.
  • NS nonstructural
  • NS3 is an approximately 68 Kda protein, and has both an N-terminal serine protease domain and an RNA-dependent ATPase domain at its C-terminus. It has been shown that the NS4A protein serves as a co-factor for the serine protease activity of NS3. NS3 functions as a proteolytic enzyme that cleaves sites liberating other nonstructural proteins necessary for HCV replication and is a validated therapeutic target for antiviral chemotherapy.
  • Symptoms of HCV infection can either be acute or chronic. Acute symptoms include decreased appetite, fatigue, abdominal pain, jaundice, itching, and flu-like symptoms. Most patients diagnosed with HCV infection with acute symptoms eventually develop chronic symptoms, which include fatigue, flu-like symptoms, joint pains, itching, sleep disturbances, appetite changes, nausea, and depression. Chronic HCV infection eventually leads to liver inflammation, fibrosis, and eventually cirrhosis all of which lead to decreased liver function and eventually liver failure.
  • Chronic hepatitis C can also be associated with extrahepatic manifestations associated with the presence of HCV such as porphyria cutanea tarda, cryoglobulinemia (a form of small-vessel vasculitis) and glomerulonephritis (inflammation of the kidney), specifically membranoproliferative glomerulonephritis (MPGN).
  • the invention provides compositions useful for treating or preventing a an HCV infection.
  • the compositions are suitable for internal use and comprise an effective amount of a HCV inhibitor and a physiologically acceptable carrier or vehicle.
  • a HCV inhibitor can be administered in amounts that are effective to treat or prevent or reduce the severity of an HCV infection in a subject.
  • additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as “appropriate for the disease, or condition, being treated”.
  • a provided compound, or composition thereof is administered in combination with another inhibitor of HCV protease, or a variant thereof.
  • a provided compound, or composition thereof is administered in combination with another antiviral agent.
  • antiviral agents include, but are not limited to, immunomodulatory agents, such as ⁇ -, ⁇ -, and ⁇ -interferons, pegylated derivatized interferon- ⁇ compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors, e.g.
  • BILN 2061 and VX-950 inhibitors of other targets in the HCV life cycle, including helicase and polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., mycophenolic acid and derivatives thereof); or combinations of any of the above.
  • IMPDH inhibitors e.g., mycophenolic acid and derivatives thereof
  • a combination of 2 or more antiviral agents may be administered. In certain embodiments, a combination of 3 or more antiviral agents may be administered.
  • the antiviral agents are selected from ribavirin or interferon. In other embodiments, the antiviral agent is ⁇ -interferon.
  • agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept® and Excelon®; treatments for HIV such as ritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and
  • compounds of the present invention are administered in combination with a monoclonal antibody or an siRNA therapeutic.
  • Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the methods of the present invention may be used to prevent, treat, or reduce the severity of cancer, an autoimmune disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone-related disorder, liver disease, or a cardiac disorder.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • Administration of an inhibitor or pharmaceutically active agent described herein can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. In some instances, administration will result in the release of the inhibitor or pharmaceutically active agent described herein into the bloodstream.
  • the inhibitor or pharmaceutically active agent described herein is administered orally.
  • compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, preferably in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, preferably in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those skilled in the pharmaceutical arts.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as, for example, water or other solvents, solubil
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using dissolution or suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, aqueous dextrose, glycerol, ethanol, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions of the inhibitor or pharmaceutically active agent described herein for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders or diluents such as starches, lactose, sucrose, glucose, mannitol, cellulose, saccharin, glycine, and silicic acid, b) binders such as, for example, magnesium aluminum silicate, starch paste, tragacanth, carboxymethylcellulose, methyl cellulose, alginates, gelatin, polyvinylpyrrolidinone, magnesium carbonate, natural sugars, corn sweeteners, sucrose, waxes and natural or synthetic gums such as acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • the inhibitor or pharmaceutically active agent described herein can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564.
  • the inhibitor or pharmaceutically active agent described herein can also be delivered by the use of monoclonal antibodies as individual carriers to which the inhibitor or pharmaceutically active agent described herein are coupled.
  • the inhibitor or pharmaceutically active agent described herein can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • inhibitor or pharmaceutically active agent described herein can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Parenteral injectable administration can be used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • One embodiment, for parenteral administration employs the implantation of a slow-release or sustained-released system, according to U.S. Pat. No. 3,710,795, incorporated herein by reference.
  • compositions can be sterilized or contain non-toxic amounts of adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, pH buffering agents, and other substances, including, but not limited to, sodium acetate or triethanolamine oleate. In addition, they can also contain other therapeutically valuable substances.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, pH buffering agents, and other substances, including, but not limited to, sodium acetate or triethanolamine oleate.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, pH buffering agents, and other substances, including, but not limited to, sodium acetate or triethanolamine oleate.
  • they can also contain other therapeutically valuable substances.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, preferably from about 1% to about 70% of the inhibitor or pharmaceutically active agent described herein by weight or volume.
  • the dosage regimen utilizing the inhibitor or pharmaceutically active agent described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; and the particular inhibitor or pharmaceutically active agent described herein employed.
  • a person skilled in the art can readily determine and prescribe the effective amount of the drug useful for treating or preventing a proliferative disorder.
  • Effective dosage amounts of the inhibitor or pharmaceutically active agent described herein, when administered to a subject range from about 0.05 to about 1000 mg of inhibitor or pharmaceutically active agent described herein per day.
  • Compositions for in vivo or in vitro use can contain about 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100.0, 250.0, 500.0 or 1000.0 mg of the inhibitor described herein.
  • the compositions are in the form of a tablet that can be scored.
  • Effective plasma levels of the inhibitor or pharmaceutically active agent described herein can range from about 0.002 mg to about 50 mg per kg of body weight per day.
  • the amount of an inhibitor or pharmaceutically active agent described herein that is effective in the treatment or prevention of cancer can be determined by clinical techniques that are known to those of skill in the art.
  • in vitro and in vivo assays can optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed can also depend on the route of administration, and the seriousness of the proliferative disorder being treated and can be decided according to the judgment of the practitioner and each subject's circumstances in view of, e.g., published clinical studies.
  • Suitable effective dosage amounts can range from about 10 micrograms to about 5 grams about every 4 h, although they are typically about 500 mg or less per every 4 hours.
  • the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours.
  • Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months.
  • the effective dosage amounts described herein refer to total amounts administered; that is, if more than one inhibitor or pharmaceutically active agent described herein is administered, the effective dosage amounts correspond to the total amount administered.
  • the dosage regimen utilizing the inhibitor or pharmaceutically active agent described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the proliferative disorder to be treated; the route of administration; the renal or hepatic function of the subject; and the particular inhibitor or pharmaceutically active agent described herein employed.
  • a person skilled in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the proliferative disorder.
  • the inhibitor or pharmaceutically active agent described herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, the inhibitor or pharmaceutically active agent described herein can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen.
  • Topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of the inhibitor or pharmaceutically active agent described herein ranges from about 0.1% to about 15%, w/w or w/v.
  • additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as “appropriate for the disease, or condition, being treated”.
  • the additional therapeutic agent is not a competitive binder for the active binding site within the target protein for the inhibitor used in the combination.
  • an inhibitor or pharmaceutically active agent provided herein, or composition thereof is administered in combination with another pharmaceutically active agent, or a variant thereof.
  • a provided compound, or composition thereof is administered in combination with one or more additional pharmaceutically active agent.
  • Such additional pharmaceutically active agents include, but are not limited to, treatments for Alzheimer's Disease such as Aricept® and Excelon®; treatments for HIV such as ritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents
  • compounds of the present invention are administered in combination with a monoclonal antibody or an siRNA therapeutic.
  • Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of this invention should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of an inventive can be administered.
  • compositions which comprise an additional therapeutic agent that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01-100 mg/kg body weight/day of the additional therapeutic agent can be administered.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the compositions comprise an amount of an anticancer inhibitor described herein, e.g., a XIAP inhibitor, and another anticancer agent which together are effective to treat or prevent cancer.
  • the amount of the anticancer inhibitor described herein and another anticancer agent is at least about 0.01% of the combined combination chemotherapy agents by weight of the composition. When intended for oral administration, this amount can be varied from about 0.1% to about 80% by weight of the composition.
  • Some oral compositions can comprise from about 4% to about 50% of the anticancer inhibitor described herein and another anticancer agent.
  • Other compositions of the present invention are prepared so that a parenteral dosage unit contains from about 0.01% to about 2% by weight of the composition.
  • the present methods for treating or preventing cancer in a subject in need thereof can further comprise administering another prophylactic or therapeutic agent to the subject being administered an anticancer inhibitor described herein.
  • the other prophylactic or therapeutic agent is administered in an effective amount.
  • the other prophylactic or therapeutic agent includes, but is not limited to, an anti-inflammatory agent, an anti-renal failure agent, an anti-diabetic agent, an anti-cardiovascular disease agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anxiolytic agent, and an opioid or non-opioid analgesic agent.
  • the anticancer inhibitor described herein can be administered prior to, concurrently with, or after an antiemetic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the anticancer inhibitor described herein can be administered prior to, concurrently with, or after a hematopoietic colony stimulating factor, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks or 4 weeks of each other.
  • the anticancer inhibitor described herein can be administered prior to, concurrently with, or after an opioid or non-opioid analgesic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the anticancer inhibitor described herein can be administered prior to, concurrently with, or after an anxiolytic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective amount range. In one embodiment of the invention, where, another therapeutic agent is administered to a subject, the effective amount of the anticancer inhibitor described herein is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that the anticancer inhibitor described herein and the other therapeutic agent act synergistically to treat or prevent cancer.
  • Antiemetic agents useful in the methods of the present invention include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, and tropisetron.
  • Hematopoietic colony stimulating factors useful in the methods of the present invention include, but are not limited to, filgrastim, sargramostim, molgramostim and epoietin alfa.
  • Opioid analgesic agents useful in the methods of the present invention include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine, methadone, isomethadone and propoxyphene.
  • morphine heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine
  • Non-opioid analgesic agents useful in the methods of the present invention include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac.
  • Anxiolytic agents useful in the methods of the present invention include, but are not limited to, buspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam, chlorazepate, clonazepam, chlordiazepoxide and alprazolam.
  • kits that can simplify the administration of a ligand that covalently binds to a target polypeptide having a lysine residue present in the active site to a subject.
  • a typical kit of the invention comprises a unit dosage form of a ligand that covalently binds to a target polypeptide having a lysine residue present in the active site.
  • the unit dosage form is a container, which can be sterile, containing an effective amount of a ligand that covalently binds to a target polypeptide having a lysine residue present in the active site and a physiologically acceptable carrier or vehicle.
  • the kit can further comprise a label or printed instructions instructing the use of the ligand that covalently binds to a target polypeptide having a lysine residue present in the active site to treat or prevent cancer.
  • the kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of another prophylactic or therapeutic agent or another anticancer agent.
  • the kit comprises a container containing an effective amount of a ligand that covalently binds to a target polypeptide having a lysine residue present in the active site and an effective amount of another prophylactic or therapeutic agent.
  • examples of other prophylactic or therapeutic agents and other anticancer agents include, but are not limited to, those listed above.
  • a compound of the present invention may be tethered to a detectable moiety.
  • a detectable moiety may be attached to a provided compound via a suitable substituent.
  • suitable substituent refers to a moiety that is capable of covalent attachment to a detectable moiety.
  • moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few.
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